L12 Female Reproduction Flashcards
What is the principal source of circulating oestrogen in premenopausal women?
Ovaries
What is the main secretory product from the ovaries?
Oestradiol
Examples of ways oestrogens can be produced
- by the ovaries
- from androgens by the actions of aromatase
- from oestrogen conjugates by hydrolysis
What are oestrogens largely responsible for?
pubertal changes in girls and secondary sexual characteristics
How is oestrogen production tightly controlled?
Oestrogen production is under tight neuroendocrine control via the HPO hormone feedback regulation axis
How do oestrogens exert their effects?
By interaction with nuclear receptors: ERα (encoded by ESR1) and ERβ (encoded by ESR2). Oestrogen receptors act as transcription factors - transcriptional regulatory effects.
How do oestrogens have positive effects on bone mass?
Osteoclasts and osteoblasts express both ERα (plays a greater role) and ERβ. They regulate bone remodelling.
Where is progesterone secreted from and when?
Progesterone is secreted by the ovary, mainly from the corpus luteum, during the second half of the menstrual cycle (secretory/luteal phase)
__, acting via its __, stimulates progesterone secretion during the normal cycle.
LH, acting via its GPCR
2 most frequent uses of progestins
- For contraception, either alone or with an oestrogen
- In combination with oestrogen for hormone therapy of postmenopausal women
Effects of progestins on the reproductive system
Progesterone decreases oestrogen-driven endometrial proliferation. This leads to the development of a secretory endometrium. The abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation.
Effect of progesterone on mammary glands
Mammary gland development requires both oestrogen and progesterone. During pregnancy, progesterone acts with oestrogen to bring about proliferation of the acini of mammary glands. Towards the end of pregnancy, the acini fill with secretions and the vasculature of the gland notably increases.
Effect of progesterone on the CNS
Increase in basal body temp of ~0.6℃ mid-cycle (correlating with ovulation)
Metabolic effects of progesterone
- increases basal insulin levels and the rise in insulin after carb ingestion, but it does not normally alter glucose tolerance
- stimulates lipoprotein lipase activity and seems to enhance fat deposition
Example of a more potent progestin that may decrease glucose tolerance
Norgestrel
Naturally occurring progestin
the endogenous steroid hormone progesterone
To which series do 17α-acetoxyprogesterone derivatives belong?
the pregnane series
To which series do 19-nortestosterone derivatives belong?
the estrane series
To which series do Norgestrel and related compounds belong?
the gonane series
What is the most widely used method for contraception?
oral contraceptive pill
2 types of oral contraception
- combination pills
- progestin-only pills
What is the pharmacologic activity of progestins based on?
the progestational activity and bioavailability of each progestin, as well as the dose
Place the following progestins in order of decreasing relative potency:
norgestrel, norethindrone, levonorgestrel
levonorgestrel > norgestrel > norethindrone
What is the active oestrogen component of oral contraceptives?
ethinyl oestradiol
How do pharmacologic doses of progestin inhibit ovulation?
- by suppressing GnRH and possibly inhibiting pituitary release of LH
- impair implantation and produce cervical mucus that retards sperm penetration
How does ethinyl oestradiol work?
- helps prevent the selection of a dominant follicle by suppressing pituitary FSH
- provides stability to the endometrium, decreasing breakthrough bleeding
- upregulates the progesterone receptor and decreases clearance, thereby potentiating the activity of the progestin
Adverse effects of OCP
- up to 12-fold increased risk of cardiovascular events in patients with cardiovascular risk factors e.g. hypertension
- increased risk of cardiovascular events in women >35 and smokers
- 2-3 fold increased risk of DVT & PE (increased clotting factors, activation of platelets, decreased fibrinolytic activity)
- 3-fold increased risk of cervical cancer among HPV carriers with 5-9 years OCP use
What should women taking oral contraceptives be regularly screened for?
