Medical Pharmacology Topics   

Sex Steroids

The major female steroids are the estogens and progesterone, both produced in the ovaries. Testosterone (also produced in the ovaries) and to ther adrenal androgens play minor roles. The major male hormone is testosterone, produced in the testis, and estrogen formrd from the aromatization of estrogen in plasma plays a minor role.

Synthesis of sex steroids by the gonads is controlled by the hypothalamus and pituitary. The hypothalamus secretes pulses of gonadotrpin releasing hormone (GnRH) into the hypothalamic-hypophyseal portal system. GnRH reaches the pituitary to stimulate the release of the gonadotropic hormones: follicle stimulating hormone (FSH) and lutenizing hormone (LH). The sex steroidsd excert feedback inhibition on the hypothalamus, inhibiting the release of gonadotropic hormones.

The gonadotropic hormones act via specific receptors couppled to adenylyl cyclase. Increased cAMP levels lead to increased synthesis of sex steroids and other reproductive effects. In males, FSH stimulates seminiferous tubes and LH stimulates androgen secretion. In females, FSH stimulates follicular growth and production of estrogen, while LH triggers ovulation and luteinization (then the corpus luteum produces both estrogen and progesterone.

Drugs that affect FSH and LH homeostasis include clomiphene, the menotropins, human chorionic gonadotropin (HCG) and danazol. The metrorphins and similar agents, and HCG are used to treat female infertility due to pituitary insufficiency. Danazol is a synthetic abdrogen used to inhibit FSH/LH output in the treatment of endometriosis. In fact, any sext steroid can inhibit FSH and LH secretion in either sex.

GnRH analogs include buselin, nafarelin, histerilin and goserelin. GnRH antagonists include cetrorelix and ganirelix. Although GnRH can be used to treat hypothalamic amenorrhea in females, he most important use of GnRH and its analogs is in the treatment of cancer, mostly prostate cancer. Leuprolide and similar "superagonists" at GnRH receptors reduce androgenic stimulation by desensitizing GnRH receptors. Alternative therapies for prostate cancer are often not desirable: surgical castration removes circulating testosterone and its proliferative effect, and diethylstilbestrol is a synthetic estrogen with unpleasant side effects.

Female Infertility Treatment

In females, FSH stimulates follicular growth and estrogen production. LH triggers ovulation and luteinization, inducing production of both estrogen and progesterone. Estrogen and progesterone mediate negative feedback on secretion of FSH and LH. However, at a critical point in the female cycle, the rising estrogen levels switch to excert a positive feedback on LH secretion.

FSH beguins the female cycle by stimulating the development of (usually) a single follicle. The growing follicle secretes increasing amounts of estradiol, the main endogenous estrogen in humans. Estradiol in turn inhibits GnRH release from the hypothalamus and induces proliferation and tickening of the endometrium.

At mid cycle, the rising estrogen levels reach a critical point and provoke an "LH surge", which in turn triggers ovulation. The ruptured follicle becomes the corpus luteum and secretes increasing amounts of progesterone, which maintains and transforms the endometrium into the highly vascular secretory endometrium needed for implantation.

If no pregnancy occurs, the corpus luteum atrophies and progesterone levels fall, leading to breakdown of the endometrium and menstruation. If pregnancy occurs, the embryo produces human chorionic gonadotropin (HCG), which prevents atrophy of the corpus luteum.

A common cause of infertility is excessive estrogenic feedback inhibition of GnRH secretion, leading to insufficient FSH levels to trigger follicle growth. A sort period of treatment with clomiphene, an estrogen antagonist, blocks estradiol-mediated feedback inhibition and allows FSH release, thus inducing ovulation. Clomiphene has the potential to overestimulate the ovaries, and is responsible for 8% of multiple pregnancies.

If infertility is the result of pituitary failure, FSH and LH can be supplied using menotropins or similar agents and HCG. Menotropins contain both FSH and LH recovered from the urine of menopausal women, and must be given intramuscularly to decrease the incidence of hypersensitivity reactions. Urofollitropin has most of the LH removed and is purified enough that can be given subcutaneously. Recombinant versions (follitropin alpha and beta) are the least antigenic but more expensive. HCG collected from the urine of pregnant women is used to mimic the "LH surge" because its activity is similar to LH, thus can induce ovulation.

To treat infertility from pituitary failure, a preparation like metrorpins is given for 14 days, followed by a single injection of HCG to induce ovulation. As with clomiphene, this often works too well, resulting in multiple births.

If infertility is the result of hypothalamic amenorrhea, GnRH or its analogs may be used. GnRH has opposite effects depending on the treatment regime. Intermitent administration results in sustained release of FSH and LH, thus inducing ovulation. But more frequent administration causes desensitization of GnRH receptors on the anterior pituitary gonadotrophs, leading to suppression of FSH and LH release and infertility.

Female Steroids

Estradiol enters the nucleus and binds the estrogen receptor, promoting a conformational change that results in dimerization.. The dimerized receptor is capable of binding to estrogen response elements EREs) located in the promoter region of estrogen-activated genes. The active estrogen receptor serves as a "skeleton" for the assembly of the functional transcription unit that determines the exact degree and character of the response.

