Contraceptives are the drugs that prevent contraception since they control fertility; they are also called anti-fertility drugs.
General Physiology of Human Reproduction
- Ovulation is the key event in the human reproductive cycle. It usually occurs on the 14th ± 2 days of 28 days cycle. During this cycle following changes occurs:
- This released ovum enters into the fallopian tube and gets fertilized by the sperm.
- The fertilized ovum gets converted into a blastocyst.
- This reaches the uterine cavity and gets implanted by 21st to 23rd day of the cycle.
- The implantation was completed by the 35th day.
- Oral contraceptives are the hormonal preparation/pills use to prevent conception, fertilized ovum.
- During pregnancy ovarian hormonal levels are very high and they prevent ovulation.
- So ovulation can be prevented either by estrogen/progesterone/both.
- So when ovulation is prevented, pregnancy is automatically prevented.
- Oral contraceptives contain estrogen/progesterone/both.
- Oral contraceptive pills are prescribed medications used to prevent pregnancy.
- Also used to reduce menstrual cramps and anemia.
- The combined oral contraceptive pill is extremely effective, at least in the absence of intercurrent illness and treatment with potentially interacting drugs.
- The estrogen in most combined preparations (second-generation pills) is ethinylestradiol, although a few preparations contain mestranol instead.
- The progestogen may be norethisterone, levonorgestrel, ethynodiol, or-in ‘third-generation pills-desogestrel or gestodene, which are more potent, have less androgenic action, and cause less change in lipoprotein metabolism, but which probably cause a greater risk of thromboembolism than do second-generation preparations.
- The estrogen content is generally 20-50µg of ethinylestradiol or its equivalent, and preparation is chosen with the lowest estrogen and progestogen content that is well tolerated and gives good cycle control in the individual woman.
- This combined pill is taken for 21 consecutive days followed by 7 pill-free days, which causes a withdrawal bleed.
- Normal cycles of menstruation usually commence fairly soon after discontinuing treatment, and permanent loss of fertility (which may be a result of early menopause rather than a long-term consequence of the contraceptive pill) is rare.
- Oestrogen inhibits the secretion of FSH via negative feedback on the anterior pituitary, and thus suppresses the development of the ovarian follicle.
- Progestogen inhibits the secretion of LH and thus prevents ovulation; it also makes the cervical mucus less suitable for the passage of sperm.
- These also modify the cervical mucosa, secretion becomes thick and slowing down sperm penetration and prevent implantation.
- Estrogen and Progestogen act in concert to alter the endometrium in such a way as to discourage implantation.
- They may also interfere with the coordinated contractions of the cervix, uterus, and fallopian tubes that facilitate fertilization and implantation.
- Potential unwanted and beneficial effects of the combined pill.
- Weight gain, owing to fluid retention or an anabolic effect, or both.
- Mild nausea, flushing, dizziness, depression, or irritability.
- Skin changes (e.g. acne and/or an increase in pigmentation).
- Amenorrhoea of variable duration on cessation of taking the pill.
- Mastalgia, migraine, chloasma, Increased vaginal secretion, Hypertension.
- Venous thromboembolism, Decreased HDL, Bleeding irregularities.
Types of Oral Contraceptives
1. Combined pills
2. Progesterone only pills
3. Postcoital (emergency pills)
4. Long-acting progesterone-only pills
5. Mini pills
6. Male pills
1. Combined Pills:
- They are daily medications containing two hormones, estrogen, and progesterone.
- Estrogens- ethinylestradiol, mestranol
- Progesterone- levonorgestrel, norethisterone, ethynodiol
- Is taken for 21 days (from the 5th day to the 21st of the 28 days cycle) a month and the last 7 days are pill-free days.
- Menstruation starts after the medication is over.
- Decreases menstrual symptoms like irregular periods and intermenstrual bleeding.
- Decrease in benign breast diseases, uterine fibroids, functional cysts.
- Hypertension and increased risk of breast cancer.
- Weight gain.
- Nausea, flushing, dizziness.
- Skin changes like acne or pigmentation.
Indications where estrogen must be avoided:
- History of blood clot disorders.
- History of stroke or heart attack.
