Combined oral contraceptives: Why, when, where?

Introduction

Polycystic ovary syndrome (PCOS), a multifactorial disorder, involves mainly reproductive but also other endocrine systems. Based on the current Rotterdam criteria, the prevalence of PCOS varies between 5% and 10% in women of reproductive age . Metabolic issues such as inflammation, increased coagulability, visceral obesity, insulin resistance, and excess androgen are considered as key features in PCOS .

Combined oral contraceptives are hormonal medications that contain both estrogen and progestin and are used for contraceptive and noncontraceptive purposes . They are currently used by more than 100 million women worldwide. From 2015 to 2017, 12.6% of women aged 15–49 in the United States reported using oral contraception, making it the second most common method of contraception in this age range. In 2009, COCs represented 8.8% of contraceptive methods employed, reaching 15.4% in more developed countries .

Progestins are synthetic steroids possessing properties of progesterone, to which they demonstrate greater bioavailability, half-life, and activity. They exert their biological effects via binding to progesterone receptor, while they confer most of their contraceptive benefit by suppressing luteinizing hormone (LH) and ovulation. Furthermore, progestins suppress midcycle peaks of follicle-stimulating hormone (FSH) and LH, render cervical mucus hostile to spermatozoids, prevent implantation due to endometrial degeneration, slow down the movement of the oocyte, and the motility of the fallopian tubes, while they reduce mobility and fertilizing capacity of the sperm. Progestins can be distinguished, based upon their chemical origin, in those derived from testosterone and those derived from progesterone ( Table 1 ). The majority of progestins used in COCs are derived from testosterone. Depending on their chemical origin, progestins vary in their potency, androgenicity, and side effects . In contrast to the long list of progestins, only few estrogenic compounds are used in COCs, mainly ethinyl estradiol (EE) and estradiol valerate. Estrogens regulate menstrual bleeding, inhibit FSH, and prevent formation of the dominant follicle. (See Table 2 .)

Combined oral contraceptives exert their contraceptive effect through suppression of the hypothalamic-pituitary-ovarian (HPO) axis as well by inhibition of the zygote implantation.

The noncontraceptive effect of COCs includes regulation of the menstrual cycle and suppression of ovarian function . Thus, COCs are the most common treatment in women with PCOS. They act beneficially at multiple levels:

Pulsatility of the gonadotropin releasing hormone (GnRH) neuron: A neuroendocrine hallmark of PCOS is persistently accelerated GnRH pulsatility, which favors pituitary synthesis of LH over FSH and contributes to increased circulating LH concentrations and LH/FSH ratios, which are typical characteristics of this disorder. Kisspeptin, a hypothalamic peptide encoded by the KiSS1 gene, is a neuromodulator and a potent stimulator of the HPO axis. Secreted upstream of GnRH, it signals directly to GnRH neurons via kisspeptin receptor to release GnRH into the portal circulation resulting to pulsatile secretion of LH and FSH from the anterior pituitary . Estrogen and progesterone, both components of COCs, modulate kisspeptin activity through sex steroid receptors . An undefinable period of treatment with COCs might lead to normalization of GnRH pulsatility.

Inhibition of endocrine secretion from the ovaries: The indirect, via suppression of the HPO axis, inhibition of ovarian endocrine function by COCs results in suppression of ovarian androgens secretion and subsequently in reduction of symptoms of hyperandrogenism. The decrease of androgens contributes, in turn, to the increase of unbound progesterone receptors in the hypothalamus, leading, thus, to normalization of GnRH pulsatility.

Other effects: Estrogens in COCs lead to increased concentrations of sex-hormone binding globulin (SHBG), which binds, among other peripherally circulating hormones, androgens. Thus, the amount of circulating free androgens decreases. Progestogens in COCs compete with androgens for the binding of the androgen receptors and inhibit 5a reductase, which catalyzes the reduction of testosterone to its active metabolite, dihydrotestosterone . Specific progestogens possess particular antiandrogenic properties by binding and blocking androgen receptors. In this way, COCs improve hair loss and acne . Also, progestogens stabilize and protect the endometrium from the constant exposure to estrogens as it is the case in PCOS.

Pharmacology of COCs

Combined oral contraceptives are administrated per os. Their side effects are those of estrogen and progestins. Enovid®, the first COC, contained mestranol and norethisterone, and it was approved by the Food and Drug Administration in May 1960. The addition of an ethinyl group to the estradiol molecule in 1938 created EE, the synthetic estrogen compound most used in all COCs. Over the years, COCs have evolved through gradual lowering of EE content, introduction of 17β estradiol, and many different progestins.

There are three molecularly distinct types of progestins according to their active chemical structure and their parent compound: estranes, gonanes, and pregnanes ( Table 1 ). The former two, derived from testosterone, were created with the addition of an ethinyl group to the molecule of testosterone to create ethisterone. The subsequent removal of a carbon atom from the 19th carbon of ethisterone converted it from an androgen to a progestogen (19-nortestosterone derivatives). They include norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel (estranes) and levonorgestrel (LNG), desogestrel (DSG), norgestrel, norgestimate (NGM), and gestodene (GSD) (gonanes) ( Table 1 ). Gonanes and estranes differ in their half-life as well as with respect to their estrogenic and antiestrogenic effects. Pregnanes derive from progesterone. They include cyproterone acetate (CPA), nestorone, and medroxyprogesterone acetate. Drospirenone (DRSP) is a spironolactone analog with antimineralocorticoid and antiandrogenic activity . The COCs are also classified according to the time they were introduced into the market in four generations ( Table 1 ). Combined oral contraceptives contain EE or estradiol valerate as an estrogen. Oral contraceptives have been related to deterioration of lipid profile although without significant changes in other metabolic outcomes, including body mass index (BMI), fasting blood glucose, fasting insulin, homeostatic model for measuring insulin resistance (HOMA-IR), and blood pressure values. Combined oral contraceptives with an antiandrogenic progestin (CPA, DRSP) are employed in the treatment of PCOS and for decades have been the most common therapeutic tool for PCOS ( Table 1 ) . Cyproterone acetate (CPA) demonstrates significant progesterone activity regarding inhibition of gonadotropin secretion. Drospirenone in therapeutic doses has antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid, and antiglucocorticoid action, while it exhibits a pharmacological profile quite similar to progesterone .

Side effects and contraindications of therapy with COCs