- Email: [email protected]
Premenstrual disorders
Accepted Manuscript Premenstrual Disorders: An Expert Review Kimberly Ann Yonkers, M.D., Michael K. Simoni, M.D. PII:
S0002-9378(17)30674-9
DOI:
10.1016/j.ajog.2017.05.045
Reference:
YMOB 11692
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 18 April 2017 Revised Date:
15 May 2017
Accepted Date: 22 May 2017
Please cite this article as: Yonkers KA, Simoni MK, Premenstrual Disorders: An Expert Review, American Journal of Obstetrics and Gynecology (2017), doi: 10.1016/j.ajog.2017.05.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Premenstrual Disorders: An Expert Review
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Kimberly Ann Yonkers, M.D.1, 2,3, Michael K. Simoni, M.D.2
From the Departments of Psychiatry1, Obstetrics, Gynecology and Reproductive
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Sciences2, Epidemiology and Public Health3, at Yale University School of Medicine.
Please address correspondence to Dr. Yonkers at: 40 Temple Street, Suite 6B, New
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Haven, Connecticut, USA
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Fax: (203) 764-6766; E-mail: [email protected] Conflicts of Interests: Dr. Yonkers has received royalties from Up-To-Date and consulting fees from Marinus and Juniper Pharmaceuticals. Word Count: Abstract: 116 words, Body: 3328, 2 tables and 74 References
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Condensation: Premenstrual syndrome treatment selection depends upon presentation and patient preference; evidence supports use of serotonin reuptake
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Running Title: Premenstrual Disorders
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inhibitors and oral contraceptives with shortened hormone-free intervals.
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Abstract Premenstrual disorders include premenstrual syndrome, premenstrual dysphoric
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disorder and premenstrual worsening of another medical condition. While the underlying causes of these conditions continues to be explored, an aberrant response to hormonal fluctuations that occur with the natural menstrual cycle and serotonin deficits have both been implicated. A careful medical history and daily symptom-
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monitoring across two menstrual cycles is important in establishing a diagnosis. Many
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treatments have been evaluated for the management of premenstrual disorders. The most efficacious treatments for premenstrual syndrome and premenstrual dysphoric disorder include serotonin reuptake inhibitors and contraceptives with shortened to no hormone-free interval. Women who do not respond to these and other interventions
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may benefit from gonadotropin releasing hormone agonist treatment.
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Keywords: premenstrual syndrome, premenstrual dysphoric disorder, premenstrual tension, menstrual cycle, premenstrual disorder, premenstrual symptoms
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Introduction Dr. Robert Frank is commonly attributed to bringing medical attention to “premenstrual
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tension” through his case series published in 1931.1 He described women who experienced “tension” in conjunction with a variety of emotional symptoms and worsening of their concurrent medical conditions, during the few days prior to
menstruation. He posited a connection between “ovarian function…and other organic
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symptoms.” In their classic paper, Greene and Dalton argued for the term
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“premenstrual syndrome” because they felt candidate symptoms prior to the onset of menses were far more extensive than “tension” and could vary from mild to severe.2 As one fast forwards to current times, a lack of clarity continues with regard to the definition of premenstrual disorders although expert societies have coalesced in support of a framework that describes various premenstrual conditions. 3 This expert review
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Definitions
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provides an update on premenstrual conditions and their management.
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Premenstrual symptom severity varies from normative, mild premenstrual molimina, to severe and disabling symptoms. The American Psychiatric Association published criteria for a severe clinical syndrome, premenstrual dysphoric disorder (PMDD), in its Diagnostic and Statistical Manual 5 (see Table 1).4 This category describes women who have at least five, predominantly affective symptoms, in association with functional impairment. However, there are also women who experience distress and impairment but are either subthreshold for PMDD or have predominantly physical symptoms who
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are best considered to suffer from premenstrual syndrome (PMS). In this instance, criteria put forth by the International Society for Premenstrual Disorders (ISPMD) and the Royal College of Obstetricians and Gynaecologists, are helpful (see Table 2).
