New Treatment Approaches for Premenstrual Disorders | Page 2

Published Online: December 01, 2005
Andrea J. Rapkin, MD

Recently, several studies have assessed the efficacy of a new OC formulation containing EE 20 μg and drospirenone 3 mg (20EE/drospirenone) administered for 24 days, followed by a 4-day hormone-free interval (24/4), in the treatment of PMDD. Yonkers and Foegh reported on a double-blind, placebo-controlled, crossover study of 20EE/drospirenone that consisted of two 3-cycle treatment periods separated by a washout cycle.38 Of the 64 women, aged 18 to 40 years, with PMDD symptoms who were randomized, 34 women initiated active treatment with 20EE/drospirenone followed by placebo, and 30 women initiated placebo followed by the new OC formulation. The change from baseline with drospirenone/20EE was significantly superior to that with placebo in the DRSP, which was the primary outcome measure, and in the secondary outcome measures (ie, the CGI-Efficacy and CGI-Severity indexes), the self-rated rating scale for premenstrual tension syndrome (PMTS), and the Endicott Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) items 1 to 14 and item 16 (Table 5).


More recently, Yonkers and colleagues conducted another double-blind, placebo-controlled, parallel-group study with 20EE/drospirenone used in a 24/4 regimen in women with PMDD symptoms.39 The study design consisted of 2 run-in menstrual cycles (the qualification phase) followed by 3 treatment cycles. Of the 449 women who were randomized, 231 were in the active-treatment group and 218 received placebo. The primary outcome measure was the 21 individual items in the DRSP. When these individual items were grouped into physical, mood, and behavioral symptoms, 20EE/drospirenone was observed to be statistically superior to placebo for all symptom groupings. Improvement occurred as early as cycle 1 and continued during all 3 cycles. In addition, 20EE/drospirenone was significantly more effective than placebo in the observer- rated (P = .023) and self-rated (P = .004) rating scale for PMTS, the observer-rated (P = .004) and self-rated (P = .014) Clinical Global Impression (CGI)-Improvement scales, the 3 functional items of the DRSP (productivity and enhanced enjoyment in social activities, both P = .003; better quality of relationships, P = .0003), and the Q-LES-Q, items 1 to 14 (P = .05). (All P values have normality correction.)

One means of assessing the effects of various agents on premenstrual symptoms is to compare response rates using the same definition. For example, response rate was defined as a score of "much" or "very much" improved on the CGI-Improvement scale in 2 studies of the SSRI sertraline and in the crossover and parallel studies of 20EE/drospirenone 24/4. In a double-blind study, women with PMDD were randomized to a flexible daily dose (50-150 mg/day) of sertraline (n = 121) or to placebo (n = 122).40 At end point, 62% of the women in the active-treatment group and 34% of the women in the placebo group were classified as responders (P <.001). In a study of intermittent sertraline, the response rate was 58% in the women receiving active treatment and 45% in the placebo group (P = .036).41 The response rates in these 4 studies are compared in Figure 3.


Counseling Women With Premenstrual Disorders

To provide effective counseling for a woman with bothersome or severe premenstrual symptoms, physicians must be empathetic and caring communicators as well as knowledgeable about this complex area of women's health. It is important to assure the patient that her symptoms are real, with a physiologic basis, and that she is not "crazy."42 The clinician or other counselor should explain the details of the menstrual cycle to the patient, especially how premenstrual symptoms occur on a cyclic basis. Because patients usually retain only part of the information they receive during a visit, physicians should provide them with interesting and practical educational materials to reinforce what is discussed. Patients should keep a daily symptom diary for at least 2 months to ensure that an accurate diagnosis of PMS or PMDD is achieved. Clinicians or other counselors should provide the diary for prospectively recording the patient's symptoms, making certain that she knows how to use it properly.