- Severe hypertension.
- Diabetes relates to blood vessel disorders.
- Poorly controlled diabetes.
- Severe headaches (migraine).
- Breast cancer.
- Liver cancer.
2. Progesterone only Pills:
- This pill is also called mini pills.
- This pill is given monthly once and it contains norgestrel.
- Used in cases where estrogen is contraindicated.
- Reasons are venous thrombosis, old age, smoking, Increased Blood pressure.
- The contraceptive effect is not so good as in combined pills.
- The mechanism of action is by causing alteration in the cervical mucus, making it inhospitable to sperms.
- Adverse reactions include irregular bleeding, weight gain, and hair loss.
3. Post Coital Emergency Pills:
- Taken after unprotected intercourse to avoid pregnancy.
- Mostly contains Levonorgestrol or levonorgestrel along with estrogen (di ethyl stilbestrol).
- Must be taken within 72 hours of unsafe intercourse and reduces the risk of pregnancy by 75%.
- Blocking ovulation.
- Altering mucus in the cervix.
- Changing endometrium.
- Nausea and vomiting took with domperidone.
- Breast tenderness.
- Bleeding between periods or heavier menstrual bleeding.
- Lower abdominal pain or cramps.
4. Long-acting Progesterone only pills:
- Used for 2-5 months.
- Mostly progesterone alone used or Medroxyprogesterone used.
- Medroxy progesterone given intramuscularly.
- Progesterone implanted subcutaneously in biodegradable capsules.
- Is also given as an intrauterine device that can show action for up to 5 years.
- Effective and safe.
- Adverse effects include irregular bleeding and headache.
5. Sequential Pill:
- Ethinyl estradiol is given from the 5th day to the 20th day and then a combination of estrogen and progesterone is given from the 21st to the 25th day of 28 days menstrual cycle.
- Weight gain.
- Nausea, Vomiting, dizziness.
- Skin changes like acne or pigmentation.
6. Mini Pill:
- These pills contain only progesterone and are given once a month.
- This contains norgestrel
- Nausea and vomiting took with domperidone.
- Breast tenderness.
- Bleeding between periods or heavier menstrual bleeding.
- Lower abdominal pain or cramps.
7. Male Pill:
- Male contraceptives or male are methods of preventing pregnancy that primarily involve male physiology.
- The most commonly used male contraceptive methods are condoms, withdrawal methods, or vasectomy.
- Pills are rarely available for men.
- Gossypol, an extract of cotton, has been studied as a male contraceptive pill. It decreases sperm production; however, this is permanent in 20% of people.
- Estrogens are synthesized by the ovary and placenta, and in small amounts by the testis and adrenal cortex.
- As for other steroids, the starting substance for estrogen synthesis is cholesterol. The immediate precursors to the estrogens are the androgenic substance androstenedione or testosterone.
- There are three main endogenous estrogens in humans: oestradiol, oestrone, and oestriol. Oestradiol is the most potent and is the principal estrogen secreted by the ovary.
- The mass ovary contains ovarian follicles, the follicles are about 40,000 in number they are formed during fetal life.
- About 400 of them developed into adult life, the rest get degenerated, but all the follicles are lost at menopause.
- Ovulation occurs due to the rupture of the ovarian follicles, this is stimulated by LH of the anterior pituitary.
- After discharging the ovum, the rest of the follicle in the ovary forms the corpus luteum.
- Estrogen is produced by the developing follicle, progesterone is produced by the corpus later.
- Effects of exogenous estrogen depend on the state of sexual maturity when the estrogen is administered.
- In primary hypogonadism: estrogen stimulates the development of secondary sexual characteristics and accelerates growth.
- Puberty changes in females such as the appearance of pubic and auxiliary hair, development of breast.
- Development and growth of Vagina, uterus, fallopian tube, and ovaries. Growth of uterus during pregnancy.
- The development of the uterus endometrium during the proliferative stage of the menstrual cycle depends on the secretions of estrogen from the ovaries.
- Stimulates protein and fat metabolism and growth of skeletal muscles.
- Libido is inspired and metabolic changes like Na+ and water retention.