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These criteria are based upon the literature and opinion of experts who worked together over the past 10 years to harmonize definitions and subcategorize premenstrual
disorders. The criteria for PMS do not stipulate a minimum number of symptoms nor
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any particular symptom. The criteria for PMDD are more stringent than those for PMS and reflect the most severe end of the spectrum for premenstrual disorders. This also
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means a greater number of women are likely to meet criteria for PMS than PMDD (see below). However, PMS and PMDD criteria share features such as symptom expression during the luteal phase of the cycle with a symptom-free period, as well as functional impairment in association with the condition.3 Problems with recall bias5 led to
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recommendations that a menstrual calendar should prospectively document the timing, duration and severity of symptom expression. The ISPMD group also articulated “variant premenstrual disorders” such as premenstrual exacerbation of another medical
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condition and progestin-induced disorders, which likely have biological bases that differ from core premenstrual disorders.3 The framework devised by the ISPMD is useful in
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guiding treatment decisions.6 In this review, we use the term PMS to refer to both PMS and PMDD, unless the finding is specific to PMDD.
Many different emotional and physical symptoms are reported by women in the premenstrual period although the frequency of a handful of symptoms stands out. In a study that included a large community and a clinical cohort of women who prospectively
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recorded symptoms, the most problematic complaints were: bloating, mood swings, lethargy, irritability, breast-tenderness, anxiety/tension and fear of being rejected.7 Symptoms were the most severe the day before and first day of menses. DSM 5 criteria
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for PMDD reflects these findings, with the exception that physical complaints are
clustered into one item. A diagnosis of PMS can be made in the absence of severe emotional symptoms if the physical manifestations are sufficiently problematic to cause
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functional impairment.
Epidemiology
Community-based studies that could provide estimates of PMDD and PMS are difficult to conduct because retrospective reports of symptom timing, the most efficient manner
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of querying large groups of women, frequently differ from prospectively gathered data.5 Of the few available surveys that relied on concurrent collection of symptom reports in community populations, the point prevalence of PMS in menstruating women was
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between 20% and 30% 8, 9 while rates of PMDD ranged from 1.2%-6.4%.9-11 Retrospective data show that both PMS and PMDD are present in women across the
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globe.12
Risk Factors
Retrospective surveys from the United States show that PMS is more prevalent in whites than African American Women, similar to other psychiatric diseases that may be
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influenced by cultural differences.13, 14 Risk does not differ among various premenopausal age groups.15 Dietary factors are shown to moderate the risk of PMS, although this may reflect the confounding influence of positive health habits in general.
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High intake of thiamine, riboflavin, non-heme iron, and possibly zinc protect against, while high potassium intake may increase the risk of PMS.16 There is also evidence that adiposity and metabolic syndrome increase risk of PMS, particularly if women are
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over 27.5 kg/m2.17, 18 Other factors associated with the development of PMS include use of nicotine cigarettes17 and early sexual abuse and trauma.19, 20 It is also clear that
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comorbidity between depressive and/or anxiety disorders and PMS is high, although it is not clear whether these conditions predispose toward PMS, or whether PMS increases the likelihood of other conditions.21 PMS appears to be familial with concordance rates that are higher among monozygotic than dizygotic twins.22, 23 However, familial risk
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Etiopathology
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differs for PMS and common mood and anxiety disorders.22
Since PMS does not occur prior to menarche, in pregnancy or postmenopausal,
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exposure to changing levels of gonadal steroids is obligatory. While research has not supported a simple excess or deficit of a hormone, it appears that a woman’s response to hormonal changes can lead to symptom expression.24 A leading theory suggests that some women may have a pathological response to either withdrawal from25 or exposure to26 the progesterone metabolite, and gamma amino butyric acid (GABA) agonist, allopregnanolone. It is notable that blockage of allopregnanolone production
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reduces premenstrual symptoms 27, 28 and some serotonin reuptake inhibitors (SRIs), which are effective treatments for premenstrual disorders (see below), also effect
hormones would be beneficial per this theory.
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allopregnanolone levels.29 Treatments that eliminate cyclic changes in ovarian
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The classic and alternative but compelling view on the pathophysiology of premenstrual disorders suggests that the deficit lies in functioning of the serotonin system and
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especially, the serotonin transporter.30 The neurotransmitter serotonin is implicated in the pathophysiology of mood and anxiety disorders as well as PMS. Sex steroids and their receptors are abundant in many brain regions that regulate emotions and behavior, such as the amygdala, and they modulate serotonin transmission.31-33 In humans,
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premenstrual symptoms can be elicited by the depletion of serotonin’s precursor, tryptophan34 and by a serotonin receptor antagonist.35 An abundance of work also shows that indices of serotonergic transmission are dysregulated in women with PMS
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(cf. Yonkers et al36 for a review).
