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209 Cards in this Set
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This hormone determines the fate of external genitalia (male with, female without) and the causes Wolffian dut development (into epididymis, vas deferens and seminal vesicles).
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Testosterone (DHT) determines the external genitalia. Recall that the lower portion of the vagina is from the endoderm of the allantois and is not a Mullerian duct structure so in AIS you still have a blind pouch vagina.
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What does gonadal development begin with the migration of the primordial germ cells from the yolk sac to the gonadal ridge?
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week 5 is the beginning of development with germ cell migration.
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Compare the time points for ovarian vs testicular development.
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Ovarian development is later, at week 9 while testicular development begins at week 7
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What happens if you are deficient in 5 alpha reductase?
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These males will have ambiguous genitalia until puberty where the high levels of testosterone will cause them to develop. (No DHT in the absence of 5 alpha reductase)
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If you are XY but do not product testosterone or have AIS (or male pseudohermaphroditism) how would you present?
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In the absence of testosterone the Wolffian ducts regress, however the Mullerian ducts remain. There would be externally feminized genitalia with the lower part of the vagina being present (from allantois) and poorly developed internal genitalia.
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What is the most common cause of female pseudohermaphroditism and how does it present?
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The female would be virilized with ambiguous genitalia possibly including clitoral-megaly. The most common cause is 21 hydroxylase deficiency in congenital adrenal hyperplasia where androgens are made in excess.
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What is the cause of a bicornate uterus?
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Failure of the Mullerian ducts to fuse into a complete uterus results in the bicornate uterus often leading to urogenital abnormalities and infertility.
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What is the H-Y antigen and where is it from?
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The H-Y antigen is from the SRY gene, it is an autosome that causes development of the gonadal medulla into the testes (cortex is absorbed)
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What are the 3 functions of SRY?
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1. Differentiation of Sertoli cells (FSH)
2. Migration of cells from the mesonephros into the genital ridges 3. Induces proliferation of cells in the genital ridges |
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Name two cofactors with SRY that are essential in testicular development
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SOX 9 and Steroidogenic Factor (SF1) are needed to activate androgens in the Leydig cell and for normal testes formation.
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What cells are responsible for the secretion of MIH and what is their stimulus?
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The sertoli cells release MIH in response to FSH stimulus.
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What are spermatogonia derived from? How about Sertoli cells?
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spermatogonia are from primordial germ cells, that are composing the seminiferous tubules with the Sertoli cells which are derived from mesenchyme.
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What 3 requirements must be met for the development of the female ovaries?
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1. migration of primordial germ cells to the gonads
2. absence of Y chromosome and thus MIF 3. presence of 2 functional X chromosomes |
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What is the ovary determining gene responsible for localized gene activity on the genital ridge in females?
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DAX1
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Wolffian ducts are also called what?
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Wolffian ducts are the mesonephric ducts and are the internal genitalia in males before differentiation
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Mullerian ducts are also called what?
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Mullarian ducts are the para-mesonephric ducts and are the internal genitalia in females before differentiation
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Fetal testosterone influences the mesonephric duct to form the ?
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Epididymis is from the proximal mesonephric duct while the ductus deferens and ejaculatory duct is its more distal portion.
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Is the spermatic chord dorsal or ventral to the ureter?
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The spermatic chord is ventral to the ureter as it loops down and in front during development.
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The urogenital fold differentiates into what?
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the urethera
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In postgestational weeks when does the fetus develop external sexual genitalia?
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about week 14
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What is the cause and what is the presentation of gonadal dysgenesis?
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In gonadal dysgenesis there is no testosterone production and no MIF. Thus the XY individual will phenotypically appear female with female external and internal genitalia. However there will be amenorrhea due to hormonal abnormalities and often streak gonads. Often due to missing portion of Y chromosome.
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Describe the presentation of an individual with Turner's syndrome.
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45 XO, fertilization with empty sperm. Webbed neck, lymphedema of hands and feet, streak gonads, short stature, aorta coarctation, infertility.
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This tumor is a malignant, frequently calcified, mixed germ-cell/sex-cord stromal tumor associated with abnormal sexual development.
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A gonadoblastoma
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XXY presents as what?
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XXY is Kleinfelter's syndrome, these males would have male external genitalia but often many female secondary sex characteristics, are MR and are sterile.
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What are the three layers of the gonads?
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1. germ cells (migrate from the yolk sac)
2. supporting cells (sertoli nurse cells) 3 intersitial cells (leydig testosterone producing cells) |
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You have a patient who has failed to mature and you are concerned about this individual reaching puberty. They also can't smell. What disorder do you suspect and how do you treat it?
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Anosmia makes you suspect Kallman's syndrome which is a failure of the GnRH neurons to migrate from the olfactory plate during hypothalamic development. Treat with pulsatile GnRH.
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What cell is responsible for the blood testes barrier?
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Sertoli supporting cells.
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What two hormones share homology with the Beta subunit of LH and FSH.
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hCG and TSH... thus hypothyroidism may also present with precocious puberty.
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What cells produce inhibins which provide negative feedback to the anterior pituitary?
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Sertoli and Granulosa cells produce inhibins which then decreases FSH as a negative feedback loop.
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Why are women not as fertile during lactation?
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PRL provides negative feedback to the hypothalamus decreasing GnRH, recall that estrogen increases PRL.
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95% of testosterone in males is made by what?
