Obstetrics and Gynecology Clinics, Volume 27 Number 3 September 2000
Copyright 2000 W. B. Saunders Company, CURRENT REPRODUCTIVE ENDOCRINOLOGY
Advances in Diagnosis and Treatment
Bruce Kessel MD
Department of Obstetrics, Gynecology, and Women’s Health, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
Premenstrual syndrome (PMS) is characterized by the occurrence of a constellation of symptoms temporally associated with the menstrual cycle. Symptoms of PMS include physical and mood changes that peak premenstrually and resolve shortly following the onset of menstrual bleeding. Historical descriptions of PMS are shrouded in mythology, and, previously, the scientific understanding of PMS was limited.
The term premenstrual syndrome was used in 1931 by Greene and Dalton to describe a constellation of physical and emotional symptoms.  The abbreviation “PMS” subsequently became a term widely recognized by the public and used by health care providers. The evaluation of PMS was hampered by the lack of agreed upon definitions or diagnostic criteria, and treatment protocols were often based on poorly designed studies. Advances in the understanding of PMS have accelerated in the past decade owing to increased attention placed on the definition and diagnostic criteria, the development of validated PMS calendars, inroads into the understanding of the underlying pathophysiology, and significant breakthroughs in therapy. The most recent scientific investigations have focused on patients with premenstrual dysphoric disorder (PMDD), a severe form of PMS with strict diagnostic criteria. To this day, the precise pathophysiology of PMS has not yet been elucidated; however, significant strides have been made in the diagnosis, treatment, and understanding of PMS.
Precise definitions of PMS have been the subject of some debate. For the purposes of this article, the definitions in the following sections are used.
Most women experiencing regular ovulatory menstrual cycles can identify premenstrual symptoms. These symptoms may include breast tenderness, pelvic heaviness or bloating, and food cravings. This symptom complex is not distressing to the woman, does not interfere with daily functioning, and is a normal sign of ovulatory cycles and not a diagnosis of PMS. Premenstrual molimina can be ascertained in the course of a gynecologic and menstrual history and are not a presenting chief complaint.
Premenstrual syndrome is a commonly used term that has been variably defined. A definition of PMS that is less strictly defined than PMDD has been proposed. PMS as a diagnosis in the Tenth Revision of the International Classification of Diseases (ICD-10) requires only a history of a single physical or mood symptom occurring in a cyclic basis.  Prospective recording and functional impairment are not required. Unfortunately, many research studies have not used a strict definition for PMS, making it difficult to evaluate and compare studies.
Premenstrual Dysphoric Disorder
Premenstrual dysphoric disorder is the current American Psychiatric Association designation for a specifically defined severe form of PMS. This disorder is listed in the appendix of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) as an entity requiring further research.  The prior designation in the DSM-IIIR was termed late luteal phase dysphoric disorder. The current diagnostic criteria for PMDD include the need for a specific constellation of symptoms, the need for prospective documentation of symptoms, and the demonstration that the symptom complex is causing functional impairment. In the literature, some reports using the term PMS have used research protocols in which the women studied often met many or all of the criteria for PMDD.
The diagnostic criteria for PMDD specifically exclude premenstrual exacerbation of a known underlying disorder. Many medical conditions respond to cyclic changes in ovarian sex steroids. A patient with a known major medical or psychiatric diagnosis in whom symptoms worsen premenstrually would not be characterized as PMDD but would maintain her primary diagnosis.
DIAGNOSTIC CRITERIA FOR PREMENSTRUAL SYNDROME AND PREMENSTRUAL DYSPHORIC DISORDER
Common symptoms of PMS include fatigue, irritability, bloating, anxiety or tension, breast tenderness, mood lability, depression, and food cravings.  The ICD-10 diagnosis of PMS requires only a history of a physical or mood symptom occurring in a cyclic fashion. Under that definition, a patient presenting with the chief complaint of PMS could be assigned this diagnosis based on history without the need for prospective documentation. This patient population will in reality include patients with PMS, patients with PMDD, and a substantial percentage of patients not meeting criteria for either diagnosis. For this reason, it is reasonable to consider prospective recording of symptoms in all patients evaluated for PMS. Patients demonstrating cyclic changes in mood or physical symptoms that do not meet criteria for PMDD would then be designated as having PMS. Most of the recent rigorous scientific studies have used patient populations meeting criteria for the DSM-IV definition of PMDD.
