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INTRODUCTION

In the past thirty years premenstrual syndrome (PMS) has emerged as a well recognized phenomenon for which effective treatments are available. Unfortunately, because of the widespread public awareness of adverse premenstrual experiences most women mistakenly believe that they have PMS. Over-the-counter remedies, often promoted by those who hope to profit by marketing a "sure cure" for a common condition, have exploited this belief. Researchers have argued that there is a need to discriminate between the usual premenstrual experience of ovulatory women (wherein premenstrual molimina forewarn of impending menstruation) and PMS wherein symptoms, particularly psychiatric, lead to major distress that is sufficient to interfere with day-to-day activities and disrupt interpersonal relationships. The challenge to the medical profession is to differentiate between these situations and to reserve the diagnosis of PMS for those with clearly identifiable social disruption. While both groups may be offered therapy, the intervention needs to be appropriately selected at the outset and effective treatment options presented in a timely manner. Those with annoying moliminal symptoms should be counseled about simple lifestyle changes that may attenuate symptoms whereas those with marked psychiatric components such as anger, anxiety, or depression warrant early intervention with medications. Although the literature on PMS has focused almost entirely on women with adverse premenstrual experiences there is evidence that 5-15% of women may experience positive changes in the premenstrum (1). Rarely do such women present challenges to the clinician. This chapter will review diagnosis, etiologic theories, and therapeutic approaches to adverse premenstrual experiences.

DEFINITIONS AND PREVALENCE:

Molimina, Premenstrual Syndrome [PMS], and Premenstrual Dysphoric Disorder [PMDD]
During the reproductive years, up to 80-90% of menstruating women will experience symptoms [breast pain, bloating, acne, constipation] that forewarn them of impending menstruation, so-called premenstrual molimina. Over 60% of women report swelling or bloating (2) although objective documentation of weight gain is lacking in most of these women (3). Cyclic breast symptoms affect 70% of women with 22% reporting moderate to extreme discomfort (4). Available data suggest that as many as 30%- 40% of these women are sufficiently bothered by molimina to seek relief. The term PMS should be reserved for a more severe constellation of symptoms - mostly psychiatric, that lead to major interference with day-to-day activities and interpersonal relationships (5). Women with this degree of symptoms probably comprise 3-5% of women in their reproductive years (6, 7, 8).
In an effort to establish the diagnosis based not only on symptoms but also their functional impact PMS has been defined as "the cyclic recurrence in the luteal phase of the menstrual cycle of a combination of distressing physical, psychological, and/or behavioural changes of sufficient severity to result in deterioration of interpersonal relationships and/or interference with normal activities" (9).
The American Psychiatric Association, following years of debate about whether to include PMS in their Diagnostic and Statistical Manual (fourth edition) (10), included as an appendix (meaning that the subject requires further study) a condition labeled Premenstrual Dysphoric Disorder (PMDD) (Table 1) (Such a designation was intended to alert psychiatrists to a combination of specific severe symptoms (mostly psychiatric in nature) that could mimic other psychiatric disorders with the exception that the symptoms recurred in the premenstrual phase of the menstrual cycle. Many of the available effective interventions for severe PMS (PMDD) fall within the domain of psychiatry.

EPIDEMIOLOGY

It is likely that PMS has emerged as a twentieth century phenomenon in part due to the fact that women's increasing control over reproduction has eliminated the cycle of repeated pregnancy and lactation that formerly characterized the lives of women from puberty to menopause (11). PMS-like behaviour has been reported both in humans and in non-human primates as long as they demonstrate menstrual cyclicity. In the non-human primate, zoologists have noted premenstrual changes in behaviour and appetite similar to those reported by women with PMS (12, 13).
PMS may affect woman at any stage of reproductive life. The common belief that PMS is a disorder of the older woman may have stemmed from the fact that mood swings in the teen are less likely to be considered an effect of menstrual cyclicity and more likely to be attributed to the "hormonal swings and heartbreaks" of adolescence. Severe PMS may start shortly after puberty and such cases tend to be recognized and brought to medical attention by a parent who recognizes the symptoms from her own experience. Little is known about the inheritance of PMS however there is support for a genetic predisposition. Surveys have found that as many as 70% of daughters of affected mothers were themselves PMS sufferers, whereas 63% of daughters of unaffected mothers were symptom free (14). PMS sufferers often relate that symptoms become progressively worse over time and since women have increasing contact with health care providers for non-pregnancy related concerns in their later reproductive years this may account for the preponderance of older women seeking help for PMS.
PMS disappears during suppression of the ovarian cycle (for example during hypothalamic amenorrhea due to excessive physical, or nutritional stress, during lactational amenorrhea, during pregnancy, and after menopause -either natural or induced) (15). It is useful when evaluating a woman with suspected PMS to confirm that PMS symptoms did indeed disappear in these circumstances if they occurred. Contrary to the popular belief there is no convincing evidence that PMS onsets after pregnancy or tubal ligation. This belief probably originated when PMS symptoms reappeared and seemed acutely worse after the hormonal "protection" of pre-existing pregnancy.

