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Steroid hormones Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg www.medpharm-sofia.eu
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Corticosteroids
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Pathways of corticosteroid biosynthesis Δ4-Androstendione Testosterone
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Glucocorticosteroids diffuse into the cell, but access to the receptor may be prevented, for example in kidney, by the enzyme 11-beta hydroxysteroid dehydrogenase, which converts active cortisol into inactive cortisone. When activated, the receptors translocate to the nucleus where they can upregulate gene transcription by action on specific DNA response elements. Glucocorticosteroid
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Rang et al. Pharmacology – 5st Ed. (2003)
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ACTIONS OF HYDROCORTISONE (CORTISOL) The effects of hydrocortisone will be described as a basic glucocorticoid hormone. There is a distinction between replacement therapy (physiological effects) and the higher doses of pharmacotherapy. (1) On inorganic metabolism (mineralocorticoid effects): cortisol increasis retention of sodium by the renal tubule, and increasis potassium excretion in the urine.
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(2) On organic metabolism (glucocorticoid effects): • Carbohydrate metabolism: gluconeogenesis is increased and peripheral glucose utilization (transport across cell membranes) may be decreased (insulin antagonism) so that hyperglycaemia and sometimes glycosuria result. Latent diabetes becomes overt. • Protein metabolism: anabolism (conversion of amino acids to protein) is decreased but catabolism continues unabated or even faster, so that there is a negative nitrogen balance with muscle wasting. Osteoporosis (reduction of bone protein matrix) occurs, growth slows in children, the skin atrophies and this, with increased capillary fragility, causes bruising and striae.
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Healing of peptic ulcers or of wounds is delayed. • Fat deposition: this is increased on shoulders, face, and abdomen. • Inflammatory response is depressed; corticosteroids can be a source of danger in infections by limiting useful protective inflammation. Neutrophil and macrophage function are depressed, including the release of chemical mediators and the effects of these on capillaries. Glucocrticosterods have antiexudative and antiproliferative effects.
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The anti-inflammatory actions of glucocorticoids are mediated by stimulation of synthesis of lipocortin, which inhibits pathways for production of eicosanoids (prostaglandins, leukotrienes, lipoxins), and platelet activating factor too. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition.
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(+) (-)
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Allergic responses are suppressed. The antigen-antibody interaction is unaffected, but its injurious inflammatory consequences do not follow. • Antibody production is reduced by heavy doses. • Lymphoid tissue is reduced (including leukaemic lymphocytes). • Renal excretion of urate is increased. • Blood eosinophils are reduced in number. • Euphoria or psychotic states may occur, perhaps due to CNS electrolyte changes. • Anti-vitamin D action.
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Overview of the hypothalamic- pituitary- adrenal axis and the immune inflammatory network
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• Reduction of hypercalcaemia chiefly where this is due to excessive absorption of calcium from the gut (sarcoidosis, vitamin D intoxication). • Urinary calcium excretion is increased and renal stones may form. • Growth reduction where new cells are being added (growth in children), but not where they are replacing cells as in adult tissues. • Suppression of hypothalamic/pituitary/adrenocor- tical feedback system (with delayed recovery) occurs with chronic use, so that abrupt withdrawal leaves the patient in a state of adrenocortical insufficiency.
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Hydrocortisone Prednisolone Nonfluorinated prednisolones Fluorinated prednisolones Methylprednisolone Betamethasone Dexamethasone Triamcinolone The most used glucocorticoids
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Structure and nomenclature of corticosteroid products and selected synthetic derivatives
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Hydrocortisone (cortisol) is the principal naturally occurring steroid; it is taken orally; a soluble salt can be given i.v. for rapid effect in emergency (whether due to deficiency, allergy, or inflammatory disease). A suspension (Hydrocortisone Acetate) can be given intra-articularly. Prednisone is a prodrug, i.e. it is converted into prednisolone in the liver. Prednisolone is predominantly anti-inflammatory glucocorticoid, biologically active, and has little sodium-retaining activity; it is the standard choice for anti-inflammatory pharmacotherapy, orally or i.m.
