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No. 66 Hormones |
Following the introduction of oral contraceptives, the number of induced abortions decreased steadily – in Switzerland between 1966 and 1998, for example, by 25%. However, improvements in sexual education and counseling may also have contributed to the lower rates of induced abortion in many countries. Today, approximately 90 million women worldwide use oral contraceptives [1]. In the earliest days of their use, the effectiveness and reliability of oral contraceptives were the issues most discussed by physicians and lay people. In the 1980s and ’90s, the safety and potential health risks of oral contraceptives became the main focus of interest. Today, women can choose from a wide range of contraceptives, and for those who opt for hormonal contraception, a broad variety of preparations are available, varying in their mixture of estrogen and/or some specific progestogen, and their mode of application. In addition to oral contraceptives, hormones can be administered as depot preparations applied by injections, implants, vaginal rings, or intrauterine systems. While the injections on the market and the implants only contain progestogens, the other application forms as well as a solution for monthly subcutaneous injection contain both estrogen and a progestogen. How hormonal contraceptives work The first oral contraceptives contained mestranol, but today, ethinylestradiol (EE), a potent synthetic derivate of estradiol, has become the main estrogenic constituent of modern oral contraceptives. EE ensures adequate control over the menstrual cycle, maintaining stable and regular bleeding patterns in most users. In addition to the estrogen component of most hormonal contraceptives, a synthetic progestogen is added to suppress ovulation and prevent hyperplastic proliferation of the endometrium which can occur as a side effect. These progestogens are derivates of either progesterone, 19-nortestosterone, or, more recently, 17α-spirolactone. The gestagenic (progestational) activity of each compound is dose dependent and targeted to the endometrium, cervix, and ovary. Some progestogens may have additional effects, such as estrogenic, androgenic, antiandrogenic, or antimineralcorticoid activity. Some of these effects are clinically relevant in choosing the type of ‘pill’ most suitable for an individual woman. Classification and types of hormonal contraceptives The broad array of clinically available hormonal contraceptives can be divided into short-acting preparations (the conventional ‘pill,’ applied orally) and long-acting depot preparations, mostly applied by injection or implant, but also by vaginal ring and an intrauterine system. Oral contraceptives are divided into two groups. Those in the first group contain a progestogen only and are called ‘POP’s (progestogen-only pills or ‘minipills’); those in the second group combine EE and some progestogen and are called ‘COC’s (combined oral contraceptive). COCs are the most commonly used form of hormonal contraceptive worldwide, mainly taken as a monophasic micropill. Micropills contain less than 50 µg (35–15 µg) of EE combined with one of the second- or third-generation progestogens which are derived from 19-nortestosterone. COCs are generally administered over a period of 21 days, followed by a pause of 1 week, when withdrawal bleeding should occur. In contrast to COCs, POPs must be administered continuously without a pause. POPs often trigger irregular bleeding patterns, which contribute to a high discontinuation rate. Because they do not normally inhibit ovulation but only change the mucus of the cervix and the endometrium and therefore act by inhibiting sperm ascension and the nidation of a fertilized ovum, POPs are less efficient in preventing an unwanted pregnancy. To guarantee effectivity, they ought to be taken at the same time every day, another factor that limits their use. Hormonal contraceptives can also be given briefly, for example, after one single unprotected sexual intercourse or in cases when a barrier method fails. In such a situation, postcoital emergency contraception (more precisely, interception!) may be administered acutely following either the Yuzpe method (two doses of 100 µg EE and 300 µg Levonorgestrel) or using a progestogen-only preparation (two doses of 750 µg Levonorgestrel). Both methods must be applied within 72 h after unprotected intercourse. Effectiveness and reliability The reliability of a contraceptive is generally measured and expressed by the Pearl index, which states the number of unwanted pregnancies per 100 years of use, or the number of pregnancies which may occur in 100 women who use the contraceptive method for 1 year. For hormonal contraceptives, the Pearl index ranges from 0–0.2 for implants up to 0.4–4.3 for POPs (table 1).
Reliability depends on the modes of action and administration. The Pearl index is considerably better for preparations which inhibit ovulation (COCs and depot progestogens) and in those associated with little risk of administration failure (long-term contraceptives, such as depot injections, implants, and intrauterine systems). Health risks Hormonal contraceptives are taken by healthy women for prophylactic purposes. Their safety standard must therefore be higher than for drugs prescribed to cure disease. Potential risk factors are of major importance when assessing the quality of hormonal contraception. One of the major health risks due to COCs is an increased incidence of cardiovascular complications such as venous thromboembolism, myocardial infarction, and cerebrovascular insults due to increased blood clotting, mainly induced by their estrogen component. EE also has a negative impact on liver function. In addition to the role of EE, the effect of the gestagenic components of COCs on the pathogenesis of cardiovascular complications has been much discussed in the last few years. While this debate is still ongoing, other important health issues of long-term oral contraceptive use must be clarified, such as various types of cancer of the female genital tract and the breast, and the effect on bone metabolism.  The cardiovascular risk of COCs. During their reproductive life, the risk for cardiovascular incidents in women is low, but it increases with age. Venous thromboembolism occurs in 32–59 out of 1,000,000 premenopausal women every year. COC use increases the risk of venous thromboembolism in all age groups.
