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2002 Selected Articles

Drospirenone
A Novel Progestin in an OC Formulation

Ian H. Thorneycroft, PhD, MD

Oral contraceptives (OCs) are the most common form of reversible birth control used by US women. ¹ Because annoying and/or potentially harmful side effects can reduce compliance with OC regimens, researchers are constantly trying to improve the tolerability and safety profile of these agents while preserving their high efficacy. Although great progress has been made in this regard, the quest for the ideal OC remains unfulfilled. For example, a recent Gallup poll commissioned by the American College of Obstetricians and Gynecologists found that 41% of US women think that OCs are associated with substantial health risks, despite the fact that a large body of data attests to the Pill’s relative safety in healthy, nonsmoking women. To achieve any substantial reduction in the high rate of unintended pregnancies in the United States, this false, largely media-driven perception must be changed.

Adverse reactions–not fear of health risks such as heart disease, stroke, or breast cancer–are the primary reason for discontinuing OCs in the first 12 months of use. ² Discontinuation rates within the first year are disconcerting, approaching 60% in one study. ³ Many discontinuers tend to choose a less reliable contraceptive method or no method, resulting in a high rate of unintended pregnancies. ³

The novel progestin drospirenone has pharmacologic properties that distinguish it from all other progestins previously used in OCs. These unique properties make it particularly desirable as an OC constituent for many women who would otherwise stop taking their birth-control pills because of unwanted side effects.

OC FORMULATION CHANGES

Since OCs were introduced more than 40 years ago, formulations have undergone many changes, including major reductions in both progestin and estrogen doses. Figure 1 illustrates the dramatic drop in estrogen content, from an initial 150 mg to 20 mg, the lowest dose currently available in the United States. This 87% reduction in estrogen dose has decreased the risk for deep vein thrombosis (DVT), as well as the incidence of adverse reactions (eg, nausea, vomiting, breast tenderness, bloating) that discouraged compliance with earlier OC formulations. ^4-7 The type of estrogen used in OCs has also changed–from mestranol to ethinyl estradiol (EE)–which has eliminated the need to metabolize the former to the latter for biologic activity.

FIGURE 1. Changes in Estrogen Doses Over Time*

*Thorneycroft IH. Change in estrogen doses with time since the introduction of oral contraceptives. Infertil Clin North Am. 2000;11:515–529.

As with estrogen, the dose of norethindrone-type progestins has also dropped dramatically, from almost 10 mg to 0.4 mg. Most norethindrone-containing OCs prescribed today contain 0.5 mg to 1 mg of the progestin–a reduction of 90% to 95%. In OCs containing levonorgestrel-type progestins, the dose has dropped from the equivalent of 250 mg to 100 mg of levonorgestrel. Major advantages associated with these decreases in progestin dose include improved lipid profiles and decreased insulin resistance. Third-generation progestins, including desogestrel, norgestimate, and gestodene, are more potent than norethindrone, but only gestodene has been shown to be more potent than levonorgestrel. ⁸

One of the main advantages of these newer progestins is their reduced androgenicity, although the clinical impact of this feature is unclear; indeed, androgenicity estimates for levonorgestrel were derived from animal experiments using doses 1,000-fold greater than that necessary to inhibit ovulation. ⁹ Although desogestrel- and gestodene-containing preparations were initially associated with an increased rate of DVT, reanalyses showed that these agents were selectively prescribed for women at high risk for this adverse reaction, and that the incidence of thrombosis was higher in the first years of use. These factors may explain the increased risk. ¹⁰ The risk of myocardial infarction may be lower with these preparations. ^11,12

A NEW PROGESTIN

The recently approved monophasic OC Yasmin contains 3 mg of drospirenone and 30 mg of EE. It has been available in Europe since November 2000, and was approved for use by the US Food and Drug Administration (FDA) in May 2001. Overall, the clinical effects and safety index of drospirenone/EE mirror those of other available OCs. It also has unique properties that make it particularly suitable for women who are displeased with other OCs’ side effects.

Pharmacology

Drospirenone differs from other progestins used in combination OCs in that it is derived from 17a-spirolactone, not norethindrone or levonorgestrel, and is chemically related to the diuretic spironolactone (Figure 2). Following ingestion, maximum serum concentrations of drospirenone are reached within 1.5 to 2 hours. The serum half-life of drospirenone is biphasic, with a mean of 2 hours for the first phase and a mean of 31 to 32 hours for the second phase (longer than that of other contraceptive progestins). It is metabolized by the cytochrome P450 enzyme system; its metabolites are inactive. Drospirenone increases sex hormone-binding globulin (SHBG) levels three- to four-fold. It does not bind to SHBG or attenuate the estrogen-stimulated rise in SHBG associated with use of other progestins. ^13,14

FIGURE 2. Drospirenone and Spironolactone Structures

The common testosterone “backbone” is in black, and the 17-carbo-lactone group common to both is in yellow; the differences are in blue and red.

