Female Contraception - Hormonal Contraceptives

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Chapter: Essential pharmacology : Estrogens, Progestins and Contraceptives

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.



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





1. 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 anti-ovulatory action is included. The progestin is a 19 nortestosterone because these have potent anti-ovulatory 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.


2. 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.


3. 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 lowdose 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.


4. Postcoital (Emergency) Contraception Currently 3 regimens are available:


a.    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.


b.    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 some what delayed. The WHO essential drug list (2001) recommended replacement of Yuzpe method by this regimen.


c. Mifepristone 600 mg single dose taken within 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 lowdose combined pill.




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:


a. 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.


b. 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 menopauselike symptoms (hot flushes, vaginal dryness, reduced libido).


Two types of preparations have been tested:


i) Long acting progestin alone—injected once in 2–3 months depending on the steroid and its amount. Two compounds have been marketed:


a.   Depot medroxyprogesterone acetate (DMPA) 150 mg at 3month intervals. After i.m. injection peak blood levels are reached in weeks and decline with a t½ of ~ 50 days.


DEPOTPROVERA 150 mg in 1 ml vial for deep i.m. injection during first 5 days of menstrual cycle. Repeat every 3 months.


b. Norethindrone (Norethisterone) enanthate (NEE) 200 mg at 2month intervals.


NORISTERAT 200 mg in 1 ml vial for deep i.m. injection during first 5 days of menstrual cycle. Repeat every 2 months.


The most important undesirable property is complete disruption of menstrual bleeding pattern and total amenorrhoea (more common with DMPA). It is not suitable for adolescent girls and lactating mothers. Use of DMPA is generally restricted to women who are unlikely to use other contraceptives effectively. NEE is shorter acting and failure rates have been higher than with DMPA.


ii) Long acting progestin + long acting estrogen once a month. These have been tested to a more limited extent, but a combination of MPA + estradiol cypionate has been approved by USFDA for i.m. injection every month. Main advantage is that they allow a reasonable menstrual bleeding pattern in most cases. Their obvious disadvantage is that they contain a long acting estrogen which has potential to harm.


All fixed dose combination injectable preparations of synthetic estrogens and progestins are not allowed in India.




These are drug delivery systems implanted under the skin, from which the steroid is released slowly over a period of 1–5 years. They consist of either—


i)                   Biodegradable polymeric matrices—do not need to be removed on expiry.

ii)                Nonbiodegradable rubber membranes—have to be removed on expiry.


NORPLANT: A set of 6 capsules each containing 36 mg levonorgestrel (total 216 mg) for subcutaneous implantation is available in some countries, but has been discontinued in the USA. Works for up to 5 years.


A progesterone impregnated intrauterine insert (PROGESTASERT) has been introduced in some countries. It contains lesser quantity of progestin which primarily acts locally on endometrium. The device is to be replaced yearly and efficacy is rated lower.


Mechanism Of Action


Hormonal contraceptives interfere with fertility in many ways; the relative importance depends on the type of method. This is summarized in Table 22.2.



1. 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.


2. 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.


3. Even if ovulation and fertilization occur, the blastocyst may fail to implant because endometrium is either hyperproliferative or hypersecre

tory 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.


4. 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.


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


Practical Considerations


Ø 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.


Ø 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


Ø 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.


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


Ø While for most women a pill containing 30 μg ethinylestradiol is sufficient, the obese may require one containing 50 μg, while those above


Ø yr age may do with 20 μg.


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

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

Ø For women who develop weight gain, acne or raised LDL cholesterol due to the androgenic action of the older 19nortestosterone 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 highdose preparations cannot be directly extrapolated to the presentday lowdose preparations which carry relatively minor risk. The following applies primarily to combined oral pill which has been most extensively used.


A. Nonserious Side Effects


These are frequent, specially in the first 1–3 cycles and then disappear gradually.


Ø Nausea and vomiting: similar to morning sickness of pregnancy.


Ø Headache is generally mild; migraine may be precipitated or worsened.


Ø 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.


Ø Breast discomfort.


B. Side Effects That Appear Later


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


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


Ø Pruritus vulvae is infrequent.


Ø 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.


Ø Mood swings, abdominal distention are occasional; especially reported with progesterone only contraceptives.


C. Serious Complications


1. 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 these pose 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 6fold 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.


The estrogen component of OC has been mainly held responsible for venous thromboembolism, while both estrogen and progestin have been blamed for the arterial phenomena. The mechanisms involved may be:


o   Increase in blood clotting factors (coagulability is enhanced).

o   Decreased antithrombin III.

o   Decreased plasminogen activator in endothelium.

o   Increased platelet aggregation.