Estrogenic agents are used in replacement therapy to treat pre-menopausal hypogonadism (Turner's syndrome, childhood hypopituitarisnm) or as port-menopausal hormone replacement therapy (HRT). Antiestrogens are used to treat cancer.

HRT prevents symptoms like osteoporosis, vasomotor disturbances and cardiovascular disease. The treatment often includes estrogen and progestin (synthetic progesterone) in combination to prevent endometrial hypoerplasia and the risk of carcinoma. Estrogen alone in females with an intact uterus is associated with increased risk of endometrial carcinoma, presumably due to the unopposed estrogenic estimulation. Addition of progestin counters this effect but may also counter the beneficial effects of estrogens regarding cardiovascular disease. Estrogen alone is appropriate HRT after hysterectomy.

HRT was thought to reduce the risk of serious cardiovascular disease, but a recent study indicates adverse effects in patients with pre-existing disease.

Representative estrogenic drugs include the synthetic estrogens (estradiol benzoate, ethinyl estradiol and mestranol), and premarin, a mixture of conjugated estrogens from the urine of pregnant mares. These agents are highly lipophilic thus are well absorbed orally or as a transdermal preparation, and are extensively plasma bound. Estradiol is rapidly metabolized in the liver, thus is not effective orally. Estradiol benzoate is a slow-release form used parenterally. Ethinyl estradiol is effectove orally. Mestranol is a prodrug, quickly demethylated in the body to ethinyl estradiol.

The estrogens have significant metabolic effects. They increase bonemass and density, increase serum HDL while decreasing LDL, have multiple effects on blood vessels to enhance vasodilation and reduce artherosclerosis, induce fluid retention, increase cholesterol secretion and decrease bile acid secretion, increase plasma hormone-binding proteins and facilitate cloth formation.

Clear-cell vaginal and cervical adenocarcinoma have been associated with in utero exposure to estrogenic agents. Other side effecst are fetal abnormalities (never give during pregnancy), increased gallblader disease, migranes, nausea and vomiting.

Non-Steroidal Estrogenic Agents

Non-Steroidal estrogenic drugs include the selective estrogen receptor modulators (SERMs, aka type I antagonists) and aromatase inhibitors. The SERMs include clomiphene, tamoxifen and naloxifene.

Tamoxifen is the drug of choice for the treatment of breast cancer in postmenopausal and some premenopausal woman. It is also effective for long-term prevetion of breas cancer recurrence. Tamoxifen is considered a functional competitive estrogen antagonist that decreases estrogenic stimulation of tumor cells, but may exhibit partial agonost activity in some settings and tissues.

Tamoxifen has a long 1/2 life (5-7 days) due to plasma protein binding, enterohepatic recirculation and accumulation in fat. It also lowers circulating cholesterol levels by inhibiting cholesterol synthesis. Adverse effects include nausea, vomiting, hot flashes, and increased risk of endometrial carcinoma (estrogenic stimulation).

Although the SERMs may reduce estrogenic stimulation of tumor cells, circulating estrogens may still influence hormonw-dependent tissue. Therefore, reducing circulating estrogen levels by inhibiting its synthesis would be beneficial in patients being treated for breast cancer with tamoxifen. This was first shown with aminoglutethimide, a non-specific inhibitor of all steroid synthesis. But aminogluthemide caused too many toxic effects. Today, a new and more selective class of drugs, the aromatase inhibitirs is being used in addition to taxinophen in order to further reduce estrogenic stimulation. The aromatase inhibitors selectively inhibit the final step in estrogen synthesis.

Currently available aromatase inhibitors include examestane, formestane and the non-steroidals ansatrozole, letrozole and vorozole. These agents lower estrogen levels, thus reducing homonal estimulation. They are useful in adjuvant therapy of breast cancer wit tamoxifen.

Progesterone and Analogs

Activation of the progesterone receptor mediates maintenance o pregnancy, development of the secretory epithelium, proliferation of acini in mammary glands, termogenic effcts in the CNS and blunting of estrogenic effects. Progesteron also has "crossover effects" at androgen receptors. They are used threapeutically in post-menopausal hormone replacement therapy and in oral contraceptives.

Contraceptive treatment entails daily doses of estrogen in combination with progestins for 21 days, then withdrawal for 7 days to allow "normal" menses. Estrogen inhibits ovulation, while progestin both inhibit ovulation and produces effects in the endometrium and cervix that prevents fertilization/implantation. A number of bi-phasic and tri-phasic preparations are avilable in which two or three different doses of one or both components are taken obver the 21 days in an attempt to lower the total dose of hormones given and thus reduce the incidence of side effects. Some progestin-only contraceptives include the "minipill", depot preparations like norplan and depo-provera, or progesteron-impregnated IUDs.