Direct exploration of brain functioning in women with and without premenstrual disorders have produced promising findings (cf Hantsoo et. Al. 37 and Comasco et al. 38). Sections of the frontal cortex exert “top-down” control on areas of the brain that receive and integrate emotional and physical input, such as the amygdala. Under appropriate hormonal conditions, differences in circuitry may lead women with PMS to have greater difficulty exerting sufficient top down control than women without premenstrual
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disorders;39, 40 this can lead to the expression of emotional symptoms, impulsivity and impaired executive function.41 Thus, treatments that stabilize emotional symptoms and
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impulsivity can be beneficial.
Evidence Based Treatments
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Treatments for PMS and PMDD fall into 4 main categories: 1) non-pharmacological approaches such as diet, exercise and psychotherapy; 2) psychotropic treatment; 3)
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hormonal agonists and antagonists; 4) vitamins and botanicals.
Non-Pharmacological Approaches: Many of these recommendations reflect positive
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health habits. Exercise, which stabilizes mood, may be helpful for mood and physical symptoms that occur premenstrually 42 but the evidence in support of this is minimal.6 There is stronger evidence, including a randomized clinical trial, that a complex
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carbohydrate diet during the luteal phase may help women with PMS presumably because this increases the amount of serotonin that is available centrally.43 Cognitive
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behavioral therapy (CBT) may be of benefit to women with PMS in that it can help women manage emotional symptoms. The most rigorous trial compared CBT to fluoxetine and found no difference between groups or additive effects of both CBT and fluoxetine. At follow-up, response to CBT was better maintained than fluoxetine but attrition was high (nearly 50%).44
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Serotonin Reuptake Inhibitors: The evidence supporting the efficacy of SRIs, administered either throughout the menstrual cycle or only during the second half of the menstrual cycle,45 is strong.46 Most studies followed criteria for PMDD although this
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class of agents is also helpful for women who are subthreshold for PMDD.47 SRI’s have a rapid onset of action for PMDD.48 An interesting implication from this is that different
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mechanisms may underly the efficacy of SRIs for PMDD compared with depression.
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Hormone Agonists and Antagonists: Even though combined oral contraceptives are commonly used as treatments for PMS, evidence in support of their efficacy is remarkably sparse. Rigorous clinical trials,49, 50 established that a combination oral contraceptive comprised of 3 mgs of the progestin drospirenone and 20 micrograms of
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ethinyl estradiol (Yaz®), taken for 24 days of a 28-day cycle is efficacious for PMDD. This oral contraceptive is approved to treat PMDD in women who desire contraception, however FDA warnings of risk for blood clots in drospirenone-containing birth control
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pills, should be considered. The shortened hormone free interval may be pivotal to the efficacy since a standard 21 day active treatment phase with these steroids was not
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effective51 while a second oral contraceptive, continuous daily levonorgestrel 90 micrograms/ethinyl estradiol 20 micrograms was helpful in a pivotal trial. 52 However, subsequent trials of daily levonorgestrel were less supportive53 and it may be the combination of the type of hormones and platform for administration that are responsible for efficacy. At this point, it is difficult to say that other oral contraceptives are effective for PMDD or PMS.
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The data in support of estrogen, either administered orally as ethynyl estradiol or via
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patch or implant is of poor quality; estrogen can also provoke symptoms in some women and can cause side effects.54 Similarly, progesterone has been advocated as a
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treatment for PMS but research in support of this treatment is of low quality.55
Gonadotropin-releasing hormones (GnRH) agonists, used in a continuous manner,
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suppress ovarian release of estrogen and ovulation leading to an improvement of PMS symptoms.56-58 Typical treatment in studies and practice is a monthly injection of leuprolide acetate 3.75 milligrams. The resulting hypoestrogenic state produces common adverse effects such as vaginitis, vasomotor symptoms and decrease in bone
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density. For this reason, and its high costs, GnRH agonist are usually reserved for
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severe cases of PMS, or as third line agents behind SSRI’s and oral contraceptives.