Smoking also contributes to the cardiovascular risk of COCs (see table 2), and thus COCs are definitely contraindicated in smoking women older than 35 years. Other risk factors for cardiovascular disease in COC users include hereditary thrombophilia (a tendency to excessive blood clotting as may occur in individuals with a genetically altered blood clotting system), high blood pressure, migraine, and chronic diseases such as diabetes. Third-generation progestogens are associated with a slightly elevated risk of venous thromboembolism compared to the first- and second-generation progestogens. However, the absolute risk remains very low and may be counterbalanced by a somewhat lower prevalence of myocardial infarction [2]. The risk of cancer in COC users. Long-term use of COCs is associated with a slight increase in the relative risk (RR) of breast cancer (RR 1.07) [3], whereas the relative risks of endometrial and ovarian cancer are considerably lower (0.5 and 0.4, respectively) in COC users. However, cervical cancer is significantly more common in COC users (RR 1.5). Apart from the particular effect of estrogens in the induction of cervical cancer, various epidemiological aspects must also be considered. For example, in women carrying the human papilloma virus, the risk of invasive cervical cancer is higher in COC users than in non-COC users [4]. The excess incidence of invasive cervical cancer is outweighed by the lower prevalence of other uterine and ovarian cancers. COCs and bone metabolism. Bone metabolism is positively influenced by circulating estrogen levels. Ovarian suppression by COCs or depot progestogens may reduce circulating estrogen levels, thereby down-regulating bone metabolism.This has been demonstrated in women of all ages taking COCs containing 20–30 µg EE. However, there is at present no indication for an adverse effect due to long-term use of COCs in women over 30 years, and even a benefit in perimenopausal women. In adolescents, intake of COCs containing as little as 20 µg and less may be associated with an impairment of peak bone mass [5]. We therefore recommend that COCs containing 15 µg of EE should not be prescribed to women of this age group. Therapeutic use of oral contraceptives COCs exert desirable effects on the uterine bleeding pattern, body weight, mood, skin disorders, and bone metabolism. Bleeding disturbances such as hypermenorrhea can be influenced positively. Even a temporarily limited amenorrhea can be induced if necessary and desired, for example, in patients with extreme dysmenorrhea (painful menstruation) who do not respond to other treatment options. Use of COCs in the menstrual cycle before the actual treatment with assisted reproduction is associated with a better response to ovarian hyperstimulation and a lower incidence of ovarian cysts [6]. Although often prescribed for this indication, COCs do not exert a positive effect on endometriosis. The antimineralcorticoid property of the new progestogen drospirenone has a positive impact on the fluid retention experienced premenstrually by many women. Not only somatic symptoms, but, to a lesser extent, premenstrual mood changes can be alleviated by COCs. The antiandrogenic potency of the progesterone-derived progestogens offers an option for the treatment of acne. Even in women suffering from polycystic ovarian disease and hyperinsulinism, oral contraceptives containing the anti-androgenic progestogen cyproteron-acetate have proved to be superior to insulin sensitizers in counteracting hyperandrogenism. Perimenopausal women, in particular, might benefit from COCs due to the positive effect on bone density and the normalizing effect on the menstrual cycle. If there are no specific risk factors and after exclusion of high blood pressure and an irregular lipid profile, liver function, and glucose metabolism, low-dose COCs can be prescribed up to the age of 50. New trends in hormonal contraception The appropriate choice of a hormonal contraceptive is based on its efficacy, safety, and also on its practicability in daily use. Beside the well-established pills, implants, and progestogen-containing intrauterine systems, new methods of application have recently become available including a vaginal ring, which can be worn for a period of 3 weeks, and a skin patch for weekly use (fig. 1). Both of these applications contain a combination of EE and a progestogen and act as ovulation inhibitors.
However, research into new types of contraception, both hormonal and nonhormonal, i.e., mechanically and chemically acting contraceptives as well as male-initiated methods, remains important. The recent increase in distinctive contraceptive methods can also put more strain on the decision process of the women and couples involved. High-quality counseling therefore becomes increasingly important, taking into account the individual’s preferences and needs and providing honest information about the range of contraceptive options.   Sibil Tschudin and Christian De Geyter are gynecologists at the University Women’s Hospital in Basel, Switzerland. Dr. Tschudin is senior registrar of the Division of Gynecological Psychosomatics; her work focuses on contraception, the treatment of premenstrual syndrome and sexual disorders, and infertility counseling. Prof. De Geyter is head of the Division of Gynecological Endocrinology and Reproductive Medicine.
Dr. S. Tschudin, Dr. C. De Geyter University Women's Hospital of Basel Gynecological Endocrinology and Reproductive Medicine Schanzenstrasse 46 4031 Basel Phone: +41 61 325 93 15 Email: s.tschudin@bluewin.ch, cdegeyter@uhbs.ch |
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