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Fluorinated glucocorticosteroids Triamcinolone has virtually no sodium retaining (mineralocorticoid) effect but has the disadvantage that muscle wasting may occasionally be severe and anorexia and mental depression may be more common at high dose. Dexamethasone and Betamethasone are similar, powerful predominantly anti-inflammatory steroids. They are longer-acting than prednisolone and are used for therapeutic adrenocortical suppression.
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Replacement glucocorticoid therapy Acute adrenal insufficiency Chronic adrenal insufficiency (Addison's disease) Congenital adrenal hyperplasia (adrenogenital syndrome) Glucocorticoid pharmacotherapy for non endocrine diseases Steroids are powerful drugs. They may cause dramatic improvement in many severe diseases as well as produce equally severe adverse effects if not properly used.
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The use of steroids in non endocrine disease is empirical and palliative, but may be life-saving. The following general principles must be observed (Tripathi, 2003): Single dose (even excessive) is not harmful. Short courses (even high dose) are not likely to be harmful in the absence of contraindications. Long-term use is potentially hazardous. No abrupt withdrawal after a corticoid has been given for more than 2 to 3 weeks: may precipitate adrenal insufficiency.
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1. Rheumatoid arthritis: corticoids are one of the last resort drugs. 2. Osteoarthritis. Intra-articular injection of steroid is rare, but may be used to control an acute exacer- bation. Repeated injections may cause joint destruction. 3. Rheumatic fever. Corticoids are used only in severe cases with myocarditis and CHF. 4. Collagen diseases: systemic lupus erythematosus, polyarteritis nodosa, dermatomyositis, nephrotic syndrome, glomerulonephritis. 5. Severe allergic reactions 6. Autoimmune diseases: autoimmune haemolytic anaemia, thrombocytopenia, active chronic hepatitis
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7. Bronchial asthma 8. Eye diseases (as eye drops or ointment) in allergic conjunctivitis, iritis, iridocyclitis, keratitis. 9. Skin diseases: Topical glucocorticosteroids are used in many exematous skin diseases 10.Intestinal diseases: ulcerative colitis, Crohn’s disease, coeliac disease 11.Cerebral oedema due to tumours, tubercular meningitis, etc. 12.Malignancies: acute lymphatic leukemia, Hodgkin’s disease and other lymphomas 13.Organ transplantations and skin allograft 14.To test adrenal-pituitary axis, etc.
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Cushing’s syndrome Osteoporosis Tendency to hyperglycaemia Negative nitrogen balance Increased appetite Increased susceptibility to infections Obesity, etc. Adverse effects of Glucocorti- costeroids Cushing’s syndrome
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Contraindications Peptic ulcer Diabetes mellitus Hypertension Pregnancy (risk foetal defects) Tuberculosis, mycoses, virosis (including Herpes simplex keratitis), and other infections Osteoporosis Psychosis Epilepsy Chronic heart failure Renal failure
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Mineralocorticoids Aldosterone (t1/2 20 min), the principal natural salt retaining hormone, has been used i.m. in acute adrenal insufficiency. After oral admini- stration, it is rapidly inactivated in the first pass through the liver but has no place in routine therapeutics, as fludrocortisone is as effective and is active orally.
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Fludrocortisone has a very great sodium-retaining effect in relation to its anti-inflammatory action and only at high doses the nonelectrolyte effects need to be considered. It is used to replace aldosterone where the adrenal cortex is destroyed (Addison's disease). Fludrocortisone is also the drug of choice in most patients with autonomic neuropathy, in whom volume expansion is easier to achieve than a sustained increase in vasoconstrictor tone. Much higher doses of fludrocortisone (0.5 to 1 mg) are required when the cause of hypotension is a salt- losing syndrome of renal origin, e.g. following an episode of interstitial nephritis.