Surgery: Refractory symptoms may require surgical intervention of total hysterectomy
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with bilateral salpingo-ophorectomy to eliminate menstrual cyclicity. To ensure a patient would benefit from such a definitive treatment, GnRH agonists should be used to produce a similar effect to assess the benefit and tolerance of a hypoestrogenic state.
Complementary Medicines: The most frequently studied complementary medicines for PMS include Vitamin B-6 (pyridoxine), Vitex Agnus Castus (Chasteberry), St. Johns
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Wort, Gingko Biloba and Evening Primrose Oil. Vitamin B-6 has received the greatest amount of attention and has been the focus of 13 trials. A Cochrane quantitative review showed benefit of B-6 in doses up to 100 mgs per day but cautions that the quality of
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most studies was low.59 Peripheral neuropathy can occur with doses of 200 mgs/day or
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higher raising safety concerns.
Vitex Agnus Castus extract has been used to treat PMS in doses of 20-40 mgs/day,
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although preparations and amounts vary among studies. The compound binds to the dopamine-2 receptor, opioid receptor and β-estrogen receptor. The European Medicines Agency registered it as “well-established” use for PMS and a recent metaanalysis showed it was more effective than placebo in 17 trials.60 However, studies
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supporting its efficacy were generally of low quality and available preparations vary in quality and quantity of the extract. 6
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The Chinese plant Ginkgo biloba L. is primarily known for its antioxidant properties, but
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some data suggest it can treat several mental health disorders and improve memory. Its effect on stress and depressive symptoms and anti-inflammatory properties may be the basis for its effect. One placebo-controlled RCT administered Ginkgo three times per day to 85 women with PMS from the luteal phase through the beginning of menses.61 Physical and psychological effects were significantly reduced by the end of the first cycle of treatment.61
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Hypericum perforatum (St. John’s Wort) may alleviate PMS symptoms via its effects on neuromodulator synthesis. Common symptoms such as bloating, food cravings, headache and fatigue were significantly decreased with daily 900 milligram tablets in a
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double-blinded placebo-controlled randomized clinical trial consisting of 36 women.62
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Mood and physical symptoms involving pain remained unaffected.62
Calcium also influences neuromodulation and has been thus become a therapeutic
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target for PMS. Studies show low calcium in women with PMS and the possibility that women with PMS may have secondary hyperparathyroidism.63 Trials with supplemental calcium in dosages as low as 500 milligram daily in women who experience moderatesevere PMS have shown significant decrease in symptoms.64, 65 However, calcium
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treatment showed a smaller effect size than fluoxetine in one small study.66
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Management Recommendations
The first step in management of PMS is to accurately establish a diagnosis. This
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requires a careful medical, gynecological, and psychiatric history that would include information on diet and exercise. Laboratory tests, such as gonadal steroid levels, are not useful. Thyroid indices can be obtained if the clinician suspects thyroid dysfunction but this would not lead to expression of cyclical symptoms. Mood and anxiety disorders may underlie premenstrual complaints in many women and clinicians may be able to identify them with careful questioning. However, retrospective report of symptom offset with the beginning of menses may be inaccurate and diagnostic certainty is enhanced
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with a menstrual calendar. The prospective calendar of symptoms a patient keeps should include at least one, but ideally two menstrual cycles because some women have cycle-to-cycle variability. This recommendation should be balanced by the
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distress a woman is experiencing, which may preclude a delay in treatment initiation. Clinicians may devise a tailored calendar for their patient based upon what she
endorses as problematic symptoms. Symptoms should be assigned a severity score
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(eg. 1-5) each day. Alternatively, there are established calendars such as the Daily
(COPE)68 that patients may use.
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Record of Severity of Problems (DRSP) 67 or the Calendar of Premenstrual Experiences
After completion of menstrual calendars, women may show: 1) symptoms that began in
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the premenstrual phase and offset at the beginning of menses or shortly thereafter (PMS or PMDD); 2) ongoing symptoms that worsen during the premenstrual phase (premenstrual worsening of another condition); 3) continuous or sporadic symptoms not
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related to a phase of the menstrual cycle (neither PMS nor PMDD). Recommendations
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outlined below depend upon the results of such an evaluation.