Premenstrual Dysphoric Disorder
The diagnostic criteria for PMDD are as follows: *
- (Not Available)
Components of the diagnostic criteria are worthy of brief discussion. There is no single symptom characteristic of PMDD but, rather, the cyclic occurrence of a symptom complex. This symptom complex may include physical and behavioral symptoms. The diagnosis of PMDD emphasizes and requires mood symptoms, whereas the diagnosis of PMS has no such requirement. This difference has resulted in a body of scientific enquiry and treatments targeted primarily for mood aspects of PMDD. Less well studied have been the subset of patients in whom physical symptoms cause distress. For the diagnosis of PMDD, one of the following four core symptoms must be present: depressed mood, anxiety/tension, affective lability, or irritability/anger. In addition to at least one of these core symptoms, a total of five symptoms must be present. To meet criteria for either PMS or PMDD, the symptom complex must have a temporal association with the menstrual cycle. Specifically, symptoms must occur premenstrually and be followed by a symptom-free interval that begins after the onset of menstruation. Generally, symptoms resolve rapidly with the onset of the menstrual flow (within hours to 1 to 2 days) and should not reoccur until after ovulation. The symptom complex must interfere with work, school, relationships, or some aspect of daily living. This requirement is specific to the diagnosis of PMDD and is not a requirement for PMS. Examples of such disruption include documented problems at work or school, relationship discord, or other functional impairment in daily living. The symptom complex must not be solely the exacerbation of a known underlying condition. These underlying conditions may be medical or psychiatric. To diagnose PMDD, the symptom complex must be documented by prospective daily recording over two menstrual cycles. This requirement is a fundamentally important standard in the diagnosis of PMDD. Prospective recording can be accomplished using several menstrual calendars.
Differential Diagnosis and Use of PMS Calendars
As noted previously, the diagnosis of PMDD requires that the symptoms are not the premenstrual exacerbation of an underlying medical or psychiatric condition. This confirmation entails a careful history and consultations as necessary. Common medical conditions that should be considered in the differential diagnosis of PMS include hypothyroidism and perimenopause. Common psychiatric conditions that should be considered include substance abuse disorders, depressive disorders, bipolar illness, panic disorder, personality disorders, and anxiety disorders. Another clinical scenario that is commonly seen is the diagnosis of PMS in a patient using hormonal therapy such as oral contraceptives. The author believes that the diagnosis of PMS should be made in the absence of hormonal therapy. Oral contraceptive pills may worsen or alleviate various symptoms of PMS and add a pharmacologic component that clouds the diagnosis. The use of prospective recording of symptoms and an awareness of the common diagnoses present in patients presenting with presumed PMS but found not to have this syndrome are helpful in the clinical evaluation of patients.
Most women presenting with a chief complaint of PMS are actually not found to have PMS, and PMS calendars are critical in this determination. One study evaluating patients presenting with presumed PMS found the following exclusionary items: (1) the absence of a symptom-free window in the follicular phase (20.5%), (2) other psychiatric diagnosis (20.1%), (3) menstrual irregularities (16.6%), (4) menopausal or perimenopausal status (10.2%), and (5) other medical disorders (8.4%).  Twenty percent or more of women presenting with a chief complaint of PMS do not have a symptom-free window following the onset of menses on prospective recording and therefore do not meet the criteria for PMS/PMDD. This finding emphasizes the benefit obtained by strictly adhering to the prospective use of PMS calendars. Several calendars have been widely used, published, and validated, including the Calendar of Premenstrual Experiences (COPE) and the Prospective Record of the Impact and Severity of Menstruation (PRISM).   Calendar items are filled out daily for 2 months and then scored. Generally, a 30% increase in scores from the follicular phase to the luteal phase is necessary for the diagnosis of PMS/PMDD, with some clinicians requiring a within-cycle increase of 50% before initiating pharmacologic therapy. Using these criteria, it is thought that premenstrual molimina occur in as many as 80% or more of reproductive-aged women, whereas the strict diagnosis of PMDD is relatively rare, occurring in 3% to 5% of reproductive-aged women.    The ICD-10 diagnosis of PMS may occur in 20% to 30% of women, but, as mentioned previously, this diagnosis has been variably defined in the literature and is not as useful as the stricter diagnostic criteria of PMDD.
