Primary Care Reports August 11, 1997

A Primary Care Guide to Premenstrual Syndromes

Author: Meir Steiner, MD, PhD, FRCPC, Professor of Psychiatry & Biomedical Sciences, McMaster University, Director, Women’s Health Concerns Clinic, St. Joseph’s Hospital, Hamilton, Ontario, Canada.

Peer Reviewers: Katherine A. Clark, DO, Assistant Clinical Professor, Wright State University School of Medicine, Department of Family Medicine, Dayton, OH; Kimberly A. Yonkers, MD, Assistant Professor, Department of Psychiatry & Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX.

Editor’s Note—Women with troublesome premenstrual symptoms are often seen by primary care physicians. Most women of reproductive age experience physical or psychological symptoms premenstrually; however, for some women these symptoms are so severe as to seriously disrupt their social and occupational functioning. These women may meet criteria for premenstrual dysphoric disorder, which is diagnosed through prospective symptom charting. In addition, there is a subgroup of women who experience premenstrual magnification of a concurrent psychiatric or medical illness. All women presenting with premenstrual complaints should be instructed to chart their symptoms prospectively for at least two menstrual cycles to facilitate diagnosis. Lifestyle and low-risk therapies have demonstrated efficacy for women with mild-to-moderate symptoms. Women who fail conservative therapies may benefit from treatment with low-dose serotonin reuptake inhibitors. Suppression of ovulation with hormonal agents is the last line of therapy and should be used only in severe, refractory cases.


Epidemiologic surveys have estimated that as many as 75% of women of reproductive age experience some symptoms attributed to the premenstrual phase of the menstrual cycle.1 More than 100 physical and psychological symptoms have been reported;2 however, most women are able to manage these symptoms through lifestyle changes and conservative therapies. This phenomenon is often classified by the generic term of Premenstrual Syndrome (PMS) and most often refers to any combination of symptoms that appear during the week prior to menstruation which resolve within a week of onset of menses.3 Conversely, 3-8% of women in this age group report premenstrual symptoms of irritability, tension, dysphoria, and lability of mood which seriously interfere with their lifestyle and relationships.4 So disruptive is the latter that a series of research diagnostic criteria for what is now labelled Premenstrual Dysphoric Disorder (PMDD) have been developed and published in the 3rd revised and 4th editions of the Diagnostic and Statistical Manual of Mental Disorders.5,6 (See Table 1.) Women who are found to meet the diagnostic criteria of PMDD do not usually respond to conservative and conventional interventions, and they often seek out the expertise of their primary care physician.6a-c


The etiology of PMS, and specifically PMDD, is still largely unknown. Attempts have been made to explain the phenomena in terms of biology, psychology, or psychosocial factors, but most of these explanations have failed to be confirmed by laboratory and treatment-based studies.

As is true for all female-specific mood disorders, the role of female sex hormones in PMDD has been considered of central importance. To date, however, studies attempting to attribute the disorder to an excess of estrogen, a deficit of progesterone, a withdrawal of estrogen, or changes in estrogen-to-progesterone ratio have been unable to find specific differences between women with PMDD and those without the disorder.7 Some investigators have suggested that progesterone and progestogens may actually provoke rather than ameliorate the cyclical symptom changes of PMDD.8 The hypothesis that ovarian cyclicity is important in the etiology of PMDD is, nevertheless, supported by some but not all studies in which the medical suppression of ovulation resulted in the disappearance of premenstrual mood disturbances and physical symptoms.9-18

The current consensus seems to be that normal ovarian function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the central nervous system and other target tissues. A psychoneuroendocrine mechanism triggered by the normal endocrine events of the ovarian cycle seems the most plausible explanation.19 This viewpoint is attractive in that it encourages investigation of the neuroendocrine-modulated central neurotransmitters and the role of hypothalamic-pituitary-gonadal (HPG) axis in PMDD.

Of all the neurotransmitters studied to date, increasing evidence suggests that serotonin (5-HT) may be important in the pathogenesis of PMDD.20-24 PMDD also shares many of the features of other mood and anxiety disorders that have been linked to serotonergic dysfunction.25-27 In addition, reduction in brain 5-HT neurotransmission is thought to lead to poor impulse control, depressed mood, irritability, and increased carbohydrate craving—all mood and behavioral symptoms associated with PMDD.28 Reciprocity between fluctuations in ovarian steroids and serotonergic function has been established in animals showing that estrogen and progesterone influence central serotonergic neuronal activity. In the hypothalamus, estrogen induces a diurnal fluctuation in 5-HT,29 whereas progesterone increases the turnover rate of 5-HT.30 More recently, several studies concluded that 5-HT function may also be altered in women with PMDD.

The current consensus is that women with PMDD may be behaviorally or biochemically sub- or supersensitive to biological challenges of the serotonergic system. It is not yet clear whether these women present with a trait or state marker of PMDD.