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Leydig cells under the influence of LH.
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What are the effects of testosterone on the lipid profile?
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testosterone increases VLDL and LDL and decreased HDL, BAD!!
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What is the link between GnRH and IGF-1 in males during puberty.
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During puberty testosterone levels rise and GnRH spikes are the cause. As a result testosterone increases IGF-1 which then promotes GnRH to increase testosterone and estradiol. In the male GnRH preferentially releases LH over FSH (perhaps due to high level of inhibins?)
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What is the result of early puberty on final height?
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Since GnRH increases the release of testosterone which unbalances the growth and ossification process of GH there is increased long bone growth but also premature closure of the epiphyseal plates resulting in shorter overall stature.
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If you are working up a tall thin male for infertility who also has gynecomastia what disorder do you have on your Ddx?
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Kleinfelters presents in this manner.
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What is the precursor product that you would screen for in CAH caused by 21 hydroxylase deficiency? How about in 11 hydroxylase deficiency?
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21 hydroxylase deficiency: screen for serum 17 ydroxylase progesterone
11 hydroxylase deficiency: screen for serum deoxycorticosterone 11 deoxycortisol |
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How do you treat 21 OHase deficiency?
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You need to give cortisol, this disease is salt wasting so replace MCC and GCC.
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How do you treat AIS?
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Surgically remove the testes from the abdomen as they are a high risk of cancer.
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The second most common cause of ambiguous genitalia is mixed gonadal dysgenesis, how does it present?
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unilateral undescended testes, contralateral streak gonad , presistent mullerian structures, some masculinization, increased risk of gonadoblastoma and wilmn's tumor. XY 46 or 45 XO.
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What are the 6 main functions of the Sertoli cell?
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1. nurture developing sperm
2. form blood sperm barrier 3. make androgen binding protein to increase local androgen levels 4. release inhibins to decrease FSH production by pituitary 5. transform androgens to estrogen via aromatase 6. Release MIH early in development |
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What 3 hormones is sperm development dependent on?
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1. estradiol
2. DHT 3. testosterone |
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What is the regulated variable in the inhibin system? Where is the sensor?
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FSH is regulated and it is sensed by the pituitary
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What is the regulated variable in the sex steroid system? Where is the sensor located?
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Estrogen and testosterone are regulated via providing inhibition on the hypothalamus
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What happens to LH/FSH if gonadal function is compromised?
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As in menopause the low estrogen releases the hypothalamus leading to reduced inhibition, thus increased levels of LH and FSH
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How is the treatment for hypothalamic hypogonadism different from the treatment of BPH or fibroids?
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Give GnRH pump to replace normal hypothalamus function if hypothalamic, give constant GnRH dosage to inhibit LH and FSH levels to shrink fibroids or the prostate
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In addition to shrinking the prostate what other favorable side effect do 5 alpha reductase inhibitors have?
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They also help inhibit hair loss in male pattern baldness.
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What hormonal influences during puberty increase bone growth?
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Both testosterone and estrogen cause the growth spurts of puberty.
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Why is FSH increased with castration?
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No inhibin produced from sertoli cells and no negative feedback from testosterone production from leydig cells.
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Name the 3 stages of spermatogenesis? What is the final product?
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The final product is a spermatozoa. T
1. proliferative phase where spermatogonia proliferate giving rise to spermatocytes and maintain their number by self renewal. 2 meiotic phase where spermatocytes undergo meiosis and reduce their chromosome number by half. 3. spermiogenic phase where the spermatids undergo morphological changes and become mobile. |
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What is the process called where there is no change in chromosome number but the sperm matures into a mature spermatozoon that is motile?
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spermiogenesis (in contrast to spermatogenesis)
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What are the 4 phases of spermiogenesis?
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1. golgi phase
2. cap phase 3. acrosomal phase 4. maturational phase (occurs in the epididymis and is the final step in maturation called capaciation) |
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Your patient has the absence of any germ cells in his testes, he has azospermia but normal LH and testosterone levels, FSH is +/-, what is your diagnosis?
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Sertoli only syndrome
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Where is testosterone synthesized in the male vs the female?
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male: T is made in the testes by leydig cells
female: T is made in the ovaries 50% and in the adrenal 25%. |
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Contrast the effects of testosterone in the pubescent male with the adult male.
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puberty: stimulates growth and function of external genitalia, stimulates sexual hair development, sebaceous gland activity increases, larynx grows, anabolic effects such as increase in height, musculature, weight, required for spermatogenesis, libido, behavior
adult: gradual development of baldness, prostatic hyperplasia, andropause |
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At hat phase of spermatogenesis does the chromosome number half
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The second phase, the meiotic phase the resulting spermatids have 1N vs their predecesors the secondary spermatocytes which are 2N.
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At what levels of the epididymis are the spermatozoa concentrated, do they mature and where are they stored?
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Spermtozoa are concentrated in the head of the epididymis, mature in the body and are stored in the tail of the epididymis.
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How long does spermatogenesis take?
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64 days, each stage takes 16 days.
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LH induces the uptake of cholesterol and its progressive conversion to pregnenolone via what enzyme?
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20,22 desmolase converts cholesterol to pregnenolone.
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MOA of finasteride and disorders it treats?
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5 alpha reductase inhibitor for BPH
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When is treatment with testosterone indicated?
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In hypogonadism, postpubertal testicular failure, delayed puberty. Also used to stimulate erythropoiesis and for osteoporosis in men.
