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783 Cards in this Set

  • Front
  • Back
Amenorrhea due to hypogonadotropic hypogonadism may result from all of the following EXCEPT:

A.Anorexia nervosa.
C.Large, non-functional pituitary tumor.
D.Long-distance running with very low body fat.
E.Transection of the pituitary stalk.
BHypogonadotropic hypogonadism refers to amenorrhea due to lack of normal secretion of thegonadotropins, LH and FSH. Patients with hyperthecosis have amenorrhea, very high testosteronesecretion with hirsutism and sometimes virilization, very high insulin resistance and hyperinsulinemia, but normal LH and FSH levels. Very low body fat decreases the GnRH pulse generator, and bothanorexia nervosa and long-distance running with very low body fat can cause amenorrhea due tohypogonadotropic hypogonadism (answers A and D are true and therefore incorrect). Notice that LH and FSH can technically fall within low normal range, yet be unable to support ovulation due to abnormalsecretion patterns. Gonadotrophs appears to be particularly susceptible to compression, so large, non-functional pituitary tumors can cause hypogonadotropic hypogonadism as well (answer C is true and therefore incorrect). Transection of the pituitary stalk, e.g. by whiplash injury in a traffic accident,prevents GnRH from reaching the gonadotrophs as so can cause hypogonadotropic hypogonadism(answer E is true and therefore incorrect).
A patient has had chronic anovulation and mild hirsutism for several years. Blood tests indicate that herserum LH:FSH ratio is higher than normal, her androstenedione (AD) and testosterone levels are elevatedand her ACTH is within normal range. All of the following findings would be expected EXCEPT:

A.Bilateral polycystic ovaries
B.Elevated serum estrogen
C.Elevated serum progesterone
D.Insulin resistance and hyperinsulinemia
E.Increased secretion of 17-OH progesterone in response to an injection of GnRH
CThis patient has classic symptoms and lab findings of PCOS (polycystic ovarian syndrome), includingchronic anovulation, mild hirsutism and an elevated LH:FSH ratio. Congenital adrenal hyperplasia couldcause excess androgens, but as a result of high ACTH stimulating adrenal androgen synthesis, so DHEAS and androstenedione would be > testosterone. An androgen-secreting tumor would typically progress tosevere hirsutism and even virilization over a period of months or a year – not multiple years. Ultrasoundimaging of PCOS ovaries typically reveals increased size and presence of multiple follicles arrested in the mid-antral phase of development (answer A is true and therefore incorrect). The increased LH stimulatesthe thecal cells to secrete excessive amounts of androgens, which cause increased hair growth (hirsutism)and are aromatized to estrogens in fat, skin and muscle (“extraglandular”) (answer B is true and therefore incorrect). Because these patients do not ovulate, they do not develop a progesterone-secreting corpusluteum (answer C is not true and therefore the correct answer). As a result, the unopposed estrogen-stimulated proliferation of the endometrium increases the risk of endometrial cancer in these patients. The increased 17-OH P response to an injection of GnRH suggests an increased sensitivity of the P450C17enzyme to LH, which may be a result of serine phosphorylation of the enzyme (answer E is true andtherefore incorrect). Interestingly, serine phosphorylation of the insulin receptor causes insulin resistance, a common finding in PCOS (answer D is true and therefore incorrect).
A 22-year-old woman has a one-year history of amenorrhea. Her day 3 plasma FSH levels are 40 mIU/ml(normal follicular FSH = 3 – 17 mIU/ml). Which of the following is the most likely diagnosis?

A.Polycystic ovary syndrome
B.Premature ovarian failure
C.Asherman’s syndrome (scarring of the endometrium)
D.Occlusion of fallopian tubes
E.Inhibin-producing tumor
BOf the listed choices, the high FSH combined with amenorrhea is best explained by premature ovarianfailure, which is the equivalent of early menopause. When no ovarian follicles remain that can develop into Graafian follicles, no inhibin B is secreted and no estrogen peak occurs, so no LH peak occurs, so noovulation occurs, so no corpus luteum forms and no progesterone or inhibin A is secreted. Withoutinhibin or estrogen, FSH and LH levels rise to about 5 times menstrual levels. PCOS is associated with high LH but low normal or low levels of FSH (answer A is incorrect). Asherman’s syndrome can preventimplantation and pregnancy, and occlusion of the fallopian tubes can prevent fertilization and pregnancy,but neither affects any hormone levels (answers C and D are incorrect). An inhibin-producing tumor would cause very low levels of FSH (answer E is incorrect).
A 26-year old woman presents with 10 months of amenorrhea and increasing facial hair over that time. A physical exam reveals mild facial hirsutism but no virilization. Prior to this episode of amenorrhea,menstrual cycles had been normal since her menarche at 13 years of age. Her laboratory results include:testosterone = 205 ng/dl (N=20-56), DHEA-S = 9 mcg/ml (N=2-7), 17-OH progesterone = 10 ng/ml (N<3), LH = 6 mIU/ml (N=2-18), FSH = 4 mIU/ml (N=3-17). Which of the following conditions most completelyexplains her combination of symptoms and findings?

A.Adrenal reticularis cell tumor
B.Congenital adrenal hyperplasia
C.Hilus cell ovarian tumor
E.Lipoid cell ovarian tumor
EFacial hirsutism in women indicates excess androgens and excess androgens can also cause anovulationand so amenorrhea. Testosterone is typically an ovarian hormone, although some testosterone is formed by peripheral conversion of androstenedione (AD) or DHEA-S. DHEA-S is typically an adrenal hormone.In this woman, excess androgens developed over a period of months, suggesting an androgen-secretingtumor. Testosterone is significantly elevated, with a very mild elevation in DHEA-S, suggesting an ovarian tumor rather than an adrenal tumor. Her LH and FSH are at the low end of normal range but theyare unable to support normal ovulation due to excessive negative feedback by the androgens. Lipoidovarian tumors usually oversecrete all of the androgens, but secrete androstenedione (not reported) > testosterone > DHEA-S. They can also oversecrete cortisol and 17-OH progesterone – 17-OH P is aprecursor for both cortisol and androstenedione. So this woman’s condition is consistent with an ovarianlipoid tumor. The correct answer to this question is probably more easily reached by eliminating the remaining choices. Adrenal reticularis cell tumors secrete primarily DHEA-S, causing very elevatedDHEA-S with perhaps a mild elevation in testosterone due to peripheral conversion (choice A isincorrect). Congenital adrenal hyperplasia results from lack of cortisol (not excess) with a resulting excess of DHEA-S; testosterone might be mildly elevated (choice B is incorrect). Ovarian hilus cells are verysimilar to testicular Leydig cells, so hilus cell tumors secrete testosterone, but DHEA-S would be normal or minimally elevated, while cortisol would be normal (choice C is incorrect). Hyperthecosis, like PCOS,is usually present since puberty and develops slowly over years. Women with hyperthecosis do have anexcess of testosterone, sometimes to the point of virilization, but do not typically have elevated cortisol and their DHEA-S is normal or minimally elevated (choice D is incorrect).
A 28-year old female at 37 weeks in her first pregnancy reports decreased fetal movement over the last 3 days. Fetal monitoring in the hospital demonstrates fetal distress. Which of the following endocrine changesin maternal blood would best support a diagnosis of fetal distress?

A.Decreased estriol
B.Decreased progesterone
C.Decreased prolactin
D.Decreased oxytocin
E.Increased prolactin
EEstriol (E3) synthesis requires placental, fetal adrenal and fetal liver function, and so can be used in laterpregnancy as an indicator of fetal well being. The fetal adrenal gland has minimal 3 βOH SHD and sosecretes primarily DHEA-S. The fetal liver hydroxylates this into 16-OH DHEA-S, which thesyncitiotrophoblasts aromatize into E3. Progesterone is synthesized from maternal LDL cholesterol and so only requires a functional placenta, not fetal well being (answer B is incorrect). Prolactin is secretedby the maternal pituitary and decidua, and so prolactin does not indicate placental or fetal function(answers C and E are incorrect). Oxytocin is secreted by the maternal posterior pituitary during labor and so does not indicate fetal well being (answer D is incorrect). Increased prolactin during pregnancy isexpected due to increased estrogen, but estradiol and estrone do not require fetal precursors and so do notindicate fetal well being (answer E is incorrect).
In managing a pregnant woman with chronic renal disease, the prognosis for continued maternal health and a successful pregnancy is improved with all of the following observations EXCEPT:

A.Her blood urea nitrogen (BUN) drops below normal non-pregnant range.
B.Her creatinine clearance remains unchanged.
C.Her renal blood flow increases to over 30% greater than non-pregnant mean.
D.The observed physiologic changes occur by the end of the first trimester.
E.Urine osmolarity varies between 100 and 1000 mOsm/L.
B.During a normal pregnancy, renal blood flow and renal plasma flow should increase to about 135% ofnon-pregnant flow by the end of the first trimester (answer C is true and thus incorrect), which increasesGFR by about 40% – and both creatinine clearance and inulin clearance measure GFR. Renal plasma flow increases in part due to the expected increase in blood volume, that reaches 40% above non-pregnantmean by mid 3rd trimester. This increase in blood volume decreases her blood urea nitrogen (answer A istrue and thus incorrect), hematocrit and plasma oncotic pressure by dilution to below non-pregnant range by the end of the first trimester (answer D is true and thus incorrect). Renal regulation of osmolarity andsalt excretion is unchanged by pregnancy, so urine osmolarity can vary normally between about 50mOsm/L and 1200 mOsm/L (answer E is incorrect).
All of the following normally increase during pregnancy EXCEPT:

A.Femoral venous pressure
D.Red blood cell mass
E.Total body water
C.During pregnancy, red blood cell mass does increase (answer D is true and thus not correct), but thenormal increase in blood volume (see answer 7) due to renal retention of salt and water (answer E is trueand thus not correct) which increases plasma volume is greater – this decreases hematocrit below the nonpregnant range. Hepatic synthesis of fibrinogen and other clotting factors increases enough to increaseplasma levels of these proteins. In fact, decreased fibrinogen is cause for concern in a pregnant woman,since it may indicate clotting is occurring somewhere, as can occur in preecclampsia (answer B is incorrect). Femoral venous pressure increases because the uterus compresses the iliac veins, and thecombination of increased venous pressure and decreased plasma oncotic pressure (see answer 7) typicallycauses ankle edema (answer A is true and thus not correct).
Which of the following cardiovascular values are expected to increase for the listed reason by the mid-secondtrimester in a normal pregnancy?

A.Diastolic blood pressure due to increased systemic vascular resistance.
B.Mean left atrial pressure due to increased cardiac output.
C.Mean left atrial volume due to increased cardiac output.
D.Pulmonary artery pressure due to increased pulmonary blood flow.
E.All of the above are true.
C.Cardiac output increases to about 30-40% above non-pregnant mean by midpregnancy due to increases inboth heart rate and stroke volume. Increased stroke volume is due in part to the increased blood volume(see answer 7). At steady state, stroke volume = filling volume, so atrial volumes increase as well. Cardiac muscle compliance and pulmonary vascular compliance both increase during pregnancy. Theincrease in cardiac muscle compliance allows the atria and ventricles to fill to this greater volume with noincrease in atrial pressure (answer B is incorrect), while the increased pulmonary vascular compliance allows the increased pulmonary blood flow with no increase in pulmonary artery pressure (answer D isincorrect). Systemic vascular resistance decreases during the second trimester due in part to decreaseduterine, renal and breast vascular resistances; this decreases diastolic blood pressure (answer A is incorrect).
During a normal pregnancy, which of the following oxygen partial pressures are typically within 10 mmHg?

A.Uterine artery and umbilical artery.
B.Uterine artery and umbilical vein.
C.Uterine vein and umbilical artery.
D.Uterine vein and umbilical vein.
E.All of the above oxygen partial pressures are typically at least 20 mmHg different.
D.Maternal oxygen diffuses from uterine blood washing against the syncitiotrophoblasts lining the outsideof the chorionic (placental) villi into the chorionic (placental) capillaries within the villi, then travels through the umbilical vein to the inferior vena cava and circulates through the fetus. Maternal uterinearterial blood oxygen partial pressure (PO2) is ≈ same as any systemic arterial PO2 ≈ 100 mmHg. But theblood washing against the chorionic villi is a mix of arterial and venous blood and the placenta uses a portion of the O2 for its own metabolism. So the best estimate of fetal umbilical vein oxygen PO2 ismaternal uterine vein PO2, so increasing maternal uterine vein PO2 and O2 content is the target forincreasing fetal oxygenation. Typically uterine vein P O2 ≈ 45 mmHg, which is within 10 mmHg of the typical umbilical vein P O2 ≈ 35 mmHg (answers B and E are incorrect). The uterine vein PO2 is thehighest in the fetal-placental circulation for the same reason that pulmonary venous PO2 is the highest inthe maternal circulation. By the time fetal-placental blood has circulated through the fetus and is returning to the placenta through the umbilical arteries, oxygen consumption by fetal tissues has removed enoughO2 to decrease PO2 to its lowest level in the fetal-placental circulation. Umbilical artery PO2 is only ≈ 20mmHg (answers A and C are incorrect), although the higher O 2 affinity of fetal hemoglobin allows thisblood to be almost 50% saturated with O2, whereas maternal blood with the same PO2 of ≈ 20 mmHgwould be only ≈ 30% saturated. In summary, as a result of blood flow, O 2 diffusion and Hb O2 affinity:

PO2 O2 saturation
Uterine artery ≈ 100 mmHg≈ 98%
Uterine vein ≈ 45 mmHg ≈ 75%
Umbilical vein≈ 35 mmHg≈ 80% (increased O2 affinity of fetal hemoglobin)
Umbilical artery ≈ 20 mmHg≈ 50%
Which of the following fetal values is greater than the corresponding maternal value during the early third trimester?

A.Aortic blood pH.
B.Aortic oxygen concentration.
C.Hemoglobin P50-O2 (oxygen partial pressure (PO2) at which Hb O2 saturation = 50%).
D.Left ventricular cardiac output per kilogram body weight.
E.Pulmonary blood flow per kilogram body weight.
DBy midpregnancy, maternal cardiac output is increased ≈ 30-40% greater than the nonpregnant mean, butfetal cardiac output (C.O.) is even higher, which allows the fetus to deliver adequate O 2 to fetal tissues.O2 delivery = C.O.• CaO2 and PO2 and cO2 in fetal aortic blood will be similar to those values in umbilicalvenous blood and significantly below those in maternal arterial blood (see answer 10) (answer B is incorrect). Fetal C.O. is high enough to ensure that fetal tissues receive ≈ 2.5 times more blood/ml O2used than do adult tissues. However, only ≈ 1/8 of fetal left ventricular C.O. flows through the fetal lungsbecause of the severe hypoxic pulmonary vasoconstriction. The remaining 7/8 of the LV C.O. flows through either the foramen ovale (right atrium to left atrium) or ductus arteriosus (beginning ofpulmonary artery to aorta). So fetal pulmonary blood flow is less than adult pulmonary blood flow(answer E is incorrect). Fetal CO 2 production ( ̊VCO2) = fetal O2 consumption ( ̊VO2) and fetal CO2 mustdiffuse across the placenta into the maternal blood to be expired from maternal lungs. This diffusionrequires a small P CO2 gradient to drive it, so fetal PCO2 > maternal venous PCO2. Maternal PaCO2 is reducedslightly due to progesterone stimulating the mother’s respiratory centers, which causes a mild respiratoryalkalosis; the higher P CO2 of fetal blood ensures that fetal aortic blood pH < maternal aortic blood pH(answer A is incorrect). Fetal hemoglobin has a higher O2 affinity than adult hemoglobin, indicated by aleft shift in the O 2 dissociation curve and a reduced P50-O2. Although actual numbers are not necessary toeliminate this answer, from answer 10, fetal umbilical arterial blood ≈ 50% saturated with O2 at the verylow P of 20 mmHg, while normal adult P= 27 mmHg (answer C is incorrect).
Preecclamsia is a disorder unique to pregnancy and characterized by:

A.Increased risk of occurrence in 20 – 30 year old women in second or later pregnancies.
B.New onset of hypertension.
C.New onset of glucosuria.
D.Onset typically in the first trimester.
E.All of the above are true.
BPreecclampsia is a disorder unique to pregnancy that includes the new onset of hypertension, proteinuriaand edema. Preecclampsia affects multiple organs but with the common denominator of vasospasm in various organ circulations. Preecclampsia occurs more commonly with first pregnancies (versus laterpregnancies), in older women (versus younger women, although the risk increases again below age 20)and in multi-fetal pregnancies (e.g., twins or triplets versus single births) (answer A is incorrect). Preecclampsia most often occurs in the last trimester of pregnancy and close to term – some patientsdevelop the disorder during labor or just postpartum (answer D is incorrect). Glucosuria is common inpregnant woman with no disease, since the normal increase in GFR increases the filtered load of glucose above the normal reabsorptive capacity of the proximal tubule (answer C is incorrect).
When compared to a normal pregnancy in the middle of the third trimester, which of the following wouldmost probably be higher in the same woman at the same gestational age, but with preecclampsia?

A.Blood platelet level (thrombocytopenia).
B.Blood volume.
C.Glomerular filtration rate.
E.Uterine blood flow.
D.Preecclampsia is characterized by sustained hypertension, proteinuria and edema after the 20th week of gestation. Mild preeclampsia is characterized by BP ≥ 140/90 mmHg with minimal pathologic (beyondthat expected in pregnancy) edema and no evidence of end-organ pathology aside from minimal proteinuria (<2.0 g/d). Severe preeclampsia is indicated by SP > 160 mmHg or DP > 110 mmHg withsignificant proteinuria (>5.0 g/d) and evidence of end-organ damage due to vasospasm and/or hemorrhage. Soluble placental factors cause abnormalities in maternal vascular function and blood thatcan lead to vasospasm, abnormal clotting, and thrombocytopenia (low blood platelets) that can result in hemorrhage (answer A is true and thus is incorrect). Renal damage prevents adequate blood volumeexpansion, leading to non-pregnant or higher hematocrit and BUN and even oliguria (answer B is true and thus is incorrect). Inadequate blood volume expansion and renal damage prevent the normal increasein renal plasma flow and glomerular filtration rate seen in pregnancy (answer C is true and thus is incorrect). Uterine vasospasm and infarctions can decrease uterine blood flow, leading to poor fetaloxygenation and poor fetal growth (answer E is true and thus is incorrect).
caloric density of carbs?
avg 4.1kcal/g, but varies
caloric denisty of ethanol?
7.1kcal/g -so drinkers have high cal, low nutrient diet
caloric density of fat?
avg 9.3kcal/g, TGs-> Fas + glycerol. Fas have high caloric value, glycerol little (it's like carbs)
caloric density of protein?
avg 4.1kcal/g. Not completely combusted due to leftover urea. Each AA has different caloric value
3 major components of enegy expenditure?
BMR, physical activity, adaptive thermogenesis (change BMR in adipose and skeletal muscle
what's thermogenesis?
making heat at rest, resembles BMR at rest
what's BMR?
caloric consumption in resting, awake, post-absorptive state. It mean no muscular activity. It is the energy required to perform basic cell and organ functions
how does sleep affect BMR?
drop 10%
how does starvation affect BMR?
drop 40% (counterproductive in dieting)
how does age affect BMR?
decreases 10% from age 20-60
how does gender affect BMR?
slightly higher in males
how does thyroid hormone affect BMR?
(↑TH→ ↑BMR). Hypothyroidism -> obese. Hyperthyroid->thin
constancy/variability in TH?
relatively constant in most people, changes seasonally
how does surface area relate to BMR?
inverse due to greater heat loss in smaller animals (e.g. mouse BMR is 10x greater than horse)
relative role of physical activity in energy expenditure?
biggest determinant
how many times more energy does brisk walking require than BMR?
4-5 times
cycling, dancing?
6-7 times
characterisitics of insulin receptor?
tetrameric, part of RTK (receptor tyrosine kinase), 2 extracellular alpha subunits disulfide bonded to 2 membrane-spanning beta subunits
what happens to receptor upon insulin binding?
autophosphorylation of intracellular beta subunits, then activates other subunits via phosphorylation
activated insulin receptor activity in skeletal muscle and adipose?
translocate glut4 to surface (in these tissues only, not in liver).
what happens when insulin removed?
glut4 goes back into vesicles (implications in insulin resistance)
how does insulin affect mitosis?
mitogenic, like all RTKs, via SH2 and SH3 domains
how does insulin signaling stop?
insulin and receptors are internalized into vesicles.
what two things can happen after termination?
retroendocytosis (vesicles re-fuse with membrane, releasing insulin), or degradation of insulin.
three steps to insulin degradation?
1)vesicles acidified, cause insulin to fall off, 2)vesicles separate into receptor vesicles and insulin vesicles, 3)insulin degrades, and receptors with reused or degraded
how does glucagon signal?
via a specific glucagon GPCR.
how do GPCRs work?
ligand binds, GTP displaces GDP, alpha subunit activates adelylyl cyclase, converts ATP to cAMP, activates PKA
what do beta and gamma subunits do?
stay behind, recruit GRK-2 (G-receptor kinase), which phosphorylates GPCR, which recruits beta-arrestin, which associates with clatherin to internalize GPCR and activates MAP kinase
how do insulin and glucagon interact?
do exactly opposite things. Glucagon promotes catabolism, and inhibits anabolism. Insulin promotes anabolism and inhibits catabolism
what four specific processes do insulin and glucagon regulate?
ketogenesis from FA oxidation, glucogenesis from proteins, glycogenolysis, lipolysis
how is energy from food divied up?
