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Pharmacology > Gonadal Steroids, GnRH, and Oxytocin > Flashcards

Gonadal Steroids, GnRH, and Oxytocin Flashcards

1
Q

How many carbons do progestins, estrogens, and androgens have?

A

Progestins - 21 C
Androgens - 19 C
Estrogens - 18 C

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2
Q

What are the three forms of estrogen and where are they present?

A
  1. Estrone - menopause
  2. Estradiol - puberty / most potent form
  3. Estriol - during pregnancy, prepping for birth
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3
Q

What portion of the estrogen is required for receptor binding?

A

Phenolic A ring -> phenyl + alcohol

-other phenolic compounds found in plastics and soy beans can also trip this receptor

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4
Q

How do synthetics estrogens differ from normal estradiol?

A

They are less susceptible to metabolism by the liver, and thus can be taken orally

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5
Q

How are estrogens formed, and where are they made pre-menopausally and post-menopausally? In pregnancy?

A

Formed via aromatase enzyme, a CYP450, from androstenedione or testosterone

Pre-menopausal: granulosa cells of ovary
Post-menopausal / men: adipose tissue
Pregnancy: placenta

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6
Q

What is the pattern of GnRH release which stimulates FSH / LH secretion at puberty? What is important feedback?

A

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)

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7
Q

How does estrogen stimulate menstrual bleeding?

A

At low doses, causes the proliferation of the endometrium which will shed after withdrawal.

At higher doses, a single dose can induce bleeding

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8
Q

What are the metabolic actions of estrogen? How does this influence cardiovascular risk?

A
  1. Salt / water retention at higher doses -> can increase blood pressure / cause edema
  2. Decreases in LDL and increases in HDL

Overall, consensus is increased CV disease risk

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9
Q

What are the two primary indications for postmenopausal hormone replacement therapy (HRT)?

A
  1. High risk of osteoporosis - especially thin, white smokers with a family history (start before bone loss)
  2. Atrophic vaginitis
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10
Q

Give two other indications for the usage of estrogens?

A
  1. Oral contraception

2. Primary hypogonadism - as in ovarian dygenesis or castration

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11
Q

What is estrogen usually given with and why?

A

A progesterone -> prevents endometrial hyperplasia and increased risk of endometrial cancer associated with monotherapy

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12
Q

In what cycle is estrogen therapy given and why?

A

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

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13
Q

Other than hypertension, why might giving estrogen be a major CV disease risk factor? What cancers can it predispose for?

A

Increases several coagulation factors, and can increase the risk of stroke, heart attacks, and venous thromboembolism

Can predispose for endometrial and breast cancers

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14
Q

How is estrogen therapy contraindicated in?

A

Estrogen-dependent neoplasms (uterine and breast cancer)

Estrogen treatment during pregnancy (especially first trimester) -> can cause feminization of males

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15
Q

What are the “natural estrogens” in clinical use?

A
  1. Estradiol
  2. Estradiol salts -> for i.m. injection, slow release
  3. Conjugated estrogens -> slow release injection
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16
Q

What are the synthetic estrogens for clinical use?

A
  1. Diethylstilbestrol
  2. Ethinyl estradiol

Much longer lasting with less first pass metabolism

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17
Q

What position in both estrogens and progestins makes a large difference in biologic activity and liver metabolism?

A

C17 substitution

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18
Q

What moiety is needed to bind the progesterone receptor?

A

The ketone moeity in the A ring (rather than alcohol)

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19
Q

What is progesterone secreted in response to?

A

Synthesized and secreted in response to the LH which induces ovulation, and is maintained by hCG of implanted trophoblast

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20
Q

What are the physiological actions of progesterone?

A
  1. Development of secretory endometrium (secretory phase)
  2. Maintaining pregnancy, suppressing menstruation and uterine contractility
  3. Mammary gland hyperplasia
  4. The 1 degree temperature rise just before ovulation
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21
Q

Other than in combination with estrogens for oral contraception / HRT, what are the monotherapy uses of progestins?

A
  1. Dysfunctional uterine bleeding
  2. Severe endometriosis
  3. Metastatic endometrial carcinoma
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22
Q

What are the current agents of choice for treating dysmenorrhea?

A

NSAIDs -> thought to be due to uterine production of prostaglandins

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23
Q

What are the four main synthetic progestins?

A
  1. Medroxyprogesterone
  2. Norethindrone
  3. Norgesterel
  4. Ethynodiol (conjugated to ethynyl group at C17)
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24
Q

What type of BC pill is no longer given and what is the standard now?

A

Progestin alone -> too low of efficacy

Standard now is estrogen + progestin combinations

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25
Q

What are the plan B formulations?

A
  1. Diethylstilbestrol - think still birth (will cause vaginal carcinoma if ineffective)
  2. Norgestrel / ethinyl estradiol
  3. Norgestrel alone
  4. Mifepristone

All must be used within 72 hours

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26
Q

What are the effects of estrogen and progesterone within the BC pill?

A

Estrogen - inhibits FSH release (prevents follicle development)
Progesterone - inhibits estrogen-induced LH surge

Both combine to inhibit ovulation

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27
Q

What are the risks associated with birth control?

A

Same as estrogen alone:
Cardiovascular disorders like more clotting and mild hypertension
Cancer - vaginal, uterine, and breast

28
Q

What is the mechanism of action of mifepristone? What does this do to adrenal steroidogenesis?

A

Competitive antagonist of both progesterone and glucocorticoid receptors (very strong)

By blocking adreno-corticoid feedback in the hypothalamus, it results in increased steroidogenesis

29
Q

What are the pharmacologic actions of mifepristone early and late in the ovarian cycle?