Premenstrual symptoms limited to the premenstrual phase (PMS or PMDD) The Royal College of Obstetricians & Gynaecologists have published guidelines that are endorsed by the National Institute for Health Care Excellence (NICE) in the United Kingdom. First line treatments, per that guideline, include exercise, vitamin B-6 (100 mgs), CBT, oral contraceptives and intermittent or continuous SSRIs.6 If a woman has
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mild symptoms, a very short duration of symptoms or does not want to undergo treatment with an oral contraceptive or SRI, it is reasonable to commence treatment with diet (complex carbohydrates during the late luteal phase), exercise, 100 mgs B-6
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and calcium (1000 mgs daily). Women who do not want medication could also try a course of CBT that is typically delivered in about 12 sessions. Women who have
moderate to severe symptoms that lead to functional impairment or women who do not
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respond to these interventions are candidates for oral contraceptives or SRI treatment. The contraceptive with the strongest efficacy data for PMS and PMDD is a
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drosperinone/estrogen preparation with a shortened hormone free interval (24 on and 4 days off).69 Women who desire contraception are appropriate for this option. Women who are on another oral contraceptive and have premenstrual mood and anxiety symptoms may benefit from switch to a drosperinone/estradiol preparation with a
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shortened hormone-free interval or the addition of an SRI.70
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Women in the moderate to severe group who do not need contraception are candidates for treatment with a SRI. Patients with regular cycles who can predict the onset of
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symptoms, can try initiating medication at symptom onset48 or after ovulation.71 Women who have difficulty predicting the onset of symptoms or ovulation, or who have not fully responded to intermittent SRI treatment should consider daily treatment. Some evidence suggests that women who have severe physical symptoms may have a superior response to daily treatment rather than intermittent SRI treatment.46 Women who have not responded to drospirenone/estradiol should also consider an SRI.6 An SRI should be continued at least one and ideally two months. If a woman does not
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respond to an SRI at a recommended dose or if she is unable to tolerate it, another SRI
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may be tried before deciding that this class of medications is ineffective.
Women who do not respond to these first line interventions, may be candidates for
treatment with a GnRH agonist, which will end monthly cycles. Women sometimes
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experience clinical worsening at the initiation of this treatment and subsequently improve. If this is continued for at least six months, supplemental estrogen and
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progestin can be given as add-back therapy in order avoid side effects without any diminished effect of the treatment. Practitioners should aim to use the lowest dose possible of both hormones to provide symptom relief and to produce a withdrawal bleed, otherwise risk a recurrence of symptoms.72 If a woman is unable to tolerate systemic
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progestin, a levonorgestrol intrauterine device (IUD) can also be used with rare side effects, although there has not been a trial on this method. For those who experience PMS symptoms from any addition of progestin, some SRI’s are effective treatment for
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vasomotor symptoms. Tibolone, an androgen and progesterone agonist, was tested with 2.5 milligrams daily as add-back in a randomized clinical trial with thirty patients on
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leuprolide with significant improvement of symptoms vs placebo.73 It is important to use continuous rather than cyclic hormone suppression so to not mimic the hormone changes of the menstrual cycle. If this is successful, and the only method that improved the woman’s symptoms, and if she has completed child-bearing, surgical treatment may be indicated. It is critical that a trial of GnRH agonist treatment be conducted prior to consideration of surgical options.
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Ongoing symptoms that worsen in the premenstruum
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It is not uncommon for women to retrospectively report isolated premenstrual symptoms and then to show symptoms during the follicular phase that are not as severe. In this case, the underlying disorder requires treatment. If the underlying disorder is a chronic
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depressive or anxiety disorder, daily treatment with an SRI may be of benefit. If
premenstrual worsening of symptoms continues despite this treatment, health habits
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should be optimized with diet, exercise and the addition of B-6 and calcium. If that is not sufficient, the dose of SRI may be increased during the luteal phase or it may be combined with a drosperinone/estradiol product. Clinicians should monitor for worsening of mood if the contraceptive is added. GnRH agonists will not substantially
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benefit women with depressive symptoms during the follicular phase. 74
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Continuous or sporadic symptoms
Women who do not have a premenstrual symptom pattern should be managed for their
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underlying condition or referred to another clinician who can manage symptoms.
