Combined hormonal contraception provides an oestrogen and a progestin; they include combined oral contraceptives, combined injectable contraceptives, vaginal ring (Nuva Ring) and transdermal patch (Evra) [17, 45].
3.3.1.1 Combined oral contraceptives
In combined oral contraceptives (COCs), the commonly used progestins are the estranes (norethindrone and norethindrone acetate), the gonanes (levonorgestrel, desogestrel, and
82 norgestimates), and the spironolactone analogue drospirenone [23, 222]. Progestogens used in COCs have different androgenic, oestrogenic and progestational activity [223]. The oestrogens are principally confined to either ethinyl oestradiol or its 3-methyl ether, menstranol. When first developed, the two principal regimens of COCs were combined and sequential. In the combined regimen all active pills contain both oestrogen and progesterone [23]. In the sequential regimen, oestrogen-only pills are taken during the first part of the cycle followed by pills containing both oestrogen and progesterone [222]. The sequential method has been largely abandoned because several studies showed a high incidence of endometrial cancer in women using this method of contraception [23, 222]. Currently, combined oral contraceptive pills are available in monophasic, biphasic, and triphasic preparations. Monophasic preparations have the same amount of oestrogen and progestin in each active pill; biphasic preparations contain two different dose combinations; and triphasic preparations have three different dose combinations [45, 224]. In the most commonly used combined method, pills containing both oestrogen and progestin are taken each day for 21 days, followed by 7 days of placebo pills, during which time most women experience withdrawal bleeding. Over the years, the oestrogen content has been reduced by a factor of 3- to 4-fold, such that the current dose of ethinyl oestradiol ranges between 20 and 35 g. Similarly, the progestin content has been substantially reduced [23, 222]. This has decreased the occurrence of unwanted effects without change in efficacy [17, 223]. Reduction of oestrogen to 20g has reduced cardiovascular mortality in OC users by 60% [223].
The probable mechanisms of contraception are:
Inhibition of ovulation: both hormones act synergistically on the hypothalamo- pituitary-ovarian axis to inhibit ovulation. The release of GnRH from the hypothalamus is prevented through a negative feedback mechanism. Consequently, there is no rise in FSH and LH during the first half of the cycle and there are no mid- cycle alterations in FSH and LH levels; as a result, the growth of the dominant follicle and subsequent ovulation does not occur [23, 45, 222, 224].
Inhibition of endometrial maturation: the progestogen component makes the endometrial lining less receptive to implantation by producing static endometrial hypoplasia (there is stromal oedema, decidual reaction, and regression of the glands) [23, 45, 222-224].
83 Thickening of cervical mucus: the progestogen alters the character of the cervical
mucus resulting in less sperm penetration [23, 45, 222-224].
Interference of tubal function: the progestogen interferes with motility and secretions of the fallopian tubes, thereby altering tubal transport of both sperm and oocyte [23, 222-224].
Medical complications may arise from use of COCs. Hypertension is due mainly to the oestrogen component, which causes an increase in plasma angiotensinogen. Vascular complications, including thromboembolic disease, myocardial infarction (MI), and stroke that may arise as a result of using COCs, are also attributed to the oestrogen component. Use of current COCs roughly triples a user’s risk of venous thromboembolism (VTE), including pulmonary embolism (PE). VTE is enhanced by risk factors such as pre-existing hypertension, diabetes, obesity, age (higher risk in those over 35 years, especially smokers), recent leg trauma, pelvic surgery, stasis (but not varicose veins), and the presence of germline mutation in the clotting system known as factor V Leiden. MI and stroke are rare conditions; they occur among COC users only in the presence of risk factors such as hypertension, diabetes, severe dyslipidemia, smoking, and age over 35. Cholelithiasis, and benign liver tumours are occasionally noted with COC use [17, 23, 45, 222, 223]. The relationship between the use of oral contraceptives and risk of cancer will be discussed in Chapter 4.
Menstrual abnormalities, including intermenstrual bleeding, hypomenorrhoea, and amenorrhoea, may also be observed with use of COCs. Minor complications noted with use of COCs include: nausea, vomiting, headache, leg cramps, mastalgia, bipedal oedema, and chloasma. Leucorrhoea has also been reported and may be due to excessive cervical mucus secretion or to increased risk of monilial infection [23, 222, 225]. Obviously, contraceptive use is not required in pregnancy; however, no adverse effects have been reported with accidental use of COCs in pregnancy [17].