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How do you increase the lipid solubility and the half life of testosterone?
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esterification of 17 alpha hydroxyl group makes testosterone last longer and more lipid soluble so it can be given IM with less hepatic toxicity than po.
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How do you make testosterone more orally available by slowing hepatic degradation?
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17 alpha hydroxylation (alkylation) increases po availability but also hepatic toxicity
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Name two inhibitors of androgen synthesis?
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GnRH analogues given continuously
Ketoconazole CYP 450 inhibitor. |
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Name 3 androgen receptor antagonists
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spironolactone- anti aldosterone also has anti androgen effects
cyproterone acetate- inhibits GnRH flutamide- non steroid blocks AR (causes GnRH spike so inhibit that as well with continuous administration) |
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MOA of Leuprolide?
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Leuprolide is a GnRH agonist
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T/F If one testes is undescended both testes will atrophy
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True, even as early as 1 year old atrophy is noted. Surgically correct asap. Also watch for intratubular germ cell neoplasia and other testicular cancers as these individuals are at a higher risk.
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What are some of the pathological findings in the tests of an XXY individual?
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In Kleinfelters syndrome there is hyperplasia of Leydig cells with elevated LH/FSH but very low testosterone, no elastic fibers around the tubule and scarring of the tubule.
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Your patient presents with exquisite testicular pain, there is a buildup of arterial blood but a venous blockage. What is the diagnosis?
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Testicular torsion where there is a hemorrhagic buildup of arterial blood that damages the testicle s, medical emergency.
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What causes a varicocele?
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an insufficent valve in the pampiniform plexus.
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You note a unilateral inflammation of the L testicle with a lymphocytic infiltration about a week after infection with what causal organism?
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Mumps!! Don't worry, not really associated with decreased infirtility
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You might be surprised to find caseating granulomas in the testes caused by what bug?
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TB
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Your patient is a young male with a painless testicular enlargement. Are you concerned about a germ cell tumor?
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Yes, young males especially if cryptorchidism is present have highest risk.
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What is the most common testicular cancer in men >60?
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lymphoma
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You biopsy a testicular cancer and see a fried egg appearance with PMN infiltration and lots of lymphs. What kind of cancer is it?
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Seminoma is most likely- a tumor of the primitive germ cell
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What marker would make you suspect a yolk sac tumor?
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alpha fetoprotein
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HPV types 16 and 18 are implicated in this type of cancer where genital warts progress to what?
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Squamous cell carcinomas are the most common
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How early is histologic evidence of atrophy noted in cryptoorchidism? Is the other testes spared?
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Evidence of atrophy as soon as 2 years of age. Atrophy causing infertility will also be noted in the IL testes as well the increased risk of cancer is bilatera.
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What testicular histology goes with Kleinfelters?
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tubular sclerosis with the absence of elastic fibers, there is Leydig hyperplasia and nodules. Increased FSH to LH ratio along with decreased testosterone as the Leydig cells are not functioning.
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What is the most common testicular tumor? Subtype?
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Germ cell tumors are most common and of these most are seminomas hitting young men 15-35 yo "pure seminoma" has a uniform population of large polygonal cells with cleared cytoplasm and prominant nucleolus.
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This testicular tumor has a homogenous fish flesh appearance. Its uniform population of polygonal cells with cleared cytoplasm and central nucleolus show fibrous septae with lymphocytic infiltrations. The appearance can look like a fried egg and these synctiotrophoblastic giant cells produce hCG. What am I?
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Seminoma. 50% of all germ cell tumors. Predisposing factors are cryptoorchidism, and testicular dysgenesis.
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This testicular tumor effects older men >65 yo. It is slow growing, has a mucoid background and the mixture of cells resembles primary and secondary spermatocytes.
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Spermatocytic seminoma, pick this one out just by age of presentation as most germ cell tumors of the testes are in young men.
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This commonly mixed GCT is more aggressive and is glandular, trabecular with papillary arrangements. The cells are mottled and are large hyperchromatic, pleomorphic nuclei with indistinct cytoplasm with frequent mitosis.
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The embryonal carcinoma is more aggressive then seminomas with more metastasis and recurrence. Think high N:C ratios and trabeculae.
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This alpha feto protein producing tumor is common in infants and children. The cells are loose and have a maze like appearance.
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Yolk sac tumors produce alpha feto protein and therefore stain brown immunohistochemically.
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This is the worst kind of GCT. It is aggressive and produces hCG which is useful as a marker. Note placental differentation into synctiotrophoblast or cytotrophoblasts.
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choriocarcinoma has the worse prognosis in testicular tumors.
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This sex cord stromal tumor is masculinizing and produces testosterone. As a result gynecomastia often results as well as precocious puberty. Characteristic granular eosinophilic cytoplasm. Most are benign.
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Leydig cell tumors. Surprisingly you can also find these in the female causing masculinization, crazy.
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What is the most common cause of penile malignancies?
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95% of penile malignancies are squamous carcinoma.
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There are two kinds of carcinoma in situ, one affects the glans and the other the shaft and skin of genital region, what are they?
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Bowen's disease- genital skin and shaft.
Erythroplasia of Queyrat- squamous glans involvement. Histology of both is the same. |
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True or false. In regards to squamous carcinoma, blacks are affected more then whites.
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True. 2/1 ratio. Also the elderly are most affected, those with HPV 16/18 and poor hygeine.
