Estrogens: Types, Production, and Function

Estrogens

• Estradiol (17β-estradiol) is the most potent estrogen produced by the ovary and the principal estrogen in premenopausal women.
• Estrone is a metabolite of estradiol with about one-third the estrogenic potency of estradiol and the primary circulating estrogen after menopause.
• It is generated from androstenedione conversion in peripheral tissues.
• Estriol is another estradiol metabolite is significantly less potent than estradiol.
• It is the principal estrogen produced by the placenta, especially during pregnancy.
• Conjugated estrogens (sulfate esters of estrone and equilin) are used for hormone replacement therapy and plant-derived versions exist.
• Synthetic estrogens (like ethinyl estradiol) undergo less first-pass metabolism, making them effective orally at lower doses.
• Selective Estrogen Receptor Modulators (SERMs) are nonsteroidal compounds that bind to estrogen receptors, exerting either estrogenic or antiestrogenic effects.
• Examples include tamoxifen and raloxifene.

Estrogen Mechanism of Action

• Steroid hormones diffuse across the cell membrane after dissociating from sex hormone-binding globulin or albumin in the plasma.
• They then bind with high affinity to specific nuclear receptors.
• Estrogens are transported in the blood bound to serum albumin or sex hormone-binding globulin.
• Estrogen has low bioavailability when taken orally due to first-pass metabolism.
• First-pass can be reduced via transdermal, intravaginal, or injection routes.
• In the liver, estrogen is hydroxylated into derivatives that are subsequently glucuronidated or sulfated.
• Parent drugs and metabolites are excreted into bile and reabsorbed via enterohepatic circulation before inactive products are excreted in urine.

Estrogen Uses and Effects

• Estrogen combined with a progestogen provides effective contraception through oral, transdermal, or vaginal routes.
• Estrogen therapy with a progestogen can stimulate secondary sex characteristics in young women with primary hypogonadism and maintain them after growth is complete.
• Estrogen/progestogen replacement therapy is used for women with premature menopause or ovarian failure.
• Naturally occurring estrogens and their derivatives are well absorbed through the GI tract, skin, and mucous membranes. Estradiol is rapidly metabolized by the liver, but bioavailability is improved with micronized estradiol, resulting in sufficient effectiveness even when taken orally.
• Synthetic estrogen analogs are well absorbed after oral administration.
• Mestranol is quickly demethylated to ethinyl estradiol, which is metabolized more slowly.
• Estradiol valerate is rapidly cleaved to estradiol and valeric acid
• Fat-soluble, and stored in adipose tissue for slow release, they have prolonged action and higher potency versus natural estrogens.
• Estrogen treatment reestablishes feedback control on hypothalamic norepinephrine secretion, reducing the frequency of "hot flashes".
• Estrogen treatment reverses postmenopausal atrophy of the vulva, vagina, urethra, and trigone of the bladder.

Estrogen Adverse Effects

• Common adverse effects of estrogen therapy are nausea and breast tenderness.
• Estrogen therapy increases risk of thromboembolic events, myocardial infarction, and breast/endometrial cancer.
• The increased risk of endometrial cancer can be offset by including a progestogen.

Selective Estrogen Receptor Modulators (SERMs)

• SERMs possess selective agonism or antagonism for estrogen receptors based on tissue type.
• SERMs include tamoxifen, toremifene, raloxifene, clomiphene, and ospemifene.
• Tamoxifen, toremifene, and raloxifene compete with estrogen for binding to estrogen receptors in breast tissue.
• Raloxifene acts as an estrogen agonist in bone, decreasing bone resorption, increasing bone density, and decreasing vertebral fractures.
• Unlike estrogen and tamoxifen, raloxifene lacks appreciable estrogen receptor agonist activity in the endometrium, and does not predispose it to endometrial cancer.