Risk Factors

Epidemiologic surveys from around the world continue to demonstrate convincingly that, for adult women, the lifetime prevalence of mood disorders is substantially higher than it is among men. Most of these studies confirm that the ratio of affected women to men is approximately 2:1, and this ratio is maintained across ethnic groups.31 The higher incidence of depression among women is primarily seen from puberty on and is less marked in the years after menopause.32 The relationship between PMDD and other psychiatric disorders is complicated by the observation that a high proportion of women presenting with PMDD have a history of previous episodes of mood disorders and that women with an ongoing mood disorder report premenstrual magnification of symptoms as well as an emergence of new symptoms. Likewise, several family studies have identified a concordance in rates of premenstrual tension between first degree female family members.32a-b

Presentation and Diagnosis

To aid in the study of menstrual cycle disorders, each menstrual cycle is characterized as containing two prominent phases; the follicular phase occurs after the onset of menses, and the luteal phase refers to the premenstrual interval. The temporal relationship between fluctuations in psychopathology and different phases of the menstrual cycle is well documented. It is therefore essential to ascertain whether the presenting premenstrual symptomatology is unique to the luteal phase or whether it is a worsening of an ongoing, persisting physical or psychiatric disorder. A definition of the follicular phase as days 7-11 and the luteal phase as days -2 through -6 is appropriate in clinical settings.

Women presenting with premenstrual complaints should be instructed to chart their symptoms daily for at least two, preferably three, menstrual cycles in order to measure within cycle symptom changes. The current emphasis is on prospective, self-report instruments that are easy to administer and score without jeopardizing validity. The Daily Record of Severity of Problems (DRSP) assesses 20 symptoms associated with PMDD and specifically measures functional impairment in work and social realms.33 The Premenstrual Record of Impact and Severity of Menstruation (PRISM)34 and the Calendar of Premenstrual Experiences (COPE)35 are more detailed one-page calendars that have also been validated and used in clinical trials. These calendars allow respondents to rate a variety of physical and psychological symptoms, indicate negative and positive life events, record concurrent medications, as well as track menstrual bleeding and cycle length.

As a result of the lack of objective diagnostic tests for PMS or PMDD, a complete history must be collected in these women. In addition to a retrospective history of the premenstrual symptomatology, this interview should also include a complete review of physical systems (including gynecological, endocrinological, allergies, etc.) and medical disorders, as well as a psychiatric history and a detailed review of family loading for mental illness. As the symptoms of anemia and thyroid disease often mirror those of PMS or PMDD, the patient should undergo laboratory investigations if there are any hints of an underlying medical cause for the symptoms. In addition, women who are suspected to meet criteria for PMDD should be assessed at least once during each cycle phase to ensure that the patient subjectively endorses phase-appropriate mood symptoms which supports their daily charting (none or minimal during follicular phase; lifestyle impairing during the luteal phase).

The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)6 multiaxial classification system includes five axes, each of a different domain of information that may help the clinician in the comprehensive and systematic evaluation of the patient. It draws attention to the various major mental disorders (Axis I) and personality disorders (Axis II); to general medical conditions (Axis III); to psychosocial and environmental factors (Axis IV); and provides a global assessment of functioning (Axis V). In using the DSM-IV criteria for PMDD (Table 1), a certain familiarity with the multiaxial system is assumed. Thus, for PMDD, criterion C is crucial in excluding any current Axis I, II, or III illness or episode. The other essential features of the DSM-IV PMDD criteria are the "on-offness" of symptoms and the emphasis on core mood symptoms (criterion A), the requirement that the symptoms must interfere markedly with lifestyle (criterion B), and, most importantly, that the disorder must be confirmed prospectively by daily ratings for at least two menstrual cycles. Prospective daily rating of symptoms is now the only acceptable means of confirming a provisional DSM-IV diagnosis of PMDD. The DRSP, PRISM, and COPE daily calendars contain the core symptoms and most of the additional symptoms considered for the DSM-IV diagnosis of PMDD. In using one of the daily calendars, the clinician must identify a priori the patient’s chief complaints and the symptoms to be followed throughout treatment. Daily symptoms are rated by the patient using scales which range from none (for a score of 0) to severe (for a score of 7 on the PRISM, 3 on the COPE). Scores for the symptoms of interest are added for the five follicular days and the five luteal days, and these total phase scores are then compared.

Investigators have typically followed a diagnostic severity criterion which is applied in addition to the criteria listed for PMDD in the DSM-IV. Conventionally, a within-cycle increase in symptom scores (worsening) of at least 30% from follicular to luteal phase scores is required in order to meet PMDD diagnostic criteria.36 More recently, it has been suggested that within-cycle worsening of at least 50% is necessary to confirm diagnosis and merit psychopharmacologic intervention.37 The within-cycle percent change is calculated by subtracting the follicular score from the luteal score, dividing by the luteal score and multiplying by 100 ([luteal-follicular/ luteal] ´ 100). Thus, a patient presenting with a mean follicular score of 20 and luteal score of 50 would demonstrate a within-cycle symptom increase of 60%. A change in score of this proportion demonstrates the "on-offness" of this symptomatology and is typical of women who meet criteria for PMDD.