The pathophysiology of PMS is not known. The relative contributions of sociocultural and genetic factors are unclear. Twin studies have suggested substantial heritability to premenstrual symptoms.  In addition to this apparent genetic predisposition, it is likely that sociocultural influences and a woman’s personal expectations influence her premenstrual symptoms. PMS seems to be cross-cultural, with PMS reported across ethnic groups and in different societies.  The particular symptoms that predominant may vary among groups. Risk factors for the development of PMS have not been clearly established.
Sex Steroid Concentrations
The cyclic nature of PMS and association with the luteal phase of the menstrual cycle led to investigations attempting to demonstrate differences in circulating sex steroids in patients with PMS when compared with normal cycling controls. One early hypothesis was that there was a deficiency in luteal phase progesterone. Multiple studies have subsequently failed to demonstrate a difference in circulating levels of estradiol or progesterone in patients with PMS and controls.  These studies have included examination of frequent (daily) sampling throughout the menstrual cycle and examination of urinary and serum metabolites of estradiol and progesterone.
Other hormones implicated in PMS have been examined with conflicting results. One recent study found no changes in adrenocorticotropic hormone, beta-endorphin, or cortisol in daily blood samples from patients with PMS when compared with controls.  Another study provides support for the hypothesis that central nervous system metabolism of progesterone may have a role in the pathophysiology of PMS. In that study, allopregnanolone levels were significantly lower on luteal phase day 26 in patients with PMS versus controls.  Allopregnanolone is a central metabolite of progesterone that interacts with the gamma-aminobutyric acid receptor system in a manner that would result in anxiolysis. A deficiency in allopregnanolone could result in enhanced anxiety in patients with PMS. Interestingly, a recent study has found that selective serotonin reuptake inhibitors (SSRIs) alter steroidogenic enzymes involved in the synthesis of allopregnanolone.  These data support interactions between neurosteroids and SSRIs relevant to the pathophysiology of PMDD.
Central Nervous System Neurotransmitters
The primary thrust of research efforts related to the pathophysiology of PMS has been directed at the impact of circulating ovarian sex steroids on central neurotransmitters. Central nervous system neurotransmitters hypothesized to have a role in the pathophysiology of PMS include the GABA system, the opiate system, and molecules involved in alterations of adrenergic or serotoninergic pathways. Much of the recent research has centered on implicating the serotoninergic system in the pathophysiology of PMDD. The following observations have been made: (1) estradiol and progesterone alter brain serotoninergic activity in vitro in animal studies; (2) serotonergic probes have different effects in patients with PMDD when compared with normal cycling controls  ; (3) serotoninergically active agents alter central neurosteroid synthesis  ; and (4) serotoninergically active agents have been shown to treat PMDD successfully in randomized clinical trials.   Taken together, these findings suggest an important role for serotoninergic activity in the pathophysiology of PMDD. Because women with PMDD and normal cycling controls seem to have the same circulating levels of estradiol and progesterone, it is hypothesized that (1) central nervous system metabolism of steroids may be different in patients with PMS   or (2) sensitivity of central nervous system neurotransmitters to circulating sex steroids is altered in patients with PMDD. Evidence for the latter hypothesis was demonstrated in a study in which patients with PMS and controls were treated with gonadotropin-releasing hormone (GnRH) agonists to obtain a symptom-free, acyclic, hypogonadal state. The research subjects were then treated with estradiol and progesterone, both of which resulted in adverse mood symptoms in patients with PMS but not in controls.  The neuroendocrine pathophysiology of PMDD is thought to be specifically tied to serotonin and not related to depression in general. Although a consensus has not been reached on this issue, it is thought that PMS and depression are distinct entities based on biochemical differences (e.g., 24-hour cortisol rhythms) and differences in pharmacologic response. Although tricyclic antidepressants are generally equally efficacious in the treatment of major depression when compared with SSRIs, this observation is not true for PMDD, in which SSRIs are significantly superior to tricyclic antidepressants having little serotoninergic activity.  