Pharmacologic profiles of progesterone and synthetic progestins differ in some respects, although they share certain hormonal effects (Table). ¹³ For example, they all exhibit progestogenic and antiestrogenic effects. In addition, except for drospirenone and cyproterone acetate, they all have androgenic effects in animal models. Of all the progestins, drospirenone most closely resembles endogenous progesterone because it exhibits both antiandrogenic and antimineralocorticoid activities. ¹⁵

Contraceptive Efficacy

Dose-ranging studies have shown that drospirenone 3 mg/EE 30 mg consistently inhibits ovulation. In a recent trial involving 52 women, this preparation was 100% successful in suppressing ovulation. ¹⁶ In the same trial, a formulation containing drospirenone 2 mg and EE 30 mg inhibited ovulation in 98% of all cycles. These findings have been supported by clinical experience: Drospirenone/EE is as effective as other currently available low-dose OCs, with a Pearl index of 0.41 (0.41 pregnancies/100 women during the first year of use). ¹⁷

Metabolic Profile

Effects of drospirenone/EE on classic metabolic indices such as plasma lipids are similar to those of other recently released OC preparations containing 30 mg of EE. That is, use has been shown to raise high-density lipoprotein cholesterol levels and reduce low-density lipoprotein cholesterol levels. ^18,19

Cycle Control

A comparative trial has shown that breakthrough bleeding (BB) rates are similar with drospirenone/EE and an OC formulation containing desogestrel 150 mg/EE 30. ²⁰ As with other OCs, the incidence of BB in drospirenone/EE users decreases over time. ^17,21

Unique Effects

Drospirenone has some unique effects secondary to its activity as a spironolactone analog and to its close resemblance to progesterone.

Antimineralocorticoid effects.–As mentioned above, drospirenone is structurally related to spironolactone and has antimineralocorticoid activity: A placebo-controlled study showed that drospirenone 2 mg increased sodium excretion. ¹⁵ A 3-mg dose of drospirenone is equivalent to approximately 25 mg of spironolactone, which is one eighth of the spironolactone dose used to treat hirsutism or acne. ²² Estrogens are known to increase levels of aldosterone and other mineralocorticoids, which can be manifested clinically by a slight rise in blood pressure and increased exchangeable sodium values–leading to bloating that may be perceived by some OC users as weight gain. Such bloating presumably reflects fluid retention secondary to estrogen-induced stimulation of the renin—aldosterone system. ¹⁹

Contraceptive progestins other than drospirenone do not produce a progesterone-like natriuresis, which may explain why patients taking combination OCs often report cyclical weight gain, breast tenderness, and other symptoms presumably secondary to water retention. ^23,24 In contrast, an open-label study demonstrated no significant weight gain in 326 women using drospirenone/EE for 13 treatment cycles. ¹⁷ Similarly, a European study comparing drospirenone/EE to an OC containing monophasic desogestrel/EE 30 mg (26 cycles, plus a 3-mo follow-up) revealed that patients using the former lost significantly more weight than did the group using the latter. ²³ Investigators proposed that drospirenone/EE might be especially useful in women who are susceptible to fluid-related weight gain.

Spironolactone has also been reported to have a beneficial effect on monthly mood swings in women who demonstrate significant changes in circulating androgens between the follicular and luteal phases. ²⁵ Because drospirenone has pharmacologic properties similar to those of spironolactone, it has been anticipated that use of this progestin might improve symptoms of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) in some patients. ²⁶ Research has borne this out: A randomized, double-blind, placebo-controlled trial conducted on 83 women with PMDD showed that improvements in mood, bloating, breast tenderness, and swelling were greater in the drospirenone/EE group than in the placebo group. ²⁷ Similarly, in the abovementioned open-label trial, subjects completed a 23-item Women’s Health Assessment Questionnaire to assess premenopausal, perimenopausal, and postmenstrual symptoms. ¹⁷ Drospirenone/EE significantly decreased premenopausal and perimenstrual symptoms, especially those related to negative affect, water retention, and concentration, suggesting that this OC’s antimineralocorticoid and antiandrogenic effects may be clinically useful in some women.

At the same time, drospirenone/EE’s antimineralocorticoid effects and the resulting potential for hyperkalemia mean that this OC formulation should not be used in women with severe renal disease, hepatic dysfunction, or a predisposition to hypokalemia. (Few of these women would be considered good candidates for any OC.) Concomitant use of nonsteroidal anti-inflammatory drugs with drospirenone/EE has not been shown to increase hyperkalemia risk in women with normal renal and hepatic function. ²⁸

Antiandrogenic properties.–Like all other contraceptive progestins, drospirenone binds to the androgen receptor; however, its binding is antagonistic. ¹³ All OCs reduce levels of free testosterone and other androgens, resulting in beneficial effects on acne and hirsutism. ^29,30 As drospirenone simultaneously reduces androgen levels, blocks androgen receptors, and does not attenuate the estrogen-mediated increase in SHBG, its therapeutic effects in this area have the potential to be greater than those of traditional OCs. Comparative trials will determine whether drospirenone/EE is more effective than other OCs in this respect, and whether women who are being treated for acne and/or hirsutism with a combination of spironolactone and an OC might do well with drospirenone/EE alone.

CONCLUSION

Adverse reactions to commonly used OCs, including BB and bloating, can lead to inappropriate use and discontinuation, possibly increasing the risk of unintended pregnancy. Despite having reduced progestin and estrogen content, many OC preparations are still less than ideal. Yasmin, a new OC combining 3 mg of drospirenone with 30 mg of EE, may offer advantages beyond its excellent contraceptive efficacy to women who might otherwise discontinue OC use because of unwanted side effects. Preliminary data suggest that drospirenone exerts antimineralocorticoid effects, producing natriuresis and a reduction in fluid retention, which may cause many undesirable OC-related symptoms.

Ian H. Thorneycroft, PhD, MD, is professor, Department of Obstetrics and Gynecology, University of South Alabama, Mobile

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