Dropsirenone/Ethinyl Estradiol (Yasmin): New Oral Contraceptive Promises Improved Tolerance and Less Side Effects
This report was reviewed for medical and scientific accuracy by Michael Divon, MD , Director of OB/GYN, Lenox Hill Hospital, New York.
With a number of clinical studies now completed, the launch of drospirenone/ethinyl estradiol (Yasmin®) in the United States and Europe is expected in the near future. An international panel of physicians involved with the development of drospirenone/ethinyl estradiol recently described the potential benefits of the new oral contraceptive (OC) to clinicians attending an industry-sponsored symposium held during the XVI FIGO World Congress of Gynecology and Obstetrics.
Part of a new OC class, Yasmin® combines drospirenone-a novel progestogen derived from 17-a-spirolactone-with ethinyl estradiol, which serves as the estrogenic component. Unlike other progestins used in current OC combinations, drospirenone has both antimineralocorticoid and antiandrogenic effects.
In introducing the new OC, symposium chairman Dr. Jean-Michel Foidart, Department of Gynecology, University of Liege, Belgium, pointed out "Yasmin® is not just another pill with a different steroid dose. As a completely new progestogen," he continued, "drospirenone offers a more favorable pharmacological profile that provides improved tolerance and a reduced incidence of side effects."
Addressing compliance issues surrounding current OCs, Dr. Mitchell Creinin, Family Planning and Family Planning Research, Department of Obstetrics and Reproductive Sciences, University of Pittsburgh, Pennsylvania, explained that 60 million women currently use oral contraceptives worldwide, but many others either refuse to take them or stop taking them because of intolerable side effects, which persist despite dramatic reductions in the estrogen and progestin doses currently used in combination OCs.
Dr. Creinin explained that Rosenberg and colleagues ( J Obstet Gynecol 1998;179:577-82) found new prescribees were more likely to discontinue OC use within the first six months compared to those who had changed prescriptions or had previously used OCs (32 percent versus 16 percent). In the United States, he added, the most common reasons cited for discontinuation are irregular bleeding (32 percent); nausea (19 percent); weight gain (14 percent); mood changes (14 percent); breast tenderness (11 percent), and headaches (11 percent).
Similarly, a study by Fuchs et al. ( J Contracept Reprod Health Care 1996;1:275-84) found that European women also commonly stopped taking their OCs because of weight gain (36 percent), headaches (34 percent), nausea and vomiting (17 percent), mood changes (17 percent), and breast tenderness (13 percent), he said.
In fact, the obvious importance of reducing these side-effects led directly to the development of Yasmin® and, particularly, drospirenone, Dr. Creinin added. Unlike other progestins available in the United States, which are all 19-nortestosterone derivatives, drospirenone behaves much like a natural progesterone in that it has antimineralocorticoid properties, he said. This enables drospirenone to counteract the "weight-gaining" tendency associated with estrogens, which is due to aldosterone-induced sodium and water retention mediated by activation of the renin-angiotensin-aldosterone system. Further, the antiandrogenic effect of drospirenone offers the potential to improve skin conditions and provides a greater sense of well-being, he added.
Dr. Wolfgang Oelkers, Chairman of Endocrinology, Department of Internal Medicine, University of Berlin, Germany, presented data from trials that demonstrated the antimineralocorticoid activity of drospirenone.
Like natural progesterone, drospirenone has affinity for both the progesterone and mineralocorticoid receptors, a characteristic that conventional progestins lack. This counterbalances the sodium-retaining effects of ethinyl estradiol-the estrogenic component used in OCs. In addition to reducing the likelihood of weight gain, he explained, this effect offers the potential benefit of preventing a rise in systolic and diastolic blood pressure (BP) that Nichols et al. 1993;91:367-76) saw in low-dose conventional OC users who were sodium sensitive.
The antimineralocorticoid effects of drospirenone were demonstrated in two early preclinical trials, he added. In the first, Dr. Oelkers and colleagues (Clin Endocrinol Metab 1991;73:837-42) found two milligrams per day of oral drospirenone, given to 12 normal young women over six days, produced an 84 mmol cumulative sodium loss, while plasma renin and aldosterone rose significantly compared to placebo. In a follow-up study, the researchers found two milligrams of drosperinone, given from cycle day five to cycle day 25 to regularly menstruating women (n = 6), suppressed ovulation and led to slight natriuresis with no BP changes, while renin and aldosterone increased slightly. In comparison, neither natriuresis nor renin or aldersterone increases were seen in six other women who received one milligram of cyproterone acetate (Cyprostat®, Androcur®), an alternative progestogen with antiandrogenic properties. Subsequently, researchers created Yasmin® by combining three milligrams of drospirenone with 30 ug ethinyl estradiol and tested the new oral OC in a six-month trial involving 20 regularly menstruating women, Dr. Oelkers said. Results again showed no rise in body weight or blood pressure.