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Androgens and antiandrogens Estrogens and antiestrogens Progestins and antiprogestins Hormonal contraceptives Sex (gonadal) hormones and antagonists  
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The biochemical pathway in the conversion of cholesterol to: androgens (Dihydrotestosterone) and estrogens (Estradiol)
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Mechanism of action Steroid hormone receptors for gonadal and adrenocortical steroids are complex proteins inside the target cell. They penetrate into the cell and bind to a receptor. Complex steroid/receptor translocates into the cell nucleus, which is the principal site of action and where RNA/protein synthesis occurs. Compounds that occupy the receptor without causing translocation into the nucleus act as antagonists, e.g. spironolactone to aldosterone, cyproterone to androgens, clomiphene to estrogens.
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Pharmacokinetics Steroid sex hormones are well absorbed through the skin. Most are subject to extensive hepatic metabolic inactivation (so much that oral administration is ineffective or requires very large doses). There is some enterohepatic recirculation, especially of estrogen, and this may be interrupted by severe diarrhoea to cause loss of efficacy. There are some nonsteroid analogues that are more slowly metabolized. Sustained-release (depot) preparations are used. The hormones in the blood extensively bind to sex-hormone-binding globulin. The plasma half live relates to the duration of cellular action, which is implied in the recommended dosage schedules.
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Androgens Testosterone is the natural androgen secreted by the interstitial cells of the testis; it is necessary for normal spermatogenesis, for the development of the male secondary sex characteristics, and for the growth, at puberty, of the sexual apparatus. It is converted by hydroxylation to the active dihydrotestosterone. Protein anabolism especially in skeletal muscles is increased by androgens. Growth of bone is promoted, but the rate of closure of the epiphyses is also hastened, causing short stature in cases of precocious puberty or of androgen overdose in the course of treating hypogonadal children.
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Pathway of synthesis of testosterone in the Leydig cells of the testes
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Metabolism of testosterone to its major active and inactive metabolites
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Androgen metabolism and actions. SHBG – sex hormone- binding globulin
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Indications for androgen therapy Testicular failure. It may be primary or secondary (due to lack of pituitary gonadotrophins). In either case replacement with androgens is often necessary. Unfortunately, the sterility is not remedied, although loss of libido and of secondary sex charac- teristics can be greatly improved. If androgen is given to a boy with delayed puberty, a growth spurt and sexual development will occur. Androgens are now little used in metastatic breast cancer because of their virilising effects.
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Androgen preparations Testosterone has extensive hepatic first-pass metabo- lism. It may be given orally or as i.m. depot injections. Mesterolone provides oral therapy. Antiandrogens (androgen antagonists) Estrogens and progestogens are physiological anta- gonists to androgens. But compounds which compete selectively for androgen receptors have been made. Cyproterone is a derivative of progesterone. It is used for reducing male hypersexuality and in prostatic cancer and severe female hirsutism.
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A formulation of cyproterone plus ethinylestradiol (Diane®) is offered for the treatment of severe female hirsutism as well as for severe acne in women; this preparation acts as an oral contraceptive too. Cyproterone causes hepatomas in rats. It is unsuitable for male contraception. Flutamide and bicalutamide are nonsteroidal antian- drogens for use in conjunction with the gonadorelins (e.g. goserelin) in the treatment of prostatic cancer. Finasteride inhibits conversion of testosterone to dihydrotestosterone. It has antiandrogen activity in tissues where dihydrotestosterone is the principal androgen: this makes it a useful drug in the treatment of benign prostatic hyperplasia.
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Spironolactone also has antiandrogen activity and may help hirsutism in women. Androgen secretion may be diminished by continued use of a gonadorelin (LH-RH) analogue. Ketoconazole (antifungal drug) inhibits androgen synthesis and may be used in prostatic cancer. Anabolic steroids Androgens are effective protein anabolic agents, but their clinical use for this purpose is limited by virilisa- tion of women. Attempts made to separate anabolic from androgenic action have been partially success- ful. All anabolic steroids have also androgenic effects.