40% lost to heat, then equally divided among cell maintenance, muscle work, internal work (also given off as heat)
how are carbs absorbed?
broken down to small saccharides by amylase. Disaccharidases on brush border cleave sugars to make monosaccharides. Lactase decreases with age.
what approach to diabetes treatment takes advantage of the above mechanism?
drugs can block amylase activity, so don't absorb carbs as much, and reduce glucose spike
how are proteins absorbed?
broken down into smaller peptides
how fats absorbed?
lipase in gut breaks TGs to glycerol, FAs, and monoglycerides. Bile helps FAs and monoglycerides get absorbed, but glycerol needs to help. TGs then resynthesized in epithelial cells, packaged in chylomicrons, and sent to periphery for absorption.
how does 100g of glucose get distributed among body tissues?
liver 60%, brain 15%, muscle 15%, fat 5%, other 5%, but it's not all metabolized by these tissues
what portion of glucose gets metabolized (used) by what tissues?
brain 70% (an obligate glucose consumer, and why hypoglycemia is so critical), muscle 20%, heart 10%, kidney 2%, and very little for rest of body
how is insulin taken up and used by muscle?
insulin stimulates glut4 transport, and breakdown by hexokinase.
how does insulin affect glycogen synthesis and breakdown?
promotes synthesis, inhibits breakdown.
what about glucokinase?
only in tissues that use glut2. Hexokinase only in tissues with glut4.
what regulates FA uptake by muscle?
amount in blood. It's insulin-independent
what regulates protein uptake by muscle?
insulin-dependent AA uptake
glucose uptake by fat?
insulin-dependent, and converted to FA and glycerol
FA uptake by fat?
70% of FA uptake is from lipoproteins using LPL
how is fat in adipocytes released?
hormone-sensitive lipase (HSL) is upregulated by glucagon and inhibited by insulin
2 ways to bring glucose to liver?
1) direct (40%), via glut2, followed by glucokinase (GK), and stored as glycogen. And 2) indirect (60%), derived from pyruvate and lactate (which are metabolites of glucose from other tissues), metabolized into glycogen. (only occurs for first 2 hours after meal ingested)
3 main effects of insulin on the liver?
1)protein, TG, glycogen synthesis, 2)AA uptake, 3)inhibits glucose-6-phosphatase to prevent glycogen breakdown
overall picture of what happens during fed state?
storage of protein, TG, glycogen. Oxidative phosphorylation by liver and muscle
what happens during 24 hr fast? To brain? Glycogen stores? Adipocytes? Muscle protein?
brain continues to consume glucose (obligate). glycogen in muscles and liver used first. adipocyte FA oxidation to provide energy for gluconeogenesis in liver. FAs in muscle breakdown to give energy to muscles. Muscle proteins breakdown, and taken up by liver for gluconeogenesis
importance of the corey cycle?
glycogen stores used up in 1 day, but brain still needs glucose.
how does it work?
lactate and pyruvate from glycolysis in blood cells, travels back to liver, where it is resynthesized into glucose for the brain to use. The energy to do this comes from FA oxidation
how much energy is stored in a person as glycogen?
900 calories (liver and muscle)
how much energy stored in protein?
24,000 calories
how much energy is stored in fat?
141,000 calories
how long can that last us?
about a month, if water and electrolytes are available
what changes occur after 24 hours of fasting?
gluconeogensis decreases due to lack of substrate (protein)
physiological changes to long fast?
brain starts using ketones (synthesized in liver from FFAs), prevents protein wasting and gluconeogenesis. Other major change is TH and symp tone drops, so less energy expenditure. Gluconeogenesis still continues a little as muscle breaks down less and less.
does brain work as well on ketones as on glucose?
not sure, but maybe subtle differences
why don't we become hypoglycemic when exercising (use up blood glucose)?
exercise upregulates glut4 in muscle INDEPENDENT of insulin, then liver replaces blood glucose by gluconeogenesis, which is stimulated to occur in two ways.
what two ways does gluconeogenesis increase during exercise?
1)lactate from muscles, and 2) increase in circulating NE and EPI (the MAIN WAY)
what effects on insulin and glucagon do circulating NE and EPI have?
stimulates glycogen breakdown, inhibits insulin production (to counter its inhibition on glucagon), and glucagon promotes gluconeogenesis
caloric density of carbs?
avg 4.1kcal/g, but varies
caloric denisty of ethanol?
7.1kcal/g -so drinkers have high cal, low nutrient diet
caloric density of fat?
avg 9.3kcal/g, TGs-> Fas + glycerol. Fas have high caloric value, glycerol little (it's like carbs)
caloric density of protein?
avg 4.1kcal/g. Not completely combusted due to leftover urea. Each AA has different caloric value
3 major components of enegy expenditure?
BMR, physical activity, adaptive thermogenesis (change BMR in adipose and skeletal muscle
what's thermogenesis?
making heat at rest, resembles BMR at rest
what's BMR?
caloric consumption in resting, awake, post-absorptive state. It mean no muscular activity. It is the energy required to perform basic cell and organ functions
how does sleep affect BMR?
drop 10%
how does starvation affect BMR?
drop 40% (counterproductive in dieting)
how does age affect BMR?
decreases 10% from age 20-60
how does gender affect BMR?
slightly higher in males
how does thyroid hormone affect BMR?
(↑TH→ ↑BMR). Hypothyroidism -> obese. Hyperthyroid->thin
constancy/variability in TH?
relatively constant in most people, changes seasonally
how does surface area relate to BMR?
inverse due to greater heat loss in smaller animals (e.g. mouse BMR is 10x greater than horse)
relative role of physical activity in energy expenditure?
biggest determinant
how many times more energy does brisk walking require than BMR? cycling, dancing? soccer, running, etc?
4-5 times, 6-7 times, 8-12 times
what's adaptive thermogenesis?
change in heat production in response to temp change or caloric intake
adaptive thermogeneis in response to cold? Change in O2 consumption?
shivering increases heat production. In small animals, this can increase oxygen consumption by 2-4 times (humans 5-10%)
how are BMR and adaptive thermogenesis related?
BMR is under normal conditions, but adaptive thermogenesis does modulate BMR, so they are inter-related
how does acute feeding affect BMR?
increase 25-40%
How does low protein diet affect energy storage?
decreases ability to store energy
how does cold temp affect energy balance? (acute)
increases sympathetic outflow, stimulates lipolysis, and UCP-1
increased UCP-1 transcription, mitochondria synthesis, brown fat hyperplasia, recruitment of brown fat in white fat deposits
mechanism for adaptive thermogenesis?
use ATP to shiver, and ion leak to increase Na/K ATPase
what does UCP-1 do?
uncouples oxidative phosphorylation, so more protons move into mitochondria, where they make electron transport chain more efficient, so burn more calories (and make more NADH, FADH2)
within what range of environmental tempuratures, do humans have relatively constant body temp?
between 55 and 115F. But above and below this, core body temp changes a lot
how does ovulation affect body temp?
slightly increase after ovulation
what regions of body need tightest control of temp?
brain and viscera
relationship between core body temp and rectal and oral temps?
close to each other
what part of body produces most heat during BMR?
brain and heart
how does time of day affect body temp?
slightly lower in the morning
4 mechanisms of heat transduction?
evaporation, conduction, convection, radiation
what method(s) of heat transfer is/are used for cooling off?
only evaporation. Works even in absence of sweating. Doesn't work if humid.
physiology of sweat production?
sympathetic nerves make it happen. There is low activity at rest. Most of fluid in ducts gets reabsorbed. But, when hot, blood flow increases, increasing fluid at glands and limiting reabsorption. Can sweat between 1 and 3 L per hour, depending on how well adapted
how much can clothing reduce heat loss?
about 50%
how does sympathetic system reduce heat loss in cold environment?
constricting skin blood vessels. Below 75F, already maximally constricted
at what temp are skin blood vessels maximally dilated?
location of 2 major temp sensors?
anterior hypothalamus, periphery
how are the sensors different?
ant. Hypo responds to hot and cold by inceasing firing, and measures temp of brain. But periphery sensors sense environmental temp, and mostly respond only to cold (a little sensitive to hot).
5 responses to cold?
vasoconstriction, shivering, behavioral changes, increase TH (over time), piloerection
3 responses to hot?
vasodiliation (withdraw symp tone), sweating, decrease heat generation
how does set point work?
determined by hypothalamus. Cooling mechanisms and heat generating mechanisms adjust according to body temp.
what raises the set point? How?
fever, via IL-1beta, which activates synthesis of PGs
how do NSAIDS reduce fever?
inhibit PG synthesis, so reduces set point
Pancreatic Islet are what percent of the pancreas?
What are the three islet cell types of the pancreas and what do they secrete?
Alpha cells-secrete glucagons, Beta cells-secrete insulin, Delta cells-secrete somatostatin
Where are these cells located in the “mini portal” system?
Beta-middle, alpha, outer edge, D- mixed at border between alpha and beta
When the blood flows through the islets of langerhans, what order does it pass through the cells?
Capillaries, Beta cells, maybe delta (fewer), alpha, then enters vein
What is the consequence of this order of blood flow?
insulin immediately acts on alpha cells, but glucagon has to go through entire circulation before acting on beta cells
What are the 4 breakthroughs that insulin has been the prototype protein for?
First isolated protein, First sequenced gene, First cloned gene, First recombinant protein used therapeutically
Insulin gene has
3 exons and 2 introns
The insulin protein’s alpha and beta chains are connected by three _____.
Disulfide bonds
When Pro-insulin is cleaved to mature insulin, what is cleaved away?
C peptide
What are the proportions of Insulin and C peptide in the mature vesicle?
Insulin is highly conserved especially the ______, residues that make the _______ bonds.
Cysteine residues, disulfide
How many amino acids different are bovine and porcine insulin from human?
Bovine=3, porcine=1
What is the variable part of the pro-insulin protein?
C peptide
Cleavage of C peptide at highly specific sites is done by ______ only expressed in _____.
Proteases, beta cells
What is the first form in insulin before proinsulin?
What are the molecular weights of Insulin, proinsulin, and preproinsulin?
6000kda, 9000kda, and 11000kda
What are the steps in the classical ER pathway?
1. Ribosome begins making protein and a signal recognition protein (SRP) binds to protein and brings to ER
2. Signal sequence receptor (SSR) brings partially synthesized protein attached to ribosome into ER and ribosome continues to synthesize rest of preproinsulin protein from the outside of the ER
3. Signal peptidase cleaves signal peptide of protein and is released into ER
4. Proinsulin is properly folded in the ER
5. Secreted to Golgi in vesicles where proteases cleave C-peptide
How long does it take to make new insulin and get it ready to secrete?
2 hours
Where does insulin released during a meal come from?
In Type II diabetes, insulin storage and release are ______ for the needs of the body.
Since insulin is difficult to measure directly, how do you measure it?
Measure C-peptide, which is not metabolized by liver and issecreted in the kidneys
What was the first company to make recombinant human insulin?
What discovery made it possible to make properly folded recombinant human insulin?
You need to make proinsulin rather than mixing alpha and beta chains.
How do you remember how glucagons is synthesized?
Remember it is very similar to insulin
Describe the structure of the glucagons molecule.
Single chain, 29 a.a., 3500kda
What percent of circulating glucagons is active?
What are the other forms of inactive glucagons?
Preproglucagon, proglucagon, little biological activity
What is the consequence of differential protease expression?
Different cells express different protease which causes selective cleavage. Once gene product can become many different protein products.
Preproglucagon is made if what two cell types?
Alpha cells of pancreas and L-cells of GI tract
What is the protein product produced by L-cells?
What does GLP I do?
Augments/ increases insulin secretion, acts on brain (sold as a drug to treat diabetics)
Where is GLP I degraded?
In the blood
Insulin secretion is subject to what 2 portal systems?
Intra-islet and hepatic
How much of the secreted insulin is removed by the liver?
50% first pass
What is the therapeutic dilemma with subQ administration of insulin?
1. Liver gets too little insulin and needs more
2. Systemic gets too much if give the portal vein [insulin]
How does the insulin get to its site of action (tissue) from vascular network?
Crosses the endothelial cells of vascular by transcytosis
What is the difference between the rate of change of insulin concentration in the vascular and interstitial spaces?
Interstium is much slower
What are the proportions of insulin decrease from pancreas to tissue?
50% lost in liver, of the remaining 50%, 40% of that is does not make it to interstitial space. So, only 30% of originally secreted insulin makes it to tissues.
What is the major regulator of insulin secretion and what is the feedback?
Glucose via negative feedback
What is the first phase of the biphasic insulin secretion?
High quick spike when stored insulin is released
What stimulates this first phase?
glucose, amino acids, sulfonylureas, glucagons, and GI hormones
What is the second phase?
slower rising, less dramatic amount of insulin, new insulin is made and released
What stimulates the second phase?
Only glucose
Of the total daily insulin secreted, what percent is basal?
What percent of daily glucose exposure is basal?
During meals _____ and _____ spike together.
Glucose, insulin
How does glucose get into the beta cell to stimulate insulin secretion?
Facilitated transport through Glut2
What enzyme is called the glucose sensor and what does it do?
Glucose kinase (GK), phosphorylates glucose on side of mitochondria
What is the consequence of excess glucose present in the beta cell?
ATP levels rise so ATP:ADP ratio rises
What happens when the ATP:ADP ratio rises?
causes depolarization of cell allowing calcium to enter cell
What is the effect of the calcium influx?
Exocytosis of secretory granules of insulin
What is the job of cAMP?
potentiates the process so anything that increases cAMP levels also increases insulin secretion (only if glucose present in first place)
When is the onset of GK-Mody disease?
During youth
What causes it?
GK mutation
Heterozygotes for GK _____.
Show decreased insulin secretion
What does this disease tell us about how the body senses glucose levels?
Glucose metabolism is how we sense glucose levels, not the actual present amount of glucose
What do different meal components do to insulin levels?
a.a., carbs, and fats all increase insulin levels, a.a. almost to the level associated with glucose feeding.
Why do glucose levels rise during protein feeding?
During the cephalic phase of digestion, what causes insulin to be secreted? How do we know?
Anticipation, incretins (GLP I) and neurological stimulation. Insulin levels are greater when glucose is given orally more insulin is secreted than glucose is given IV
What are the effects of the PANS on insulin secretion?
Parasympathetic tone stimulates basal insulin secretion
Stimulation of SANS alpha receptors _____ insulin secretion while stimulation of beta receptors ______ secretion.
Blocks, stimulates
What does isoproterenol do to insulin secretion?
Why does an increase in SANS tone decrease insulin secretion?
b/c alpha receptors dominate
Why is glucagons called counter-regulatory?
almost everything that inhibits insulin secretion promotes glucagons secretion and vice versa
What are the two major regulators of glucagons secretion?
(1) Glucose-negative feedback -à High glucose = low glucagon
(2) Insulin-negative feedback à alpha cells immediately see insulin secretion b/c of the intra-hepatic blood flow so glucagon secretion is immediately inhibite
What is the one exception to everything of opposite for insulin and glucagon secretion?
Amino acids stimulate both insulin AND glucagons secretion
Why is this exception important?
glucagon promotes glucose synthesis while insulin promotes glucose breakdown so the overall glucose level is constant in a protein only diet, if only insulin was secreted then the person would become hypoglycemic b/c basal glucose levels would fall without glucagons to balance it.
Somatostatin is a single chain, ____ a.a. peptide with one ______ bond.
14, disulfide
____% of somatistatin is made in delta cells of pancreas while ____% is made in the gut
25%, 75%
What is the main job of somatistatin?
To inhibit the secretion of everything.
DM is leading cause of what three conditions?
adult blindness, renal failure, amputations. (also 2-4x more CVD)
% diabetics type I, II?
5% type I, 95% type II
two classifications of type I DM?
primary (autoimmune destruction). Secondary (physical destruction)
relative role of genetics is type I DM?
monozygotic twins 50% chance. So big environmental too
what HLAs are associated with type I DM?
DR3, DR4 haplotypes. DR2 appears protective. But none of these are absolutely required.
risk of type I to general pop?
risk to parents of affected child?
risk to offspring?
8% father, 3% mother. Don't know why difference
risk to sibling?
risk to HLA identical sibling?
risk to sibling with no HLA identity?
evidences for virus-induced type I?
insulinitis (inflammation of pancreas), epidemiological clusters occur, viral titers in some type Is, animals can get type I if infected, in-vitro beta cells can be killed by certain viruses
what is only proven viral cause of type I?
congenital rubella gives 20% chance of infant getting type I
evidences for immunologic cause of type I?
insulinitis, associated with other autoimmune diseases, prevalence of anti-islet cell Abs (ICAb). High ICAb when diagnosed and falls after years pass.
possible chain of events for developing type I?
HLA linked genes, islet cell susceptibility, viral interaction with islet cells, immune response -> ICAb, beta cell failure, hyper alpha fxn
when do sxs manifest (in life of disease)
after 80-90% of beta cells gone, and often after traumatic event
is better to treat before sxs show up?
if therapy exists, and is very very safe, and if screening is very sensitive (especially with DM I being very rare)
% of DM pts that are obese?
four classes of DM type II?
regular DM, gestational (always comes back later), MODY (mature onset DM of the young), impaired glucose tolerance.
what is MODY?
mature onset of diabetes in the young. 20-30yo, otherwise healthy. Due to mutation in glucogenesis pathway (such as glucokinase)
what is IGT?
impaired glucose tolerance. It's prediabetic. Pts usually become obese, then get IGT, then DM. Each year, 7% of IGT pts get DM
procedure for OGTT?
oral glucose tolerance test. Fast 14-18 hrs, measure glucose, then feed known amount of glucose, and measure over 3 hrs.
normal glucose levels (fasting, OGTT 30-90 minutes, and OGTT 120min)?
fasting <126. OGTT 30-90 minutes <200, OGTT 120 minutes <140. Must be all of these to be normal
what glucose is diagnostic of DM?
symptoms **AND*** (fasting >126, **OR** OGTT-2hr >200)
4 organs contributing to hyperglycemia in DM?
liver (increased glucogenesis, due to insulin resistance, hyperglucagonemia, corey cycle, more FA use), muscle (main culprit in DM, less uptake of glucose), pancreas (high insulin or burned out pancreas and little insulin), adipose (similar to muscle)
how does a real meal and OGTT differ in insulin and glucose response in DM?
in mild DM, other molecules stimulate insulin production, so glucose stays under control. In severe DM, insulin cannot be made
first step to developing DM?
insulin resistance due to aging, obesity, physical inactivity
how does body respond to initial insulin resistance?
produce more insulin. It occurs in IGT, metabolic syndrome or syndrome X
two ways to have beta cell failure?
apoptosis, or stop making insulin
after beta cell failure, what happens?
glucose diposal rates decrease dramatically (but can improve with adequate control), increased hepatic glucose output, and decreased insulin secretion
evidence that insulin resistance is first step in disease process?
non-diabetic children of diabetics with high insulin sensitivity (Si-insulin) much less likely to develop DM later in life
factors that contribute to having insulin resistance?
genetics, obesity, aging, some meds, rare disorders
4 conditions resulting from insulin resistance? (even in absence of DM)
HTN, dyslipidemia, atherosclerosis, PCOS (poly cystic ovarian syndrome)
diagnosis for syndrome X (metabolic syndrome)? Has 3 of what 5 risk factors?
1. Obesity (men>40in, women>35in) 2. TGs>150 3. Low HDL (men<40, women<50) 4. BP>130/85 5. Fasting glucose >110
three endocrine mediators adipose secretes?
adipokines, cytokines, chemokines
what's adiponectin?
an adipokine (only secreted by adipose), which promotes insulin sensitivity
what's resistin?
an adipokine that promotes insulin resistance
what other adipokine is there?
what cytokines do adiipocytes secrete?
TBFa, IL6, IL1beta, and inflammatory ones
role of chemokines secreted by adipocytes?
attract macrophages by chemical gradient, hay clusters of macrophages in fat
what happens physiologically and chemically to adipose tissue as fat accumulates?
adipocytes get bigger and more numerous. Adiponectin decreases, resistin increases. This is reversible in early DM via exercise and weight loss
how does inflammation iccur from insulin resistance?
free FAs (which increase during insulin resistance due to cells "starving" of glucose) activate inflammatory pathway. Pathway is advantageous during regular fasting, so conserve glucose.
how does inflammation occur due to obesity?
fat has high number of macrophages, which produce inflammatory cytokines (more fat->more inflammation)
what is basal glucose uptake?
Rd (rate of disposal). 70% of this is non-insulin mediated uptake (NIMGU), of which the brain is most responsible
what is IMGU?
insulin-mediated glucose uptake. This is 30% of Rd
how does hyperglycemia occur during fasting?
all from glucogenesis (overproduction)
how does hyperglycemia occur after a meal?
insulin resistance, glucose from food, IMGU doesn't upregulate enough, as it does in normal persons
how does NIMGU and IMGU change during feeding?
in normal persons, IMGU becomes much larger than NIMGU
what two things to control iin order to treat hyperglycemia?
overproduction and insulin resistance need to be treated.
postprandial or fasting hyperglycemia more dangerous?
possible causes of insulin resistance?
(mutated insulin gene, incomplete conversion of proinsulin to insulin), (antagonists like hormones, Abs, FFAs), receptor or pathway defects
in type II DM, glucose transport defective in which part of the process?
translocation of glut4 to membrane decreased due to inflammation
4 different types of assaults on CV system due to hyperinsulinemia and insulin resistance?
hyperlipidemia, hyperglycemia, HTN, hypercoag/inflammation
step therapy for DM with FBG<140?
1) diet/exercise, 2)monotherapy with metformin or sulfonylurea, or others if criteria are met. 3)combo metformin + sulfonylurea 4) triple oral therapy, add insulin, refer to endocrinologist, 5)insulin-dependent
how does beta cell fxn and insulin resistance change over course of disease?
beta cell fxn declines over life of disease, but insulin resistance stops getting worse around the time of diagnosis
disadvantages of insulin therapy?
more insulin resistance, more CV risk, weight gain, hypoglycemia
what role does basal insulin play?
is 50% of all-day insulin, prevents glucose overproduction
characteristics of bolus insulin?
occurs after meal, peaks in 1 hr, 10-20% of daily insulin after each meal
onset, peak, duration of endogenous insulin?
30-60 min, 2-4 hrs, 6-10hrs
lispro, aspart?
15-30 min, 1-2hrs, 4-6 hrs
1-2hr, 4-6hr, 10-20hr
1-2hr, no peak, 24hrs
what is BIDS?
bedtime insulin + daytime sulfonylurea (to decrease nightime hepatic glucose production, decrease glucose toxicity on beta cells which increases beta cell response to sulfonylurea, and only 1 shot with limited side effects.
what insulin is used in BIDS?
70/30 or 75/25 right before dinner (long/short)
what's exenatide?
