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221 Cards in this Set

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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).
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?

C.Inhibin A
D.Inhibin B
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)
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
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