Estrogens, Progestins and Contraceptives

 Chapter 22

Estrogens, Progestins and Contraceptives

ESTROGENS

These are substances which can induce estrus in spayed animals. It was established in the year 1900 that ovaries control female reproductive function through a hormonal mechanism. Allen and Doisy (1923) found that an alcoholic extract of ovaries was capable of producing estrus and devised a simple bioassay method. The active principle was obtained in pure form in 1929 and soon its chemical structure was worked out.

Natural estrogens

• Estradiol is the major estrogen secreted by the ovary. It is synthesized in the graafian follicle, corpus luteum and placenta from cholesterol. Steps depicted on the right-hand side are carried out. Further steps are shown below. 

• Estradiol is rapidly oxidized in liver to estrone which is hydroxylated to form estriol. All three are found in blood, but estradiol is the most potent estrogen. Small quantity (2–20 μg/day) of estradiol is derived in human males also from aromatization of testosterone in the testes and extraglandular tissues. In mare, large quantity of equilin is produced which has 1/5 estrogenic potency of estradiol

Synthetic estrogens

• Natural estrogens are inactive orally and have a short duration of action due to rapid metabolism in liver. To overcome this, synthetic compounds have been produced:

1. Steroidal Ethinylestradiol, Mestranol, Tibolone
2. Nonsteroidal Diethylstilbestrol (stilbestrol) Hexestrol, Dienestrol

The nonsteroidal compounds assume a trans configuration as depicted below and sterically resemble natural estrogens.

Regulation of secretion

• The daily secretion of estrogens in menstruating women varies from 10– 100 μg depending on the phase of the cycle. Secretion starts from the graafian follicle under the influence of FSH and the blood level rises gradually during the follicular phase. Due to the modest preovulatory FSH surge, estrogens further rise transiently. After ovulation, corpus luteum continues to secrete estrogens till about two days before menstruation. Estrogens exercise feedback inhibition of FSH (also LH at higher concentrations) by direct action on pituitary as well as through hypothalamus.

• During pregnancy, placenta secretes large quantities of estrogens, reaching a peak of upto 30 mg/day at term. Their level declines sharply after delivery. In the postmenopausal women, daily production of estrogen has been estimated as 2–10 μg—derived primarily by extraglandular aromatization of adrenal androgens.

ACTIONS

Sex organs

• The estrogens bring about pubertal changes in the female including growth of uterus, fallopian tubes and vagina. Vaginal epithelium gets thickened, stratified and cornified. They are responsible for the proliferation of endometrium in the preovulatory phase, and it is only in concert with estrogens that progesterone brings about secretory changes.

• In the absence of progesterone (anovulatory cycles) withdrawal of estrogens alone produces menstruation. If modest doses of estrogen are given continuously without added progesterone —menstruation is delayed but breakthroughbleeding occurs at irregular intervals. However, the normal event which triggers menstruation is progesterone withdrawal—such bleeding cannot be suppressed even by high doses of estrogens. Estrogens increase rhythmic contractions of the fallopian tubes and uterus and induce a watery alkaline secretion from the cervix—favorable to sperm penetration. They also sensitize the uterus to oxytocin. Deficiency of estrogens is responsible for atrophic changes in the female reproductive tract that occur after menopause.

Secondary sex characters

• Estrogens produced at puberty cause growth of breasts—proliferation of ducts and stroma, accumulation of fat. The pubic and axillary hair appear, feminine body contours and behaviour are influenced. Acne is common in girls at puberty as it is in boys—probably due to small amount of androgens produced simultaneously; administration of estrogens to suppress pituitary-gonadal axis causes regression of acne.

Metabolic effects

• Estrogens are anabolic, similar to but weaker than testosterone. Therefore, small amount of androgen may be contributing to the pubertal growth spurt even in females. Continued action of estrogen promotes fusion of epiphyses.

• Estrogen is important in maintaining bone mass primarily by retarding bone resorption. Osteoclast pit formation is inhibited and there is increased expression of bone matrix proteins such as osteonectin, osteocalcin, collagen and alkaline phosphatase. It promotes positive calcium balance, partly by inducing renal hydroxylase enzyme which generates active form of Vit D3.

• Both osteoblasts and osteoclasts express estrogen receptors (ERs). The major action of estrogens is to reduce maturation and activity of osteoclasts by modifying regulatory cytokine signals from osteoblasts. The direct action on osteoclasts is to accelerate their apoptosis.

• Pharmacological doses of estrogens can cause mild salt and water retention—edema occurs in predisposed patients, but it can be treated with diuretics. BP may rise after prolonged use. Combination contraceptives containing higher doses of estrogens and progestins impair glucose tolerance: normal blood sugar is not affected but diabetes may be precipitated, or its control vitiated. However, amounts used for HRT and low dose contraception do not affect carbohydrate metabolism.

•  Estrogens decrease plasma LDL cholesterol while HDL and triglyceride levels are raised. The raised HDL: LDL ratio is probably responsible for rarity of atherosclerosis in premenopausal women. However, blood coagulability is increased due to induction of synthesis of clotting factors (factors II, VII, IX and X). Fibrinolytic activity in plasma also tends to increase. Estrogens have been shown to induce nitric oxide synthase in vascular endothelium. The increased availability of nitric oxide could promote vasodilatation. They increase lithogenicity of bile by increasing cholesterol secretion and reducing bile salt secretion. Plasma levels of sex hormone binding globulin (SHBG), thyroxine binding globulin (TBG) and cortisol binding globulin (CBG) are elevated—but without any change in hormonal status.

Mechanism of action 

• Estrogens bind to specific nuclear receptors in target cells and produce effects by regulating protein synthesis. Estrogen receptors (ERs) have been demonstrated in female sex organs, breast, pituitary, liver, bone, blood vessels, heart, CNS and in certain hormone responsive breast carcinoma cells. The ER is analogous to other steroid receptors: agonist binding to the ligand binding domain brings about receptor dimerization and interaction with ‘estrogen response elements’ (EREs) of target genes. Gene transcription is promoted through certain coactivator proteins. On binding an estrogen antagonist, the receptor assumes a different conformation and interacts with other corepressor proteins inhibiting gene transcription

• Two ERs designated ERα and ERβ have been identified, cloned and structurally characterized. Most tissues express both subtypes but ERα predominates in uterus, vagina, breast, hypothalamus and blood vessels, while ERβ predominates in prostate gland of males and ovaries in females. Estradiol binds to both ERα and ERβ with equal affinity, but certain ligands may have differing affinities. More importantly ERα and ERβ may have a different pattern of interaction with coactivators and corepressors. Few nongenomic rapid actions of estrogens in certain tissues mediated through the same ER have also been observed.

PHARMACOKINETICS

• Estrogens are well absorbed orally and transdermally, but natural estrogens are inactive by the oral route due to rapid metabolism in liver. Estradiol esters injected i.m. are slowly absorbed and exert prolonged action. Natural estrogens in circulation are largely plasma protein bound—to SHBG as well as to albumin.

• Estradiol is converted to estrone and vice versa in liver. Estriol is derived from estrone. All three are conjugated with glucuronic acid and sulfate— excreted in urine and bile. Considerable enterohepatic circulation occurs due to deconjugation in intestines and reabsorption—ultimate disposal occurs mostly in urine.

Preparations and dose

• All estrogen preparations have similar action. Their equivalent parenteral doses are— Estradiol 0.1 mg = Ethinylestradiol 0.1 mg = Mestranol 0.15 mg = Conjugated estrogens 10 mg = Estriol succinate 16 mg = Diethylstilbestrol 10 mg.