Conclusion
Premenstrual disorders vary in terms of the severity and timing of symptom onset. Treatments are well studied and include lifestyle changes for women with mild symptoms and use of a SRI or contraceptive with drosperinone/estradiol and shortened 17
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hormone free interval for women with moderate to severe premenstrual symptoms, including PMDD. Only a fraction of women will require use of a GnRH agonist or
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the absence of a GnRH trial that shows benefit.
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surgery. Surgical removal of uterus, tubes and ovaries should not be contemplated in
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PRIOR JC, VIGNA Y, SCIARRETTA D, ALOJADO N, SCHULZER M. Conditioning exercise decreases premenstrual symptoms: a prospective, controlled 6-month trial. Fertil Steril 1987;47:402-8.
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KORNSTEIN SG, PEARLSTEIN TB, FAYYAD R, FARFEL GM, GILLESPIE JA. Low-dose sertraline in the treatment of moderate-to-severe premenstrual syndrome: efficacy of 3 dosing strategies. Journal of Clinical Psychiatry 2006;67:1624-32. YONKERS KA, KORNSTEIN SG, GUEORGUIEVA R, MERRY B, VAN STEENBURGH K, ALTEMUS
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PEARLSTEIN TB, BACHMANN GA, ZACUR HA, YONKERS KA. Treatment of premenstrual
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YONKERS KA, BROWN C, PEARLSTEIN TB, FOEGH M, SAMPSON-LANDERS C, RAPKIN A. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005;106:492-501.
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HALBREICH U, FREEMAN EW, RAPKIN AJ, et al. Continuous oral levonorgestrel/ethinyl
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W YATT KM, DIMMOCK PW, ISMAIL KMK, JONES PW, O'BRIEN PMS. The effectiveness of GnRHa with and without ‘add-back’ therapy in treating premenstrual syndrome: a meta analysis. BJOG: An International Journal of Obstetrics & Gynaecology 2004;111:585-93. BROWN CS, LING FW, ANDERSEN RN, FARMER RG, ARHEART KL. Efficacy of depot
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Ginkgo biloba L. in treatment of premenstrual syndrome. Journal of alternative and complementary medicine (New York, NY) 2009;15:845-51. CANNING S, W ATERMAN M, ORSI N, AYRES J, SIMPSON N, DYE L. The efficacy of
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Hypericum perforatum (St John's wort) for the treatment of premenstrual syndrome: a
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Evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol Metab 1995;80(7):2227-32.
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THYS-JACOBS S, STARKEY P, BERNSTEIN D, TIAN J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. American Journal of Obstetrics and Gynecology 1998;179:444-52.
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SHOBEIRI F, ARASTE FE, EBRAHIMI R, JENABI E, NAZARI M. Effect of calcium on premenstrual syndrome: A double-blind randomized clinical trial. Obstetrics & gynecology science 2017;60:100-05. YONKERS KA, PEARLSTEIN TB, GOTMAN N. A pilot study to compare fluoxetine, calcium,
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MORTOLA JF, GIRTON L, BECK L, YEN SSC. Diagnosis of premenstrual syndrome by a
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simple, prospective, and reliable instrument: The Calendar of Premenstrual Experiences. Obstetrics and Gynecology Clinics of North America 1990;76:302-07. 69.
LOPEZ LM, KAPTEIN AA, HELMERHORST FM. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database of Systematic Reviews
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2012;2:CD006586.
YONKERS KA, CAMERON B, GUEORGUIEVA R, ALTEMUS M, KORNSTEIN SG. The Influence of Cyclic Hormonal Contraception on Expression of Premenstrual Syndrome. J Womens
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Health (Larchmt) 2016.
HALBREICH U, BERGERON R, YONKERS KA, FREEMAN E, STOUT AL, COHEN L. Efficacy of
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intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol 2002;100:1219-29.
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SEGEBLADH B, BORGSTROM A, NYBERG S, BIXO M, SUNDSTROM-POROMAA I. Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder. Am J Obstet Gynecol 2009;201:139.e1-8.
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73.
DI CARLO C, PALOMBA S, TOMMASELLI GA, GUIDA M, DI SPIEZIO SARDO A, NAPPI C. Use of leuprolide acetate plus tibolone in the treatment of severe premenstrual syndrome. Fertil Steril 2001;75:380-4.
