Premenstrual Syndrome/Premenstrual Dysphoric Disorder Treatment

Table 1.

Symptoms	21 Active	7 Hormone Free	P Value
Pelvic pain	21%	70%	<.001
Headaches	53%	70%	<.001
Breast tenderness	19%	58%	<.001
Bloating/swelling	16%	38%	<.001
Use of pain meds	43%	69%	<.001

Hormone Withdrawal Symptoms in Oral Contraceptive Users

Source: Sulak et al. Obstet Gynecol. 2000;95:261-266

American College of Obstetricians and Gynecologists. Clinical management guidelines for obstetricians-gynecologists: premenstrual syndrome. ACOG Practice Bulletin 15. Washington DC: ACOG 2000.
Premenstrual dysphoric disorder. In: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington DC: American Psychiatric Association, 2000:771-774.
Halbreich U, Borenstein J, Pearlstein T, Kahn LS. The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD). Psychoneuroendocrinology. 2003;28:1-23.
Sternfeld B, Swindle R, Chawla A, Long S, Kennedy S. Severity of premenstrual symptoms in a health maintenance organization population. Obstet Gynecol. 2002;99:1014-1024. Abstract
Graham CA, Serwin BB. A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive. J Psychosom Res. 1992;36:257-266. Abstract
Backstrom T, Hansson-Malmstrom Y, Lindhe BA, et al. Oral contraceptives in premenstrual syndrome: a randomized comparison of triphasic and monophasic preparations. Contraception. 1992;46:253-268. Abstract
Joffe H, Cohen LS, Harlow BL. Impact of oral contraceptive pill use on premenstrual mood: predictors of improvement and deterioration. Am J Obstet Gynecol. 2003;189:1523-1530. Abstract
Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000; 95:261-266. Abstract
Rosenberg MJ, Waugh MS, Meehan TE. Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation. Contraception. 1995; 51:283-288. Abstract
Huber LR, Hogue CJ, Stein AD, et al. Contraceptive use and discontinuation: Findings from the contraceptive history, initiation, and choice study. Am J Obstet Gynecol. 2006;194:1290-1295. Abstract
Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol. 1998;179:577-582. Abstract
Willis S, Sulak P, Coffee A, Kuehl T. Greater inhibition of the pituitary-ovarian axis in oral contraceptive users with a shortened hormone free interval. Contraception. 2006;74:100-103. Abstract
Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 mcg) and ethinyl estradiol (15 mcg) on ovarian activity. Fertil Steril. 1999;72:115-120. Abstract
Schlaff WD, Lynch AM, Hughes HD, Cedars MI, Smith DL. Manipulation of the pill-free interval in oral contraceptive users: the effects on follicular suppression. Am J Obstet Gynecol. 2004; 190:943-951. Abstract
Baerwald AR, Olatunbosun OA, Peirson RA. Ovarian follicular development is initiated during the hormone-free interval of oral contraceptive use. Contraception. 2004; 70:371-377. Abstract
Coffee A, Kuehl TK, Willis SA, Sulak PJ. Oral contraceptives and premenstrual symptoms: Comparison of a 21/7 and extended regimen. Am J Obstet Gynecol. 2006;195:1311-1319. Abstract
Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drosperinone-containing oral contraceptive formulation. Contraception. 2005;72:414-421. Abstract
Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a new low-dose oral contraceptive with drosperinone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492-501. Abstract
Nakajima ST, Archer DF, Ellman H. Efficacy and safety of a new 240day oral contraceptive regimen of norethindrone acetate 1mg/ethinyl estradiol 20 mcg (Loestrin 24Fe). Contraception. 2007;75:16-22. Abstract
Killick SR, Fitzgerald C, Davis A. Ovarian activity in women taking an oral contraceptive containing 20 mcg ethinyl estradiol and 150 mcg desogestrel: effects of low estrogen doses during the hormone-free interval. Am J Obstet Gynecol. 1998;179:S18-24. Abstract
Sulak P, Kuehl T, Coffee A, Vandever M, Reape K. Evaluation of pituitary-ovarian axis suppression with three different oral contraceptive regimens. Obstet Gynecol. 2007;109:102S.
Sulak PJ, Willis SA, Kuehl TJ, Coffee A, Clark J. Headaches and oral contraceptives: Impact of eliminating the standard 7-day placebo interval. Headache. 2007;47:27-37. Abstract