GLP-1 analog
what's pramlintide?
amylin analog (also secreted from beta cells to slow gastric emptying, antiglucagon, suppress appetite, for type I and II. Hypoglycemia is side effect
morning hyperglycemia?
can occur as gradual rise, immediate rise, or level through night, then rise
general dosing considerations for insulin?
half basal, half bolus. Need 1/2 units/kg/day divided into 3 injections per day. Adjust short-acting to carbs in meal
types of diabetic complications?
microvascular, macrovasular, GO, derm, rheumatologic, emotional
what are the microvascular complications?
retinopathy, nephropathy, neuropathy (60-70% of diabetics)
causes of microvascular complications?
basement membrane thickening, endothelium death, pericyte death
results of DCCT and Kimamoto studies on DM tx?
intensive treatment reduced HbA1c to 7% (instead of 9), much less retinopathy and nephropathy
main determinant of development and progression of microvascular complications?
severity and duration of glucose control
how to manage retinopathy?
screen, prevent, treat (eye exams annually for type II, q 5 yrs for type I, eye photographs, and control of glucose and BP. Photocoagulation-laser therapy, ACEIs
how to manage nephropathy?
yearly 24hr urine collection for microalbuminemia, and freq BP measurement
what are the types of neuropathy?
general (hand and glove), sensory (can't feel stuff on feet), motor (foot mangled)
4 elements of foot exam?
pedal pulse, inspection, vibration (128Hz), monofilament
top causes of death in diabetics?
ischemic heart disease, other heart disease, and stroke
how does CV disease occur in DM?
hyperglycemia, high FFAs, insulin resistance, all results in vasoconstriction, inflammation, thrombosis (atherogenesis)
3 non-reversible risk factors for CHD?
aging, male, genetic
7 reversible risk factors?
dyslipidemia, HTN, obesity, hyperglycemia, hyperinsulinemia, smoking, EtOH
how to reduce CV risk?
glycemic control, BP control (ACEIs), dyslipidemia control, ASA, no smoking
ASA therapy?
recommended for diabetics >30yo and at least one risk factor
derm complications?
dry skin from less sweating due to neuropathy, fungus infections, yeast infections, acanthosis nigricans, necrobiosis lipoidica (immunologic, tx w/ steroids), eruptive xanthomas
rheumatologic complications?
stiff hands (prayer sign), trigger finger, carpel tunnel, adhesive capsulitis, charcots joint.
GI complications?
gastroparesis, bacteria overgrowth, constipation, diarrhea
emotional complications?
stress, depression, poor social support, paralyzing beliefs, discouraging results, unclear plan, DM taking control of them
function od ApoA-I?
cofactor for LCAT (lecithin XOL acetyltransferase)
two disorders that lead primarily to combined hyperlipidemia?
dysbetalipoproteinemia, familial combined hyperlipidemia (FCHL)
three disorders that mainly to hypertriglyceridemia?
LPL deficiency, ApoC-II deficiency (which are both hyperchylomicronemias) familial hypertriglyceridemia
three condtions that lead to low HDL?
familial ApoA-1 deficiency, familial LCAT deficiency, Tangier disease
cause, lipids, manifestations of dysbetalipoproteinemia?
homozygosity for ApoE2, which has low affinity for hepatic receptors, so decreases clearance of ApoE-containing lipoproteins. Manifestation requires homozygosity PLUS a cofactor like DM, obesity, pregnancy, hypothyroidism, or any inceased chylomicron production or VLDL. Lipids are high chylomicrons and TG. Pts get premature atherosclerosis, CHD, palmar xanthomas, tuberous/tuberoeruptive xanthomas on elbows and knees (virtually diagnostic). Picture?
cause, lipids, manifestations of familial hyperTGemia?
unknown genetic defect (maybe high TG synthesis, low VLDL lipolysis), high TG (mostly VLDL), or high VLDL and chylomicrons. No unique signs, but usually start in adulthood, whereas LPL or ApoC-II deficiency signs start in childhood, and can rule out FCHL because FHTG shows normal LDL
four potential outcomes of plaque rupture?
partial removal of thrombogenic core (occlusion of rupture site, and healing as a complicated lesion, 2) sudden stenosis from massive bleeding into lesion 3) occlusion of lumen by thrombus (partial or complete), 4) propagation thrombus gives rise to embolus downstream
CETP cause, lipids, and manifestations?
genetic CETP deficiency. CETP usually exchanges XOL esters of HDL against TG ot other lipoproteins, so if deficient, it reduces HDL catabolism. HDL is >150, no early atherosclerosis, but no pretective effect either because low hepatic clearance.
what are the borderline range values for TC and LDL?
TC 200-239, LDL 130-159. obviously above and below these values is high and normal respectively.
four conditions that lead primarily to hypercholesterolemia?
familial hyperXOLemia (FH), familial defective ApoB (FDB), polygenic HyperXOLemia, familial CETP deficiency, and secondary hyperXOLemias
elevates Lp(a)?
not usually measured in plasma. if high, correlates with atherosclerosis. it is basically an LDL particle with ApoB, to which apo(a) is atached by S-S bond. Cause of elevation unknown. SImilar to plasminogen
how does enzyme HL work? what does it do to VLDL remnants and HDL?
hepatic lipase. attaches to heparin sulfate on hepatocytes. converts VLDL remnants to LDL, and may help HDL uptake into liver
what is XOL metabolism and reverse XOL transport?
XOL metabolism if liver and peripheral cells, reverse means from peripheral cells to liver. (LCAT is enzyme for this)
function of Apo(a)?
unknown function, but associated with high CHD, is homologous to plasminogen, may compete with plasminogen
FCHL cause, lipids, manifestations?
dominant inherited, unstable lipoprotein phenotype, maybe make too much VLDL. TG is high if VLDL overproduction occurs, but if not, then high LDL. High incidence of CHD, often with type II DM, syndrome X
what is in the core and membrane of liporproteins?
core has TGs, esterified XOL, antioxidants. Membrane has phopholipids, unesterified XOL, apolipoproteins
four roles of apolipoproteins?
req'd for assembly of lipoprotein particles, give stability to particle, determine recognition by receptors, can help as cofactors for enzymes in lipoprotein metabolism
main consequences of thrombus or embolus formation secondary to atherosclerosis?
ischemic stroke, CHD (angina, MI), peripheral vascular disease (legs), intermittent claudication (gangrene)
main function of ApoB-100?
uptake of LDL (but also VLDL, IDL).
main function of Apob-48?
on chylomicrons. made from same gene as ApoB-100, but gets truncated in intestinal cells that edits the RNA (inserts stop codon). That way, it's not recognized by LDL receptor
how to image atherosclerosis?
angiography deceiving because shows only lumen, so use doppler, B-mode ultrasonography, IV ultrasound, NMR, ultra-fast computer tomography. what lab tests measure level of atherosclerosis? % surface area (Sudan stain), cross-section of lesion, intimal/medial ration, XOL content of artery, uptake of radio-labeled antibodies in arterial wall
FDB? cause, lipids, manifestations?
familial defective ApoB, mutation in receptor binding domain of ApoB-100, so reduced binding to LDL receptors. lipoproteins and manifestation like FH (high LDL, normal chylomicrons, mild reduced HDL, premature atherosclerosis, CHD, xanthomas, is only other disorder besides FH to have NB tendon xanthomas. QUESTION. what is pop frequency, and profile of LDL particles? 1:700, and individuals still have normal LDL, just some is defective
most MIs and non-hemmhoragic stroke caused by what?
rupture of lipid-rich plaque with thrombi. What region of the lesion do most plaques rupture? 2/3 in shoulder region, where pro-inflammatory cytokines (TNFa, and ILs and metalloproteinases (secreted by macrophages) mechanically weaken the fibrous cap. the ramainder ruptures occur at top of lesion. Core lipids have high thromboplastin (tissue factor), so are highly thrombotic
what are the dangerous effects of hyperTGemia?
life-threatening pancreatitis. How much can treatment of hyperXOLemia reduce MI incidence? 5 year 30-40% reduction
what are lipoprotein phenotypes?
they are combinations of types of lipoproteins over others, and characteristics of plasma and arteries. what are the basic types, and distinguishing characteristics? 6 types: type I) high chylomicrons only. type V) high chylomicrons and VLDL. type III) high chylomicrons and VLDL remnants. (notes on these... high chylomicrons-->lactescent plasma. chylomicrons don't penetrate arterial wall, and aren't atherogenic unless VLDL remnants are high as in type III. main complication for I and V is pancreatitis). Type IV) high VLDL only, with high CHD. Type IIa, IIb) have high LDL alone or high LDL and VLDL, which both are highly atherogenic
what is LCAT, where made, what does it do?
glycoprotein made in liver, req'd for reverse XOL transport (by freeing up acceptor sites for free XOL on HDL particles. It also catalyzes the transfer of FAs from sn-2 position of lecithin to free XOL. What cofactor is req'd, and what happens if LCAT deficient? ApoA-1 req'd. familial deficiency results in high ratio of free to esterified XOL, hyperlipidemia, premature CHD, kidney disease, corneal opacities.
what changes in the vessel wall are associated with early and late lesion?
advanced lesions usually don't penetrate elastic lamina, only intimal thickening, and can sometimes cause eneurysms. early lesions are covered by intact endothelium, and a little luminal narrowing. which plaques have highest propensity to rupture? atheroma and lipid-rich pre-atheroma, even though have limited stenosis. Fibrous and calcified plaques are more stable, but cause more chronic conditions (angina, and have more stenosis)
what is major effect of familial ApoA-1 deficiency?
Low LDL (along with familial LCAT deficiency and Tangier disease). what is the cause, and manifestations? autosomal recessive mutation of ApoA-1, leads to atherosclerosis, planar xanthomas, and corneal apacities
order of density between classes of lipoproteins?
least dense: chylomicrons, VLDL, IDL, LDL, HDL, Lp(a) most dense. What are some patterns of expression of apolipoproteins on the different lipoproteins? B-48 only on chylomicrons, CI, CII, CIII always together (and found on chylomicrons, VLDL, HDL), B-100 found on all but chylomicrons and HDL. E found on all but LDL, Lp(a). HDL has A-I, A-II, A-IV. A-IV also found on chylomicrons
what is major effect of Tangier disease?
low LDL (along with familial LCAT deficiency and familial ApoA-1 deficiency). cause and manifestations? caused by autosomal codominant mutation of ABC-A1 transporter (used for XOL efflux), manifested by high XOL in tonsils (large,orange tonsils), and other lymphoid tissues, as well as Schwann cells (neuropathy), and macrophages. less atherosclerosis than expected because low TC
what is major effect of familial LCAT deficiency?
low LDL (along with familial ApoA-1 deficieny and Tangier disease). what are causes and manifestations? caused by dysfunctional LCAT (essential for reverse XOL transport by esterifying free XOL accepted by HDL, so as XOL ester is transferred into core, particle accepts additional XOL). surprisingly, no increase in atherosclerosis and CHD, but can cause corneal apacities, kidney disease, proteinuria, anemia
Where's ApoA-IV found?
HDL, chylomicrons (unknown function). Where's ApoB-48 found? chylomicrons (helps chylomicron synthesis and secretion)
Where's ApoB-100 found?
VLDL, IDL, LDL, Lp(a) (helps with VLDL synthesis, secretion, and is ligand for LDL receptor). Where's ApoC-I found? chylomicrons, VLDL, HDL
Where's ApoC-II found?
chylomicrons, VLDL, HDL (cofactor for LPL). Where is ApoC-III found? chylomicrons, VLDL, HDL. (inhibits lipoprotein binding to receptors)
function of ApoC-II?
obligatory cofactor for LPL, which is expressed on endothelial surface and activated by ApoC-II on chylomicrons, VLDL, HDL. What does LPL do next? cleave TGs in core of particle, TGs taken up into peripheral cell for storafe in fat cells or metabolized by muscle.
CETP? where made? what does it do?
made in liver, transfers CE and TG b/t lipoproteins (direction determined by levels in donor and acceptor particles). But the major effect is to move CE from HDL to VLDL in exchange for TG. what happens if deficient? deficiency leads to high HDL CE, but not premature atherosclerosis
polygenic hyperXOLemia, cause, lipids, manifestations?
unknown genes, occurs in 5% of population, of which only a small % has FH, FDB, or secondary hyperXOLemia. Lipids LDL>220, type IIa or IIb. manifestations: atherosclerosis. how diagnose? differential diagnosis, so rule out others 1) If FH, 1/2 of 1st degree relatives have hyperXOLemia and xanthomas are frequent, 2)if FHCL, less than 10% of relatives have hyperXOLemia. 3)if VLDL is high, then it's FCHL
what is secondary hyperXOLemia? three dietary causes?
due to diet rich in XOL and saturated fats, which suppress hepatic LDL receptors. Also, hypercaloric diets stimulate VLDL production, and ethanol raises VLDL secretion (TG) and HDL. endocrine causes? DKA leads to excessive release of fatty acids, causing high TGs and VLDL synthesis. Type II DM causes high chylomicrons and VLDL due to decreased LPL activity. Also, insulin resistance stimulates hepatic VLDL synthesis, and down-regulates LD receptors. Hypothyroidism, Cushing syndrome (too much cortisol, or glucocorticoid treatment), and estrogen or oral contraceptive use has modest effecct, but exacerbate hyperTGemia.
LPL, located where?, how works?, req's what cofactor?,
on most tissues, especially adipose, muscle, cardium. gets secreted, attached to heparan sulfate on endothelium (is released by IV heparin (drug side effect)). cleaves FAs from TGs and p'lipids in chylomicrons and VLDL, which have on their surface ApoC-II (the req'd cofactor). What does a deficiency of LPL or ApoC-II cause? what happen during normal fasting? familial hyperchylomicronemia. During fasting, LPL activity in adipose decreases, but increases in muscle and heart
where's ApoA-I found?
HDL (stuctural). Where's ApoA-II found? HDL (unknown function)
what is the normal range for HDL?
should be 40 or above. HDL is inversely correlated with CHD. how does HDL levels change in women over time, and using HDL, what is a superior indicator of CHD risk? HDL decreases after menopause. LDL/HDL ratio is superior indicator than LDL or TC
evidence for LDL role in atherosclerosis?
high XOL in lesions, especially the foam cells and lipid pool; animals with lower XOL diets don't have atherosclerosis; epidemiological studies show correlation b/t XOL and atherosclerosis; migration studies of asians in U.S.; high LDL causes CHD in mice with LDL receptor deficiency; diet and drugs lower XOL, slows progression of atherosclerosis and CHD. what other lipoproteins are involved? high B-VLDL, TGs, and Apo-A II, but not chylomicrons, apoA-1 or LCAT. HDL reduces CHD.
what are borderline and high levels for TGs?
borderline 150-199, high 200-499. normal is below these, and very high is above these. how do CHD risk and TG levels correlate? High TGs go along with hypercholesterolemia most often, and so higher CHD, but independently, TGs don't cause atherogenenesis
cause, liporprotein changes, and manifestations of familial hyperXOLemia?
one of four disorders leading to hyperXOLemia. caused by mutated LDL receptor. results in high LDL and TC (type IIa hyperlipoproteinemia). chylomicrons aren't affected becuase even though they use LDL via ApoE, they have alternate receptors. HDL mildly reduced. manifestation is atherosclerosis and CHD in childhood, tendon xanthomas, esp achilles, hands, knees, and tuberous xanthomas, xanthelasma, corneal ring (arcus), and NB tendon xanthoma (only in FH and FDB. QUESTION... what are the population frequencies of FH and onset of CHD? homozygous 1:million, causes 6-10X increase in LDL, die in teens. hetero 1:500, causes 2-3 X increase in LDL, die in adulthood. TGs usually normal, HDL slightly reduced.
3 meanings of aretriosclerosis?
conventional (most prevalent, mainly from hypercholesterolemia, get plaques that may rupture); Restinosis injury (hardening secondary to stent placement, loss of elasticity, proliferation of smooth muscle cells, no XOL role); Graft atherosclerosis (after transplantation, chronic activation of T cells leads to atherosclerosis). Risk factors for conventional atherosclerosis? hypercholesterolemia, low HDL, HTN, smoking, DM, obesity, estrogen deficiency (menopause), family Hx of CHD, being male
what is an inherited hyperlipidemia of variable lipoprotein phenotype that is not stable over time?
familial combined hyperlipidemia (FCHL). (this causes combined hyperlipidemia along like dysbetalipoproteinemia) what are the characteristic changes in lipoproteins, and manifestations? incr. VLDL, and possibly LDL (and possibly LDL normal, but # particles increased (hyperapobeta-lipoproteinemia, incr apoB-100), low HDL. manifestations are high incidence of CHD, often with DM II, and syndrome X
stages of atherosclerosis?
1) adaptive intimal thickening by smooth muscle cells and proteoglycans at predilection sites 2) initial lesion (type I), microscopic accumulation of lipids in endothelium, macrophages recruited, take up oxidized LDL, turn into foam cells. 3) fatty streak (type II) raised lesions, mostly macrophage foam cells, intact endothelium, but surface expression different 4) intermediate lesion, pre-atheroma, translational (type III) more SMC in intima, and take up lipids, more extracellular conn tissue, fibrous cap forms, and apoptosis/necrosis of foam cells begins 5)atheroma, fibro-lipid plaque (type IV) eccentric lesion, thin fibrous cap, rich necrotic core, defects in endothelium, but no thrombi, permeable to macrophages 6) fibroatheroma (Type Va) thick fibrous cap, more collagen, (fibrous plaque, like type IV), capillary neovascularization in deep layers with infiltrating lipids, macrophages, t cells, immunoglobulin-rich 7) calcified plaque (type Vb) rich in extra- and intracellular Ca. 8) Fibrotic plaque (type Vc) mostly collagen, with little lipid, and 9) complicated plaque (type VI) same as V, but signs of hemmhorage (platelets, fibrin in lesion), fissure in cap, deep plaque erosion, ot thrombus. which lesions are "advanced lesions"? IV-VI
difference b/t men and women XOL, CHD, etc.?
men have higher TC until women, and women have less CHD until menopause. After menopause, TC and CHD increase markedly. Which is a better indicator of CHD, TC or LDL? LDL is a better indicator of CHD risk
besides upregulating stuff on arterial cells, what other effects does oxidation of LDL have on the cells?
many pathways are sensitive to oxidation, and regulate growth, differentiation, and death, so atherogenesis can result from stimulation of these pathways that leads to chronic inflammation, which goes along with impairment of NO dilation. what can be done to prevent this? low LDL, but also antioxidants (before lesions are formed)
where's ApoE found?
chylomicron remnants, VLDL, IDL, HDL (ligand for binding to LDL receptor LRP). where's Apo(a) found? Lp(a) (function unknown)
what are the causes, lipids, and manifestations of hyperchylomicronemia?
LPL or ApoC-II deficiency (freq 1:500), homozygotes only manifested, TG>1000, or even 10,000, high VLDL in elderly. fasting plasma stored in fridge is lactescent. since chylomicrons and VLDL also have XOL, TC is high too. signs/sxs are failure to thrive as infant, abdominal pain, pancreatitis, eruptive xanthomas, hepato- and splenomegaly. How does this affect CHD? no increase in CHD
formula to calculate LDL?
rationale is that VLDL is usually 1/5 of TGs, but if TG>400, it's not accurate. Levels also must be drawn on fasting, or else chylomicrons will be present
ApoE function?
recognized by LDL receptor (aka B/E receptor) for uptake of chylomicron remnants, VLDL, IDL, and HDL. what are the differences iin affinity of LDL receptor for ApoE, B, and variation in ApoE? receptor has much higher affinity for E than B. and hay three alleles for ApoE (E2, 3, 4), and therfore six phenotypes. E3 is by far the most common allele. E2 has low affinity (1% as much) if homozygous for E2, have dysbetalipoproteinemia. Interestingly, E4 homozygotes have higher risk of Alzheimer's
manifestations of atherosclerosis?
MI is often first sign. what are the various levels of onset of atherosclerosis in humans? starts in utero, depending on mother's diet. fatty streaks by age 10, aorta 30-50% covered by age 35. in cranial arteries, onset is much later and less extensive. Coronary arteries in myocardium free of lesions. branch points more common due to hemodynamics there.
what are lipoproteins?
complex particles that transport XOL and TGs through plasma. What are apolipoproteins? surface proteins on lipoproteins that help recognition and uptake of lipoprotein particles by cellular receptors or that convey enzymatic activity.
besides oxidation of LDL, what other factors promote lesion formation?
hemodynamic factors (changed gene expression by endothelium), physical damage, infectious agents (esp with TH1 response), chronic inflammation, HTN, DM, high reactive sugars. What immune responses are protective? TH1-> TH2 switch, antibodies to OxLDL (however responses to other antigens like heat shock proteins and chlamydiae make it worse).
besides diet and endocrine changes, what other things can lead to secondary hyperXOLemia?
liver disease (obstructive, cirrhosis, hepatoma, viral hepatitis), kidney disease (chronic uremia/dialysis, nephrotic syndrome), immune disease (systemic lupus erythematosus). What drugs can do this? thiazides, Bblockers, cyclosporin, tamoxifen, protease inhibitors
what is the exogenous pathway?
transport of lipids from intestine to peripheral tissues and liver. WHat is endogenous pathway? transport of lipids from liver to peripheral tissues
How does high LDL lead to foam cells?
it actually downregulates LDL receptors on macrophages, but LDL gets oxidized by proteoglycans in arterial wall, which oxidized LDL is then recognized by scavenger receptor A (SRA), CD36, and others. What effect does OxLDL have on arterial cells? upregulates adhesion molecules, cytokines, and growth factors by SMCs, macrophages, and endothelium.
biological roles of XOL?
modulates fluidity in cell membranes, helps form lipid rafts (along with sphingomyelin), precursor for hormones, corticoids, and bile acids, and it covalently modifies hedgehog to set up morphogen gradients.
three processes that regulate TC?
dietary intake, biliary excretion/elimination, de novo synthesis
XOL utilization, and elimination?
