COMBINED ESTROGEN–PROGESTOGEN CONTRACEPTIVES Combined estrogen–progestogen contraceptives were considered by previous IARC Working Groups in 1998 and 2005 (IARC, 1999, 2007). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation. 1. Exposure Data 1.1 Identification of the agents See the Monographs on Estrogen-only Combined hormonal contraceptives consist Menopausal Therapy and Combined Estrogen– of an estrogen and a progestogen, and act Progestogen Menopausal Therapy. primarily by preventing ovulation through the inhibition of the follicle-stimulating hormone and luteinizing hormone. The progestogen 1.2 Use of the agents component also renders the cervical mucus rela- tively impenetrable to sperm, and reduces the Information for Section 1.2 is taken from receptivity of the endometrium to implantation IARC (2007), McEvoy (2007), and Sweetman (IARC, 2007). (2008). A variety of innovations have been devel- oped since combined hormonal contraceptives 1.2.1 Indications were first available in the late 1950s, including Oral, intravaginal, injectable and transdermal changes in drug components, doses used, and the estrogen–progestogen combinations are used for temporal sequencing of exposure to drugs. The the prevention of conception in women. dominant trends have been towards less andro- A short-course, high-dose regimen of an genic progestogens, lower doses of estrogen and oral estrogen–progestogen combination is used progestogen, the near abandonment of hormonal in women for the prevention of conception after contraceptives with an estrogen-only phase, a unprotected intercourse (postcoital contracep- proliferation of different product formulations, tion, “morning-after” pills) as an emergency and continuing development of novel delivery contraceptive. systems (IARC, 2007). Certain oral estrogen–progestogen combi- nations have been used for the treatment of moderate acne vulgaris in females 15 years of 283 IARC MONOGRAPHS – 100A age or older who are unresponsive to topical anti- progesterone receptors varies considerably, and acne medication. determines the daily doses required to produce An estrogen–progestogen combination of endometrial differentiation. Drospirenone has ethinylestradiol with drospirenone can be used the lowest affinity (typical daily dose, 3 mg), for the treatment of pre-menstrual disorders. while the later gonanes have the greatest affinity (0.05–0.15 mg daily dose). 1.2.2 Dosages The schedule by which exposure to the drugs occurs may also vary. Most commonly, a constant The large number of products that are combination of estrogen and progestogen is currently available differ in several respects, used for 3 weeks of a 4-week cycle. The doses of including the estrogen compound used and its progestogen and (less often) estrogen may vary dose, the progestogen used, the schedule of expo- in two or three phases followed by a drug-free sure to the drugs, and the route of administration. phase. Sequential exposure regimens that used Identical formulations may carry different brand prolonged exposure to estrogen-alone are no names in different countries or even within the longer used (IARC, 1999), but a short, 5-day, same country. [These products and their ingre- estrogen-only sequence has been re-introduced. dients are presented in Annexes 1–3 of Vol.91 of Cycle lengths shorter and longer than 4 weeks the IARC Monographs (IARC, 2007).] may be used with the aim of limiting the dura- The most common estrogen in combined tion of menses or eliminating menses altogether. hormonal contraceptives is ethinylestradiol. Injection of an estrogen and progestogen Other estrogens have been used, including was used early on in the development of mestranol (a prodrug of ethinylestradiol) and, hormonal contraception, and remains avail- more recently, estradiol. In the early combined able. Innovations in drug delivery have gener- hormonal contraceptives, doses of estrogen in ated transdermal patches and a vaginal device. the range of 100–150 µg were commonly used. Hormonal intrauterine contraceptive devices are Contemporary combined hormonal contracep- also available. tives may be classified by estrogen dose into ‘high-dose’ (50 µg or more), ‘moderate-dose’ (a) Contraception (30–35 µg), and ‘low-dose’ (15–20 µg). (i) Oral dosage A variety of progestogens are used in combined hormonal contraceptives. Currently, Combined estrogen–progestogen oral progestogens are often distinguished as ‘first- contraceptives are usually classified according generation’ estranes (such as norethynodrel or to their formulation: preparations containing norethisterone), ‘second-generation’ gonanes 50 µg of estrogen; preparations containing less (such as levonorgestrel or norgestimate), ‘third- than 