Female Reproductive Endocrinology II week 4

Question 1

Explain the hormonal changes that occur (and the cells involved) in the following phases of the reproductive cycle:

Early to mid-follicular phase

mid- to late-follicular phase to ovulation

Early- to mid-luteal phase

Late-luteal phase and menstruation

Answer 1

See attached figure

1. Early to mid-follicular phase (begins with the start of menses)
   a. High tonic levels of LH and FSH drive development of Graafian follicles
   b. Follicles secrete increasing levels of estrogen
   c. Increasing estrogen inhibits release of GnRH and decreases the sensitivity of pituitary to GnRH causing FSH to decrease (negative feedback on LH secreting cells is less strong)
   d. Fall in FSH results in follicle atresia of all but the dominant follicle; the dominant follicle survives because it has a larger number of FSH receptors
2. Mid- to late-follicular phase to ovulation
   a. When the circulating level of estrogen reaches a high enough level for long enough (about two days), estrogen produces a positive feedback on the hypothalamus and the pituitary that causes a surge in LH (large) and FSH (smaller)
   b. This effect can be seen in a set of measurements made 3 days before the LH surge to 2 ½ days after the surge; the LH surge is driven by the increase in estrogen production that occurs from -72 hours to -24 hours.
   b. The LH surge triggers ovulation
3. Early- to mid-luteal phase
   a. The corpus luteum produces increasing amounts of progesterone, estrogen and inhibin
   b. This produces a powerful negative feedback of the hypothalamic-pituitary-ovary axis and “shuts down” hormone secretion
4. Late-luteal phase and menstruation
   a. If pregnancy does not result, the corpus luteum spontaneously degenerates after about 12 days and secretion of progesterone and estrogen decreases
   b. Negative feedback on hypothalamus-pituitary decreases, GnRH secretion increases as does the secretion of LH and FSH
   c. The next cycle thus begins. Multiple follicles are recruited due to the increased levels of FSH.

Question 2

What are the effects of estrogen on the hypothalmus and pituitary during the LH surge?

Answer 2

1. sensitizes anterior pituitary to GnRH
2. stimulates hypothalamus neurons to increased release of GnRH

Question 3

Hormonal changes during the ovarian cycle affect all elements of the femal reproductive tract.

What are the effects of estrogen and progesterone on the following parts of the female reproductive tract?

oviducts

uterus

cervix

vagina

Answer 3

3. Effects of estrogen and progesterone on reproductive tract
   a. Hormonal changes during the ovarian cycle affect all elements of the female reproductive tract
   b. The oviduct (site of fertilization of ovum)
   i. Estrogen is necessary for maintaining cilia, secretory epithelium, and muscular contraction
   ii. Progesterone has effects that are opposite of those of estrogen (increases secretions, decreases contractility-see attached figure)
   c. Uterus
   i. Estrogen is necessary for maintaining the uterus and its blood supply
   - Myometrium increases contractility and excitability and its level of spontaneous activity increases
   - Endometrial stromal size increases due to cell proliferation and edema
   - Increased number and size of glandular invaginations
   - Induces synthesis of intracellular receptors for progesterone in the endometrium
   ii. Progesterone effects on the uterus include:
   - Further increase in stromal size
   - Stimulates synthesis of thick secretions rich in glycoproteins, sugars and amino acids
   - enlargement of myometrial cells but decreases the excitability of uterine musculature
   iii. At the end of the luteal phase and the spontaneous break down of the corpus luteum, estrogen and progesterone production falls. The endometrium, which had been prepared for implantation of a fertilized ovum, responds to the fall in hormone levels by shedding its surface layer. Menstruation ensues.
   d. Cervix
   i. Exposure to estrogen during the follicular phase leads to:
   - Increased vascularization and edema
   - Relaxation of the musculature
   - Epithelium secretes more glycoproteins (mucus is stretchy, clear and thin; facilitates sperm penetration)
   ii. Exposure to progesterone during luteal phase leads to:
   - Reduced secretions
   - Thick, less stretchy mucus that forms what amounts to a plug
   - More active musculature, making cervix firmer
   e. Vagina
   i. Exposure to estrogen causes:
   - Increased mitotic activity of surface epithelium with tendency to keratinize
   - Changes in vaginal fluids