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Introduction

Menstrual-related symptoms are common and sometimes debilitating, often resulting in frequent healthcare visits, pharmacologic management, and even surgical intervention. Ovulation is a prerequisite of premenstrual disorders with symptoms only occurring during the luteal phase of ovulatory cycles then disappearing after the onset of menstruation. Mild symptoms, which include breast tenderness, bloating / swelling, and pelvic heaviness, usually do not interfere with daily activities and are experienced occasionally by almost all ovulatory women. Premenstrual syndrome (PMS) is a premenstrual disorder characterized by bothersome adverse somatic and/or affective symptoms.^[1] As defined by the American Psychiatric Association, premenstrual dysphoric disorder (PMDD) is the most severe type of premenstrual disorder associated with significant impairment.^[2] Studies have documented the detriment in quality of life parameters and the economic toll in lost productivity and treatments with PMS/PMDD.^[3,4]

Because ovulation is necessary as an etiologic factor in PMS/PMDD, therapies that inhibit ovulation and the associated hormonal fluctuations would seem reasonable treatment options. This column will focus on hormonal management, specifically with various oral contraceptive (OC) regimens.

Standard 21/7 Oral Contraceptive Regimens

Several studies designed to assess the effects of standard 21/7 OC regimens (21 active combination pills of estrogen and progestin followed by 7 placebo days) on premenstrual symptoms have shown inconsistent results, often showing minimal or no improvement,^[5-7] while in another study, the standard 21/7 design was actually shown to induce premenstrual type symptoms. In this prospective study of 21/7-day OC users, participants were divided into groups: new starts and current long-term users who had taken OCs for a minimum of 1 year and asked to monitor their daily symptoms of pelvic pain, headaches, nausea or vomiting, bloating or swelling, and breast tenderness.^[8] During the next 2 full cycles of OCs, current long-term users had more symptoms during the 7-day hormone-free interval (HFI) than during the 21 days of active pills ( Table 1 ). The increase in symptoms began during the third week of active pills and peaked during the 7-day HFI. The prevalence of moderate-to-severe pelvic pain in current users was 27% to 29% during the HFI in cycles of 1 and 2 compared to 2% to 6% during the active-pill weeks.

Similar symptom patterns were seen in the new-start group during their first 3 OC cycles. Headache, bloating or swelling, and breast tenderness decreased during the 3 cycles to approach the same levels of current users suggesting partial treatment of these symptoms with cyclic OC use.

Menstrual Symptoms and the Hormone-Free Interval

Menstrual-related symptoms including headache, mood swings, abdominal cramping, bloating, and breast tenderness are long recognized side effects associated with OC use.^[9-11] These symptoms in part may actually be induced by the 7-day HFI due to lack of pituitary-ovarian suppression during this 7-day placebo interval with today's low-dose OCs. Over the past 4 decades, doses of hormones in OCs have been greatly reduced while the 7-day HFI has persisted. With high-dose OCs of the past, hormonal levels persisted into the week off. This is not the case with today's low-dose OCs (35 mcg ethinyl estradiol or less). During the standard 7-day HFI, suppression of follicle-stimulating hormone (FSH) production and release from the pituitary is attenuated, leading to ovarian follicular development and endogenous estradiol production.^[12-15] Endogenous estradiol levels have been documented to increase at the end of the 7-day HFI, peak in the first half of the active pill cycle, and then decline during the last week of active pills as follicular regression is occurring.^[13] This decline in endogenous estradiol levels during the last week of active pills may be responsible for the estrogen-withdrawal symptoms beginning to appear during the last week of active pills with further exacerbation of premenstrual type symptoms during the subsequent 7-day HFI.^[8,16] This documented pituitary-ovarian escape with its associated symptoms, follicular development, and possible ovarian cyst formation and ovulation, has led to the redesign of standard OC regimens with all recently US Food and Drug Administration (FDA)-approved OC products deviating from the 21/7 concept.

Shortening the 7-day Hormone-Free Interval

Shortening the standard 7-day HFI to 4 days has been shown to provide greater pituitary ovarian inhibition, resulting in less follicular development and endogenous estradiol production.^[12,13] Two OC products that use 24 days of active combined therapy and a shortened 4-day HFI (24/4) were approved by the FDA in 2006: ethinyl estradiol (EE) 20 mcg / drospirenone (DRSP) 3 mg [Yaz] and EE 20 mcg / norethindrone acetate 1 mg [Loestrin24FE].

The DRSP/EE 3 mg/20 mcg in the 24/4 regimen also received an additional FDA indication for PMDD based on 2 key studies. The first was a double-blind, placebo-controlled, crossover study conducted by Pearlstein and colleagues in women with PMDD were assigned to either EE/DRSP 20 mcg/3 mg in 24/4 regimen or placebo.^[17] Using Daily Record of Severity of Problems scores, the investigators documented that the mean decrease from baseline while using drospirenone/EE was significantly greater than for placebo (-12.47, P < .001). Additionally, in the Clinical Global Impressions-Improvement scale, a positive response was reported in 61.7% of the subjects while taking drospirenone/EE vs 31.8% of subjects on placebo (P = .009).