Even before a diagnosis of PMS or PMDD has been made, the physician or counselor can help the patient identify ways to adjust her lifestyle to manage stress that can contribute to premenstrual symptoms. Patients should be encouraged to seek nonthreatening support from family and friends. In addition, they should be instructed about how to initiate lifestyle modifications, such as exercise, dietary changes, appropriate use of vitamin and mineral supplements, and stress management, including relaxation and cognitive behavioral approaches. Available pharmacotherapeutic options should be discussed, keeping in mind the patient's personal preferences, side effects, the cost of the treatments being considered, and her needs. For example, use of an OC might be the best first-line treatment choice for a woman who also has contraceptive needs, which can be reversed if so desired. OCs also have noncontraceptive health benefits of which the patient should be informed. Finally, the patient should be assured that she can try different therapeutic options until she finds the one most suitable for her.


A variety of approaches have been used to treat premenstrual symptoms. Lifestyle modifications, such as regular physical activity and dietary/nutritional changes, can reduce premenstrual symptoms in some women. Nonpharmacologic options are the easiest forms of treatment to implement, based on appropriate counseling, and can be tried by any woman as she charts her symptoms in a daily symptom record for at least 2 cycles to enable her physician to arrive at a correct diagnosis.

Several pharmacologic options have been shown to be effective and should be evaluated in light of the patient's individual needs and preferences. Some agents, such as particular SSRIs, are effective in many patients but also can be expensive and cause unwanted side effects. Other options, such as GnRH agonists, may be of limited use for similar reasons. Combination OCs are often used to treat premenstrual symptoms, even with a lack of evidence-based support, although new research is revealing more supportive data. OC formulations containing progestin drospirenone have been shown to be effective in treating symptoms of PMDD in controlled studies.

Counseling women about the nature of their symptoms and the variety of treatment possibilities provides much-needed reassurance in many instances and makes it feasible to individualize therapy based on the patient's preferences, treatment cost, and the most likely means of restoring patient comfort, function, and overall health.

Address correspondence to: Andrea J. Rapkin, MD, David Geffen School of Medicine at UCLA, Department of Obstetrics and Gynecology, 10833 Le Conte, Room 27-165 CHS, Los Angeles, CA 90095-1740;

1. ACOG Practice Bulletin. Premenstrual syndrome. Obstet Gynecol. 2000;95:end of issue 4.

2. Mortola JF, Girton L, Beck L, Yen SS. Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: the calendar of premenstrual experiences. Obstet Gynecol. 1990;76:302-307.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

4. Steege JF, Blumenthal JA. The effects of aerobic exercise on premenstrual symptoms in middle-aged women: a preliminary study. J Psychosom Res. 1993;37:127-133.

5. Ginsburg KA, Dinsay R. Premenstrual syndrome. In: Ransom SB, ed. Practical Strategies in Obstetrics and Gynecology. Philadelphia, Pa: WB Saunders Co; 2000:684-694.

6. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444-452.

7. Johnson S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001;56:163-170.

8. Walker AF, De Souza MC, Vickers MF, Abeyasekera S, Collins ML, Trinca LA. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health. 1998;7:1157-1165.

9. Freeman EW, Stout AL, Endicott J, Spiers P. Treatment of premenstrual syndrome with a carbohydrate-rich beverage. Int J Gynaecol Obstet. 2002;77:253-254.

10. Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.

11. Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials. 1996;17:60-68.

12. Johnson SR. Premenstrual syndrome therapy. Clin Obstet Gynecol. 1998;41:405-421.

13. Preston JD, O'Neal JH, Talaga MC. Antidepressant medications. In: Handbook of Clinical Psychopharmacology for Therapists. 3rd ed. Oakland, Calif: New Harbinger Publications, Inc; 2002:163-180.

14. Physicians' Desk Reference, 58th ed. Montvale, NJ:Thomson PDR; 2004.

15. Sundström-Poromaa I, Bixo M, Bjorn I, Nordh O. Compliance to antidepressant drug therapy for treatment of premenstrual syndrome. J Psychosom Obstet Gynaecol. 2000;21:205-211.

16. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch Gen Psychiatry. 1999;56:932-939.

17. Pearlstein TB, Stone AB, Lund SA, Scheft H, Zlotnick C, Brown WA. Comparison of fluoxetine, bupropion, and placebo in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol. 1997;17:261-266.

