PSIO 467 QUESTIONS EXAM 2
Identify the protein hormone that plays a role in gestational diabetes.
Human chorionic somatomammotropin (hCS) or human placental lactogen (hPL) Inhibits maternal glucose uptake to shift glucose toward fetus (anti-insulin effect) Gestational diabetes
Describe the current hypothesis for the initiation of labor.
Hypothesis for initiation of labor • Increased placental estrogen secretion: 1. Promotes formation of gap junctions between myometrial cells (functionally links myometrial cells and permits coordinated contraction) 2. Stimulates progressive increase in number of uterine oxytocin receptors (increased uterine responsiveness to oxytocin) 3. Increases production of prostaglandins (stimulate cervical softening and uterine contraction) - Increase in placental estrogen secretion mediated by placental CRH
Explain the timing of the hCG injection relative to egg retrieval.
hCG administered approximately 34 h prior to retrieval
Describe the endocrine regulation of lactation and the stimuli that initiate milk ejection and synthesis.
prolactin and oxytocin have positive feedback and dopamine is inhibited
Define adrenarche and menarche.
• Adrenarche - increased androgen secretion due to adrenal steroidogenesis precedes activation of ovaries; associated with development of axillary & pubic hair • Menarche - activation of ovaries & onset of menstrual cycles; may be delayed if very thin or physically active
Explain the clinical significance of progesterone supplementation during the first trimester.
• By ~ 10-12 weeks, placental steroidogenesis is sufficient to support pregnancy • CL -> placenta shift • Progesterone supplementation for luteal phase defect or IVF discontinued at ~ 12 weeks
Describe the roles of inhibin in follicular development, hormone production, and ovulation.
• Member of glycoprotein hormone family (~250 amino acids; a and b subunits) • Synthesized in granulosa cells • Production and secretion of inhibin is stimulated by FSH • Exerts negative feedback on gonadotrope in anterior pituitary • Suppresses FSH release but not LH During follicular phase estradiol (& inhibin) act on the anterior pituitary and suppress LH & FSH
Define parturition.
the act of labor and delivery in the birth of a child (process by which uterine contractions lead to childbirth) • Usually occurs ~ 38 weeks after fertilization (40 weeks gestation) • Trigger for initiation of labor not completely understood • Increased levels of oxytocin clearly regulate and promote labor once it has begun
Explain why estrogen is administered to an egg donor's recipient and why it (along with progesterone) must continue until the end of the 1st trimester if the recipient is pregnant.
to inhibit LH and FSH
Explain the diagnostic use of Day 3 labs, hysterosalpingogram (HSG), and semen anlysis.
tool to assess infertility -day 3: FSH > 10 mIU/mL indicates poor prognosis -Hysterosalpingogram (HSG): X-ray with contrast dye to show blocked tubes -semen analysis: Normal count, motility, morphology? Oligospermia - few sperm cells are ejaculated (low sperm count;<20 million/ml) Azoospermia - no sperm cells are ejaculated
Explain the clinical significance of hCG in blood and urine and its use for infertility treatment.
*hCG in urine or blood is used to diagnose early pregnancy **hCG can be used clinically to mimic LH surge in infertile women (triggers ovulation)
Explain the differences between 28-day cycle mono-phasic, 28-day cycle multi-phasic, extended hormone, extended cycle, and continuous use combination pills.
-28-day cycle mono-phasic pill (e.g., Loestrin) Constant estrogen + progestin for 21 days followed by 7 days placebo Withdrawal bleeding occurs while on placebo due to drop in hormone levels -28-day cycle multi-phasic pill (e.g., Ortho Novum 7/7/7) Varying doses of estrogen + progestin for 21 days followed by 7 days placebo -28-day cycle extended hormone combination pill e.g, 24 days estrogen + progestin, 4 days placebo (Yaz) May reduce menstrual-related symptoms -Extended cycle mono-phasic combination pill (Seasonale) Constant estrogen + progestin for 84 days followed by 7 days placebo Only 4 withdrawal bleeds per year -Continuous use mono-phasic combination pill (Lybrel) Constant estrogen + progestin with no breaks No withdrawal bleeds
Describe the basic mechanism of action and clinical uses for clomiphene citrate (clomid), letrozole (Femara), FSH, GnRH antagonist, and hCG in fertility treatment.
-Clomiphene citrate (Clomid) Estrogen antagonist (blocks negative feedback by estradiol and thus stimulates FSH & LH secretion) -Letrozole (Femara) Aromatase inhibitor (prevents conversion of androgens to estrogens - lower estradiol levels permit more FSH & LH secretion) -Human chorionic gonadotropin (hCG) Ovulation occurs approximately 36 h after hCG injection -FSH: Ovaries are stimulated to produce multiple eggs with FSH Vaginal ultrasound and blood estradiol are used to determine when follicles are appropriate for egg retrieval -GnRH antagonist prevents early ovulation (inhibits gonadotrope secretion to prevent LH surge)
Explain why administration of exogenous androgens would decrease sperm production.
-Exogenous androgen administration results in increased testosterone level in the circulation which will send a negative feedback to the pituitary and there will be low LH secretion. When there's low LH, the Leydig cells are not stimulated to produce testosterone and so the "local" testosterone level will be low and this will cause a failure of sperm maturation
Describe the actions of testosterone during sexual differentiation, puberty and sexual maturity.
