ABSTRACT

Premenstrual syndrome, the recurrent luteal phase deterioration in quality of life due to disruptive physical and psychiatric symptomatology, is a distinct clinical condition caused by an abnormal central nervous system response to the hormonal changes of the female reproductive cycle. Better definition and research based on strict inclusion/ exclusion criteria have allowed the development of successful treatments that are tailored to the severity of the lifestyle disruption and the specific individual constellation of symptoms. Charting and simple lifestyle changes may improve coping skills for many women. However, more severely affected individuals often require medical interventions to augment central serotonin/ norepinephrine levels or to suppress the hormonal changes of the menstrual cycle. For extended coverage of this and related topics, please see our FREE on-line web- text www.endotext.org.

INTRODUCTION

In the past fifty 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, the term PMS has found usage in popular vernacular as a noun, adjective and verb (I’m PMS ing”). Over-the-counter remedies, often promoted by those who hope to profit by marketing a “sure cure” for a common condition, have exploited the fact that many women believe they suffer from PMS. 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 or where more troublesome symptoms (PMS) are an annoyance) from Premenstrual Dysphoric Disorder (PMDD) 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 conditions and to offer appropriate and timely interventions.

Those with annoying premenstrual symptoms should be counseled about simple lifestyle changes that may attenuate these whereas those with marked psychiatric components such as irritability, 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 continues to be used; however, for the reasons mentioned above it may encompass a wide range of severity and therefore is not particularly useful in defining cohorts for research or in directing the most appropriate therapeutic interventions.

PMDD should be reserved for a more severe constellation of symptoms, mostly psychiatric, that lead to periodic 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).

Premenstrual Dysphoric Disorder now appears in the Diagnostic and Statistical Manual of Mental Health Disorders (fifth edition) of the American Psychiatric Association. After years of debate about whether this should be included as a distinct psychiatric condition (9,10), the importance of alerting psychiatrists to the critical involvement of the menstrual cycle in psychiatric disorders is now widely accepted (Table 1).

(Adapted from: American Psychiatric Association: Diagnostic and Statistical manual of Mental Health Disorders, 5^th edition. Washington D.C.2013 ) (11)

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 (13). 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 (14, 15).

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 (16). 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) (17). It is useful when evaluating a woman with suspected PMS to confirm that PMS symptoms did indeed disappear in these circumstances. Contrary to the popular belief, there is no convincing evidence that PMS begins 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 or lactation.

PMS disappears after natural, medically or surgically induced menopause although the reintroduction of exogenous hormone replacement therapy may be associated with the reappearance of symptoms (18, 19). Typically, the use of sequential progestin triggers PMS symptoms in susceptible women whereas continuous combined hormone replacement therapy is less likely to be associated adverse mood changes.

DIAGNOSIS

In 2008 an international multidisciplinary group of experts met at a face-to-face consensus meeting in Montreal, Canada, to review current definitions and diagnostic criteria for Premenstrual Disorders (PMD) (20). This group defined “Core Premenstrual Disorders (Core PMD) and Variant Premenstrual Disorders (Variant PMD)” as shown in Table 2 below.

History

Physicians should make an effort to enquire about premenstrual 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 molimina /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 and selecting appropriate therapy.

A typical woman with PMDD may relate that she is a productive employee and good mother for most of the month. However, starting sometime after ovulation (often 7-10 days prior to menstruation) she awakens in the morning with feelings of irritability, 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 may experience menopausal-like hot flashes and night sweats and often reports sleep disruption with vivid dreams. She states that premenstrually she overreacts to things that her children 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, children. Minor things that her spouse says may be enough to trigger an argument, and nothing the spouse says can appease her. Although she would like to be held and comforted at such times, she reports that she cannot stand to be touched. In severe cases, 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 sounding history as diagnostic of PMDD. Researchers have found that many other psychiatric conditions worsen premenstrually (so-called premenstrual exacerbation); 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 . 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 3). Information should be sought about stresses related to the woman's occupation and family life, as these may tend to exacerbate PMDD. Past medical and psychiatric diagnoses may be relevant in that a variety of medical and psychiatric disorders may show premenstrual exacerbation.

Table 3Key elements of a prospective symptom record used for the diagnosis of PMDD.