DIAGNOSIS

History 

Physicians should make an effort to enquire about PMS symptoms as part of the menstrual and reproductive history of all women of reproductive age. For the woman with few symptoms this provides education about PMS and may forestall fears that she is "losing her mind" should symptoms emerge in the later reproductive years. For the woman with significant symptoms this will create the opportunity for counseling and reassurance and will set the stage for establishing the diagnosis.

A typical PMS sufferer may describe being a productive employee and good mother for most of the month. However starting sometime after ovulation (often 7-10 days prior to menstruation) she awakes in the morning with feelings of anger, anxiety, or sadness. At work she may experience feelings of paranoia and wonder if co-workers are picking on her. Often she will report that she has difficulty concentrating on the task at hand. She finds she overreacts to things that her kids normally do around the house and this makes her feel like a bad mother. She may feel down but be unable to understand why because she knows she has a good spouse, a good job, and healthy, happy, kids. She may report that minor things that her spouse has said may be enough to trigger an argument and that nothing he says can appease her. Although she needs to be held and comforted at such times she reports that she cannot stand to be touched. She may try to isolate herself by locking the door to her room or unplugging her telephone. Occasionally depression, anger and aggression, or anxiety may be extreme resulting in concerns for the welfare of the affected woman or her family members.

Caution is needed in immediately accepting such a typical history as diagnostic of PMS. Researchers have found that many other psychiatric conditions worsen premenstrually (so-called premenstrual magnification) hence an individual with an underlying psychiatric disorder may recall and relate the symptoms that were most severe in the premenstrual week while ignoring the lower level of symptoms that exist throughout the month (18). Only by obtaining a prospective symptom record over a one to two month period can the clinician have confidence in the diagnosis. Any calendar used for this purpose must obtain information on four key areas: symptoms, severity, timing in relation to the menstrual cycle, and baseline level of symptoms in the follicular phase [Table 2]. Information should be sought about stresses related to the woman's occupation and family life as these may tend to exacerbate PMS. Past medical and psychiatric diagnoses may be relevant in that a variety of medical and psychiatric disorders may show premenstrual exacerbation.

Several of the medical interventions described below will work for both PMS and other psychiatric conditions so that a pretreatment diagnosis is important in determining the most appropriate long term management of the condition.

Typically PMS symptoms appear after ovulation and worsen progressively leading up to menstruation. About 5-10% of PMS sufferers experience a brief burst of typical PMS symptoms coincident with the midcycle fall in estradiol that accompanies ovulation (19) [Figure 1]. PMS symptoms resolve at varying rates after onset of menstruation. In some women there is almost immediate relief from psychiatric symptoms with the onset of bleeding while for others the return to normal is more gradual. The most severely affected women report symptoms on setting shortly after ovulation (two weeks before menstruation) and resolving at the end of menstruation. Such individuals typically report having only one "good week" per month. [Figure 2] If this pattern is longstanding then it becomes harder and harder for interpersonal relationships to rebound during the good week with the result their condition may start to take on the appearance of a chronic mood disorder. [Whenever charting leaves the diagnosis in doubt a three month trial of medical ovarian suppression (see below) will usually provide a definitive answer.]

Figure 1. Circulating gonadotropin, estradiol, and progesterone concentrations correlated to symptom severity in a woman with midcycle and premenstrual PMS symptoms -so-called pattern C PMS. Daily Menstrual distress Questionnaire Score (MDQ) reflect PMS symptom severity throughout the menstrual cycle.