- In adults with primary amenorrhoea: estrogen, given cyclically with a progestogen, induces an artificial cycle.
- In sexually mature women: estrogen (with a progestogen) is contraceptive.
- At or after menopause: estrogen replacement prevents menopausal symptoms and bone loss. Estrogens have several metabolic actions, including mineralocorticoid (retention of salt and water) and mild anabolic actions.
- They increase plasma concentrations of high-density lipoproteins, a potentially beneficial effect that may contribute to the relatively low risk of atheromatous disease in premenopausal women compared with men of the same age.
- Estrogens increase the coagulability of blood and increase the risk of thromboembolism. This effect is dose-related.
- As with other steroids, estrogen binds to type 4 nuclear receptors. There are at least two types of estrogen receptor, termed ERα; and ERβ, the roles of which are currently being investigated using mice in which the gene coding one or other of these has been ‘knocked out.
- Binding is followed by interaction of the resultant complexes with nuclear sites and subsequent genomic effects-either gene transcription (i.e. DNA-directed RNA and protein synthesis) or gene repression (inhibition of transcription).
- In addition to these ‘classic’ intracellular receptors, some estrogen effects, in particular its rapid vascular actions, may be initiated by interaction with membrane receptors.
- Acute vasodilatation caused by 17-β-oestradiol is mediated by nitric oxide, and a plant-derived (Phyto-) estrogen called genistein (which is selective for ERβ, as well as having quite distinct effects from inhibition of protein kinase C) is as potent as 17- β-oestradiol in this regard.
- Oestrogen receptor modulators (receptor-selective estrogen agonists or antagonists) are mentioned briefly immediately below this section.
- Natural estrogen: Estradiol, Estrone, Estriol
- Semisynthetic estrogens: Ethinyl estradiol, Mestranol, Quinestrol
- Synthetic estrogens: Diethylstilbestrol, Methallenosstrol, Chlorotrianisene
- Non-steroidal agents with estrogenic activity: Hexestrol, Dienestrol, Benzestrol, Methallenoestril.
- Many preparations (oral, transdermal, intramuscular, implantable, and topical) of estrogens are available for a wide range of indications.
- These preparations include natural (e.g. estradiol, estriol) and synthetic (e.g. mestranol, ethinylestradiol, stilbestrol) oestrogens.
- Estrogens are presented either as single agents or combined with progestogen.
Replacement therapy for:
- Primary ovarian failure (e.g. Turner’s syndrome).
- Secondary ovarian failure (menopause) for flushing, vaginal dryness and to preserve bone mass.
- Prostate and breast cancer (these uses have largely been superseded by other hormonal manipulations)
- To treat estrogen-sensitive breast cancer (tamoxifen).
- To induce ovulation (clomiphene) in treating infertility.
- Natural as well as synthetic estrogens are well absorbed in the gastrointestinal tract, but after absorption, the natural estrogens are rapidly metabolized in the liver, whereas synthetic estrogens are degraded less rapidly.
- There is a variable amount of enterohepatic cycling, which forms the basis for drug interaction because broad-spectrum antibiotic use alters bowel flora and can thereby render oral contraception ineffective. Most estrogens are readily absorbed from the skin and mucous membranes.
- They may be given topically in the vagina as creams or pessaries for local effect. In the plasma, natural estrogens are bound to albumin and a sex steroid-binding globulin.
- Natural estrogens are excreted in the urine as glucuronides and sulfates.
- To induces menses in primary and secondary amenorrhoea.
- To reduced disturbing menopausal syndrome.
- Post menopausal osteoporosis.
- Acne and Hirsutism.
- Oral contraceptives.
- Tenderness in the breasts, nausea, vomiting, anorexia, retention of salt and water with resultant edema, and increased risk of thromboembolism.
- Used intermittently for postmenopausal replacement therapy, estrogens cause menstruation-like bleeding.
- Estrogen causes endometrial hyperplasia unless given cyclically with a progestogen. When administered to males, estrogens result in feminization.
- Oestrogen administration to pregnant women can cause genital abnormalities in their offspring. Carcinoma of the vagina was more common in young women whose mothers were given stilbestrol in early pregnancy in a misguided attempt to prevent miscarriage.