The effect of COCs on lactation has not yet been established [17]. However, COC use is probably associated with a reduction in milk production and alteration of the quality of milk (reduction of protein and fat content) [45, 222]. Moreover, a substantial dose of the COC steroids are ingested by the infant, with effects that are as yet unknown [17, 45, 222].
Because of the unwanted effects associated with use of COCs, there are medical contraindications to their use. These include unexplained vaginal bleeding; circulatory diseases past or present (severe hypertension, valvular heart disease, VTE, MI, or stroke);
84 family history of DVT/PE; known thrombogenic mutations (i.e. factor V Leiden; prothrombin mutation; protein S, protein C, or antithrombin deficiencies); active systemic lupus erythematosus (SLE); uncontrolled diabetes; cigarette smokers over the age of 35 years; current or prior breast cancer; and active liver or gall bladder disease [23, 45, 222, 223]. Certain antibiotics, anticonvulsants, anti-tuberculosis, and antiretroviral drugs (ARVs) may affect the bioavailability of steroid hormones and, hence, reduce the effectiveness of COCs [17, 45, 223, 224]. Gastrointestinal conditions such as vomiting and diarrhoea may also reduce the efficacy of COCs [223-225].
COCs provide protection against health disorders including pelvic inflammatory disease (PID), endometriosis, fibroids, functional ovarian cysts, benign breast disease, osteopenia, autoimmune disorders of the thyroid, progression of rheumatoid arthritis, and iron deficiency anaemia. They have also been shown to reduce the incidence of endometrial, ovarian, and colorectal cancers. Correction of menstrual abnormalities including regulation of menstrual cycle, reduction of dysmenorrhoea, menorrhagia, premenstrual tension syndrome, and Mittelschmerz (one-sided lower abdominal pain associated with ovulation) syndrome, may also be achieved with use of COCs. They are also used in the treatment of acne, hirsutism, hyperandrogenism, and polycystic ovary syndrome (PCOS) [23, 222, 223]. COCs are highly effective at preventing pregnancy, and the reversibility is prompt (ovulation returns within 3 months of withdrawal of the drug in 90% of cases) [222]. The potential benefits of COCs exceed the risks, in the absence of contraindications.
3.3.1.2 Vaginal ring
The vaginal ring (Nuva Ring) releases ethinyl estradiol 15g daily, and etonogestrel (a metabolite of desogestrel) 120g daily. The ring is worn high in the vagina for 3 weeks, it is then removed and after 1 week (after the withdrawal bleeding) a new ring is inserted. Fitting by a health professional is not required. About 10 to 15% of users of the vaginal ring report vaginal-related symptoms such as slight discomfort, a sensation of foreign body, leucorrhoea, vaginitis, or coital problems [23, 45, 222].
3.3.1.3 Transdermal patch
The transdermal patch delivers norelgestromin 150g, the active metabolite of norgestimate, and ethinyl estradiol 20g daily for a 7-day period. Three consecutive 7-day patches are applied in a typical cycle, followed by a 7-day patch-free period to allow withdrawal bleeding. Application sites include the buttocks, lower abdomen, upper outer arm, and upper
85 torso excluding the breast. Contraceptive patch users may have application site reactions [23, 45].
3.3.1.4 Combined injectable contraceptives
Combined injectable contraceptives (CICs) contain the naturally occurring oestrogen, oestradiol, and a progestogen [17]. The preparations are medroxyprogesterone acetate 25mg with oestradiol cypionate 5mg (Cyclofem/Cyclo-provera), and norethisterone enanthate 50mg with oestradiol valerate 5mg (Mesigyna/Norigynon) [225]. Use of “natural” oestrogens in CICs has a favourable impact on lipid metabolism and cardiovascular effects compared to the synthetic oestrogen used in COCs. Each injection should be given on the same date of each month (about every 4 weeks) The contraceptive effect is by inhibition of ovulation [17].
The combined contraceptive vaginal ring, combined contraceptive patch, and combined injectable contraceptives are relatively new, and therefore, there are few data on their long- term effects. Nevertheless, because the vaginal ring and the transdermal patch contain steroids that are used in COCs, rates of serious unwanted effects may be similar and some of the non-contraceptive benefits discussed above may accrue to users of these methods [17, 23].