XOL cannot be broken down, but it is secreted by liver as VLDL, then half comes back as LDL. Steroid-producing tissues take up large amounts of XOL. reverse XOL transport important for homeostasis. How is XOL absorbed? solubilized by bile acids then absorbed. It is then either transported back into intestinal lumen, or esterified into chylomicrons (TG-rich). reverse transport back into intestine is important for XOL homeostasis, and to gaurd against plant sterols, and other things
ABC transporters?
ATP-binding cassette. They are either full or half transporters. ABCA1 is important for XOL efflux. ABCG5 and G8 are half transporters important for XOL homeostasis, and if mutated cause beta sitosterolemia (high plant sterols in the blood, aka pseudo FH). How are ABCs regulated? by LXR/RXR heterodimers. LXRs can be activated by oxysterols to inhibit XOL absorption
major source of endogenous XOL?
is LDL, taken up into cells by LDL receptors upregulated when XOL is low. The opposite happens when XOL is high. What other change occurs to limit XOL when it's high in cells? upregulate XOL export via ABC transporters, which pass on XOL to ApoA-I, which is located primarily on HDL. LCAT also assists.
how do macrophages differ in their regulation of XOL?
they take up toxic levels of LDL via scavenger receptors (SR-A), which are not down-regulated by high XOL. This built-in protection shows that down-regulation of XOL synthesis and LDL receptors isn't enough to control XOL levels. What is the significance of ABCA1 in macrophages? it helps efflux XOL to extracellular acceptors, and if mutated (tangier's disease), macrophages build up huge levels of XOL (yellow tonsils, xanthomas). HDL is also low in tangier's, which shows that ABCA1 is important to help load XOL onto HDL. Reverse transport is enhanced by ApoE on macrophages (great ligand for LDL receptor)
what is ACAT? what does it do?
esterifies XOL so it can be stored in a non-toxic form in lipid droplets
these help maintain intracellular XOL homeostasis. SRE is sterol regulatory element, and the BP is the binding protein. XOL inhibits SREBP, which binds to promotors for FPP synthase (to make farnesyl pyrophosphate), squalene synthase, and HMG CoA synthase and reductase (as well as LDL receptor). How are these a neg feedback system? HMG CoA synthase and reductase, as well as geranyl-to-farnesyl pyrophosphate, and squalene, are all steps in XOL synthesis.
physical nature and location of SREBPs?
synthesized as inactive, integral membrane proteins in the ER, with both the N and C termini in the cytoplasm. How do they exert their effects? when XOL is low, a second ER protein, SCAP (SREBP cleavage-activating protein) comes into contact with SREBP, and directs it to the golgi where it's acted upon by Site1 protease (cleaves the linker), followed by cleavage of the n-terminus by a second protease, freeing the HLH-zip domain to enter the nucleus, bind the DNA, and promote transcription
what does Insig do?
In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig-1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus
how are LXR/RXR nuclear receptors involved in XOL homeostasis?
ligands of either LXR or RXR can activate the heterodimers to promote the transcription of Cyp7A (for bile acid synthesis), SREBP, ABC sterol transporters (in both intestines and macrophages). what are ligands for LXR and RXR? LXR includes the oxysterols 22OH XOL and 25OH XOL (which accululate when intracellular XOL is high). RXR ligand is 9-cis retinoic acid
What is the endogenous pathway for lipoprotein metabolism?
Liver makes XOL, packages it in VLDL with apolipoproteins and TGs. In the periphery, TGs are released, leaving IDL and LDL particles, which can either deliver XOL to peripheral cells, or recycle back to the liver and be taken up via LDL receptor. The liver removes 2/3 of all LDL particles.
What is the exogenous pathway of XOL metabolism?
Intestinal epithelial cells form chylomicrons made of XOL, TGs, and apolipoproteins. TGs are delivered to the periphery, and small amount of XOL, but most is delivered to the liver through apoE-mediated LDL reception.
What is reverse XOL transport?
Extra XOL in peripheral cells is taken up by HDL to go back to the liver. “Nascent” HDL is synthesized by the intestine and contains only apoA-I. ApoA-I picks up XOL from peripheral cells forming HDL. Lecithin-cholesterol acetyltransferase (LCAT) converts free XOL on the HDL surface to XOL freeing up space on the surface of the HDL so it can pick up more XOL and the HDL becomes bigger. HDL is carried back to the liver by 3 possible mechanisms: (1) Cholesterol ester transfer protein (CETP) can transfer its XOL ester to VLDL remnants, IDL, and LDL in exchange for TGs. The VLDL, IDL, and LDL then recycle the XOL ester back to the liver eventually. (2) Some HDL have apoE, attained with transfer from other lipoproteins. (3) Hepatic uptake via the SR-B1 receptor. But SR-B1 does not internalize the HDL. It selectively extracts XOL esters and then releases the HDL.
How much XOL do we need to survive?
Cells need 2.5mg/dL, but there is a 10:1 ratio of plasma to cellular XOL concentration, so serum XOL needs to be at least 25mg/dL.
What are goals for LDL levels in different risk populations?
Moderate risk for CHD goal is <130. Moderate risk means no familial hx and no other risk factors, or young adults with FH, or adults with FH and no other risk factors. Groups with high risk goal is <100. High risk means family hx of CAD or ≥2 risk factors, or with Fhand family hx of CAD or other risk factors, or existing CAD, or after CABG (coronary artery bypass graft), or low HDL and family hx of CAD
2 fates for synthesized XOL?
Bile or VLDL
Every 1% decrease in XOL gives how much reduction in chance of having a coronary event?
How do bile sequestrants reduce XOL?
Bile not reabsorbed in gut, so hepatocytes upregulate LDL receptors, reducing serum XOL
How do statins work? Side effects? Used for primary or secondary prevention?
HMG CoA Reductase inhibitors, the rate-limiting step in XOL synthesis. Less XOL means more LDL receptors expressed. Can cause myopathy and increase in liver enzymes (ALT, AST). They have been shown to reduce strokes in primary and secondary prevention.
How is Niacin used in XOL therapy?
Reduces secretion of VLDL, so less XOL in plasma
How do selective XOL absorption inhibitors work?
Ezetimibe blocks XOL absorption by binding to Niemann-Pick C1 like 1 protein in the intestines with no effect on lipid-soluble vitamin absorption. They are particularly helpful with statins because allow reduction in statin dose
How to treat FH refractory to traditional treatments?
All lipid-lowering drug therapies rely on reduction of LDL receptors, but if deficient (as in FH), then can do plasma-phoresis (like dialysis), or liver transplant so new liver has LDL receptors (but immunosupression is a big problem too)
How does Vit D promote mineralization of osteoid?
Raises the blood calcium to the necessary levels for mineralization
What is the disease of vit D deficiency?
What effect does vit D have on GI?
Increase calcium and phosphorous absorption (upregulation of a calcium binding protein) via binding as a heterodimer on an RXR that promotes transcription of proteins
What effect does vit D have on blood?
Raises blood calcium and phosporous
How are vit D and toll receptors related?
Promote members of the immune system through toll receptor pathway (so vit D deficiency can lead to higher rate of infection)
There are three forms (by alternate splicing). Parathyroid related protein, and is expressed in many tissues, but is very high in neonates. It shares a receptor with PTH. It’s very high in malignancy (esp. breast, prostate, squamous), and can lead to hypercalcemia
What’s HHM?
Humoral Hypercalcemia of Malignancy. (due to overexpression of PTHrP in malignancy)
What hormones decrease bone resorption?
Calcitonin and estrogen
What hormones increase bone resorption?
PTH, PTHrP, glucocorticoids, thyroid hormone, high dose vit D
What hormones increase bone formation?
Low-dose PTH/PTHrP, growth hormone, vit D metabolism, insulin, androgens (males with hypogonadism have low bone density)
What hormones decrease bone formation?
What’s Forteo?
A recombinant PTH analogue to increase bone formation
Two conditions that describe too little bone?
Osteomalacia, osteoporosis
Two conditions described by too much bone?
Osteopetrosis, paget’s disease
2 conditions that describe too little calcium?
Hypoparathyroidism, osteomalacia
2 conditions that describe too much calcium?
Hyperparathyroidism, HHM
How to determine bone density?
Not x-ray anymore (not sensitive until >30% lost). So, use bone densitometry, or others
What happens in paget’s disease?
High bone resorption, and overcompensatory bone resorption
What does bone cancer do to bones?
Causes osteoclasts to work more than usual (so eat up bones)
What causes osteopetrosis?
Deficiency in osteoclasts, so overproduction of bone
What’s the effect of high PTHrP on PTH?
Decreases it because of neg feedback
What’s secreted by the anterior pit?
TSH, ACTH, GH, Gonadotrophic hormones, prolactin
What’s secreted by posterior pit?
Oxytocin and ADH
What hormone is secreted by pituitary in response to GnRH from hypothalamus?
Follicle stimulating hormone (FSH), and Leuteinizing hormone (LH)
What hormone is secreted by pituitary in response to GHRF (Growth Hormone Releasing Factor) from hypothalamus? And what is the inhibitory hpituitary hormone?
Growth hormone (GH). Inhibitory is somatostatin
What hormone is secreted by pituitary in response to TRH (thyrotropin releasing hormone) from hypothalamus? And what is the inhibitory hormone?
Thyroid secreting hormone (TSH) and prolactin. The inhibitory hormone is somatostatin. But prolactin is negatively inhibited by dopamine.
What hormone is secreted by pituitary in response to VIP (vasoactive intestinal peptide) from hypothalamus? And what is inhibitory hormone?
Prolactin. Inhibitory is dopamine
What hormone is secreted by pituitary in response to CRH (corticotrophin releasing hormone and vasopressin from hypothalamus?
ACTH (adrenocorticotrophin)
Where is the pituitary gland?
Below hypothalamus, in the sells turcica inside the sphenoid bone, and surrounded by the sphenoid sinus (can access through nasal canal, rather than skull). The optic chiasm is directly in front of the pituitary, so if pituitary has tumor, it can impinge on optic chiasm and cause vision problems.
How is hypothalamus and pituitary connected in their blood and nerve supply?
Blood comes from superior hypophaseal artery and forms a portal system with anterior pituitary. At base of hypothalamus, it becomes a capillary bed (called the median eminence), then forms venules into the anterior pituitary, so hormones go directly to ant. Pit. Ant Pit also gets some direct blood from middle hypophaseal artery.
How is blood supply to post pit?
Inferior hypophaseal artery, and short vessels into ant pit. The post pit receives input to release hormones from neurons from hypothalamus.
When does corticotopin releasing hormone (CRH) cause release of cortisol from adrenals?
Causes ACTH to go up first. Stress, tissue injury, maintenance of BP
What is the CRH receptor?
A 7-TM receptor
How do circadian rhythms affect cortisol?
Causes cortisol to be released in varying amounts throughout day, lowest at night, highest in morning
What stimulates CRH release from hypothalamus?
NE, ACh, 5-HT, IL-1. CRH then stimulates pituitary to release ACTH, which stimulates adrenals to release cortisol
What is cortisol’s role in negative feedback?
Acts on both the anterior pit and hypothalamus to decrease secretion
What molecule does ACTH come from?
POMC (proopiomelanocortin), which is also a precursor to other molecules too. ACTH acts on adrenals to release cortisol
What is Addison’s disease?
Adrenal insufficiency, no cortisol to provide negative feedback, so CTH and ACTH levels go high. High levels of ACTH also mean high melanin (both come from POMC), which causes pigmentation of the skin, skin creases, nails, and gums
TSH and TRH and TH pathway/axis?
TRH is a tripeptide released from hypothalamus to stimulate TSH secretion from ant. Pit. The TSH (which is made of a common beta subunit with unique alpha subunit) binds TSH receptor (a 7-TH receptor) to stimulate release of TH. TH is either T3 or T4 (# of iodine). T3 is more active, but T4 is higher concentration. TH inhibits TSH secretion.
What regulates TSH secretion? (besides TRH)
Cold increases TSH (because TH increases metabolic rate). dopamine inhibits TRH release from hypothalamus. GCs inhibit TSH release.
Gonadotropins (LH and FSH) pathway, regulation?
GnRH from hypothalamus stimulates release of FSH and LH. FSH stimulates ovaries to produce estrogen and testes to poduce testosterone, both of which exert negative feedback on hypothalamus to decrease GnRH release.
What else (besides testosterone and estrogen) regulates GnRH release?
Inhibin is a hormone from follicle cells that inhibit gonadotroph release. The higher cortex also controls GnRH release such as brain trauma can cause early puberty, and elite athletes and anorexics have low GnRH
What is primary hypothyroidism?
A thyroid gland problem, causing low T4 (can’t make it), and high TSH, trying to give neg feedback, but doesn’t work
What is secondary hypothyroidism?
A pituitary ot hypothalamus problem, causing low T4 due to no stimulus. If giving TRH as a diagnostic test, pituitary failure will mean no TSH secretion. If it’s a hypothalamus failure, then delayed or small amount of TSH. But these are not conclusive, just supportive
What is goiter?
Large thyroid, but does not indicate function, can be hypo-normo-, or hyper-thyroid hormone. However, it can press on neck causing difficultly breathing and decreased activity. It can cause short stature, deafness, mental retardation. Can be caused by iodine deficiency or Grave’s disease, but Grave’s disease also causes large eyes
Thyroid follicles and C-cells?
Follicle cells have thyroid hormone inside. C-cells secrete calcitonin, and are distinct from follicle cells. Low TSH causes flat, empty follicle cells.
How is TH made?
Iodine taken up by thyroid cells via Na-Iodine symporter (NIS). The iodine is oxidized by peroxidases, placing them on tyrosine residues on thyroglobulin. 2 iodinated thyroglobulins then become covalently attached (coupled), then transported into colloid space, and later endocytosed back into the T cell where fuse with lysosomes. Proteolytic cleavage of the coupled thyroglobulin releases 3-4 T3 and T4 molecules. Unused iodine is recycled
Stucture of TH?
Tyrosine etherized to 6-carbon ring (so two rings). Iodine is attached to 3 and 5 carbon positions. T3 has no 5’ iodine (on second ring) and is the most biologically active version. Reverse T3 has no 5-carbon iodine on tyrosine ring, and has no biological activity.
How does TSH promote TH release?
Activates cAMP pathway to activate NIS by PKA phosphorylation and activates PKC. NIS is a 13-TM receptor only on basolateral side of T-cells. NIS is on other cells in the body, but thyroid is only tissue that expresses thyroid peroxidase needed to make TH.
Dietary iodine?
Required intake is 50mcg per day, but there is an additional 10mcg recycled per day, so daily usage is actually 60mcg. Average American diet has 250mcg. Any excess goes out urine. Out of the 60mcg, 35 go into urine, 15 in feces, and 10 recycled.
What is the Wolf-Chaikoff effect?
High doses of iodine decrease TH production by decreasing peroxidase activity, hydrogen peroxide formation, adenylyl cyclase activity (inhibiting NIS), release of T3/T4. The effect is overcome after 2 days due to increase of NIS activity induced by low thyroid cells iodine concentration.
T4 versus T3 synthesis?
T4 is made exclusively from the thyroid (about 80-100mcg/day), while T3 is made in the thyroid (6-8mcg/day) but mostly by converstion from T4 in ther periphery (24mcg/day)
How is T3 and T4 trasnported around?
>99% bound to protein, with T3 being 5-10 times more active and 10 times higher free concentration. Changes in binding proteins (including displacement by drugs) can affect TH levels, but long-term levels not affected by this.
What is the relative binding affinities of proteins that bind T3 and T4?
TBG (thyroxine binding golbulin) has higher affinity for T4 than T3, and binds 70% of TH. Transthyretin (prealbumin) equally binds T3 and T4, and binds 15% of TH. Albumin has low binding affinity for T3 and T4, but has large binding capacity because there is so much albumin
How is T4 metabolized?
De-iodinases. D1 and D2 remove iodine from outer ring to make active T3. D1 and D3 remove iodine from inner ring to make inactive reverse T3. De-iodinases have seleno-cysteine in active center, and are inhibited by fasting, illness, glucocorticoids, drugs, and during fetal life
Besides de-iodination, how else is TH metabolized?
Sulfination (increase water-solubility), glucuronidation (increases water-solubility), ether bond cleavage, oxidative deamination
How is thyroid involved in development?
TH helps CNS development and increase linear growth. Hypothyroid in mother leads to lower birth weight and IQ. The TH axis starts at weeks 12-16, and TH therapy in hypothyroidism (1/4500 births) can increase IQ
Molecular mechanism of TH action?
Enters cells through ATP receptor, enters nucleus, and binds to Thyroid receptor (TR). TR (either alpha in heart, or beta in liver) heterodimerizes with RXR to induce transcription of genes and activate MAP kinase pathway. Without TH, TR represses transcription
What effect does TH have in energy metabolism?
Increases BMR and core body temp
What are the effects of TH on heart, liver, muscle, and GI?
Heart: increase HR. Liver: decrease XOL synthesis. Muscle: increase strength and turnover. GI: increase motility
What lab values are done for thyroid stuff?
T4, free T3, T4, TSH, thyroglobulin, Antibodies to peroxidase or thyroglobulin antibodies (thyroid immune disease). In hypothyroid, T4 and T3 are low, and TSH is high. In hyperthyroid, it’s opposite.
Procedures to test for thyroid conditions?
Readioactive iodine scan to detect large thyroid in grave’s disease or cold nodule in cancer which can increase or decrease iodine uptake. Thyroid ultrasound or aspiration of thyroid cells can also be done.
Characterisitics of hypothyroidism?
Myxedematous (dry skin, swellings around the lips and nose, mental deterioration, and low BMR), feeling cold, weakness, hoarse, weight gain, mental slowness, constipated, decreased reflexes, missing lateral eyebrows, protruding tongue. Occurs 4:1 women to men, and increases with age. Usually caused by destruction of thyroid, but 5% due to destruction of pituitary. Can be iodine deficiency, autoimmune attack, or from surgery or radioactive iodine
How to treat hypothyroidism?
0.1-0.15 mg T4 per day, start low for patients with CAD
Characteristics of hyperthyroidism?
Weight loss, sweating, flushing, heat intolerance, increase heart failure, muscle weakness/wasting, amenorrhea, fine skin, hypercalcemia, osteoporosis, protrusion of eyes. Usually causes by Grave’s disease (antibodies that stimulate extra TH production). Toxic nodules also a common cause, or possibly thyroiditis increasing TH release. Incidence 4:1 to 8:1 in women:men
How to treat hyperthyroid?
Antiperoxidase drugs (blocks iodine binding). 1-2 yrs therapy needed in 50%, or lifelong in 50%. Has mild immunosuppresive effect. Can use radioactive iodine. Surgery rare.
Regional anatomy of the pituitary?
In the cavernous sinus, which also contains CN III, IV, V, VI. The sella turcica usually covered by dura to block CSF, but empty sella syndrome has no dura, so CSF can put pressure on pituitary, causing sxs or no sxs
Development of the pituitary? And cell types and their products?
Post from 3rd ventricle, ant. from oral invagination. Produces hormones by week 10-12. Pit1, Prop1, and Hesx1 are growth factors for differentiation of thyrotroph, somatotroph, and lactotroph cells. In the anterior pituitary, there are acidophils (thyrotrophs 3-5% for TSH, gonadotrophs 10-15% for LH/FSH, and corticotrophs 15-20% for ACTH), and Basophils (somatotophs 40-50% for GH, lactotrophs 10-15% for prolactin). Some basophils can secrete both GH and prolactin.
How is growth hormone release controlled?
GnRH stimulates secretion and somatostatin inhibits secretion. Ghrelin from stomach and brain also increase secretion. During sleep is when most is released, and levels vary throughout day. Beta blockers and L-arginine promote secretion, and insulin drops BG, which stimulates secretion of GH, glucagon, cortisol. Obesity decreases GH and may confound diagnosis of GH disorder.
What is action of GH on hypothalamus?
Inhibits GnRH release.
What is effect of GH on liver?
Stimulates to produce IGF-1, which stimulates growth plates, and inhibits release of GnRH and GH. IGF-1 levels are more steady then GH, so good indicator of GH levels.
What is the JAK-STAT pathway?
Growth factors bind to 2 different receptors and cause dimerization to induce this pathway. So, to block excess GH, there are agents to block the receptors.
OGTT and GH?
Test for Gh levels using oral glucose tolerance test, which would cause hyperglycemia and stop GH secretion, but if GH is very high, then it will stay high.
Two major effects of GH excess?
Gigantism (growth plates continue to be stimulated), and acromegaly (bones grow outward causing wide face and hands)
How is prolactin regulated?
Mainly by negative feedback from dopamine. Too much prolactin can interfere with gonadotroph release, so interfere with menstrual cycle, and cacn cause infertility. Is also causes galactorrhea. In men, it can cause galactorrhea (milk secretion), impotence, infertility. If hypersecretion is due to tumor, can impinge on optic nerves, but tumor can be treated very well by dopamine to shrink tumor and decrease secretion.
What’s another name for ADH (secreted from the post pit)?
Vasopressin or arginine vasopressin (AVP)
Similarity between oxytocin and ADH?
Both stored and secreted by post pit. Both are 9 AA compounds. They are cyclic with internal disulfide bond. They have short half-lives, and are made by cleavage of neurophysins
How is ADH and oxytocin made from neurophysins?
ADH from neurophysin II, stimulated by nicotine. Oxytocin made from neurophysin I, stimulated by estrogen
What are V1 and V2 receptors for?
ADH receptors. V1 is coupled to PLC, causes vasoconstriction on vascular smooth muscle, liver, platelets, cerebrum, pituitary corticotrophs. V2 is coupled to adenylate cyclase→PKA and acts in renal CT and TALH to conserve water to insert AQP2 into apical tubular membrane. AQP3 and 4 are constitutively expressed on basolateral mambrane.
What controls ADH release?
Primarily Na osmolarity. But also hyperglycemia in the presence of insulin as well as ura are small stimuli for ADH release. EtOH inhibits ADH release. mOsm<280 = no ADH secreted. ≥295mOsm, is maximal antidiuresis, but not max ADH release. At 290mOsm, thirst kicks in too. Also, the NTS (which responds to the baroreceptors) inhibits ADH secretion. Severe volume changes override osmolarity control of ADH
How does thirst center work?
Located in anterior hypothalamus to an unknown stimulus. Osmotic threshold is beterrn 285 and 290 mOsm/kg, and is also stimulated by volume depletion.