1. Daily listing of symptoms
2. Ratings of symptom severity throughout the month
3. Timing of symptoms in relation to menstruation
4. Rating of baseline symptom severity during the follicular phase

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

Typically premenstrual 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 (21) (Figure 1). Premenstrual 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 that symptoms begin shortly after ovulation (two weeks before menstruation) and resolve 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 that the 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

Figure 2

One example of such a calendar record, the PRISM Calendar (Prospective Record of the Impact and Severity of Menstrual symptoms) (Figure 3) (9) 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 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 PMDD and other more chronic conditions (Figure 4). Other charting instruments, including the validated Daily Record of Severity of Problems (DRSP), the Premenstrual Symptoms Screening Tool (PSST), and the Calendar of Premenstrual Experiences (COPE), have been recently reviewed (22).

Figure 3

Figure 4

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)

ETIOLOGY

Although many theories of etiology have been proposed and disproved for this poorly understood condition, contemporary work suggests that PMDD is the result of an aberrant response of central neurotransmitters to normal changes in gonadal steroids during the menstrual cycle.

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.

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 (24,25). Estrogen has been shown to alleviate clinical depression in hypoestrogenic women in double-blind clinical trials (26). The addition of sequential progestin therapy to estrogen replacement triggers characteristic PMS-like mood disturbance in some susceptible postmenopausal women (19). 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 (27, 28). Selective serotonin reuptake inhibitors (SSRIs) have been shown to relieve hot flashes in breast cancer survivors made menopausal by chemotherapy (29). 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].

An emerging theory as to causation of PMDD involves a progesterone metabolite, allopregnanolone (ALLO), which acts centrally as a neuroactive steroid. As with progesterone, ALLO increases in the luteal phase and declines just prior to onset of menses. ALLO has a stimulating effect on the GABA-A receptor similar to alcohol and benzodiazepines with anxiolytic and sedative properties. One possibility is that women with PMDD have developed tolerance to the sedating GABA-a enhancing effects of ALLO (30). Preclinical and early clinical work have suggested that blockade of the production of ALLO with a 5-alpha reductase inhibitor can attenuate symptoms of PMDD (31).

THERAPY

Many women suffering from PMDD 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. Typically affected women will suffer for long periods before seeking treatment, and most will have tried a variety of ineffective over-the–counter “PMS remedies”. 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 about causation of PMDD in the past 50 years 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 most of these purported treatments.

Antidepressant Therapy

A range of newer antidepressant medications that augment central serotonin activity have been shown to alleviate severe premenstrual syndrome (66, 67). 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 PMDD from the late 30s until menopause.

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

Figure 6

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 women with PMDD would prefer to medicate themselves only during the symptomatic phase of the menstrual cycle. Recent studies have demonstrated that luteal phase therapy and even symptom-onset therapy may be effective for many women with PMS (68, 69). Practically speaking, it makes sense to start a trial of SSRI therapy 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 or symptom-onset therapy (70) to determine if the benefit is maintained.

Medical Ovarian Suppression

Suppression of cyclic ovarian function may afford dramatic relief for the woman with severe and long lasting symptoms (71, 72) (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

Danazol (200 mg bid) will effect ovarian suppression in approximately 80% of women with prompt relief from symptoms (53). It also reduces breast pain and menstrual flow. However, danazol is an impeded androgen and at a dosage of 200 mg bid may have side effects that limit its use, such as hot flashes, muscle cramps, hirsutism or a worsening of the lipid profile. Because of this, the use of danazol has been largely supplanted by ovarian suppression with gonadotropin-releasing hormone agonists (GnRH Ag).

Gonadotropin releasing hormone agonists effect rapid medical ovarian suppression, thereby inducing a pseudo-menopause and affording relief from PMS (71, 72). This approach may effectively alleviate other less common menstrual cycle-related conditions such as asthma, epilepsy, migraine and irritable bowel syndrome (65). 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. 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. For women approaching menopause, 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).

Though less well studied depo-medroxyprogesterone acetate (depo-MPA) (150 -300 mg IM q3m) may provide a cheaper way to attenuate symptoms of PMDD in women who require contraception. The major drawback to this approach is that a substantial percentage of women will get irregular bleeding and gradual weight gain. Patients should always be counseled about the potential for protracted anovulation following use of this medication.

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