Oestrogen Receptor Modulator:
- Raloxifene, a ‘selective estrogen receptor modulator’, has antiestrogenic effects on the breast and uterus but oestrogenic effects on bone, lipid metabolism, and blood coagulation.
- It is used for the prevention and treatment of postmenopausal osteoporosis and reduces the incidence of estrogen receptor-positive breast cancer, although its role in the therapy of breast cancer is undefined. Unlike estrogen, it does not prevent menopausal flushes.
- Antioestrogens compete with natural estrogens for receptors in target organs.
- Tamoxifen has antiestrogenic action on mammary tissue but oestrogenic action on plasma lipids, endometrium, and bone.
- It produces mild estrogen-like adverse effects consistent with partial agonist activity.
- The tamoxifen-estrogen receptor complex does not readily dissociate, so there is interference with the recycling of receptors.
- Tamoxifen up-regulates transforming growth factor-β, decreased function of which is associated with the progression of malignancy, and which has a role in controlling the balance between bone-producing osteoblasts and bone-resorbing osteoclasts.
- Clomiphene inhibits estrogen binding in the anterior pituitary, so preventing the normal modulation by negative feedback and causing increased secretion of GnRH and gonadotropins.
- This results in a marked stimulation and enlargement of the ovaries and increased estrogen secretion.
- The main effect of their antioestrogen action in the pituitary is that they induce ovulation. It is used in treating infertility caused by a lack of ovulation.
- Twins are common, but multiple pregnancies are unusual.
- It is secreted from the corpus luteum from the healing scar of the ovary after ovulation.
- It is synthesized in the placenta, adrenal, and testes.
- It is secreted during the last month of pregnancy. It is an important intermediate in the synthesis of steroids.
- Progesterone inhibits ovulation, advanced pregnancy, stabilizes uterus, and enlargement of breast.
- The natural progestational hormone (progestogen) is progesterone . This is secreted by the corpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy. Small amounts are also secreted by the testis and adrenal cortex.
- Progestogens act, as do other steroid hormones, on nuclear receptors. The density of progesterone receptors is controlled by estrogens.
- Natural: Progesterone.
- Derivatives of progesterone: Hydroxyprogesterone, Dehydrogesterone, Methoxy-progesterone.
- Derivatives of testosterone: Ethisterone, Dimethisterone.
- Derivatives of 19-nor testosterone: Norethisterone, Norethynodrel, Norgestrol, Lynesterol.
- There are two main groups of progestogens.
- The naturally occurring hormone and its derivatives (e.g. hydroxyprogesterone, medroxyprogesterone, dydrogesterone). Progesterone itself is virtually inactive orally, because after absorption it is metabolized in the liver, and hepatic extraction is nearly complete.
- Other preparations are available for oral administration, intramuscular injection, or administration via the vagina or rectum.
- Testosterone derivatives (e.g. norethisterone, norgestrel, and ethynodiol) can be given orally. The first two have some androgenic activity and are metabolized to give oestrogenic products.
- Newer progestogens used in contraception include desogestrel and gestodene; they may have less adverse effects on lipids than ethynodiol and may be considered for women who experience side effects such as acne, depression, or breakthrough bleeding with the older drugs.
- However, these newer drugs have been associated with higher risks of venous thromboembolic disease.
- Premenstrual stimulation of estrogens and preparations of the endometrium for menstrual cycle. Menstrual occurs when progesterone level falls.
- Pregnancy is sustained because of progesterone secretion.
- It neutralizes Oxytocin of the pituitary and protects pregnancy by preventing uterine contraction.
- During pregnancy, menstruation is inhibiting and the development of the breast is due to progesterone.
- The birth passage is relaxed by progesterone and so it widens to facilitate the birth of a baby.
- Protein metabolism is decreased with progesterone.
- Estrogen-progesterone in combination may be synergistic or opposite, competitive depends upon the stage of the sex life of women.
- Progesterone acts, in turn, on estrogen-primed endometrium, stimulating the secretory phase of the cycle, which renders the endometrium suitable for the implantation of a fertilized ovum. During this phase, cervical mucus becomes more viscous, less alkaline, less copious, and in general less welcoming for sperm.