• The oral potencies differ from the above due to differing extents of first pass metabolism. Estradiol is inactive orally, conjugated estrogens and estriol succinate undergo partial presystolic metabolism, while in case of ethinylestradiol, mestranol and diethylstilbestrol the oral and parenteral doses are practically the same.

• The preferred route of administration of estrogens is oral. Intramuscular injection is resorted to only when large doses have to be given, especially for carcinoma prostate

1. Estradiol benzoate/cypionate/enanthate/valarate: 2.5–10 mg i.m.; OVOCYCLIN-P 5 mg inj, PROGYNON DEPOT 10 mg/ml inj.
2.  Conjugated estrogens: 0.625–1.25 mg/day oral; PREMARIN 0.625 mg, 1.25 mg tab, 25 mg inj (for dysfunctional uterine bleeding).
3. Ethinylestradiol: for menopausal syndrome 0.02–0.2 mg/day oral; LYNORAL 0.01, 0.05, 1.0 mg tab, PROGYNON-C 0.02 mg tab.
4. Mestranol: acts by getting converted to ethinylestradiol in the body: 0.1–0.2 mg/day oral; in OVULEN 0.1 mg tab, with ethynodiol diacetate 1 mg.
5. Estriol succinate: 4–8 mg/day initially, maintenance dose in menopause 1–2 mg/day oral: EVALON 1, 2 mg tab, 1 mg/g cream for vaginal application in atrophic vaginitis 1–3 times daily.
6. Fosfestrol tetrasodium: initially 600–1200 mg slow i.v. inj for 5 days, maintenance 120–240 mg/day oral or 300 mg 1–3 times a week i.v. HONVAN 120 mg tab, 60 mg/ml inj 5 ml amp.
7. Dienestrol: 0.01% topically in vagina: DIENESTROL 0.01% vaginal cream.

Transdermal estradiol

• A transdermal patch (Estradiol-TTS) has become available in 3 sizes, viz. 5, 10 and 20 cm2 delivering 0.025 mg, 0.05 mg and 0.1 mg respectively in 24 hr for 3–4 days. The usual dose in menopause is 0.05 mg/day which produces plasma estradiol levels seen in premenopausal women in the early or mid follicular phase. Cyclic therapy (3 weeks on, 1 week off) with estradiol-TTS is advised with an oral progestin added for the last 10–12 days. Beneficial effects of estradiol-TTS on menopausal symptoms, bone density, vaginal epithelium and plasma Gn levels are comparable to those of oral therapy, but improvement is serum lipid profile is less marked.

• Systemic side effects of estradiol-TTS are the same as with oral estrogens but are milder. Oral therapy delivers high dose of the hormone to the liver and increases synthesis of several proteins. Estradiol-TTS avoids high hepatic delivery: consequently, plasma levels of TBG, CBG, angiotensinogen and clotting factors are not elevated— risk of thromboembolic phenomena may not be increased.

• ESTRADERM-MX: Estradiol 25, 50 or 100 μg per 24 hr transdermal patches; apply to nonhairy skin below waist, replace every 3–4 days using a different site; add an oral progestin for last 10–12 days every month. Recently a combined estradiol 50 μg + norethisterone acetate 0.25 mg patch has become available in some. Countries (ESTRAGEST-TTS). Two weeks of estradermTTS followed by 2 weeks estragest-TTS with patches changed twice weekly is used for total transdermal HRT. A gel formulation of estradiol for application over skin is also available. OESTRAGEL 3 mg/5 g in 80 g tube; apply over the arms once daily for HRT.

ADVERSE EFFECTS

Most of the adverse effects of estrogens are described with oral contraceptives and with HR. In addition, dose dependent adverse effects noted when use is made for other indications are—

1. Suppression of libido, gynecomastia and feminization when given to males. 
2. Fusion of epiphyses and reduction of adult stature when given to children. 
3. Stilbestrol given to pregnant women, especially during first trimester (as test of pregnancy or otherwise)—increased the incidence of vaginal and cervical carcinoma in the female offspring in childhood or early adulthood. Other genital abnormalities are possible in the female as well as male offspring. Estrogens are contraindicated during pregnancy. 
4. In postmenopausal women, estrogens can increase the risk of irregular bleeding and endometrial carcinoma (5–15 fold). A progestin given concurrently blocks the risk. 
5. Estrogens can accelerate the growth of existing breast cancer, but low-dose estrogen only HRT does not appear to increase the risk of developing new breast cancer (see p. 302). 
6. Long-term estrogen therapy doubles the incidence of gallstones. Benign hepatomas are more common in women taking estrogens in their teens and twentys. 
7. Migraine, epilepsy and endometriosis may be worsened by estrogens.

USES

Currently, the two most common uses of estrogens are as contraceptives and for hormone replacement therapy in postmenopausal women, but there are some other indications as well. 

Hormone replacement therapy (HRT)

• Due to cessation of ovarian function at menopause women suffer a number of physical, psychological and emotional consequences. Medical problems related to menopause are:

• Vasomotor disturbances Hot flushes, chilly sensation, inappropriate sweating, faintness, paresthesias, aches and pains. 

• Urogenital atrophy Change in vaginal cytology and pH, vaginal dryness, vulval shrinkage, dyspareunia, vaginitis, itching, urinary urgency, predisposition to urinary tract infection.

• Osteoporosis Loss of osteoid as well as calcium → thinning and weakening of bone → minimal trauma fractures especially of femur, hip, radius, vertebrae. 

• Dermatological changes Thinning, drying and loss of elasticity of skin, wrinkles, thin and listless hairs. Psychological/Cognitive disturbances Irritability, depressed mood, loss of libido and self-confidence, anxiety and dementia.

• Increased risk of cardiovascular diseases coronary artery disease, myocardial infarction, stroke.

• The vasomotor symptoms tend to subside over a few years, but the other changes progress continuously.
• Estrogen ±progestin HRT or ‘menopausal hormone therapy’ (MHT) is highly efficacious in suppressing the perimenopausal syndrome of vasomotor instability, psychological disturbances and atrophic changes, but several recent findings have emphasized a number of risks and limitations of long-term HRT, so that the whole outlook has changed.

• The dose of estrogen used in HRT is substantially lower than that for contraception. Typically, conjugated estrogens are used 0.625 mg/day (equivalent to ethinylestradiol 10 μg) either cyclically (3 weeks treatment 1 week gap) or continuously, but there is a trend now to use lower doses (0.3–0.45 mg/day). A progestin (medroxy progesterone acetate/norethisterone 2.5 mg daily) is added for 10–12 days each month. Though the progestin may attenuate the metabolic and cardiovascular benefits of estrogen, it is needed to block the increased risk of dysfunctional uterine bleeding and endometrial carcinoma due to continuous estrogenic stimulation of endometrium. Estrogen alone is used in hysterectomized women and when a progestin is not tolerated or is contraindicated. Transdermal estradiol (with oral or transdermal progestin) appears to have certain advantages (see above) and is preferred by some.

Menopausal symptoms and atrophic changes

• The vasomotor symptoms respond promptly and almost completely. They are the primary indication for using HRT which improves general physical, mental and sexual well-being as well. Genital and dermal atrophic changes are arrested; vulval and urinary problems resolve. Vaginal application of estrogen is effective in relieving local symptoms.

Osteoporosis and fractures

• HRT restores Ca2+ balance; further bone loss is prevented, and the excess fracture risk is nullified. When used for this purpose, HRT should be initiated before significant bone loss has occurred, because reversal of osteoporosis is none or slight. Calcium + vit D supplements and exercise aid the beneficial effect of HRT. However, accelerated bone loss starts again on cessation of HRT. The ‘Women’s health, osteoporosis, progestin-estrogen’ trial (2002) has shown that even lower doses of conjugated estrogens (0.3, 0.45 mg/day) increased bone mineral density in postmenopausal women, though 0.625 mg/day was more effective. Notwithstanding the above, appreciation of the other risks of HRT (see below) has dislodged estrogen from its prime position in the treatment of osteoporosis compared to raloxifene and bisphosphonates.

