Before addressing the specific OCs containing drospirenone, it is important to understand some key points about OC formulations. Combination oral contraceptive pills (COCs) contain both an estrogen and a progestin. There are essentially three variables to consider in OC formulations. The first variable is the dose of estrogen. All available COCs contain ethinyl estradiol (EE) in varying amounts, with the lowest available dose being 15 μg EE and the highest 50 μg EE. The EE component is primarily responsible for the fluid retention side effects of the COCs. Lowering the dose of EE has decreased many side effects; however, it has also been associated with a higher incidence of intermenstrual bleeding than the original formulations, which all contained greater than 50 μg EE.42
In addition, although the half-life of EE is constant, with the lower estrogen doses used in the more recent formulations, EE is cleared from the circulation within only 2–3 days after the last active pill. This rapid clearance may allow FSH levels to rise and follicular development to occur within several days of the hormone-free interval in the OC pack.43
The second variable is the type and dose of the progestin. There are three classes of progestins (synthetic progesterone-like compounds) in COCs: progesterone (17α-acetoprogesterone) derivatives, testosterone (19-nortestosterone) derivatives, and sprinolactone (17α-spironolactone) derivatives. The 17α-acetoprogesterone derivatives, referred to as pregnanes, are similar to the structure of progesterone itself. The testosterone derivatives are the most commonly used and fall into two major categories: estranes (norethindrone, norethindrone acetate, and ethynodiol acetate) and gonanes (norgestrel, levonorgestrel, norgestimate, desogestrel, and gestodene). By chemically altering testosterone, most of the androgenic properties are removed or substantially decreased, but all retain at least some degree of androgenicity. The only spironolactone-derived compound is drospirenone making this progestin the only progestin not derived from a sex steroid.
The effects of progestins are related to the compound’s interactions with a number of receptors, including the receptor for progesterone, androgens, estrogen, glucocorticoids, and mineralocorticoids. The ability to either stimulate or block native interaction with such receptors mediates both the desirable and the undesirable side effects of some of the available progestins. Of note, acne and weight gain are commonly cited side effects of COCs which could be mediated by the progestin effect on the androgen and the glucocorticoid receptors respectively. Despite the efficacy of first and second generation progestins in preventing pregnancy, significant undesirable side effects, such as acne, water retention, and bloating limit the use for other indications. Third generation alternatives, such as norgestimate or desogestrel, have some advantages but still possess some androgenic activity. Unlike the other progestins, drospireone has antimineralocorticoid (aldosterone antagonist) and antiandrogenic properties44
and is pharmacologically similar to endogenous progesterone.45
The lack of antimineralocorticoid activity in other progestins may account for the sodium and water retention, minor elevations in blood pressure, and “pill hypertension” seen in some individuals.46
The antimineralocorticoid effect of drospirenone has the potential to counteract the influence of estrogen-induced fluid retention that can affect some women who use low-dose COCs and reduce the incidence and severity of side effects related to fluid retention, such as swelling of the extremities, breast tension, and body weight. The antiandrogenic effects have the potential to positively impact dermatologic conditions such as acne and hirsutism.
With the unique characteristics of drospirenone, a COC containing EE and this novel progestin was believed to show promise in areas where other OCs have fallen short. In cohort studies of women with premenstrual symptoms comparing drospirenone and other progestins, there were beneficial trends when compared to other formulations. Foidart demonstrated these trends when comparing drospirenone to desogestrel.47
Sangthawan found that the prevalence of water retention, in addition to other potentially negative effects (weight gain, irritability, anxiety) was reduced by half in the EE/drospirenone group while remaining unchanged in an EE/levonorgestrel group.48
The third variable is the dosing pattern. The majority of COCs are administered in a standard 21/7 regimen, such that the EE and the progestin are given on days 1–21, followed by placebo pills on days 22–28, constituting the hormone-free interval. As with the estrogenic component, the lower doses of the progestins in the newer COCs are also cleared from the circulation within a few days after stopping the steroid-containing pills, allowing lutenizing hormone (LH) levels to rise. Therefore, ovulation may occur if the new cycle of active pills is not started exactly seven days after the last active pill was taken. In one randomized trial with a 20 μg EE formulation, when the hormone-free interval was five days, in lieu of the historical seven days, there was greater suppression of ovarian follicular size and endogenous estradiol levels.49
Use of a 3–4 day hormone-free interval appears to provide a sufficient level of both EE and progestin in the circulation to suppress both gonadotropins until the new cycle of active pills is begun. Newer formulations of COCs (24/4) have decreased the hormone-free interval to four days by providing active medication on days 1–24 and placebo pills on days 25–28. The decrease in the number of days without steroid ingestion should result in constant suppression of LH and follicle-stimulating hormone (FSH) levels and prevent follicular growth during the hormone-free interval. Constant inhibition of follicular development and endogenous estradiol synthesis throughout each month of oral contraceptive use should decrease the incidence of unscheduled bleeding as well as the incidence of escape ovulation and pregnancy that occurs with typical oral contraceptive use. In addition, the shortening of the hormone-free interval should decrease several of the adverse hormonal withdrawal symptoms experienced during the seven day hormone-free interval in the standard COC regimens.