How do histamine, nicotine, anesthetics, vincristine, cyclophosphamide, barbiturates, metoclopramide, and clofibrate affect ADH?
Stimulate ADH secretion
How do PGE2, Ang II, ACh, beta agonists affect ADH?
Stimulate ADH secretion
How do hyperkapnia and hypoxia affect ADH?
Stimulate ADH secretion
How do phenytoin, EtOH, ANP, alpha agonists, and halothane affect ADH?
Inhibit ADH secretion
How is synthetic ADH designed?
a.k.a. DDAVP. AAs 1 and 8 altered so it has longer half-life, but same potency. Given intranasally (least proteolysis), but also in oral ans SQ forms.
What is neurogenic diabetes insipidus?
Can’t make ADH (>80% of ADH-secreting neurons aren’t functioning). Usually still have detectable ADH, just low. Patients have to drink a lot, but DDAVP is only real therapy, and goal is slight hypotonicity (hypertonicity is more dangerous).
What is nephrogenic diabetes insipidus?
Either deficient V2 receptor (X-linked, and variably mutated) or AQP2 mutation. Patients don’t respond well to DDAVP therapy
What’s SIADH?
Due to CNS injury, release to much ADH, leading to increased ECF, decreased aldo and increased ANP and natriuresis. Therapy is lithium or certain abx to block receptor, and limit fluids
What is the water-deprivation test for ADH? Alternative tests?
Normal patients have high ADH, and it’s good for differentiating between partial and severe ADH deficiency. Nephrogenic diabetes has high ADH, but unresponsive. Can also infuse hyperosmolar saline, which should have same effect. Or can give DDAVP, which should concentrate the urine, but if nephrogenic diabetes, urine won’t be more concentrated.
3 phases of human growth?
Intrauterine (1.2-1.5cm/week), childhood (6cm/year), adolescence (9-10cm/year)
Length versus height in kids?
Using length (lying down) is more reliable and accurate than height (standing up) for at least the first 3 years.
Height velocity during growth?
Rapid at birth, and slows withl age, then stays about constant until pre-adolescence.
Peak of height groth timing for boys and girls?
Surge in height velocity begins 2 years before peak velocity is reached, and girls start 2 years earlier than boys, but boys peak velocity is higher than girls. Girls stop growing at 14-15, boys at 17-18.
What growth factors promote growth in-utero?
Insulin (big babies in gestational diabetes, with risk of hypoglycemia at birth), and IGF-I and IGF-II
What growth factors promote growth during childhood?
GH (role of Pit1, Prop1 important for this), TH. If GH is deficient, growth will slow or stop at 6mo to 1 yr. If TH is deficient, there will be slow growth immediately at birth.
What growth factors are important in adolescence?
GH and TH, as well as sex hormones. Estrogen causes closure of growth plates. If estrogen receptor mutations, growth doesn’t stop.
Where does GH act on the epiphyseal growth plate?
On non-dividing cells in the resting zone, which is most distal. It causes them to release IGF-I to cause local proliferation of the second zone. To assess growth plate, look at left hand (less likely to be injured), to look for fusing of the growth plate with the bone
What is first sign of puberty in males and females?
Testicular growth and breast growth. Estrogen causes increase in GH
Causes of short stature?
(1) Genetic, so normalize according to mean of parent’s height (MPH), but which doesn’t account for any non-genetic height deficits in parents, (2), constitutional growth delay (late bloomers), occurs in 5% of children, late puberty, will reach normal height eventually. (3) nonendocrine disorders such as turner syndrome (45X) since a gene on X chromosome affects growth. Patients continue to grow until normal time, just slower, GH therapy can add about 5 inches. Down syndrome also truncates height. (4) other reasons such as chronic liver or kidney or pulmonary disease, malnutrition, congenital heart disease (can’t eat enough to keep up with heightened metabolic rate), intrauterine growth retardation, metabolic storage diseases. (5) Psychosocial dwarfism (will become normal if removed from neglected home), and (6) chondroodysplasias (defective growth plate such as fibroblast receptor mutation)
Endocrine disorders leading to stunted growth?
(1) GH or receptor deficiency due to hypothalmic defect (GnRH deficiency commonly due to child radiation treatment on brain) or pituitary defect (GnRH receptor problem or GH deficiency) GH deficiency can be due to GH gene mutation, idopathic, Pit/Prop mutation (no cells to make GH), or destructive lesion of pituitary such as tumor). (2) GH insensitivity
How does glucocortiocoid excess (Cushing’s) affect growth?
Can stunt growth
How does Rickets affect growth?
Stunt due to inability to calify bones
How can sex steroid hormone deficiency affect growth?
Stunt growth due to lack of adolescence growth spurt
What endocrine disorders can cause tall stature?
GH excess (pituitary gigantism), or precocious puberty (taller at first, but growth ends early, so end up shorter than usual
What genetic disorders lead to tall stature?
Klinefelter syndrome (47 XXY males), but have gonadal failure due to fibrosis of testes. Marfan syndrome, a connective tissue and aortic arch problem (Abraham Lincoln). Homocystinuria, and Soto syndrome
Basic job of cortex and medulla of adrenals?
Cortex is ectoderm-derived, makes hormones. Medulla is neuroderm-derived, makes EPI, and hormones made from cortex enhances production of medulla products
What does the zona glomerulosa of the adrenal cortex do?
Produces mineralocorticoids like aldo
What does the zona fasciculata of the adrenal cortex do?
Makes glucocorticoids like cortisone, cortisol, corticosterone. Is very lipid-dense
What does the zona reticularis of the adrenal cortex do?
Produces sex hormones
What stimulates release of cortisol and aldo?
ACTH from pituitary (which is released under the stimulation of CRF from the hypothalamus) stimulates release of aldo from the zona glomerulosa and cortisol from the zona fasciculata. Cortisol, but not aldo or androgens, feeds back to hypothalamus and pituitary to turn off CRF and ACTH
How is blood supply in adrenals arranged?
Blood enters cortex, and goes into medulla, so hormones from cortex can have effects on release of NTs from medulla
Steps of adrenal and gonadal hormone synthesis?
Starts with XOL, acted on my CYP to make pregnenolone, and then through distinct pathways to each hormone. 21-OHase and 11-OHase are needed for both aldo and cortisol. 17-OHase is needed for androgens and cortisol (but not aldo).
Cortisone/cortisol relationship?
Cortisone is precursor to cortisol, but the enzyme that converts it comes in two isoforms. Type 1 (in the liver and adipose) converts cortisone into cortisol to promote fat storage. Type 2 (in the kidney) converts cortisol into cortisone, so it has no effect there. Cortisone has less biological activity.
What happens if 21OHase deficient?
It is the most common adrenal insufficiency. It backs up glucocorticoid and mineralocorticoid synthesis, so ACTH levels go up since there is no cortisol to inhibit it. Therefore, the sex hormones pathway gets very stimulated and in males causes early puberty but shorter stature as an adult. In females it results in ambiguous genitalia (enlarged clitoris). Females are often misdiagnosed as polysystic ovarian syndrome, and some patients have mineralocorticoid deficiency causing hypotension.
What is treatment for 21OHase deficiency?
ACTH suppression by glucocorticoid therapy (cortisone, prednisone, dexamethasone), but too much will impair growth. Can also replace mineralocortoids (fludrocortisone)
How to test for 21OHase deficiency?
Give ACTH. If already maxed out, will not increase production of corticoid precursors
What happens in 11OHase deficiency?
Less common than 21OHase deficiency. 11OHase in required in androgens and cortisol (not aldo/mineralocorticoids). So, high Aldo leads to high retention of Na and water and HCO3-, but excretion of K and H+ (so hypokalemia). and major sx is Hypertension due to 11-desoxycortisol and deoxycorticosterone accumulation (acts like aldo). The high aldo also causes reduced renin secretion, which is normally 90% of control over aldo (while ACTH has 10% control).
What are RAAS-dependent causes of mineralocorticoid excess?
Vomiting, diuretics, edema, renal ischemia, barterr’s syndrome, renin-producing tumors
What are RAAS-independent causes of excess mineralocorticoids?
Aldo-producing adenoma or hyperplasia, congenital adrenal hyperplasia, 11OHase deficiency, 17OHase deficiency (but not 21OHase deficiency), licorice ingestion, glucocorticoid-suppressible hyperaldosteronism
Relationship between EPI and cortisol?
Both are released in response to “fight or flight” or stress, and both activate catabolism.
What are the effects of glucocorticoids on the liver?
Cause glycogenolysis by activating enzymes in the pathway
What are the effects of glucocorticoids on adipose?
What are the effects of glucocorticoids on muscle?
Proteinolysis to provide substrate for glucogenesis
What are the effects of glucocorticoids on glucose?
Maintains levels during fasting and increases during stress
What are the effects of glucocorticoids on pancreas?
Decrease insulin secretion
What are the effects of glucocorticoids on adrenals?
Increase epinephrine synthesis
What are the effects of glucocorticoids on kidneys?
Decrease calcium reabsorption
What are the effects of glucocorticoids on bone?
Decrease bone synthesis
What are the effects of glucocorticoids on GI?
Decrease absorption of Ca++ and Mg++ and PO4
What are the effects of glucocorticoids on skin?
Antiproliferative for fibroblasts and keritinocytes
What are the effects of glucocorticoids on heart?
Increase contractility
What are the effects of glucocorticoids on blood vessels?
Increase reactivity to pressors
What are the effects of glucocorticoids on thymus?
Involution and decrease lymphocytes
What are the effects of glucocorticoids on monocytes?
Decrease proliferation and antigen presentation, decrease IL-1, IL-6, TNF-alpha
What are the effects of glucocorticoids on granulocytes?
Demargination by decreasing adhesion molecules
What are the effects of glucocorticoids on inflammation?
Decrease leukotrienes, PGs, COX2
What are clinical characteristics of cortisol deficiency?
Addison’s disease. Think JFK. General and muscle weakness, loss of appetite and weight, increased pigmentation (due to high melatonin since ACTH is also made from POMC), hypotension, hyponatremia, hyperkalemia (all due to high ACTH and therefore aldo), anemia.
Causes of glucocorticoid deficiency?
Primary adrenal causes (high ACTH) can be autoimmune, tuberculosis, adrenal hemorrhage, tumor. Or central lesion (pituitary or above) which gives low ACTH, and no pigmentation. It can be a pituitary tumor, radiation to head, head trauma, infections, or isolated ACTH deficiency
How to test for cortisol deficiency?
Cortosyn stimulation test to stimulate cortisol reserve. In normal patients, will increase to >18mcg/dL in 30-45 minutes, but if not, then there is a defect in the pathway.
What is cortisol excess disease called? What are the forms?
Cushing’s disease. It can be ACTH-dependent (70% pituitary, 5% are ectopic production by a tumor) or ACTH-independent (20% adrenal adenoma, 2% adrenal carcinoma, 2% macronodular hyperplasia, 1% surreptitious or factious glucocorticoid administration
Sxs of cushing’s disease?
Extra cortisol causes weight gain, moon facies, HTN, stretch marks, glucose intolerance, proximal muscle weakness, menstrual cycle dysfunction, easy bruising, osteoporosis, hypokalemic alkalosis (rare)
What is glucocorticoid therapy used for? And common complications of their use?
Respiratory conditions, IBD, RA, chronic skin conditions, immunosuppresive. Complications include osteoporosis, HTN, glucose intolerance, skin thinning, central obesity, and usually not fully reversible upon discontinuation
Examples of glucocorticoids used therapeutically?
Prednisone, methylprednisolone, prednisolone, fludocortisone (mineralocorticoid), dexamethasone (20-25x more potent and much longer half-life (about 12-18 hours instead of 6-8 minutes)
How to screen for cushing’s disease?
Overnight dexamethasone suppression test. Give at 11pm-midnight, then measure cortisol at 8am. Normal persons will decrease >20% mcg%. Can confirm with 24hr urine free cortisol
What patients should be suspected if having primary aldosteronism?
Hypertensive with easily provoked hypokalemia. Should measure renin and aldo levels, since high aldo suppresses renin, while other hypokalemic states have high renin. Can be confirmed with 24hr urine aldo production test and suppression using saline for 3 days.
What is pheochromocytoma? Rules of 10? How to screen?
Overgrowth of adrenal medulla and overproduction of epinephrine, leading to HTN, HA, sweating, palpitations. Rules of 10: 10% are extra-adrenal, 10% are bilateral, and 10% are malignant. Screen by measuring plasma metanephrine, confirm by 24hr urine epinephrine metabolite test. Some tumors have only one metabolite elevated.
What is osteogenesis imperfecta?
Malformed skeleton due to disease of collagen, so messes up bones, even though minerals are normal
Primary and secondary hormones to regulate bones and calcium?
Calcitonin, PTH, PTHrP, vit D. secondary are gonadal and adrenal steroids and TH
Functions of calcium?
Cell signaling, neural transmission, muscle contraction, blood coagulation, enzyme cofactor, membrane functions, biomineralization
Which pool of blood calcium is regulated?
The diffusible, non-protein-bound pool. About 30% is bound to albumin and globulins, and 10-15% bound to bicarb, citrate, phosphate, others. About 50% is free ionized. The salt and free forms are regulated, and is near saturated. If too high, can cause tissue calcification and kidney stones (usually CaPO4).
Bone calcium is distributed between what forms?
Inorganic (non-cellular) 69%, and organic (cellular) 22%, which is mostly in collagen (90%), but also in proteoglycans, sialoproteins, gia-containing proteins, alpha-2HS-glycoproteins, growth factors, cytokines.
Rate of bone formation versus bone resorption?
Formation rate is faster up until adulthood, but actual point when it’s equal is debated, and depends on diseases and drugs. After that, bone resorption is always faster than formation. However, the two processes are linked so that if one increases, so does the other.
How fast is bone turnover?
About 250mg Ca per day, or about 10% of skeleton per year. This is why bone treatments take a long time. Trabecular bone turns over faster than compact bone
What is bone modeling?
Mechanical forces affecting bone shape. Example is jaw bone, whose shape is helped by mechanical forces. In long bones, the mechanical stress lines exist where most force is exerted
How do osteoblasts work?
Exert canaliculi when attached to communicate with other OBLs in the area. They have many receptors (PTH is most important, but also growth hormones, PGE2, TGF-beta, vit D, estrogen, and others). They are inhibited by corticosteroids. Their most importnant product is collagen, a triple helix laid down in a staggered ray, so ends never adjacent to other ends (just end-to-end). When they become buried in bone, they are osteocytes.
Characteristics of osteoclasts?
Multi-nucleated, and receptor-poor, so respond to few stimuli
What is cortical versus trabecular bone?
Cortical is solid, dense, and remodelind is slow. Trabecular is net-like, so more surface area for remodeling to occur, and provides mechanical strength.
Characteristics of bone mineralization?
Hardens collagen and other proteins, and occurs in holes between collagen fibers with hydroxyapatite. The Gla domain of collagen get carboxylated, so it can adhere to Ca on hydroxyapatite crystals. If not calcified, can get osteomalacia, so bones bend and break.
35 should be A
What is OBL OCL coupling?
OBLs and OCLs secreting signals that activate each other. So, normally OCLs secrete signals to OBLs to activate bone formation. In osteoporosis, the coupling is not transduced correctly.
What is effect of calitonin on OCLs?
Strong signal to stop bone resorption and shrivel up
Life cycle of OCLs?
Start out as bone marrow progenitors, then fuse to become multinucleate cells under the influence of PTH, IL-1, vit D. These cells attach to hydroxyapatite, polarize, and resorb bone. OCLs then go into apoptosis, which is promoted by TGF and estrogen. Estrogen treatment to inhibit bone resorption works, but has many side effects. PTH and IL-1 inhibit OCLs
How do OCLs perform resorption?
Polarization creates extensions that make spaces between OCL and bone. HCl is secreted into the spaces to degrade mineral component. Proteases are secreted (that are optimally active in acid environment) to dissolve the collagen. The only way cancer cells can degrade bone is by activating OCLs because OCLs are only cells with the proper machinery
What is difference between remodeling in cortical versus trabecular bone?
Trabecular remodeling occurs on the bone surface, but in a tunneling fashion through the cortical bone (resorption in front, formation in back)
How do OCLs and OBLs mature?
OBL precursors express RANK ligand. OCL precursors express RANK. When RANK ligand binds to RANK, OCLs fuse. A protein called osteoprogenin (OPG) binds RANK to prevent OCL maturation. Antibodies that do the same thing are in clinical trials to prevent OCL activity.
What does measuring TRAP-Tartate resistant acid phosphate tell you?
It is secreted by OCLs, so high levels show high OCL activity
What does measurement of urine collagen peptides tell you?
Collagen peptides increase due to high OCL activity
What is alk phos measured for?
It’s a product of OBLs, so can measure how well treatment is working.
Imaging and histology to measure bone growth and degradation?
Imaging not sensitive enough, and hitology is invasive to get section
Calcium absorption?
About 0.4 – 1.5 g ingested per day, but 15-20% absorbed (mostly in duodenum). Low serum Ca increases PTH and vit D. But growth, pregnancy, and lactation can change absorption through hormone-independent mechanisms
Dietary sources of Ca?
Ca citrate supplements are best. Calcium in juice not very bioavailable. Phosphrous (such as in soda) binds Ca, and is not absorbed.
How is calcium absorbed in gut?
Active and passive transport
What hormones affect ca absorption?
Vit D is most important, but PTH and calcitonin affect vit D. Estrogens and GH and glucocorticoids too. Glucocorticouds inhibit absorption, promote OCL and inhibit OBL, and increase mineral excretion
How does calcium excretion work? How controlled?
99% reabsorbed in kidney, both transcellular and paracellular, in LOH and proximal tubule. Inhibited by furosemide (Ca-wasting). Distal tubule absorbs 10% of filtered load. Stimulatesd by PTH, inhibited by calcitonin. Vit D has trivial effect. Reabsorption stimulated by thiazides (inhibit Na and Ca excretion)
Amount of Ca excretion per day?
50-250mg/day (0.5-1% of filtered load). If hyperPTH, then decreased Ca clearance, and so high serum Ca
Characteristics of PTH molecule?
Secreted from parathyroid glands (4-8 of them), 84 AAs. First 25-30 are the active part. The remaining part may have other activity besides PTH receptors. PTH is cleaved from prepro and pro versions.
Effects of PTH on bone?
Increases OCL activity. Constant high PTH causes resorption, but intermittent causes bone formation (this is theory behind Forteo)
Effect of PTH on kidney?
Decrease Ca excretion, increase Phosphorous excretion, so hyperparathyroid causes high serum Ca, low serum P
Effect of PTH on GI?
Increase Ca and P absorption (indirectly through vit D)
Effect of PTH on blood?
Increases Ca, decreases P (due to effect on kidney
What is the PTH receptor?
What is CaSR?
Calcium-sensing receptor, works like PTH receptor, only with Ca as ligand. This is the main way that PTH is regulated. PTH gland has CaSR, and changes in PTH are large in comparison to small changes in Ca. CaSR is also in kidney. Vit D and Phosphorous also affect PTH
2 Roles of calcitonin? where secreted from?
Secreted from C cells in thyroid and other neurons. It has two roles. One is Ca homeostasis, the other is as an NT that has local vasodilatory effects. CT sequence is complex, and not conserved well across animal kingdom. Salmon CT is more potent than human CT.
What is effect of CT on bone?
Inhibit OCL activity
Effect of CT on kidney?
Increase Ca excretion and P excretion. The enhancing P excretion is the one way CT does the same thing as PTH. Otherwise, they are direct opposites of each other. Still, the effects of CT on the kidney are much less drastic than PTH effects
Effects of CT on the GI tract?
Mildly inhibits Ca absorption
Effects of CT on blood Ca and P?
Decrease Ca (helps bone formation and decreases P slightly
How is CT regulated?
High Ca causes high CT (which is opposite of PTH). It is also affected by age, gender, and GI state
Types of vit D?
1,25(OH)2D. it is cholecalciferol (D3) in animals, and ergocalciferol (D2) in plants (used in most supplements because cheaper, but probably less absorbed)
How is vit D made in the skin?
Cholesterol is turned into 7-dehydrocholesterol, which is then converted by UV light into pre-vit D-3, and then vit D3. It is released into the blood, attaches to vit D binding proteins, and goes to liver (gets released from binding protein, and 25-hydoxylase makes D3 into 25-OH vit D). It is then rereleased into the blood and attaches to vit D binding proteins. Vit D then goes to kidney, gets released from binding protein and enters proximal tubule. There, 1-alpha-hydroxylase makes Vit D3 into 1,25 OH vit D (which is the biologically active form). The inactivation pathway (24-hydroxylase) is also in the kidney. The active form then leaves the kidney, binds to binding protein, and goes to target cells (enters nucleus and heterodimerizes with RXR to transcribe genes).
Causes of vit D deficiency?
No sun, liver disease, kidney disease. The last one is most important because supplements don’t help (can’t convert), so must treat with active form to prevent bone disease.
How to measure vit D levels?
Measure 25-OH vit D because it is the most stable
What are the membrane effects of vit D?
Cause Ca flux, and other effects through a peptide preceptor-like molecule on surface (this is in addition to nuclear effects)
What stimulates 1-alpha-hydroxylase production?
Low Ca is MAIN stimulus. Also, PTH, low P, estrogen/androgens, prolactin, placental lactogen, GH, CT. A multiplier effect occurs because Ca directly stimulates production, but also PTH, which enhances it tooNote: 1-alpha hydoxylase is the enzyme that makes 1,25 OH2 vit D
What inhibits 1-alpha-hydroxylase production?
High Ca, high P, and 1,25 (OH) vit D (direct negative feedback)
Effect of Vit D on bone?
Promotes mineralization of osteoid, but only by increasing Ca levels, and increases resorption at toxic doses.
Effect of vit D on kidneys?
Minimal effect to decrease Ca excretion and P excretion
Effect of vit D on GI?
The MAIN effect of vit D. increase Ca absorption by many mechanisms, but mostly by increasing synthesis of Ca binding proteins. It also increases P absorption by similar mechanism.
Effect of Vit D on blood Ca and P?
Increase both (by effects on Gi absorption mainly
Effect of vit D on 24-hydroxylase production?