Cardiovascular events Since 

• Since hypertension and cardiovascular disease are rare in premenopausal women, and estrogens improve HDL : LDL ratio, retard atherogenesis, reduce arterial impedance, increase NO and PGI2 production and prevent hyperinsulinaemia, it was believed that estrogen therapy in postmenopausal women will have a protective cardiovascular influence. This was supported by early reports relying mainly on retrospective/ epidemiological studies and those using surrogate markers to indicate that HRT in otherwise healthy women reduced risk of coronary artery disease (CAD), myocardial infarction (MI) and stroke. This lead to the extensive use of HRT; a segment of doctors contended that menopausal women should take HRT for the rest of their lives. In the past decade many large scale placebo controlled randomized interventional trials and cohort studies have yielded opposite results. The ‘Heart and estrogen/ progestin replacement study’ (HERS and HERS II) conducted in older women with preexisting cardiovascular disease found that HRT triples the risk of venous thromboembolism, initially increases risk of MI and affords no secondary prophylaxis of CAD in the long-term. 

• The larger ‘women’s health initiative’ (WHI) study conducted in over 16000 younger women without CAD found 24% increase in CAD, 40% increase in stroke and doubling of venous thromboembolism with the use of combined HRT. It was terminated prematurely in 2002. The increased risk of MI was attributed to the progestin component, since women who took estrogen alone had no increase in the incidence of MI. The committee on safety of medicines (CSM) of UK has estimated that ~20 out of 1000 women aged 60–69 years and not using HRT develop venous thromboembolism over 5 years; 4 extra cases occur in those taking estrogen alone, while 9 extra cases occur in those taking combined HRT. Thus, progestin use adds to the risk.

Cognitive function and dementia:

• Contrary to earlier belief, the ‘women’s health initiative memory study’ (WHIMS) conducted among older women (65–79 years) has failed to detect any protection against cognitive decline by ether estrogen alone or combined HRT. There was infact a slight global deterioration. Surprisingly, the incidence of dementia (Alzheimer’s) was doubled

Cancer:

• That estrogens enhance the growth of breast cancer has been well recognized. However, it was contended that small replacement doses of estrogens will not induce new cancer. This appears to be supported by the estrogen alone arm of WHI study in hysterectomized women, as the occurrence of breast cancer was actually lower (but insignificantly). However, in the combined HRT group, a significantly higher incidence of cancer breast occurred, indicating that medroxyprogesterone was the culprit. The prospective observational cohort ‘Million women study’ (MWS) in the UK found a marginally higher incidence of breast cancer with estrogen alone, but a clearly higher one with estrogen + progestin. Some other studies have also implicated the progestin, and the CSM of UK has drawn similar conclusions. Thus, the protective effect of progestin on endometrial cancer appears to be counter balanced by the procardiogenic effect on the breast.
• Estrogen is well known to induce endometrial hyperplasia and its continuous use unopposed by progestinresults in irregular uterine bleeding. In the long-term it predisposes to endometrial carcinoma. The MWS has supported this contention. The standard practice is to give combined HRT to women with an intact uterus. However, a Cochrane Database Review has concluded that lower dose unopposed estrogen does not increase endometrial carcinoma risk; may be used in women with intact uterus when a progestin is contraindicated. A small protective effect of combined HRT on colorectal carcinoma has been detected by the WHI study, but this needs to be confirmed.

 Gallstone, migraine:

• Estrogens slightly increase the risk of developing gallstones, while progestins may trigger migraine.
• Tibolone It is a 19-norsteroid developed specifically to be used for HRT, which combines estrogenic and pregestational properties with weak androgenic activity. In a dose of 2.5 mg daily, it suppresses menopausal symptoms and lowers the raised Gn levels. No endometrial stimulation has been noted. Urogenital atrophy, psychological symptoms, libido and osteoporosis are improved similar to other forms of HRT. Contraindications are the same as for conventional HRT but increase in breast cancer risk appears to be less than with combined HRT.
• Weight gain increased facial hair and occasional vaginal spotting may be noted. LIVIAL 2.5 mg tab, one tab daily without interruption; institute therapy only after the women has been menopausal for atleast 12 months.

 Senile vaginitis

• Estrogens change vaginal cytology to the premenopausal pattern and are effective in preventing as well as treating atrophic vaginitis that occurs in elderly women. Oral therapy may be given but more commonly a topical preparation is used; an antibacterial may be combined. They help in overcoming infection and relieve symptoms of Kraurosis vulvae.

Delayed puberty in girls

• It may be due to ovarian agenesis (Turner’s syndrome) or hypopituitarism. In both, pubertal changes are brought about by estrogen treatment, except the rapid gain in height for which growth hormone and/or a small dose of androgen may be added. Usually cyclic treatment is given; some prefer to start with a lower dose and gradually attain the full replacement dose.

 Dysmenorrhoea

• While PG synthesis inhibitors are the first line drugs, cyclic estrogen therapy (often with added progestin to ensure withdrawal bleeding) benefits by inhibiting ovulation (anovular cycles are painless) and decreasing prostaglandin synthesis in endometrium; but this should be reserved for severe cases.

Acne

• It occurs at puberty due to increased androgen secretion in both boys and girls. Estrogens benefit by suppressing ovarian production of androgen by inhibiting Gn release from pituitary; cyclic treatment (with added progestin) is quite effective. Use in boys is out of question. Even in girls, topical therapy with antimicrobials, tretinoin and other drugs is preferred.

Dysfunctional uterine bleeding

• A progestin given cyclically is the rational and effective therapy. Estrogens have adjuvant value.

Carcinoma prostate

• Estrogens are palliative; produce relief in primary as well as metastatic carcinoma prostate by suppressing androgen production (through pituitary). Fosfestrol is preferred by some as it is concentrated in the prostate where it may antagonise androgen. High doses are needed. GnRH agonists with or without androgen antagonist are preferred.

ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) 

• Two nonsteroidal compounds clomiphene citrate and tamoxifen citrate previously grouped as estrogen antagonists have been in use since 1970s,

• but their differing antagonistic and agonistic actions depending on species, target organ and hormonal background could not be explained. The recent discovery of two estrogen receptors (ERs) and that ligand binding could change their configuration in multiple ways allowing interaction with different coactivators and corepressors in a tissue specific manner has paved the way for development of compounds with unique profile of agonistic and antagonistic actions in different tissues. These drugs have been designated ‘selective estrogen receptor modulators’ and two new compounds Raloxifene and Ormeloxifene have been marketed. It has been demonstrated that the conformation of ER after binding tamoxifen or raloxifene is different from that after binding estradiol.

Antiestrogens

Clomiphene citrate 

• It binds to both ERα and ERβ and acts as a pure estrogen antagonist in all human tissues, but the racemate displays weak agonistic action in rats. It induces Gn secretion in women by blocking estrogenic feedback inhibition of pituitary. The amount of LH/FSH released at each secretory pulse is increased. In response, the ovaries enlarge, and ovulation occurs if the ovaries are responsive to Gn. Antagonism of peripheral actions of estrogen results in hot flushes. Endometrium and cervical mucus may be modified.