- cardiovascular risk factor
- cervical cancer
Contraindications to combination oral contraceptive use
pregnancy, increased thromboembolic risk, smoking & >35, hepatoma, breast/endometrial cancer, uncontrolled HTN, history of cerebrovascular or CVD, undiagnosed vaginal bleeding
Examples of progestin-only pills (‘minipill’)
- Ortho Micronor, Nor-QD
- Ovrette
Type and dose of progestin in Ortho Micronor
0.35mg norethindrone
Type and dose of progestin in Ovrette
0.075mg levonorgestrel
Target population for administration of progestin-only contraception
- women with contraindications to oestrogen
- breastfeeding mothers
- older women
Progestin-only administration results in…
lower steady state levels and a shorter half-life compared with concomitant administration with oestrogen
Major side effect of progestin-only pills
breakthrough bleeding (40-60%)
Besides breakthrough bleeding, what other side effects are associated with progestin-only pills?
acne and persistent ovarian cysts
(risks associated with progestin-only pills are minimal)
Example of a subdermal implant and what is consists of
Norplant is a subdermal implant that consists of 6 capsules providing levonorgestrel
Significance of low concentrations of progestin in subdermal implant
no real effect on FSH
What causes erratic bleeding associated with subdermal implants?
irregular serum peaks (often prolonged) and declines in serum oestrogen levels
By 5 years of using Norplant, >50% of the cycles are ovulatory. However, ovulatory cycles have been associated with…
luteal phase insufficiency
Most common side effect of subdermal implants
menstrual disturbances (40-80%, especially in the first 2 years)
8-fold increased risk of __ is associated with subdermal implant use
ovarian cyst formation
What happens when the supply of eggs in ovaries declines?
Ovulation becomes irregular and the ovarian follicles fail to develop and secrete normal amounts of oestrogen. Low levels of oestrogen result in increased FSH secretion.
Main symptoms of menopause
- vasomotor symptoms (hot flushes) - about 75-85% of women
- osteoporosis
- depression
How is menopause treated?
HRT: oestrogen, progestin, or in combination
Which therapy provides the best treatment for severe vasomotor symptoms, reducing their frequency and severity?
oestrogen therapy
How does oestrogen therapy act?
via the inhibition of bone resorption, to improve both bone mineral density and fracture rate
The effect of cessation of oestrogen therapy for menopause
A rapid and progressive loss of bone mineral content
Examples of SERMs used in the treatment of osteoporosis
Clomiphene, Tamoxifen, Raloxifene, Toremifene, Ospemifene, Baxedoxifene
What is Clomiphene, how does it work and what is it used for?
- SERM
- acts as a weak oestrogen agonist and moderate antagonist
- used to treat PCOS
- prevents oestrogen feedback inhibition of GnRH, thereby increasing FSH & LH
Side effect of Clomiphene
multiple births
What is Tamoxifen and what is it used for?
- SERM
- prodrug that is converted to active metabolites in the liver (i.e. 4-hydroxytamoxifen)
- both estrogenic and anti-estrogenic
- acts as an antagonist at ER in breast tissue (forms an ER complex that recruits corepressors of DNA transcription to inhibit HER2 and breast cancer cell proliferation)
Tamoxifen is associated with an increased risk of…
endometrial cancer (because it can stimulate proliferation of endometrial cells)
What is Toremifene used to treat?
metastatic breast cancer
Clinical indication of Raloxifene
osteoporosis - has strong estrogenic effects on bone and lipid metabolism
What is Ospemifene used to treat?
dyspareunia (painful intercourse)
Clinical indications of Baxedoxifene
used to treat vasomotor symptoms associated with menopause and osteoporosis
Example of an anti-progestin
Mifepristone, a synthetic steroid compound
How does Mifepristone work?
- acts as a progesterone receptor antagonist when progesterone is present (in the absence of progesterone, it acts as a partial agonist)
- competitive antagonist at GC receptor
What is Mifepristone approved for?
medical termination of pregnancy through 49 days of gestation - causes breakdown of the decidua, leading to detachment of the blastocyst from the endometrium
How is Mifepristone administered?
as a single dose, followed by a prostaglandin (e.g. misoprostol) 48 hours later to stimulate uterine contractions
Major adverse effects of Mifepristone
anorexia, nausea, vomiting, abdominal pain, fatigue, heavy uterine bleeding