-Fetal development of internal reproductive tract directly affected by testosterone -Fetal development of male external genitalia and prostate requires conversion of testosterone to DHT by 5 a-reductase in target tissues -Puberty: Maturation of internal reproductive tract and external genitalia at puberty; Testes enlarge and become capable of spermatogenesis, Penis and scrotum enlarge -Adulthood: Sexual maturity (peak testosterone and sperm production)
Compare the hormonal regulation of ovarian function during the follicular phase (including both tonic LH secretion and the LH surge) and the luteal phase
-Follicular phase: LH stimulates production and secretion of androgens from cholesterol precursor by theca cells, FSH stimulates estrogen production and secretion by granulosa cells Late in follicular phase, elevated estradiol + FSH stimulates development of LH receptors inhibin Synthesized in granulosa cells (Suppresses FSH) -luteal phase: Remaining theca and granulosa cells differentiate into luteal cells expressing LH receptors, LH stimulates progesterone (also to a lesser extent estradiol) synthesis and secretion -Tonic (basal) LH secretion controls ovarian steroidogenesis • Estradiol secretion during follicular phase • Estradiol and progesterone during luteal phase • Involves negative feedback by estrogen and progesterone -LH surge causes ovulation • Neuroendocrine reflex arc of positive feedback triggered by sustained, elevated estradiol levels
Describe the endocrine regulation of testicular function by Kisspeptin neurons, GnRH, FSH, LH, and inhibin.
-Kisspeptin neurons in hypothalamus play role in negative feedback by androgens on GnRH secretion in males, Kisspeptin neuron activity increases at puberty -GnRH: positively stimulates the anterior pituitary to secrete LH and FSH -FSH: positively stimulates sertoli cells -LH: postitvely stimulates leydig cells -inhibin: from the sertoli cells, negatively regulates the anterior pituitary (haults secretion of LH and FSH)
Describe the series of events necessary for normal sexual differentiation for males, including the roles of SRY, AMH (MIF), 5 a-reductase and DHT. Include mention of the Wolffian and Mullerian ducts and the internal and external reproductive tracts.
-Mullerian Ducts -> Female Reproductive Tract Wolffian Ducts -> Male Reproductive Tract -Fetal development of male external genitalia and prostate requires conversion of testosterone to DHT by 5 a-reductase in target tissues -SRY = Sex determining region on the Y chromosome Differentiation of gonads into testes (formation of seminiferous tubules), Production of Anti-Mullerian Hormone (AMH; MIF) by Sertoli cells, Production of testosterone by Leydig cells
Identify the anatomical compartments involved in oogenesis, fertilization, and development and maintenance of fetus
-Ovary: Production of oocytes (eggs) & hormones -Oviduct (Fallopian tube) Fimbria: Picks up mature ovum from ovary Ampulla: Site of fertilization Isthmus: Ovum/embryo transport to uterus -Uterus Endometrium:Site of embryo implantation; glandular Myometrium: Expulsion of fetus at birth; muscular -Cervix:Selective barrier between uterus & vagina -Vagina:Site of sperm deposition; birth canal
Explain the gonadostat theory as it relates to male puberty.
-Pre-pubertal inhibition of GnRH secretion Immature hypothalamus -Sensitivity of the hypothalamus to negative feedback by testosterone decreases at puberty Initial trigger not known; Kisspeptin neuron activity increases at puberty -Removal of inhibition results in increased GnRH secretion -LH & FSH begin to increase first at night then throughout day as well -Leads to increased testosterone production by testes
Describe the roles of progesterone and estrogen during pregnancy.
-Progesterone: secreted by corpus luteum primes endometrium while embryo develops in oviduct Stimulates endometrial secretions (glycogen) by oviducts & uterus Prepares endometrium for implantation Inhibits uterine contractility (prevents premature labor) Promotes formation of cervical mucus plug Prepares mammary glands for lactation -estrogen: Elevated estradiol stimulates cervix to secrete thin, watery mucus necessary for sperm penetration Ciliary movement draws oocyte into tube (stimulated by estrogen) Estriol (E3) is major estrogen of pregnancy Roles in pregnancy Stimulates myometrial growth Prepares mammary glands for lactation
Explain the mechanisms of action for the 2 main types of IUDs
-Steroid-free IUDs (Copper T) May prevent implantation by producing local inflammatory response in endometrium Copper produces inflammatory response which inhibits sperm motility (white blood cells kill sperm) -Progestin-containing IUDs (Mirena [levonorgestrel]) Inflammatory response May suppress ovulation Thicken cervical mucus (prevent sperm penetration) Inhibit motility of oviduct & uterus (delays sperm transport and/or transport of fertilized ovum) Disrupts endometrium
Explain the role of two distinct populations of kisspeptin neurons in negative and positive feedback in females. Include mention of the AVPV, ARC, ERa receptors, GnRH neurons, and GPR54 (Kiss 1R).
-Two populations of Kisspeptin neurons: Anteroventral periventricular nucleus (AVPV): neurons involved in positive feedback (LH surge) by sex steroids, females have 25 times greater Kisspeptin neurons than males Arcuate nucleus (ARC):neurons involved in negative feedback by sex steroids -Kisspeptin neurons express classic ERa receptors -GPR54 - Kisspeptin receptor (Gq-type G protein) on GnRH neurons (GnRH neurons lack classic ERa receptors) -Sex steroids (i.e., E2) regulate Kisspeptin gene expression
Describe the process of oogenesis from oogonia through mature ovum and indicate when and where these events happen in the body.