Increase catabolism of 24-hydroxylase.
Effect of vit D on OBLs?
Increases function and increases collagen
Effect of vit D in macrophages and OCLs?
Inhibits differentiation of them
Effect of vit D on PTH?
Decreases PTH
Effect of vit D on immune function?
Increase innate immunity of the skin
Effects of vit D on cancer?
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Highest LH and FSH levels?
B Highest LH and FSH occur with mid-cycle peak on day 14; the LH peak is necessaryfor ovulation, but the FSH peak may just be coincidental.
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Highest progesterone level?
C Occurs with maximal corpusluteum function during mid-luteal phase
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Highest estrogen level?
B Occurs with maximal dominantfollicle function just prior to LH peak
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Most rapid endometrial proliferation?
B Estrogen stimulates endometrialproliferation, so this coincides with E2 peak
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Cumulus mass expansion?
B Expansion of cumulus granulosacells (granulosa cells surrounding the oocyte) is necessary forovulation. LH receptors are induced on membrana granulosa cells (granulosa cells near the basement membrane of the follicle) late in the follicular phase and the LHpeak stimulates them to secrete growth factors that stimulate cumulus granulosa cell expansion.
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Thickest secretory endometrium?
C Progesterone stimulates secretory changes in the endometrium, so the thickest secretory endometrium occurs during the progesterone peak in the mid-luteal phase
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 LH and prostaglandin receptor expression on granulosa cells is induced?
B LH and prostaglandin receptor expression on membrana granulosa cells (granulosa cells near thebasement membrane of the follicle) are induced late in the follicular phase as a result of prolonged FSH stimulation. The LH surge stimulates these granulosa cells to initiate cumulus expansion (see Q5) andsecrete progesterone, which stimulates prostaglandin synthesis. Prostaglandins stimulate ovarianepithelial cells to secrete their lysosomal contents, initiation formation of the stigma (opening) through which the cumulus mass (cumulus granulosa cells and 2 ̊ oocyte) is released onto the surface of the ovary.
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Selection of the dominant follicle from the cohort is complete by the end of this period?
A Selection of the dominant follicle from the recruited cohort occurs by day 6. Other cohortfollicles may survive for a few days after this, but they have been committed to eventually go through atresia (cell death) by day 6
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Completion of meiosis I?
B The LH surge initiates the resumption of meiosis. Primary oocytes in follicles are arrested in prophase ofmeiosis I. The LH surge allows the completion of meiosis I to form a 2 ̊ oocyte, which is arrested again in metaphase of meiosis II. Only fertilization by a sperm will allow completion of meiosis II.
A.Days 1 – 6 B.Days 9 – 15 C.Days 19 – 23 D.Days 25 – 28 Luteinization of granulosa and theca cells begins?
B Luteinization begins with the LH surge and LH effects continue even as plasma LH levels fall because ofincreases LH receptor expression on lutein cells (granulosa lutein and theca lutein). Lutein cells secrete progesterone, inhibin A and estrogen
The secondary rise in FSH responsible for recruitment of a cohort of small Graafian follicles during themenstrual cycle typically begins during: A.Endometrial proliferation. B.Late luteal (during luteolysis). C.Menses. D.Peak progesterone secretion. E.Peak estrogen secretion.
B As shown on the diagram, the secondary rise in FSH that recruits the cohort of small Graafian follicles begins about day 25 of the cycle when loss of the corpus luteum (luteolysis) decreases plasma levels ofinhibin A, estrogen and progesterone (answer D is incorrect). Both inhibin A and estrogen inhibit FSHsecretion, so as they decrease, FSH increases, recruiting a cohort of about 10 – 20 of follicles that happen to have developed to the early Graafian stage at that time. The fall in estrogen prevents endometrialproliferation (answer A is incorrect) and the fall in progesterone causes endometrial ischemia. Menseswill begin about 3 days later (answer C is incorrect) at the beginning of the follicular phase of the cycle (answer E is incorrect).
Of the following choices, the greatest variation in menstrual cycle length in normal women occurs during: A.Endometrial proliferation. B.Inhibin A secretion. C.Progesterone secretion. D.Secretion of GnRH in low frequency but high amplitude pulses. E.The ovulatory phase.
A Menstrual cycle length varies due to differences in the length of the follicular phase – the ovulatory(answer E is incorrect) and luteal phase lengths do not normally vary. As shown on the diagram, endometrial proliferation occurs during the follicular phase. Inhibin A and progesterone secretion occurduring the luteal phase (answers B and C are incorrect), and the high progesterone is responsible for thelow frequency, high amplitude GnRH pulses during this phase (answer D is incorrect).
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Express FSH receptors in 2 ̊ and early 3 ̊ follicles and express LH and FSH receptors in preovulatory follicles?
A Membrana granulosa cells display this pattern – see answer to Q5 and Q7.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Secrete androgen binding protein (ABP) and inhibin?
D Sertoli cells within the seminiferous tubules of testes respond to FSH stimulation to secrete inhibin andandrogen binding protein (ABP). ABP binding testosterone ensuring the local testosterone supply needed for spermatogenesis.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Present in a multiple layers in primordial follicles?
E Primordial follicles have a single layer of non-mitotic granulosa cells. Primary follicles have one to twolayers of cuboidal granulosa cells.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above During folliculogenesis, first appear in secondary follicles?
B Secondary follicles have multiple layers of granulosa cells and develop layers of theca cells as well.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Hormone-secreting cells found in the interstitial spaces between seminiferous tubules?
C Leydig cells are interstial cells within the testes (outside of the seminiferous tubules) that secretetestosterone in response to LH.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Secrete BMP15 and GDF9 factors needed for transition of primary to secondary follicle?
E The primary oocyte within the follicle secretes the BMP15 and GDF9 needed for the transition fromprimary to secondary follicles – this does not require FSH or LH, although high levels of FSH cansomewhat increase the rate of the early steps of folliculogenesis.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Major product is androstenedione?
B Theca cells are androgen-secreting cells outside of ovarian follicles that secrete primarilyandrostenedione, some of which is converted to testosterone.
A.Granulosa cells B.Theca cells C.Leydig cells D.Sertoli cells E.None of the above Tight junctions of these cells contribute to the blood-testis barrier?
D Sertoli cells form much of the seminiferous tubule walls and their junctional complexes contribute to the blood-testes barrier. Sertoli cells (much like granulosa cells in ovarian follicles) act as “nurse” cells fordeveloping spermatocytes during spermatogenesis.
Which of the following is true of follicular and ovarian development? A.Follicular development begins at puberty, about a year prior to menarche (first menstruation). B.Ovarian development requires the presence of germ cells with two functional X chromosomes at thegenital ridge by week six in the embryo. C.The peak number of primordial follicles occurs just prior to puberty. D.All stages of follicular development require gonadotropin stimulation. E.Ovaries develop from mullerian ducts present in XX fetuses.
B Ovaries will not develop from the undifferentiated gonad unless germ cells have migrated to the genital ridge at the end of the fifth week in the embryo, and those germ cells have two functional Xchromosomes. (Women with a single X chromosome, XO or Turner’s syndrome do not develop ovaries –they have no gonads at all.) Primordial follicles are formed within the fetal ovary and initial recruitment of some number of primordial follicles each day to begin development starts at mid-gestation andcontinues through menopause (choice A is incorrect). All primordial follicles that begin follicular development with either progress or ovulation (no more than 400 – 500 in a woman’s life-time) or gothrough atresia (programmed cell death – the rest of the 4 to 7 million formed in the fetal ovaries). Thusthe peak number of primordial follicles occurs during mid-gestation before significant atresia has begun (choice C is incorrect). The pre-antral stage of follicular development – primordial to primary tosecondary to early tertiary (Graafian) – is considered gonadotropin independent, since LH and FSH arenot required for this development to occur (choice D is incorrect). Elevated levels of FSH do appear to accelerate this process in women over 38 years of age. Mullerian ducts are not part of the gonad, butdevelop into the fallopian tubes, uterus and upper vagina in the absence of testosterone (choice E isincorrect).
Which of the following is true of ovulation? A.Progesterone-stimulated prostaglandin synthesis by granulosa cells contributes to stigma formation. B.LH-stimulated expansion of theca cells contributes to the formation of the ovulated mass. C.The LH peak stimulates the estrogen peak. D.The LH peak stimulates the oocyte to complete meiosis II and form an ovum just prior to ovulation. E.All of the above are true.
A The LH peak responsible for ovulation causes:i) the oocyte to finish meiosis I (answer D is incorrect – meiosis II is only completed with fertilization)ii) cumulus granulosa cell expansion (answer B is incorrect) and iii) secretion of progesterone by granulosa membrana cells, which stimulates prostaglandin secretion,which act on ovarian epithelial cells to initiate stigma formation for the exit of the cumulus masscontaining the oocyte. The estrogen peak of at least 200 pg/ml for about 2 days (day 11 – 13) followed by a rapid decreaseappears to initiate an LH surge that peaks on day 14 (answer C is incorrect).
In the testes of a normal 20-year old male: A.Spermatozoa first achieve motility in the epididymis. B.Inhibin and testosterone are secreted by cells within the seminiferous tubules. C.LH stimulates both testosterone and inhibin secretion. D.Spermatogonia are found closer to the lumen of the seminiferous tubules than spermatids. E.Synthesis of about 90% of the circulating estrogens occurs.
A Spermatozoa released into the lumen are not motile, but are transported to the epididymis, where they achieve motility after about two weeks. Sertoli cells within the seminiferous tubules secrete inhibin inresponse to FSH, while Leydig cells found in the interstitial spaces between the tubules secretetestosterone in response to LH (answers B and C are incorrect). Spermatogenesis begins during puberty in the seminiferous tubules of the testes. Spermatogonia located next to the basement membrane of thetubule (answer D is incorrect) divide mitotically and differentiate into 1 ̊ spermatocytes. 1 ̊ spermatocytesgo through meiosis I to become 2 ̊ spermatocytes with 23 chromosomes each containing 2 sister chromatids. 2 ̊ spermatocytes go through meiosis II to become haploid spermatids in which eachchromosome is a single chromatid. Spermatids are found near the lumen of the tubule, and undergospermiogenesis in which they shed excess cytoplasm and assume the final spermatozoon shape. Immotile spermatozoa are released into the tubule lumen and are moved to the epididymis, where they achievemotility after about two weeks. Only 10-30% of circulating estrogens are aromatized in the testes – therest are aromatized by peripheral tissues (answer E is incorrect).
Which of the following is true of normal testicular development? A.It requires the presence of XY germ cells at the genital ridge by week six in the embryo. B.Testes develop from wolffian ducts present in XY fetuses. C.It requires SRY gene function for differentiation of Sertoli cells and testis formation. D.It requires testosterone stimulation for differentiation of Leydig cells. E.All of the above.
C. Testicular development from the undifferentiated gonad requires gonadal cells (not germ cells) to expressthe SRY gene on the Y chromosome. Unlike an ovary, testes formation will occur even if primordial germcells do not migrate to the genital ridge (choice A is incorrect) – but there will be no spermatogenesis without the germ cells. Wolffian ducts are not part of the gonad, but develop into the epididymis, vasdeferens and seminal vesicle under the influence of testosterone secreted by the fetal testes (choice B isincorrect). Leydig cells secrete testosterone after differentiating as part of testes development (choice D is incorrect).
The rate of loss of primordial follicles increases when a woman reaches ~37 years of age. A decrease in which of the following hormones is most closely associated with this increased rate of loss? A.Androstenedione B.FSH C.Inhibin A D.Inhibin B E.LH
D In most women, the number of Graafian follicles that develop in the ovary begins to decrease in the mid-to-late 30s. Since Graafian follicles of all sizes (early antral through pre-ovulatory) secrete inhibin B, serum levels of inhibin B typically begin to fall at this time. The decrease in inhibin B allows an increasein FSH levels (choice B is incorrect), which appears to increase the rate of initial recruitment ofprimordial follicles – although this transition does not actually require FSH, higher levels of FSH appear to be able to increase recruitment rate. Since all recruited follicles that are not ovulated undergo atresia,the increased rate of initial recruitment of primordial follicles increases the rate of loss of primordialfollicles. Therefore, around an average age of 37 years old, the rate of loss of primordial follicles accelerates, causing a more rapid loss of ovarian reserve. This transition can occur earlier in women withpremature ovarian failure. Androgens and LH do not affect the initial recruitment of primordial folliclesand so do not affect the ovarian reserve (choices A and E are incorrect). Inhibin A is secreted by corpus luteum cells and suppresses FSH during the mid-luteal phase, but inhibin B secreted by the combined Graafian follicles in the ovaries is responsible for regulation of overall serum levels of FSH and so isassociated with ovarian senescence (choice C is incorrect).
A 22-year-old woman with a normal adult female appearance has a one-year history of amenorrhea. Herday 3 plasma FSH levels are 40 mIU/ml (normal follicular FSH on day 3 = 2.5 – 10.2 mIU/ml). Which of the following is the most likely diagnosis? A.Gonadal dysgenesis (failure of ovaries to develop during gestation) B.Hyperprolactinemia C.Inhibin-secreting tumor D.Kallman’s syndrome (failure of GnRH neurons to develop) E.Premature ovarian failure
E Of the listed choices, the high FSH combined with amenorrhea is best explained by premature ovarianfailure, which is the equivalent of early menopause. When no ovarian follicles remain that can developinto Graafian follicles, no inhibin B is secreted and no estrogen peak occurs, so no LH peak occurs, so no ovulation occurs, so no corpus luteum forms and no progesterone or inhibin A is secreted. Withoutinhibin or estrogen, FSH and LH levels rise to about 5 times menstrual levels. A woman without ovarieswould not have gone through pubertal changes and never would have begun menstruating (choice A is incorrect). Hyperprolactinemia would be expected to suppress LH and FSH levels by suppressing GnRHsecretion (choice C is incorrect). An inhibin-producing tumor would cause very low levels of FSH(choice D is incorrect). LH and FSH levels would be essentially undetectable in Kallman’s syndrome due to the lack of GnRH (choice E is incorrect).
Studies of hormone replacement therapy in post-menopausal women have indicated definite: A.Benefits for hot flashes and vaginal dryness. B.Benefits for protection against breast cancer with estrogen alone. C.Benefits for protection against myocardial infarctions. D.Increased risk for colorectal cancer. E.All of the above.
A Hormone replacement therapy provides definite benefits for hot flashes, vaginal dryness and osteoporosis. The possible benefits for breast cancer and myocardial infarctions with estrogen-only contraceptives arecontroversial and combined estrogen-progesterone oral contraceptives increase the risk for both (choice Band C are incorrect). Oral contraceptive may provide a benefit for colorectal cancer, although the data are controversial (choice D is incorrect).
Which of the following best describes a 20-year old XY patient with complete androgen insensitivity due toa non-functional androgen receptor? (Gonads/Internal genitalia/External genitalia/Breast morphology) A.Ovaries/Uterus but no epididymis/Female/Adult female breasts B.Ovaries/No uterus no epididymis/Underdeveloped male/Pre-pubertal breasts C.No gonads/Uterus and epididymis/Female/Pre-pubertal breasts D.Undescended testes/No uterus, no epididymis/Female/Adult female breasts E.Undescended testes/Epididymis but no uterus/Underdeveloped male/Pre-pubertal breasts
D Analysis of abnormalities of sexual differentiation must always follow the same pattern: 1 = gonadal differentiation (ovaries, testes or none); 2 = differentiation of internal genitalia (Wolffian, Mullerian, both or neither); 3 = external genitalia at birth and pre-pubertal; 4 = pubertal changes.1) Gonadal differentiation is typically determined by sex chromosomes: XY with SRY = testes; XX =ovaries; one X without SRY or spontaneous embryonic gonadal regression = none. 2) Wolffian and Mullerian differentiation depends on androgens (usually testosterone) and MIF:•Testosterone (or equivalent androgen stimulation) from 10 weeks to gestation causes Wolffiandevelopment into epididymis, vas deferens and seminal vesicle; absence of androgens cause regression. •MIF from 10 weeks to gestation prevents Mullerian development into fallopian tubes, uterus and uppervagina; these structures will develop in the absence of MIF.3) External genital differentiation depends on dihydrotestosterone (DHT) converted from testosterone by 5-alpha-reductase. With DHT, external genitalia will be male; without DHT or high androgens,external genitalia will be female; with androgens other than DHT, genitalia may be ambiguous.4) Pubertal changes require activation of the GnRH/LH/FSH regulatory axis and gonadal steroids. In this case of androgen insensitivity, gonads will differentiate into testes due to the XY genotype(choices A, B and C are incorrect) and secrete testosterone and MIF. Without receptors, testosteronecannot stimulate Wolffian duct differentiation so there is no epididymis. Testicular secretion of MIF prevents Mullerian ducts from differentiating so there is no uterus (choice E is incorrect). With noandrogen receptors, the DHT cannot stimulate differentiation of male external genitalia, so externalgenitalia will be female – and without a scrotum, the testes remain undescended (helps exclude choices B and E). At puberty, testosterone secretion increases, but with no androgen effect, the testosteronearomatized to estrogen can stimulate breast development (helps exclude B, C and E).
A neonate with predominantly female external genitalia but some clitoromegaly is identified as having anXY genotype with a 5-alpha-reductase deficiency. Which of the following is the most likely result of acomplete examination? A.Ovaries and a uterus, but no epididymis or vas deferens. B.Ovaries, but no uterus, no epididymis and no vas deferens. C.No differentiated gonads, but a uterus, epididymis, and vas deferens are present. D.Undescended testes, but no uterus, no epididymis and no vas deferens. E.Undescended testes, no uterus, but epididymis and vas deferens are present.
E Using the analysis pattern given above for an XY baby with 5-alpha-reductase deficiency: Gonads will differentiate into testes due to the XY genotype (choices A, B and C are incorrect) andsecrete testosterone and MIF. Testosterone stimulates Wolffian duct differentiation so there is anepididymis and vas deferens (choice D is incorrect and helps exclude choices A and B). Testicular secretion of MIF prevents Mullerian ducts from differentiating so there is no uterus (Helps excludechoices A and C). Without DHT, this baby’s external genitalia are predominantly female, but thetestosterone has had enough androgen effect to cause some cliteromegaly. Without a scrotum, the testes remain undescended.
During normal puberty in girls, estrogen stimulates: A.Breast development (thelarche), pubic hair growth (pubarche) and initiation of menses (menarche). B.Breast development (thelarche) and initiation of menses (menarche), but not pubic hair growth(pubarche). C.Breast development (thelarche) and pubic hair growth (pubarche) but not initiation of menses (menarche). D.Breast development (thelarche) but not pubic hair growth (pubarche) or initiation of menses(menarche). E.Pubic hair growth (pubarche) and initiation menses (menarche), but not breast development (thelarche),
D During female puberty, estrogen stimulates breast development (thelarche). Increased activity of theGnRH/LH/FSH regulatory pathway stimulates the ovarian hormonal synthesis to establish the menstrual cycle – estrogen alone is unable to cause a menstrual cycle (choices A, B and E are incorrect). Pubic hair growth (pubarche) is normally due to adrenal androgen stimulation (choice C is incorrect and helpsexclude choices A and E).
Lactational amenorrhea results from: A.The stress of breast-feeding B.Oxytocin stimulation of the myometrium C.Suppression of GnRH pulses D.Stimulation of afferent neurons from the breast to regulate posterior pituitary function E.Malnutrition
C Suckling initiates a neural reflex that maintains an elevated prolactin during breast feeding. High prolactinlevels inhibit GnRH pulsatile activity enough to prevent normal LH and FSH pulsatile secretion and soprevent ovulation (even though LH and FSH might still fall within their normal ranges). Stess-induced amenorrhea is also called functional amenorrhea and typically results from psychologic stress (breastfeeding is not typically a psychologic stress because of its psychologic benefits), excessive exercise orpoor nutrition (choices A and E are incorrect). Suckling also stimulates a neural reflex arc that increases oxytocin secretion from the posterior pituitary, which contracts the myoepithelial cells of the breast(choice D is incorrect). The oxytocin-induced ejection of milk into the nipple is called the milk letdownreflex. Oxytocin also stimulates myometrial contractions, which is important during labor (choice B is incorrect) but not in lactational infertility.
An absence of sperm capacitation would most probably result in: A.Absence of meiotic activity in the sperm. B.Failure of the sperm to exit the epididymis. C.Immotile sperm. D.Inability to achieve typical head, mid-piece and tail morphology. E.Inability to undergo the acrosome reaction.
E Sperm deposited in the female genital tract undergoes capacitation in the reproductive tract fluids. During capacitation, the flagellar tail becomes hyperactive and ZP3 receptors are exposed on the head. When thesperm reaches the cumulus mass containing the oocyte in the ampula of the fallopian tube, the sperm ZP3receptors bind to the ZP3 protein of the zona pellucida, which triggers the acrosome reaction to release proteases that hydrolyze the zona pellucida. Both the enzymes and the hyperactive flagella are needed forthe sperm to penetrate the zona. The first sperm to penetrate the zona binds to the 2 ̊ oocyte membrane,initiating the cortical granule reaction that prevents polyspermy by preventing any other sperm from binding to or penetrating the zona. Since capacitation occurs in the female reproductive tract, the spermhave already finished their meiotic activity and achieved their final morphology through spermiogenesis(see answer 3) – these occurs in the seminiferous tubules of the testes (choices A and D are incorrect). Similarly, they have already matured in the epididymis, where they gained motility (choice C isincorrect). Ejaculation requires that the sperm have left the epididymis, moved through the vas deferensand out through the urethra (choice B is incorrect).
During the first two weeks of embryonic development following a normal fertilization: A.By day 2, the embryo has arrived in the uterine cavity as a morula. B.Embryonic cells differentiate into trophoblast cells and an inner cell mass during implantation. C.Implantation begins two to three days after the embryo hatches from the zona pellucida. D.Implantation occurs while the corpus luteum is highly active in hormone secretion. E.All of the above are true.
