Parfenova - Physiology Flashcards
(55 cards)
1
Q
What are the primary and secondary female repro organs?
A
- Primary: ovaries
- Secondary:
1. Fallopian tubes (oviducts)
2. Uterus
3. Cervix
4. Vagina
2
Q
What happens in the ovaries?
A
-
Oogenesis: production of female gametes during
the fetal period - Maturation of oocytes ready for fertilization -> follicle is the site of oocyte development and hormone production
- Ovulation: expulsion of a the mature oocyte (14d)
- Production of the F steroid hormones (estrogen and progesterone) and peptide hormones inhibin and activin
3
Q
Ovarian/menstrual cycle
A
- Cycle of monthly changes in the uterus and ovary: rise and fall of F repro hormones and processes, beginning with menstruation
1. Follicular phase: days 1-14
2. Ovulation: day 14
3. Luteal phase: days 14-28 - Essential part of sexual repro: 1) production of eggs, 2) production of repro hormones, 3) prep of uterus for pregnancy
4
Q
Follicular Phase: stages and cellular involvement
A
- Oocyte maturation: days 1-14
-
Developmental stages:
1. Primordial follicle
2. Primary follicle
3. Preantral/early antral follicles
4. Mature follicle (first meiosis) -
Theca cells: 3-5 cell layers next to basal lamina required for developing follicle and ovulation
1. 1o function hormone production: androgen-producing cells (PROGESTERONE) -
Granulosa cells: cell lining of the ovarian follicle; estrogen, progesterone, inhibin, activin production
1. Proliferate with oocyte maturation
5
Q
How many follicles survive?
A
- About 1 in 10,000
- 99.99% undergo atresia (degenerate)
6
Q
Ovulation phase
A
- Day 14 of the cycle
- Mature secondary oocyte released from the follicle to the ovarian surface (0.12 mm)
7
Q
Luteal phase
A
- Days 14-25 of the cycle -> post-ovulation
- Formation of corpus luteum, with secretion of:
1. Estrogen
2. Progesterone
3. Inhibin, activin - Regression after 10 days if no fertilization occurs (days 25-28 of the cycle)
8
Q
What are the key regulators of the F reproductive cycle?
A
- BRAIN
1. Hypothalamus: GnRH (11 AA peptide)
2. Anterior pituitary: LH and FSH (gonadotropin glycoproteins) - OVARIES: steroid (estrogen and progesterone) and peptide (inhibin and activin) hormones
9
Q
From what are steroid hormones derived?
A
- Cholesterol: low density lipoproteins from the liver are the main provider of cholesterol for steroid hormone synthesis
10
Q
What are the key female sex steroid hormones?
A
- ESTROGENS: all work via the same estrogen receptors, so they can compete
1. 17-beta estradiol/E2 (major estrogen): most potent; ovaries, adrenals, adipose
2. Estrone/E1: weak estrogen that can be an E2 precursor
3. Estriol/E3: E2 metabolite; weakest estrogen - PROGESTERONE
11
Q
How is progesterone produced by the ovaries?
A
- Cellular producers: 1) theca cells, 2) granulosa cells (follicular phase), 3) corpus luteum (major source after ovulation)
-
Key enzyme: cholesterol desmolase (CYP11A1)
1. Localized in theca cells, and regulates rate of synthesis of pregnenelone and progesterone (3-beta not rate-limiting; see attached image) - Regulation: LH (ant pit)
12
Q
How is estrogen produced by the ovaries?
A
- Cellular producers: 1) granulosa cells (follicular phase), 2) corpus luteum (luteal phase)
- Precursors: pregnenelone, progesterone, androgens (androstenedione: can also be converted to estrone/E1 via aromatase)
-
Key enzymes:
1. Theca cells: cholesterol desmolase
2. Granulosa cells: 17-beta hydroxysteroid dehydrogenase (cell-specific localization), aromatase - Regulation: LH and FSH (ant pit)
13
Q
What is the 2-cell gonadotropin concept?
A
- Theca AND granulosa cells both in control of estrogen synthesis
- Cholesterol desmolase in theca cells
- 17-beta hydroxysteroid dehydrogenase and aromatase in granulosa cells
14
Q
What are the functions of the granulosa cells?
A
- Nourish oocyte
- Secrete chemical messengers that influence oocyte and theca cells
- Secrete antral fluid
- Site of action for FSH and estrogen in control of follicle devo during early/middle follicular phases
- Express aromatase, which converts androgen (from theca cells) to estrogen
- Secrete inhibin, which INH FSH secretion via action on ant pit
- Site of action for LH induction of changes in oocyte and follicle culminating in ovulation and formation of corpus luteum
15
Q
Describe the hormone production/variation in the menstrual cycle (image).
