Menstrual Disorders
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Since antiquity, the temporal relationship between menses and the lunar phases has inspired names for menstruation, such as the “period.” The regularity of menses was easily appreciated by the ancients, even if they had no understanding of its cause or purpose. Ancient physicians viewed menstruation as a process of detoxification and, throughout history, myths and superstitions have perpetuated negative attitudes toward menses.1
The health care profession has an obligation to provide and to promote education on menstruation and related subjects, which must start with itself. Clinicians must have a thorough understanding of reproductive physiology before they can impart that knowledge to their patients, and must be sensitive to the need to present the information in a positive context that fosters healthy attitudes toward sexual and reproductive functions. An educated understanding of normal reproductive processes is a powerful tool for addressing the symptoms and disorders of menstruation.
Some menstrual disorders, such as dysmenorrhea, can be explained in a physiologic framework that both educates and provides the foundation for appropriate treatment. Unfortunately, others, such as the premenstrual syndrome, remain poorly understood. This chapter considers several medical problems that are temporally linked with menstruation, and their pathophysiology when that is known.
Historical Views of Menstruation and Menstruating Women
Recorded history includes a wide variety of myths regarding menstruation and menstruating women. In ancient times, menstruating women commonly were thought possessed
by an evil spirit. Aristotle (384-322 B.C.), the Greek philosopher, student of Plato, and teacher of Alexander the Great, said that a menstruous woman could dull a mirror with a look, and that the next person to peer into it would be bewitched. Pliny, born in 23 A.D., consulted approximately 2,000 available books by physicians while writing his treatise, Historia Naturalis, a resource used throughout the Dark Ages; more than a hundred copies, all 37 volumes, still exist. Pliny wrote extensively on menstruation, including the following2:
by an evil spirit. Aristotle (384-322 B.C.), the Greek philosopher, student of Plato, and teacher of Alexander the Great, said that a menstruous woman could dull a mirror with a look, and that the next person to peer into it would be bewitched. Pliny, born in 23 A.D., consulted approximately 2,000 available books by physicians while writing his treatise, Historia Naturalis, a resource used throughout the Dark Ages; more than a hundred copies, all 37 volumes, still exist. Pliny wrote extensively on menstruation, including the following2:
Contact with it turns new wine sour, crops touched by it become barren, grafts die, seeds in gardens are dried up, the fruit of trees falls off, the edge of steel and the gleam of ivory are dulled, hives of bees die, even bronze and iron are at once seized by rust, and a horrible smell fills the air; to taste it drives dogs mad and infects their bites with an incurable poison. If a women strips herself naked while she is menstruating and walks around a field of wheat, the caterpillars, worms, beetles, and other vermin will fall off from the ears of corn. All plants will turn of a yellow complexion on the approach of a woman who has the menstrual discharge upon her. Bees will forsake their hives at her touch, for they have a special aversion to a thief and a menstruous woman, and a glance of her eyes suffices to kill a swarm of bees.
Throughout early history, the fear of blood spawned many ancient taboos. Almost universally, menstruating women were isolated and prevented from handling food. Most primitive peoples regarded women as unclean during menstruation and subjected them to segregation and special rituals. It is therefore not surprising that, even with growing sophistication, negative attitudes toward menstruation persisted into modern times.
In 19th and early 20th century Europe, menstruation was commonly associated with antisocial behavior.3 In 1845, a domestic servant who murdered one of her employer’s children was acquitted on the grounds of insanity due to obstructed menstruation. In 1851, a woman was acquitted of murdering her baby niece due to insanity arising from disordered menstruation. As recently as 1984, Dalton argued that the premenstrual phase of the cycle was associated with an increased incidence of crime, jailing for alcoholism, poor academic performance, sickness in industry, and hospitalization for accidents.4 However, careful studies have found no significant variations in cognitive or motor functions across the menstrual cycle,5,6,7 and 8 suggesting that, to a large extent, behaviors merely reflect societal expectations. Unfortunately, even today, expectations and attitudes toward menstruation are influenced heavily by old traditions and social and cultural beliefs.