50 µg of estrogen (usually 20–35 µg); those generation’ gonanes (gestodene and desogestrel), containing less than 50 µg of estrogen with two and ‘fourth-generation’ drospirenone. An addi- sequences of progestogen doses; those containing tional class of progestogens, the pregnanes less than 50 µg of estrogen with three sequences (eg. cyproterone and chlormadinone), may of progestogen doses; and those containing three also be used. Estranes are highly androgenic, sequences of estrogen (eg. 20, 30, 35 µg) with a while pregnanes and drospirenone have anti- fixed dose of progestogen. androgenic activity. The later gonanes are less Although the progestogen content of the androgenic than the earlier compounds in that formulations also varies, oral contraceptives series. The affinity of individual progestogens for are usually described in terms of their estrogen 284 Combined estrogen–progestogen contraceptives content. The estrogenic or progestogenic domi- (b) Postcoital contraception nance of an oral contraceptive may contribute When an emergency contraceptive kit is used to hormone-related adverse effects, and may be for postcoital contraception, two tablets of an useful in selecting an alternative formulation estrogen–progestogen contraceptive (each tablet when unacceptable adverse effects occur with a containing ethinylestradiol 50 µg and levonorg- given formulation. estrel 0.25 mg, for a total dose of ethinylestradiol Most fixed combinations are available as 21- or 100 µg and levonorgestrel 0.5 mg) are adminis- 28-day dosage preparations (conventional-cycle tered orally within 72 hours after unprotected oral contraceptives). Some 28-day preparations intercourse, repeating the dose 12 hours later. contain 21 hormonally active tablets and seven Several other regimens employing short- inert or ferrous-fumarate-containing tablets; course, high-dose oral combinations of ethi- other 28-day preparations contain 24 hormonally nylestradiol and norgestrel or levonorgestrel active tablets and four inert or ferrous-fumarate- have been used for postcoital contraception. containing tablets. One of the most widely used regimens consists One fixed-combination extended-cycle oral of an oral dose of 100 µg of ethinylestradiol and contraceptive is available as a 91-day dosage 1 mg of norgestrel (administered as two tablets, preparation containing 84 hormonally active each containing 50 µg and 0.5 mg of the drugs, tablets and seven inert tablets. Another extended- respectively) within 72 hours after unprotected cycle oral contraceptive is available as a 91-day intercourse, with a repeat dose 12 hours later. preparation with 84 hormonally active tablets Alternative combination regimens that have containing estrogen–progestogen and seven been used consist of a dose of 120 µg of ethinylestra- tablets containing low-dose estrogen. diol and 1.2 mg of norgestrel or 0.5–0.6 mg of (ii) Intravaginal dosage levonorgestrel within 72 hours after intercourse, Each vaginal contraceptive ring containing repeating the dose 12 hours later. ethinylestradiol and etonogestrel is intended to be used for one cycle which consists of a 3-week 1.2.3 Trends in use period of continuous use of the ring followed by a At the time of writing, more than 100 1-week ring-free period. After a 1-week ring-free million women worldwide, an estimated 10% period, a new ring is inserted on the same day of all women of reproductive age, use combined of the week as in the previous cycle. Withdrawal hormonal contraceptives, most as oral prepa- bleeding usually occurs within 2–3 days after rations. A higher proportion of women receive removal of the ring. these drugs in developed countries (16%) than (iii) Transdermal dosage in developing countries (6%). Proportions of When used for contraception, the transdermal ‘ever use’ higher than 80% have been reported system (containing ethinylestradiol 0.75 mg and for some developed countries. In developing norelgestromin 6 mg) is applied once weekly for countries, 32% of women are estimated to have 3 weeks, followed by a 1-week drug-free interval, ever used hormonal contraception, but there is then the regimen is repeated. Systemic exposure extreme variability between countries. In many to estrogen is greater with the transdermal system countries, these preparations are mainly used than with oral contraceptive preparations. by women of a younger age and a higher level of education, and who have greater access to health care (UN, 2004). 285 IARC MONOGRAPHS – 100A The UN (2004) has compiled data from was available on the prevalence or duration of multiple sources on worldwide patterns of use of these products prior their discontinuation. combined hormonal contraceptive use. It was esti-