Gonadal Steroids, GnRH, and Oxytocin Flashcards
How many carbons do progestins, estrogens, and androgens have?
Progestins - 21 C
Androgens - 19 C
Estrogens - 18 C
What are the three forms of estrogen and where are they present?
- Estrone - menopause
- Estradiol - puberty / most potent form
- Estriol - during pregnancy, prepping for birth
What portion of the estrogen is required for receptor binding?
Phenolic A ring -> phenyl + alcohol
-other phenolic compounds found in plastics and soy beans can also trip this receptor
How do synthetics estrogens differ from normal estradiol?
They are less susceptible to metabolism by the liver, and thus can be taken orally
How are estrogens formed, and where are they made pre-menopausally and post-menopausally? In pregnancy?
Formed via aromatase enzyme, a CYP450, from androstenedione or testosterone
Pre-menopausal: granulosa cells of ovary
Post-menopausal / men: adipose tissue
Pregnancy: placenta
What is the pattern of GnRH release which stimulates FSH / LH secretion at puberty? What is important feedback?
Pulsatile -> continuous activation of GnRH would lead to suppression of FSH / LH release.
Feedback by estrogen inhibits GnRH release and ultimately FSH release, but will cause an LH surge at higher levels (LH surge needed for ovulation)
How does estrogen stimulate menstrual bleeding?
At low doses, causes the proliferation of the endometrium which will shed after withdrawal.
At higher doses, a single dose can induce bleeding
What are the metabolic actions of estrogen? How does this influence cardiovascular risk?
- Salt / water retention at higher doses -> can increase blood pressure / cause edema
- Decreases in LDL and increases in HDL
Overall, consensus is increased CV disease risk
What are the two primary indications for postmenopausal hormone replacement therapy (HRT)?
- High risk of osteoporosis - especially thin, white smokers with a family history (start before bone loss)
- Atrophic vaginitis
Give two other indications for the usage of estrogens?
- Oral contraception
2. Primary hypogonadism - as in ovarian dygenesis or castration
What is estrogen usually given with and why?
A progesterone -> prevents endometrial hyperplasia and increased risk of endometrial cancer associated with monotherapy
In what cycle is estrogen therapy given and why?
It is given 3 weeks on and 1 week off, with progesterone in the 3rd week to allow for bleeding in the week off.
Estrogen therapy is the #1 cause of postmenopausal bleeding, and this is also a confusing symptom of endometrial cancer
Other than hypertension, why might giving estrogen be a major CV disease risk factor? What cancers can it predispose for?
Increases several coagulation factors, and can increase the risk of stroke, heart attacks, and venous thromboembolism
Can predispose for endometrial and breast cancers
How is estrogen therapy contraindicated in?
Estrogen-dependent neoplasms (uterine and breast cancer)
Estrogen treatment during pregnancy (especially first trimester) -> can cause feminization of males
What are the “natural estrogens” in clinical use?
- Estradiol
- Estradiol salts -> for i.m. injection, slow release
- Conjugated estrogens -> slow release injection
What are the synthetic estrogens for clinical use?
- Diethylstilbestrol
- Ethinyl estradiol
Much longer lasting with less first pass metabolism
What position in both estrogens and progestins makes a large difference in biologic activity and liver metabolism?
C17 substitution
What moiety is needed to bind the progesterone receptor?
The ketone moeity in the A ring (rather than alcohol)
What is progesterone secreted in response to?
Synthesized and secreted in response to the LH which induces ovulation, and is maintained by hCG of implanted trophoblast
What are the physiological actions of progesterone?
- Development of secretory endometrium (secretory phase)
- Maintaining pregnancy, suppressing menstruation and uterine contractility
- Mammary gland hyperplasia
- The 1 degree temperature rise just before ovulation
Other than in combination with estrogens for oral contraception / HRT, what are the monotherapy uses of progestins?
- Dysfunctional uterine bleeding
- Severe endometriosis
- Metastatic endometrial carcinoma
What are the current agents of choice for treating dysmenorrhea?