THERAPIES FOR PHYSICAL SYMPTOMS
Most of the recent scientific research has focused on the DSM-IV definition of PMDD and has targeted therapies for mood symptoms. Less attention has been placed on troubling physical symptoms, including headaches, bloating, and breast tenderness.
Menstrual migraines and premenstrual headaches may be triggered by declining estrogen levels in the luteal phase and have been shown to respond to several therapeutic interventions. Some of the therapies for menstrual migraines are standard approaches to migraines, such as use of nonsteroidal anti-inflammatory drugs and sumatriptan.  Sumatriptan has been specifically studied in the context of menstrual migraines, with 73% and 81% of women responding to sumatriptan administration for migraine attacks.  Hormonal manipulations include administering estrogen in the late luteal phase to attenuate the premenstrual decline (transdermal estrogen, 0.1 mg), and the use of GnRH agonists with hormone add-back to eliminate all menstrual cyclicity.  An open trial of continuous bromocriptine therapy also demonstrated a significant reduction in menstrual migraines. 
Cyclic mastalgia is a frequent complaint in the outpatient obstetrics and gynecology setting.  Treatments shown to alleviate breast pain include danazol (Danocrine), tamoxifen, and oral contraceptive pills. A recent randomized clinical trial of Danocrine showed significant improvements in mastalgia scores when compared with placebo. In that trial, 100 women were randomized to receive placebo or low-dose Danocrine (200 mg/day), and the Danocrine was administered only in the luteal phase of the cycle.  Another randomized clinical trial compared placebo, Danocrine, and tamoxifen. Danocrine and tamoxifen were highly effective for cyclic mastalgia, achieving pain relief in 72% and 65% of women, respectively.  A double-blind controlled trial of an oral contraceptive has also demonstrated reduction in premenstrual breast pain.  These same medications did not relieve mood symptoms of PMS in these trials.
Limited data are available on abdominal bloating. Exercise and oral contraceptives, which reduce breast symptoms, have also been shown to reduce fluid symptoms.   A randomized trial of magnesium supplementation demonstrated a reduction in symptoms of fluid retention and breast tenderness.  One study of bromocriptine demonstrated a reduction in breast tenderness and bloating. Several trials of spironolactone have demonstrated a reduction in abdominal bloating, with some studies showing an improvement in other PMS symptoms in addition to bloating. 
NONPHARMACOLOGIC THERAPIES FOR PREMENSTRUAL SYNDROME
Nonpharmacologic therapies for mood symptoms of PMS or PMDD have not been subjected to large multicenter randomized clinical trials. Small studies suggest that several nonpharmacologic therapies are of general health benefit and fare well from a risk/benefit ratio despite the relative lack of data. These studies have included patient populations with well-defined PMDD and less strictly defined PMS.
Symptom Charting and Validation of PMS
Patients with PMS often benefit by validation of the diagnosis by a health care provider. A discussion of the proposed pathophysiologies of PMS as a neuroendocrine syndrome is reassuring to some patients. Some patients benefit from charting and recording of symptoms. Charting symptoms lends validation to the diagnosis and may be helpful from the standpoint of anticipating when symptoms are likely to occur, providing an increased sense of control for the patient.
A primary example of a nonpharmacologic therapy with little harm is exercise. Most of the published studies on exercise and PMS have shown a benefit. These studies are hampered by small study size and the inability to double blind. Exercise seems to reduce mood symptoms and physical symptoms of breast tenderness and bloating.  One proposed underlying pathophysiology is the enhancement of central opiate activity associated with exercise. Because of other significant health benefits of regular exercise and data suggesting the relief of PMS symptoms, exercise can be considered a first-line therapy among the nonpharmacologic interventions.