The Premenstrual Syndrome and Premenstrual Dysphoric Disorder
The simplest definition of the premenstrual syndrome (PMS) is a common sense one: cyclic physical and behavioral symptoms that appear in the days preceding menses and interfere with work or lifestyle, followed by a symptom-free interval. Premenstrual dysphoric disorder (PMDD) describes a severe form of PMS that some consider a distinct
clinical entity, characterized by prominent symptoms of irritability, anger, internal tension, dysphoria, and mood lability.9
clinical entity, characterized by prominent symptoms of irritability, anger, internal tension, dysphoria, and mood lability.9
Historically, the phrase “premenstrual syndrome” was used first by Greene and Dalton in their report of 84 cases in 1953.10 However, R.T. Frank, then the chief of obstetrics and gynecology at Mt. Sinai Hospital in New York City, generally is credited with having first described PMS, in 1931:11
The group of women to whom I refer especially complain of a feeling of indescribable tension from 10 to 7 days preceding menstruation which in most instances continues until the time that the menstrual flow occurs. The patients complain of unrest, irritability, like jumping out of their skin and a desire to find relief by foolish and ill considered actions. Their personal suffering is intense and manifests itself in many reckless and sometimes reprehensible actions. Not only do they realize their own suffering, but they feel conscience-stricken toward their husbands and families, knowing well that they are unbearable in their attitude and reactions. Within an hour or two after the onset of the menstrual flow complete relief from both physical and mental tension occurs.
An extraordinary array of different physical and behavioral symptoms has been attributed to PMS. The most common physical symptoms include abdominal bloating, extreme fatigue, breast tenderness, and headaches, all occurring in 50-90% of cases. The most prevalent behavioral symptoms of PMS are mood lability, irritability, depressed mood, increased appetite, forgetfulness, and difficulty with concentration, occurring in 50-80% of cases. Other less common symptoms include anxiety or tension, easy crying, thirst, acne, gastrointestinal upset, hot flushes, palpitations, dizziness, and lower extremity edema. Symptoms of PMS typically arise during the last 7-10 days of the cycle.12
Premenstrual symptoms are very common, reported by up to 75% of women with regular menstrual cycles. However, because women naturally relate symptoms and behaviors to menstruation retrospectively, estimates of their frequency are subjective and inherently biased.13 Moreover, both men and women have been conditioned to expect symptoms during the premenstrual phase of the cycle, such as fluid retention, pain, and emotional lability, and not surprisingly, they report such symptoms when asked in retrospect.14 The power of conditioned response was illustrated in a classic study by Ruble, in which 44 undergraduates at Princeton University were deliberately deceived about the phase of their menstrual cycle.15 A mock electroencephalogram was performed, complete with electrodes attached to the head, after being described as a new technique that could predict the onset of menstruation. Subjects were informed that they were premenstrual (expected menses in 1-2 days) or intermenstrual (expected menses in 7-10 days), and only those led to believe they were premenstrual reported increased symptoms of pain, water retention and changes in eating habits—a self-fulfilling prophesy. Subjects tend to comply with what they believe is the investigator’s hypothesis, and in studies of PMS, no differences in symptoms can be demonstrated when the purpose of the study is disguised or expectations are manipulated.16,17 and 18 Carefully designed prospective studies have revealed that some women who have no demonstrable cyclic premenstrual symptoms or changes in cognitive function nonetheless believe that they do,13 even including some diagnosed with PMDD.5, 19, 20 When strictly defined based on prospective symptom diaries, clinically significant PMS occurs in 20-30% and PMDD affects 2-8% of women.9, 21,22,23 and 24
Diagnostic Criteria
The diagnosis of both PMS and PMDD depends on the presence of typical symptoms, their timing, severity, and the exclusion of other diagnoses. Both diagnoses require a prospective symptom diary documenting specific cyclic symptoms associated with the luteal and menstrual phases of the cycle and evidence of socioeconomic dysfunction.25 The specific collection of symptoms in a given individual is much less important than the cyclic nature of the symptom complex and its temporal relationship with menses. When symptoms are charted accurately, as much as 40% of women presenting with presumed PMS do not exhibit the distinctly cyclic pattern required for diagnosis and actually have another mood or anxiety disorder.26
The most commonly used criteria for diagnosis of PMS are those proposed by investigators at the University of California at San Diego.12, 27 The diagnostic critera were based on prospective symptom diaries of women in whom underlying medical conditions and psychiatric disorders were carefully excluded, and on an analysis of cycle phase defined by daily urinary steroid metabolites.27 A symptom survey instrument known as the Calendar of Premenstrual Experiences (COPE) was constructed, including the 10 most commonly reported physical symptoms and the 12 most commonly reported behavioral symptoms, with each ranked on a 4-point Likert scale of severity across the menstrual cycle.12
Name _ Month/Year _ Age _
Begin your calendar on the first day of your menstrual cycle. Enter the date below the cycle day. Day 1 is your first day of bleeding. Shade the box above the cycle day if you have bleeding. ▪ Enter an X for spotting ×.