1 Oogonia (germ cells) in fetal ovary undergo mitotic proliferation 2 By20 weeks gestation some oogonia are surrounded by single layer of follicular cells to form primordial follicle 3 Oogonia within primordial follicles begin first meiotic division and become primary oocytes prior to birth 4 Beginning at birth the pool of primordial follicles gives rise to continuous trickle of developing follicles 5 After puberty, a gonadotropin- independent signal causes a select cohort to initiate growth and development each month 6 Selected primordial follicles grow and develop to become pre-antral (secondary) follicles 7 Developing theca and granulosa cells become capable of estrogen synthesis and secretion 8 Mature Graafian follicle bulges from surface of ovary 9 Follicle undergoes changes in preparation for ovulation 10 Endocrine signal triggering ovulation is LH surge which produces three major changes 11 Follicle ruptures and oocyte is ovulated (released into peritoneal cavity)
Distinguish between genetic, gonadal, and phenotypic sex.
1. Genetic sex XY XX 2. Gonadal sex Testes Ovaries 3. Phenotypic sex Male Female
Describe the roles of germ cells in spermatogenesis and androgen synthesis.
1. Germ cells- Spermatogonia -spermatogenesis: Conversion of undifferentiated germ cell (spermatogonium) into specialized, motile sperm (spermatozoa) -andgrogens: FSH stimulates Production of androgen binding protein (ABP) which maintains high testosterone levels in vicinity of developing germ cells (100-fold greater in lumen of seminiferous tubule than in general circulation)
For the protein hormones identify the site of production, hormones that share structural similarity, when the hormones are detectable, and the functions of the hormones.
1. Human chorionic gonadotropin (hCG) Site of production? Syncytiotrophoblast Structural similarity? LH** Glycoprotein family When detectable?~ 6 days after implantation* Peaks at 9-12 weeks Functions? Signals implantation of embryo Prevents luteolysis (maintains corpus luteum) Stimulates luteal production of progesterone Stimulates fetal testosterone production 2. Human chorionic somatomammotropin (hCS) or human placental lactogen (hPL) Site of production? Syncytiotrophoblast Structural similarity? GH & PRL Somatomammotropin family When detectable? After 6th week of pregnancy Functions?Rises progressively in 2nd and 3rd trimester, Stimulates fetal growth, Growth & development of mammary gland, Inhibits maternal glucose uptake to shift glucose toward fetus (anti-insulin effect) 3. Corticotropin releasing hormone (CRH) Site of production? Syncytiotrophoblast Structural similarity? Hypothalamic CRH When detectable? 1st trimester Rises progressively in 2nd and 3rd trimester Functions? Stimulates fetal anterior pituitary ACTH, which in turn stimulates fetal adrenal cortex secretion of cortisol (fetal lung development) and DHEA (placental estrogen production)
Distinguish between and provide examples of mammogenic, lactogenic and inhibitory hormones that prepare the breast during pregnancy
1. Mammogenic hormones (promote cell proliferation) • Estrogen • Growth hormone • Stimulate duct development (growth & branching) and alveolar formation (hypertrophy & hyperplasia) • Inhibits milk secretion 2. Lactogenic hormones (promote milk production) • Prolactin • Human chorionic somatomammotropin (hCS; also hPL) • Induces enzymes for alveolar milk synthesis Inhibitory hormones (inhibit milk secretion) 3. Inhibitory hormones (inhibit milk secretion) • Estrogen • Progesterone
What is 5 a-reductase deficiency?
5 a-reductase deficiency XY genotype -Deficiency in enzyme required for conversion of testosterone to DHT -DHT required for fetal development of external genitalia and prostate -Normal internal genitalia (testes and ducts) -Incomplete masculinization of external genitalia (may appear female or ambiguous at birth) -Increased testosterone production at puberty results in masculinization
Identify 3 protein hormones and 2 steroid hormones that are important in pregnancy.
A. Protein hormones 1. Human chorionic gonadotropin (hCG) 2. Human chorionic somatomammotropin (hCS) or human placental lactogen (hPL) 3. Corticotropin releasing hormone (CRH) B. Steroid hormones 1. Progesterone 2. Estrogen
Discuss recruitment of follicles into the developing cohort.
After puberty, a gonadotropin- independent signal causes a select cohort to initiate growth and development each month • Cohort is ~10-20 follicles in 20Y women and only ~4-5 in 40Y women
Distinguish between primary and secondary amennorhea.
Amenorrhea - failure to have menstrual cycles Primary - absence of menses in woman who has never menstruated • Turner's Syndrome (XO genotype) - ovaries fail to develop (can be detected by high LH & FSH) • Androgen insensitivity (XY genotype) - individuals appear female • Gonadotropin deficiency - e.g., panhypopituitarism or isolated LH and/or FSH deficiency Secondary - cessation of menses in woman who has menstruated previously • Pregnancy • Breastfeeding (high PRL suppresses GnRH &FSH) • Prolactin secreting adenoma • Menopause (follicle depletion) • Extreme exercise or weight loss (role of leptin?) • Stress (suppresses GnRH)
Distinguish between androgen insensitivity, Turner's syndrome and congenital adrenal hyperplasia.
Androgen insensitivity (AI) • Male genotype and development of testes • Complete AI can lead to female phenotype (Woffian ducts do not develop and Mullerian ducts regress) XO (Turner's syndrome) • Female genotype but ovaries do not develop Congenital adrenal hyperplasia (CAH) • Elevated fetal androgen in females with severe CAH causes development of ambiguous external genitalia
What is androgen insensitivity?