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How would your suspected organism change upon age groups as the causal factor of epididymitis and orchitis?
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kids- URI malformation
sexually active adults- Chlamydia trachomatis and N gonorrhoeae Elderly- enterobacteria |
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You note a caseating testicular granuloma (giant cells, acid fast bacteria) as a part of a systemic disease. What disease is this?
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Tuberculus orchitis and it's on the rise.
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Your patient has mononuclear intersitial inflammation rich in plasma cells (chronic ), there is obliterative endarteritis and /- gummas. What disease?
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Syphilis. often presents at the testes first.
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Your patient is concerned that since he has the mumps that he will be infertile, what do you tell him?
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Mumps orchitis only uncommonly causes sterility in contrast to the common belief.
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Contrast hypospadias with epispadias.
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Hypospadias has the urethra opening on the bottom of the penis while episapdis has the urethra on the dorsal side of the penis.
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Most common testicular tumor in men > 60?
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lymphoma of the tests presents in men > 60.
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Your patient has a testicular tumor with elevated hCG levels. From what kind of tissue did his tumor develop?
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The elevated hCG implies choriocarcinoma. This type of extra embryonic germ cell tumor is from the actual chorionic tissue which is why it secretes the same maker.
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Contrast condyloma acuminatum and verrucous carcinoma types of genital warts.
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Condyloma acuminatum is a type of genital wart from HPV infected koilocytes with shrunken nuclei and clear cytoplasm filled with virons. Forms warts at the base of the glans.
Verrucous carcinoma is a locally aggressive genital wart that invades downward but doesn't metastasize. |
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What zone of the prostate surrounds the urethra/ the ejaculatory duct? What zone is most likely effected by cancer?
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ejaculatory duct surrounded by central zone. urethra surrounded by transitional zone where BPH strikes. The remaining peripheral zone is where cancer is most often found.
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What does BPH stand for?
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Benign prostatic hyperplasia. The cell number increases. Not hypertrophy an enlargement of the cells as in the left ventricle.
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What cells would you see in acute vs chronic prostatitis?
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acute = neutrophils as is usually due to bacterial infection ie E. coli or enterobacteria
chronic = lymphs, plasma cells and macrophages often due to unknown etiology |
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What type of a tumor is an adenocarcinoma
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Adenocarcinoma- cancer of a glandular structure ie the prostate
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What is the histologic presentation of prostate adenocarcinoma?
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Increased N:C ratio
Prominant nucleoli atypical glands lined by single layer of malignant cuboidal to columnar cells -no basal cell layer grossly appears as a yellowish nodule |
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How does prostatic cancer metastasize?
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Mostly it goes to bone. Note that bone lesions will be found by increased alk phosphate. Also note that very very high PSA is indicitive of cancer while moderate high indicates BPH.
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How does 17 hydroxylase block present in CAH?
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This blocks the rightward synthesis so you have a salt retaining disorder with undervirilization. No cortisol and no sex steroids.
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How does 11 hydroxylase block present in CAH?
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11 OHase
salt retaining verilizing increased deoxycorticosterone (not aldo) |
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How does 3 Beta Hydroxysteroid Dehydrogenase present in CAH?
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The absence of 3BHD means that all 3 pathways are blocked.
Thus there is salt wasting and underverilization. |
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How does 21 OHase deficiency in CAH present?
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21 OH ase deficency presents with increased 17 hydroxyprogesterone. It is salt wasting with no cortisol and an increase in sex steroids causing virilization
hyperkalemia metabolic acidosis also result recall that aldo exchanges Na for K and H+ |
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What is the most common disorder of CAH and how do you test for it?
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Most common CAH is 21 OHase deficency. Test for the precursor 17 hydroxyprogesterone. Correct inbalance by giving cortisol and glucose and fluids.
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Why are the adrenal glands oversized in CAH and what other physical signs might be present?
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Increased ACTH will cause hyperplasia and also skin changes (dark spots)
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In a female with 21 OH deficiency how do her internal/ external genitalia develop?
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Since there is no MIF internal genitalia develop normally. However since there is such a high level of androgens there would be virilization of the genitalia. Note that this is actually easier to catch then a male infant with CAH as his virilization is not as noteworthy but he can still die from adrenal crisis.
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What is McCune Albright syndrome? How do you treat it?
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Triad: precocious puberty, cafe au lait spots and polyostic fibrous dysplasia. Is due to a mutation in the LH/FSH receptor causing hypersecretion of estrogen. May develop breasts at a very very young age. Block with selective estrogen-R modulators or aromatase inhibitors.
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What is testotoxicosis? How do you treat it? What is its parallel in the female.
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testotoxicosis is a constiutitively active LH receptor in the testes vamping up secretion of testosterone. The treatment is ketokonazole and spironolactone.
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What is the screening test for the most common CAH?
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look for 17 OH progesterone buildup signaling 21 OHase deficency.
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What age does normal puberty begin for each sex? What bone age for puberty? When do you start to worry about delayed growth/ precocious puberty?
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Normal puberty for females is from 8-13 and males from 9-14. Worry with females if earlier then 8 and boys is before 9. Bone growth however for girls is 101/2 and boys is 11 1/2 so 21/2 years after gonadarche.
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Describe order of pubertal development in males and females and Tanner stages
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Boys first have enlargement of testes >3mm at about 11 yo. Then pubic hair and penile enlargement with growth acceleration close to 14 yo.