One example of such a calendar record, the PRISM Calendar (Prospective Record of the Impact and Severity of Menstrual symptoms [Figure 3]) (13) allows rapid visual confirmation of the nature, timing, and severity of menstrual cycle- related symptomatology and at the same time provides information on life stressors and current use of PMS therapies. Although symptoms are rated in severity on a scale from 1-3 the actual interpretation of the calendar requires no mathematical calculations. An arms length assessment of the month-long calendar usually allows a rapid distinction to be made between PMS and other more chronic conditions. [Figure 4]

Figure 3. One example of a Prospective Record of the Impact and Severity of Menstrual symptoms -the PRISM calendar. (reproduced by permission of S. Maddocks and R.L. Reid)

Another validated scale, the Daily Record of Severity of Problems (DRSP) (19 b, 19c), is modeled on the DSM IV criteria for PMDD. This 21 item questionnaire focuses on physical, psychological and functional symptomatology  of PMDD has seen increasing use in clinical research studies involving PMDD.

Figure 4. Arms-length assessment of a completed PRISM calendar reveals a pattern of symptoms consistent with PMS.

Positive premenstrual changes associated with enhanced mood or performance are reported by up to 15% of women. Increased energy, excitement and well-being have been associated with increased activity, heightened sexuality and improved performance on certain types of tasks during the premenstrual phase. (1)

Physical Findings 

There are no characteristic physical findings in women with PMS. When seen in the follicular phase of the cycle PMS sufferers typically appear entirely normal. Premenstrually, a woman presenting with an acute episode of PMS may appear anxious, tearful, or angry depending on the nature of her symptom complex.

A thorough physical exam including gynecological examination is recommended in the assessment of all women being evaluated for PMS. Organic causes of PMS-like symptoms must be ruled out. Marked fatigue may result from anemia, leukemia, hypothyroidism, or diuretic-induced potassium deficiency. Headaches may be due to intracranial lesions. Women attending PMS clinics have been found to have brain tumours, anemia, leukemia, thyroid dysfunction, gastrointestinal disorders, pelvic tumours including endometriosis, and other recurrent premenstrual phenomena such as arthritis, asthma, epilepsy, and pneumothorax (20).

Blood Work

There is no endocrine test that helps in establishing the diagnosis in most circumstances. In a woman in whom the natural ovarian cycle has been disguised following hysterectomy a serum progesterone determination at the time of symptoms may help to confirm the link between symptoms and the luteal phase of the cycle. At times a CBC and/or sensitive TSH may be indicated to rule out anemia, leukemia, or thyroid dysfunction as an explanation for symptoms.

ETIOLOGY 

"We have multitudes of facts, but we require as they accumulate, organizations of them into higher knowledge; we require generalizations and working hypotheses."
-Hughlings Jackson 1835-1911

Since the 1950s a wide range of etiologic theories have been advanced to explain the varied manifestations of PMS. PMS has been attributed to altered levels or ratios of estrogen and progesterone, androgen excess, fluid retention, endogenous hormone allergy, vitamin and trace element deficiencies, prolactin excess, hypoglycemia, bacterial and yeast infections, thyroid dysfunction, endogenous opiate addiction and withdrawal, abnormal metabolism of essential fatty acids leading to prostaglandin E1 deficiency, and altered calcium metabolism to mention a few (15) [Table 3].

Like other areas of confusion and uncertainty, the area of PMS is an attractive one for those promoting unorthodox treatments for personal gain. Many of the theories that underlie such interventions lack biological plausibility and appear to have emerged as a means to market specific therapeutic products. Much effort has been expended by conscientious investigators in an effort to rigorously evaluate the promotional claims of others. Randomized controlled trials have failed to confirm the efficacy of many of these purported treatments.

Other theories, while having some biological plausibility, have not or cannot be confirmed with available diagnostic techniques. No one theory has gained universal acceptance although consensus is developing that in some susceptible women normal swings in gonadal hormones appear to mediate changes in the activity of central neurotransmitters such as serotonin, that in turn incite profound changes in mood and behaviour. Although it is likely that many of the physical symptoms (breast tenderness, bloating constipation) are the direct effect of gonadal steroids it is intriguing that treatment of PMS with selective serotonin reuptake inhibitors will ameliorate the severity of not only psychological but also physical complaints (20b).