A
- All hormones at very low levels at the beginning of the cycle
- Estrogen max during ovulation, stimulating production of LH and FSH by anterior pituitary —> ovulatory surge
-
Progesterone remains low during first 14 days, then picks up during luteal phase
1. Important hormone for pregnancy and implantation (released by corpus luteum)
16
Q
How does the ovary feedback on the brain in the early/middle follicular phases?
A
- FSH and LH stimulate production of estrogen by follicular cells
- Estrogen at low concentrations negatively feeds back on the ant pit, INH LH and FSH secretion
17
Q
How does the ovary influence brain function mid-cycle?
A
- Immediately before ovulation, estrogen at HIGH concentrations, eliciting positive feedback:
1. Hypothalamus: INC GnRH production
2. Ant pit: a) upregulates GnRH receptors and b) INC pituitary gonadotrophs (FSH, LH) - Ovulatory surge: high FSH and LH triggers ovulation of mature oocyte
18
Q
How does the ovary control brain function in the luteal phase?
A
- Progesterone is the major hormone during this phase
- Negative feedback on the ant pit: INH secretion of FSH and LH
19
Q
How is estrogen transported in blood? MOA?
A
- 98% bound, 2% free: goal is estrogen delivery to target organs, and INC stability of estrogen (several hours)
1. Beta globulin (SHBG/SSBG): high affinity binding (45-70%)
2. Albumin: low affinity (30-50%)
3. Non-bound: 2% - Effects:
1. Genomic (long-lasting): ER-alpha, ER-beta (nuclear receptors)
2. Non-genomic (rapid): plasma membrane receptors too
20
Q
What are the reproductive target organs and effects of estrogen in the F?
A
-
Uterus/ovary/breast: stimulates growth
1. Uterus/vagina: maturation
2. Uterus: maintenance of pregnancy - Fallopian tubes: stimulates ciliary activity
- Brain/ant pit: feedback effects on FSH, LH, GnRH, and prolactin; stimulates prolactin secretion
21
Q
What are the effects of estrogen in the bones, liver, heart, and blood vessels?
A
- Bones: regulates growth, preserves bone density, and prevents osteoporosis
- Liver: regulates cholesterol production, DEC LDL cholesterol
- Heart: cardioprotective effects
- Blood vessels: anti-atherosclerotic effects, reduces plaque formation
22
Q
Hormone replacement study conclusions (4)
A
- No effect on the incidence of coronary heart disease
- Reduced the risk of hip fracture
- Estrogen has NOT increased the risk of breast cancer
- A slight increase in the risk of stroke
23
Q
What are the target organs and effects of progesterone in females?
A
- Major source: ovaries and corpus luteum -> INC 1-2 days before ovulation
- Uterus: prep of endometrium for pregnancy, regulates secretory activity during luteal phase, implantation of fertilized ovum, maintenance of pregnancy, DEC spontaneous contractions of the uterus, reduces GnRH, suppresses ovulation
- Breasts: regulates development
- Brain/ant pit: negative feedback effects on FSH, LH secretion
- INC body temperature
24
Q
How does the basal body temp vary during pregnancy? Why?
A
- Estradiol peaks 1-2 days before ovulation, and progesterone INC 1-2 days before ovulation
- Temp INC by 0.5 to 1.0o the day after ovulation
1. Mechanism: progesterone from corpus luteum in luteal phase - Best time for fertilization the 12-24 hours of ovulation -> BEFORE the basal body temp INC
25
Inhibin and activin
- Produced in granulosa cells
- INHIBIN: negative feedback on ant pit, INH FSH secretion -\> reduction of estrogen production
- ACTIVIN: positive feedback on ant pit, stimulating FSH secretion -\> stimulation of estrogen production
26
What is the 1o male sex organ? Functions? Temp?
- TESTES
- _Functions_: 1) hormone production, 2) sperm production
- External location to maintain _lower temp_ (3oC lower than core body temp): _required for sperm production_ (INC temp in testes reduces sperm production/count)
1. Also required for most effective M sex hormone production (in animal studies)
27
What are the key structures/cells in the M gonads?
- SEMINIFEROUS TUBULES (1): sperm production (30 million/day)
- INTERSTITIAL/LEYDIG CELLS (2): testosterone production -\> LH (ant pit) control
- SERTOLI CELLS (3): support/nursing cells -\> FSH (ant pit) and testosterone control
28
What are the functions of the sertoli cells?
- Provide factors needed for devo and protection of sperm; "Nourish” developing sperm
- **Blood-testis barrier**
- Produce **SHBG** for testosterone transport
- Produce **inhibin** (negative feedback to ant pit)
- Produce **estrogens** from testosterone
- Produce growth factors to activate Leydig cells
- Elimination of defective sperm (phagocytosis)
- Secrete **AMH** to regress embryonic female Müllerian ducts
29
What hormones are involved in the control of male reproduction?