• The chief use of clomiphene is in sterility due to failure of ovulation: 50 mg once daily for 5 days starting from 5th day of cycle. Treatment is given monthly. Conception occurs in many women who previously were amenorrhoeic or had anovular cycles. If 1–2 months treatment does not result in conception—the daily dose may be doubled for 2–3 cycles (max 200 mg/day). The antiestrogenic effect of clomiphene on developing follicle, endometrium or cervical mucus can be counterproductive. Luteal phase dysfunction has also been blamed for therapeutic failures. Addition of menotropins or chorionic gonadotropin on the last 2 days of the course improves the success rate

• Clomiphene is well absorbed orally, gets deposited in adipose tissue and has long t½ of ~6 days. It is largely metabolized and excreted in bile.

Adverse effects

• Polycystic ovaries, multiple pregnancy, hot flushes, gastric upset, vertigo, allergic dermatitis. Risk of ovarian tumour may be increased.

• Other uses

• To aid in vitro fertilization Clomiphene given with Gns causes synchronous maturation of several ova—improves their harvesting for in vitro fertilization.

• Oligozoospermia: In men also clomiphene increases Gn secretion → promotes spermatogenesis and testosterone secretion. For male infertility— 25 mg daily given for 24 days in a month with 6 days rest for upto 6 months has been recommended. However, success rates are low.

• CLOMID, FERTOMID, 25, 50 mg tab. CLOFERT, CLOME 25, 50, 100 mg tab

Fulvestrant

• It is the first member of a distinct class of ER ligands called ‘selective estrogen receptor down regulators’ (SERDs) or ‘pure estrogen antagonists’ that has been introduced for the treatment of metastatic ER positive breast cancer in postmenopausal women which has stopped responding to tamoxifen. In contrast to tamoxifen, it inhibits ER dimerization so that ER interaction with DNA is prevented and receptor degradation is enhanced. The ER is thus down regulated resulting in more complete suppression of ER responsive gene function. This along with its higher affinity for the ER probably accounts for its efficacy in tamoxifen resistant cases. Fulvestrant is administered as monthly i.m. injections; is slowly absorbed and has an elimination t½ of more than a month.

Selective estrogen receptor modulators (SERMs)

Tamoxifen citrate 

• Though chemically related to clomiphene, it has complex actions; acts as potent estrogen antagonist in breast carcinoma cells, blood vessels and at some peripheral sites, but as partial agonist in uterus, bone, liver and pituitary. Inhibition of human breast cancer cells and hot flushes reflect antiestrogenic action, while the weak estrogen agonistic action manifests as stimulation of endometrial proliferation, lowering of Gn and prolactin levels in postmenopausal women as well as improvement in their bone density.

• A decrease in total and LDL cholesterol without any change in HDL and triglyceride level reflects estrogenic action. Similar to estrogen HRT, it increases the risk of deep vein thrombosis by 2–3 times.

• Tamoxifen is the standard hormonal treatment of breast cancer in both pre- and postmenopausal women, though aromatase inhibitors are gaining prominence. In early cases it is given as postmastectomy adjuvant therapy, while in advanced cases it is a constituent of palliative treatment. Response rates are high in ER-positive breast carcinomas, but some ER-negative tumours also respond suggesting additional nonhormonal mechanism of action. It is also effective following surgery in cancer of male breast.

• Based on large epidemiological studies which have shown 45% reduction in the incidence of ERpositive breast cancer, it has been approved for primary prophylaxis of breast cancer in high-risk women. Recurrence rate in ipsilateral as well as contralateral breasts is reduced by tamoxifen, but benefits of prophylactic therapy beyond 5 years are not proven; outcomes may even be worse.

• Improvement in bone mass due to antiresorptive effect, and in lipid profile are the other benefits of tamoxifen therapy. However, endometrial thickening occurs and risk of endometrial carcinoma is increased 2–3 fold.

• Tamoxifen is effective orally; has a biphasic plasma t½ (10 hours and 7 days) and a long duration of action. Some metabolites of tamoxiphen are more potent antiestrogens. The drug is excreted primarily in bile.

• Dose 10–20 mg BD. TAMOXIFEN, MAMOFEN, TAMODEX 10, 20 mg tabs. Male infertility: May be used as alternative to clomiphene

Side effects

• Hot flushes, vomiting, vaginal bleeding, vaginal discharge, menstrual irregularities, increased risk of venous thromboembolism. Dermatitis, anorexia, depression, mild leucopenia and ocular changes are infrequent. It is much less toxic than other anticancer drugs.

• Toremifene It is a newer congener of tamoxifen with similar actions, uses and adverse effects.

Raloxifene

• This SERM is an estrogen partial agonist in bone and cardiovascular system, but an antagonist in endometrium and breast. It has high affinity for both ERα and ERβ, and has a distinct DNA target the ‘raloxifene response element’ (RRE).

• Several long term multicentric studies have convincingly shown that raloxifene prevents bone loss in postmenopausal women; bone mineral density (BMD) may even increase by 0.9– 3.4% over years in different bones, particularly the lumbar vertebrae. The risk of vertebral fracture is reduced to half, but not that of long bones except ankle.

• In postmenopausal women raloxifene reduces LDL cholesterol, probably by upregulating hepatic LDL receptors. In contrast to estrogen HRT there is no increase in HDL and triglyceride levels. Follow up studies have shown that raloxifene reduces the risk of breast cancer by 65%, though the protection was confined to ER-positive breast cancer.

• Raloxifene does not stimulate endometrial proliferation and there is no increase in the risk of endometrial carcinoma. It does not relieve vasomotor symptoms of menopause; rather hot flushes may be induced in some women.

• Raloxifene is absorbed orally but has low bioavailability due to extensive first pass glucuronidation. The t½ is 28 hours and major route of excretion is faeces.

Side effects

• Hot flushes, leg cramps are generally mild; vaginal bleeding is occasional. The only serious concern is 3-fold increase in risk of deep vein thrombosis and pulmonary embolism. However, similar risk attends estrogen HRT.

• Raloxifene is a first line drug for prevention and treatment of osteoporosis in postmenopausal women; Ca2+ and vit D supplements enhance the benefit; bisphosphonates are the other first line drugs. It has no use in men. Dose: 60 mg/day.

• benefit: bisphosphonates are the other first line drugs. It has no use in men. Dose: 60 mg/day.

Ormeloxifene

• A distinct new SERM which acts as estrogen antagonist in breast and uterus. It suppresses endometrial proliferation by regulating their ER. Excessive uterine bleeding with anovular cycles occurring near menopause is normalized. However, vaginal epithelium and cervical mucus are not altered. It may have contraceptive property.

• Ormeloxifene is approved for treatment of dysfunctional uterine bleeding. Side effects are nausea, headache, fluid retention, weight gain, rise in BP and prolongation of menstrual cycles. Dose: 120 mg twice weekly for 2–3 months, followed by 60 mg weekly for another 3 months. SEVISTA 60 mg tab.

AROMATASE INHIBITORS

• Aromatization of ‘A’ ring of testosterone and androstenedione is the final and key step in the production of estrogens (estradiol/estrone) in the body. In addition to the circulating hormone, locally produced estrogens appear to play an important role in the development of breast cancer. Though some aromatase inhibitors (AIs) were produced in the past, three recent ‘third generation’ AIs Letrozole, Anastrozole and Exemestane have demonstrated clinical superiority in the treatment of breast cancer.