If more than one symptom is listed in a category (ie, nausea, diarrhea, constipation), you do not need to experience all of these. Rate the most disturbing of the symptoms on the 0-3 scale below.
Weight: Weigh yourself before breakfast. Record your weight in the box below date. Symptoms: Indicate the severity of your symptoms by using the 1-3 scale below. Rate each symptom at about the same time each evening.
0 = None (symptoms not present) 2 = Moderate (interferes with normal activities)
1 = Mild (noticeabe but not troublesome) 3 = Severe (intolerable, unable to perform normal activities)
Other Symptoms: If there are other symptoms you experience, list and indicate severity. Medications: List any medications taken and enter an X on the corresponding day(s).
Bleeding | ||||||||||||||||||||||||||||||
Cycle Day | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 |
Date | ||||||||||||||||||||||||||||||
Weight | ||||||||||||||||||||||||||||||
Symptoms | ||||||||||||||||||||||||||||||
Acne | ||||||||||||||||||||||||||||||
Bloating | ||||||||||||||||||||||||||||||
Breast tenderness | ||||||||||||||||||||||||||||||
Dizziness | ||||||||||||||||||||||||||||||
Fatigue | ||||||||||||||||||||||||||||||
Headache | ||||||||||||||||||||||||||||||
Hot flashes | ||||||||||||||||||||||||||||||
Nausea, diarrhea, constipation | ||||||||||||||||||||||||||||||
Palpitations | ||||||||||||||||||||||||||||||
Swelling (hands, ankles, feet) | ||||||||||||||||||||||||||||||
Angry outbursts, arguments, | ||||||||||||||||||||||||||||||
violent tendencies | ||||||||||||||||||||||||||||||
Anxiety, tension, nervousness | ||||||||||||||||||||||||||||||
Confusion, poor concentration | ||||||||||||||||||||||||||||||
Easy crying | ||||||||||||||||||||||||||||||
Depression | ||||||||||||||||||||||||||||||
Food cravings (salt, sweets) | ||||||||||||||||||||||||||||||
Forgetfulness | ||||||||||||||||||||||||||||||
Irritability | ||||||||||||||||||||||||||||||
Increased appetite | ||||||||||||||||||||||||||||||
Mood swings | ||||||||||||||||||||||||||||||
Overly sensitive | ||||||||||||||||||||||||||||||
Wish to be alone | ||||||||||||||||||||||||||||||
Other symptoms | ||||||||||||||||||||||||||||||
1. | ||||||||||||||||||||||||||||||
2. | ||||||||||||||||||||||||||||||
Medications | ||||||||||||||||||||||||||||||
1. | ||||||||||||||||||||||||||||||
2. |
The COPE survey instrument yields reliably reproducible scores that correlate well with those derived from administering the Profile of Mood States29 and the Beck Depression Inventory.30 A number of other scales can be used for diagnosis of PMS, including the Moos Menstrual Distress Questionnaire (MDQ),31 the Premenstrual Assessment Form (PAF),32, 33 and the Prospective Record of the Severity of Menstruation (PRISM).34 The COPE survey remains among the most popular, primarily because analysis of data derived from its use has revealed that virtually all women with PMS can be identified using a simplified list of six behavioral symptoms and four physical symptoms, yielding a set of diagnostic criteria that can be applied easily in a patient interview, as follows:12
Self-report of 1 or more affective symptoms and 1 or more somatic symptoms during the 5 days preceding menses in each of three menstrual cycles:
Affective Symptoms
Somatic Symptoms
Depression
Breast tenderness
Angry outbursts
Abdominal bloating
Irritability
Headache
Confusion
Swollen extremities
Social withdrawal
Fatigue
Relief from symptoms within 4 days after the onset of menses, without recurrence before cycle day 12.
Absence of any medications, hormone therapy, drug or alcohol use.
Socioeconomic dysfunction, as indicated by one of the following:
Discord in the relationship with a partner, confirmed by the partner
Parenting difficulties
Poor work/school performance or attendance
Increased social isolation
Legal problems
Suicidal ideation
Seeking medical care for somatic symptoms
According to guidelines from the National Institute of Mental Health (NIMH),35 the diagnosis of PMS also should require at least a 30% increase in the severity of symptoms over the 5 days before menses, compared with the 5 days after onset of menses. Based on the UCSD and NIMH criteria, it is estimated that approximately 5% of women of reproductive age can be diagnosed with disruptive PMS.36,37 and 38
The most commonly used criteria for the diagnosis of PMDD are those proposed by the American Psychiatric Association, as they appear in the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV):39
Symptoms occur regularly during the last week of the luteal phase in most menstrual cycles during the past year, remit within a few days after the onset of menses, and always are absent in the week after menses.