A

Early - Prevents ovulation by preventing progesterone binding at hypothalamus / pituitary
Late - Blocks uterine maintenance - inducing bleeding

30
Q

What are the therapeutic uses of mifepristone?

A
  1. Abortion in early pregnancy, along with prostaglandins
  2. Plan B
  3. Progesterone-sensitive tumors - blocks their growth
31
Q

What are two important estrogen receptor competitive antagonists?

A
  1. Tamoxifen

2. Clomiphene

32
Q

How does the configuration of the double bonds in tamoxifen / clomiphene determine activity?

A

Trans - antiestrogens
Cis - estrogen agonists

Understand that this is in vitro. In vivo, isomerization occurs and makes activity more unpredictable

33
Q

What is clomiphene used for and why?

A

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
34
Q

What is tamoxifen primarily used for?

A

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
35
Q

What is leuprolide and what is it used for?

A

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

36
Q

What are the three aromatase inhibitors (and hence antiestrogens), and which are irreversible / reversible?

A

Irreversible: Exemestane (gonna X out that aromatase)

Reversible: Letrozole, Anastrozole
->reversibly bind the heme of aromatase CYP

37
Q

What are aromatase inhibitors used for in post-menopausal women?

A

Breast carcinoma, since concentration of E2 in tumor will be 10x higher than plasma (different story in pre-menopausal)

38
Q

What are aromatase inhibitors used for in pre-menopausal women?

A

Induction of ovulation in infertility -> drop in E2 levels will cause negative feedback removal in these infertile women, causing LH to spike, triggering ovulation

39
Q

What is the most potent androgen in males, and what is the primary feedback control?

A

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

40
Q

What are the physiological actions of testosterones in embryonic development and in puberty?

A

Embryonic - virilization of urogenital tract, developing male phenotype

Puberty - development of male build, anabolic effects (nitrogen-retaining activity)

41
Q

Are there any anabolic steroids which are not androgenic (virilizing)?

A

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

42
Q

For patients with gonadal or pituitary dysfunction leading to delayed puberty, what must be co-administered to ensure normal development?

A

Testosterone must also be given with balanced human growth hormone (must ensure a balanced hormone environment)

43
Q

When must delayed puberty be treated?

A

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
44
Q

When can anabolic steroids be used in the hospital?

A

During minor injury or surgery to prevent negative nitrogen balance, in combination with good nourishment

45
Q

How do anabolic steroids used for muscle building probably exert their effects?

A

Since the steroid receptor is normally saturated, they may act as an antagonist to the glucocorticoid receptor, blocking its catabolic effects

46
Q

Who are androgens contraindicated for in why?

A
  1. Children -> virilization and disturbances in growth and bone development
  2. Pregnant women -> maculinization of female fetus can result
47
Q

What are the virilizing effects that can occur in women due to androgens?

A

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

48
Q

What are the untoward effects of androgens on men?

A

Azoospermia - due to inhibition of gonadotropin secretion (FSH / LH)
Gynecomastia (from aromatase conversion)

49
Q

What are the general toxic effects of androgens?

A

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

50
Q

Can androgens be used in breast cancer?

A

Yes, as a chemotherapy, act as an anti-estrogen. Side effects may make this not useful

51
Q

What are the four primary androgen drugs?

A
  1. Testosterone salts
  2. Oxandrolone
  3. Methyltestosterone
  4. Fluoxymesterone
52
Q

What is Danazol and what is it used for?

A

An ethinyl derivative of testosterone -> used in treatment of endometrosis by inhibiting FSH / LH

53
Q

What is the most effective inhibitor of testosterone synthesis?

A

Leuprolide

54
Q

What drug is an antiandrogen by blocking 5alpha-reductase?

A

Finasteride

55
Q

What is the mechanism of action of cyproterone acetate and what is it used for?

A

Competitive antagonist of dihydrotestorone -> used for inhibition of libido of male sex offenders and severe hirsutism

Inhibits many virilization effects

56
Q

What drugs are used in combination with leuprolide for the treatment of prostate cancer and what is their mechanism of action?

A

Flutamide or bicalutamide (less hepatotoxic)

-> nonsteroidal competitive antagonist of androgen receptor

57
Q

What is the mechanism of action of abiraterone acetate and what is it used for?

A

Inhibits testosterone synthesis by inhibiting CYP17A1 (17alpha hydroxylase), an enzyme needed to make androgens from progestins

Used for treatment of castration-resistant prostate cancer

58
Q

What is the mechanism of action of spironolactone? What is it used for?

A

Competitive antagonist for androgen receptor (as well as aldosterone receptor)
-> used for treatment of female hirsutism (like cyproterone acetate)

59
Q

What causes endometriosis and what are two primary drugs used for its treatment?

A

Excess estrogen levels, especially in reproductive years

Can be treated with GnRH analogs:
Leuprolide
Nafarelin

60
Q

What are uterine fibroids?

A

Benign tumors in muscle layers of uterus -> most common benign neoplasm in females, which are estrogen-sensitive

61
Q

How are uterine fibroids treated?

A

Since they are estrogen sensitive, same as endometriosis:

  1. Leuprolide
  2. Nafarelin
62
Q

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?

A

Cetrorelix acetate: GnRH antagonist

Preferable because there is no initial increase in symptoms (those drugs take a while to desensitize GnRH receptors)

63
Q

What receptor is expressed on uterine smooth muscle which can stimulate uterine contraction?

A

Oxytocin - Gq receptor which is upregulated as pregnancy goes on

64
Q

What is oxytocin used for?

A

Induction or labor or augmentation of abnormal labor (it also stimulates prostaglandin / leukotriene synthesis for further labor)

65
Q

What is the oxytocin antagonist and what is it used for?

A

Atosiban
-> suppression of pre-term labor

Gotta BAN that baby

Pharmacology (54 decks)

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