Sex Steroids

Overview of Sex Steroid Biosynthesis

Pathway Þ see graph below

progesterone (P) and corticoids Þ 21 carbons

androgens Þ 19 carbons

estrogens (E) Þ 18 carbons

Pharmacodynamics:

steroids mostly bound to sex hormone binding globulin (SHBG) and albuminÞ only free hormone active

Ý SHBG: Ý estrogen, hyperthyroidism, pregnancy

ß SHBG: androgens, corticoids, insulin, IGF-1

Estrogen

Production: mainly ovaries in women; extraglandular conversion of androstenedione and testosterone (T) in men; after menopause women also rely on peripheral conversion

thecal cells produce androstenedione and testosterone, which is converted to estradiol by aromatase by the granulosa cells

estradiol 17b is the most potent estrogen (synthetic)

estradiol can be oxidized to estrone or hydrated to estriol in liver

pregnancy: Ý estrogen requirements; estrogen comes from androstenedione of fetal adrenal gland

post menopause: most estrogen comes from extraglandular conversion of androstenedione and testosterone

in men: role of estrogen is unknown

Natural estrogens – less potent than synthetic hormones

include estradiol (strongest; produced in ovary); estrone (less potent); estriol (metabolite, very little effect)

(1) Oral estrogen – conjugated estrogen – e.g., estrone sulfate piperazine and conjugated equine estrogens (from pregnant mares’ urine; called Premarin) Þ active component after metabolism is estrone

(2) Transdermal estradiol via patch – avoids 1^st pass effect in liver, no Ý in hepatic proteins; topical creams available

(3) Vaginal rings and subcutaneous pellets

(4) Vaginal creams – estrone, estradiol and conjugated equine estrogens; systemic absorption depends on vaginal atrophy; can lead to endometrial proliferation

(5) Estrogen replacement therapy (ERT)–ß demineralization of trabecular bone (inhibit) osteoclastsÞ ß osteoporosis

eliminates estrogen deficiency symptoms (hot flashes, night sweats and vaginal dryness)

ß risk of coronary artery disease Þ Ý HDL and may ß atherosclerosis

risk of low-dose estrogens: endometrial hyperplasia and carcinomaÞ eliminate risk with supplemental progestins

also possible Ý breast cancer risk (not proven)

Synthetic Estrogens – have ethinyl group at position 17, more potent than natural estrogen – found in birth control pills

e.g., ethinyl estradiol and mestranol; current contraceptive pills contain 30 to 35 m g of ethinyl estradiol

mestranol Þ rapidly metabolized to ethinyl estradiol after absorption

Oral Contraceptives and their Effects

ESTROGEN	Antithrombin III	Clotting Cascade	Renin substrate	SHBG
Conjugated estrogens	No effect	No effect	Slight increase	Increase
Oral, micronized estradiol	Slight decrease	No effect	Slight increase	Increase
Estradiol path	No effect	No effect	No change	Increase
Ethinyl estradiol	Decrease	Increased factors VII, IX, X, Xc	Increased	increase

Excretion – in urine as glucuronides and sulfates

Estrogen antagonists – mixed agonist/antagonist actions; no effect on estrogen-deficient individuals

Short-acting antagonists Þ time dependent mixed agonists-antagonists

Long-acting antagonists Þ mixed estrogen agonists; agonist/antagonist activity depends on organ, tissue, cell type

exaples:

nafoxidine

Clomiphene–non-steroidal; binds estrogen receptor; induces ovulation in women with chronic anovulation

Cl-628

Tamoxifen – non-steroidal; estrogen agonist and antagonist; predominant effects on breast tissue so used in treatment of breast cancer; post-menpoausal agonist effects include ß antithrombin III, ß cholesterol, ß LDL, Ý HDL, Ý SHBG, ß FSH; can cause endometrial polyps, hyperplasia, carcinoma

interferes with effects of endogenous estrogen causing perception of estrogen deficiency and Ý GnRHÞ Ý FSH and LH

Progesterone

Production (in females): from corpus luteum during the luteal phase of the menstrual just after ovulation

placenta begins to produce progesterone during the 2^nd and 3^rd week of pregnancy, through parturition

Excretion: in urine as glucuronides and sulfates

Natural Progesterone – progestin

progesterone is orally inactive unless given in micronized form at very high doses every 6 hours (impractical)
administered as vaginal suppositories or intramuscular injection of progesterone in oil (irritating)

Synthetic Progesterone Þ orally active agents with long half lives; once daily administration

19-norestosterone derivatives Þ progestins found in all oral contraceptive pills – converted to norethindrone

e.g., Norethynodrel, norethindrone acetate, ethynodiol diacetate and norethindrone enanthate

structurally related to Mifeprisone (RU-486); norgestrel family includes levonorgestrel