Androgen insensitivity (formerly called testicular feminization) XY genotype -Deficiency in androgen receptors on target cells -Defect in gene controlling androgen receptor expression (may be partial or complete) Affects actions of T and DHT -Because SRY is present, gonad becomes testes and Sertoli cells make AMH -Complete androgen insensitivity can lead to female phenotype at birth -Testosterone levels may be normal to high (available for peripheral aromatization to estrogen) -Patient may present with primary amenorrhea (lack of menstrual cycles) in late teens
Identify the anatomical compartments involved in androgen production
Androgen production (testosterone) • Leydig cells of testes (vascularized interstitial cells) Express LH receptors; LH stimulates: Androgen (testosterone, T) production from cholesterol precursor
Describe how the ovulated oocyte is drawn into the oviduct. Discuss roles of enodosalpinx, myosalpinx and perisalpinx.
Arrival of egg in oviduct • Oviducts lined with ciliated cells that beat from fimbria toward uterus • Endosalpinx- Ciliated cells, Secretory cells • Myosalpinx- Muscle • Perisalpinx- Vascularized
Define "assisted reproductive technology".
Assisted reproductive technology (ART) - any procedure where both sperm and oocytes are handled outside body
Distinguish between the 3 types of milk (colostrum, transitional, mature) produced by lactating mothers.
Colostrum (first 5 days post-partum) • Low fat • Low carbohydrate • High protein (includes antibodies) Transitional milk (days 5-10) • Change in composition Mature milk (after day 10) • High fat (mostly triglycerides) • High carbohydrate • Low protein • Minerals and fat-soluble vitamins • Composition dependent on mother's diet and time of feeding episode (watery "fore" milk versus high fat "hind" milk)
Identify 2 non-oral forms of steroidal contraception that contain both estrogen and progestin, 2 forms that contain only progestin, and compare their mechanisms of action to oral contraceptives.
Combination (estrogen + progestin) -Transdermal patch (Ortho Evra) Skin patch containing estrogen + progestin Replaced weekly -Vaginal contraceptive ring (Nuva Ring) Intravaginal delivery of estrogen + progestin Ring is kept in place for 21 days and removed for a 7-day ring-free week Progestin only -Injectible (Depo Provera; medroxyprogesterone acetate) Intramuscular injection every 3 months May suppress ovulation -Implant (Implanon; etonogestrel) One subdermal, flexible implant effective for 3 years May suppress ovulation
Explain why progesterone is administered after egg retrieval and why it must continue until the end of the 1st trimester if the patient is pregnant.
Daily progesterone to support early pregnancy
Explain the clinical use of Pitocin and prostaglandins for delivery induction.
Delivery can be induced with oxytocin (Pitocin) and prostaglandins
Identify the anatomical compartments involved in sperm delivery
Delivery system • Reproductive tract ducts and secretory glands ducts include: Seminiferous tubules Epididymis Vas deferens Ejaculatory ducts Urethra Secretory glands include: Seminal vesicles Prostate Cowper's gland (Bulbourethral gland)
Explain how a woman with Turner syndrome can give birth via egg or embryo donation.
Donor eggs Likelihood of live birth is determined by age of woman who produced the egg (not the birth mother) Egg donors are typically in their 20s Recipient candidates include women who are older, have undergone premature ovarian failure, or have or are carriers of genetic abnormalities
Describe the roles of FSH in follicular development, hormone production, and ovulation.
FSH: stimulates estrogen production and secretion by granulosa cells, stimulates androgen aromatization to estradiol (via Gs receptor), Late in follicular phase, elevated estradiol + FSH stimulates development of LH receptors (preparation for ovulation), Production and secretion of inhibin is stimulated by FSH
Describe the symptoms, causes and potential treatment of dysmenorrhea.
Dysmenorrhea - painful menstrual cramps • Excessive uterine contractions • Overproduction of prostaglandins • Treated with non-steroidal anti-inflammatory drugs (NSAIDS; aspirin or ibuprofin)
Distinguish between and provide examples of galactopoietic and galactokinetic hormones.
Galactopoietic hormones • Act on alveolar epithelial cells to stimulate milk production • PRL • Growth Hormone Galactokinetic hormone • Acts on alveolar myoepithelial cells to produce milk ejection, i.e., milk let-down • OT
Describe ectopic pregnancy, spontaneous abortion (miscarriage), and gestational diabetes.
Ectopic pregnancy • Embryo implants outside uterus (95% in fallopian tube, rarely in abdomen or on cervix); pregnancy cannot continue to birth • Occurs in 1-2% of all conceptions • Characterized by slowly rising hCG & low progesterone • Diagnosed by ultrasound Spontaneous abortion (miscarriage) • Loss of a fetus during pregnancy due to natural causes • Often results from fetal genetic abnormalities, usually unrelated to the mother; may also result from infection, uterine abnormality, hormonal factors, incompetent cervix, or immune responses • Estimated that up to 50% of all fertilized eggs are aborted spontaneously, usually before woman knows she is pregnant • Occurs in ~ 10% of clinically recognized pregnancies (after detection of heartbeat at ~ 6 weeks) • Risk increases with maternal age Gestational diabetes • High blood glucose levels during pregnancy in women who have never had diabetes before • Characterized by maternal insulin resistance and insufficient pancreatic insulin secretion • ~7-10% of all pregnancies (and rising!) • Diagnosed by oral glucose tolerance test at 24-28 weeks • Treated during pregnancy with special meal plans, scheduled physical activity, daily blood glucose testing and insulin injections • Resolves spontaneously with delivery • Although these women are at increased risk for Type 2 diabetes later in life
Describe the mechanisms of action for post-coital contraception ("morning after pill").