3. Rise in BP: occurred in 5–10% women taking the earlier pills. This again is less frequent and smaller in magnitude with the lowdose pills of today. If the BP rises, best is to stop OCs—BP normalizes in the next 3–6 months. Both the estrogen and progestin components are responsible for this effect, probably by increasing plasma angiotensinogen level and renin activity which induces salt and water retention.


4. Estrogen tends to raise plasma HDL/LDL ratio (beneficial), but the progestin nullifies this benefit: lipid profile is not significantly altered by low dose OCs, except that triglyceride level may rise marginally which poses no excess risk.


5. Genital carcinoma: an increased incidence of vaginal, cervical, and breast cancers was feared on the basis of animal data, but extensive epidemiological data over the past 30 years has repeatedly shown that oral as well as injected contraceptives do not increase the occurrence of these cancers in the general population. How ever, risk is increased in predisposed individuals. Growth of already existing hormone dependent tumour may be hastened.


Epidemiological data has recorded minor increase in breast cancer incidence among current OC users, but not among past users. Since breast cancer is rare in young women, this finding is considered inconsequential.


A protective effect against endometrial carcinoma has been shown for the progestin component. Prolonged suppression of gonadotropic stimulation of ovary may account for the lower incidence of ovarian malignancy noted in contraceptive users.


6. Benign hepatomas: which may rupture or turn malignant; incidence of this rare tumour appears to be slightly higher in OC users.


7. Gallstones: Estrogens increase biliary cholesterol excretion; incidence of gallstones is slightly higher in women who are taking OCs, or after long-term use.




The combined oral contraceptive pill is absolutely contraindicated in:


Ø Thromboembolic, coronary and cerebrovascular disease or a history of it.

Ø Moderatetosevere hypertension; hyperlipidaemia.

Ø Active liver disease, hepatoma or h/o jaundice during past pregnancy.

Ø Suspected/overt malignancy of genitals/ breast.

Ø Prophyria.

Ø Impending major surgery—to avoid postoperative thromboembolism.


Relative Contraindications

(requiring avoidance/ cautious use under supervision)


Ø Diabetes: control may be vitiated.


Ø Obesity


Ø Smoking


Ø Undiagnosed vaginal bleeding


Ø Uterine leiomyoma: may enlarge with estrogenic preparations; progestin only pills can be used.


Ø Mentally ill


Ø Age above 35 years


Ø Mild hypertension


Ø Migraine


Ø Gallbladder disease





Contraceptive failure may occur if the following drugs are used concurrently:


a)    Enzyme inducers: phenytoin, phenobarbitone, primidone, carbamazepine, rifampin. Metabolism of estrogenic as well as progestational component is increased.


b)    Suppression of intestinal microflora: tetracyclines, ampicillin, etc. No deconjugation of estrogens excreted in bile their enterohepatic circulation is interrupted blood levels fall.


With both types of interacting drugs, it is wise to switch over to a preparation containing 50–80 μg of ethinylestradiol or to use alternative method of contraception.


Other Health Benefits


Apart from benefits due to prevention of unwanted pregnancy and the risks during delivery, use of oral contraceptives affords certain other beneficial effects as a bonus:


Ø Lower probability of developing endometrial and ovarian carcinoma; probably colorectal cancer as well.


Ø Reduced menstrual blood loss and associated anaemia; cycles if irregular become regular; premenstrual tension and dysmenorrhoea are ameliorated.


Ø Endometriosis and pelvic inflammatory disease are improved.


Ø Reduced incidence of fibrocystic breast disease and ovarian cysts.




It is a nonsteroidal estrogen antagonist or SERM developed at CDRI, India and introduced in the National Family Welfare Programme as an oral contraceptive. It probably acts as an anti-implantation agent by inducing embryo uterine asynchrony, accelerated tubal transport and suppression of decidualization. It prevents conception as long as taken, with return of fertility on withdrawal. Failure rate of 1–3% has been recorded. Pituitary, ovarian and other endocrine functions do not appear to be affected.


The menstrual cycle is not disturbed in most women, but in 6–10% it may be lengthened irregularly.


The usual side effects of hormonal contraceptives have not been noted. No derangement of laboratory tests including blood sugar and lipid profile have been detected. No teratogenic, mutagenic or carcinogenic effect has been observed so far. However, if pregnancy occurs centchroman should be discontinued immediately.


Centchroman has a long plasma t½ (about 1 week). The recommended dose is 30 mg twice weekly for 12 weeks followed by once a week as long as fertility is to be suppressed. More experience has to be gained to decide its role as a contraceptive.


CENTRON, SAHELI 30 mg tab.


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