REPORTS Ovulation Suppression of Premenstrual Symptoms Using Oral Contraceptives Patricia J. Sulak, MD Abstract the diagnostic criteria published by the Managing premenstrual symptoms at the most American College of Obstetricians and fundamental level necessitates careful consideration Gynecologists2 for PMS and by the American of female reproductive biology. Inhibiting ovulation Psychiatric Association for PMDD.3 However, using hormonal agents is a reasonable approach for research on premenstrual symptoms in gen- reducing premenstrual symptoms, but the benefits of eral may provide strategies for effective agents such as gonadotropin-releasing hormone ago- treatments for PMS and PMDD. nists and the synthetic androgen danazol are largely offset by their adverse effects and costs. Combination Ovulation Suppression oral contraceptives provide an alternative that is widely accepted by women experiencing premen- Premenstrual symptoms occur almost strual symptoms and by their physicians; and newer exclusively in ovulatory cycles; therefore, formulations with lower levels of estrogen and prog- inhibiting ovulation could be expected to estin, administered using a monthly regimen with a reduce or eliminate these symptoms. shortened pill-free interval, appear promising for Gonadotropin-releasing hormone (GnRH) alleviating patient distress from severe premenstrual agonists can be used to suppress ovulation symptoms. and effectively alleviate premenstrual symp- (Am J Manag Care. 2005;11:S492-S497) toms. However, because using GnRH ago- nists leads to a hypoestrogenic state, he biology of menstrually related “add-back” hormone therapy with estrogen symptoms involves either direct or or estrogen/progesterone is necessary to pre- Tindirect interaction of the ovarian vent menopausal symptoms such as hot cycle with key hormones, neurotransmit- flashes and to minimize bone loss that could ters, or other substances.1 A menstruating occur with steady use.4 These agents are woman may experience symptoms in the costly and are not recommended for long- late luteal phase of her ovulatory cycle term use. throughout her childbearing years. To pro- Another hormonally mediated possibility, vide relief for women who suffer moderately the synthetic androgen danazol, suppresses or severely from any combination of these ovulation as well, but its use is limited by an symptoms, it would seem prudent to seek a array of adverse effects. These include solution that works in tandem with female weight gain; decreased high-density lipopro- physiology to restore health-related quality tein cholesterol, which may increase the of life and an overall sense of well-being with risk of cardiovascular disease; and, at higher the fewest possible adverse effects. doses, the possibility of greater facial hair Symptoms related to the menstrual cycle growth and severity of acne.4 Like GnRH may be limited to mild discomfort or extend agonists, danazol is not recommended for to premenstrual syndrome (PMS) or to long-term use. premenstrual dysphoric disorder (PMDD), Combination oral contraceptives (OCs), which would include severe emotional and which contain estrogen and one of several somatic impairment. Only limited research on alleviation of menstrual symptoms has Address correspondence to: Patricia J. Sulak, MD, Scott & White been conducted to date on women meeting Hospital and Clinic, 2401 S. 31st Street, Temple, TX 76508. S492 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2005 Ovulation Suppression of Premenstrual Symptoms Using Oral Contraceptives progestins, are commonly prescribed hor- start her new pill pack on time. In addition, monal agents providing a variety of noncon- individual women metabolize medications traceptive health benefits, aside from differently, and faster metabolism may jeop- preventing pregnancy. Combination OCs ardize the efficacy of low-dose pills. have been widely used to treat physical pre- menstrual symptoms. Women and their The Standard OC Regimen physicians have a high level of comfort with In studies of women with premenstrual their use, and OC users benefit from their symptoms, OCs have typically been ad- relatively low cost and positive effects on the ministered using a standard regimen (21/7 menstrual cycle. regimen) consisting of 21 days of estrogen- Few controlled trials have evaluated OCs plus-progestin pills, followed by 7 pill-free for their effects on premenstrual symptoms, days (in some regimens, placebo pills may and past studies demonstrated little differ- be taken on pill-free days to increase the ence in the experience of OC users and likelihood of timely resumption). This 21/7 nonusers in this regard.5,6 Evidence for OC regimen closely mimics a woman’s average effects on premenstrual symptoms is weak- 28-day cycle—indeed, the regimen was ened, according to a recent review of the developed with this average cycle in mind— medical literature, by the fact that early and is also used with other contraceptive studies were conducted using OCs with the methods, such as the patch and the