Emergency post-coital contraception ("Morning after pill") Effectiveness depends on timing Suppresses LH surge when taken prior to the day before woman's LH surge May blunt, delay or not affect LH surge when taken closer to the woman's LH surge resulting in release of ova resistant to fertilization May interfere with sperm migration Not effective when taken after fertilization has occurred Not effective when taken after implantation has occurred
Identify three roles of the LH surge prior to ovulation.
Endocrine signal triggering ovulation is LH surge which produces three major changes 1. Stimulates follicular prostaglandin production 2. Stimulates differentiation of theca & granulosa cells into luteal cells 3. Reinitiates meiosis of the oocyte -LH surge causes ovulation • Neuroendocrine reflex arc of positive feedback triggered by sustained, elevated estradiol levels Elevated progesterone in luteal phase prevents second LH surge occurs approximately 36 hours prior to ovulation
Describe the symptoms, causes and potential treatment of endometriosis.
Endometriosis - cyclic growth of endometrial cells outside uterus • Endometrial tissue dislodges from uterus and grows in other regions • Can cause inflammation of surrounding tissue and scar tissue formation • Pain related to expansion and contraction of endometrial tissue during menstrual cycle • Can be treated with birth control pills or GnRH agonist (e.g., Lupron)
Identify the major estrogen of pregnancy.
Estriol (E3) is major estrogen of pregnancy
Explain how the production of progesterone and estrogens during pregnancy requires cooperation between the mother, placenta, and two fetal organs. Identify the key enzymes involved (17α-hydroxylase, 16α-hydroxylase, sulfatase and aromatase), where the enzymes are located (fetal adrenal, fetal liver, placenta), and what the substrates and products are for these enzymes.
Estrogen: Requires cooperation between fetus and placenta (fetoplacental unit) Placenta lacks enzymes required for conversion of progesterone to androgens (16 α-hydroxylase-located in maternal and fetal liver & 17 α-hydroxylase-located in mother and fetal adrenal) Fetus lacks enzymes required for conversion of androgens to estrogens (sulfatase and aromatase- both located in the placenta)
Distinguish between the estrogens: estrone, estradiol, and estriol.
Estrogens (subscript refers to number of hydroxyl groups attached to steroid rings): Estrone (E1) • Intermediate potency • Produced by peripheral conversion of adrenal androgens in post-menopausal women Estradiol (E2) • Most potent estrogen • Secreted by granulosa cells of ovary • Principal estrogen in non-pregnant pre menopausal women Estriol (E3) • Least potent estrogen • Produced in large quantities by placenta in pregnant women • Produced in small quantities by liver in non-pregnant women
Define cryptorchidism and explain its consequence.
Failure of testes to descend (cryptorchidism) can lead to infertility if not corrected (irreversible damage to germ cells)
Explain the process of luteolysis and the roles of luteotropins (LH and hCG) and luteolysins.
Fate of corpus luteum (CL) is determined by balance of factors • Luteotropins prolong the life of the CL • LH stimulates CL growth and steroid biosynthesis in non-pregnant women • hCG (human chorionic gonadotropin) released after implantation of embryo stimulates CL growth and steroid biosynthesis in pregnant women • Luteolysins induce luteolysis (degeneration and phagocytosis of luteal cells) • In non-pregnant women the CL functions for 14 days
Distinguish between first, second and third generation combination birth control pills.
First pill marketed for general use in 1960 -Combination pill -150 μg estrogen: Ethinyl estradiol, mestranol (converted to ethinyl estradiol in body), Prevent breakthrough bleeding by stabilizing endometrium -10 mg (10,000 μg) progestin: Norethindrone, Prevent ovulation -Side effects included coronary thrombosis, nausea, dizziness, vomiting, pelvic pain, breast tenderness, and weight gain Second generation pills -< 50 μg estrogen + progestin -Amount of estrogen was lowered to reduce cardiovascular risk -New progestins (e.g., levonorgestrel) with lower androgenic effect were developed to minimize alterations to lipid profile and glucose intolerance Third generation (current) pills -20-30 μg estrogen + 100-3000 μg progestin Newer progestins (norgestimate, desogestrel) Fewer side effects reported
Explain how the placenta is composed of both embryonic (syncytiotrophoblast) and maternal (decidual) tissue.
Formation of the placenta (temporary endocrine tissue) (cont.) -Derived from both embryonic and maternal tissue 1) maternal: Decidua is highly-vascularized, maternally-derived endometrium of pregnancy 2) embryo: Some trophoblasts fuse and penetrate endometrium to form syncytiotrophoblast -Thin barrier (chorionic tissue) separates fetal and maternal blood -Gas exchange (O2, CO2), Nutrients (glucose), Immune barrier -Hormone production -Placenta is major endocrine organ of pregnancy
Describe the constituents and functions of seminal fluid.
Functions • Vehicle for sperm transport • Alkaline pH to buffer acidic pH of vaginal secretions • Prolongs life of sperm Constituents of seminal fluid • From seminal vesicles • Prostaglandins - stimulate contraction of smooth muscle in female reproductive tract to aid movement of sperm • Fructose - primary energy source for sperm • Semenogelins and fibronectin - spontaneous coagulation after ejaculation to form gel matrix • From prostate • Buffers - alkaline pH, promotes viability • Prostate-specific antigen (PSA) - enzyme aids breakdown of gel matrix to release motile sperm (process of liquefaction)
Describe the role of alveolar epithelial and myoepithelial cells in milk synthesis, secretion, and ejection
Galactopoietic hormones • Act on alveolar epithelial cells to stimulate milk production • PRL • Growth Hormone Galactokinetic hormone • Acts on alveolar myoepithelial cells to produce milk ejection, i.e., milk let-down • OT
Describe the hormonal regulation of the menstrual cycle by LH, FSH, estradiol, and progesterone.