Diet, Vitamins, and Herbs
Dietary interventions have long been suggested for treating PMS symptoms, with little supporting research. Dietary recommendations have ranged from reducing caffeine to altering carbohydrate or protein intake. No specific diet has been demonstrated to be effective for PMS. Carbohydrate intake and cravings have been examined to some extent. The ingestion of carbohydrates may result in an increase in the availability of tryptophan, thereby allowing increased serotonin synthesis. One study has documented an improvement in PMS symptoms with the ingestion of a carbohydrate-rich beverage in the luteal phase of the menstrual cycle. 
Studies of vitamins, minerals, and essential fatty acids have been hampered by mixed results, poor study design, or lack of a rigorous definition of PMS. Multiple studies have been performed on the use of vitamin B6 with mixed results, although some data suggest a possible benefit.  With the exception of calcium, essential fatty acids and other vitamin supplements have had mixed results or have not been well studied. A recently proposed hypothesis suggests that patients with PMS are calcium deficient. A randomized clinical trial of calcium carbonate (1200 mg of calcium) versus placebo demonstrated a 48% reduction in symptoms in the treatment group versus a 30% reduction with placebo. This study was a large ( n = 497), multicenter, randomized clinical trial. 
Many herbs would be of interest in the treatment of PMS but have not yet been evaluated in randomized clinical trials. St. John’s wort is increasingly used by many women with PMS, although limited data support this use in the published literature. Other herbs reputed to be beneficial for PMS, including chaste tree extract, ginko biloba, black cohosh, and others, have not been subjected to adequate trials.
Relatively little attention has been placed on the possible benefits of cognitive-behavioral therapy and relaxation response as an aid to patients with PMS. In one controlled study, relaxation response resulted in a greater reduction in symptoms of PMS when compared with charting of PMS symptoms and leisure reading.   Cognitive-behavioral therapy may also be of benefit to some patients with PMS.   Several studies are investigating the possibility that bright light therapy may be of benefit for patients with PMS.  Because the risks of such therapies are low, further research in this area is warranted.
PHARMACOLOGIC THERAPIES FOR PREMENSTRUAL DYSPHORIC DISORDER
Pharmacologic therapies are directed at either eliminating the fluctuations in endogenous ovarian sex steroids associated with menstrual cyclicity or lessening the impact of circulating sex steroids on central nervous system neurotransmitters through treatment with centrally acting drugs. The mainstay of pharmacologic therapy and the agents studied in the largest clinical trials are the SSRIs. Other effective therapies include other psychotherapeutic drugs and GnRH analogues assessed in smaller studies (Table 1) .
|Therapy|| Typical Dose
|Fluoxetine||10-20 mg/d|| |
|Sertraline||25-50 mg/d|| |
|Alprazolam||0.25 mg tid (luteal)|| |
|Buspirone||15 mg bid (luteal)|||
|GnRH analogues||Varies by product|| |
|PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; SSRIs = selective serotonin reuptake inhibitors; GnRH = gonadotropin-releasing hormone; tid = three times daily; bid = twice daily.|
When administered in a continuous fashion, GnRH agonists modulate pituitary GnRH receptors, with the subsequent induction of a hypoestrogenic amenorrheic state. Initial studies of GnRH analogues were performed to demonstrate the dependence of PMS on cyclic ovarian steroid production.  Subsequently, several studies have demonstrated the efficacy of GnRH analogues in the treatment of PMS. The concern with GnRH analogue treatment is the impact of prolonged hypoestrogenism with regard to symptoms of menopause, accelerated bone loss, and the possible increase in cardiovascular risk. Several investigators have examined the use of GnRH agonists combined with the addition of hormone replacement therapy (add-back therapy) for PMS.  These trials have shown efficacy for PMS and PMDD. The cost and side effects of GnRH agonist therapy and the emerging data on the efficacy of SSRIs have made this modality a less commonly used therapy.