Several lines of evidence from clinical medicine support this interrelationship between estrogen or lack of estrogen effect (perhaps mediated by progestin induced depletion of estrogen receptors) and central serotonergic activity (21). Estrogen has been shown to alleviate clinical depression in hypoestrogenic women in double-blind clinical trials (22,23). The addition of sequential progestin therapy to estrogen replacement triggers characteristic PMS-like mood disturbance in some susceptible postmenopausal women (17). Anti-estrogens given for ovulation induction may, at times, provoke profound mood disruption. Women with premenstrual syndrome show a surprisingly high frequency of premenstrual and menstrual hot flashes (85% of PMS sufferers vs 15% of non- PMS controls) that are typical of those experienced by menopausal women (25,24). Some (26), but not all (26b) selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have been shown to relieve hot flashes. In each of these circumstances a decrease in exposure to estrogen has been linked to mood disturbance and in each case a decrease in serotonin activity (inferred from the response to SSRIs) appears to be the proximate cause [Figure 5].

Figure 5. A hypothetical depiction of the interrelationship between gonadal steroid fluctuations and central changes in serotonin activity to explain the timing of symptoms in PMS. When serotonin levels or activity fall below an arbitrary level (that may be influence by stress, heredity, or other factors) symptoms of anger, anxiety, or depression may emerge (depicted by gray areas).

THERAPY

"Clearly defined disease….is the physician's preference and is generally assured the best treatment. Anything else runs a serious risk of inappropriate labeling, misunderstanding, inadequate treatment, and rejection of the patient"
-D R Lipsitt 1982 (27)

Many women suffering from PMS have suffered the fate of those with other poorly defined illnesses that lack a discrete diagnostic test. All too often their concerns have been dismissed as "a normal part of being a woman" and therapy has been denied. Women presenting to PMS clinics often report consulting numerous health care providers before finding one who gave credence to their concerns. Typically they will have tried a number of ineffective over-the-counter PMS remedies and will have sought out practitioners who promote miracle cures for any and all ills for their own financial gain. It has been said that a woman's choice to seek out unorthodox and often unproven treatments for distressing or life threatening conditions is less a reflection of her irrationality than it is a denunciation of conventional medicine's inability to meet her needs.

Lifestyle modification

1) Communication strategies

When an individual is suffering to a degree that requires more than simple counselling and reassurance, measures aimed at lifestyle modification should first be explored. She should be encouraged to discuss the problem with those individuals who are central to her life including spouse, other family members, and even a sympathetic co-worker. Often confrontations can be avoided if an understanding spouse or friend recognizes the cause for her upset and defers discussion of the controversial subject until another time. Strategies for stress reduction can be helpful. Communication skills and assertiveness may be improved with counselling. Group counselling in a program supervised by a clinical psychologist may be invaluable. While it is useful for PMS sufferers to learn to anticipate times in the month when vulnerability to emotional upset and confrontation may be greatest, the strategy of making important decisions "only on the good days", as espoused in some PMS clinics, falls apart if premenstrual symptoms last for more than just a few days per month. For some women premenstrual symptoms may last for a full three weeks and advising them to restrict their important activities to the remaining days of the month is neither helpful nor warranted. Interventions aimed at reducing symptoms are more appropriate in this circumstance.

2) Diet

While there have been many books written which describe specific "PMS diets" few of the recommendations contained therein are founded on scientific fact. Several simple dietary measures may afford relief for women with PMS.

Most women with PMS, despite feelings of bloating and tension, show no absolute increase in weight, no change in girth and no signs of peripheral edema (3). Older medical texts described an unexplained condition called "idiopathic edema" in which occasional women suddenly developed peripheral edema and weight gain associated, in most cases, with acute psychiatric symptoms. It is likely that this disorder was in fact an unusual form of PMS associated with acute fluid retention. Sudden shifts from low-sodium, low-carbohydrate intake to a diet high in these constituents can account for weight gain of as much as 5 kg in twenty four hours (28). Cravings for salty and sweet foods are commonly reported by PMS sufferers and these dietary alterations may account for unusual cases of premenstrual edema. For this reason reduction in the intake of salt and refined carbohydrates may help prevent edema and swelling in occasional women with this manifestation of PMS.

Although a link between methylxanthine intake and premenstrual breast pain has been suggested, available data are not convincing (29, 30). Nevertheless, a reduction in the intake of caffeine may prove useful in women where tension, anxiety, and insomnia predominate.
Several lines of evidence indicate that there is a tendency to increased alcohol intake premenstrually (31) and women should be cautioned that excessive use of alcohol is frequently an antecedent factor in marital discord.