D. Implantation typically begins on day 6 – immediately after the blastocyst hatches from the zona pellucidain the uterine cavity (choice C is incorrect). Fertilization probably occurred within 12 hours of ovulation,on day 15, which would be day 21 of the menstrual cycle – the mid-luteal phase when the corpus luteum is secreting high levels of progesterone, as well as secreting estrogen and inhibin A. The first embryonicdivision occurs just over one day after fertilization, by the third day an 8-cell morula has formed withinthe fallopian tubes still encased in the zona pellucida and by five days after fertilization (day 20 of the cycle), the embryo has become a blastocyst in which the outer trophoblast cells have differentiated fromthe inner cell mass cells; this blastocyst arrives in the uterine lumen (choices A and B are incorrect)
Clomiphene citrate is often used to induce ovulation in women being treated for infertility. Which of the following best describes the primary mechanism by which clomiphene citrate promotes ovulation? A.Clomiphene activates FSH receptors increase recruitment of a cohort of follicles. B.Clomiphine activates LH receptors to initiate an LH surge. C.Clomiphene activates pituitary estrogen receptors to initiate an LH surge. D.Clomiphene reduces negative feedback on the hypothalamus to increase FSH levels and promote growth of dominant follicles. E.Clomiphine reduces negative feedback on the hypothalamus to initiate an LH surge.
D. Clomiphene citrate decreases estrogen activity (choices A, B and C are incorrect), which reducesnegative feedback on FSH, which allows a larger rise in plasma FSH. This larger amount of FSH morestrongly recruits a cohort of early Graafian (3 ̊) follicles and promotes dominant follicular growth enough to often select two or more dominant pre-ovulatory follicles. This can result in ovulation of multiple 2 ̊ oocytes. The estrogen peak generated by the dominant follicle (usually only one) probably generates theLH surge (choice E is incorrect).
Which of the following are true concerning endometriosis and its treatment? A.Endometriosis is a condition in which endometrial tissue is found within the myometrium (smooth muscle) of the uterus. B.Pelvic pain due to endometriosis is reduced by estrogen. C.Oral contraceptives are used in the treatment of endometriosis because of their estrogenic effects. D.Prostaglandin synthesis within endometriosis lesions may contribute to pain and inflammation inendometriosis. E.All of the above.
D Endometriosis refers to the presence of endometrial tissue outside of the uterus (choice A is incorrect) –adenomyosis refers to endometrial tissue found within the myometrial smooth muscle. The ectopicendometrial tissue responds to menstrual cycle hormonal fluctuations and so inflames and becomes ischemic during luteolysis and menses, causing menstrual pain (dysmenorrheal) and other symptoms.Endometrial inflammation and ischemia – regardless of location of the tissue – appears to be mediated byprostaglandin synthesis. Estrogen induces COX-2, which increases prostaglandin synthesis and PGE2 induces aromatase, creating a positive feedback on prostaglandin synthesis, inflammation and pain(choice B is incorrect). Oral contraceptives are used to treat endometriosis because the progesteronepresent in the contraceptive prevents the normal amount of estrogen-stimulated proliferation and inflammation if used continuously (choice C is incorrect).
Which of the following are true concerning placental steroids during the second trimester of a normalpregnancy? A.Fetal androgens provide the major precursors for progesterone synthesis. B.Maternal LDL-cholesterol provides the major precursor for estrone and estradiol synthesis. C.Maternal LDL-cholesterol provides the only precursor for DHEA synthesis. D.Estriol (E3) synthesis requires a precursor modified by a fetal hydroxylase. E.Estetrol (E4) provides the majority of estrogenic effects for the mother.
D The fetal pituitary produces large quantities of DHEA-S. The fetal liver expresses 15-OHase and 16-OHase, which are not expressed in children or adults. Placental sulfatase and aromatase act on 16-OH DHEA-S to produce estriol (E3), which is a partial agonist for the estrogen receptor. Placental sulfataseand aromatase act on 15,16(OH) 2-DHEA-S to produce estetrol (E4), which is a competitive antagonist ofthe estrogen receptor (choice E is incorrect). Placental progesterone is synthesized from maternal LDL-cholesterol (choice A is incorrect). The placenta, like granulosa cells, lacks P450c17 (17-OHase activity) and so cannot synthesize androgens (choice C is incorrect) or estrogens (choice B is incorrect) fromcholesterol. Maternal and fetal testosterone and androstenedione can be aromatized by the placenta intoestradiol (E2) and estrone (E1), respectively.
A patient has a positive hCG laboratory test on day 24 of her menstrual cycle. Which of the followingovarian structures will be most directly affected by hCG? A.Corpus luteum B.Large Graafian follicles C.Primary oocyte D.Primordial follicles E.Secondary follicles
A Human chorionic gonadotropin (hCG) present in maternal blood on day 24 (luteal phase) of the menstrualcycle indicates successful implantation of an embryo, which is secreting hCG into the maternalcirculation. The hCG will bind to LH receptors on corpus luteum cells, preventing luteolysis and maintaining the pregnancy. Embryonic hCG must maintain corpus luteum function until the maturingplacenta is capable of secreting enough progesterone and estrogen to do so – this luteal-placental shiftoccurs at about 7 – 10 weeks of gestation. Large Graafian follicles are present in the ovary during the follicular phase, but not during the lutealphase. The rise in FSH during luteolysis of one menstrual cycle and the early follicular phase of the nextcycle (see diagram with answer to Q1) stimulates development of small Graafian follicles recruited into the cohort for that month. All except the dominant follicle will go through atresia and the dominant pre-ovulatory follicle will ovulate and turn into the corpus luteum. Follicles of all sizes from primordialfollicles up through small Graafian will be present (along with the corpus luteum) during the luteal phase – but without FSH, they cannot develop into the large or pre-ovulatory stages. During the follicular phase,follicles of all sizes, including large and eventually pre-ovulatory Graafian follicles are present in theovary (choice B is incorrect). Primary oocytes are not directly affected by any of the gonadotropins – FSH, LH or hCG (choice C is incorrect). Primordial and primary follicles do not express high levels ofLH receptors and so will not be directly affected by the hCG (choices D and E are incorrect).
During a normal pregnancy, human placental lactogen (hPL): A.Cross-reacts on both LH and FSH receptors. B.Daily production peaks at 10 weeks then fall to a low level for the rest of the pregnancy. C.Induces labor (parturition). D.Indirectly assures fetal supplies of glucose and amino acids. E.Is synthesized primarily by the decidua.
D Human placental lactogen (hPL) increases maternal insulin resistance, which decreases maternal insulinmediated glucose uptake and amino acid uptake, diverting maternal glucose and amino acids to placentaltransporters for fetal use. Maternal insulin resistance also increases maternal lipolysis, providing free fattyacids for use as cellular fuel by maternal tissues. Like HCG, HPL is a protein hormone secreted by syncitiotrophoblasts (choice E is incorrect), but hPL does not share an alpha subunit with LH, FSH, hCGand TSH and so will not cross-react on their receptors. HPL is structurally similar to prolactin and growthhormone and can cross-react on their receptors at high doses (choice A is incorrect). HPL can be detected at about 5 weeks gestation and increases steadily throughout pregnancy. In contrast, hCG can first bedetected in maternal blood by about day 24, rises to a peak at about 8 weeks, then falls to a lower level forthe remainder of gestation (choice B is incorrect). Oxytocin can induce myometrial contractions during parturition, but hPL has no role in parturition (choice C is incorrect).
Using your knowledge of the negative feedback loops operative during reproductive endocrine physiology andcompared to the normal, non-pregnant range, which answer best predicts the serum LH and FSH levels in awoman taking a combination oral contraceptive? (Serum LH and serum FSH) A. Above normal range/above normal range B.Above normal range/within normal range C. High end of normal range/below normal range D. Below normal range/high end of normal range E. Below normal range/below normal range
E The pharmacological dose of estrogen in combination oral contraceptives inhibits both LH and FSHsecretion.
Both combination and progestin-only contraceptives: A.Prevent ovulation equally well B.Increase cyclic mood swings C.Increase the risk of ovarian cancer D.Thicken cervical mucus E.All of the above are true
D Progesterone thickens the cervical mucus, which hinders sperm transport and so decreases the chance offertilization. Progestin-only contraceptives inhibit LH and FSH enough to prevent ovulation most of thetime, but do not completely suppress ovulation - only estrogen-containing combination contraceptives completely suppress ovulation (choice A is incorrect). One of the non-contraceptive benefits ofcombination oral contraceptives is that they decrease cyclic mood swings (choice B is incorrect), as wellas improving acne and decreasing menstrual cramps. Neither combination nor progestin-only contraceptive increase the risk of ovarian cancer (choice C is incorrect) and combination oralcontraceptives decrease the risk of ovarian cancer, perhaps by maintaining reduced gonadotropin levels.
Two main functions of the ovaries during reproductive years?
(1) to produce a single dominant follicle every cycle that produces E2 and ovulates a mature oocyte at about midpoint in each cycle. And (2) to make the CL which produces P and E2 to prepare the uterus for implantation
How to identify PGCs histologically?
PGCs are primordial germ cells in the hindgut at the genital ridge of the embryo. Three characteristics are (1) large size, (2) alk phos stain, (3) lipid droplets
What’s required for ovary development?
Two normal Xs plus PGCs (germ cells)
What’s required for testes formation?
Two normal sex chromosomes (usually X and Y) and SRY (sex-determining region on the Y), but no PGCs needed, only somatic gonadal tissue. DHT (dihydrotestosterone) is also needed for male differentiation, and is derived from T reduction
What cell type do PGCs derive from?
From blastocyst → unspecilized somatic cell→ PGC (under influencs of BMP)
What does SRY do?
Causes sertoli cell formation (which are the nurse cells for sperm and make up seminiferous tubules)
What hormone(s) act on sertoli cells, and what do they secrete?
Bind FSH to secrete inhibin (neg feedback for FSH), MIF, and ABP (bind and concentrate local testosterone to highert levels)
What hormone(s) act on leydig cells, and what do they secrete?
Leydig cells are the interstitial cells of the testes (between seminiferous tubules made of sertoli cells) which bind LH and HCG. And leydig cells can convert LDL into testosterone.
How does germ cell (primordial follicle) count change throughout a female’s life?
As fetus, max out at 7x10^6, then by birth 2-3x10^6, and by puberty, down to 2-3x10^5. At age 50, about 1000 left. The process in atresia, it goes on throughout woman’s life. No explanation for it. PGCs are precursors to oogonia, but do not start developing until 10th week gestation
What is the indifferent stage of gonadal development?
About 6 weeks, gonads can become either testes or ovaries. But in months 2-5, XX individuals PGCs become oogonia and developm to become primary oocytes
What is a primary/immature oocyte?
PGCs develop into oogonia, which proliferate in months 2-5. During this time, some enter meiosis and get arrested at dictyate stage, which is considered primary oocyte stage. It then gains a basal lamina and flat granulosa cell layer, to become a primordial follicle
What are the identifiable features of a primordial follicle?
immature oocyte, single granulosa cell layer, and basal lamina. They all contain an immature oocyte arrested at meiosis I, and are all formed by end-of-term. After flat cells become cuboidal, and become 1-2 layers thick, and express FSH receptors, then it is considered a primary follicle. Primordial follicles are a pool of non-growing follicles from which growing follicles are derived
What is a primary follicle?
A primordial follicle becomes a primary follicle with them help of NOBOX protein. The granulosa cells become cuboidal, proliferate, and express FSH receptors.
Interaction between granulosa cells and oocyte in a primary follicle?
Gap junctions form via connexins (Cx37) between granulosa cells and oocyte, so that the granulosa cells can be like “nurse” cells to the oocyte (this is similar role as sertoli cells to spermatogonia). It is a different Cx (43) than connects granulosa cells to granulosa cells. The granulosa cells also secrete GRP3 which inhibits meiosis in oocyte (via high levels of cAMP in oocyte).
Why are the gap junctions between granulosa cells and oocyte so important?
They are necessary for fertility because they help with the secretion of species-specific zona pellucida proteins which the sperm recognizes and blocks polyspermy
What characterizes a secondary follicle?
2-8 layers of granulosa cells, theca cells outside basal lamina, LH and PGs receptors present (that’s because theca cells are the ones that have LH receptors). Theca cells also accompanied by angiogenesis (mechanism unknown), which is important for exposure to hormones from the blood. Now, FSH binding causes fluid-filled antrum to start developing
What characterizes a tertiary follicle?
aka Antral follicle. Large antrum present due to coalescing of fluid-filled spaces. Attains aromatase function
What characterizes a Graafian follicle?
Theca cells produce androgens (converted to estradiol E2 by granulosa cells). Oocyte now surrounded by granulosa cells called cumulus granulosa cells and are different from the membrane granulosa cells.
Timeline for folliculogenesis?
From primordial follicle to secondary follicle (pre-antral), takes average 300 days. From antral to graafian (antral) takes only 40-50 days.
Timing and description of recruitment and selection of follicles?
Day 1-7 is menses and recruitment. The FSH surge (due to lack of estrogen and inhibin that was coming from corpus luteum) recruits 10-20 small graafian follicles. At day 6, one is selected to be the dominant one, and as it grows (the other recruited ones die), produces a large surge of estrogen, which precedes the LH surge.
Why does the corpus luteum die at about day 25?
The effect of LH from the LH surge lasts only about 10 days, and if there is no HCG (which can also bind LH receptors) coming from an implanted blastocyst, then the CL dies, dropping estrogen and inhibin A levels, which leads to a small FSH surge, initiating recruitment for one more cycle.
Why does FSH start going down after recruitment?
Due to the rising estrogen from the newly selected and growing dominant follicle (which has increasing aromatase activity, stimulated by FSH).
Why does estrogen go back up after the LH surge is over?
The corpus luteum starts producing high levels of estrogen and inhibin A
When are progesterone and inhibin A levels high in the menstrual cycle?
Rise at time of the LH surge, and peak at about day 20 to 25. They are both secreted only by corpus luteum, so they are low or absent at all other times in the cycle.
Why does FSH also peak slightly at the time of the LH surge? And why does LH rise at the time of the FSH surge (day 25 to 6)?
Probably because they are secreted from the same cell (gonadotropes) in the anterior pituitary
Why the cramping and pain prior to menstruation?
Decreases progesterone (from dying corpus luteum), leads to PG production and so endometrial inflammation and ischemia. That occurs in any endometrial tissue, anywhere in the body (as in endometriosis)
When does endometrial proliferation occur?
Begins about day 7 (at end of menses), when high estrogen levels are present in the absence of progesterone. Progesterone (as in oral contraceptives) inhibits proliferation slightly to completely.
How does the dominant follicle increase estrogen levels so much?
Develops more and more aromatase activity to convert the androgens provided to it by theca cells into estrogen. FSH stimulates aromatase activity
What is the two-cell model for ovarian steroid production?
LH stimulates theca cells to make androgens from XOL. FSH stimulates granulosa cells to convert androgens into estrogen (by stimulating aromatase).
How does LH surge cause ovulation?
Stops meiotic block, and causes maturation of cumulus cells (from oocye EGF-like secreted factors)
How do cumulus granulosa cells and oocytes depend on each other?
Oocyte prevents cumulus apoptosis by secreting GDF9 and BMP15. And oocye depends on granulosa cells for protection and “nursing”
How does stigma formation and oocyte release occur?
LH surge and progesterone causes PG production and causes lysozymes to be released from follicles that degrade the epithelial cells of the ovary wall. The oocyte-cumulus complex is released from the follicle by activated plasmin that degrades the follicular wall.
Fate of the corpus luteum?
Makes estrogen and progesterone. If egg is not fertilized, it dies by apoptosis (luteolysis). If egg is fertilized, it continues living longer, and secretes progesterone
What cell types are in the corpus luteum, and what do they secrete?
They are still granulosa cells and theca cells, but they have new, mixed properties. Apparently theca-lutein cells secrete estrogen, and granulosa-lutein cells secrete progesterone.
What is the role of FSH in graafian follicle selection?
Antral fluid FSH rises, and induces expression of aromatase; receptors for LH, P4, ad PGs; and activation of 3-betaHSD required to make progesterone. Independent(?) of FSH, the selected follicle also undergoes mitosis for several generations
What level and duration of estradiol is required before the LH surge occurs?
≥200pg/ml for ≥50 hrs of estradiol, a surge of estradiol will occur 24-48 hrs later
Major events in female puberty?
LH, FSH, estogen levels rise. Breast, uterine, and vaginal growth occur. Axillary and pubic hair develop. Menarche
Phases of the menstrual cycle?
Follicular (proliferative) is day 1-LH surge. Ovulatory phase in LH surge. Luteal (secretory) phase is LH surge to menses
In what phase of menstrual cycle does variability occur (for same person and between people)
Follicular (proliferative) phase is variable. Luteal phase is much more fixed
What is the range for normal variability in menstrual cycle length?
24-35 days. The least variability occurs in middle reporductive years
Where is GnRH made, and what controls its release?
It is a decapeptide, made in arcuate nucleus of hypothalamus, secreted into anterior pituitary, controlled by opioids, catecholamines, and unknown mediators. Progesterone enhances opioid activity, so inhibits GnRH pulse.
Pattern of GnRH release? Significance?
Released in pulses (roughly every 60 minutes), leading to LH and FSH pulses. However, since GnRH has t1/2 of only 2-4 minutes, it is hard to measure, so LH pulses measured instead. Pulses of GnRH restore LH and FSH release. Constant release inhibits LH and FSH release. GnRH pulses begin at puberty and never stop.
What has higher concentration, LH or FSH?
LH is higher, even though both are pulsatile in response to pulsatile GnRH
Difference in LH pulse pattern between follicular and luteal phase of menstrual cycle?
Follicular phase is high frequency, low amplitude. Luteal phase is low frequency, high amplitude. These patterns coorespond to which hormone dominates during each phase. In the follicular phase, estrogen dominates (from dominant follicle) and stimulates proliferation of endometrium. In luteal phase, progesterone dominates (from corpus luteum), and stimulates secretion. Also, high frequency GnRH favors LH release (leads to LH spike that effects last through luteal phase), while low frequency GnRH favors FSH release (effects last through proliferative phase).
5 things the LH surge causes?
Luetinization of granulosa cells, maturation of oocyte (45XX to 23X), resumption of meisosis, expansion of cumulus cells, expression of PGs for stigma formation and rupture
Basic medicinal chemistry and pharmacology of GnRH analogues?
They are substituted at cleavage sites to prevent cleavage (extend half-life), but active moiety is preserved so same affinity for receptor. Causes initial flare (due to new GnRH levels that start out seeming like a pulse), then stark decrease in LH and FSH pulse due to constant stimulation of receptors. The biggest use is in prostate cancer (testosterone-dependent) as an alternative to castration. Or in endometriosis (estrogen-dependent).
Advantage of GnRH antagonists over agonists?
No biphasic flare. However, they are daily parenteral only for now (cetorelix or ganorelix)
How use GnRH pulses therapeutically?
Use a pump to give GnRH pulses to restore LH and FSH pulses. This can restore menorrhea in anorexic women, or other hypothalmic conditions
What does FSH stimulate granulosa cells to release?
Estradiol and inhibin
LH stimulates the release of what from theca cells?
LH and hCG stimulate the release of what from corpus luteum?
Progesterone and inhibin
3 layers of endometrium?
Compact, spongy, and basal layer. The compact and spongy layers make up the functional layer, and is shed every menses. It is regenerated from the basalis every cycle.
Another name for LH?
ICSH (interstitial cell stimulating hormone). Which is much more descriptive, since the theca cells of the ovary and the leydig cells of the testes have LH receptors, and they are the interstitial cells of their respective organs. That makes it easy to remember that it is the granulosa cells and the sertoli cells that have FSH receptors.
What do leydig cells and theca cells do with LDL XOL?
Theca cells make AD>>T. Leydig cells make T. In ovaries, the granulosa cells turn the AD into T>>E1, and T into E2 via aromatase activity
Timing of luteolysis and menstruation?
3 days after luteolysis begins, bleeding starts (due to lack of estrogen, progesterone, and inhibin, but mostly progesterone), which leads to PG synthesis and ischemia (necrosis)
How is testes development different from ovary development?
Both start as PGCs at gonadal ridge at week 4-5, but testes develop much faster, occuring in week 6-7, and done by week 12. (this is important because testes are more important in male development than ovaries in female development). Descent of testes occurs between months 7-9, and sometimes not until after birth.
Endocrine function of testes?
accomplished by interstitial cells of testes (leydig cells) producing 95% of testosterone in circulation. LH pulses every 90 minutes bind to LH receptors on leydig cells (hCG can also bind, but lasts much longer) to make T from LDL. T feeds back to ant pit to inhibit LH secretion.
T in circulation?
Most T is bound in circulation. Only 1-2% is free and active. 30% is bound to SHBP (steroid hormone binding protein), which is made in the liver, increased by estrogen, decreased by androgen. 68% is bound by albumin
Testosterone circadian rhythms?
Maximal is 2-4AM, minimumm between 4-6PM. It is not regulated by LH pulses, and variability decreases with age.
Estrogen in men?
10-30% produced in testes, the rest in periphery (mostly fat, muscle, liver). Using aromatase to convert T to E2
Effects of androgens in men?
Masculinization, body growth, muscle development, libido, sexual potency, aggresssiveness, and high amounts lead to gonadal atrophy due to inhibition of LH, so leydig cells stop working
Exocrine function of testes?
Testes produce sperm in 70cm of seminiferous tubules, which make up 70-80% of testes. The tubules are lined with sertoli cells, and sperm empty into the rete testes then epididymis, then ductus deferens
Order of development of sperm from outer edge (between sertoli cells) to inner lumen of seminiferous tubules?
Spermatogonia (46XY), then primary spermatocyte (46XY), then secondary spermatocyte (23X or Y), then spermatid (23X or Y), then sperm/spermatozoa (23X or Y)
FSH in sperm development?
FSH (even lower than in women) binds to sertoli cells to stimulate protein and aromatase production. Makes androgen binding protein (ABP) and inhibin. T from leydig cells (formed under stimulation of LH receptors) migrates into sertoli cells to augement sperm production.
What is the role of inhibin secreted from sertoli cells in response to FSH?
Inhibin is the major secretory product of sertoli cells, and works to enhance LH-stimulated production of T from leydig cells. It also works at the pituitary to decrease FSH release and hypo to decrease GnRH release(classic neg feedback).