Question 4

What are the effects of estrogen on the following systems/processes?

bone

liver

electrolyte balance

thyroid fxn

Answer 4

Estrogen (E) has widespread effects on many physiological systems and functions:

Bone

• E inhibits PTH-mediated bone resorption (protects against osteoporosis)
• E triggers growth spurt (long bones) and fusion of epiphyseal plates (cessation of growth)
• E facilitates effects of PTH on kidney resulting in greater production of active form of vitamin D (and hence increased absorption of calcium in the GI tract) Liver
• E increases the production of plasma proteins involved in the transportation of hormones
• E increases HDL and VLDL and increases triglycerides
• E lowers cholesterol and LDL (lack of estrogen thus makes vascular disease more likely)

Electrolyte balance

• E stimulates formation of angiotensinogen and aldosterone
• E enhances reabsorption of Na in the kidney

Thyroid function

-E sensitizes thyrotrophes in pituitary to TRH and exaggerates TSH secretion

Question 5

Explain the mechanism for the initiation of menstruation.

Answer 5

Question 6

Combination oral contraceptives contain a combo of synthetic estrogen and synthetic progesterone.

What are the effects of these hormones in inhibiting pregnancy?

Answer 6

Combination oral contraceptives

1. Contain a combination of synthetic estrogen and synthetic progesterone
2. Prevents ovulation by inhibiting gonadotropin secretion
   a. Estrogen prevents FSH secretion, thus inhibiting the selection and development of a dominant follicle
   b. Progesterone prevents the LH surge, thus preventing ovulation
3. Other effects of estrogen include
   a. endometrial stabilization (less breakthrough bleeding)
   b. increased number of intracellular progesterone receptors (potentiating the effects of progesterone)
4. Other effects of progesterone
   a. decidualization of the endometrium (making it “hostile” to implantation
   b. thickening cervical mucus (more difficult for sperm to penetrate)
   c. ovum transport slowed and/or fallopian tube secretions altered
5. Taken for three weeks and then withdrawn for one week.
6. When used “perfectly” the failure rate is 0.1% (one woman in 1000 will become pregnant during the first year of use). The typical failure rate in the US is 3%.

Question 7

What are the effects of progestin-only pills in decreasing risk of pregnancy?

Answer 7

Progestin-only pills

1. Contain synthetic progesterone compounds
2. Thickens cervical mucus
3. Alters endometrium to inhibit implantation
4. Inhibits ovulation
5. Must be taken daily (no pill-free period) at 24 hour intervals
6. Perfect use failure rate is 0.5%, but typical failure rate ranges from 1.1% to 13.2%

Question 8

What is menopause? What occurs during menopause?

When does menopuase typically occur?

Answer 8

A. Is the permanent cessation of menstrual cycling

B. Typically occurs between 45-55 years of age (range 35-65)

C. Menopause is the result of ovarian failure

1. The responsiveness of follicles to LH and FSH is reduced
2. Follicles produce less estrogen
3. Fewer follicles ovulate, so less progesterone is produced
4. Negative feedback of estrogen on pituitary decreases and hence LH and FSH levels increase
5. The adrenal cortex becomes the major producers of the sex steroids in post-menopausal women

Question 9

What are the consequences of menopause?

Answer 9

Consequences are:

1. Vaginal dryness and thinning of vaginal wall
2. Breast tenderness
3. Loss of muscle tone and strength
4. Decreasing bone density (brittle bones) and increased risk of osteoporosis
5. Increased risk of CV disease/heart attack