Letrozole

• t is an orally active nonsteroidal compound that reversibly inhibits aromatization all over the body, including that within the breast cancer cells, resulting in nearly total estrogen deprivation. Proliferation of estrogen dependent breast carcinoma cells is suppressed to a greater extent than with tamoxifen. Letrozole is rapidly absorbed with 100% oral bioavailability, large volume of distribution, slow metabolism and a t½ of ~40 hours. Randomized clinical trials have established its utility in:

1. Early breast cancer: as adjuvant therapy after mastectomy in ER+ive cases. Extension of prophylaxis with letrozole beyond the standard 5-year tamoxifen treatment continues to afford protection, whereas continuation of tamoxifen is not useful. Survival is prolonged in patients who have positive axillary lymph nodes.
2. Advanced breast cancer: Current guidelines recommend letrozole as first line therapy because of longer time to disease progression and higher response rate obtained with it compared to tamoxifen. It is also effective as second line treatment when tamoxifen has failed.

Adverse effects

• Hot flushes, nausea, diarrhea, dyspepsia and thinning of hair are the side effects. Joint pain is common, and it can accelerate bone loss, but there is no endometrial hyperplasia or increased risk of endometrial carcinoma. Risk of venous thromboembolism is also not increased, and there is no deterioration of lipid profile. Dose: 2.5 mg BD oral.

• LETOVAL, LETROZ, FEMARA, ONCOLET 2.5 mg tab. Though contraindicated in premenopausal women, letrozole was clandestinely promoted and tested as an ovulation inducing fertility drug. This was stopped after media outcry.

Anastrozole

• Another nonsteroidal and reversible (Type 2) AI, more potent than letrozole and suitable for single daily dosing. It accumulates in the body to produce peak effect after 7–10 days. Anastrozole is useful as adjuvant therapy in early ER+ive breast cancer as well as for palliation of advanced cases in postmenopausal women. In early cases, tumor recurrence time was found to be longer than with tamoxifen. Risk of new tumor appearing in the contralateral breast was also lower with anastrozole. A longer time to disease progression compared to tamoxifen has been obtained in advanced ER+ive breast cancer. Many tamoxifen resistant cases responded with increased survival. Side effects are hot flushes, vaginal dryness, vaginal bleeding, nausea, diarrhoea, thinning of hair. Arthralgia and acceleration of osteoporosis are prominent. However, it does not predispose to endometrial carcinoma or to venous thromboembolism.

Exemestane: 

• This steroidal and irreversible (Type 1) inhibitor of aromatase acts like a suicide substrate by covalent binding to the enzyme. As a result, >90% suppression of estradiol production is obtained. However, like androstenedione, it has weak androgenic activity. Exemestane has been found beneficial in early breast cancer by reducing the risk of disease progression when it was substituted for tamoxifen as adjuvant therapy. In advanced breast cancer, longer survival, increased time to disease progression and fewer treatment failures have been obtained with exemestane. It is administered orally and is well tolerated. Adverse effects are similar to other AIs.

PROGESTINS

• These are substances which convert the estrogen primed endometrium to secretory and maintain pregnancy in animals spayed after conception (Progestin = favoring pregnancy).

• At the turn of the last century, it became apparent that ovaries secrete two hormones, and that corpus luteum was essential for maintenance of pregnancy. Progesterone was isolated in 1929, but its full therapeutic potential has been exploited only after the 1950s when a large number of orally active synthetic progestins were developed.

Natural progestin

• Progesterone, a 21-carbon steroid, is the natural progestin and is derived from cholesterol. It is secreted by the corpus luteum (10–20 mg/day) in the latter half of menstrual cycle under the influence of LH. Its production declines a few days before the next menstrual flow. If the ovum gets fertilized and implants—the blastocyst immediately starts producing chorionic gonadotropin which is absorbed and sustains the corpus luteum in early pregnancy. Placenta starts secreting lots of estrogens and progesterone from 2nd trimester till term. Men produce 1–5 mg progesterone per day from adrenals and testes— its role if any, in males is not known.

Synthetic progestins

• A number of synthetic progestins with high oral activity have been produced. These are either progesterone derivatives (21 C) or 19-nortestosterone derivatives (18 C).

• The progesterone derivatives are almost pure progestins, have weaker antiovulatory action and are used primarily as adjuvants to estrogens for HRT in postmenopausal women, threatened abortion, endometriosis, etc. for selective pregestational effect. The older 19-nortestosterone derivatives developed in the 1950-60s have additional weak estrogenic, weak androgenic, anabolic and potent antiovulatory action: are used primarily in combined contraceptive pills. Norgestrel has a 13-ethyl substitution (termed gonane)—is more potent (especially its levo isomer levonorgestrel) 

• In the 1980-90s a number of other gonane 19-nortestosterone compounds were introduced, of which desogestrel has been marketed in India. Desogestrel and norgestimate are prodrugs. In addition to being very potent progestins they have strong antiovulatory action (gestodene inhibits ovulation at as low as 40 μg/day dose), and little or no androgenic property. Therefore, they do not antagonise the beneficial action of estrogens on lipid profile and are preferable in women with hyperandrogenemia. High antiovulatory potency allows reduction of ethinylestradiol dose when these are combined in oral contraceptives.

• se are combined in oral contraceptives. The newer 19-norprogesterone derivative nomegestrol has antiandrogenic property, is less antiovulatory, but has strong effect on endometrium

ACTIONS

• The main function of progesterone is preparation of the uterus for nidation and maintenance of pregnancy. The latter is due to prevention of endometrial shedding, decreased uterine motility and inhibition of immunological rejection of the foetus: progesterone depresses T-cell function and cell-mediated immunity (CMI)

Uterus 

• Progesterone brings about secretory changes in the estrogen primed endometrium: hyperemia, tortuocity of glands and increased secretion occurs while epithelial proliferation is suppressed. It is lack of pregestational support which causes mucosal shedding during menstruation.

• Continued action of progesterone (as when pregnancy occurs) brings about decidual changes in endometrium—stroma enlarges and becomes spongy, glands atrophy. It also decreases sensitivity of myometrium to oxytocin

Cervix 

• Progesterone converts the watery cervical secretion induced by estrogens to viscid, scanty and cellular secretion which is hostile to sperm penetration.

 Vagina 

• Progesterone induces pregnancy like changes in the vaginal mucosa—leukocyte infiltration of cornified epithelium.

Breast 

• Progesterone causes proliferation of acini in the mammary glands. Cyclic epithelial proliferation occurs during luteal phase, but continuous exposure to progesterone during pregnancy halts mitotic activity and stabilizes mammary cells. Acting in concert with estrogens, it prepares breast for lactation. Withdrawal of these hormones after delivery causes release of prolactin from pituitary and milk secretion starts.

CNS 

• High circulating concentration of progesterone (during pregnancy) appears to have a sedative effect

Body temperature 

• It causes a slight (0.5o C) rise in body temperature by resetting the hypothalamic thermostat and increasing heat production. This is responsible for the higher body temperature seen during the luteal phase.

Respiration 

• Progestins in relatively higher doses stimulate respiration, as occurs during pregnancy.

Metabolism 

• Prolonged use of oral contraceptives impairs glucose tolerance in some women. This has been ascribed to the progestational component. Progestins, especially those with androgenic activity (19-nortestosterone derivatives) tend to raise LDL and lower HDL levels. This may reduce the beneficial effect of estrogen used concurrently in HRT or in contraceptives. Micronized oral progesterone formulation (referred to as ‘natural progesterone’ introduced recently has been shown not to counteract the beneficial effect of estrogen on LDL and HDL.