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Anabolic steroids (Nandrolone) may no longer be used in osteoporosis. They benefit some patients with aplastic anaemia. Hereditary angioedema may be prevented. Anabolic steroids can prevent the calcium and nitrogen loss in the urine that occurs in patients bedridden for a long time and they have therefore been used in the treatment of some severe fractures. The use of anabolic steroids in conditions of general wasting despite nutritional support may be justifiable in extreme debilitating disease, such as severe ulce- rative colitis, and after major surgery. In the later stages of malignant disease they may make the patient feel and look less wretched. Their general use as tonics is scandalous, as is their use in sport.
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Estrogens Estrone and estradiol are both natural estrogens. Estrogens are responsible for the normal development of the female genital tract, of the breast, and of the female secondary sex character- istics. The pubertal growth spurt is less marked in females than in males, probably because estro- gens have less protein anabolic action than do androgens, although they are as effective in promoting closure of epiphyses.
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The biosynthetic pathway for the estrogens
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Neuroendocrine control of gonadotrophin secretion in females
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Blood estrogen concentrations must be above a critical level for the maintenance of both prolife- rative and (together with progesterone) secretory phases of the uterine endometrium. If the estro- gen level falls too low, uterine bleeding follows. Estrogens are necessary for the maintenance of normal pregnancy and for the accompanying breast hyperplasia. The vagina is more sensitive to estrogens than is the endometrium.
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The menstrual cycle, showing plasma levels of pituitary and ovarian hormones and histologic changes
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Hormonal relationships of the human menstrual cycle
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Estrogen preparations Ethinylestradiol (t1/2 13 h) is a synthetic agent of first choice for contraceptive use; it is effective by mouth. Estradiol and estriol are orally active mixed natural estrogens. Their TTS can be effective and convenient for women who dislike oral therapy. Conjugated estrogens (Premarin®) are orally active mixed natural estrogens containing 50–65% estrone obtained from the urine of pregnant mares. Stilboestrol (diethylstilbestrol) is used in androgen dependent cancers (breast, prostate).
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Replacement therapy in hypoestrogenaemia. This term refers to decreased estrogen production due to ovarian disease, or to hypothalamic/pituitary disease (hypogonadotropic hypogonadism). Treat- ment is by cyclic estrogen (conjugated estrogens or ethinylestradiol for 21 days) plus a progestogen, medroxyprogesterone for the last 10 to 14 days of estrogen treatment. An alternative treatment is the oral contraceptive. Unless the cause of the hypoovarian state is primary ovarian failure, treatment should be stopped after every third cycle to see if spontaneous menstruation will occur.
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Postmenopausal hormone replacement therapy (HRT). It is the use of estrogen treatment to reverse or prevent problems due to the loss of ovarian hormone secretion after the menopause, whether physiological or induced. The tissues sensitive to estrogen include brain, bone, skin, cardiovascular and genitourinary system. The two aims of HRT are: (1) To reduce the everyday symptoms of estrogen loss: hot flushes, insomnia, lethargy and depression, vaginal dryness. (2) To prevent the long-term complications asso- ciated with estrogen deficiency: osteoporotic fractures and coronary heart disease.
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All types of HRT (estrogen with or without progestogen) are effective in reducing the hot flushes experienced by more than 50% of postmenopausal women. The benefit is highest during the first year of treatment when 80% of women report a reduced likelihood of flushes. The other major value from HRT is the relief of vaginal dryness. Vaginal admini- stration (as a cream, ring, pessary, or tablet) is the most effective route for treatment of these symptoms. There are three types of regimen used for HRT: (1) Women without uterus take continuous estrogen alone.
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(2) Women require estrogen combined with progestogen to prevent endometrial proliferation. a) In the “sequential” regimen, women take estrogen without a break, and add a progestogen from appro- ximately the 14th to 28th day of each cycle. The first course is started on the 1st day of menstruation (if present), and 28-day cycles of treatment follow thereafter without interval. b) In the “continuous” regimen, appropriate only for women who have been amenorrhoeic for more than one year, fixed dose combinations of estrogen and progestogen are taken without a break.