18. Evans SM, Haney M, Levin FR, Foltin RW, Fischman MW. Mood and performance changes in women with premenstrual dysphoric disorder: acute effects of alprazolam. Neuropsychopharmacology. 1998;19:499-516.

19. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/ progestin. J Clin Endocrinol Metab. 1991;72:252A-252F.

20. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209-216.

21. O'Brien PM, Abukhalil IE. Randomized controlled trial of the management of premenstrual syndrome and premenstrual mastalgia using luteal phase-only danazol. Am J Obstet Gynecol. 1999;180(1 pt 1):18-23.

22. Hahn PM, Van Vugt DA, Reid RL. A randomized, placebo-controlled, crossover trial of danazol for the treatment of premenstrual syndrome. Psychoneuroendocrinology. 1995;20:193-209.

23. Danocrine® [package insert]. New York, NY: Sanofi-Synthelabo; 1996.

24. Vellacott ID, Shroff NE, Pearce MY, Stratford ME, Akbar FA. A double-blind, placebo-controlled evaluation of spironolactone in the premenstrual syndrome. Curr Med Res Opin. 1987;10:450-456.

25. Wang M, Hammarback S, Lindhe BA, Backstrom T. Treatment of premenstrual syndrome by spironolactone: a double-blind, placebo-controlled study. Acta Obstet Gynecol Scand. 1995;74:803-808.

26. Oelkers W. Drospirenone, a progestogen with antimineralocorticoid properties: a short review. Mol Cell Endocrinol. 2004;217:255-261.

27. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62:29-38.

28. Graham CA, Sherwin BB. A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive. J Psychosom Res. 1992;36:257-266.

29. Bäckström T, Hansson-Malmström Y, Lindhe BÅ, et al. Oral contraceptives in premenstrual syndrome: a randomized comparison of triphasic and monophasic preparations. Contraception. 1992;46:253-268.

30. 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.

31. Yasmin®. Physicians' Desk Reference, 59th ed. Montvale, NJ: Thomson PDR; 2005:930-938.

32. Freeman EW, Kroll R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Womens Health Gend Based Med. 2001;10:561-569.

33. Apter D, Borsos A, Baumgartner W, et al. Effect of an oral contraceptive containing drospirenone and ethinylestradiol on general well-being and fluid-related symptoms. Eur J Contracept Reprod Health Care. 2003;8:37-51.

34. Foidart JM, Wuttke W, Bouw GM, Gerlinger C, Heithecker R. A comparative investigation of contraceptive reliability, cycle control and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel. Eur J Contracept Reprod Health Care. 2000;5:124-134.

35. Sangthawan M, Taneepanichskul S. A comparative study of monophasic oral contraceptives containing either drospirenone 3 mg or levonorgestrel 150 microg on premenstrual symptoms. Contraception. 2005;71:1-7.

36. Borenstein J, Yu HT, Wade S, Chiou CF, Rapkin A. Effect of an oral contraceptive containing ethinyl estradiol and drospirenone on premenstrual symptomatology and health-related quality of life. J Reprod Med. 2003;48:79-85.

37. Sillem M, Schneidereit R, Heithecker R, Mueck AO. Use of an oral contraceptive containing drospirenone in an extended regimen. Eur J Contracept Reprod Health Care. 2003;8:162-169.

38. Yonkers KA, Foegh ML. A new low-dose, drospirenone-containing oral contraceptive (OC) with a new dosing regimen is effective in reducing premenstrual dysphoric disorder (PMDD) [abstract]. Fertil Steril. 2004;82:O-255, S102-S103.

39. Yonkers KA, Brown C, Pearlstein TB, et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492-501.

40. Yonkers KA, Halbreich U, Freeman E, et al. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA. 1997;278:983-988.

41. Halbreich U, Bergeron R, Yonkers KA, Freeman E, Stout AL, Cohen L. Efficacy of intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2002;100:1219-1229.

42. Griswold D. Menstruation and related problems and concerns. In: Youngkin EQ, Davis MS. Women's Health: A Primary Care Clinical Guide. Upper Saddle River, NJ: Pearson Education, Inc; 2004:145-164.

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