Upon completion of the two-cycle prospective diagnostic assessment phase, women may qualify for one of the following diagnostic categories:

A. PMDD: Women who receive this diagnosis meet criteria for PMDD only. They have no other concurrent psychiatric disorder or unstable medical condition but may have a history of a past psychiatric disorder. They have charted symptoms daily for at least two cycles, and their chief complaints include one of the four core symptoms and at least five of the 11 total symptoms (Table 1). The symptoms have occurred with most menstrual cycles during the past year and have interfered with social or occupational roles. Their symptoms demonstrate clear worsening premenstrually and remit within a few days after the onset of the follicular phase. In addition, worsening between the follicular and luteal phases must be at least 30%.

B. PMS: Women who receive this diagnosis do not meet all DSM-IV criteria for PMDD but do demonstrate symptom exacerbation premenstrually. Only one troublesome symptom is required for this diagnosis, although the symptom must be restricted to the luteal phase of the menstrual cycle, reach a peak shortly before menstruation, and cease with the menstrual flow or soon after.

C. Premenstrual Magnification: Women who receive this diagnosis may meet most of the diagnostic criteria for PMS or PMDD but, in the process of being assessed, have also been identified to have a current major psychiatric disorder or an unstable medical condition. Medical disorders that are commonly exacerbated during the luteal phase include migraine headaches, allergies, asthma, seizures, and genital herpes. Psychiatric conditions that can be magnified include depression, anxiety, panic, bulimia, substance abuse, mania, and psychosis.

D. Other Psychiatric Diagnosis Only: These women do not demonstrate premenstrual symptoms that meet criteria for PMDD but do meet DSM-IV criteria for another psychiatric disorder. Women meeting criteria for Intermittent Depressive Disorder or Cyclothymia may also fall into this category, where the cyclical nature of their symptoms does not necessarily match the phases of their menstrual cycle.

E. No Diagnosis: In these women, the diagnosis of PMS or PMDD cannot be made, and medical, gynecological, and psychiatric screening is negative. These women experience disruptive symptoms that tend to occur throughout the cycle. It is often difficult to delineate the exact problem. Careful examination of the entire diary, especially the follicular phase, and discussion with the patient may show low-grade psychiatric or medical problems such as situational, vocational, or marital stress, irritable bowel syndrome, chronic fatigue syndrome, headache, fibromyalgia or other pain syndromes, as well as sleep disorders.

Applying these criteria to women who seek help for premenstrual complaints will facilitate the primary care physician in planning management interventions.


Women who present with an Axis I, II, or III disorder and premenstrual magnification should be treated for the primary disorder at the discretion of the supervising clinician. Referral to an appropriate specialist is often indicated for newly diagnosed disorders.

A wide range of therapeutic interventions has been tested in the treatment of premenstrual symptoms. For women who do not meet criteria for PMS, PMDD, or other physical and psychological disorders, conservative treatments are appropriate, and management without pharmacologic interventions should be encouraged. Unfortunately, there have been few randomized controlled trials (RCT) to determine the efficacy of these more conservative interventions (see Table 2); however, there is some evidence that these patients may best respond to individual or group psychotherapy in combination with lifestyle changes. Recommended dietary changes (especially during the luteal phase) should include the reduction or limitation of tobacco, chocolate, caffeine, and alcohol. Some women report improvement with small, frequent complex carbohydrate meals and vitamins and minerals when taken in moderation. Patients should be encouraged to decrease excess sodium in the diet when edema or fluid retention occurs and, if possible, to reduce weight to within 20% of their ideal weight. Regular exercise is important and particularly effective when combined with the regular practice of stress management techniques. Patients should also be taught to review their own monthly diaries and identify triggers to symptom exacerbation.


Women who meet criteria for PMS should also be encouraged to practice lifestyle changes and may respond to some of the tested low-risk therapies (see Table 3):

a. Vitamin B6 has demonstrated mixed efficacy in clinical trials, with most trials demonstrating ambiguous or negative results using a wide range of dosing strategies from 50 mg daily to 500 mg daily.38 Because of reports of peripheral sensory neuropathy, dosing in clinical practice should not exceed 150 mg daily to be given during the last two weeks of each cycle.

b. Calcium 1000 mg daily demonstrated significant improvement in one clinical trial.39 No untoward side effects were reported with this dose.

c. Oral magnesium 360 mg daily from the fifteenth day of the menstrual cycle to the onset of menstrual flow significantly improved premenstrual pain and negative affect in one RCT.40

d. Optivite is a vitamin/mineral supplement that was superior to placebo in one RCT.41 Clinically, up to six Optivite tablets daily during the luteal phase of the menstrual cycle may relieve symptoms.

e. Vitamin E (alpha tocopherol) was superior to placebo in women with benign breast disease who scored the severity of their premenstrual symptoms before and after two months of Vitamin E therapy.42 Vitamin E therapy can safely be used at 400 IU daily.