Following up on Dr. Oelkers presentation, Dr. Foidart focussed on two large, randomized, open label, clinical trials that compared the contraceptive efficacy of drospirenone/ethinyl estradiol, at 30 ug ethinyl estradiol and three milligrams of drosperinone over 28,000 cycles, to desogestrel/ethinyl estradiol (Marvelon®), a conventional OC, at 30 ug ethinyl estradiol and 150 ug desogestrel, respectively, over 14,000 cycles.
Ultimately, he said, results indicated both preparations provided effective contraception, very low Pearl Indices-the number of unintended pregnancies per hundred women per year-and cycle control. However, antimineralocorticoid and antiandrogenic benefits of drospirenone/ethinyl estradiol were apparent when this group was compared to women receiving the conventional progestin.
With respect to body weight, an increase in mean body weight in the desogestrel/ethinyl estradiol group was seen from month (cycle) five onward, while the mean body weight per cycle in the drospirenone/ethinyl estradiol group remained slightly below baseline values throughout the study. This difference between drospirenone/ ethinyl estradiol and desogestrel/ethinyl estradiol was statistically significant and demonstrated that drospirenone/ethinyl estradiol keeps body weight permanently lower relative to the commonly used OC, Dr. Foidart said. "While the majority of women in both groups maintained a stable body weight within two kilograms of their baseline weight," he explained, "the percentage of women who gained more than two kilograms during the trial was consistently higher in the Marvelon® [desogestrel/ethinyl estradiol] group. Conversely, the percentage of women who lost more than two kilograms during the trial was consistently higher in the Yasmin® [drospirenone/ethinyl estradiol] group." Six pregnancies occurred during the study (three in each group), but none were considered to have resulted from method failures, he added. In addition, during the six months prior to the study, results showed the incidence of premenstrual symptoms was higher in the drospirenone group than in the desogestrel group, but such symptoms were lower during treatment. The rates of dysmenorrhea were identical in both groups, but symptoms were milder and less severe in the drospirenone group compared to those receiving the conventional OC.
The antiandrogenic effects of drospirenone were evident in terms of the improvements seen in pre-existing acne and seborrhea among women receiving the drug, he said, and BP remained essentially unchanged. Dr. Foidart concluded that drospirenone/ethinyl estradiol provided effective oral contraception with excellent cycle control, good tolerability, and weight loss conferring significant benefits in women susceptible to weight gain due to water retention.
Follow-up studies from the drospirenone and desogestrel trials have confirmed the antiandrogenic benefits of dropsirenone, according to Dr. Wolfgang Wuttke, Chairman of Endocrinology, University of Gottingen, Germany. He pointed out that while intermenstrual bleeding, weight gain, and mood changes exert a negative impact on compliance with low-dose combined OCs, the positive benefits associated with these agents-notably, contraception and relief from premenstrual syndrome (PMS)-can have exactly the opposite effect. Consequently, an oral contraceptive that minimizes adverse events while enhancing positive benefits would be more likely to be accepted by women as a continuing contraceptive therapy, he said.
Indeed, this knowledge has formed the rationale for follow-up studies of the effects of drospirenone on skin, hair, and overall well-being, he added. Data from the drospirenone-desogestrel comparison trials indicate drospirenone/ethinyl estradiol is associated with ongoing lessening of acne lesions on the face within three months of commencing therapy, he said. Further, in a European survey pertaining to PMS, women who had taken drospirenone/ethinyl estradiol for just three months reported improvements in their symptoms compared to symptoms experienced during pre-treatment cycles. Similar findings of improved well-being were reported by women in the United States after taking the drug for six months. Improvements in well-being were further corroborated by women who participated in the drospirenone-desogestrel comparison trials over one- and two-year time frames, he added. Conducted in Belgium, researchers sent questionnaires to women, asking them to compare how they felt after the trials ended to how they felt while taking drospirenone/ethinyl estradiol or the conventional OC.
Responses clearly indicated that insofar as their overall well being, sexual desire, skin, hair, and disposition before and during menses, women who had taken drospirenone/ethinyl estradiol felt worse following the trial, when they returned to their conventional preparations. "These were significantly different responses than the ones we received from the Marvelon® group," Dr. Wuttke said, "and the responses also showed Yasmin® was more highly recommended [for continued therapy] than Marvelon®."
Such findings clearly indicate that drospirenone/ ethinyl estradiol is a well-tolerated OC that improves body weight, skin appearance, PMS symptoms, and overall feelings of well-being, which may result in better long-term compliance.