Pituitary 

• Progesterone is a weak inhibitor of Gn secretion from pituitary. It decreases the frequency of LH pulses by action on hypothalamic pulse generator but increases the amount of LH secreted per pulse. Administration of progestin during follicular phase suppresses the preovulatory LH surge and prevents ovulation; synergises with estrogen for this action. The gonane 19-nortestosterone derivatives are potent antiovulatory drugs

Mechanism of action

• Unlike other steroid receptors, the progesterone receptor (PR) has a limited distribution in the body: confined mostly to the female genital tract, breast, CNS and pituitary. The PR is normally present in the nucleus of target cells. Analogous to ER, upon binding the hormone PR undergoes dimerization, attaches to progesterone response element (PRE) of target genes and regulates transcription through coactivators. The antiprogestins also bind to PR, but the conformation assumed is different from agonist bound receptor and opposite effects are produced by interaction with corepressors.

• Estrogens have been shown to increase PR density, whereas progesterone represses ER and enhances local degradation of estradiol.

PHARMACOKINETICS

• Progesterone, unless specially formulated, is inactive orally because of high first-pass metabolism in liver. It is mostly injected i.m. in oily solution. Even after an i.m. dose it is rapidly cleared from plasma, has a short t½ (5–7 min). It is nearly completely degraded in the liver—major product is pregnanediol which is excreted in urine as glucuronide and sulfate conjugates. However, effects of progesterone last longer than the hormone itself.

• A micronized formulation of progesterone has been developed for oral administration. Microfine particles of the drug are suspended in oil and dispensed in gelatin capsules. Absorption occurs through lymphatics. Though bioavailability is low, effective concentrations are attained in the body.

• Most of the synthetic progestins are orally active and are metabolized slowly; have plasma t½ ranging from 8–24 hours

Preparations and dose

1. Progesterone: 10–100 mg i.m. (as oily solution) OD; PROGEST, PROLUTON, GESTONE 50 mg/ml inj., 1- and 2-ml amp; 100–400 mg OD oral: NATUROGEST, OGEST 100, 200, 400 mg caps containing micronized oily suspension. 
2. Hydroxyprogesterone caproate: 250–500 mg i.m. at 2–14 days intervals; PROLUTON DEPOT, MAINTANE INJ, PROCAPRIN 250 mg/ml in 1- and 2-ml amp. 
3. Medroxyprogesterone acetate: 5–20 mg OD–BD oral, 50–150 mg i.m. at 1–3-month interval; FARLUTAL 2.5, 5, 10 mg tab., PROVERA, MEPRATE, MODUS 2.5, 10 mg tab, DEPOT-PROVERA 150 mg in 1 ml inj. (as contraceptive). Has weak androgenic and antiestrogenic property. 
4. Dydrogesterone: 5–10 mg OD/TDS oral; DUPHASTON 5 mg tab. It has poor antiovulatory action: may be preferred when contraceptive effect is not required. 
5. Norethindrone (Norethisterone): 5–10 mg OD–BD oral; PRIMOLUT-N, STYPTIN, REGESTRONE, NORGEST 5 mg tab; REGESTRONE HRT, NORETA HRT 1 mg tab (for HRT); NORISTERAT 200 mg/ml inj (as enanthate) for contraception 1 ml i.m every 2 months; has androgenic, anabolic and antiestrogenic activity. 
6. Lynestrenol (Ethinylestrenol): 5–10 mg OD oral; ORGAMETRIL 5 mg tab. Has additional androgenic, anabolic and estrogenic activity. 
7. Allylestrenol: 10–40 mg/day; GESTANIN, FETUGARD, MAINTANE 5 mg tab. Has been especially used for threatened/habitual abortion, PROFAR 25 mg tab.
8. Levonorgestrel: 0.1–0.5 mg/day; DUOLUTON-L, OVRAL 0.25 mg+ ethinylestradiol 0.05 mg tab. Has androgenic, anabolic and antiestrogenic property. 
9. Desogestrel 150 μg + ethinylestradiol 30 μg (NOVELON) tab, 1 tab OD 3 week on 1 week off cyclic therapy. (Other preparations are given with oral contraceptives).

ADVERSE EFFECTS

• Breast engorgement, headache, rise in body temperature, edema, esophageal reflux, acne and mood swings may occur with higher doses. 

• Irregular bleeding or amenorrhoea can occur if a progestin is given continuously. 

• The 19-nortestosterone derivatives lower plasma HDL levels—may promote atherogenesis, but progesterone and its derivatives have no such effect. 

• Long-term use of progestin in HRT may increase the risk of breast cancer. 

• Blood sugar may rise, and diabetes may be precipitated by long-term use of potent agents like levonorgestrel.
• Intramuscular injection of progesterone is painful. 

• Given in early pregnancy, progestins can cause masculinization of female foetus and other congenital abnormalities.

Their use for diagnosis of pregnancy is now contraindicated.

USES

As contraceptive Most common use (see later).

Hormone replacement therapy (HRT) 

• In nonhysterectomised postmenopausal women estrogen therapy is supplemented with a progestin for 10–12 days each month to counteract the risk of inducing endometrial carcinoma. A progesterone derivative lacking androgenic activity is preferred.

Dysfunctional uterine bleeding 

• It is often associated with anovular cycles. Continued estrogenic action on endometrium (causing hyperplasia) without progesterone induction and withdrawal resulting in incomplete sloughing leads to irregular, often profuse bleeding. A progestin in relatively large doses (norethindrone 20–40 mg/ day or equivalent) promptly stops bleeding and keeps it in abeyance as long as given. Subsequently cyclic treatment regularizes and normalizes menstrual flow. A progestin with inherent estrogenic action is preferred; often supplemental dose of estrogen is combined

Endometriosis 

• It is due to the presence of ectopic endometrium; manifestations are dysmenorrhoea, painful pelvic swellings and infertility. Continued administration of progestins induces an anovulatory, hypoestrogenic state by suppressing Gn release. The direct action on endometrium prevents bleeding in the ectopic sites by suppressing menstruation. Treatment for a few months causes atrophy and regression of the ectopic masses; therapy can be withdrawn in many cases after 6 months without reactivation. Fertility returns in a good percentage. Progestin treatment of endometriosis is cheap and generally well tolerated, but not all cases respond and recurrences. are frequent. Danazol is an effective alternative. Other drugs used are GnRH agonists and antiprogestins.

Premenstrual syndrome/tension 

• Some women develop headache, irritability, fluid retention, distention and breast tenderness a few days preceding menstruation. When depression predominates, it has been labelled ‘premenstrual dysphoric disorder’. Fluoxetine and other SSRIs given daily on symptom days dampen irritability and mood changes in majority of women. If severe, premenstrual syndrome requires suppression of ovulation by combined estrogen-progesterone treatment given cyclically. Relatively higher dose of progestin is generally used. Progestins are added to estrogen when it is used for severe dysmenorrhoea.

Threatened/habitual abortion 

• In most such patients there is no progesterone deficiency; administration of excess hormone is of no benefit. Progestin therapy may be considered in those patients who have established deficiency. However, progestins are briskly promoted and almost routinely prescribed in India. There is some recent evidence of its efficacy in preventing premature delivery in high-risk pregnancy. If such use is made—a pure progestin without estrogenic or androgenic activity should be employed.

Endometrial carcinoma 

• Progestins are palliative in about 50% cases of advanced/ metastatic endometrial carcinoma. High doses are needed.

ANTIPROGESTIN

Mifepristone 

• It is a 19-norsteroid with potent competitive antiprogestational and significant antiglucocorticoid as well as antiandrogenic activity. Given during the follicular phase, its antiprogestin action results in attenuation of midcycle Gn surge from pituitary → slowing of follicular development and delay/failure of ovulation. During the luteal phase, it prevents secretory changes normally brought about by progesterone.

• Later in the cycle, it blocks progesterone support to the endometrium, unrestrains PG release from it—this stimulates uterine contractions. Mifepristone also sensitizes the myometrium to PGs and induces menstruation. If implantation has occurred, it blocks decidualization, conceptus is dislodged, HCG production falls, secondary luteolysis occurs–progesterone secretion decreases and cervix is softened.