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A popular alternative to estrogen therapy is the drug Tibolone (Livial®), which is a synthetic steroid with weak estrogenic, progestogenic, and andro- genic properties. It is administered as a daily oral dose of 2.5 mg to suppress vasomotor symptoms and to prevent postmenopausal osteoporosis. The main adverse effect is vaginal bleeding, which needs investigation if persistent. Vasomotor menopausal symptoms may occasionally be helped by low doses of clonidine.
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Adverse effects of HRT The most common reasons for withdrawal are irregular or withdrawal bleeding and breast pain. The more serious complications are venous thromboembolism and cancer of the endometrium or breast. These risks are small. The risk of gallstones may be increased up to 2-fold. The effect of estrogens on the lipid balance is favourable, but the addition of a proge- stin (gestodene or desogestrel) reverses the balance.
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Estrogen pharmacoterapy – indications: Contraception Menstrual disorders Senile vaginitis Inhibition of lactation (but no longer) Androgen-dependent carcinoma (prostate cancer) To reduce sexual urge in men Epistaxis in recurrent cases (e.g. teleangiectasia) NB: Atrophic rhinitis as well as acne may benefit.
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Antiestrogens Selective antagonists of the estrogen receptor are used either to induce gonadotrophin release in anovulatory infertility, or to block stimulation of estrogen-receptor-positive carcinomas of the breast. Clomiphene is structurally related to stilbestrol. It is a partial agonist. Clomiphene blocks hypothalamic estrogen receptors so that the negative feedback of natural estrogens is prevented and the pituitary responds by increased secretion of gonadotrophins, which may induce ovulation. Clomiphene is administered during the early follicular phase of the menstrual cycle.
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Tamoxifen is a nonsteroid competitive estrogen antagonist on target organs. Although available for anovulatory infertility (20 mg daily on days 2, 3, 4 and 5 of the cycle) its main use now is in the treatment of estrogen-dependent breast cancer. Treatment with tamoxifen delays the growth of metastases and increases survival; if tolerated it should be continued for 5 years. Tamoxifen is also the hormonal treatment of choice in women with estrogen-receptor-positive metastatic breast cancer. Approximately 60% of such patients respond to initial hormonal manipulation, whereas less than 10% of estrogen-receptor-negative tumours respond.
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Progesterone and progestins (progestogens) Progesterone (t1/2 5 min) is produced by the corpus luteum and converts the uterine epithelium from the proliferative to the secretory phase. It is necessary for successful implantation of the ovum, and is essential throughout pregnancy in the last two-thirds of which it is secreted in large amounts by the placenta. It acts particularly on tissues that are sensitized by estrogens. Some synthetic progestogens are less selective, having varying estrogenic and androgenic activity, and these may inhibit ovulation, though not very reliably.
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Progestogens are two principal kinds: Progesterone and its derivatives: dydrogesterone, hydroxyprogesterone, medroxyprogesterone (t1/2 28 h), etc. Testosterone derivatives: norethisterone and its prodrug ethynodiol (t1/2 10 h); levonorgestrel, desogestrel, gestodene, gestronol, norgestimate. Clinical uses The clinical uses of progestational agents are ill-defined, apart from contraception, the menopause, and postmenopausal HRT.
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Other possible uses include • menstrual disorders, e.g. menorrhagia, endometriosis, dysmenorrhoea, and premenstrual syndrome (with doubtful efficacy) • breast and endometrial cancer. Application of the available progestogens (some used only in combined formulations) include: • oral: norethisterone, dydrogesterone, gestodene, desogestrel, levonorgestrel, medroxyprogesterone • suppositories or pessaries: progesterone • injectable: progesterone, hydroxyprogesterone, medroxyprogesterone.
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Adverse effects of prolonged use of progestins include virilisation, raised blood pressure, and adverse trend in blood lipids. Gestodene, desogestrel, and norgestimate may have less affinity for androgen receptors and therefore less unfavourable effect on blood lipids; however the first two of these may have a higher risk of thrombosis. Antiprogestogens Mifepristone is a pure competitive antagonist at progesterone and glucocorticoid receptors. Clinical trials of oral use in hospital outpatients have shown it to be safe and effective in terminating pregnancy.