Females present with breast bud development at about 11 yo. Brown acceleration occurs and then menarche. Tanner stage two has first palpable breast tissue with minimal hair growth. Tanner 3 increased growth of hair and breast tissue Tanner 4 you see areolus with more hair Tanner 5 is mature with hair spreading to the thighs and aerouls meeting the contour of the breast. |
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Is male precocious puberty of female more worrisome?
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Males have a 50% chance of having CNS abnormality ie hamartoma.
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What is the main inhibitory factor against FSH?
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inhibin. If the granulosa or sertoli cells are dysfunctional there is little negative feedback via inhibin on the pituitary and so FSH/LH are higher.
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Evaluation of delayed puberty might proceed how?
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History and exam
height and growth rate on chart bone age Labs: TSH, prolactin, LH, FSH, estradiol, CBC, ESR, Basic pannel Karyotype if elevated gonadotropins |
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Evaluation of precocious puberty?
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height and growth rate (crossing %tiles)
breast tanner stage/ testicular stage bone age, is it advanced or consitutional? |
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When would you use a GnRH stimulation test?
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To determine if the cause of precocious puberty is central due to GnRH responsive signals or is peripheral in which case levels would not change with stimulation test.
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What labs might you order to determine the cause of precocious puberty ?
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head MRI in males looking for CNS tumor
hCG levels LH/FSH levels (suppressed if peripheral source) GnRH stim test (no peak if peripheral) hCG in boys adrenal/ovarian ultrasound looking for genital tumors as peripheral source. |
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What is tamoxifen, what are its risks?
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Tamoxifen is a weak estrogen agonist, it blocks the effects of estrogen but in unopposed form can increase risk for endometrial cancer in females. It is used for suppressing peripheral precocious puberty in females. Also use aromatase inhibitor.
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How do you block androgen production/ conversion?
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spironolactone and ketoconazole if peripheral, for central give lupron GnRH agonist.
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What is benign thelarche?
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isolated breast development in girls <2 yo with no other pubertal signs. No treatment needed.
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What is benign premature adrenarche?
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pubic hair and axillary hair grown in female earlier then 8 or male earlier then 9 yo. No other signs of puberty. Often due to DHEAS. No treatment needed.
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Damage from iron deposition in the hypothalamus causes what disorder? What is the disease?
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Hemochromatosis deposits iron in the hypothalamus causing hypogonadotropic hypogonadism.
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An increase in what hormone causes gynecomastia?
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Increased estrogen. Often seen with Kleinferlter's XXY. Treat with estrogen converter blocker (aromatase blocker)
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Describe the significance of the homology in the alpha subunit of FSH, LH, hCG, TSH and PRL.
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High PRL exerts negative feedback on the pituitary down regulating FSH/LH due to homology. Thus lactating females have less of a chance to get pregnant.
Also in hypothalamic kids high TSH levels can also cause delayed puberty. ie hypogonadotropic or central hypogonadism. Similarly precocious puberty can be caused by hCG secreting tumors mimicking the ability of FSH and LH to kick the ovarian/testicular cells into producing sex hormones. |
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Two most common causes of erectile dysfunction?
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hyperlipidemia, hypertension
Also note significant anxiety (social, psychological factors). May also be neurogenic, or iatogenic (what other meds). Treat with Viagra a PDE inhibitor. |
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what is the most common pituitary tumor and how does it influence puberty?
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The prolactinoma. PRL is an acquired defect and causes down-regulation of LH/FSH due to homology.
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Your patient has delayed puberty with low LH, FSH and low testosterone. What might you test next?
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Test PRL to see if he has a prolactinoma causing his hypogonadotropic hypogonadism.
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Your patient with delayed puberty has high FSH (due to lack of inhibin) and normal LH with low testosterone. What do you test next?
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Karyotype to see if its Kleinfelter's with progressive fibrosis and destruction of Leydig cells.
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Your patient has high LH, FSH, T and E. However they have ambiguous feminized genitalia. How do you treat?
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This is AIS with a mutation in the androgen receptor. Thus this is probably a feminized XY with a blind pouch vagina. Remove testes due to cancer risk and estrogenation will be fine so continue raising child as a female.
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What lab tests might make you think acquired hypergonadotropic hypogonadism ie cytotoxic trauma to the testes in a male?
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Initial rise in FSH due to loss of inhibin followed by increase in LH and decline in testosterone. Late treatment might be with testosterone replacement.
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Your patient with pubertal delay has HA, blurred vision and gyndeomastia. What do you suspect?
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pituitary tumor, stalk compression inhibits DA inhibition of PRL so breast development might occur. Also do MRI of pituitary looking for gonadotropin tumor. FSH and LH levels will be high but testosterone will be low as the hormones are non functional from the tumor.
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When is androgen supplementation contraindicated in men?
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With prostate cancer which is androgen sensitive.
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Why are oral androgens not recommended?
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hepatotoxicity.
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Name 3 treatments for male hypogonadism
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1 androgen replacement (worry about T sensitive cancers and polycythemia and LDL elevation along with BPH)
2. gonadotropin therapy with hCG for 12-18 months 3. pulsatile GnRH therapy takes 18-24 months |
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Differentiate between physiologic, drug induced, endocrine and tumor causes of gynecomastia
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physiologic- normally occurs neonatally, pubertally and in aging
drug- antiandrogens spironolactone, flutamide, psychoactive drugs like phenothiazines and antidepressants, alcohol, heroin,marijuana endocrine- primary hypogonadism, hyperprolactinemia, hyperthyroidism, AIS tumors- GCT (hCG stimulates estrogens), leydig cell tumors (E +T), feminizing adrenal tumors making E. |
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When is there the highest number of oogonia in the ovary. What is the number at birth and at puberty?