Anecdotal evidence suggests that small, more frequent meals may occasionally alleviate mood swings. Based on recent evidence that cellular uptake of glucose may be impaired premenstrually, there is, at least, some theoretical basis for this dietary recommendation (31, 32). Carbohydrates may exhibit mood altering effects through a number of mechanisms (33) and attempts to improve premenstrual symptoms through dietary supplements have met with limited success (34). Several lines of evidence indicate that there is a tendency toward increased consumption of alcohol premenstrually (30) and women should be cautioned that excessive use of alcohol is frequently an antecedent factor in familial discord. Calcium supplementation has been shown to be marginally superior to placebo in a randomized placebo controlled trial (35).

3) Exercise

Exercise is reported to reduce premenstrual molimina in women running in excess of 50 km/cycle (36). Lesser amounts of regular aerobic exercise may relieve PMS symptoms, at least temporarily, in many women (37). As part of an overall program of lifestyle modification, exercise may reduce stress by providing a time away from the home and by providing a useful outlet for any anger or aggression. Some PMS sufferers report that exercise promotes relaxation and helps them sleep at night.

Medical Interventions

The primary factor directing the selection of therapy should be the intensity and impact of premenstrual symptoms. Symptoms that are causing major disruption to quality of life rarely respond to lifestyle modification alone and efforts to push this approach often do nothing more than delay effective therapy. Conversely, minor symptoms or symptoms that are short-lived each month seldom justify major medical interventions.

Attention should always initially be directed to symptoms for which simple, established treatments exist. For example, dysmenorrhea or menorrhagia may be satisfactorily relieved with prostaglandin synthetase inhibitors or oral contraceptives.

Mefenamic acid (500 mg tid) in the premenstrual and menstrual weeks has outperformed placebo for the treatment of PMS in some but not all clinical trials (38, 39). It is likely that many of the end stage mediators of PMS symptomatology are prostaglandins hence this prostaglandin synthetase inhibitor may be working through a general inhibition of prostaglandin activity. Due to this it is an ideal adjunct for any woman with coexisting dysmenorrhea and menorrhagia. In practice however, its effectiveness for premenstrual symptomatology, particularly psychological symptoms, seems quite variable. Mefenamic acid is contraindicated in women with known sensitivity to aspirin or those at risk for peptic ulcers.

Oral Contraceptives (OC) in the Management of PMS

Despite being one of the most commonly used medications among women of reproductive age the OC has been given to women with premenstrual complaints for 40 years without a clear understanding of what to expect in terms of symptom duration or severity. We know that the OC will reduce menstrual cramps and flow and by so doing may improve the entire premenstrual/ menstrual experience for some women. However many women will discontinue OC use due to distressing premenstrual symptomatology and of those women using the OC some will report the onset of premenstrual symptoms at an earlier stage in the menstrual cycle than in non OC cycles.

The first systematic studies to examine the effects of the OC on PMS found little difference in PMS symptoms between OC users and non users (40) nor were there significant differences between agents with differing progestational potencies (40a). Monophasic and triphasic preparations showed similar rates of symptomatology (41). Continuous use of combined hormonal contraceptives has been shown to reduce or eliminate premenstrual symptoms in many women (41 a)

A new OC preparation containing a novel progestin with diuretic effects (drospirenone) has undergone the most rigorous testing in normal women and women with strictly defined Premenstrual Dysphoric Disorder [PMDD]. Though the evidence supporting a role for fluid retention as an etiologic component of PMS is lacking (41b) many women are distressed by feelings of bloating and edema. In controlled clinical trials this new OC has been shown to offer relief from both physical and psychological manifestations of PMS with an improvement in health related quality of life (41c, 41d, 41e).

Published data in regard to the efficacy of pyridoxine (Vitamin B6) have been contradictory (42), however, this medication in proper dosages (100 mg OD) is, at worst, a safe placebo that becomes one part of an overall management plan for the women with distressing molimina that should include lifestyle modification and changes in diet. Patients should be cautioned that these medications do not work for all women and that increasing the dose of pyridoxine in an effort to achieve complete relief of symptoms may lead to peripheral neuropathy. Pyridoxine should be discontinued if there is evidence of tingling or numbness of the extremities.

Neither progestin therapy (43, 44) nor oil of evening primrose (45) have been shown to be efficacious for PMS in controlled clinical trials.