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Other progesterone derivatives Danazol is a derivative of the progestogen – ethisterone, a modified testosterone. It has partial agonist androgen activity and is described as an “impeded” androgen; it has little progestogen activity. It is a relatively selective inhibitor of pituitary gonadotrophin secretion (LH, FSH) affecting the surge in the mid-menstrual cycle more than basal secretion. This reduces ovarian function, which leads to atrophic changes in the endometrium. In males it reduces sperma- togenesis. Androgenic unwanted effects occur in women (acne, hirsutism, and rarely, enlargement of the clitoris). It is chiefly used for: endometriosis, mastitis, gynaecomastia, precocious puberty, menorrhagia, and hereditary angioedema.
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Hormonal contraception in women comprises: Progestogen alone, e.g. Levonorgestrel (Escapelle®, Postinor®) Estrogens alone are not completely reliable. At the necessary dose, they can also cause thromboembolism and endometrial cancer. An appropriate dose of estrogen + progestogen gives excellent reliability with good menstrual cycle control.
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Combined hormonal contraceptives are conveni- ently started on the first day of the cycle (first day of menstruation) and continued for 21 days (this is immediately effective, inhibiting the first ovulation). It is followed by a period of 7 days when no pill is taken, and during which bleeding usually occurs. Thereafter, regardless of bleeding, a new 21-day course is begun, and so on, i.e. active tablets are taken daily for 3 weeks out of 4. For easy compliance, some combined pills are packaged so that the woman takes one tablet every day without interruption (21 active then 7 dummy).
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The pill should be taken about the same time (to within 12 hours) every day to establish a routine. The monthly bleeds that occur 1–2 days after the cessation of active hormone administration are hormone withdrawal bleeds not natural men- struation. They are not an essential feature of oral contraception, but women are accustomed to mon- thly bleeds and they provide monthly reassurance of the absence of pregnancy. Numerous field trials have shown that progestin- estrogen combinations, if taken precisely as directed, are the most reliable reversible contraceptives known.
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Combined oral contraceptives are defined as 1st, 2nd or 3rd generation by the progestogen component 1st generation progestogens containing a fixed amount of an estrogen and a progestin in each active tablet are termed “mono- phasic”. Other pills employ variable ratios between estrogen and progestin, in 2 (biphasic) or 3 (triphasic) periods within the menstrual cycle. The dose of progestin is low at the beginning and higher at the end, the estrogen remaining either constant or rising slightly in mid-cycle.
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The objective is to achieve effective contraception with minimal distortion of natural hormonal rhythms. The advantages claimed for these techniques are diminished adverse metabolic changes, e.g. blood lipids, and a particularly reliable monthly bleeding pattern without loss of contraceptive efficacy. Monophasic contraceptives Cilest®, Jeanine®, Yasmine®, Yasminelle® Biphasic contraceptives: Anteovin® Triphasic contraceptives Tri-Minulet®, Triquilar®, Tri-Regol®
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It is now appreciated that the earlier preparations had much more estrogen than was necessary for efficacy. It seems probable that 20 mcg estrogen is about the limit below which serious loss of efficacy can be expected. Indeed in patients whose hepatic enzymes are likely to be induced, e.g. those taking antiepileptic or some antirheumatic drugs, it is advisable to use a preparation containing 50 mcg or more of estrogen to avoid loss of efficacy due to increased estrogen metabolism (elimination of breakthrough bleeding is a guide to adequacy of dose).
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Subsequent fertility After stopping the pill, fertility that is normal for the age the woman has now reached is restored, although conception may be delayed for a few months longer in younger and as much as a year in older users. Effect on an existing pregnancy Although progestogens can masculinise the female fetus, the doses for contraception are so low that risk of harming an undiagnosed pregnancy is extremely low, probably less than 1 in 1000 (the background incidence of birth defects is 1–2%).