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highest number of oogonia 6-7 million at 20 weeks gestation. At birth 1-2 million remain and at puberty 400,000 remain. Of these 10-30 are recruited for monthly ovulation.
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In what stage of meiosis I is the primary oocyte arrested?
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the primary oocyte is arrested in prophase I for years waiting in the ovary.
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T/F Primary oocytes are diploid.
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true the primary oocyte is arrested in meiosis I before meiosis II where the oocyte becomes haploid.
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In males just before meiosis I is complete the cell reduces to two secondary spermatocytes that are haploid 23. How does this step differ in oogenesis?
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The reduction produces a secondary oocyte and a polar body. The secondary oocyte is then arrested in meiosis II waiting for fertilization.
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What is required for the formation of the second polar body in oogenesis?
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Fertilization is needed for the continuation of meiosis II.
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How does the genetic content of the first and second oocyte polar bodies differ?
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1st polar body is haploid with 2N. The second polar body is haploid but has 1N.
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What hormone is predominant in the proliferative phase vs the secretory phase.
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estrogen = proliferation of endometrium
secretory phase = progesterone |
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What are the 3 pre-antral follicles and the 2 antral follicles in follicular development?
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pre-antral- primordial, primary, secondary follicle
antral- tertiary and graafian follicle |
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T/F The graffian follicle con contain a primary or secondary oocyte that is extruded during ovulation.
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True. Either is held within the graafian follicle.
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The zona pellucida is what and when does it develop on the oocyte?
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The zona pellucid appears in the primary follicle in the 2nd pre-antral stage. It is a glycoprotein coat that helps with sperm attachment.
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At what stage does the oocyte develop receptors for FSH, androgen and estrogen and become hormonally reactive granulosa cells. At this time the theca cells also develop LH receptors.
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Hormonal activity begins in the final pre antral stage of the secondary follicle
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At what stage do the granulosa cells proliferate acquiring LH receptors and a fluid filled space develops within the granulosa cell layer called what?
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This is the first antral stage when the tertiary follicle contains a primary oocyte.
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At this stage the first meiotic division is completed giving rise to a 2ndary oocyte and the 1st polar body. Prior to ovulation the cumulus oophorus stalk breaks off and the oocyte floats freely within the corona radiata halo of granulosa cells. What is this final antral stage?
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The graafian follicle is ready for ovulation!
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Once ovulation has occured what is the remaining shell of the follicle and what does it begin to secrete until it shrivels up in another 11 days and becomes the what?
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The corpus luteum is the empty follicle which begins to secrete estrogen and progesterone to change the stratus functionalis preparing for a fertilized ovum. With fertilization hCG is secreted for 9 weeks until the placents is able to secrete progesterone. In teh absence of fertilization the corpus luteum shrivels up at 11 days and becomes the corpus albicans with a decrease in progesterone produciton.
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What is the role of the corpus luteum?
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The corpus luteum secretes estrogen and progesterone after the graffian follicle has been released. This changes the stratus functionalis of the uterus to promote implantation. If fertilization occurs hCG production continues for 9 weeks and if no fertilization the corpus leuteum atrophies to the corpus albicans at day 11.
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What are the actions of FSH in the granuosa cell?
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FSH in teh granulosa stimualtes proliferation of the granulosa cells, increase in LH/FSH receptors, increased aromatization of androgens to estrogens and production of activin/inhibin.
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Contrast the role of activin and inhibin.
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The granulosa cells secrete both. Inhibin down regulates FSH from the pituitary. Activin suppresses androgen production in the theca cells leading to an estrogenic microenvironment.
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What is the one exception of the inhibitory role of estrogen at the level of hte hypothalamus and pituitary.
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If estradiol is over 200 pg/ml for 50 hours it becomes stimulatory for the LH surge instead of inhibitory to the pituitary as it is usually.
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Is progesterone inhibitory or excitatory during the luteal phase?
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Progesterone is inhibitory in the leuteal phase when it is at high concentrations, it shuts off the pituitary preceding menstruation.
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What are the two main layers of the endometrium? What kind of epithelium is it? What layer is shed and what are its two components?
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The endometrium is simple columnar epithelium with tubular glands. The deepest part is the stratum basalis which has the bases of the glands and is not shed. The stratum functionalis is shed and is componsed of the stratum spongiosum the thick intermediate layer and the stratum compactum that sits most superficially.
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How does the stratum functionalis become ischemic and begin to shed?
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The spiral arteries are hormonally sensitive and constrict in response to hormonal signals ie lowering levels of progesterone and estrogen lead to sloughing of the endometrium.
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when in the cycle is the following:
LH peak ovulation fertilization happens here implantation |
LH peak: day 14
Ovulation: 12 hours later day 15 only takes 3 minutes to get the oocyte to the ampulla fertilization occurs day 16-17 endometrium becomes receptive around day 20 and then the embryo implants on day 21. |
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Where is the blood supply from to the myometrium, the basal layer and the functional layer of the endometrium?