SERM Uses and Pharmacokinetics

• Tamoxifen is used to treat metastatic breast cancer and as adjuvant therapy after mastectomy or radiation for breast cancer
• Tamoxifen and raloxifene can be used prophylactically to reduce breast cancer risk in high-risk patients.
• Raloxifene is approved for preventing and treating osteoporosis in postmenopausal women.
• Clomiphene treats infertility from anovulatory cycles.
• Ospemifene treats dyspareunia (painful sexual intercourse) related to menopause.
• SERMs are rapidly absorbed after oral administration and undergo enterohepatic cycling.
• Tamoxifen is metabolized by CYP450 isoenzymes, including CYP3A4/5 and CYP2D6, which form active metabolites.
• Patients with a CYP2D6 genetic polymorphism may produce less active metabolite, reducing tamoxifen activity.
• Raloxifene is rapidly converted to glucuronide conjugates through first-pass metabolism and has primary excretion through the bile into feces.

SERM Adverse Effects

• Hot flashes and nausea are the most frequent adverse effects of tamoxifen and toremifene.
• Tamoxifen therapy has been linked to endometrial hyperplasia and malignancies due to its estrogenic activity in the endometrium.
• Tamoxifen is subject to drug interactions due to being metabolized by CYP450 isoenzymes. It also inhibits CYP3A4 and P-glycoprotein.
• Raloxifene common adverse effects are hot flashes and leg cramps, plus increased risk of thromboembolic events and retinal vein thrombosis.
• Concurrent Cholestyramine significantly reduces the absorption of raloxifene; avoid concurrent use.
• Raloxifene should not be taken by women who have a past or active history of venous thromboembolic events.
• Clomiphene adverse effects are dose-related, including headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement while also increasing the risk of multiple births (twins or triplets).

Progestogens

• Progesterone is produced by the corpus luteum (during the second half of the menstrual cycle) and the placenta which responds to luteinizing hormone (LH).
• In females, progesterone promotes development of a secretory endometrium for embryo implantation.
• High progesterone levels inhibit gonadotropin production and prevent further ovulation.
• If conception does not occur, the decline in progesterone stimulates menstruation.
• If conception takes place, progesterone secretion continues, maintaining pregnancy and reducing uterine contractions.

Progestogen Uses, Action, and Pharmacokinetics

• Major clinical uses are for contraception or hormone deficiency treatment.
• Progestogens are often used in combination with estrogens for contraception
• Progesterone itself isn't used widely as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability.
• Contraception uses synthetic progestogens (progestins) that are stable to first-pass metabolism for lower oral doses.
• Synthetic progestins include desogestrel, dienogest, drospirenone, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, and norgestrel.
• Medroxyprogesterone acetate is an injectable contraceptive, and the oral form is a common progestin component of postmenopausal HT.
• Progestins are used for dysfunctional uterine bleeding, dysmenorrhea, endometriosis and infertility management.
• Micronized progesterone is rapidly absorbed after oral administration, with a short plasma half-life, is almost completely metabolized by the liver, and has glucuronidated metabolite excretion primarily by the kidney.
• Synthetic progestins are less rapidly metabolized.
• Oral medroxyprogesterone acetate has a half-life of 30 days.
• Medroxyprogesterone acetate injected intramuscularly or subcutaneously has a half-life of about 40 to 50 days and provides approximately 3 months of contraceptive activity.
• Other progestins have half-lives of 1 to 3 days, for once-daily dosing.

Progestogen Adverse Effects

• Major adverse effects are headache, depression, weight gain, and libido changes.
• Progestins from 19-nortestosterone have some androgenic activity due to structural similarity to testosterone and can cause acne/hirsutism.
• Norgestimate and drospirenone are less androgenic progestins preferred in women with acne.
• Drospirenone may raise serum potassium, and concurrent use with other drugs that increase potassium may increase the risk of hyperkalemia.