vaginal high estrogen doses commonly employed at ring. Women who take hormonal contracep- that time. The reduced estrogen doses in tives using this standard regimen have a current OC formulations may result in a monthly withdrawal bleed that traditionally decreased degree of ovarian inhibition com- has assured them that they are not pregnant. pared with that afforded by older OCs, espe- However, the standard regimen’s 7-day cially during the pill-free interval.7 pill-free interval is associated with signifi- In the female reproductive system, the cant drawbacks. For example, commonly degree of follicular activity during OC use is used low-dose OC formulations have a very dependent on the type and dose of steroids real potential for reduced ovarian inhibition used, the type of regimen, user adherence, during this interval. Also, OC users may and individual metabolic responsiveness to experience an increase in monthly hor- the OC prescribed.7 Early OC formulations mone-withdrawal symptoms—pelvic pain, with high doses of estrogen and progestin headaches, bloating, and breast tender- caused many adverse effects, including nau- ness—during the pill-free interval. sea, breast tenderness, and fluid retention. Hormone-related symptoms were as- These symptoms resulted in a high rate of sessed in a study of women of childbearing premature discontinuation of use, and age who used OCs and kept daily symptom therefore hormone doses in combined OCs diaries.9 Women who requested OCs were have been reduced. OCs inhibit follicular recruited from an obstetrics and gynecology development, and high-dose OCs maintain practice without regard to the presence of steroid levels sufficient to suppress ovarian premenstrual symptoms. Of the 262 evalu- function during the pill-free interval; with able women, 193 were current OC users at low-dose OCs, however, effective serum lev- study entry and 69 women were catego- els of ethinyl estradiol (EE) are maintained rized as new starts because they had had no for only 2 to 3 days after administration is recent OC use (26 had not previously used suspended, and follicular development may OCs and 43 were former OC users). The resume because of inadequate endocrine various low-dose OCs used by the study suppression.8 participants contained 35 µg EE or less as Patient adherence is another crucial fac- the estrogen component plus different pro- tor when low-dose OCs are used. The risk of gestins and were administered in the stan- ovulation is at its maximum during the 7- dard 21/7 regimen. Participants were day pill-free interval, and the risk of preg- significantly more likely to experience hor- nancy increases substantially for a woman mone-withdrawal symptoms during the 7 using these formulations if she does not pill-free days than during the 21 days of VOL. 11, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S493 REPORTS from the effect of estrogen withdrawal on Table 1. Commonly Reported Hormone-withdrawal the vasculature. Symptoms in Women Using OCs Current and new-start OC users both experienced significantly more pelvic pain Hormone or cramps during the pill-free interval than Treatment Pill-free Symptoms (21 days, %) (7 days, %) P Value while taking active pills (each P <.001). In addition, current and new-start OC users Pelvic pain 21 70 <.001 both reported an increase in bloating and Headaches 53 70 <.001 swelling that started during the active-pill week before the pill-free interval. For all Breast tenderness 19 58 <.001 cycles studied, current and new-start OC Bloating/swelling 16 38 <.001 users both reported significantly more bloat- Use of pain medications 43 69 <.001 ing or swelling during the pill-free interval compared with active-pill weeks (58% vs OCs indicates oral contraceptives. 19%, P <.0001). Source: Reference 9. In this study, breast tenderness was also more common in new-start than in current OC users. The current OC users tended to active hormone use. The percentage of experience a greater degree of breast tender- women reporting hormone-withdrawal ness during the week before the pill-free symptoms during the 21 days of pill use interval that peaked during the pill-free and the 7-day pill-free interval is shown interval; 16% experienced breast tenderness in Table 1. during active-pill weeks versus 38% during Women who were current OC users of the pill-free interval (P <.001).9 more than 12 months’ duration experi- enced headaches more commonly during Using a Shorter Pill-free Interval the pill-free interval than during active-pill Low-dose OC formulations provide a less- use. New-start OC users had significantly er degree of ovarian inhibition during the more headaches during the pill-free inter- standard 7-day pill-free interval compared val than during active-pill use in cycle 2 with higher doses.10 Shortening the pill-free (71% vs 49%, P <.001) but not in cycle 1 interval would be logical in an attempt to (71% vs 62%). This increase in the inci- maintain ovulation suppression with low- dence of headaches probably stemmed dose OC formulations.