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The functional layer is fed by the hormonally sensitive spiral arteries.
The basal layer by the basal artery. The myometrium by the radial artery. |
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How does the genetic material differ between a primary spermatocyte, secondary spermatocyte and a spermatid?
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primary spermatocyte = 46, 4N
1st meiotic division secondary spermatocyte = 46, 2N 2nd meiotic division spermatid = 23, N |
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The differentiation of what marks the formation of the primary follicle.
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The zona pellucida GP coat
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At what stage do the granulosa cells signal the hormonal development of theca cells which will be responsive to LH and become increasingly vascularized.
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The secondary follicle develops theca cells and increases its vascularization.
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Following the LH surge the graafian follicle undergoes the second half of meiosis-I. The cell is at _N and there is a __ polar body.
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The cell at this point just before ovulation is a secondary oocyte and has 23: 2N with a 2N polar body.
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In the mid luteal phase what hormones are inhibiting the HPO axis?
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There is a high peak of progesterone, estrogen and inhibin all exerting a negative influence on the pituitary leading to menstration.
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How does the GnRH pulse generator change between the luteal and follicular phases?
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follicular phase- 1 pulse per hour
luteal- once every 3-4 hours, decreased frequency due to inhibition from progesterone, estrogen and inhibin. That allows LH and FSH to begin to rise. |
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Name 3 therapeutic uses of estrogens
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hypogonadism, menopause to help with vasomotor instability and for contraception to prevent ovulation
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What is the physiological function of estrogen
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growth and development of female reproductive organs
secondary sex characteristics linear bone growth and hastening of epiphyseal closure sensitization of tissues to progesterone via upregulating progesterone receptors stimulation of LH surge increases HDL, lowers LDL but increases TG increases clotting factors causes endometrium to proliferate during the follicular stage. |
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Risks of estrogen uses
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cardiovascular problems ie stroke, MI
cancer- cervical, endometrial, breast increases TG galbladder disease nausea migranes thromboembolism HTN |
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Why in some patient populations is raloxifene a better SERM then tamoxifen?
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tamoxifen is an antagonist at the breast (breast cancer prevention) but an agonist at the endometrium while raloxifene does not stimulate endometrial proliferation lessening the risk of uterine cancer.
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How might you increase the fertility of a patient with PCOS other then by controlling T2D with Metformin?
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Clomiphene is an oral drug that increases GnRH and induces ovulation (partial estrogen blocker upregulates GnRH)
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Name a full antagonist of estrogen administered monthly by IM for the treatment of breast cancer
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Fulvestrant is an E antagonist.
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Contrast the location of synthesis of E and P
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E is synthesized in the ovary by granulosa cells under the stim of FSH. In men and postmetapusal women mostly the conversion is made in fat by aromatase. Progesterone is mainly made by the corpus luteum and the placenta but in postmenopausal women more is made by the adrenal cortex. In men some is also made by the testes
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Name a anti progestin progesterone antagonist used to terminate pregnancy.
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mefipristone- drops the baby like a stone, given with prostaglands for expulsion
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What is the effect of estrogen on the lipid profile?
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increased TG
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What changes are made to estrogen to make it have a longer half life and be less degraded by first pass hepatic metabolism.
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esterification of C17 gives it a longer half life and increased lipid solubility. Ethinyl modification on C17 makes estradiol more orally available.
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Describe the ideal SERM
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antagonist at the breast and endometrium
agonist at the bone, CNS and heart |
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Your patient presents with amennorhea. What do you do for an initial workup?
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History and physical
pregnancy test ßhCG rule out elevated prolactin- 10% have prolactinoma which inhibits GnRH Draw LH/FSH 5 days after menses and LH should = FSH Androgen levels only indicated if hirsuitism or acne present GnRH challenge only useful in precocious puberty to tell if central/peripheral |
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Your amennorheic female has low LH, low FSH and low E2 <60. What do you suspect?
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hypogonadotropic hypogonadism
either GnRH deficency from Kallman's syndrome or induced hypothalamic amenorrhea due to stress, exercise, anorexia |
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Your amenorrheac female rpesents with high FSH and or LH what congenital disorder will you test for?
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This may be Turner's syndrome where high LH/FSH is trying to wake up an atropic gonad. Ovten there is premature ovarian failure (women <40 yo- may be gonadal dygenesis, due to mosaic XX/XO). Perform a karyotype
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What 3 things during menstruation are a sign that it was an ovulatory cycle?
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cramping, bloating and breast tenderness indicate ovulation. These signs would be absent in gonadal dysgenesis and ovarian failure which is most often autoimmune. Always look for thyroid disease, diabetes and B12 pernicious anemia.
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An amennorheac female's testosterone comes back at 400. Does she have PCOS? Any other possibilities?
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She has a tumor secreating androgens causing hirsuitism.Testosterone >200 or DHEA-S>800 is indicative of a tumor
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How would you treat hypothalamic pituitary defects:
defective GnRH pulse generator Prolactinoma Requesting fertility help |
Replace GnRH pulse generator with pump, HRT or OCP
Give dopamine agonist ie bromocryptine or carbergoline to decrease PRL- surgery Pregnancy: clomipene (partial E agonist), pergonal (recombinant FSH/LH), pulsatile GnRH pump |
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How do you test for menopause? When is the average age? When is it abnormal?
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Average age is 51, abnormal if before 40. Test by very high FSH levels due to no negative feedback from estrogen/progesterone.
