7.8. Female sexual endocrinology.

Question 1

I. Anatomy of female gonads (just take a look)
1. What are the features of female gonads?

Answer 1

• The female gonads are the ovaries, and these are connected to the uterus via the fallopian tubes.
• In the ovary there is a cortex, medulla, and hilum.

Question 2

I. Anatomy of female gonads (just take a look)
2. What are the structures in female ovary?

Answer 2

• In the ovary there is a cortex, medulla, and hilum.

Question 3

I. Anatomy of female gonads (just take a look)
3. What is the cortex of ovary lined with? What is the function?

Answer 3

• The cortex is lined with germinal epithelium and the female’s oocytes – each egg within its own follicle.
• The dominant follicle is the site of steroid hormone synthesis, which can be paracrine or endocrine in function.
  => Both functions act to support the ova development and potential fertilization, as well as acting on tissues such as the breasts, uterus, and bones (increases OPG activity => resulting in bone formation)

Question 4

II. Cyclic reproductive function – menstrual cycle
1. What are the main features of Cyclic reproductive function – menstrual cycle?

Answer 4

Question 5

II. Cyclic reproductive function – menstrual cycle
2A. What are the phases of ovarian cycle?

Answer 5

I – Follicular phase
- Development of follicles stimulated by FSH
- Rise in ovarian [estradiol] triggers a LH surge, which causes ovulation
- Duration is quite variable (~14 days)

II – Luteal phase
- Follicle transforms into a corpus luteum
- Length of this phase is constant = 14 days
- w/o pregnancy, the corpus luteum dies -> menses

Question 6

II. Cyclic reproductive function – menstrual cycle
2B. What happen in follicular phase of ovarian cycle?

Answer 6

• Development of follicles stimulated by FSH
• Rise in ovarian [estradiol] triggers a LH surge, which causes ovulation
• Duration is quite variable (~14 days)

Question 7

II. Cyclic reproductive function – menstrual cycle
2C. What happen in Luteal phase of ovarian cycle?

Answer 7

• Follicle transforms into a corpus luteum
• Length of this phase is constant = 14 days
• w/o pregnancy, the corpus luteum dies -> menses

Question 8

II. Cyclic reproductive function – menstrual cycle
3A. What are 3 phases of endometrial cycle?

Answer 8

I – Menses
II – Proliferative phase
III – Secretory phase

Question 9

II. Cyclic reproductive function – menstrual cycle
3B. In endometrial cycle,
what happen in I – Menses?

Answer 9

• 2 to 6 days
• Marked by menstrual bleeding
  => decline of estrogen and progesterone levels; the endometrial functional layer will be destroyed

Question 10

II. Cyclic reproductive function – menstrual cycle
3C. In endometrial cycle,
what happen in II – Proliferative phase?

Answer 10

• Endometrium proliferates thanks to progesterone

Question 11

II. Cyclic reproductive function – menstrual cycle
3D. In endometrial cycle,
what happen in III – Secretory phase?

Answer 11

• Stroma cells of endometrium enlarge and become more eosinophilic – necessary during pregnancy

Question 12

III. Ovarian hormone synthesis
1. What happen during Ovarian hormone synthesis?

Answer 12

Question 13

III. Ovarian hormone synthesis
2. How is free cholesterol transferred into the mitochondrial matrix?

Answer 13

• Free cholesterol is transferred into the mitochondrial matrix in a steroidogenic acute regulatory (StAR) protein dependent manner

Question 14

III. Ovarian hormone synthesis
3. What happen during Androgen production in the ovary?

Answer 14

Question 15

IV. Regulation of Ovarian hormone synthesis
1. What happen in Regulation of Ovarian hormone synthesis?

Answer 15

Question 16

IV. Regulation of Ovarian hormone synthesis
2. What is the first important hormone produced in Regulation of Ovarian hormone synthesis?

Answer 16

• Neurons in the arcuate nucleus and the pre-optic area of the HT secrete GnRH

Question 17

IV. Regulation of Ovarian hormone synthesis
3. What is the molecular mechanism of GnRH?

Answer 17

• GnRH binds to Gq-coupled receptors on the gonadotroph membrane, which cause the release of the gonadotropic cells (LH + FSH)

Question 18

IV. Regulation of Ovarian hormone synthesis
4. What is the role of gonadotropic
cells (LH + FSH)?

Answer 18

• LH binds to receptors (Gs) on theca cells
• FSH binds to receptors (Gs) on granulosa cells
  +) PKA stimulates synthesis of enzymes: activins + inhibins