Oral contraceptive pills are often prescribed for PMS by obstetricians/ gynecologists despite the lack of clear evidence for efficacy. Although it is widely recognized that oral contraceptives will decrease dysmenorrhea, the effectiveness of these agents for the mood symptoms of PMS/PMDD is not established. A double-blind, placebo-controlled trial of one oral contraceptive found a reduction in bloating and breast pain but no significant reduction in mood symptoms.  Other studies of the effect of oral contraceptives on PMS symptoms are ongoing. Although a subset of women with PMS may receive some benefit from oral contraceptives, there are no substantive data suggesting efficacy of oral contraceptives for PMDD. Limited studies suggest that danazol, a synthetic androgen, may benefit patients with PMS. At doses resulting in amenorrhea, danazol can be associated with untoward androgenic side effects. Luteal phase administration of low-dose danazol has been used successfully for mastalgia with little impact on mood symptoms. Natural progesterone administered in a wide range of doses and routes of administration was a mainstay of PMS therapies several decades ago despite the absence of clinical trials supporting such use. Since that time, several studies have examined the use of natural progesterone versus placebo for PMS symptoms, with generally negative results.  
A number of psychotherapeutic agents that are not SSRIs have demonstrated efficacy for PMS in small clinical trials. These drugs generally fall into the category of anxiolytics or antidepressants with regard to their primary Food and Drug Administration indication. Anxiolytic drugs with published data relative to patients with PMS include alprazolam and buspirone. Alprazolam is a benzodiazepine class anxiolytic that reduces PMS symptoms with luteal phase administration at doses of 0.25 mg orally three times daily.   Because of dependence and tolerance issues associated with benzodiazepines, clinicians should be careful when selecting patients for this therapy. Buspirone is a nonbenzodiazepine anxiolytic that has shown benefit for PMS in two placebo-controlled trials. Luteal phase administration in doses ranging from 25 to 60 mg/day were used in these trials.  Clomipramine, an antidepressant with serotonin and noradrenaline reuptake-inhibiting properties, has been beneficial for PMS at doses ranging from 25 to 75 mg/day.  Other antidepressants that have significant serotoninergic activity (e.g., venlafaxine, nefazodone) are also likely to be effective for PMDD.
Selective Serotonin Reuptake Inhibitors
Currently SSRIs are considered first-line therapy in the pharmacologic management of PMDD. SSRIs were developed for the treatment of major depression and act by selectively inhibiting neuronal reuptake of serotonin. As research increasingly implicated serotoninergic mechanisms in the pathophysiology of PMS, investigators examined the efficacy of SSRIs for PMDD. Multiple studies have now confirmed that SSRIs are highly effective in the pharmacologic management of PMDD. Two large multicenter randomized clinical trials have specifically examined fluoxetine and sertraline. In the fluoxetine trial, 313 women were randomized to receive placebo or fluoxetine at doses of 20 and 60 mg/day.  The diagnostic criteria were characteristics of late luteal phase dysphoric disorder (the DSM-IIIR antecedent of PMDD). Fluoxetine at doses of 20 and 60 mg/day resulted in a 53% improvement in PMS symptoms, with the higher dose associated with significantly more side effects. More recently, the results of a multicenter randomized clinical trial of sertraline at doses of 50 to 150 mg have been reported.  The diagnostic criterion for this trial was PMDD according to the DSM-IV. In addition to a 62% improvement in symptoms, the trial demonstrated an improvement in social function. Several smaller studies have demonstrated efficacy with other SSRIs, including paroxetine, fluvoxamine, and citalopram.    Research has examined the efficacy of administering SSRIs solely in the luteal phase of the menstrual cycle. Currently, fluoxetine, sertraline, and citalopram all have published data supporting their administration in a cyclic fashion during the luteal phase.    In the citalopram study, luteal phase administration was found to be even more effective than constant administration. Many clinicians caring for patients with PMS initiate SSRIs at doses lower than the typical starting doses listed for the treatment of depression. Typical SSRI doses for initiation of therapy for PMDD are fluoxetine, 10 mg, sertraline, 25 mg, and paroxitene, 5 to 10 mg.