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Carcinoma of the breast and cervix may be unaffected or very slightly increased in incidence; hepatoma (very rare) is increased. The risk to life seems to be less than that of moderate smoking (10 cigarettes/day). Carcinoma of the ovary and the endometrium are substantially reduced. Total insidence of cancer is unaltered. Effect on menstruation (it is not true menstrua- tion) is generally to regularise it, and often to diminish blood loss, but amenorrhoea can occur. In some women “breakthrough” intermenstrual bleeding occurs, especially at the outset, but this seldom persists for more than a few cycles. Premen- strual tension and dysmenorrhoea are much reduced.
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Libido is greatly subjected to psychosocial influences, and removal of fear of pregnancy may permit enthusiasm for the first time. It is likely that direct pharmacological effect (reduction) is rare. There is evidence that the normal increase in female-initiated sexual activity at the time of ovulation is suppressed. Cardiovascular complications Incidence of venous thromboembolism is increased in pill users. It is lowest in the 20–35 mcg pill and rises progressively with the 50 and 100 mcg preparations.
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The small increase in hypertension, cerebrovascular event, and acute myocardial infarction is principally confined to smokers. Increased arterial disease also appears to be associated with the type of progestogen in the combined pill. The “3rd generation” pills appear to carry a higher risk of venous thrombosis, but may have a lower risk of arterial thrombosis because their lower androgen activity leads to slightly higher HDL levels than older pills. The progestogen-only pill does not significantly affect coagulation.
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Major surgery (in patients taking estrogen- progestogen contraceptives and postmenopausal hormone replacement therapy). Because of the added risk of venous thromboembolism (surgery causes a fall in antithrombin) it has been advised that these oral contraceptives should be withdrawn, if practicable, 4 weeks before all lower limb operations or any major elective surgery (and started again at the first menstruation to occur more than 2 weeks after surgery). But increase in clotting factors may persist for many weeks and there is also the risk of pregnancy to be considered (plainly, alternative contraception should be used). An alternative is to use low molecular weight heparin.
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Hepatic function may be impaired as may drug- metabolizing capacity. Gallbladder disease and vascular hepatocellular adenomas occur (rare). Cervical ectropion (erosion) incidence is double (it is a harmless condition). Crohn's disease is more frequent. Decreased glucose tolerance occurs, perhaps due to a peripheral effect reducing the action of insulin. Plasma lipoproteins may be adversely affected; least where the progestogen is desogestrel or low dose norethisterone.
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Plasma proteins Estrogens cause an increase in proteins, particularly the globulins that bind hydrocortisone, thyroxine, and iron. As a result, the total plasma concentration of the bound substances is increased, though the concentration of free and active substance remains normal. This can be misleading in diagnostic tests, e.g. of thyroid function. This effect on plasma proteins passes off about 6 weeks after cessation of the estrogen.
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Absolute contraindications for use of contraceptives include: A personal history of thromboembolic venous, arterial, or cardiac disease or severe or multiple risk factors for these. • Transient cerebral ischaemic attacks without headache. • Infective hepatitis, until 3 months after liver function tests have become normal, and other liver diseases including disturbances of hepatic excretion, e.g. cholestatic jaundice.
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• Migraine, if there is a typical aura, focal features, or if it is severe and lasts > 72 hours despite treatment, or is treated with an ergot derivative (use with caution is acceptable if there is no aura, focal features, or if it is controlled with a 5-HT1- receptor agonist) • Carcinoma of the breast or of the genital tract, past or present. • Other conditions including: systemic lupus erythematosus, porphyria, undiagnosed vaginal bleeding.
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Relative contraindications or uses of hormo- nal conraceptives with caution, include: •Family history of venous thromboembolism or arterial disease •Diabetes mellitus which may become more difficult to control •Hypertension (if blood pressure exceeds 160/100 mm) •Smoking > 40 cigarettes per day (15 cigarettes/day enhances the risks of circulatory disease (x 3) •Age over 35 years (avoid if > 50 years) •Obesity (avoid if body mass index >39 kg/m2 •Long-term immobility •Breast feeding (until weaning or for 6 months after birth).