NSAIDs -> thought to be due to uterine production of prostaglandins
What are the four main synthetic progestins?
- Medroxyprogesterone
- Norethindrone
- Norgesterel
- Ethynodiol (conjugated to ethynyl group at C17)
What type of BC pill is no longer given and what is the standard now?
Progestin alone -> too low of efficacy
Standard now is estrogen + progestin combinations
What are the plan B formulations?
- Diethylstilbestrol - think still birth (will cause vaginal carcinoma if ineffective)
- Norgestrel / ethinyl estradiol
- Norgestrel alone
- Mifepristone
All must be used within 72 hours
What are the effects of estrogen and progesterone within the BC pill?
Estrogen - inhibits FSH release (prevents follicle development)
Progesterone - inhibits estrogen-induced LH surge
Both combine to inhibit ovulation
What are the risks associated with birth control?
Same as estrogen alone:
Cardiovascular disorders like more clotting and mild hypertension
Cancer - vaginal, uterine, and breast
What is the mechanism of action of mifepristone? What does this do to adrenal steroidogenesis?
Competitive antagonist of both progesterone and glucocorticoid receptors (very strong)
By blocking adreno-corticoid feedback in the hypothalamus, it results in increased steroidogenesis
What are the pharmacologic actions of mifepristone early and late in the ovarian cycle?
Early - Prevents ovulation by preventing progesterone binding at hypothalamus / pituitary
Late - Blocks uterine maintenance - inducing bleeding
What are the therapeutic uses of mifepristone?
- Abortion in early pregnancy, along with prostaglandins
- Plan B
- Progesterone-sensitive tumors - blocks their growth
What are two important estrogen receptor competitive antagonists?
- Tamoxifen
2. Clomiphene
How does the configuration of the double bonds in tamoxifen / clomiphene determine activity?
Trans - antiestrogens
Cis - estrogen agonists
Understand that this is in vitro. In vivo, isomerization occurs and makes activity more unpredictable
What is clomiphene used for and why?
Treatment of infertility
- > tends to block estrogen receptor in hypothalamus and pituitary, decreasing negative feedback
- > leads to increased FSH / LH levels, and subsequent increased gametogenesis + steroidogenesis
What is tamoxifen primarily used for?
Palliative treatment of estrogen receptor +, estrogen dependent breast cancer (blocks proliferation)
- > has fewer toxic effects, and usable in both pre and post menopausal women
- > may increase risk of endometrial or uterine cancers, however
What is leuprolide and what is it used for?
GnRH analog - prolonged stimulation of GnRH receptor will desensitize and inhibit release of FSH and LH (needs to be pulsatile)
Used as an anti-estrogen, anti-androgen, and in the treatment of uterine fibroids as well as endometriosis
What are the three aromatase inhibitors (and hence antiestrogens), and which are irreversible / reversible?
Irreversible: Exemestane (gonna X out that aromatase)
Reversible: Letrozole, Anastrozole
->reversibly bind the heme of aromatase CYP
What are aromatase inhibitors used for in post-menopausal women?
Breast carcinoma, since concentration of E2 in tumor will be 10x higher than plasma (different story in pre-menopausal)
What are aromatase inhibitors used for in pre-menopausal women?
Induction of ovulation in infertility -> drop in E2 levels will cause negative feedback removal in these infertile women, causing LH to spike, triggering ovulation
What is the most potent androgen in males, and what is the primary feedback control?
Dihydrotestosterone -> made via 5-alpha reductase of testosterone
Primary feedback control -> estrogen (precursor is also testosterone), inhibits GnRH and FSH/LH release. Testosterones also do this.
Estrogens also have some androgenic effect as well
What are the physiological actions of testosterones in embryonic development and in puberty?
Embryonic - virilization of urogenital tract, developing male phenotype
Puberty - development of male build, anabolic effects (nitrogen-retaining activity)
Are there any anabolic steroids which are not androgenic (virilizing)?
No -> it is due to the same receptor being expressed in different tissues. You can’t simply make gains without also looking like a dude
For patients with gonadal or pituitary dysfunction leading to delayed puberty, what must be co-administered to ensure normal development?