The second study was a double-blind, randomized clinical trial that randomized 449 women with symptoms of PMDD to either a DRSP/EE 3 mg/20 mcg OC administered in a 24/4 regimen or placebo.^[18] The participants charted their symptoms by completing the Daily Record of Severity of Problems. Defining response as a 50% decrease in daily symptom scores, 48% of the active-treatment group and 36% of the placebo group were responders (relative risk, 1.7; 95% CI, 1.1 to 2.6; P = .015). The norethindrone acetate/ EE 24/4 regimen compared with a 21/7 day regimen documented shorter, lighter withdrawal bleeding, but published data regarding premenstrual symptoms are not currently available.^[19]

Adding Estrogen to the Hormone-Free Interval

Adding low-dose estrogen to the HFI has been shown to also produce greater pituitary ovarian suppression. Addition of 10 mcg EE to 5 of the 7 days of a desogestrel-containing OC resulted in less ovarian residual activity.^[20] In a study comparing 3 OCs containing levonorgestrel 150 mcg and EE 30 mcg, the extended regimen of 84 days followed by 7 days of 10 mcg of EE (84/7EE [Seasonique]) provided greater pituitary-ovarian suppression compared to with the 84/7 regimen (Seasonale) and the 21/7 regimen (Portia).^[21] Although not powered to assess symptoms, the 84/7EE group also had a tendency for reduced headaches. Because premenstrual symptoms are due to hormonal fluctuations and adding estrogen to the typical 7-day HFI of OCs has been documented to provide greater suppression, these regimens have the potential to reduce premenstrual type symptoms.

Eliminating the Hormone-Free Interval With Continuous Oral Contraceptives

Because ovulation and its associated hormonal milieu are responsible for PMS/PMDD and standard 21/7 OC regimens can duplicate these symptoms, eliminating the HFI could be a potential treatment. This concept was evaluated in a single center prospective study utilizing a 168-day OC regimen consisting of 3 mg DRSP/30 mcg EE assessing incidence and severity of premenstrual-type symptoms.^[16] Two measurement tools, the Scott and White Mood Scale and the Penn State Daily Symptom Report, were used during 21/7-day regimens, followed by the continuous regimen of 168 days of active pills. The 102 patients who completed the study were divided into 2 groups based on their PMS scores during the baseline 21/7 cycles: those with high cyclic variability (100% increase in symptoms from the first half to the second half of the last 21/7 day cycle; n = 55), or with low cyclic variability (little or no cyclic change; n = 47). PMS-type symptoms decreased significantly in all segments of the 168-day extended regimen compared with the standard 21/7 cycle (P < .001). Subjects with high cyclic variability during the 21/7 baseline cycles had significantly lower (P < .001) symptoms scores during the 168-day continuous regimen than did subjects with low cyclic variation (Figure 1).

Enlarge

Daily Mean Symptoms Scores for Patients with High and Low Cycle Variability Receiving 21/7- and 168-Day Oral Contraceptive Regimen

Comparison of daily scores for 17 items using the DSR17 for the 2 21/7 DRSP/EE OC cycles followed by the 168 day extended DRSP/EE OC regimen for 55 patients with high cyclic variations in mood during the last 21/7 cycle and 47 with low cyclic variation. Groups differ(P < .0001), treatment days differ (P < .0001), and group by treatment day interactions are significant (P = .042).

Source: Coffee AL. Am J Obstet Gynecol. 2006;195:1311-1319.

This study not only confirmed the worsening of PMS-type symptoms in women receiving a 21/7-day OC, but also documented a positive impact of a continuous regimen on symptoms among women who had high symptom scores during the baseline 21/7 cycles. In the same study, follow up analysis also revealed a reduction in headache scores during the continuous regimen.^[22] Headaches decreased significantly during the continuous regimen compared with the 21/7 regimen (P < .0001). Improvement was also seen in work productivity and involvement in activities.

Conclusion

Although selective serotonin reuptake inhibitors are still the first-line agents used for the treatment of premenstrual mood symptoms, many patients do not want to take this type of medication. Hormonal management of PMS and PMDD is based on the principle that suppression of ovulation eliminates premenstrual symptoms. Unfortunately, 21/7 OC regimens can replicate the symptoms of PMS and results from studies using OCs to treat PMS and PMDD have been mixed. Therefore traditional 21/7 OCs should not be used for treatment of PMS/PMDD. However, recent modifications in OC regimens, including shortening, adding estrogen to, or eliminating the HFI are all potential treatments that can greatly improve the quality of life of many women.

Supported by an independent educational grant from Bayer

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