• Mifepristone is a partial agonist and competitive antagonist at both A and B forms of PR. In the absence of progesterone (anovulatory cycles, after menopause) it exerts weak progestational activity—induces predecidual changes. The weak agonistic action is not manifest in the presence of progesterone.

• The antiglucocorticoid action of usual doses is also not manifest in normal individuals because blockade of negative feedback at hypothalamicpituitary level elicits ACTH release → plasma cortisol rises and overcomes the direct antiglucocorticoid action. Amelioration of Cushing’s symptoms has been obtained with large doses.

• Pharmacokinetics Mifepristone is active orally, but bioavailability is only 25%. It is largely metabolized in liver by CYP 3A4 and excreted in bile; some enterohepatic circulation occurs; t½ 20–36 hr.

• Interaction with CYP 3A4 inhibitors (erythromycin, ketoconazole) and inducers (rifampin, anticonvulsants) has been reported.

Uses

Termination of pregnancy of up to 7 weeks: 

• 600 mg as single oral dose causes complete abortion in 60–85% cases. To improve the success rate, current recommendation is to follow it up 48 hours later by a single 400 mg oral dose of misoprostol. This achieves >90% success rate and is the accepted nonsurgical method of early first trimester abortion. In place of oral misoprostol, a 1 mg gemeprost pessary can be inserted intravaginally. Mifepristone administered within 10 days of a missed period results in an apparent late heavy period (with dislodged blastocyst) in upto 90% cases.

• This procedure is generally safe, but prolonged bleeding and failed abortion are the problems in some cases. Anorexia, nausea, tiredness, abdominal discomfort, uterine cramps, loose motions are the other side effects.

Cervical ripening 

• 24–30 hours before attempting surgical abortion or induction of labour, mifepristone 600 mg results in softening of cervix; the procedure is facilitated.

Postcoital contraceptive 

• Mifepristone 600 mg given within 72 hr of intercourse interferes with implantation and is a highly effective method of emergency contraception. The menstrual cycle, however, is disturbed.

Once-a-month contraceptive 

• A single 200 mg dose of mifepristone given 2 days after midcycle each month prevents conception on most occasions. Administering mifepristone in late luteal phase to dislodge the embryo (if present) and to ensure menstruation irrespective of conception, has also been tried. These alternative methods of contraception, though attractive, may prolong/disrupt the next menstrual cycle and thus be difficult to use continuously. There is little experience with these methods and they are not popular.

Induction of labour 

• By blocking the relaxant action of progesterone on uterus of late pregnancy, mifepristone can induce labour. It may be tried in cases with intrauterine foetal death and to deliver abnormal foetuses.

Cushing’s syndrome 

• Mifepristone has palliative effect due to glucocorticoid receptor blocking property. May be used for inoperable cases. Other uses under evaluation are—in endometriosis, uterine fibroid, certain breast cancers and meningioma. Other recently developed antiprogestins are Onapristone (a pure antagonist) and Gestinone (more efficacious in endometriosis).

HORMONAL CONTRACEPTIVES

• These are hormonal preparations used for reversible suppression of fertility. Because of our alarming population trends, antifertility drugs are the need of the day. In developing countries particularly, the mortality rate has declined, and birth rate has increased due to urbanization. In the earlier part of 20th century, methods of contraception used (condoms, diaphragms, spermicidal creams, foam tablets, etc.) were intimately related to sexual intercourse, therefore, despised by most couples. These also have higher failure rate. Rock and Pincus (1955) announced the successful use of an oral progestin for contraception, separating fertility control from coitus.

• It was soon discovered that addition of a small quantity of an estrogen enhanced their efficacy; combined pills have become the most popular method of contraception, particularly because the hormone content of the pills has been reduced, minimizing the potential harm and affording other health benefits.

FEMALE CONTRACEPTION

• Over 100 million women worldwide are currently using hormonal contraceptives. With these drugs, fertility can be suppressed at will, for as long as desired, with almost 100% confidence and complete return of fertility on discontinuation. The efficacy, convenience, low cost and overall safety of oral contraceptives (OCs) has allowed women to decide if and when they will become pregnant and to plan their activities. A variety of oral and parenteral preparations are now available offering individual choices.

TYPES OF METHODS

Oral

• Combined pill It contains an estrogen and a progestin. With accumulated experience, it has been possible to reduce the amount of estrogen and progestin in the ‘second generation’ OC pills without compromising efficacy but reducing side effects and complications. ‘Third generation’pills containing newer progestins like desogestrel with improved profile of action have been introduced in the 1990s. Ethinylestradiol 30 μg daily is considered threshold but can be reduced to 20 μg/day if a progestin with potent antiovulatory action is included. The progestin is a 19- nortestosterone because these have potent antiovulatory action. Used alone the ovulation inhibitory dose (per day) of the currently used progestins is estimated to be—levonorgestrel 60 μg, desogestrel 60 μg, norgestimate 200 μg, gestodene 40 μg, but the amount in the pill is 2–3 times higher to attain 100% certainty. While both estrogens and progestins synergise to inhibit ovulation, the progestin ensures prompt bleeding at the end of a cycle and blocks the risk of developing endometrial carcinoma due to the estrogen. One tablet is taken daily for 21 days, starting on the 5th day of menstruation. The next course is started after a gap of 7 days in which bleeding occurs. Thus, a cycle of 28 days is maintained. Calendar packs of pills are available. This is the most popular and most efficacious method.

• Phased regimens These have been introduced to permit reduction in total steroid dose without compromising efficacy. These are biphasic or triphasic. The estrogen dose is kept constant (or varied slightly between 30–40 μg), while the amount of progestin is low in the first phase and progressively higher in the second and third phases. Phasic pills are particularly recommended for women over 35 years of age or when other risk factors are present.

• Minipill (progestin only pill) It has been devised to eliminate the estrogen, because many of the long-term risks have been ascribed to this component. A low-dose progestin only pill is taken daily continuously without any gap. The menstrual cycle tends to become irregular, and ovulation occurs in 20–30% women, but other mechanisms contribute to the contraceptive action. The efficacy is lower (96–98%) compared to 98–99.9% with combined pill—look for pregnancy if amenorrhoea of more than 2 months occurs. This method is less popular.

• Postcoital (emergency) contraception Currently 3 regimens are available:

1. Levonorgestrel 0.5 mg + ethinylestradiol 0.1 mg (2 OVRAL tablets) taken as early as possible but within 72 hours of unprotected intercourse and repeated after 12 hours. Till recently, this regimen called the ‘Yuzpe method’ has been the most popular. It is estimated to prevent 3 out of 4 possible pregnancies, but nearly 50% women experience nausea and 20% vomit.
2. Levonorgestrel alone 0.75 mg taken twice with 12 hour gap within 72 hours of intercourse. Trials conducted globally by the WHO taskforce on postovulatory methods of fertility control have found this regimen to be 2–3 times more effective and better tolerated. Incidence of vomiting is only 6% and other side effects are also less. However, the next period may be somewhat delayed. The WHO essential drug list (2001) recommended replacement of Yuzpe method by this regimen.
3. ) Mifepristone 600 mg single dose taken within 72 hours of intercourse has been used in China, Europe and few other countries with high success and fewer side effects than Yuzpe method. Emergency postcoital contraception should be reserved for unexpected or accidental exposure (rape, condom rupture) only, because all regimens have higher failure rate and side effects than regular low-dose combined pill.