Question 19

IV. Regulation of Ovarian hormone synthesis
5. The role of activins and inhibins

Answer 19

• FSH binds to receptors (Gs) on granulosa cells
  => PKA stimulates synthesis of enzymes: activins + inhibins
• The activins and inhibins feed back only on FSH production by the anterior pituitary
  +) Activin = positive feedback, inhibin = negative feedback

Question 20

IV. Regulation of Ovarian hormone synthesis
6. The role of The estrogens and progestins in hormone synthesis regulation

Answer 20

Question 21

IV. Regulation of Ovarian hormone synthesis
7. What is the consequence of High level of estradiol (during the late follicular phase)

Answer 21

High level of estradiol (during the late follicular phase) enhances the sensitivity of gonadotrophs to GnRH

Question 22

IV. Regulation of Ovarian hormone synthesis
8. What are the hormones regulate LH + FSH production?

Answer 22

CRH, β-endorphin, PRL and leptin/ghrelin regulate LH + FSH production

Question 23

IV. Regulation of Ovarian hormone synthesis
9. Make a schematic diagram of Regulation of Ovarian hormone synthesis

Answer 23

Question 24

V. Regulation of gonadotropin synthesis
1. What happen in Regulation of gonadotropin synthesis?

Answer 24

Question 25

V. Regulation of gonadotropin synthesis 2. What happen after Binding of GnRH to the receptor?

Answer 25

Binding of GnRH to the receptor on the gonadotrophic membrane activates the PLC pathway: Gq -> ↑PLC -> IP3 -> ↑[Ca2+]IC => LH + FSH release

Question 26

V. Regulation of gonadotropin synthesis 3. What is the role of PKC in Regulation of gonadotropin synthesis?

Answer 26

- PKC stimulates gene transcription and synthesis of gonadotropins (LH + FSH) by phosphorylation

Question 27

V. Regulation of gonadotropin synthesis 4. What is the role of estradiol In the late follicular phase?

Answer 27

In the late follicular phase, estradiol enhances the GnRH sensitivity in the anterior pituitary, which causes a much larger release of LH

Question 28

VI. Oocyte maturation 1. What are the events in Oocyte maturation?

Answer 28

Question 29

VI. Oocyte maturation 2. What does Primordial germ develop into?

Answer 29

Primordial germ cells develop into oogonia -> oogonia undergo mitotic divisions -> some enter meiosis 1 and become primary oocytes (- Meiosis 1 arrest at prophase 1 (initially, this arrest is caused by the lack of proteins required for meiosis 1 to occur – later, higher levels of cAMP maintains arrest))

Question 30

VI. Oocyte maturation 3. How does Primordial follicles form?

Answer 30

Primordial follicles form when primary oocytes are surrounded by pre-granulosa cells

Question 31

VI. Oocyte maturation 4. What happen when Primary follicles form?

Answer 31

Primary follicles form granulosa cells (cuboidal) - Zona pellucida formscontains ZP1, 2, 3 (proteins) - Number of FSH receptors on the granulosa cells increase

Question 32

VI. Oocyte maturation 5. What happen when secondary follicles form?

Answer 32

Question 33

VI. Oocyte maturation 6. What happen when Tertiary (antral) follicles form?

Answer 33

antrum develops within (fluid-filled space)

Question 34

VI. Oocyte maturation 7. What are the 3 types of Granulosa cells of the tertiary and Graafian follicle?

Answer 34

1. Mural granulosa cells: - farthest away from oocyte, most metabolically active, large quantities of LH receptors 2. Cumulus granulosa cells (cumulus oophorus): - innermost = corona radiata, shed with oocyte upon ovulation 3. Antral granulosa cells: - faces the antrum, after ovulation they become luteal cells

Question 35

VI. Oocyte maturation 7B. What are the features of Mural granulosa cells

Answer 35

farthest away from oocyte, most metabolically active, large quantities of LH receptors

Question 36

VI. Oocyte maturation 7C. What are the features of Cumulus granulosa cells?

Answer 36

Cumulus granulosa cells (cumulus oophorus): innermost = corona radiata, shed with oocyte upon ovulation

Question 37

VI. Oocyte maturation 7C. What are the features of Antral granulosa cells?

Answer 37

faces the antrum, after ovulation they become luteal cells

Question 38

VI. Oocyte maturation 8. A few hours before ovulation, what happen to primary oocyte? What is the molecular mechanism?

Answer 38

Question 39

VI. Oocyte maturation 9. A few hours before ovulation, primary oocyte completes meiosis 1 due to LH surge => Make a schematic diagram to demonstrate this

Answer 39

A few hours before ovulation, primary oocyte completes meiosis 1 due to LH surge - LH surge inhibits inhibitory effects of the cGMP on the PDE (disinhibition) -> ↓cAMP -> meiotic resumption - MAPK pathway proteins arrest meiosis at metaphase 2meiosis 2 completed upon fertilization

Question 40

VI. Oocyte maturation 10. What is dominant follicle?

Answer 40

The one that has the most FSH receptors remaining = dominant follicle

Question 41

VII. Steroidogenesis in the dominant follicle 1. What are the 2 types of cells participating in Steroidogenesis in the dominant follicle?