Hormonal regulation • Negative feedback of estradiol on LH & FSH in follicular phase • Antral follicles secrete estradiol • Lack of progesterone permits progressive rise of LH • Suppression of FSH secretion by estradiol contributes to atresia of smaller follicles • Positive feedback of estradiol on LH • Rapid rise of estradiol precedes LH surge by 9-24h • Estradiol prepares body for fertilization • LH surge • Converts follicle from estradiol- to progesterone-secreting tissue • Inhibin diminishes FSH surge
Explain the significance of rising levels of circulating oxytocin and uterine oxytocin receptors during labor.
Increased levels of oxytocin clearly regulate and promote labor once it has begun -labor initiation: Stimulates progressive increase in number of uterine oxytocin receptors (increased uterine responsiveness to oxytocin) - Oxytocin & strength of uterine contraction • Plasma oxytocin levels increase from Stage 1 to Stage 2 • Increased number of uterine oxytocin receptors results in stronger contractions during Stage 2
Define infertility.
Infertility - inability to achieve pregnancy after 12 months of unprotected intercourse More than 15% of couples in the United States suffer from infertility Fertility declines significantly after age 35 Cost of infertility treatment often not covered by health insurance
Define intrauterine insemination (IUI).
Intra-uterine insemination (IUI) Washed sperm are placed in uterus by catheter just prior to expected time of ovulation
Define ICSI and indicate when it is appropriate.
Intracytoplasmic sperm injection (ICSI) Originally used when rates of fertilization were expected to be poor (e.g., oligospermia) but technique is now used routinely
What is Klinefelter's syndrome?
Klinefelter's syndrome - most common type of primary hypogonadism (defect is at gonadal level) -XXY genotype -Male phenotype at birth but failure to mature sexually at puberty -At puberty, testes become fibrotic and seminiferous tubules are largely destroyed -Low to low-normal circulating testosterone levels -Elevated LH levels (indicates testicular failure) -High estrogen:androgen ratio can lead to feminization -Treated with androgen replacement
Describe the roles of LH in follicular development, hormone production, and ovulation.
LH: stimulates production and secretion of androgens from cholesterol precursor by theca cells, stimulates androgen production (via Gs receptor), Elevated estradiol induces expression of LH receptors by granulosa cells in preparation for ovulation, Endocrine signal triggering ovulation is LH surge which produces three major changes: 1. Stimulates follicular prostaglandin production 2. Stimulates differentiation of theca & granulosa cells into luteal cells 3. Reinitiates meiosis of the oocyte LH stimulates progesterone (also to a lesser extent estradiol) synthesis and secretion, LH stimulates CL growth and steroid biosynthesis in non-pregnant women, Tonic (basal) LH secretion controls ovarian steroidogenesis, LH surge causes ovulation
Explain lactational amenorrhea.
Lactational amenorrhea • Lack of menstrual cycles during lactation • Suckling and high PRL suppress GnRH release (lactation inhibits LH & FSH secretion) • Can afford some level of contraception (although unreliable) • Duration of effect is highly variable
Describe the roles of leydig cells
Leydig cells (vascularized interstitial cells) • Express LH receptors; LH stimulates: • Androgen (testosterone, T) production from cholesterol precursor Testosterone produced by Leydig cells can diffuse into interstitial space, Sertoli cells (ABP), or systemic circulation • T in systemic circulation carried by sex hormone-binding globulin (SHBG; ~60%) and albumin (~35%) produced by liver; ~2% is free hormone
Describe the causes, consequences, and treatment of a luteal phase defect.
Luteal phase defect - short luteal phase (< 14 days) • Due to; Poor follicle production, Premature demise of corpus luteum, Failure of uterine lining to respond to normal levels of progesterone • Increases risk of recurrent miscarriage • May be treated with progesterone supplementation
Describe hormonal methods of male contraception currently under investigation.
Male hormonal contraception How it works: Inhibits spermatogenesis by suppressing LH & FSH Current studies: Androgen, Androgen + Progestin, Androgen + GnRH antagonist
Explain the mechanisms of action for RU-486 (mifepristpme)/PGE1 (misoprostol).
Medication abortion How it works: RU-486 (mifepristone) is progesterone antagonist (binds tightly to progesterone receptors but doesn't evoke progesterone's normal effects); blocks progesterone action Prostaglandin E1 (PGE1; misoprostol) stimulates uterine contractions and fetal expulsion
Describe the cause and symptoms of menopause, including the hormonal profile of hMG.
Menopause (starts at ~45-55 years) • Cessation of reproductive cycles • Gradual process • Depletion of follicles • Estrogen levels decrease from 300 mg/day to ~20 mg/day • LH & FSH increase (reduced negative feedback by estradiol) • Most symptoms are caused by estradiol deficiency (Chronically elevated LH & FSH *, Vaginal dryness, Hot flashes, Accelerated bone loss, Increased risk of heart disease) -Human menopausal gonadotropin (hMG), purified from urine of post-menopausal women, can be used clinically to treat infertility (LH/FSH stimulate growth of follicles and suppress atresia)
Describe the series of events necessary for normal sexual differentiation for females.
