Managing premenstrual symptoms at the most fundamental level necessitates careful consideration of female reproductive biology. Inhibiting ovulation using hormonal agents is a reasonable approach for reducing premenstrual symptoms, but the benefits of agents such as gonadotropin-releasing hormone agonists and the synthetic androgen danazol are largely offset by their adverse effects and costs. Combination oral contraceptives provide an alternative that is widely accepted by women experiencing premenstrual symptoms and by their physicians; and newer formulations with lower levels of estrogen and progestin, administered using a monthly regimen with a shortened pill-free interval, appear promising for alleviating patient distress from severe premenstrual symptoms.
(Am J Manag Care. 2005;11:S492-S497)
The biology of menstrually related symptoms involves either direct or indirect interaction of the ovarian cycle with key hormones, neurotransmitters, or other substances.1 A menstruating woman may experience symptoms in the late luteal phase of her ovulatory cycle throughout her childbearing years. To provide relief for women who suffer moderately or severely from any combination of these symptoms, it would seem prudent to seek a solution that works in tandem with female physiology to restore health-related quality of life and an overall sense of well-being with the fewest possible adverse effects.
Symptoms related to the menstrual cycle may be limited to mild discomfort or extend to premenstrual syndrome (PMS) or to premenstrual dysphoric disorder (PMDD), which would include severe emotional and somatic impairment. Only limited research on alleviation of menstrual symptoms has been conducted to date on women meeting the diagnostic criteria published by the American College of Obstetricians and Gynecologists2 for PMS and by the American Psychiatric Association for PMDD.3 However, research on premenstrual symptoms in general may provide strategies for effective treatments for PMS and PMDD.
Premenstrual symptoms occur almost exclusively in ovulatory cycles; therefore, inhibiting ovulation could be expected to reduce or eliminate these symptoms. Gonadotropin-releasing hormone (GnRH) agonists can be used to suppress ovulation and effectively alleviate premenstrual symptoms. However, because using GnRH agonists leads to a hypoestrogenic state, "add-back" hormone therapy with estrogen or estrogen/progesterone is necessary to prevent menopausal symptoms such as hot flashes and to minimize bone loss that could occur with steady use.4 These agents are costly and are not recommended for long-term use.
Another hormonally mediated possibility, the synthetic androgen danazol, suppresses ovulation as well, but its use is limited by an array of adverse effects. These include weight gain; decreased high-density lipoprotein cholesterol, which may increase the risk of cardiovascular disease; and, at higher doses, the possibility of greater facial hair growth and severity of acne.4 Like GnRH agonists, danazol is not recommended for long-term use.
Combination oral contraceptives (OCs), which contain estrogen and one of several progestins, are commonly prescribed hormonal agents providing a variety of noncontraceptive health benefits, aside from preventing pregnancy. Combination OCs have been widely used to treat physical premenstrual symptoms. Women and their physicians have a high level of comfort with their use, and OC users benefit from their relatively low cost and positive effects on the menstrual cycle.
Few controlled trials have evaluated OCs for their effects on premenstrual symptoms, and past studies demonstrated little difference in the experience of OC users and nonusers in this regard.5,6 Evidence for OC effects on premenstrual symptoms is weakened, according to a recent review of the medical literature, by the fact that early studies were conducted using OCs with the high estrogen doses commonly employed at that time. The reduced estrogen doses in current OC formulations may result in a decreased degree of ovarian inhibition compared with that afforded by older OCs, especially during the pill-free interval.7
In the female reproductive system, the degree of follicular activity during OC use is dependent on the type and dose of steroids used, the type of regimen, user adherence, and individual metabolic responsiveness to the OC prescribed.7 Early OC formulations with high doses of estrogen and progestin caused many adverse effects, including nausea, breast tenderness, and fluid retention. These symptoms resulted in a high rate of premature discontinuation of use, and therefore hormone doses in combined OCs have been reduced. OCs inhibit follicular development, and high-dose OCs maintain steroid levels sufficient to suppress ovarian function during the pill-free interval; with low-dose OCs, however, effective serum levels of ethinyl estradiol (EE) are maintained for only 2 to 3 days after administration is suspended, and follicular development may resume because of inadequate endocrine suppression.8
Patient adherence is another crucial factor when low-dose OCs are used. The risk of ovulation is at its maximum during the 7-day pill-free interval, and the risk of pregnancy increases substantially for a woman using these formulations if she does not start her new pill pack on time. In addition, individual women metabolize medications differently, and faster metabolism may jeopardize the efficacy of low-dose pills.
The Standard OC Regimen
In studies of women with premenstrual symptoms, OCs have typically been administered using a standard regimen (21/7 regimen) consisting of 21 days of estrogen-plus-progestin pills, followed by 7 pill-free days (in some regimens, placebo pills may be taken on pill-free days to increase the likelihood of timely resumption). This 21/7 regimen closely mimics a woman's average 28-day cycle—indeed, the regimen was developed with this average cycle in mind—and is also used with other contraceptive methods, such as the patch and the vaginal ring. Women who take hormonal contraceptives using this standard regimen have a monthly withdrawal bleed that traditionally has assured them that they are not pregnant.
However, the standard regimen's 7-day pill-free interval is associated with significant drawbacks. For example, commonly used low-dose OC formulations have a very real potential for reduced ovarian inhibition during this interval. Also, OC users may experience an increase in monthly hormone-withdrawal symptoms—pelvic pain, headaches, bloating, and breast tenderness—during the pill-free interval.