f. Evening Primrose Oil (gamma linolenic acid) has not demonstrated efficacy superior to placebo in several RCTs and should not be recommended as treatment for PMS or PMDD.43

g. Naproxen sodium improved pain and behavior in one RCT when taken seven days premenstrually44 and menstrual migraine specifically in another RCT when it was taken daily.45

h. Mefenamic acid was superior to placebo for improving physical and mood symptoms in one RCT;46 however, the use of this medication should be limited (7-10 days) because of gastric side effects.

i. Spironolactone 100 mg daily from day 12 of the menstrual cycle until the first day of the next menstrual cycle significantly reduced bloating compared to placebo in one RCT.47 The potential for diuretic abuse and serious contraindication of potassium supplements necessitates the use of this drug for severe symptoms only.

j. Bromocriptine of at least 5 mg daily has demonstrated significant improvement in premenstrual mastodynia48 but has not demonstrated efficacy with the mood symptoms associated to the premenstruum. RCT evidence suggests that a dosing range of 1.25-7.5 mg daily during the luteal phase of the menstrual cycle is appropriate for clinical use.

Women who continue to experience severe premenstrual symptoms after the commencement of low-risk therapies may be considered for the pharmacotherapies indicated for PMDD.


Therapeutic interventions for women who meet criteria for PMDD who fail conservative therapies range from treatment of the most troublesome symptoms with psychotropic medications to hormonal therapy to eliminate ovulation.

Listed below is a summary of the RCT evidence for the most common therapies used to treat PMDD. It is important to note that only studies that used prospective diagnostic criteria that could meet the DSM-IV PMDD classification6 have been cited.

I. Psychotropic Medications (See Table 4)

a. Serotonin Reuptake Inhibitors (SRIs). SRIs have proven to be very successful in the treatment of PMDD symptoms. Of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine 20 mg daily has been proven superior to placebo in several RCTs.37,49-52 Sertraline 50-150 mg daily53 and paroxetine 10-30 mg daily54 have also demonstrated efficacy in single RCTs. Pilot studies have demonstrated the efficacy of intermittent SRI dosing during the last two weeks of the menstrual cycle;55-56 however, these finding have yet to be confirmed by a larger RCT. The SRI clomipramine has also been proven superior to placebo in two RCTs, using 25-75 mg daily57 or during the luteal phase of each menstrual cycle only.58 Thus, the SRIs to date have demonstrated their effectiveness in significantly improving the psychological and physical symptoms of PMDD as compared to placebo, with only mild, mostly tolerable side effects. The side effects profile is similar between SRIs, and the most troublesome include headache, nausea/gastrointestinal upset, sleep disturbance/insomnia, tremulousness, sweating, dry mouth, and anorgasmia. These side effects can usually be managed through dosing changes, the use of intermittent vs. daily dosing schedules, or by switching to other SRI compounds.

b. Benzodiazepines (Anxiolytics). Because of the mood disorder component of PMDD, benzodiazepines, particularly anxiolytics, have also been tested for the treatment of this disorder. Alprazolam has successfully alleviated the symptoms of PMDD in several59-62 but not all63 RCTs. The risk of dependence and concerns regarding withdrawal prompted investigators to test the efficacy of alprazolam vs. placebo when administered in the luteal phase only. Patient-modified dosing was allowed, and efficacious dosing ranged from 0.25 to 5 mg daily for 6-14 days prior to menstruation.59-62 Sedation and drowsiness were the two most frequently identified side effects of this treatment. Significant improvements in mood and physical symptoms were reported for the positive studies.56-62 The 5-HT1A partial antagonist busiprone has also demonstrated efficacy in one RCT when administered with a mean daily dose of 25 mg, for the 12 days prior to menstruation.64

II. Hormonal Therapy (See Table 5)

a. GnRH Agonists. GnRH agonists can reversibly suppress the menstrual cycle, and this is often called "medical ovariectomy" or "medical menopause." GnRH agonists have proven to be very successful in most but not all clinical trials. Unfortunately, the long-term use of GnRH agonists has been inhibited by the occurrence of side effects which mimic menopause and the potential for hypoestrogenism and osteoporosis. Preliminary evidence suggests that "add-back" therapy with low-dose estrogen and progesterone replacement therapy may prevent some of these side effects.15 The suggested dosing for the various agonists include: buserelin (400-900 mcg daily, intranasally),12,13 subcutaneous D-Trp6-Pro9-NEt-GnRH (50 mcg daily),16 subcutaneous Histrelin (100 mcg daily),15 and monthly subcutaneous goserelin (3.6 mg).66 Intramuscular depot leuprolide (3.75 mg per month) was significantly superior to saline placebo in one RCT,9 whereas at the dose of 7.5 mg per month, it was not.65 Intramuscular leuoprolide at 3.75-7.5 mg monthly or intranasal buserelin 400-900 mcg daily are the most appropriate GnRHa treatments for clinical use. Addback therapy should consist of conjugated estrogen 0.625 mg daily (Monday-Saturday) and 10 mg of medroxyprogesterone acetate daily for 10 days during every fourth menstrual cycle.