Mullerian Ducts -> Female Reproductive Tract NO testosterone, MIF, or SRY gene
Describe the neuroendocrine reflex pathway involved in the progression of labor.
Neuroendocrine reflex promotes labor • Positive feedback loop • Ultimately, pressure on cervix is relieved by delivery
Describe the possible fates of developing follicles (ovulation versus atresia).
Only about 450 oocytes will be ovulated in a lifetime - More than 99% undergo atresia (degeneration) Beginning at birth the pool of primordial follicles gives rise to continuous trickle of developing follicles • Once a follicle resumes development the oocyte is destined for one of two fates: 1. It will reach maturity and be ovulated 2. It will undergo atresia (degeneration) • Prior to puberty, all developing follicles and the oocytes within them undergo atresia Mature Graafian follicle bulges from surface of ovary • Follicle may be 15-20 mm in diameter shortly before ovulation • Generally only one antral follicle (containing one primary oocyte) will reach this stage of development while all others undergo atresia
Identify the actions of estradiol and progesterone on the ovary, oviduct, uterus, and cervix during the menstrual cycle.
Ovary: LH surge Luteolysis (preparation for next cycle) Oviduct: Growth of ciliated cells Uterus: Proliferation of endometrial lining Increased myometrial contractility Cervix: Thin, watery mucus
Identify two causes of oviduct blockage.
Oviduct blockage • Prevents union of ovum and sperm • May be voluntary (tubal ligation) or due to disease (e.g., endometriosis) • Ovaries continue to ovulate and produce hormones
Explain what is meant by anovulatory cycles and how they can be treated with clomiphene citrate.
Ovulation does not occur • Clomiphene citrate (Clomid) treatment may restore ovulation • Estrogen antagonist • Blocks negative feedback by estradiol • Target is hypothalamus and anterior pituitary • Stimulates LH & FSH secretion • Taken early in follicular phase to stimulate development of follicles • May increase risk of multiple gestation
Identify the hormone detected by ovulation predictor kits
Ovulation predictor kits • LH in urine • two lines indicates LH surge
Describe the three phases of the ovarian cycle (follicular, ovulatory, and luteal) during the menstrual cycle
Phases of ovarian cycle: Follicular (days 1-14; variable) • Cohort of 8-15 primary follicles begins to develop • FSH stimulates development of antral follicles & estradiol • ~ day 6 one follicle becomes dominant while others undergo atresia • Late in follicular phase granulosa cells express LH & FSH receptors Ovulatory (day 14) • LH surge stimulates ovulation of mature follicle within 24-36 h Luteal (days 15-28; must be 14 d) • Corpus luteum forms & then degenerates in non-pregnant women
Describe the three phases of the uterine cycle (menstrual, proliferative, and secretory) during the menstrual cycle.
Phases of uterine cycle: Menstrual • 1st day of menstruation is day 1 • Menses is discharge of blood & endometrial tissue Proliferative • Estradiol stimulates growth of glandular endometrium Secretory • Progesterone simulates secretion of nutrients (glycogen) capable of sustaining embryo
Describe the symptoms, causes and potential treatment of PCOS.
Polycystic ovarian syndrome (PCOS) • Characterized by insulin resistance, ovarian hyperandrogenism, and anovulation • Patients exhibit insulin resistance & hyperinsulinemia • Insulin stimulates high LH:FSH ratio • PCOS often associated with obesity • Multiple small ovarian cysts secrete excess androgen • Hirsutism (dark, thick hair on their face, chest, abdomen and back) • Elevated LH stimulates overproduction of androgen while low FSH slows aromatization • Dietary control, exercise, clomiphene citrate and/or insulin-lowering medication (i.e., metformin) may stimulate ovulation
Distinguish between primordial, pre-antral and antral follicles.
Primordial: By 20 weeks gestation some oogonia are surrounded by single layer of follicular cells to form primordial follicles • Oogonia not incorporated into follicles degenerate prior to birth • Primordial follicles are reservoir from which all oocytes in adult arise Pre-antral: Selected primordial follicles grow and develop to become pre-antral (secondary) follicles • Formation of zona pellucida(mucopolysaccharide layer separating oocyte from granulosa cells) • Proliferation of granulosa cells • Differentiation of cells outside basement membrane into theca cells antral: Developing theca and granulosa cells become capable of estrogen synthesis and secretion • Theca cells express LH receptors and granulosa cells express FSH receptors • Estradiol is secreted by granulosa cells into antrum • Antral follicle growth and development is gonadotropin- dependent
Explain how the hormonal composition and mechanism of action of the mini-pill differs from that of the combination pill and the populations for which the mini-pill is recommended
Progestin only pills (POPs; mini-pill) -Contain no estrogenic compound Mechanism of action for POPs: -Doesn't consistently inhibit ovulation (doesn't always block LH surge) -When ovulation is not suppressed, normal menses occurs -Interferes with sperm transport & implantation -Thickens cervical mucus (prevent sperm penetration) -Inhibits motility of oviduct & uterus (delays sperm transport and/or transport of fertilized ovum) -Disrupts endometrium Who should use POPs? -Breastfeeding mothers (added contraceptive effect of PRL): Estrogen in combination pills can decrease quantity and quality of breast milk, POPs should be initiated after milk supply is established -Women over age 40 (lower fertility and increased cardiovascular risk factor) -Smokers (increased cardiovascular risk factor) -Diabetics with vascular disease -Migraine sufferers (may have increased stroke risk)
Distinguish between the progestogens progesterone and progestin.
