Steroid Drugs

Estrogens

• Estradiol, Estrone (Climara, Estrace etc.)
• conjugated estrogens (Premarin)
• Diethylstilbestrol (DES, Stilphostrol)

Mixed Estrogen:Progesterone

Estrogen; Progestin (Brevicon®, Demulen®, Desogen®, Enovid®, Genora®, Levlen®, Loestrin®, Lo/Ovral®, Modicon®, Nelova®, Nordette®, Norinyl®, Norlestrin®, Ortho-Cept™, Ortho-Cyclen®, Ortho-Novum®, Ortho-Tri-Cyclen®, Ovcon®, Ovral®, Tri-Levlen®, Tri-Norinyl®, Triphasil®)

Androgens

• Danazol (Danocrine)
• Methyltestosterone (Android, Testred, Virilon)
• Testosterone (Andro, depoAndro, Depo-T, Androderm)

Anti-androgens

• Bicalutamide (Casodex)
• Finasteride (Propecia, Proscar)

Effects of Gonadotropins

• FSH increases sperm production in testis.
• FSH & LH control androgen production from Leydig cells.
• FSH ãrecruitsä follicle in ovary.
• LH induces ovulation in the primary (antral) follicle in the ovary.

FSH and LH in the Testis

• FSH stimulates gametogenesis (sperm production) in testis.
• Androgens produced in the interstitial Leydig cells under LH control.
• Sertoli cells also produce mullerian duct inhibiting factor, inhibin (inhibit FSH release) and activin (similar to TGF-beta, releases FSH).

Androgens in humans

• 8 mg T daily in males; 95% from leydig cells, 5% from adrenal.
• Testis produces lesser amounts of DHT, androsterone and dehydroepiandrosterone (DHEA), pregnenolone and progesterone.
• 0.6 ug T/dL in males, 0.03 ug/dL in females from ovary, adrenal and peripherally-converted steroids.

Androgen effects.

• Increased pubic, axillary and facial hair in pubertal males and females.
• Sebaceous glands produce more oil, skin becomes thicker.
• Larynx thickened. Epiphyseal closure.
• Growth of prostate and seminal vesicles (along w/ skin these are 5alpha-DHT-mediated effects).

About 65% of circulating testosterone is bound to sex hormone-binding globulin (SHBG), a speicif protein produced by the liver. This protein is increased in plasma by estrogen, by thyroid hormone, and in patients with cirrhosis of the liver. It is decreased b y androgen and growth hormone and is lower in obese individuals. (See the potential significance of these in the next lecture).

Metabolism of Androgens.

Testosterone can be metabolized to either dihydrotestosterone (DHT) by 5 alpha-reductase or to estradiol by aromatase enzymes. Notice above that DHT is reponsible for many of the peripheral effects of testosterone. It is probably also true that estradiol is responsible for many of the central (brain and spinal cord) effects of testosterone, including the developmental effects of testosterone on behaviors as well as those behavioral effects in adults. In fact, Baulieu has demonstrated aromatase in the brain, suggesting the brain is a gland producing estradiol.

Gonadotropin effects in Ovary

• FSH begins follicular development of the next primary follicle.
• LH stimulates further development, increasing estradiol production.
• LH stimulates ovulation of primary oocyte.
• At ovulation follicle fills with blood which is replaced by thecal cells which produce mostly progesterone. 

The Ovary and Oocytes

The fetal ovary has more eggs or oocytes than it will ever have later in life. During fetal development the human ovary has as many as 7 million eggs. When a baby girl is born she has under 1 million, by the time she gets to puberty she has less than half of those remaining. During the approximately 40 years she is fertile she will actually ovulate fewer than 500 of those. Thus selection of which oocytes will go on to be ovulated is an important, but not well understood event.

We know that selection of the oocyte that will be part of the primary follicle ovulated in a given cycle is stimulated by the FSH released in the previous cycle (that is, the follicle develops for a month). One gynecologist refers to the ovary as the only gland that lasts only a month. As the follicle grows it contains granulosa cells that produce estradiol and other steroids from cholesterol. We will see that this production is controlled by LH stimulation of cAMP.

Other sources of estrogens.

The major estrogens from the ovary are estradiol-17-beta (E2), estrone (E1) and estriol (E3). E2 is the major estrogen in women. E1 and E3 come most from E2 metabolism in the liver. During pregnancy, much estrogen comes from the fetoplacenta. Equine estrogens-equilin and equilenin-and their congeners are unsaturated in the B and A rings and are excreted in large quantities in urine. Interestinlay, stallion urine is the best source of this, although pregnant mare serum is also used. E2 levels vary across the menstrual cycle from lows of 50 pg/mL in early follicular phase (just after menses) to 350-850 pg/mL during the preovulatory peak (at midcycle).

Possible relationships between plasma proteins and hormones

Steroid Synthesis from Cholesterol

Steroid Production

• LDL cholesterol uptake
• C esters
• Intracellular cholesterol at mitochondrion
• cholesterol --> Pregnenolone
• Pregnenolone --> every other steroid

Estrogens, Estradiol, Estrone, Estropipate (Climara, Estrace)

• Several naturally occurring estrogens: estradiol (left), estrone, estriol.
• 7 years of Estrogen needed to improve osteoporosis (Framingham study).

Conjugated Estrogens (Premarin)

• Water soluble salts of sulfate esters from estrone and equine sources.
• Used for gonadotropin hormone dysfunction
• Reduced osteoporotic hip fractures 25%

MOA for some E effects

• Estrogens increase pituitary mass (increased protein synthesis?)
• Reduce FSH and LH levels.
• Short-term increases endometrial proliferation but long-term the opposite.
• Favorably affect blood lipids, reducing LDLs, particularly in post-menopause.

Testosterone (Andro, depoAndro, Androderm, Testoderm)

• It is the primary steroid of male mammals.
• Used in congenital or acquired hypogonadism and breast carcinoma in post-menopausal women.

MOA for Testosterone

• Schedule C-III because of athletic use.
• It has both organizational and activational effects.
• Secreted from testis, ovary and adrenals.
• Exogenous inhibits GnRH, LH and FSH thus shutting down endogenous T secretion.
• Affects blood cell production, calcium balance and glucose levels.
• Target cells include: muscle, adipose cells, ejaculatory glands (prostate and seminal vesicles), penis, larynx, scrotum and brain.
• Closure of epiphysis is controlled by androgens.
• It is used when endogenous T is low, I.e. hypogonadism.

Danazol (Danocrine)

• Used to treat endometriosis by atrophying ectopic endometrial tissue.
• Use with fibrocystic breast disease because it inhibits growth of breast cancer tissue.

MOA for Danazol

• It shows weak androgenic activity with anti-estrogenic effects.
• It inhibits LH and FSH thus lowering endogenous steroid levels.
• Higher doses cause amenorrhea.

Finasteride (Propecia, Proscar)

• Treatment of benign prostatic hypertrophy.
• Reduces prostate size (although it decreases urine flow in only <50% of pts.)
• Reduces prostate-specific antigen which may mask prostatic carcinoma.

MOA of Finasteride

• Specific inhibitor of 5-alpha reductas blocking DHT production. DHT induces second sexual development including prostate tissue.
• Does not seem to affect other steroid levels: estradiol or cortisol or other hormones: PRL, TSH or T4.

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