b. Estradiol. Estradiol treatment can suppress ovulation and thus has been proven effective in reducing the symptoms of PMDD, although adjunct progestogen therapy is necessary to prevent endometrial hyperplasia. Luteal phase only administration of Premarin was ineffective in one RCT;67 however, transdermal estradiol or estradiol implants combined with luteal phase noresthisterone, medroxyprogesterone, or dydrogesterone improved physical and mood symptoms in three RCTs.18,68,69 Transdermal estradiol (100-200 mcg patches) applied twice weekly with low-dose progestogen addback daily from day 17 to 26 of each cycle is appropriate for clinical use.

c. Danazol. Danazol is a synthetic androgen, capable of suppressing the HPG axis. While danazol has been proven to be superior to placebo in several RCTs,70-73 the adverse effect profile of this treatment is considerable and is the result of both its androgenic activity and anti-estrogen properties. The most prominent adverse events are amenorrhea, acne, and weight gain. Tested doses include 100-400 mg daily, and both mood and physical symptoms improved significantly when compared to placebo. The most prominent side effect at this dosing range was altered menstrual cycle length. One study of women with PMS found that danazol 200 mg daily from the onset of symptoms to the onset of menses significantly improved mood symptoms and bloating compared to placebo.74 Clinical dosing at 200-400 mg daily is appropriate.

d. Progesterone. Progesterone has been shown to be no more effective than placebo in treating PMS or PMDD symptoms in the majority of trials and should not be used as a primary treatment for these disorders.62,75

e. Oral contraceptives. Oral contraceptives suppress ovulation while maintaining menstruation due to periodic steroid withdrawal. Oral contraceptives have their own side effects, which are often similar to the symptoms of PMS or PMDD. The one RCT testing oral contraceptives in this population was a negative study that supported the conclusions of other less rigorous research.76 Until additional studies ahve been done, oral contraceptives should not be used to treat PMS or PMDD.

To date, no one intervention has proven to be effective for all women with PMDD. SSRIs, as well as clomipramine, continue to be proven as efficacious in women with PMDD who have failed conservative treatment, and they are currently the first treatment of choice. Alprazolam and buspirone have demonstrated efficacy in the reduction of psychological symptoms in RCTs; however, side effects and possible dependence inhibit maximum efficacy.

The last line of treatment for women with PMDD who do not report efficacy with the symptom-modifying drugs are the GnRH agonists. Due to the potential long-term side effects of this treatment, low-dose estrogen-progesterone addback should be considered over the short-term. Estradiol and danazol may also be effective, and gynecological interventions, such as surgery, may need to be considered.10,11

Assessment of Efficacy

Patients should be assessed every two weeks (i.e., during the follicular and luteal phases, respectively) within the first month of commencing therapy, and they should be instructed to continue to chart symptoms daily. Dosing strategies vary; however, most recent investigations have demonstrated the efficacy of most therapeutic drugs at low doses. If efficacy has not been attained after several dosing increases, other treatment options should be considered. There is also increasing evidence that response will be relatively immediate in this population; therefore, if there is no change in symptomatology an alternate therapy should be considered within 2-3 menstrual cycles. Continued symptom charting will help to track efficacy, symptom response to dosing changes, symptoms upon termination of therapy, and real vs. perceived side effects. For example, women who report headaches or nausea as side effects are often surprised to see that they rated these symptoms just as severe prior to commencing therapy.

Investigators have yet to reach a consensus on how to define efficacy. Clinically, the easiest way to define efficacy is by the reduction of luteal symptoms so that the luteal symptoms remit significantly or the follicular to luteal difference is less than 30%. What has become obvious is that the intervention alone cannot predict efficacy, and more consideration is now being given to past psychiatric history as well as to family psychiatric history, especially of mood disorders in the families of women with PMDD.


The recent inclusion of research diagnostic criteria for PMDD in the DSM-IV validates the findings that some women in their reproductive years have extremely distressing emotional and behavioral symptoms premenstrually and should help clinicians recognize these women. PMDD can be differentiated from PMS, which is primarily reserved for milder physical symptoms and minor mood changes, as well as premenstrual magnification, which occurs when physical and/or psychological symptoms of a concurrent psychiatric and/or medical disorder are magnified during the premenstruum.

The etiology of PMS and PMDD is still largely unknown. The current consensus seems to be that normal ovarian function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the central nervous system and other target tissues.

Increasing evidence suggests that 5-HT may be important in the pathogenesis of PMDD. The serotonergic system is in close reciprocal relationship with gonadal hormones. Women with PMDD may be behaviorally or biochemically sub- or supersensitive to biological challenges of the serotonergic system. It is not yet clear whether these women present with a trait or state marker of PMDD.

In order to apply the DSM-IV criteria for PMDD, women must chart symptoms daily for at least two cycles, and their chief complaints must include one of the four core symptoms (irritability, tension, dysphoria, and lability of mood) and at least five of the 11 total symptoms. The symptoms should have occurred with most menstrual cycles during the past year and have interfered with social or occupational roles. In addition, the charting of troublesome symptoms should demonstrate clear worsening premenstrually and remit within a few days after the onset of menstruation. Changes in symptoms from the follicular to luteal phase should be at least 30% to make a diagnosis of PMDD.