- Progesterone exerts negative feedback on the hypothalamus and pituitary, decreasing the release of LH.
- It also has a thermogenic effect, causing a rise in body temperature of about 0.5°C at ovulation, which is maintained until the end of the cycle.
- If implantation of the ovum does not occur, progesterone secretion stops, triggering menstruation.
- If implantation does occur, the corpus luteum continues to secrete progesterone, which, by its effect on the hypothalamus and anterior pituitary, prevents further ovulation.
- The chorion (an antecedent of the placenta) secretes human chorionic gonadotrophin (HCG), which maintains the lining of the womb during pregnancy.
- For reasons that are not physiologically obvious, HCG has an additional pharmacological action in stimulating ovulation.
- As pregnancy proceeds, the placenta develops further hormonal functions and secretes a gamut of hormone variants (often with post-translational modifications), including gonadotrophins as well as progesterone and estrogens.
- Progesterone secreted during pregnancy controls the development of the secretary alveoli in the mammary gland, while estrogen stimulates the lactiferous ducts.
- After parturition, estrogens, along with prolactin are responsible for stimulating and maintaining lactation, whereas high doses of exogenous estrogen suppress this.
- Progesterone controls the later secretory phase and has negative feedback effects on both the hypothalamus and anterior pituitary.
- If a fertilized ovum is implanted, the corpus luteum continues to secrete progesterone.
- After implantation, human chorionic gonadotrophin from the chorion becomes important, and later in pregnancy progesterone and other hormones are secreted by the placenta.
- Injected progesterone is bound to albumin, not to the sex steroid-binding globulin. Some are stored in adipose tissue.
- It is metabolized in the liver, and the products, pregnanolone, and pregnanediol are conjugated with glucuronic acid and excreted in the urine.
- To prevent the threatened operation in the first three months of pregnancy
- The recession of endometrium cancer occurs if a large dose of progesterone is administered
- To control bleeding during and after delivery
- Use as replacement therapy during irregular bleeding.
- As contraceptives:
- With estrogen in the combined oral contraceptive pill.
- As injectable or implantable progesterone-only contraception.
- As part of an intrauterine contraceptive system.
- Progesterone with a high dose of estrogen use as contraceptives.
- As progesterone-only contraceptive pill.
- Use in cystic fibrosis.
- If a high dose of progesterone with a lower dose of estrogen is administered in the first week of the menstrual cycle it helps in conceiving.
- It is a pill of contraception, a pill to conceive, depends upon the time of administration.
- In endometrial carcinoma; use in breast and renal cancer has declined.
- Nausea, breast discomfort, headache, fatigue, mental depression, and rarely liver damage.
- Weak androgenic actions, acne, fluid retention, weight change, depression, change in libido, breast discomfort, premenstrual symptoms, irregular menstrual cycles, and breakthrough bleeding.
- There is an increased incidence of thromboembolism.
- Poorly validated uses have included various menstrual disorders.
Progestogens and Antiprogestogens
- Medical termination of pregnancy: mifepristone (partial agonist) combined with a prostaglandin (e.g. gemeprost).
- The endogenous hormone is progesterone. Examples of synthetic drugs are the progesterone derivative medroxyprogesterone and the testosterone derivative norethisterone.
- Mechanism of action involves intracellular receptor/altered gene expression, as for other steroid hormones. Oestrogen stimulates the synthesis of progesterone receptors, whereas progesterone inhibits the synthesis of estrogen receptors.
- The main therapeutic uses are in oral contraception and estrogen replacement regimens, and to treat endometriosis.
- The antiprogestogen mifepristone, in combination with prostaglandin analogs, is an effective medical alternative to surgical termination of early pregnancy.
- Mifepristone is a partial agonist at progesterone receptors. It sensitizes the uterus to the action of prostaglandins. It is given orally and has a plasma half-life of 21 hours.
- Mifepristone is used, in combination with a prostaglandin (e.g. gemeprost; see below), as a medical alternative to surgical termination of pregnancy.