Premenstrual mastalgia which affects up to 70% of women in reproductive age may occur in isolation from other PMS symptoms and, as such, should be considered a moliminal symptom. Low dose danazol (100 mg OD) for several cycles followed by maintenance doses in the luteal phase only (50 mg OD) (46) can bring about dramatic relief of mastalgia in most women.  However higher dosages (400 mg OD) may be required to relieve other PMS symptoms (46b, 47). Mastalgia may also respond to tamoxifen (10 mg daily) (48), but has not been shown to respond to diuretics, medroxyprogesterone acetate, or pyridoxine.

The routine use of diuretics in the treatment of PMS should be abandoned. Most women show only random weight fluctuations during the menstrual cycle despite the common sensation of bloating (48b). In the absence of demonstrable weight gain it is likely that this symptom may result from constipation and/or bowel wall edema rather than from an overall fluid accumulation. In rare cases, ingestion of salt and refined carbohydrates has been shown to result in true fluid retention. In cases where a consistent increase in weight can be documented or where edema is demonstrable, limitation of intake of salt and refined carbohydrates should be tried first. If such dietary restrictions fail to relieve premenstrual fluid accumulation, use of a potassium-sparing diuretic, such as spironolactone, may be considered (49, 49b). Continued use of a diuretic activates the renin -angiotensin -aldosterone system resulting in rapid rebound fluid accumulation as soon as the diuretic is discontinued. Weight takes approximately two to three weeks to return to normal after discontinuation of a diuretic in some people. Unfortunately this leaves the affected women with the impression that she has to have a diuretic to maintain normal fluid balance.

Spironolactone may improve PMS through mechanisms other than its diuretic effect. Spironolactone exhibits a steroidal structure and is the compound from which drospirenone ( see above – 41b, 41c) was derived. Studies have shown spironolactone to be beneficial in PMS for both physical and mood symptoms (49,49b).

Some women report overriding symptoms of anxiety and tension or insomnia in the premenstrual week (50). New short-acting anxiolytics or hypnotics such as alprazolam (.25 mg po bid) or triazolam (.25 mg po qhs) respectively may be prescribed sparingly for such individuals (51, 52). Buspirone has also proven useful for anxiety and may be particularly helpful in circumstances where SSRIs evoke sexual dysfunction (53).

Estrogen withdrawal has been implicated in menstrually-related migraines and recent evidence indicates that estrogen supplementation commencing in the late luteal phase and continued through menstruation may alleviate headaches in some women (54, 55, 56). As discussed below, if headaches are severe and are unrelieved by short term estrogen supplementation they can often be nicely controlled by intramuscular or oral sumatriptan therapy (57) or by medical ovarian suppression with GnRH agonists (58, 59) and continuous combined hormone replacement therapy (59b).

ANTIDEPRESSANT THERAPY

A range of newer antidepressant medications that augment central serotonin activity have been shown to alleviate severe premenstrual syndrome. (53, 60, 61).Since these agents will also relieve endogenous depression a pretreatment diagnosis, achieved by prospective charting, is very important. Practically speaking, many women who attend a gynecology clinic to seek relief from premenstrual symptoms express reservations about taking an antidepressant, particularly if a short term endpoint (3-6 months away) is not likely. Long term therapy may be required to control symptoms of PMS from the late 30s until menopause.

For patients in whom PMS psychiatric symptoms predominate antidepressant therapy may provide excellent results [Figure 6]. Selective serotonin re-uptake inhibitors, such as fluoxetine, sertraline, paroxetine, fluvoxamine, and velafaxine (a serotonin and norepinephrine re-uptake inhibitor) have all been successfully employed.

Figure 6. Hypothetical depiction of how drugs that elevate serotonin activity can alleviate PMS.

Symptom profiles may help in selecting the most appropriate agent (i.e. fluoxetine in patients where fatigue and depression predominate; sertraline if insomnia, irritability, and anxiety are paramount). SSRIs have been associated with loss of libido and anorgasmia, which are particularly distressing to this patient population and appropriate pretreatment counseling is essential.

Tricyclic antidepressants (TCA) have not generally been effective with the exception of clomipramine, a TCA with strong serotoninergic activity. Intolerance to the side effects of TCAs is common.