Progestins are synthetic analogs of progesterone, amoung them hydroxyprogesterone caproate and medroxygesterone acetate. 19-nortestosterone derivatives that poses both progestational and androgenic activity include norethindrone, norgestrel, deogestrel and others. In order to make these agents orally effect, some are substituted at the 19 position. Because of this substitution, these compounds are structurally similar to testosterone, therefore produce some effects at the androngen receptors. The gonanes, norgestrel, desogestrel and norgestimate, have the least androgenic activity of sinthetic 19-substituted progestin.

The progestins are highly lipophilic, extensively bound to plasma membranes and metabolized in the liver. Analogs such as hydroprogesterone and medroxyprogesterone are used as injected slow release forms, in a depot form from which they are slowly absorbed into the systemic circulation, providing progesterone activity for several months. Some are inactive forms that are metabolised to progesterone. The 19-substituted compounds are orally effective.

Progestin may lead to hirsutism, but al reduces the risk of endometrial and ovarian cancer. Estrogen may increase blood presure (5-10%), increase risk of breast cancer or bening hgepatoma, and increase risk of thromboembolic or other cardiovascular disorders. Minor side effects include headache, nausea and edema. Estrogen can also normalize menstrual irregularities.

Progesterone-only contraceptives may cause irregular breakthroug bleeding, edema, weight gain, depression, headache, and impaired fertility upon withdrawal.

Estrogen/progestin contraceptives are contraindicated if the patien suffers from cardiovascular disease, hormone-dependent neoplasia, liver tumors or liver disfunction, and pregnancy. Smoking, age, diabetes, hypertension and gallblader disease may increase the potential risk for serious complications. Other drugs that induce hepatic enzymes (barbituates, rifampin, phenitoin) or interfere with enterohepatic cyclin (ampicillin, tetracyclin) will reduce the efficacy of oral contraceptives.

Post-coital contraception is achieved by preparations like plan-B (levonogestrel) and preven (levonogestrel plus ethinil estradiol) or by using a competitive progesterone antagonist like mifepristone. The mechanism of action of plan-B and preven is unclear. They are taken within 72 hours after intercourse, are 75% effective, and they may causenausea, vomiting, headache and cramps.

Mifepristone may be used in combination with misoprostol (?). It breakdowns the endothelium, disrupts normal ovulation and menstrual cycling, blocks progesteron-mediated stimulation, and increases plasma levels of glucocorticoids (also a glucociorticoid antagonis). Adverse effects include bleeding, nausea, vomiting, abdominal pain and fatigue. Mifepristone may also be used in hormonal control therapy (endometriosis, breast cancer, etc.).

Male Steroids

Testosterone enters cells and acts by activating the androgen nuclear receptor, in a way similar to estrogen. In some tissues, testosterone in converted to dihydrotestosterone by 5a-reductase. Dihydrotestosterone has a higher affinity for the androgen receptor than testosterone. These two steroids mediate different process. Testosterone is responsible for penile, scrotal and vocal cord enlargement during development, spermatogenesis, muscle mass increase, male libido and sexual performance. Dihydrotrstoasterone increases body and facial hair, but also acne, prostate enlargement, and scalp hair recession.

Adrogens are used clinically in replacement therapy (hypogonadism), to treat breast cancer, stimulate erythropoiesis and to treat a rare condition called hereditary angioneurotic edema.

Testosterone is rapidly metabolized by the first pass effect, thus is not effective orally. It also binds higly to plasma proteins. Testosterone esters ( propionate, enanthate, cypionate) have a slower absoption. Alkylated testosterone (methyltestosterone, alkyltestosterone) and the synthetic danazol are effective orally but may lead to hepatic toxicity. Testosterone can also be administered transdermally.

Androgen antagonists may be steroidal (cyproterone acetate and megesterol acetate) or non-steroidal (flutamide, nilutamide and bicalutamide). Flutamide is used in the treatment of prostatic cancer, with survival rates similar to castration. Adverse effects ionclude gynecomansia, impotence, and hepatotoxicity. Gynecomansia arises from the conversion of excess testosterone to estrogen by aromatase. Cyproterone does not have this side effect because of its progestational activity. Bicalutamide is now replacing flutamine because it is less hepatotoxic and can be taken only once a day.

Other drugs with antiandrogenic activity include spironolactone and cimetidine. Finasterine is an inhibitor of 5a-reductase (Type II) , i.e. inhibits the conversion of testosterone to dihydrotestosterone, used to treat bening prostatic hypertrophy and male pattern baldness. It seems that overestimulation of the hair follicle by dihydrotestosterone leads to hair loss. Finasterine will prevent hair loss, but the effect lasts only as long as the drug is administered. It is contraindicated in women, especially if are or will become pregnant, and in patients with liver impairment.

At high doses, androgens have an anabolic effect, thus are known as anabolic steroids. Megadoses of androgens enhance altltic peerformance in certain setings only, but have many dangerous side effects: depressed spermatogenesis (from inhibition of gonadotropic hormone release), feminization due to conversion of excess androgens to estrogens by aromatization (or masculinization in females), arherosclerosis (decreased HDL levels), edema, weight gain, hepatic disorders and probabi cancer, and behavioural changes.

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