New progestins: desogestrel, gestodene and norgestimate Þ ß androgenic effects

21-Carbon progestins Þ from acetylation of 17a OH-progesterone; e.g. medroxyprogesterone acetate (Provera)

Action as Anti-estrogens – progesterone ß estradiol receptor concentration

interfere with DNA transcription activation by occupied estrogen receptors Þ can lead to atrophy of endometrium

induce enzymes which metabolize estrogens in target tissue

RU-486 (Mifeprisone) – 19-nortestosterone derivative; long half-life, receptor affinity 5x that of native progesterone

agonist effects in absence of progesterone

high binding affinity to glucocorticoid receptorÞ useful for treatment of Cushings’s Syndrome

abortifacient – disrupts decidualized endometrium, disrupts implantation, Ý myometrial contraction in response to pregnancy, Ý prostaglandin secretion, Ý uterine contraction through non-prostaglandin pathways

Androgens – testosterone and androstenedione

Production: primarily made in testis (Leydig cells) and ovary, also adrenal cortex–unknown physiological role in women

androstenedione and testosterone are prohormones; androstenedione Þ estrogen or testosterone

testeosterone Þ estrogen or dihydrotestosterone (DHT; acts as intracellular mediator by binding androgen receptor (AR) with 10x greater affinity than testosterone; DHT-AR is more active in binding DNA than testosterone-AR)

Excretion: in urine (inactive free steroids or water-soluble conjugates) metabolites include androsterone, etiocholanolone

Administration: testosterone is not effective orally or by parenteral injection

oral testosterone is promptly degraded by liver (1^st Pass Effect); parental testosterone rapidly metabolized

therapeutically modified androgens are more soluble to reduce the rate of catabolism and the androgenic potency is Ý

Target Organ Response for Steroid Hormones

Estrogen and Progesterone

effects of estrogen: growth and development of vagina, uterus, and Fallopian tubes; enlargement of breasts through promotion of ductal growth, stromal development and fat accretion; body molding Þ shaping of skeleton and epiphyses of long bones during growth spurts; generation of secondary sex characteristics

effects of progesterone: works with estrogen to prepare endometrium for pregnancy; suppression of uterine contractions Þ maintains pregnancy; transplantation immunity Þ prevents immunologic rejection of fetus; initiates growth of mammary acini required for lactation (works with E)

Effect of Androgens on Reproductive Tract – promotes growth and function of prostate and seminal vesicles; testosterone Þ differentiation of Wolffian duct to epididymis, vas deferens and seminal vesicles; DHT Þ virilization of urogenital sinus and tubercle into male external genitalia, urethra and prostate

androgens and FSH together promote sprematogenesis

Contraception

Progestins alone for Contraception

Minipill – 0.35 mg norethidrone – Ý cervical mucus and endometrium becomes hostile to implantation

pregnancy rates: 1.1 - 0.6 per 100 women in first year of use
side effect: irregular bleeding (60%)

Norplant – 6 silastic capsules containing levonorgestrel implanted subcutaneously Þ effective 5 years

suppresses LH surge, similar effects on cervical mucus and endometrium
pregnancy rates: 0.2 per 100 women
side effects: irregular menses (80%), requires surgical insertion and removal

Deprovera–intramuscular injection (150 mg) every 3 mo.; progestin blocks LH surge, clears from body in 6-8 mo.

side effects: weight gain, depression, bloating

Combination oral contraceptive pills – ethinyl estradiol plus progestins

progestin Þ thickened cervical mucus (barrier to sperm and infection), thin decidualized endometrium, no LH surge

ethinyl estradiol ß endometrial side effects and enhances effectiveness – ß FSH Þ suppresses follicular activity

effectiveness depends on compliance Þ pregnancy rate 0.1% to 3%; young, unmarried poor at highest risk (10-20 %)

complications: principally vascular, dose dependent

(1) Venous thrombosis, stoke, and myocardial infarction more common in older dose (Ý mestranol or ethinyl estradiol)

ß risk in younger women; Ý risk with smoking – ß in antithrombin III and Ý in clotting factors

(2) Current combinations (30-35 m g ethinyl estradiol) cause slight Ý in thrombin (offset by Ý finbrinolytic activity)

cerebrovascular thrombosis risk unclear; no Ý in stoke

Facts about Birth Control Pills

ß risk endometrial cancer–by 50% after 12 mo. of use; max risk reduction after 3 yrs, but protective effects last 15 yrs

ß risk epithelial ovarian cancer–by 40%; protective effect Ý with duration and lasts 10-15 years after use

CDC concluded that there is no Ý risk of invasive cervical cancer; Ý risk of carcinoma in situ is due to enhanced detection of disease

breast cancer Þ no overall Ý risk

hypertension – high dose preparations Þ 5% incidence; low dose Þ no clinically significant HTN