What is the role(s) of seroli cells? (two secretory products and one physical role)
Line seminiferous tubules, produce inhibin and androgen binding protein, and maintain the blood-testes barrier via tight junctions from seroli cell to cell. Also has aromatase activity
Components of the blood-testes barrier?
Sertoli cells (with tight junctions) and myoid cells that sourround the sertoli cells
What process advances spermatogonia into primary spermatocytes, and primary spermatocytes into secondary spermatocytes?
Mitosis for the first, meiosis for the second.
Effect of temp on testes?
Spermatogenesis requires temp about 2.2C lowere than core body temp. But, endocrine function is normal at body temp (so normal testosterone, erections, ejaculation).
Hormones required for spermatogenesis?
FSH and T
Role of epididymis in sperm development?
Storage and maturation. Epididymis is where they gain motility
Inhibin A versus inhibin B?
Inhibin A is secreted by corpus luteum (during luteal phase). Inhibin B is secreted by graafian follicles during follicular phase. both inhibit FSH release, and therefore less recruitment.
How are inhibin B levels used?
To determine number of graafian follicles a woman has (decreases with age). As woman ages, less inhibin means more FSH (rises gradually over woman’s life), and so more recruitment each cycle, PGCs get used up faster, but fewer reach the antral stage, so fewer graafian follicles. By age 37, recruitment is 2x normal.
What is menopause? Caused by? Timing?
Last menstrual period. Caused by fall below critical number of PFs, so cannot generate a dominant follicle. Doesn’t happen all at once. Become irregular first. Usually happens about 15 years after the accelerated decline in PFs
What is the ovarian reserve?
The extra number of PFs. At age 37, the number is about 25,000, and starts to decline rapidly.
Definition and etiology of premature menopause?
Menopause before age 40. Can be autoimmune, genetic, iatrogenic, infectious, idiopathic
Use for, and benefits of, HRT?
Hormone relacement therapy is FDA approved for control of hot flashes (estrogen and estrogen/progesterone treatments same efficacy, but with progeterone is protective against CA) and osteoporosis. But, it may be cardioprotective and anti-colon cancer. It improves skin health.
Info about hot flashes?
Happen in 80-85% of menopausal women, entire body temp rises, HR, sweating. Leads to sleep disturbance, irritibility, mood swings.
Treatments for hot flashes besides HRT?
Cooler environment; phytoestrogens; clonidine; magestrol; SSRI/SNRI therapy; (Vit E, Dong Quai, black cohosh not effective)
Effects of menopause (besides hot flashes)?
Vaginal atrophy, vaginal dryness (treat with estrogen cream), osteoporosis (osteoclast activity higher than osteoblast), and affects trabecular bone, not cortical bone which decreases with age independent of estrogen.
Risk factors for bone fractures?
Female, advanced age, estrogen deficiency, caucasian, low BMI (less aromatase=less estrogen), family hx, smoking, hx of fractures, low dietary Ca, low physical activity, glucocorticoid use
WHO criteria for osteoporosis in postmenopausal women?
Normal is T score above -1. Low bone mass is -2.5 to -1. Below -2.5 is osteoporosis. The sooner HRT is used after menopause, the less bone loss will occur
Besides HRT, treatments for prevention of osteoporosis?
Bisphosphanates, SERMs, calcitonin, PTH
HRT effects on skin?
Receptors on keratinocytes, dermal fibroblasts, blood vessels, and hair follicles. It promotes collagen formation and epidermal water content.
HRT effect on weight?
No effect
HRT effect on endometrium?
Hyperplasia and bleeding (and increased cancer risk) if CE only. But if CE/MPA (estrogen + progesterone), bleeding stops and cancer risk goes away.
HRT and heart disease?
Can’t prevent heart disease when already present (no secondary prevention). CE at an early age seems to protect against heart disease, but CE/MPA increase risk.
Definitive risks for HRT?
CHD and Breast cancer with CE/MPA. Uterine cancer for CE. Thromboembolism for both.
Controversial disease prevention benefits of HRT?
Breast cancer and CHD (CE only), and colorectal cancer (any)
5 contraindications for HRT?
Breast cancer, thromboembolic disease, endometrial cancer, acute liver or heart disease
Same structures between male and female babies give rise to same genitalia?
No, internal ones from different structures (Mullerian ducts in females and wolffian ducts in males… the unused one degrades in each sex). External genitalia from same anlagen
First sign of testicular development?
Sertoli cells (not from PGCs) migrate to form testicular cords and later enclose germ cells. At 60 days, seminiferous tubules discernable, between which are interstitial leydig cells (also not from PGCs).
First sign of ovarian development?
At week 10-11, ovaries first become recognizable. At that point is when primary oocytes turn into primordial follicles
What is needed for proper internal genitalia in males? where does each hormone come from?
Wolffian ducts must differentiate under influence of T from leydig cells, and Mullerian ducts must degrade under influence of MIF from sertoli cells.
What is needed for proper internal genitalia to form in females?
Interal genitalia form from Mullerian ducts in the absence of any hormones, but since there is no anti-wolffian factor, sometimes wolffian remnants persist.
What is gonadal dysgenesis?
Gonads do not develop normally. Usually results in female (default) genitalia, commonly with male genotype, and problem not discovered until puberty when secondary sexual characteristics do not develop.
what is the Testes determining factor?
What activates MIF?
SOX9 and MIS-R
Activity of HPG axis in life?
Active during fetal life, fluctuates in first 0-2 years of life, then very suppressed until puberty (juvenile pause). HPG axis activation leads to leydig cell activation
GnRH and LH pulses in puberty?
Starts out with just nocturnal pulses in GnRH (and therefore LH) in early puberty. Then, by late puberty pulsatile LH is stable 24 hours a day just like adults.
Characteristics of male puberty?
Testicular size increases 11 (LH/FSH). Genitalia size increases 11.5 (DHT). Pubic hair increases 12 (DHT). Height spurt 13.5 (E)
major stages of female puberty?
Thelarche (breast development) 10 (E), adrenarche (pubic and axillary hair development) 11 (Adrenal androgens), growth spurt 12 (E), menarche (menstrual bleeding) 12.5 (LH/FSH)
What are the tanner stages?
Specific criteria for external genitalia development, required for pubertal age office visits.
Percentage of menstrual cycles that are ovulatory after menarche?
First 2 years 50-90% anovulatory. By year 5, less than 20% anovulatory
Fertility begins in boys?
Hard to estimate, but approximately 14
Skeletal growth differences between boys and girls?
Before puberty, girls 5.5cm/yr, boys 5cm/yr. during puberty girls 8cm/yr, boys 10cm/yr, and even though start 2 years later, lasts longer.
Muscle growth during puberty?
Lags behind skeletal spurt about 1 yr. not change appreciably in females. Males get 25% more stength, and continues through about age 25. It is androgen-driven
Fat changes during puberty?
In males, lose fat in limbs, get truncal fat at end of puberty, reach about 12% body fat. Females have continuous gain in body fat throughout puberty, especially in arms, lower trunk, and hips. Reach about 18% body fat by end of puberty.
Changes in breast size with menstrual cycle?
Proliferation peaks in late luteal phase, and regression follows each menses. Contour and molding is determined by fat
Hormones involved in breast development?
Estrogen stimulates breast development at puberty (causes development of the ductal system), but full differentiation requires progesterone (needed for the lobuloalveolar system that develops in pregnancy), insulin, cortisol, thyroxine, prolactin, and growth hormone. Prolactin can overcome mild deficiencies in these. Prolactin and adrenal steroids are needed for milk secretion during lactation. After development, breast no longer depends on steroid hormones
Breast size, function, symmetry?
Assymmetry is common, can be fixed with surgery, not hormones, and size has no bearing on function
Where does prolactin come from?
“wings” of the ant pit, where the lactotropes are. Prolactin is very similar to growth hormone. Its release is primarily controlled by inhibition by dopamine, but TRF is a prolactin releasing factor. So DA antagonists (metoclopramide) cause prolactin secretion, while DA agonists (like L-Dopa) inhibit prolactin secretion.
Effect of estrogen on prolactin secretion? What other things increase secretion?
Hypertrophies the lactrotropes, so increases prolactin secretion. Sleep, food, stress, exercise, orgasm. Levels always highest at night.
Causes of hyperprolactinemia? And when to measure prolactin levels?
Hypothalmis hyperprolactinemia, pituitary hyperprolactinemia, DA agonists, Thyroid dysfunction, chronic renal failure (not cleared). Test at 8:00am and should be less than 20
Prolactin in pregnancy?
Rises 10-20 fold (due to estrogen-induced lactotrope hypertrophy). Is secreted by both pituitary and uterine decidua (former endometrium). Lactation does not occur because high estrogen and progesterone. The progesterone competes for the prolactin receptor. Progesterone causes development of ductules during first pregnancy. True alveoli appear in 3rd month of pregnancy, and nipples become more pigmented
What triggers lactation after pregnancy?
Sudden drop in estrogen and progesterone due to loss of placenta. Within 24 hrs, levels are back to pre-pregnancy levels. First fluid is colostrum, not true breast milk. Prolactin gradually declines, but stays up during lactation as stimulated by suckling
How does the milk-letdown reflex work?
Not by mechanical suction. Oxytocin from post pit causes contraction of myoepithelial cells to empty alveoli. It is 8AA, similar to vasopressin. Oxytocin is released after afferent stimulation of suckling, or centrally upon baby crying or emotions
How does milk actually move through the breast and out the nipple?
Ducts empty into 15-20 areolar apertures. Then, with stimuli, milk fills lactiferous sinuses below the areolar apertures. Compression then expresses the milk
Immune benefits of breat milk?
IgA protects baby’s gut. IgG provides short term humoral immunity
How lactation can be prevented post-partum?
Maintain high estrogen and progesterone, give DA agonists, or tight breast binders can diminish engorgement in immediate post-partum period
How does lactational amenorrhea work?
Through the DA/beta-endorphin system, high levels of prolactin inhibit release of GnRH, FSH, LH. This is the same thing as a pituitary adenoma secreting prolactin
What is capacitation?
Changes that enable sperm to carry out fertilization. It consists of changes in the head which enable the acrosome reaction, binding sperm (unmasked) ZP3 receptor to ZP3 on zona pellucida, and penetrate zona pellucida. Also changes in tail that make it hyperactive. Usually occurs when sperm is in contact with vaginal fluids
Cervical mucous affect sperm success?
Periovulatory mucous is thin and watery, and the external is of the cervix is open. However, luteal mucous is thick and the external os is closed.
Describe the acrosome reaction?
Sperm binds to ZP3, activates proteases to dig into zona pellucida, tail is hyperactivated to help it bore through.
Describe the cortical granule reaction?
It functions to prevent polyspermy. When first sperm fully penetrates ZP, calcium release initiates cortical granules on inside of oocyte to polymerize into proteinaceous matrix that is inpenetrable to other sperm. ZP is also remodeled to prevent entry as well. People on Ca channel blockers get polyspermy. An early block is Na channels changing the membrane potential to block polyspermy
What is the site of fertilization?
Ampulla of oviduct
Time course of fertilization and implantation?
Fertilization must occur within 12-24 hours after ovulation. 4 days after ovulation, oocyte is already morula (still with ZP) and almost out of the oviduct. By day 4.5-5 after fertilization, it is a blastocyst (which is made of inner cell mass, perimeter cells/trophoblasts, and inner fluid collection. At day 5.5-6, ZP released and implantation occurs.
Role of endometrium in pregnancy? The myometrium?
Grows in response to estrogen (from granulosa cells) during proliferative phase, and then prepared for implantation under influence of progesterone (from corpus luteum) during luteal phase. It forms the maternal part of the placenta, and contains many blood vessels. In contrast, the myometrium remains quiescent during pregnancy, but at parturition expels the fetus, placenta, and fetal membranes.
3 phases of implantation?
(1)Hatching (rupture of ZP, blastocyst escapes); (2)Adhesion; (3)Invasive (trophoblasts penetrate uterine epithelium, and embryo completely embeds in endometrium)
The role of hCG from syntiotrophoblast?
Binds to LH receptors on corpus luteum to prevent luteolysis. Thus, the CL of the cycle becomes the CL of pregnancy. The progesterone it secretes prevents myometrial contraction, cervical dilation, and supports the secretory function of the endometrium
At what point does placenta make enough hormones to support the pregnancy without help from the CL of pregnancy?
At about 7 weeks the placenta makes enough progesterone (from maternal LDL), and continues to increase until end of pregnancy. At week 10, CL no longer makes progesterone. In IVF, or if ovary gets damaged, progesterone is given for 10 weeks since no CL to make it. Progesterone circulates in maternal and fetal circulation.
% infertile couples in U.S.?
15%, based on 1 year unprotected sex without conception.
Etiologies for infertility?
Sperm disorders (30%) anovulation/oligoovulation (30%), tubal disease (16%), idiopathic (14%), peritoneal factors like scar tissue (10%)
WHO criteria for normal semen analysis?
Volume>2ml, conc>20x10^6/ml, initial forward motility>50%, normal norphology>30%
ways to detect if ovulation is normal?
Regular menses, midluteal serum progesteron, urinary LH, basal body temp (highest at ovulation), ultrasound, endometrial biopsy
Common treatment for male factor infertility?
Insemination, ICSI (intracytoplasmic insemination, sperm injection into oocyte), donor
Common treatment for anovulation infertility?
Ovulation induction
Common treatment for tubal occlusion infertility?
IVF vs surgery
Common treatments for endometriosis infertility?
Ovulation or IVF
Common treatment for low ovarian reserve infertility?
Oocyte donation
How to induce ovulation?
Clomiphene citrate, blocks central estrogen feedback, so endogenous FSH increases. Can also give direct gonadotropins to stimulate ovaries directly to release eggs. Aromatase inhibitors will also work due to less estrogen, so less neg feedback, and more FSH
Common age for endometriosis?
52% are 26-35, but 91% are between 19 and 45. So, mostly in middle reproductive years
What is presentation/manifestation of endometriosis?
Dysmenorrhea is most common. But also infertility, deep dyspareunia (painful sex), pelvic mass (endometrioma), others
Definitive ways to diagnose endometriosis?
Laproscopy, laparatomy, biopsy. However, CA-125, pelvic exam, history, imaging, emperic medical therapy are all unreliable. Also, it can be brown, black, clear, red, chocolate… so many false negatives possible due to variability in appearance
How to treat pain of endometrriosis?
NSAIDS, estrogen suppression (progestins, danazol, GnRHa, GnRHa + add-back, continuous OCPs, or miscellaneous things like opioids, TCAs, SSRIs)
Pathway for inflammation in endometriosis?
Estrone and estradiol (converted back and forth with 17beta-HSD 1 and 2). Estradiol stimulates PG production from arachadonic acid. PGs activate aromatase to convert more androgens into estrogens, completing a viscious cycle
Oral contraceptives to treat endometriosis?
Good to suppress estrogen, and reduces endometrium. Usually tried after NSAIDS. Can cause breakthrough bleeding, weight gain, breast tenderness, bloating, nausea.
Progestins to treat endometriosis?
High levels prevent endometrial growth. At physiologic levels it stabilizes endometrium
How does danazol treat endometriosis?
Androgen derivitive, buit can’t be acted on by aromatase. Androgens also shrink endometrium. However, it is a teratogen, and its strong androgenic effects limit its use (acne, edema, weight gain, hirstuism, voice changes) as well as antiestrogenic effects (atrophic vaginitis, breast reduction, uterine spotting, flushes, sweats, decreased libido). However, new cervical ring form lowers systemic effects.
GnRH agonists to treat endometriosis?
Biphasic flare, then pseudomenopause symptoms due to lack of estrogen from constant (not pulsatile) stimulation of GnRH receptors. Expensive too. Causes bone loss, vaginal dryness, vasomotor sxs, mood alteration, decreased libido. However, if given in low doses, side effects lessened, and still get limited efficacy
What is add-back therapy in endometriosis treatment? Examples?
Oversuppression of GPO axis by GnRH agonist can be partially compensated for by adding sex steroids to reduce side effects. Examples are estrogen+/- progestin, progestin+/- bisphosphanates, Tibolone (estrogen, progestin, testosterone), others. There is a therapeutic window where endometriosis pain is relieved and bone density still maintained
What is adenomyosis? Sxs? Treatment?
Endometrium in myometrium→enlarged, tender uterus. Sxs include dysmenorhea and infertility. It is treated with analgesics, oral contraceptives, GnRH agonists, hysterectomy (often leading to diagonosis).
What is leiomyomata?
Also known as fibroids or myomas. Benign smooth muscle tumors of the uterus. They are more common in African americans, are genetic. Can be submucosal, intramural, or subserosal.
Sxs and treatment of leiomyomata?
Usually asymptomatic, but can cause menorrhagia/anemia, infertility/miscarriage, pregnancy complications, pain. If parastitic, can make own blood supply. Can treat pain with analgesics, oral contraceptives. Try to shrink it with GnRH agonists, uterine artery embolism, or surgery.
Likelihood of embryo reaching blastocyst stage?
Only about 30% of emryos can reach the blastocyst stage. The blastocyst is the first stage of differentiation. The trophoblast (outer) cells become the fetal part of the placenta. The inner cell mass makes the hormones that will rescue the CL from apoptosis
Components of the trophoblast?
Two cell types: the syncytiotrophoblast which emerges from the other type, the cytotrophoblast.
How hormonal production by the placenta controlled/designed/carried out?
Placenta is made from syncitiotrophoblast and cytotrophoblast. Together they make their own HPO axis. The cytotrophoblast acts like its own hypothalamus and secretes GnRH, TRH, Somatostatin, CRH. The syncytiotrophoblast responds, acting like a pituitary and ovary by making its own hCG and steroids.
Blastocyst rescue of CL? Ovary starts to secrete what?
By starting to secrete hCG about 6 days after fertilization, the CL is rescued, and hCG is detectable by day 9 of ovulation. The ovary then starts to produce relaxin, estrogen, inhibin, and progesterone.
Alpha and beta subunit of hCG?
Alpha subunit is shared between LH, hCG, and others. So, test is for beta subunit, which is predominantly produced during first trimester. Alpha is made throughout pregnancy
hCG levels for pregnancy tests?
Hospital version can detect 5 (at about day 10 after LH surge). Home tests detect 25 (the level at about day 12). hCG doubles every 48 hours for the first 10 weeks of pregnancy.
Placental hCG synthesis?
Cytotrophoblasts make GnRH, which stimulate syncytiotrophoblasts to make hCG. Inhibin inhibits GnRH production, and activin does the opposite.
What are the actions of hCG?
(1)rescues CL from apoptosis, (2)part of implantation signal, (3)promotes progesterone formation in placenta, (4)promotes thyroid hormone, (5)stimulates fetal testis and fetal adrenal
What is hPL?
Human placental lactogen (aka human chorionic growth hormone or human chorionic sommatomammotropin). A single chain 111 AA peptide produced by syncytiotrophoblast as high as 1g/day at by end of term. It has 3% somatotropic activity as growth hormone, and 50% the lactotropic activity of prolactin.
3 main effects of lactogen?
Stimulates maternal insulin production and insulin resistance as well as mobilizes FFAs (both of which prioritize nutrients for the fetus). It also has a mammotropic effect on breast growth
Effect of high prolactin on amniotic fluid?
Helps regulate fluid and electrolyte balance in amniotic fluid (solely by decidua prolactin). Note: it is prolactin that allows salmon to switch from fresh to salt water environment.
Steroid hormones secreted by syncytiotrophoblast?
Progesterone and estrogen.
What happens if placenta is 17 hydroxylase deficient?
Can’t make DHEA from pregnenolone or estrogen from progesterone. So, with the higher levels of progesterone, and no enzyme to convert it, progesterone builds up too much. Can give DHEA to bypass the deficiency.
Estrogens and androgens in pregnancy?
E1 (estrone) and E2 (estradiol) are found in both pregnant and nonpregnant females, but only in pregnancy are E3 (estriol) and E4 (estetrol) found. All androgens are converted to estrogen by aromatase during pregnancy, to protect fetus from virilization. But, aromatase cannot convert 19-nor steroids found in oral contraceptives, which is why they can’t be taken in pregnancy)
How does fetus degrade estrogens?
By sulfurylation and hydroxylation.
Significance of estriol in pregnancy?
First novel estrogen in pregnancy, at week 8. Only fetal liver has 16-alpha-hydroxylase to make 16-alpha-OH-DS, which is transported to placenta to be sulfatased to 16-alpha-PH-DHEA, which is then aromatased to estriol, and goes into mother’s blood. If estriol is high, then healthy fetus (part of the triple screen)
Significance of estetrol?
Second novel estrogen made in pregnancy, at week 20. Only fetal liver can make 15,16-alpha-di-OH-DS, which is processed into estetrol (E4) similar to E3. It binds to Estrogen recepto and has no biological activity (an antagonist)
4 lowest androgenicity progestins?
Norgestimate, gestodene, desogestrel, drospirenone
3 mechanisms for oral contraceptives effectiveness?
Prevents ovulation by estogen neg feedback on FSH & LH, prevents implantation (too high progesterone), thickens cernical mucus to impair sperm transport
Effect of oral contraceptives on prolactin?
Increases prolactin
Side effects of BCPs, in order of frequency?
Breakthrough bleeding, Nausea, weight gain, mood changes, breast tenderness, HA
Cardiovascular risks of BCPs?
MI (especially if smoke and even more if smoke and >35), HTN, thromboembolism
HTN as contraindication to BCPs?
No, not a contraindication, just manage it.
Which cancers have increased risk with BCPs?
Probably none. Only debatable one is breast cancer. It is protective against ovarian and endometrial. Of course, this only applies to combo pills, not estrogen-only
Non-contraceptive benefits to BCPs?
Cycle control, improve acne, improve hirsutism, decrease cramps, decrease mood swings, decrease pelvic pain.
Utility and problems with mini-pill?
Progestin only, so without estrogen, get breakthrough bleeding, poor cycle control, slightly less effective than combo pill. Used sometimes for lactatin women. They thicken mucus, and atrophy endometrium, but do not completely suppress ovulation, and estradiol fluctuates.
Norplant and Depo-provera?
Norplant inserted in arm, lasts at least 3 years. Depo-provera injection lasts 3 months, IM shot