Answer 41

1. Theca cells 2. Mural granulosa cells

Question 42

VII. Steroidogenesis in the dominant follicle 2A. What are the features of theca cells?

Answer 42

Question 43

VII. Steroidogenesis in the dominant follicle 2B. What are the effects of LH on theca cells?

Answer 43

Question 44

VII. Steroidogenesis in the dominant follicle 3. What are the featues of mural granulosa cells

Answer 44

Question 45

VIII. Ovulation 1. What are the 5 steps of ovulation?

Answer 45

Question 46

VIII. Ovulation 2. What happen prior to ovulation?

Answer 46

Prior to ovulation, the large pre-ovulatory follicle presses against the ovarian surface and generates a stigma ( a poorly vascularized bulge)

Question 47

VIII. Ovulation 3. What is the consequence of LH surge?

Answer 47

LH surge induces release of inflammatory cytokines and hydrolytic enzymes from theca + granulosa cells => these enzymes break down the follicle wall, tunica albuginea and surface epithelium

Question 48

IX. Corpus luteum 1. What happen after ovulation?

Answer 48

Question 49

IX. Corpus luteum 2. What is Regression of corpus luteum involved?

Answer 49

- Regression of corpus luteum appears to involve release of prostaglandin (PGF2α) from both the lutein cells and the uterus

Question 50

IX. Corpus luteum 3. What will Corpus luteum turn into?

Answer 50

- Corpus luteum ultimately turns into corpus albicans (scar), and it is later absorbed => If pregnancy occurs, hCG is released by syncytiotrophoblasts and maintains corpus luteum

Question 51

IX. Corpus luteum 4A. What happen during Steroidogenesis in the corpus luteum?

Answer 51

Question 52

IX. Corpus luteum 4B. What is the role of Theca lutein cells?

Answer 52

Uptake of cholesterol and induce production of androstenedione => will diffuse into the granulosa cell and produce estradiol-17β

Question 53

IX. Corpus luteum 4C. What is the role of Granulosa lutein cells?

Answer 53

Uptake of cholesterol -> pregnenolone -> progesterone (LH signal) + estradiol

Question 54

X. Ovarian cycle - Follicular phase 1. What happen at the end of luteal phase?

Answer 54

Question 55

X. Ovarian cycle - Follicular phase 2A. What happen at the Start of follicular phase?

Answer 55

Question 56

X. Ovarian cycle - Follicular phase 2B. At the start of Follicular phase, what will FSH do?

Answer 56

- FSH will recruit preantral follicles => 20 antral follicles are recruited

Question 57

X. Ovarian cycle - Follicular phase 2C. At the start of Follicular phase, what is the fate of follicles?

Answer 57

- Follicles will mature into dominant follicles and produce more estrogen (granulosa cells) => [estradiol] is below 200pg/mL = threshold (+)-feedback of LH + FSH

Question 58

X. Ovarian cycle - Follicular phase 2D. At the start of Follicular phase, what is the role of Estradiol + inhibin?

Answer 58

Estradiol + inhibin will have an inhibitory effect on FSH production - Only those follicles will keep developing, which express enough FSH receptors - Only 1 dominant follicle will be selected Will produce a huge amount of estradiol (peak) and inhibin ( => FSH production↓)

Question 59

X. Ovarian cycle - Follicular phase 2E. At the start of Follicular phase, what happen When estradiol production exceeds 200pg/mL?

Answer 59

- When estradiol production exceeds 200pg/mL, it will indue (+)-feedback for LH production (+ a little bit for FSH as well) => rapid ↑ in LH production before ovulation (peak of estradiol is PRIOR to the peak of LH)

Question 60

X. Ovarian cycle 3. What happen during Ovulation?

Answer 60

- Luteinization takes place -> progesterone production↑ + estradiol production↑ -> (+)-feedback to LH production is reduced => ending of LH surge after ovulation

Question 61

X. Ovarian cycle 4A. What happen during luteal phase?

Answer 61

Question 62

X. Ovarian cycle 4B. What will corpus luteum do during luteal phase?

Answer 62

produces high amount of progesterone and estrogen (+ inhibin)

Question 63

XI. Endometrial cycle 1. What happen during Proliferative phase?

Answer 63

Question 64

XI. Endometrial cycle 2. What is the role of estrogen during proliferative phase?

Answer 64

- Proliferation and differentiation of the endometrium stimulated by estrogen secreted by developing follicles -> endometrial glands formed, covered with secretory epithelial cells => Estrogen induces the synthesis of growth factors, which causes the development of components of the endometrium = IGF, TGF, EGF

Question 65

XI. Endometrial cycle 3. What is the consequence of the increase in progestin receptor expression during proliferative phase?