Treatment options range from the conservative lifestyle and stress management to treatment with psychotropic medications and hormonal or surgical interventions to eliminate ovulation for the more extreme cases.

SSRIs, as well as clomipramine, continue to be proven as efficacious in women with PMDD who have failed conservative treatment. These interventions have demonstrated excellent efficacy with almost immediate relief and minimal side effects. Recent investigations of SRIs have also demonstrated success at low doses. Most investigators now suggest that if efficacy has not been attained after several dosing increases, other treatment options should be considered. There is also evidence of success with GnRH agonists, estradiol, and danazol. Unfortunately, many women are unable to tolerate the side effects of these interventions.

Taken together, these data indicate that treatment may be accomplished by either eliminating the hormonal trigger or by reversing the sensitivity of the serotonergic system.


1. American College of Obstetrics and Gynecology Committee. Premenstrual syndrome. Int J Gynecol Obstet 1995;50:80-84.

2. Budeiri DJ, et al. Clinical trials of treatment of premenstrual syndrome: Entry criteria and scales for measuring treatment outcomes. Br J Obstet Gynaecol 1994;101:689-695.

3. World Health Organization. Mental, Behavioral and Developmental Disorders. Tenth Revision of the International Classification of Diseases (ICD-10). Geneva: World Health Organization, 1992.

4. Johnson SR. The epidemiology and social impact of premenstrual symptoms. Clin Obstet Gynecol 1987;30: 367-376.

5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Washington, DC, American Psychiatric Association, 1987:367-369.

6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, American Psychiatric Association, 1994:717-718.

6a. Klein TA. Office gynecology for the primary care physician, part II: Pelvic pain, vulvar disease, disorders of menstruation, premenstrual syndrome, and breast disease. [Review]. Med Clin N Am 1996;80:321-336.

6b. Szewczyk M, Chennault SA. Women’s health. Depression and related disorders. [Review]. Primary Care Clin Office Pract 1997;24:83-101.

6c. Allan TR, Goldstein L. Selective serotonin reuptake inhibitors in the treatment of mood disorders in primary care: Depression and premenstrual syndrome. Connecticut Med 1996;60:215-219.

7. Roca CA, et al. Implications of endocrine studies of premenstrual syndrome. Psychiatr Ann 1996;26:576-580.

8. Hammarback S, et al. Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogen-progestogen postmenopausal replacement therapy. Acta Obstet Gynecol Scand 1985;64:393-397.

9. Brown CS, et al. Efficacy of depot leuprolide in premenstrual syndrome: Effect of symptom severity and type in a controlled trial. Obstet Gynecol 1994;84:779-786.

10. Casper RF, Hearn MT. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am J Obstet Gynecol 1990;162:105-109.

11. Casson P, et al. Lasting response to ovariectomy in severe intractable premenstrual syndrome. Am J Obstet Gynecol 1990;162:99-105.

12. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand 1988;67:159-166.

13. Hussain SY, et al. Buserelin in premenstrual syndrome. Gynecol Endocrinol 1992;6:57-64.

14. Mezrow G, et al. Depot leuprolide acetate with estrogen and progestin add-back for long-term treatment of premenstrual syndrome. Fertil Steril 1994;62:932-937.

15. Mortola JF, et al. Successful treatment of severe premenstrual syndrome by combined use of gonadotrophin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab 1991;72:252A-252F.

16. Muse KN, et al. The premenstrual syndrome. Effects of a ‘medical ovariectomy.’ N Engl J Med 1984;311:1345-1349.

17. Smith RN, Studd JW. Estrogens and depression in women. In: Lobo RA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. New York: Raven Press; 1993:129-135.

18. Watson NR, et al. Treatment of severe premenstrual syndrome with estradiol patches and cyclical oral norethisterone. Lancet 1989;2:730-732.

19. Rubinow DR, Schmidt PJ. The treatment of premenstrual syndrome—forward into the past. N Engl J Med 1995;332:1574-1575.

20. Steiner M, et al. Serotonin and gender specific psychiatric disorders. Int J Psychiatry Clin Pract 1997;1:3-13.

21. Rapkin A. The role of serotonin in premenstrual syndrome. Clin Obstet Gynecol 1992;35:629-636.

22. Rojansky N, et al. Imipramine receptor binding and serotonin uptake in platelets of women with premenstrual changes. Gynecol Obstet Invest 1991;31:146-152.

23. Steiner M. Female-specific mood disorders. Clin Obstet Gynecol 1992;35:599-611.

24. Yatham LN. Is 5-HT1A receptor subsensitivity a trait marker for late luteal phase dysphoric disorder? A pilot study. Can J Psychiatry 1993;38:662-664.