- _GnRH_ (hypothalamus): LH & FSH secretion (ant pit)
- _FSH_ (ant pit: transported via blood to testes): stimulates sperm production in Sertoli cells
- _LH_ (ant pit): stimulates testosterone production in Leydig cells
- _Testosterone_ (Leydig cells): stimulates sperm production (with FSH) via action on sertoli cells
1. Secondary sex characteristics in males
2. Negative feedback to anterior pituitary (LH)
- _Inhibin_ (Sertoli cells): (-) feedback to ant pit (FSH)
- NOTE: hormones are measured as part of infertility evaluation (balance important for normal sperm production)
30
What are the key regulators in the biosynthesis of androgens in the M?
- ENZYMES: cholesterol desmolase (CYP11A1), 17-beta hydroxysteroid dehydrogenase
- HORMONES: LH from ant pit upregulates CYP11A1
- TESTOSTERONE PRECURSORS: pregnenelone, progesterone, dehydroepiandrosterone (DHEA), androstenedione
- ACTIVE METABOLITE OF TESTOSTERONE: DHT (dihydrotestosterone)
- Testosterone production: 4-10mg daily
31
Is DHT or testosterone more metabolically active?
DHT
32
How is serum cholesterol related to testosterone and estrogen?
- No correlation b/t cholesterol and testosterone levels in blood
- Cholesterol inversely associated w/the circulating estrogen level in men
1. INC levels of estradiols in statin group
33
When does testosterone production begin/peak in fetal development? What does it do?
- Begins at 8 weeks, and peaks around 12-18 wks gestation
1. Produced by Leydig cells
- Differentiation of fetal GU tract (prostate, seminal vesicles)
- Gender determination
- Masculinization of external genitalia
34
How do testosterone and estradiol production vary with age?
- Levels of all sex steroids drop at birth
- Transient "_mini-puberty_" in early infancy (2-3 mos): some studies suggest this has to do w/brain devo
- Puberty rise: 10-15 y/o
- Max levels at reproductive age: 20-50 y/o
- Reduction w/aging (\>55 years) by up to 50%
1. Testosterone level stays pretty high in old age (about 20-30% reduction from repro age)
2. Estradiol INC in older men
35
What are the testosterone-transporting plasma proteins? Goals?
- 98% bound, 2% free:
1. Beta globulins (SSBG/SHBG): high affinity binding (60%)
2. Albumin: low affinity binding (38%)
3. Bioavailable = albumin-bound + free
- Goals:
1. Testosterone delivery to target organs
2. INC stability of testosterone (several hrs)
36
What are the negative feedback mechanisms of the HPA for control of male hormones?
- Testes: leydig cells (testosterone) and sertoli cells (inhibin)
- Testosterone targets: 1) INH GnRH secretion from the hypothalamus, 2) INH LH secretion from the ant pit
- Inhibin targets: INH FSH secretion from ant pit
37
What are the genomic MOAs of testosterone?
- _Long-term_: INC protein synthesis in androgen-responsive target cells (require several hours)
- _Membrane-permeable_: converted by 5-alpha reductase to DHT
- Binds cytoplasmic receptor protein (AR: androgen receptor), and is transported to the nucleus -\> binds DNA and initiates RNA transcription
38
What are the non-genomic MOAs of testosterone?
- _Fast responses_: androgen-responsive cells
- _Receptor-mediated responses_: T and DHT bind to IC and membrane-bound androgen receptors
- _2nd messenger cascades_:
1. Cyclic nucleotide signaling
2. Protein phosphorylation
3. Lipid mediators
4. IC Ca, etc.
39
What are the effects of T and DHT in the male?
- Testosterone stimulates spermatogenesis (sertoli)
- Maintains func of male genital tract (seminal vesicles - T; prostate - DHT)
- Induces male secondary sex characteristics
- Stimulates protein anabolism, regulates bone growth
- Required for sex drive; may induce aggressive behavior
- Feedback INH of GnRH from hypothalamus (T) and LH secretion from ant pit (T)
40
What are the effects of androgens (T and DHT) on male secondary sex character?
- Opposes action of estrogen on breast growth
- Hair growth (DHT): stimulates pubic, chest & facial hair; baldness: hair recession (DHT)
- Skin: Increases thickness and secretion of sebaceous glands (DHT) -\> can cause acne
- Stimulates muscle growth (T)
- Stimulates bone growth and Ca retention
- Increases basal metabolism
- Increases RBC (stimulates erythropoietin)
- May enhance aggressive behavior
- May fight depression
- Decreases body fat
- May enhance sex drive (T is the hormone of desire for both sexes)
41
How is estrogen produced in the male?