Five or more of the following symptoms must be present, including at least one among the first four:
Feeling sad, hopeless, or self-deprecating
Feeling tense, anxious, or “on edge”
Marked lability of mood, interspersed with frequent tearfulness
Persistent irritability, anger, and increased interpersonal conflicts
Decreased interest in usual activities that may be associated with withdrawal from social relationships
Difficulty concentrating
Feeling fatigued, lethargic, or lacking in energy
Marked changes in appetite that may be associated with binge eating or certain food cravings
Hypersomnia or insomnia
A subjective feeling of being overwhelmed or out of control
Other physical symptoms such as breast tenderness or swelling, headaches, sensations of “bloating” or weight gain with tightness of fit of clothing, shoes, or rings, or joint or muscle pain
The symptoms are of comparable severity (but not duration) to those of a mental disorder, such as a major depressive episode or a generalized anxiety disorder, and cause obvious and marked interference with work, usual activities, or relationships.
The symptoms may be superimposed on another disorder but are not merely an exacerbation of the symptoms of another disorder.
It is important to note that whereas the diagnosis of PMS requires both affective and somatic symptoms, the diagnosis of PMDD can include, but does not require, somatic symptoms. Another distinction between the two disorders is that PMDD may be superimposed on another psychiatric disorder, whereas the diagnosis of PMS can only be made in their absence.
The diagnoses of PMS and PMDD must be differentiated from other underlying psychiatric disorders, which are common among women with similar symptoms.26,40,41 Medical conditions, such as hyperthyroidism and hypothyroidism, also should be excluded. A study involving a group of women evaluated in a specialty PMS clinic found that 13% had a distinct affective psychiatric disorder, 38% had premenstrual exacerbation of an underlying depressive or anxiety disorder, and only 44% actually met strict diagnostic criteria for PMS.42 Women with PMS often have a history of a previous major depressive episode and also are at increased risk for major depression in the future.43, 44 Women who have no demonstrable symptom-free interval during the follicular phase of the cycle merit careful evaluation for a mood or anxiety disorder.
Migraine headache and symptoms of chronic fatigue syndrome and irritable bowel syndrome frequently are more pronounced during the premenstrual phase of the cycle. However, in women with these syndromes, symptoms also occur at other times in the cycle.45
Pathophysiology
Scientific evidence for the mechanism(s) involved in PMS and PMDD has been difficult to produce, but there has been no shortage of theories; the list is impressive:
Low progesterone levels
High estrogen levels
Falling estrogen levels
Changes in the estrogen/progesterone ratio
Increased aldosterone activity
Increased rennin-angiotensin activity
Increased adrenal activity
Endogenous opiate withdrawal
Subclinical hypoglycemia
Central changes in catecholamines
Responsiveness to prostaglandins
Vitamin deficiencies
Excess prolactin secretion
In his original description of PMS, R.T. Frank summarized 15 cases, theorized that the problem resulted from an excess of female sex hormones due to inadequate excretion, and reported that he could provide relief by withdrawing blood from his patients. Accordingly, he applied treatments designed to increase excretion, such as calcium lactate, caffeine, and laxatives. For severe cases, he prescribed pelvic irradiation to cause ovarian failure. In 1934, S. Leon Israel proposed the opposite theory—that PMS was caused by defective luteinization, progesterone deficiency, and relative hyperestrogenism.46
The role of ovarian steroid hormones in PMS is suggested strongly by the lasting reponse to oophorectomy in women unresponsive to medical therapy47, 48 and by the dramatic decrease in symptoms after suppression of the hypothalamic-pituitary-ovarian axis by treatment with a long-acting gonadotropin-releasing hormone (GnRH) agonist.49,50,51 and 52 However, studies comparing serum estrogen and progesterone levels have failed to identify any consistent differences between women with and without PMS/PMDD.53,54 and 55 Moreover, an early onset of menses induced by treatment with a progesterone antagonist during the luteal phase does not decrease or otherwise change the symptoms of PMS, even when progesterone levels are maintained by simultaneous treatment with hCG.56, 57 In women with PMS treated with a GnRH agonist, symptoms recur when exogenous estrogen or progesterone is added to the treatment regimen, but not in those receiving add-back placebo treatment, and not in normal women receiving the same treatment.58 Studies involving well-defined patient populations also have failed to demonstrate any differences in the levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, sex hormone-binding globulin, and aldosterone between women with and without symptoms of PMS, in any phase of the menstrual cycle.59 Taken together, these observations suggest that the symptoms of PMS are not caused directly by endocrine events during the luteal phase, but reflect an abnormal response to normal cyclic changes in ovarian steroid hormone levels.