Antiprogestins

• Mifepristone is a progesterone antagonist with partial agonist activity.
• Mifepristone results in abortion of the fetus due to interference with progesterone needed to maintain pregnancy when administered to females early in pregnancy.
• To induce uterine contractions, mifepristone is often combined with the prostaglandin analog misoprostol administered orally or intravaginally.
• Major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion.

Contraceptives

• Interference with ovulation is the most common pharmacologic intervention for pregnancy prevention.

Contraceptive - Combination Oral Contraceptives

• Products with a combination of an estrogen and a progestin are the most common type of oral contraceptives.
• Monophasic pills contain a constant estrogen/progestin dose given over 21 to 24 days.
• Active pills are taken for 21 to 24 days in most oral contraceptives, followed by 4 to 7 days of placebo, for a total regimen of 28 days.
• Withdrawal bleeding occurs during the hormone-free (placebo) interval. Most combination pills use ethinyl estradiol.
• Common progestins are norethindrone, norethindrone acetate, levonorgestrel, desogestrel, norgestimate, and drospirenone.
• Use of extended-cycle contraception (84 active pills followed by 7 days of placebo) results in less frequent withdrawal bleeding.
• Constant oral contraceptive product usage (active pills taken every day) is also available.
• Extended-cycle contraception and constant usage is highly effective in achieving contraception.

Contraceptive - Transdermal Patch

• Transdermal patch containing ethinyl estradiol and the progestin norelgestromin is an alternative to combination oral contraceptives.
• Apply one contraceptive patch each week for 3 weeks to the abdomen, upper torso, or buttock, and no patch is worn during the 4th week, and withdrawal bleeding occurs.
• Transdermal patch efficacy is comparable to oral contraceptives, but is less effective in women weighing greater than 90 kg.
• Contraindications and adverse effects for the patch are similar to those of oral contraceptives.
• Total estrogen exposure with the transdermal patch may be greater than that seen with oral contraceptives, increasing the risk of adverse events such as thromboembolism.

Contraceptive - Vaginal Rings, Progestin-Only Pills, and Injectables

• Vaginal ring containing ethinyl estradiol and etonogestrel is the alternative.
• Inserted into vagina for 3 weeks, then removed. No ring during the fourth week, and withdrawal bleeding occurs.
• Contraceptive vaginal ring has efficacy, contraindications, and adverse effects similar to oral contraceptives.
• Progestin-only pills (usually norethindrone) are called mini-pills, are taken daily on a continuous schedule.
• Progestin-only pills deliver a low, continuous drug dosage.
• Less effective than combination products and produce irregular menstrual cycles more frequently. Also lacks effects on milk production, and it is a safe method for breast-feeding patients.
• Progestin-only can be used for patients who are smokers, are intolerant to estrogen, or have contraindications to estrogen-containing products.
• Medroxyprogesterone acetate, injectable, is administered intramuscularly or subcutaneously every 3 months.
• Weight gain is a common adverse effect.
• Many women experience amenorrhea with medroxyprogesterone acetate due to this product providing high sustained levels of progestin.
• Return of fertility may be delayed for several months after medroxyprogesterone acetate, after discontinuation.

Contraceptive - Progestin Implants/IUDs and Postcoital Contraception

• Etonogestrel implant offers contraception for about 3 years after subdermal placement.
• Implant is nearly as reliable as sterilization, with a totally reversible effect surgically. Principal side implant effects are irregular menstrual bleeding and headaches.
• Progestin intrauterine device (IUD): A levonorgestrel-releasing intrauterine system, offers a highly effective method of contraception for 3 to 5 years depending on the system.
• This is a suitable method for women desiring long-term contraception and those who have contraindications to estrogen therapy.
• Avoid in patients with pelvic inflammatory disease or a history of ectopic pregnancy.
• Postcoital/emergency contraception: Reduces the probability of pregnancy after an episode of coitus without effective contraception to between 0.2% and 3%.
• High levonorgestrel doses, or high ethinyl estradiol doses plus levonorgestrel. For emergency contraception, uses Should be taken as soon as possible post unprotected intercourse, and preferably within 72 hours for maximum effectiveness.
• The progestin-only emergency contraceptive regimens are generally better tolerated.
• Ulipristal [ue-li-PRIS-tal] an alternative progesterone agonist/antagonist.
• This is for emergency contraception within 5 days of unprotected intercourse. Women over age 35 who smoke will increase the risk of adverse events

Female hormone interactions and risks.