ANDROGENS AND ANABOLIC STEROIDS
- Androgen is the hormone that controls the building up of proteins and male secondary sex characteristics.
- Natural androgen is testosterone that is secreted mainly from the testis, adrenal cortex, and also in the ovary.
- Testosterone is the main natural androgen. It is synthesized mainly by the interstitial cells of the testis, and in smaller amounts by the ovaries and adrenal cortex.
- Androgen is formed in the fetal testis under the influence of maternal gonadotropin. It causes descent of the testis, later no androgen forms until puberty
- At puberty, the hypophysial cells stimulate the leading cells to produced androgen. It leads to the development of testis and secondary sexual characters.
- Adrenal production of androgens is under the control of adrenocorticotrophic hormone (corticotrophin). As for other steroid hormones, cholesterol is the starting substance. Dehydroepiandrosterone and androstenedione are important intermediates. They are released from the gonads and the adrenal cortex and converted to testosterone in the liver.
- In general, the effects of exogenous androgens are the same as those of testosterone and depend on the age and sex of the recipient.
- If administered to boys at the age of puberty, there is the rapid development of secondary sexual characteristics maturation of the reproductive organs like prostate, seminal vesicles, and the external genitals are also stimulated.
- The life and fertility of spermatozoa is maintained
- Development of secondary sexual characters like the appearance of mustache, beard, pubic and auxiliary hair, etc.
- Growth of larynx, thickening of vocal cord, and loudness of voice.
- The anabolic effects can be accompanied by the retention of salt and water.
- The skin thickens and may darken, and sebaceous glands become more active (which can result in acne).
- The bony structure becomes more heavy and strong because of the stimulation by an anabolic fraction of the testosterone.
- Muscular development is more in males compared to females because of the stimulation by an anabolic fraction of the testosterone, which increased protein metabolism.
- Blood volumes and RBCs are more in males compared to females because of the stimulation by an anabolic fraction of the testosterone.
- Water percentage is more in males since anabolic fraction stimulates Na+ and water retention.
- High temperature inhibits testicular activity. Libido is inspired by the male.
- Physiological and behavioral changes like the feeling of well-being and an increase in physical vigor, and may increase libido. Whether they are responsible for sexual behavior as such is controversial, as is their contribution to aggressive behavior.
- Administration of ‘male’ doses to women results in masculinization, but lower doses (e.g. 300µg/day testosterone patches) restore plasma testosterone to normal female concentrations and improve sexual dysfunction in women following ovariectomy, without adverse effects.
Mechanism of Action
- In most target cells, testosterone works through an active metabolite, dihydrotestosterone, to which it is converted locally by a 5α-reductase enzyme.
- In contrast, testosterone itself causes virilization of the genital tract in the male embryo and regulates LH/ICSH production in anterior pituitary cells.
- Testosterone and dihydrotestosterone modify gene transcription by interacting with intracellular receptors.
- Its well absorbed when given by the oral route, undergoes metabolism in the liver, and hence ineffective therapeutically.
- Rejuvenate testis and in importance to increased testicular secretion
- It prevents body atrophy in old people.
- Use in severe trauma and prolonged illness.
- To overcome osteoporosis in old people.
- In women, testosterone can be used to produced symptomatic relief from breast cancer
- It is also used to check uterine bleeding in menorrhagia.
- Liver damage decreased release of gonadotropin hormones, increased salt, and water retention leads to edema.
- In female-produced acne, masculinization.
- Testosterone itself can be given by subcutaneous implantation or by transdermal patches.
- Various esters (e.g. enanthate and propionate) are given by intramuscular depot injection. Testosterone undecanoate and mesterolone can be given orally.
- Androgens can be modified chemically to alter the balance of anabolic and other effects. Such ‘anabolic steroids’ (e.g. nandrolone) increase protein synthesis and muscle development, but clinical use (e.g. in debilitating disease) has been disappointing.
- They are used in the therapy of aplastic anemia, and (notoriously) abused by some athletes. Unwanted effects are described above, under Androgens. In addition, cholestatic jaundice, liver tumors, and increased risk of coronary heart disease are recognized adverse effects of high-dose anabolic steroids.