Injectable

• These have been developed to obviate need for daily ingestion of pills. They are given i.m. as oily solution; are highly effective; over 50 million women have used them so far. Their major limitations are:

1. Animal data has indicated carcinogenic potential but there is no proof yet from human studies despite 30 years of experience. No increase in overall risk of cervical, ovarian or hepatic cancer has been noted by a WHO sponsored study. Breast cancer risk may be slightly increased in younger women (< 35 yr). The logistics of administration and supervision for mass use are considered inadequate in developing countries. Use effectiveness in field conditions is low. In India approval has been granted for use only under close supervision, but not on mass scale under the National Programme.
2. Menstrual irregularities, excessive bleeding or amenorrhoea are very common; incidence of amenorrhoea increases with increasing duration of use. Return of fertility may take 6–30 months after discontinuation; permanent sterility may occur in some women. Weight gain and headache occur in >5% subjects. Bone mineral density may decrease in long-term users due to low estrogen levels caused by Gn suppression. This may also produce menopause-like symptoms (hot flushes, vaginal dryness, reduced libido). 

MECHANISM OF ACTION

• Hormonal contraceptives interfere with fertility in many ways; the relative importance depends on the type of method. This is summarized.

• Inhibition of Gn release from pituitary by reinforcement of normal feedback inhibition. The progestin reduces frequency of LH secretory pulses (an optimum pulse frequency is required for tiggering ovulation) while the estrogen primarily reduces FSH secretion. Both synergise to inhibit midcycle LH surge. When the combined pill is taken both FSH and LH are reduced and the midcycle surge is abolished. As a result, follicles fail to develop and fail to rupture— ovulation does not occur.

• The minipill and progestin only injectable regimen also attenuate LH surge but less consistently—ovulation occurs in ~ 1/3 cycles. However, pregnancy is still prevented by direct actions on the genital tract.

• Thick cervical mucus secretion hostile to sperm penetration is evoked by progestin action. As such, this mechanism can operate with all methods except postcoital pill.

• Even if ovulation and fertilization occur, the blastocyst may fail to implant because endometrium is either hyperproliferative or hypersecretory or atrophic and in any case out of phase with fertilization—not suitable for nidation. This action appears to be most important in case of minipills and postcoital pill

• Uterine and tubal contractions may be modified to disfavour fertilization. This action is uncertain but probably contributes to the efficacy of minipills and postcoital pill. 

• The postcoital pill may dislodge a just implanted blastocyst or may interfere with fertilization/ implantation.

Practical considerations

• Discontinuation of all OCs results in full return of fertility within 1–2 months. There may even be a rebound increase in fertility—chances of multiple pregnancy are more if conception occurs within 2–3 cycles. With injectable preparations, return of fertility is delayed. The cycles take several months to normalize or may not do so at all. They are to be used only if the risk of permanent infertility is acceptable.

• If a woman on combined pills misses to take a tablet, she should be advised to take two tablets the next day and continue as usual. If more than 2 tablets are missed, then the course should be interrupted, an alternative method of contraception used, and next course started on the 5th day of bleeding. 

• If pregnancy occurs during use of hormonal contraceptives—it should be terminated by suction-aspiration, because the risk of malformations, genital carcinoma in female offspring and undescended testes in male offspring is increased.

• While for most women a pill containing 30 μg ethinylestradiol is sufficient, the obese may require one containing 50 μg, while those above 40 yr age may do with 20 μg. 

• If breakthrough bleeding occurs—switch over to a pill containing higher estrogen dose.

• In women with contraindications for estrogen (see below), a progestin only contraceptive may be used.

• For women who develop weight gain, acne or raised LDL cholesterol due to the androgenic action of the older 19-nortestosterone progestin— a newer progestin (e.g., desogestrel) lacking androgenic action may be preferable.

ADVERSE EFFECTS

• Since contraceptives are used in otherwise healthy and young women, adverse effects, especially long-term consequences assume great significance. The adverse effects are dose dependent; most of the past data with high-dose preparations cannot be directly extrapolated to the present-day low-dose preparations which carry relatively minor risk. The following applies primarily to combined oral pill which has been most extensively used.

Nonserious side effects

1. Nausea and vomiting: similar to morning sickness of pregnancy. 
2. Headache is generally mild; migraine may be precipitated or worsened.
3. Breakthrough bleeding or spotting: specially with progestin only preparations. Amenorrhoea may occur in few, or the cycles may get disrupted: especially with injectables and minipill. 
4. Breast discomfort

Side effects that appear later

• Weight gain, acne and increased body hair may be noted due to androgenic action of older 19-nortestosterone progestins. The newer ones like desogestrel lack this effect. 

• Chloasma: pigmentation of cheeks, nose and forehead, similar to that occurring in pregnancy. 

•  Pruritus vulvae is infrequent.  

• Carbohydrate intolerance and precipitation of diabetes in few subjects taking high dose preparations; but this is unlikely with the present pills. Many large studies have found no link between OC use and development of diabetes.

• Mood swings, abdominal distention is occasional; especially reported with progesterone only contraceptives.

Serious complications

• Leg vein and pulmonary thrombosis: The older preparations increased the incidence of venous thromboembolism, but this is found to be only marginal with the newer reduced steroid content pills. However, even this poses significant risk in women >35 years of age, diabetics, hypertensives and those who smoke. The risk normalizes shortly after stopping the OC. 2. 

• Coronary and cerebral thrombosis resulting in myocardial infarction or stroke: A 2 to 6-fold increase in risk was estimated earlier, but recent studies have found no increased incidence with the low dose pills in the absence of other risk factors

MALE CONTRACEPTIVE

The only way to suppress male fertility by drugs is to inhibit spermatogenesis. Though considerable effort has been made in this direction and effective drugs have been found, no satisfactory/ acceptable solution is yet tangible. Reasons are—

• Complete suppression of spermatogenesis is relatively difficult without affecting other tissues: millions of spermatozoa are released at each ejaculation vs a single ovum per month in women. 
•  Spermatogenesis takes 64 days. A drug which even completely inhibited spermatogenesis will take a long latent period to produce infertility. Similarly, return of fertility will be slow. 
•  Gonadotropin suppression inhibits testosterone secretion as well, resulting in loss of libido and impotence: unacceptable to all men and to most spouses.
• Risk of adverse effects.
• Most importantly—men don’t get pregnant: few would be ready to bear the contingency of regular medication so that their sexual partners do not become pregnant.

Drugs and approaches tried are—

• Antiandrogens Act by direct action on testes; cause unacceptable loss of libido.

• Estrogens and progestins Act by suppressing Gns— cause unacceptable feminization. 

• Androgens They inhibit Gns but have poor efficacy; combination with progestin is more efficacious, preserves libido, but is still not reliable.

• Superactive Gn RH analogues They inhibit Gn release after continued action; also inhibit testosterone secretion— produce impotence, loss of libido. 

• Cytotoxic drugs Cadmium, nitrofurans and indoles suppress spermatogenesis, but are toxic, often produce irreversible action.

• Gossypol It is a nonsteroidal compound, obtained from cotton seed; has been studied in China. It is effective orally—causes suppression of spermatogenesis in 99%.men and reduces sperm motility—infertility develops after a couple of months; fertility is restored several months after discontinuation. However, about 10% men remain oligozoospermic for long periods after discontinuation. During treatment serum LH and testosterone levels do not change libido and potency are not affected. It has no hormonal or antihormonal activity: mechanism of action is uncertain; probably involves direct toxicity on seminiferous epithelium.

• Suggested dose is 20 mg/day for 2–3 months, followed by 40–60 mg/week.

• Most important adverse effect is hypokalemia (due to renal loss of K+) with its attendant muscular weakness (even paralysis). Other side effects are—edema, diarrhoea, breathlessness and neuritis.