The side effects of SSRIs include gastrointestinal tract disturbance, sleep problems, lethargy, and sexual dysfunction. Side effects are usually self-limited. In clinical practice, the SSRI-induced sexual dysfunction has been a significant issue, and the incidence is higher than that reported in the Physician’s Desk Reference or premarketing clinical trials. Intermittent luteal phase administration using low doses ameliorates the sexual dysfunction in many patients. Because patients with PMS are by definition of reproductive age, there is a concern regarding medication use and the risk of pregnancy. All psychotropic medications cross the placenta, and, because the risks of these broad classes of drugs in pregnancy are not completely known, patients should be advised to use contraception. The available data on SSRI exposure during pregnancy have been reassuring. 
Premenstrual syndrome and PMDD are increasingly recognized as medical entities that adversely affect the quality of life of a subset of women. When research criteria or the strict definition of PMDD are used, the prevalence of PMS is thought to range from 3% to 5% among reproductive-aged women. Although the precise pathophysiology is not known, it is increasingly believed that women with PMS have an altered sensitivity of central neurotransmitters, particularly serotoninergic, to normal circulating levels of estradiol and progesterone. Significant advances have been made in pharmacologic therapy for PMDD, with the largest clinical trials demonstrating efficacy of the SSRIs. These studies show relief of distressing mood symptoms and improvements in parameters of social function in most patients.
1. Ader DN, Browne MW: Prevalence and impact of cyclic mastalgia in a United States clinic-based sample. Am J Obstet Gynecol 177:126, 1997
2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, DC, American Psychiatric Association, 1994, p 715
3. Blake F, Salkovskis P, Gath D, et al: Cognitive therapy for premenstrual syndrome: A controlled trial. J Psychosom Res 45:307, 1998
4. Bloch M, Schmidt PJ, Su TP, et al: Pituitary-adrenal hormones and testosterone across the menstrual cycle in women with premenstrual syndrome and controls. Biol Psychiatry 43:897, 1998
5. Boyle CA: Management of menstrual migraine. Neurology 53:S14, 1999
6. Brown CS, Ling FW, Farmer RG, et al: Buspirone in the treatment of premenstrual syndrome. Drug Ther Suppl August:112, 1990
7. Eriksson E, Hedberg MA, Andersch B, et al: The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome. Neuropsychopharmacology 12:167, 1995
8. Facchinetti F, Bonellie G, Kangasniemi P, et al: The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. Obstet Gynecol 86:911, 1995
9. Freeman E, Rickels K, Sondheimer SJ, et al: Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 264:349, 1990
10. Freeman EW, Rickels K, Sondheimer SJ, et al: A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 274:51, 1995
11. Freeman EW, Rickels K, Sondheimer SJ, et al: Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: A randomized controlled trial. Arch Gen Psychiatry 56:932, 1999
12. Freeman EW, Rickerls K, Sondheimer SJ: Fluvoxamine for premenstrual dysphoric disorder: A pilot study. J Clin Psychiatry 57(suppl 8):56, 1996
13. Goodale IL, Domar AD, Benson H: Alleviation of premenstrual syndrome symptoms with the relaxation response. Obstet Gynecol 75:649, 1990
14. Graham CA, Sherwin BB: A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive. J Psychosom Res 36:257, 1992
15. Greene R, Dalton K: The premenstrual syndrome. BMJ 1:1007, 1953
16. Griffin LD, Mellon SH: Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A 96:13512, 1999
17. Herzog AG: Continuous bromocriptine therapy in menstrual migraine. Neurology 48:101, 1997
18. Janiger O, Riffenburgh R, Kersh R: Cross cultural study of premenstrual symptoms. Psychosomatics 13:226, 1972
19. Johnson SR: The epidemiology and social impact of premenstrual symptoms. Clin Obstet Gynecol 30:367, 1987
20. Kendler K, Karkowski L, Corey L, et al: Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry 155:1234, 1998
21. Kontostolis E, Stefanidis K, Navrozoglou I, et al: Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol 11:393, 1997
22. Lam RW, Carter D, Misri S, et al: A controlled study of light therapy in women with late luteal phase dysphoric disorder. Psychiatry Res 86:185, 1999