- End product of cholesterol conversion to steroids
- Produced from testosterone by aromatase in liver (80%), testes, muscle, brain, and fat cells
- Small amounts (1/5 of female level)
- Necessary for male fertility during repro age
- Present in seminiferous tubules (control of spermatogenesis)
- Production INC with age, and in obese men
42
What is hyperandrogenism?
- Use of anabolic androgenic steroids: synthetic variants of testosterone (100x HRT doses)
1. _Anabolic_: enhance performance, endurance, and muscle-building
2. _Androgenic_: INC male sex characteristics
- Banned by all major sports association, incl the Olympics since 2004
- 2010 study: 5.9% of students reported use (more common in HS students, boys)
- _Names_: Anavar, Equipoise, Cialis, Deca Durabolin, Winstrol Depot, Dianabol, Anadrol, Sustanon 250, Testosterone Enanthate, Nolvadex, Clenbuterol, and Testosterone Cypionate
43
What are the clinical uses of anabolic steroids?
- Hormone replacement therapy (HRT):
1. Steroid hormone deficiency
2. Delayed puberty
3. Diseases that result in loss of lean muscle mass (cancer, AIDS, etc.)
44
What are some of the complications of anabolic steroid use?
- Reduced spermatogenesis, testicular atrophy
- Breast enlargement possible in men (testosterone is converted by aromatase to estradiol)
- Masculinization in F (voice deepening, facial hair)
- Liver and kidney disease, including cancer
- Heart problems, incl heart attack, HTN
- Neuropsychiatric effects: aggression, mood swings, anxiety, psychotic symptoms, INC or DEC libido, depression, suicidal thoughts
45
Is there a market for testosterone drug therapy? What does the FDA say?
- Yes: millions of prescriptions, and over a billion dollar market
1. Medical use for men with low testosterone due to medical condition, like genetic failure of testicles to produce testosterone, but \>25% of prescriptions w/o blood testing for testosterone level
- FDA in 2014: alert stating that it is investigating the risk of stroke, heart attack, and death in men taking testosterone products
46
How are the actions of T and DHT different (table)?
- DHT is more potent than T
- Bind to the same IC receptor
- Conversion of T to DHT in target tissues (via 5-alpha reductase)
47
5-alpha reductase deficiency: genetics, internal/external gonads, hormones, puberty
- Aka, male pseudohermaphroditism
48
What are 5-alpha reductase INH used for?
- Baldness
- Prostate hyperplasia
- Prostate cancer: DHT is a major hormone controlling prostate growth
- Examples: Avodart, Propecia, Jalyn, Proscar
49
How do most forms of hormonal contraception INH ovulation?
- They act on the pituitary and hypothalamus via _negative feedback_ to INH ovulation
- Examples: OC's with estrogen and progesterone, or depo provera via injection
50
Describe the hormonal regulation of the menstrual cycle.
- **FSH** INC: ripening follicles in the ovary, and sensitizing granulosa cells to LH
- Estrogen starts to rise during proliferative phase: endometrial enrichment and proliferation of glands and stroma
- **LH surge** -\> ovulation -\> LH very sensitive to progesterone, so straight up and straight down
- Corpus luteum granulosa cells luteinized, and start to produce **progesterone**, bringing LH down -\> endometrium luteinized by progesterone (luteal phase)
- If no fertilization, **progesterone and estrogen fall,** and endometrium becomes fragmented, and menstruation occurs
- Day 1 is the first day of the menstrual cycle/menstruation
51
What happens to the endometrium during the luteal phase?
- More glycogen and vascularity to endometrium in preparation for implantation of zygote
52
On what day of the menstrual cycle does bleeding begin?
Day 1
53
How does the histo of the endometrium vary during the menstraul cycle?
- Withdrawal of hormones -\> menstrual phase
- _Proliferative_: endo thickening
- _Secretory_: luteal, progesterone, lots of glands, glycogen, and blood vessels
54
How is the dominant egg selected? What hormones are involved?
- 2 ways by which egg is selected to be dominant
- Oocytes recruited
1. Primordial to primary and secondary influenced by **AMH**
2. 2nd phase **FSH**-dependent, pushing forward the dominant follicle (_inhibin_ and _estradiol_ also involved)
3. 1 dominant follicle selected each month
55
What happens to LH in the late follicular phase and ovulation?
- As dominant follicle is selected, FSH induces LH receptors in granulosa cells
- Surge represents a switch from (-) feedback control of LH secretion by ovarian hormones (estradiol and progesterone) to (+) feedback
- Freq of LH pulses continues to be about one per hour, but amplitude INC dramatically
