Gonadal Hormones II Flashcards
Hormonal Profiles in the Menstrual Cycle
Synthesis of Estrogens
- In premenopausal women the most important natural estrogen secreted is estradiol produced by the ovary
- Estradiol is formed from testosterone or androstenedione precursors in the ovaries (follicular granulosa cells and theca cells) by aromatase
- Estrone and estriol are synthesized from estradiol largely by the liver, plus some peripheral conversion of androgens by aromatase in other tissues - In postmenopausal women
- Adipose tissue produces estrogen
- Adrenals produce estrone from DHEA (dehydroepiandrosterone) - Synthetic estrogens commonly used ethinyl estradiol, and diethylstilbesterol
- In men, most estrogens occurs from extra-gonadal conversion of testosterone, DHEA and androstenedione
Synthesis: Estrogens and Progesterone
Synthesis: Progestins
- In women the most important natural progestin produced and secreted is progesterone
- Produced in the ovaries and adrenals, as well as placenta during pregnancy
- Serves as a precursor for estrogens, androgens and adrenocorticoids - Synthetic progestins commonly used include:
- L-norgestrel
- Norethindrone
- Medroxyprogesterone - Progestins are produced by the testes in men
Androgen, Estrogen and Progesterone Synthesis (image)
Actions and Effects: Estrogens and Progestins
- Circulating estrogen bind to SHBG while progestins bind to CBG; some binding to albumin; ~1-2% free
- Hormone effects by estrogen and progestins are mediated by nuclear receptor events resulting in protein synthesis and responses in target tissues
- Two Estrogen Receptors: ⍺-estrogen and β-estrogen receptors
- Normal sexual maturation
- Female secondary sex characteristics
- Breasts, reproductive tract
- Behaviour, sense of well-being - Ovulatory (menstrual cycle) and control of parturition (birth)
- Development of the endometrial lining - Bone turnover and density; reduce resorption
- Adipocyte deposition and blood coagulation
- Growth; puberty spurt in stature and development and growth plate (epiphysis) closure
Actions and Effects: Progesterone
- Modulation of CHO metabolism
- Control of pregnancy; suppression of ovulation
- Adipocyte deposition
- Sexual maturation; breasts, reproductive tract
- Behaviour, mood
What are the 4 Clinical Applications – Estrogens and Progestins and gonadal inhibitors
- Fertility control (use in fertile women)
- Hormone Replacement Therapy
- Ovulation Induction (infertile women)
- Cancer Chemotherapy and Other Uses
Clinical Applications – Estrogens and Progestins and gonadal inhibitors
1. Fertility Control (use in fertile women)
- Oral contraceptives can convey health benefits that are unrelated to contraception
- Reduced risk of some cancers: ovarian, endometrial
- Reduced risk of ovarian cysts
- Lower incidence of ectopic pregnancy
- Amelioration of acne, hirsutism, endometriosis - Two categories of oral contraceptives exist:
- Combination of oral estrogens/progestins
- Continuous therapy with progestins only
Clinical Applications - Fertility control combined oral contraception
Combined oral contraception - most common use of administered estrogens/progestins
- Combination of synthetic estrogen (ethinylestradiol) with 1 of 9 progestins (L-norgestrel, norethindrone)
- Most common regimen consists of a 21-day cycle of steroids followed by 7 days of none
- Mono, bi, tri-phasic combinations: vary [progestin]
- Combination contraceptives prevent pregnancy
- Gonadotropin suppression inhibiting ovulation by estrogen and progestin feedback inhibition on hypothalamic-pituitary axis; FSH and LH
- Thicken cervical mucus (inhibit sperm penetration) and reduce motility in tubes
- Progestins also protect endometrium
- Risk of pregnancy is substantially increased if 2 or more doses are missed; need compliance!
Clinical Applications - Fertility control progestin-only contraceptive “mini pill”
Progestin-only contraceptive “mini pill”
- Developed to avert the adverse effects of estrogens in combination preparations
- Slightly higher failure rate
- Higher incidence of menstrual disturbances (e.g. irregular bleeding, amenorrhea)
- Progestin-only preparation is taken daily; contains either norgestrel or norethindrone
- Androgenic effects possible
Alternatives to “daily pill” available:
- Norplant-2; L-norgestrel silastic capsules; placed SC in arm; lasts up to 5 years
- Medroxyprogesterone (Depo-Provera); IM depot injection of crystals every 3 months
- Progesterone intrauterine devices (IUD); Low dose delivered continuously locally
Post-coital contraception
- Large doses of estrogens alone or with progestins can prevent pregnancy after unprotected intercourse
- Must be taken within 72 hours of intercourse → makes the endometrium unreceptive to blastocyst for implantation
- Mifepristone: potent antiprogestin
- Blocks progesterone’s actions on endometrium necessary for implantation; endometrial shedding and luteolysis ensue
- Usually given with PGE analogue to increase efficacy
Clinical Applications – Estrogens and Progestins and gonadal inhibitors
2. Hormone Replacement Therapy
- Hormone Replacement Therapy
Congenital primary hypogonadism
- Failure of ovary development; infertile usually
- Treatment is usually begun around puberty at 11-13 years of age; mimic physiology of puberty
- Low dose of estrogen (days 1-21 of each month)
- Add progestin at initial uterine bleeding
- Adult maintenance dose of both
Menopause (and surgical removal of ovaries)
- Natural ovarian failure or surgery result in decreases estrogen and progesterone and various physiologic and psychologic changes
- Reduction in genitalia size (atrophy)
- Depression, loss of libido, lack of energy
- Hot flashes – vasomotor spasm
- Loss of bone density; osteoporosis; fractures
- Cardiovascular disease-atherosclerosis
Estrogens plus progestins are used based on symptoms and patient needs
Progestins antagonize estrogen stimulated endometrial growth
Clinical Applications – Estrogens and Progestins and gonadal inhibitors
3. Ovulation Induction (infertile women)
- Ovulation Induction (infertile women)
- 20-30% of infertility due to anovulatory conditions
- Several classes of agents used as therapy:
- GnRH analogues → if there is a functional pit/ovary
- FSH/LH → if there is a functional ovary
- Clomiphene citrate: a partial estrogen receptor agonist
- Assumes functional hypo/pituitary and ovary
- Used to inhibit negative feed back inhibition by estrogen of hypothalamus-pituitary-gonad axis
- FSH levels increase enhancing follicular recruitment
- Single ovulation occurs with a single course of therapy
- Normal ovulatory function likely not return
- Repeat until pregnant as normal
Clinical Applications – Estrogens and Progestins and gonadal inhibitors
4. Cancer Chemotherapy - and other uses
- Advanced prostate cancer: Diethylstilbesterol (very powerful synthetic estrogen)
- Selective estrogen receptor modulators (SERMs)
- Tamoxifen
- Used in the treatment of early and advanced breast cancer in women of all ages
- Acts as an estrogen receptor antagonist in breast cancer (ER positive) - Estrogen synthesis inhibitors
- Anastrozole – Exemestane – Letrozole
- Aromatase enzyme inhibitors
- Can be used alone or with tamoxifen for the treatment of breast cancer
Adverse effects of estrogen and progestins
Mild Effects:
- Nausea
- Headaches
- Endocrine changes
Moderate Effects:
- Weight gain
- Vaginal and uterine tract infections due to reduced mucus
- Breakthrough bleeding
- Depression
Severe Effects:
- Hepatic dysfunction and dyslipidemias
- Breast cancer
- Thromboembolic disease due to increased coagulation activity
- Myocardial infarctions and atherosclerosis
- Hypertension and cerebrovascular disease