Testosterone must also be given with balanced human growth hormone (must ensure a balanced hormone environment)
When must delayed puberty be treated?
In the time of normal puberty
- > treating late may lead to variable and incomplete results
- > also, be sure not to treat prematurely, may just be late bloomers
When can anabolic steroids be used in the hospital?
During minor injury or surgery to prevent negative nitrogen balance, in combination with good nourishment
How do anabolic steroids used for muscle building probably exert their effects?
Since the steroid receptor is normally saturated, they may act as an antagonist to the glucocorticoid receptor, blocking its catabolic effects
Who are androgens contraindicated for in why?
- Children -> virilization and disturbances in growth and bone development
- Pregnant women -> maculinization of female fetus can result
What are the virilizing effects that can occur in women due to androgens?
Acne, growth of facial hair, coarse voice, and menstrual irregularities due to inhibition of FSH / LH. Can lead to prominent musculature and hypertrophy of the clitoris in long-term use
What are the untoward effects of androgens on men?
Azoospermia - due to inhibition of gonadotropin secretion (FSH / LH)
Gynecomastia (from aromatase conversion)
What are the general toxic effects of androgens?
Edema - associated sodium retention -> like estrogen
Jaundice - especially with alkyl-derivates. Not so bad with testosterone esters -> preferred form
May cause liver cancer or hepatitis
Can androgens be used in breast cancer?
Yes, as a chemotherapy, act as an anti-estrogen. Side effects may make this not useful
What are the four primary androgen drugs?
- Testosterone salts
- Oxandrolone
- Methyltestosterone
- Fluoxymesterone
What is Danazol and what is it used for?
An ethinyl derivative of testosterone -> used in treatment of endometrosis by inhibiting FSH / LH
What is the most effective inhibitor of testosterone synthesis?
Leuprolide
What drug is an antiandrogen by blocking 5alpha-reductase?
Finasteride
What is the mechanism of action of cyproterone acetate and what is it used for?
Competitive antagonist of dihydrotestorone -> used for inhibition of libido of male sex offenders and severe hirsutism
Inhibits many virilization effects
What drugs are used in combination with leuprolide for the treatment of prostate cancer and what is their mechanism of action?
Flutamide or bicalutamide (less hepatotoxic)
-> nonsteroidal competitive antagonist of androgen receptor
What is the mechanism of action of abiraterone acetate and what is it used for?
Inhibits testosterone synthesis by inhibiting CYP17A1 (17alpha hydroxylase), an enzyme needed to make androgens from progestins
Used for treatment of castration-resistant prostate cancer
What is the mechanism of action of spironolactone? What is it used for?
Competitive antagonist for androgen receptor (as well as aldosterone receptor)
-> used for treatment of female hirsutism (like cyproterone acetate)
What causes endometriosis and what are two primary drugs used for its treatment?
Excess estrogen levels, especially in reproductive years
Can be treated with GnRH analogs:
Leuprolide
Nafarelin
What are uterine fibroids?
Benign tumors in muscle layers of uterus -> most common benign neoplasm in females, which are estrogen-sensitive
How are uterine fibroids treated?
Since they are estrogen sensitive, same as endometriosis:
- Leuprolide
- Nafarelin
What is the newest and hippest drug for the treatment of both endometriosis and uterine fibroids? How does it work? Why might it be preferable to Leuprolide or Nafarelin?
Cetrorelix acetate: GnRH antagonist
Preferable because there is no initial increase in symptoms (those drugs take a while to desensitize GnRH receptors)
What receptor is expressed on uterine smooth muscle which can stimulate uterine contraction?
Oxytocin - Gq receptor which is upregulated as pregnancy goes on
What is oxytocin used for?
Induction or labor or augmentation of abnormal labor (it also stimulates prostaglandin / leukotriene synthesis for further labor)
What is the oxytocin antagonist and what is it used for?
Atosiban
-> suppression of pre-term labor
Gotta BAN that baby