25. Endicott J. The menstrual cycle and mood disorders. J Affective Disord 1993;29:193-200.

26. Pearlstein TB, et al. Prevalence of axis I and axis II disorders in women with late luteal phase dysphoric disorder. J Affective Disord 1990;20:129-134.

27. Wurtman JJ. Depression and weight gain: The serotonin connection. J Affective Disord 1993;29:183- 192.

28. Meltzer HY. Serotonergic dysfunction in depression. Br J Psychiatry 1989;155:25-31.

29. Cohen IR, Wise PM. Effects of estradiol on the diurnal rhythm of serotonin activity in microdissected brain areas of ovariectomized rats. Endocrinology 1988;122:2619-2625.

30. Ladisich W. Influence of progesterone on serotonin metabolism: A possible causal factor for mood changes. Psychoneuroendocrinology 1977;2:257-266.

31. Weissman MM, Olfson M. Depression in women: Implications for health care research. Science 1995;269:799-801.

32. Weissman MM, et al. Affective disorders. In: Robins LN, Regiers DA, eds. Psychiatric Disorders in America. New York: Free Press; 1991:53-80.

32a. Kendler, et al. Genetic and environmental factors in the etiology of menstrual, premenstrual, and neurotic symptoms; a population-based twin study. Psychol Med 1992;22:85-100.

32b. Freeman, et al. Effects of medical history factors on symptom severity in women meeting criteria for premenstrual syndrome. Obstet Gynecol 1988;72:236-239.

33. Endicott J, Harrison W. The daily record of severity of problems. Available from Dr. Endicott, New York State Psychiatric Institute, Biometrics Unit, 722 West 168th Street, New York, NY 10032.

34. Reid RL. Premenstrual syndrome. Curr Probl Obstet Gynecol Fertil 1985;8:1-57.

35. Mortola JF, et al. Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: The calendar of premenstrual experiences. Obstet Gynecol 1990;76:302-307.

36. National Institute of Mental Health. NIMH Premenstrual Syndrome Workshop Guidelines; April 14-15, 1983; Rockville, MD: National Institute of Mental Health.

37. Steiner M, et al. Fluoxetine in the treatment of premenstrual dysphoria. N Engl J Med 1995;332:1529- 1534.

38. Kleijnen J, et al. Vitamin B6 in the treatment of premenstrual syndrome—A review. Br J Obstet Gynaecol 1990;97:847-852.

39. Thys-Jacobs S, et al. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med 1989;4:183-189.

40. Facchinetti F, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol 1991;78:177-181.

41. London RS, et al. Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: A double-blind longitudinal study. J Am Coll Nutrition 1991;10:494-499.

42. London RS, et al. Efficacy of alpha-tocopherol in the treatment of premenstrual syndrome. J Reprod Med 1987;32:400-404.

43. Budeiri DJ, et al. Is evening primrose oil of value in the treatment of premenstrual syndrome. Controlled Clin Trials 1996;17:60-68.

44. Facchinetti F, et al. Naproxen sodium in the treatment of premenstrual syndromes: A placebo controlled study. Gynecol Obstet Invest 1989;28:205-208.

45. Sances G, et al. Naproxen sodium in menstrual migraine prophylaxis: a double-blind placebo controlled study. Headache 1990;30:705-709.

46. Mira M, et al. Mefenamic acid in the treatment of premenstrual syndrome. Obstet Gynecol 1986;68:395-398.

47. Vellacott ID, et al. A double blind, placebo controlled evaluation of spironolactone in the premenstrual syndrome. Curr Med Res Opin 1987;10:450-456.

48. Andersch B. Bromocriptine and premenstrual symptoms: A survey of double blind trials. Obstet Gynecol Surv 1983;38:643-646.

49. Stone AB, et al. Fluoxetine in the treatment of late luteal phase dysphoric disorder. J Clin Psychiatry 1991;52:290-293.

50. Menkes DB, et al. Fluoxetine’s spectrum of action in premenstrual syndrome. Int Clin Psychopharmacol 1993;8:95-102.

51. Wood SH, et al. Treatment of premenstrual syndrome with fluoxetine: A double-blind, placebo- controlled crossover study. Obstet Gynecol 1992;80:339-344.

52. Su TP, et al. Fluoxetine in the treatment of premenstrual disorder. Neuropsychopharmacology 1997;16:346-356.

53. Yonkers KA, et al. Sertraline in the treatment of premenstrual dysphoric disorder. Psychopharmacol Bull 1996;32:41-46.

54. Eriksson E, et al. The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome. Neuropsychopharmacology 1995;12:167-176.

55. Smoller JW, Halbreich U. Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. Abstract. Biol Psychiatry 1997;41:120S.

56. Steiner M, et al. Intermittent fluoxetine dosing in the treatment of women with premenstrual dysphoria. Abstract. Psychopharmacol Bull 1997 (in press).

57. Sundblad C, et al. Clomipramine effectively reduces premenstrual irritability and dysphoria: a placebo controlled trial. Acta Psychiatr Scand 1992;85:39-47.