• Women are likely to use barriers for contraception Oral contraceptives are associated with a decreased risk of cervical cancer along with ovarian (Oral contraceptives are associated with a decreased risk of cervical and ovarian cancer):
• Oral contraception has cerebrovascular, thromboembolic, estrogen, neoplasms, liver disease and pregnancy are contraindications for oral contraceptions.
• Combination oral contraceptives should not be used in patients over 35 who are heavy smokers.
• Rifampin, bosentan may reduce the contraceptive significantly Avoid use or utilize a barrier. Normal flora alterations from antibiotic may reduce contraceptive effectiveness Use of alternate contraception during antibiotic therapy.

Androgens

• Androgens are a group of steroids that have anabolic/masculinizing effects and synthesized by Leydig cells.
• Other androgens secreted by the testes are 5x-dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) in small amounts..
• Controlled by gonadotropin-releasing hormone from the hypothalamus
• • Negative trohic hormones produces testosterone Normal maturation in male, Sperm production Increased synthesis of muscle proteins and hemoglobin and Decreased bone resportion.
• Synthetic modifications of the androgen structure modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone) and separate anabolic and androgenic effects.

Androgens - Mechanism of Action and Uses

• Like the estrogens and progestins, androgens bind to a specific nuclear receptor in a target cell .
• Testosterone itself is the active ligand in muscle and liver and it must be metabolized to derivatives, such as DHT in other tissues (cells of the prostate, seminal vesicles, epididymis, and skin)
• Androgenic steroids are used for males with primary hypogonadism.
• Anabolic steroids can be used to treat chronic HIV/cancer wasting.
• (Unapproved use) is to increase lean body mass, muscle strength, and endurance in athletes and body builders
• DHEA: antiaging performance hormone enhancer but there is no definitive aging evidence.
• Danazol ( weak androgen) endometriosis(ectopic growth of the endometrium) and fibrocystic breast disease.

Androgens - Adverse Effects and Pharmacokinetics

• Females: masculization, acrne, growth of facial hair. deepening of the voice, male pattern boldness and excessive Menstrual irregularities may also occur but dont use with pregnancy because of feminization.
• Males Excesses androgen can cause priapism, inpotence, decreased Spermatogenesis and gynecomastia Cosmetic change as females but stimulates prostate growth. In children Sexual maturation High doeses results in hepatic abnormalities Increased aggression and rage
• General effect Increase LDL, decreased HDL causes fluid retention leading to edema. Alpha is ineffective orally and 17 esters cypionate/enathate is administered Topical gels, buccal tablets and transdermal patches is administered Testosterone increases with 1:1 relative ration and androgen to anabolic activity Lcation allows the hormone and half life increases. Associated with the 12-alkylarted androgens, effective given Fluoxymesterone allows for longer effect: The fluoxymesterone will have androgenic to anabolic
• Oxandrolong is 3 to 13 times better than esterone and will produce adverse effects can cause alkylated with the derivatives will create Hepatic Alversative to fluoxymesteros and oranolone (Alkylarted) less effective given more adverse effects and liver damage.

Androgens - Antiandrogens

• finasteride and Dutasterde inhibits 5a: decreases formation of dht for treatment prostatic hyperplasia.
• Antiandrogens acts as inhibitors of target and are ffective to prostatic cancer Flutamide, Bicalutamide, Enzalutamide, Nilumatinde are inhibitors to prostate cell targets