Answer 65

- Myometrium: ↑sensitivity to oxytocin receptor induced by estrogen - Body temperature slightly decreases before ovulation

Question 66

XI. Endometrial cycle 4A. What happen during Secretory phase?

Answer 66

Question 67

XI. Endometrial cycle - Secretory phase 4B. What happen in early secretory phase?

Answer 67

Early secretory phase: development of nucleolar channel system

Question 68

XI. Endometrial cycle - Secretory phase 4C. What happen in Middle-late secretory phase?

Answer 68

- Pre-decidualization: enlargement of stromal cells - ↑ vascularization of the endometrium - ↑ secretory capacity of the endometrial glands - Functional layer of the endometrium form => Zona compacta: upper (less glandular) layer => Zona spongiosa: lower (more glandular) layer

Question 69

XI. Endometrial cycle 5A. What happen during menstrual phase?

Answer 69

Question 70

XI. Endometrial cycle 5B. What do cells produce during menstrual phase?

Answer 70

- Cells start to produce PGF2α and matrix metalloproteases

Question 71

XII. Effects of estrogen 1. What are the 6 effects of estrogen?

Answer 71

1. Bone formation 2. Liver 3. Cardiovascular 4. Integument (skin) 5. Adipose tissue 6. CNS

Question 72

XII. Effects of estrogen 2. What is the effect of estrogen on Bone formation?

Answer 72

- Promotes the survival of osteoblasts, apoptosis of osteoclasts, closure of epiphyseal plate - Calciotropic, intestinal absorption of Ca2+

Question 73

XII. Effects of estrogen 3. What is the effect of estrogen on Liver?

Answer 73

- LDL receptor↑ - Circulating HDL↑ - CBG, TBG, SHBG↑

Question 74

XII. Effects of estrogen 4. What is the effect of estrogen on Cardiovascular?

Answer 74

Question 75

XII. Effects of estrogen 5. What is the effect of estrogen on Integument (skin)?

Answer 75

- Proliferation of keratinocytes - Collagen synthesis (with progesterone, by inhibiting matrix metalloproteinases) - Glycosaminoglycan – wound healing

Question 76

XII. Effects of estrogen 6. What is the effect of estrogen on Adipose tissue?

Answer 76

Adipose tissue: LPL↓, HLP↓ => lipolysis↑ (long-run)

Question 77

XII. Effects of estrogen 7. What is the effect of estrogen on CNS?

Answer 77

neuroprotection

Question 78

XIII. What are the Effects of progesterone?

Answer 78

- Setpoint of thermoregulation (↑body temperature during ovulation) - Pre-menstrual dysphoria (rapid drop in progesterone = mood change) - Sensitize ventilation response to PCO2

Question 79

XIV. Transport and metabolism of estrogen and progesterone 1. How is estrogen transported? (give %)

Answer 79

- Free = 2-3% - Bound: albumin = 60% + SHBG = 38%

Question 80

XIV. Transport and metabolism of estrogen and progesterone 1. How is Progesterone transported? (give %)

Answer 80

- Free = 2-3% - Bound: albumin = 80% + CBG = 18% (corticosteroid binding globulin)

Question 81

XV. Sexual intercourse of the female 1. What is the neural pathway of Sexual intercourse of the female?

Answer 81

Afferentation is through sacral somatosensory fibers

Question 82

XVI. Menopause 1. What is Menopause?

Answer 82

- Termination of reproductive function in women - Menstruation comes to an end (only a few functional follicles remain the ovaries)

Question 83

XVI. Menopause 2. What is the molecular mechanism of menopause?

Answer 83

- ↓estradiol and progesterone production (mood changes) - Lack of (-)-feedback: LH + FSH levels may be higher due to an increased GnRH production

Question 84

XVI. Menopause 3. What are the symptoms of Menopausal syndrome?

Answer 84

Menopausal syndrome: hot flashes, night sweats, mood changes, loss of libido

Question 85

XVI. Menopause 4. What are the physical changes due to menopause?

Answer 85

Physical changes: atrophy of the vaginal epithelium, osteoporosis, ↓vaginal secretions