58. Sundblad C, et al. Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome. Neuropsychopharmacology 1993;9:133-145.

59. Smith S, et al. Treatment of premenstrual syndrome with alprazolam: Results of a double-blind, placebo-controlled, randomized crossover clinical trial. Obstet Gynecol 1987;70:37-43.

60. Harrison W, et al. Treatment of premenstrual dysphoria with alprazolam. Arch Gen Psychiatry 1990;47:270-275.

61. Berger CP, Presser B. Alprazolam in the treatment of two subsamples of patients with late luteal phase dysphoric disorder: A double-blind, placebo-controlled crossover study. Obstet Gynecol 1994;84:379- 385.

62. Freeman EW, et al. A double-blind trial of oral progesterone, alprazolam, and placebo in the treatment of severe premenstrual syndrome. JAMA 1995;274:51-57.

63. Schmidt PJ, et al. Alprazolam in the treatment of premenstrual syndrome: A double-blind, placebo- controlled trial. Arch Gen Psychiatry 1993;50:467-473.

64. Rickels K, et al. Buspirone in the treatment of premenstrual syndrome [Letter]. Lancet 1989;i:777.

65. Helvacioglu A, et al. Premenstrual syndrome and related hormonal changes. J Reprod Med 1993;38:864-870.

66. West CP, Hillier H. Ovarian suppression with the gonadotrophin-releasing hormone agonist goserelin (Zoladex) in management of the premenstrual tension syndrome. Hum Reprod 1994;9:1058-1063.

67. Dhar V, Murphy BE. Double-blind randomized crossover trial of luteal phase estrogens (Premarin) in the premenstrual syndrome (PMS). Psychoneuroendocrinology 1990;15:489-493.

68. Magos AL, et al. Treatment of the premenstrual syndrome by subcutaneous oestradiol implants and cyclical oral norestisterone: Placebo controlled study. BMJ 1986; 292:1629-1633.

69. Smith RN, et al. A randomized comparison over 8 months of 100 micrograms and 200 micrograms twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndrome. Br J Obstet Gynecol 1995;102: 475-484.

70. Hahn PM, et al. A randomized, placebo-controlled crossover trial of danazol for the treatment of premen-strual syndrome. Psychoneuroendocrinology 1995;20:193-209.

71. Gilmore DH, et al. Danazol for premenstrual syndrome: A preliminary report of a placebo-controlled double-blind study. J Int Med Res 1985;13:129-130.

72. Deeny M, et al. Low dose danazol in the treatment of premenstrual syndrome. Postgrad Med J 1991;67:450-454.

73. Watts JF, et al. A clinical trial using danazol for the treatment of premenstrual tension. Br J Obstet Gynaecol 1987;94:30-34.

74. Sarno AP, et al. Premenstrual syndrome: Beneficial effects of periodic, low-dose danazol. Obstet Gynecol 1987;70:33-36.

75. Altshuler LL, et al. Pharmacological management of premenstrual disorder. Harvard Rev Psychiatry 1995;2: 233-245.

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

Physician CME Questions

10. Which of the following features are included in the diagnostic criteria for Premenstrual Dysphoric Disorder?

a. Retrospective rating of symptoms for at least one year

b. Symptoms cause disruption of social or occupational function

c. A 75% within-cycle increase in at least 8 physical symptoms

d. No history of mood disorders

e. All of the above

11. Which of the following would alert you to premenstrualmagnification?

a. History of recurrent unipolar depression treated with antidepressants

b. Some mood symptoms worsen premenstrually but depression is troublesome throughout the entire menstrual cycle

c. Severe breast tenderness premenstrually

d. a and b

e. a and c

12. Which of the following statements is true?

a. All women who report symptoms of premenstrual syndrome should be treated with serotonin reuptake inhibitors.

b. Over 90% of women who report symptoms of premenstrual syndrome meet DSM-IV criteria for PMDD.

c. A stepwise approach to the treatment of women with premenstrual syndrome is necessary starting with conservative therapies and progressing through low risk therapies prior to considering pharmacologic treatments.

d. Women who do not meet criteria for premenstrual syndrome or PMDD are hypochondriacs.

e. All of the above

13. Efficacy of treatment for PMDD can be defined as:

a. the patient reports no improvement in social or occupational functioning.

b. within cycle worsening remits or is reduced to < 30%.

c. the patient discontinues all treatment because side effects are worse than symptoms.

d. all of the above.

e. none of the above.

14. Prospective daily calendars can be used to:

a. confirm diagnosis.

b. assess treatment efficacy.

c. compare reported side effects to symptoms which were present at baseline.

d. educate the patient about symptom triggers.

e. all of the above.

Readers are invited . . .

Readers are invited to submit questions or comments on material seen in or relevant to Primary Care Reports. Send your questions to: Reader Questions, Primary Care Reports, c/o American Health Consultants, P.O. Box 740059, Atlanta, GA 30374. Or, you can reach the editors and customer service personnel for Primary Care Reports via the Internet by sending mail to: or miriam_timmerman@ You can also visit our home page at We look forward to hearing from you.