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What is the Ddx of PCOS
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Labs would show incresed LH/FSH ratio >2.5 with insulin resistance. Differential might also be Cushings, CAH, hyperprolactinemia, androgen secreting tumor
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LH is usually higher then FSH. When is this exception and why?
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Exception with FSH being higher then LH is the last 3 days of the luteal phase and this is when the next follicles are being chosen.
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The first step in evaluating an amenorrheac woman?
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pregnancy test, don't look for zebras.
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Your patient is obese, 33 and infertile. You suspect PCOS but due to her age >30 you also suspect?
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Suspect obesity caused amenorrhea and treat with weight loss if her LH/FSH ratio not elevated and no history of insulin resistance.
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Your patient has hirsuitism. What drug might you recommend? How would you change this reccomendation if she wanted to get pregnant?
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Recommend spironolactone but that will cross the BBB. Discontinue at least 3 months prior to trying to get pregnant.
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Contrast the cells of the endo vs exocervix.
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Endocervix is closer to the ox with the exocervix on the exterior ring. Endocervix is glandular columnar epithelium while the exocervis is squamous.
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What are koilocytes and what infection do they indicate?
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koilocytes indicate HPV investion. They are cells with perinuclear clearing. Infection is usually on the transitional zone around the cervix where the cells change from columnar to squamous.
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What are the recommended guidelines for pap smears?
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Begin at 21 or when sexually active. Do yearly. If over 30 and 2 negatives come back wait 3 years until the next pap. If the woman has a hysterectomy still get a pap as HPV can cause cancer in the vagina as well.
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How is endometrial histology different in the proliferative vs the secretory phases of endometrial growth?
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proliferative- E directed, growing straignt tubular glands with active mitosis
secretory- progesterone from corpus luteum, torturous glands/ spiral arteries, more glycogen production |
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Most common cause of dysfunctional uterine bleeding in adolescents specifically
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anovulation (either too little estrogen or unopposed estrogen)
In older women may be endometritis, complications, leiomyomas. |
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Define endometriosis
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abnormally located endometrium outside the uterus.
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You note a follicular cervicitis. What obligate intracellular pathogen causes this specific type of cervicitis as well as urethritis lymphogramuloma venerum, endometriosis and salpingitis?
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Chlamydia trachomatis. Most common etiologic factor causing infertility. Treatment is tetracycline.
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Which of the following is not a risk factor for cervical carcinoma: infection with HPV, HIV, cigarette smoking, diet, multiple sexual partners.
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All but diet. Do pap smear to rule out cervical carcinoma. Diagnosis is confirmed with biopsy and colposcopic examination.
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Contrast type I and type II endometrial adenocarcinoma
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Risk factors for adenocarcinoma: Obesity, T2D, early menarche and late menopause, PCOD, Lynch Disease (colon, endometrium and ovary), HTN, anovulatory cycles
type I adenocarcinoma- good prognosis, high levels of estrogen, premenopausal women with hyperplasia, minimal invasion, more commonly caucasian. type II adenocarcinoma- no correlation with estrogen, post menopausal, no hyperplasia, more common in black or hispanic women, high grade with invasion and poor prognosis. |
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What am I? Most common tumor of the uterus, derived from fibroblast like cells, show up mid reproductive years with irregular bleeding, mass effects and infertility.
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Liomyoma- benign and slow growing fibroids are well circumscribed, treat with surgery.
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T/F liomyosarcomas derive from long standing leiomyomas.
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False. No connection. Leiomyocsarcomas are from smooth muscle but they are fast growing, bulky masses invading the uterine wall de novo. Like to metastasize to the lung. Look like spindle cells. Survival is poor.
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This tumor is fleshy and necrotic arising from malignant trophoblasts. See anaplastic cells derived often from a previous pregnancy. Associated with hyatidiform moles.
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Choriocarcinoma. Measure hCG levels.
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You biopsy a mass on your patient and it has hemorrhagic nodules with cysts, adhesions and fibrosis. Contains both glands and stroma. Lots of hemosiderin laden macrophages. The patient complains of dysmenorrhea, infertility and pelvic pain. What is your diagnosis.
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endometriosis. Recall that since the tissue is hormonally sensitive that the pain can actually come and go with her cycle. Pathogenesis-not well understood theory of "regurgitation of shed functional tissue into the fallopian tubes" or metaplasia of normal tissue.
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Name a few risk factors for ovarian cancer.
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Nulliparity, family history, most occur in older women post menopausal. Genetic risk is increased with BRCA1 (17q21) gene which increases breast and ovary cancer risk and BRCA2 which is only associated with ovarian cancer.
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What is the most frequent ovarian tumor?
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serous epithelial tumor- usually bilateral, benign tumors surrounded by thin layer of cells without stromal invasion, psammoma bodies
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Which is more common, ovarian epithelial or germ cell tumors?
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Epithelial cell tumors are up to 70% of all ovarian tumors. They are either serous, mucinous, clear cell or endometrioid.
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How is the prognosis for a teratoma different between women and men.
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In men teratomas are almost always malignant.
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What are the most common tumors of the ovary in adults?
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Serous and Mucinous epithelial tumors are the most common.
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T/F metastases to the ovary are more common then primary ovarian tumors.
Give example. |
True. Krukenberg tumors are adenocarcinomas of the stomach that have metastasized to the ovary (signet ring cells)
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