Progestogens: Progesterone - Naturally produced by body Progestins - Synthetic
Explain the gonadostat theory as it relates to female puberty.
Puberty (8-12 years) • Nocturnal bursts of GnRH/LH due to decreased sensitivity of hypothalamus to negative feedback (gonadostat theory)
Describe the process of luteinization, the endocrine products of the corpus luteum (progesterone and estradiol), and the regulation of the hormone products.
Remnants of ruptured follicle undergo process of luteinization to form corpus luteum • Remaining theca and granulosa cells differentiate into luteal cells expressing LH receptors • LH stimulates progesterone (also to a lesser extent estradiol) synthesis and secretion • Progesterone (and estradiol) secretion increases as size of corpus luteum increase
Define andropause and explain its cause.
Senescence (Andropause; starts at ~ 45-50 years) Gradual decline in reproductive function (circulating testosterone and sperm production)
Describe the roles of sertoli cells
Sertoli cells ("nurse" cells) 1. Express FSH receptors; FSH stimulates: • Production of androgen binding protein (ABP) - maintains high testosterone levels in vicinity of developing germ cells (100-fold greater in lumen of seminiferous tubule than in general circulation) • Synthesis and secretion of inhibin - member of glycoprotein hormone family; inhibits anterior pituitary gonadotrope secretion of FSH but not LH • Mitosis of spermatogonia • Spermiation 2. Maintain blood-testis barrier - tight junctions between cells 3. Phagocytize abnormal sperm and excess cytoplasm 4. Secrete fluid that nourishes sperm and provides transport medium
Identify the anatomical compartments involved in spermatogenesis
Spermatogenesis (sperm production) • Seminiferous tubules of testes (~50% mass of testis) - Site of sperm production • Germ and Sertoli cells ("nurse" cells) Express FSH receptors
Distinguish between spermatogenesis, spermatocytogenesis, spermiogenesis, and spermiation.
Spermatogenesis - Conversion of undifferentiated germ cell (spermatogonium) into specialized, motile sperm (spermatozoa) spermatocytogenesis- meitotic division and meiosis spermiogenesis- Differentiation & Packaging spermiation- making spermatozoa from spermatids
Explain the importance of placental CRH during pregnancy.
Stimulates fetal anterior pituitary ACTH, which in turn stimulates fetal adrenal cortex secretion of cortisol (fetal lung development) and DHEA (placental estrogen production)
Explain the cellular mechanism of androgen action.
T in systemic circulation carried by a carrier protein (mostly SHBG) Only free T is biologically active -free T enters the cell and 5alpha reductase splits it into DHT and T, then an inactive receptor binds these two and brings them to the nucleus where the receptor is activated which makes the RNA that leads to androgen action
Distinguish between a traditional surrogate and a gestational surrogate.
Traditional surrogate Surrogate is inseminated with sperm from male of infertile couple (no IVF involved); surrogate is genetically related to child Gestational carrier Carries pregnancy created by egg and sperm of two other individuals (requires IVF); gestational carrier is not genetically related to child
Describe the sequence of events for sperm transport, capacitation, fertilization, early embryo development, and implantation. Identify roles of estradiol and progesterone.
Transport of sperm through cervix • Elevated estradiol stimulates cervix to secrete thin, watery mucus necessary for sperm penetration Sperm storage and capacitation (activation) • Final maturation of sperm • Occurs in female reproductive tract • Removal of inhibitory substances in semen (e.g., prostaglandins) • Enhances ability of sperm to fertilize oocyte • Necessary for acrosomal reaction (release of proteases to clear path through zona pellucida) Penetration of oocyte by sperm • Membrane of sperm head fuses with membrane of oocyte • Stimulates completion of meiosis • Causes cortical reaction to block polyspermy • Restores diploid state
Explain the two-cell (theca and granulosa cells), two- gonadotropin (androgen and estrogen) model of follicular steroidogenesis.
Two-cell, two-gonadotropin model of follicular steroidogenesis • LH stimulates production and secretion of androgens from cholesterol precursor by theca cells • FSH stimulates estrogen production and secretion by granulosa cells • Major end product is estradiol Theca cells • Analogous to Leydig cells of testis • LH stimulates androgen production (via Gs receptor) • Lack aromatase Granulosa cells • Analogous to Sertoli cells in seminiferous tubules • FSH stimulates androgen aromatization to estradiol (via Gs receptor) • Lack 17 a-hydroxylase (cannot synthesize androgens from pregnenolone) • Surround and nourish developing germ cell • Late in follicular phase, elevated estradiol + FSH stimulates development of LH receptors (preparation for ovulation)
Identify the hormones involved in uterine involution
Uterine contraction and involution (stage 3 of labor) • Uterus shrinks to pre-pregnancy size • Remaining endometrial tissue disintegrates • 4-6 weeks to complete • Due to rapid decline in estrogen & progesterone • Facilitated by oxytocin release in lactating mothers
Explain why the pill must be taken every day.
You have to take it at the same time every day because the level of the hormone lowers over time
Distinguish between the Yupzee regimen, Plan B and Plan B One step.
Yupzee regimen Two high doses of estrogen + progestin combination pill given 12 h apart (100 mg ethinyl estradiol + 0.5 mg levonorgestral) Associated with nausea and vomiting Plan B Two high doses of progestin-only pill (0.75 mg levonorgestral) given 12 h apart Better tolerated As effective as Yupzee regimen Plan B One Step One very high dose of progestin-only pill (1.5 mg levonorgestral) As effective as Plan B