- Androgens and the hormonal control of the male reproductive system.
- Gonadotrophin-releasing hormone from the hypothalamus acts on the anterior pituitary to release both follicle-stimulating hormones, which stimulate gametogenesis, and luteinizing hormone (also called interstitial cell-stimulating hormone), which stimulates androgen secretion.
- The endogenous hormone is testosterone; intramuscular depot injections of testosterone esters are used for replacement therapy.
- Mechanism of action is via intracellular receptors.
- Effects depend on age/sex and include the development of male secondary sexual characteristics in prepubertal boys and masculinization in women.
- Derivatives of testosterone: Nandrolone phenylpropionate, Nandrolone decanoate.
- Derivatives of methyltestosterone: Oxymetholone, Oxandrolone, Stanozolol, Methly testosterone.
- Protein metabolism: They promote protein metabolism. This manifests as an increase in muscle mass and body weight.
- Anti catabolic effects: The catabolic effects of glucocorticoids are counteracted and a positive nitrogen balance is produced.
- Miscellaneous: Progestational activity and decrease in bone resorption which prevents osteoporosis.
- In chronic illness to accelerate the rebuilding of tissues.
- To promote growth in hypogonadal children and pituitary dwarfs.
- Breast cancer in females.
- Androgens (testosterone preparations) as hormone replacement in:
- Male hypogonadism due to pituitary or testicular disease
- Hyposexuality following ovariectomy (e.g. 300µg/day patches).
- Both estrogens and progestogens have antiandrogen activity, estrogens mainly by inhibiting gonadotropin secretion, and progestogens by competing with androgens in target organs. Cyproterone is a derivative of progesterone and has weak progestational activity. It is a partial agonist at androgen receptors, competing with dihydrotestosterone for receptors in androgen-sensitive target tissues.
- Through its effect in the hypothalamus, it depresses the synthesis of gonadotropins. It is used as an adjunct in the treatment of prostatic cancer during the initiation of GnRH treatment.
- It is also used in the therapy of precocious puberty in males, and masculinization and acne in women.
- It also has a central nervous system effect, decreasing libido, and has been used to treat hypersexuality in male sexual offenders.
- Flutamide is a non-steroidal antiandrogen used with GnRH in the treatment of prostate cancer.
- Drugs can have antiandrogen action by inhibiting synthetic enzymes.
- Finasteride inhibits the enzyme (5α-reductase) that converts testosterone to dihydrotestosterone, which has a greater affinity than testosterone for androgen receptors in the prostate gland.
- Finasteride is well absorbed after oral administration, has a half-life of about 7 hours, and is excreted in the urine and feces.
- It is used to treat benign prostatic hyperplasia, although α1-adrenoceptor antagonists, terazosin or tamsulosin, are more effective (working by the entirely different mechanism of relaxing the smooth muscle in the capsule of the prostate gland). Surgery is the preferred option (especially by surgeons).
- If given orally, testosterone is rapidly metabolized in the liver. It is therefore usually injected.
- Virtually all testosterone in the circulation is bound to plasma protein-mainly to the sex steroid-binding globulin.
- The elimination half-life of free testosterone is short (10-20 minutes). It is inactivated in the liver by conversion to androstenedione.
- This has weak androgenic activity in its own right and can be reconverted to testosterone, although approximately 90% of testosterone is eliminated as metabolites rather than the parent compound.
- Synthetic androgens are less rapidly metabolized, and some are excreted in the urine unchanged.
- Antiandrogens (e.g. flutamide, cyproterone) are used as part of the treatment of prostatic cancer.
- 5α-Reductase inhibitors (e.g. finasteride ) are used in benign prostatic hypertrophy.
- Cholestatic jaundice, Liver damage, Sodium, and water retention on prolonged use.
- Unwanted effects of androgens include eventual decrease of gonadotrophin release, with resultant infertility, and salt and water retention leading to edema. Adenocarcinoma of the liver has been reported.
- Androgens impair growth in children (via premature fusion of epiphyses), cause acne, and lead to masculinization in girls.
- Adverse effects of testosterone, replacement, and monitoring for these are reviewed by Rhoden & Morgentaler.
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