The menstrual cycle is associated with significant changes in the opioid,60 gammaaminobutyric acid (GABA),61 and serotonin neurotransmitter systems,62 suggesting a possible pathophysiologic mechanism for PMS. Lower midcycle and luteal phase serum b-endorphin levels have been observed in women with PMS, compared to normal women.63,64 and 65 The anxiolytic actions of certain progesterone metabolites that act as ligands for the GABA-A receptor61 and the effectiveness of alprazolam (a short-acting benzodiazepine) in relieving symptoms of PMS66 suggest the disorder might involve a disturbance in the GABA-ergic system. However, studies comparing the levels of anxiolytic progesterone metabolites in women with and without PMS have observed no consistent differences.55, 67 Several lines of evidence suggest that the mood symptoms of PMS may relate to serotonin depletion. Whole blood serotonin concentrations and platelet serotonin uptake and imipramine binding (a marker of CNS binding and serotonergic activity) during the luteal phase are lower in women with PMS than in asymptomatic women.68,69,70,71 and 72 Symptoms of PMS are aggravated by acute dietary tryptophan depletion, which suppresses brain serotonin synthesis,73 and relieved by treatment with fenfluramine, a serotonin agonist,74 or fluoxetine, a serotonin reuptake inhibitor (SRI). Moreover, mood symptoms in women with PMDD receiving treatment with fluoxetine promptly return after treatment with metergoline, a serotonin antagonist.75 The weight of current evidence thus suggests strongly that PMS and PMDD result from an abnormal or exaggerated effect of cyclic changes in
ovarian steroid hormones on central neurotransmitter mechanisms and that serotonin, in particular, plays an important role in their pathophysiology.
ovarian steroid hormones on central neurotransmitter mechanisms and that serotonin, in particular, plays an important role in their pathophysiology.
In general, thyroid function is normal in women with PMS.76 Approximately 10% of women with PMS have demonstrably abnormal thyroid function, but the prevalence is not significantly different from that of subclinical hypothyroidism in the general population. Overall, the thyroid-stimulating hormone (TSH) response to thyroid-releasing hormone (TRH) is normal. Although abnormal responses (both exaggerated and blunted) are observed more often in women with PMS,77 they occur just as often during the follicular phase as in the luteal phase. Moreover, the effect of treatment with thyroxine is no different from that of placebo, even in patients with an abnormal response to TRH.
Several studies have found evidence to suggest that genetic factors might predispose to PMS and PMDD. A large twin study found that PMS was highly heritable, with environmental factors also contributing.78 The correlation between menstrual symptoms in mothers and daughters and between sisters suggests a genetic influence, but also might merely reflect a learned or conditioned response, at least to some extent.79, 80 Whereas many have speculated that differences in personality, stress levels, or coping mechanisms may play a role in PMS, there is little or no evidence to support the hypothesis.81,82 and 83
Some evidence suggests that women with PMS ingest more alcohol than others and that women with a family history of alcoholism exhibit more premenstrual anxiety and other behavioral symptoms, but a link between alcoholism and PMS has not been established.84, 85 Efforts to identify vitamin deficiencies in women with PMS have failed. Studies comparing serum levels of vitamin A and vitamin E in women with and without PMS have observed no significant differences.86, 87 The results of treatment with vitamin B6 generally are unimpressive and inconsistent.88, 89 A number of studies have found that intracellular magnesium concentrations are lower in women with PMS than in asymptomatic control women, but the significance of the observation remains unclear.90,91,92 and 93
Treatment
The key to effective treatment of PMS and PMDD is accurate diagnosis, which rests primarily on the collection of objective evidence that the patient’s symptoms are clearly cyclic, as documented by use of the COPE survey or other similar calendar-based screening tool over the interval spanning three menstrual cycles.