Most PMS sufferers would prefer to medicate themselves only during the symptomatic phase of the menstrual cycle. Recent studies have demonstrated that luteal phase therapy may be effective for many women with PMS (62). Practically speaking a trial of SSRI therapy should be commenced with continuous use. After a woman has determined the optimal response that can be achieved with continuous therapy it is reasonable for her to try luteal phase-only therapy to determine if the benefit is maintained.

Symptoms have been shown to recur rapidly following cessation of SSRIs (62b)

MEDICAL OVARIAN SUPPRESSION

Suppression of cyclic ovarian function may afford dramatic relief for the woman with severe and long lasting symptoms (63) [Figure 7]. In each case therapy should be directed toward suppression of cyclic ovarian activity while ensuring a constant low level of estrogen sufficient to prevent menopausal symptomatology and side effects.

Figure 7. Hypothetical depiction of how medical or surgical elimination of ovarian steroid fluctuations can stabilize central serotonin activity and eliminate PMS.

As a rule, although oral contraceptives suppress ovulation they seldom relieve psychiatric symptoms of PMS, perhaps because ovarian steroidogenesis is replaced by exogenous synthetic steroids (40).

Danazol 200 mg bid will effect ovarian suppression in approximately 80% of women with prompt relief from symptoms (47). Higher doses up to 200 mg qid may be required in the remaining women in order to achieve complete menstrual suppression. Danazol, at a dosage of 200 mg bid, has relatively few side effects; these may include hot flushes, muscle cramps, and occasional cases of epigastric pain, fine tremor, or insomnia. In the woman without preexisting hair growth, hirsutism is rarely a problem at these dosages when treatment is limited to one year or less. In the individual with preexisting acne or increased body hair alternative interventions should be considered. The use of danazol causes a shift to a more unfavourable lipid profile which is likely to have little impact when danazol is used on a short term basis. In the patient who tolerates danazol well, and in whom symptomatic relief is dramatic, this effect is the primary concern that will influence decision-making about long term treatment.

Gonadotropin releasing hormone agonists (GnRH Ag) effect rapid medical ovarian suppression thereby inducing a pseudomenopause and affording relief from PMS (64, 64(b)). This approach may effectively alleviate other less common menstrual cycle-rlated conditions such as asthma, epilepsy, migraine and irritable bowel syndrome (59). This approach is unsatisfactory in the long term not only because of the troublesome menopausal symptoms it evokes but also because if creates an increased risk for osteoporosis and ischemic heart disease. When combined with continuous combined hormone replacement therapy GnRH Ag afford excellent relief from premenstrual symptomatology without the attendant risks and symptoms resulting from premature menopause (64(b)). The major drawback to this therapeutic approach is the expense of medication and the need for the patient to take multiple medications on a long term basis.

A simpler and less expensive approach involves the use of depo-medroxyprogesterone acetate (depo-MPA)(150 mg IM q3m). This approach results in rapid suppression of cyclic ovarian function without attendant menopausal symptomatology. The major drawback to this approach is that a substantial percentage of women will get irregular bleeding and gradual weight gain. At times depo-MPA induces long lasting anovulation which may be problematic for aye woman who wishes future fertility. Patients should always be counseled about the potential for protracted anovulation following use of this medication.

SURGICAL THERAPY

Medical approaches to PMS should be exhausted prior to surgery (hysterectomy and oophorectomy) for debilitating PMS. Clinical trials have clearly shown this therapy to be effective (65,66, 67). For the woman in whom there is unequivocal documentation that premenstrual symptoms are severe and disruptive to lifestyle and relationships and in whom conservative medical therapies have failed (either due to lack of response, intolerable side effects, or prohibitive cost) the effect of medical ovarian suppression should be tested. At times this therapy (a GnRH Ag and continuous combined hormone replacement therapy) can be maintained until menopause with satisfactory symptom control. Some women, despite complete relief of symptoms, cannot afford or choose not to take this combination of medications for prolonged intervals (as long as 10-15 years from diagnosis until menopause in some cases).

In these specific circumstances a surgical option may be considered. In the circumstance where family is complete and permanent contraception is desired, the pros and cons of oophorectomy for lasting relief from premenstrual symptomatology should be discussed with the patient. In many women the progestin component of hormone replacement therapy when given sequentially may induce an apparent recrudescence of PMS-like symptoms and when given continuously may result in unwanted irregular bleeding. Accordingly hysterectomy at the time of oophorectomy is a consideration that allows subsequent replacement with low dose estrogen alone.

Figure 8.