23. Morse CA, Dinnerstein L, Farrell E, et al: A comparison of hormone therapy, coping skills training, and relaxation for the relief of premenstrual syndrome. J Behav Med 14:469, 1991
24. Mortola JF: Applications of gonadotropin-releasing hormone analogues in the treatment of premenstrual syndrome. Clin Obstet Gynecol 36:753, 1993
25. Mortola JF, et al: Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab 72:252A, 1991
26. Mortola JF, Girton L, Beck L, et al: Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: The calendar of premenstrual experiences. Obstet Gynecol 76:302, 1990
27. Murray SC, Muse KN: Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and add-back therapy. Fertil Steril 67:390, 1997
28. 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 180:18, 1999
29. Patuszak A, Schick-Boschetto B, Zuber C, et al: Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 269:2246, 1993
30. Prior JC, Vigna Y, Alojada N: Conditioning exercise decreases premenstrual symptoms: A prospective controlled three-month trial. Eur J Appl Physiol 55:349, 1986
31. Ramcharan S, Love EJ, Fick GH, et al: The epidemiology of premenstrual symptoms in a population-based sample of 2650 urban women. J Clin Epidemiol 45:377, 1992
32. Rapkin AJ, Morgan M, Goldman L, et al: Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet Gynecol 90:709, 1997
33. Reid RL: Premenstrual syndrome. Current Problems in Obstetrics, Gynecology, and Fertility 8:1, 1985
34. Rivera-Tovar AD, Frank E: Late luteal phase dysphoric disorder in young women. Am J Psychiatry 147:1634, 1990
35. Roca CA, Schmidt PJ, Bloch M, et al: Implications of endocrine studies in premenstrual syndrome. Psychiatr Ann 26:576, 1996
36. Sayegh R, Schiff I, Wurtman J, et al: The effect of a carbohydrate-rich beverage on mood, appetite, and cognitive function in women with premenstrual syndrome. Obstet Gynecol 86:520, 1995
37. Schmidt PJ, Nieman LK, Danaceau MA, et al: Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 338:209, 1998
38. Smith S, Rinehart JS, Ruddock VE, et al: Treatment of premenstrual syndrome with alprazolam: Results of a double-blind, placebo-controlled, randomized crossover clinical trial. Obstet Gynecol 70:37, 1987
39. Steiner M, Korzekwa M, Lamont J, et al: Intermittent fluoxetine dosing in the treatment of women with premenstrual dysphoria. Psychopharmacol Bull 33:771, 1997
40. Steiner M, Steinberg S, Stewart D, et al: Fluoxetine in the treatment of premenstrual dysphoria. N Engl J Med 332:1529, 1995
41. Su TP, Schmidt PJ, Danaceau M, et al: Effect of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonin agonist m-chlorophenylpiperazine in women with premenstrual syndrome and controls. J Clin Endocrinol Metab 82:1220, 1997
42. Sundblad C, Hedberg MA, Eriksson E: Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: A placebo-controlled trial. Neuropsychopharmacology 9:133, 1993
43. Thys-Jacobs S, Starkey P, Bernstein D, et al: Calcium carbonate and the premenstrual syndrome: Effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 179:444, 1998
44. Walker AF, De Souza MC, Vickers MF, et al: Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health 7:1157, 1998
45. Wang M, Hammarback S, Lindhe BA, et al: Treatment of premenstrual syndrome by spironolactone: A double-blind, placebo-controlled study. Acta Obstet Gynecol Scand 74:803, 1995
46. Wikander I, Sunblad C, Andersch B, et al: Citalopram in premenstrual dysphoria: Is intermittent treatment during luteal phases more effective than continuous medication throughout the menstrual cycle? J Clin Psychopharmacol 18:390, 1998
47. World Health Organization: Mental, behavioral and developmental disorders. In Tenth Revision of the International Classification of Diseases (ICD-10). Geneva, World Health Organization, 1996
48. Wyatt KM, Dimmock PW, Jones PW, et al: Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: Systematic review. BMJ 318:1375, 1999
49. Yonkers KA, Halbreich U, Freeman E, et al: Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment: A randomized controlled trial. JAMA 278:983, 1997
50. Young SA, Hurt PH, Benedek DM, et al: Treatment of premenstrual dysphoric disorder with sertraline during the luteal phase: A randomized, double-blind, placebo-controlled crossover trial. J Clin Psychiatry 59:76, 1998Print This Post