A number of medications have proven beneficial to women with PMS or PMDD, including SRIs,94, 95 alprazolam (a benzodiazepine),66, 96, 97 and GnRH agonists.51, 98 Accumulated evidence indicates that certain oral contraceptives,99,100 and 101 exercise,102, 103 relaxation techniques,104, 105 and spironolactone106,107,108 and 109 also have some value. Older treatment regimens involving progesterone or progestins,110,111,112,113 and 114 tricyclic antidepressants, monoamine oxidase inhibitors, lithium, evening primrose oil,115 essential free fatty acids,116 dietary restrictions, vitamin supplements, and ginkgo biloba generally are not effective.
The Placebo Response
The strange sounding word placebo derives from the Latin verb meaning “I shall please.” Clinicians and patients have been conditioned to observe a prescription ritual. Many patients seem to feel that their complaints are not taken seriously unless a medication is prescribed. However, placebo is more than a pill; it is a process.117
The process begins with confidence in the clinician and extends to the patient’s own healing system. Interaction with a clinician provides a better understanding of a patient’s symptoms, eliminates some unfounded fears, and offers hope for improvement. Many of the treatments for PMS that provide women with a greater sense of control, even simple measures such as changes in diet and lifestyle, can yield benefits. The very process of making detailed, prospective observations of events in life can improve one’s sense of self-control, which is intrinsically therapeutic.
Leon Eisenberg penned some very insightful thoughts regarding the placebo response, which plays a prominent role in the therapeutics of PMS and PMDD118:
So emphatically does the phrase “placebo response” discredit the psychosocial aspects of the therapeutic encounter that it may be time to eradicate it from our language. Let us replace it by some such term as “the response to care,” “the response to the doctor,” or “the healing response” in order to emphasize that it is (a) powerful, (b) no less “real” than drug actions, and (c) embedded in every therapeutic transaction… Its mechanisms are some compound of the arousal of hope, the comfort of reassurance, taking an active rather than a passive role in managing the illness experience, and reinterpreting the meaning of the illness… It is perverse that “placebo” has almost become an epithet implying charlatanism rather than a descriptor of a fundamental characteristic of medical practice… We ought equally to seek an understanding of the healing response rather than disdaining it, as the “hard” scientist does, or being deceived by it, as practitioners often are.
Treatments for Premenstrual Syndrome and Premenstrual Dysphoric Disorder | ||
Demonstrated Effective | Possibly Effective | Ineffective |
Serotonin reuptake inhibitors | Oral contraceptives | Progesterone |
Alprazolam | Diuretics | Vitamins |
GnRH agonists | Exercise | Dietary restrictions |
Serotonin Reuptake Inhibitors
There is substantial evidence for the effectiveness of SRIs in the treatment of PMS and PMDD.94, 95, 119 Fluoxetine, in a daily dose of 20 mg, has demonstrated sustained efficacy for relieving both somatic and mood symptoms, and generally is well-tolerated.120,121,122 and 123 Other SRIs also are effective, including sertraline (50-150 mg daily),124, 125 paroxetine (20-30 mg daily),126 and citalopram (20-30 mg daily).127 Venlafaxine (50-200 mg daily), which inhibits the reuptake of both serotonin and norepinephrine, also has efficacy,128 as do other antidepressants that inhibit serotonin reuptake or antagonize its action, such as clomipramine129, 130 and nefazodone.131
Although SRIs and related drugs are administered most commonly on a continuous daily basis, an intermittent treatment regimen limited to the luteal phase, or one beginning at the onset of symptoms, can be equally or more effective while offering the potential advantages of lower cost and fewer side effects.127, 130, 132, 133 In some clinical trials, treatment for as few as 3 days was effective.134, 135 However, some women require higher doses or continuous treatment to achieve benefit.136,137 and 138
Alprazolam
Alprazolam, a benzodiazepine, is another medication that may be useful in the treatment of PMS and PMDD,66, 96, 97 although its effectiveness may be limited to the relief of depressive symptoms. Because the drug also has addictive potential, it generally is considered a second-line agent and is best used only intermittently.
Gonadotropin-Releasing Hormone Agonists
The clinical utility of GnRH agonists in the treatment of PMS/PMDD was first demonstrated in 1984.139 Although now an established treatment,51, 98 GnRH agonists generally are more effective for relieving irritability and physical symptoms than for the treatment of prominent symptoms of depression or dysphoria.51, 140 GnRH agonist treatment is associated with the well-known symptoms of hypoestrogenism (e.g., hot flushes), which can be severe, and prolonged use invites longer-term consequences (bone mineral depletion).141 However, these limitations can be negated largely by simultaneous “add-back” treatment with low doses of estrogen or estrogen and progestin, which does not reduce the overall efficacy of GnRH agonist therapy.49, 142,143 and 144
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