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HAMMARBACK S, BACKSTROM T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo.
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74.
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TABLE 1: DSM 5 PREMENSTRUAL DYSPHORIC DISORDER* A. In most menstrual cycles, the following symptoms must be present in the final week before the onset of menses, start to improve within a few days after the onset of menses, and become minimal or absent in the week postmenses. At least one of the symptoms must be either (1), (2), (3), or (4) and the individual must experience at least five total symptoms: 1. marked affective lability (e.g., mood swings; feeling suddenly sad or tearful or increased sensitivity to rejection) 2. marked irritability or anger or increased interpersonal conflicts 3. marked depressed mood, feelings of hopelessness, or self-deprecating thoughts 4. marked anxiety, tension, feelings of being “keyed up,” or “on edge” 5. decreased interest in usual activities (e.g., work, school, friends, hobbies) 6. subjective difficulty in concentration 7. lethargy, easy fatigability, or marked lack of energy 8. marked change in appetite, overeating, or specific food cravings 9. hypersomnia or insomnia 10. a sense of being overwhelmed or out of control 11. physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of “bloating,” weight gain B. The symptoms are associated with clinically significant distress or interference with work, school, usual social activities, or relationships. C. The disturbance is not merely an exacerbation of the symptoms of another disorder. D. Criterion A should be confirmed by prospective daily ratings during at least two symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication or other treatment) or another medical condition (e.g., hyperthyroidism). * AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013
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Table 2: Premenstrual Syndrome*
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1) Physical and or emotional symptoms 2) Symptoms are present during the luteal phase and abate as menstruation begins 3) A symptom-free week 4) Symptoms are associated with significant impairment during the luteal phase
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*Definition is based upon the International Society for the Premenstrual Disorder Expert Consensus Group; O'BRIEN PMS, BACKSTROM T, BROWN C, et al. Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Archives of Women's Mental Health 2011;14:13-21.
29
S0002-9378(17)30674-9
DOI:
10.1016/j.ajog.2017.05.045
Reference:
YMOB 11692
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 18 April 2017 Revised Date:
15 May 2017
Accepted Date: 22 May 2017
Please cite this article as: Yonkers KA, Simoni MK, Premenstrual Disorders: An Expert Review, American Journal of Obstetrics and Gynecology (2017), doi: 10.1016/j.ajog.2017.05.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Premenstrual Disorders: An Expert Review
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Kimberly Ann Yonkers, M.D.1, 2,3, Michael K. Simoni, M.D.2
From the Departments of Psychiatry1, Obstetrics, Gynecology and Reproductive
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Sciences2, Epidemiology and Public Health3, at Yale University School of Medicine.
Please address correspondence to Dr. Yonkers at: 40 Temple Street, Suite 6B, New
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Haven, Connecticut, USA
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Fax: (203) 764-6766; E-mail: [email protected] Conflicts of Interests: Dr. Yonkers has received royalties from Up-To-Date and consulting fees from Marinus and Juniper Pharmaceuticals. Word Count: Abstract: 116 words, Body: 3328, 2 tables and 74 References
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Condensation: Premenstrual syndrome treatment selection depends upon presentation and patient preference; evidence supports use of serotonin reuptake
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Running Title: Premenstrual Disorders
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inhibitors and oral contraceptives with shortened hormone-free intervals.
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Abstract Premenstrual disorders include premenstrual syndrome, premenstrual dysphoric
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disorder and premenstrual worsening of another medical condition. While the underlying causes of these conditions continues to be explored, an aberrant response to hormonal fluctuations that occur with the natural menstrual cycle and serotonin deficits have both been implicated. A careful medical history and daily symptom-
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monitoring across two menstrual cycles is important in establishing a diagnosis. Many
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treatments have been evaluated for the management of premenstrual disorders. The most efficacious treatments for premenstrual syndrome and premenstrual dysphoric disorder include serotonin reuptake inhibitors and contraceptives with shortened to no hormone-free interval. Women who do not respond to these and other interventions
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may benefit from gonadotropin releasing hormone agonist treatment.
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Keywords: premenstrual syndrome, premenstrual dysphoric disorder, premenstrual tension, menstrual cycle, premenstrual disorder, premenstrual symptoms
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Introduction Dr. Robert Frank is commonly attributed to bringing medical attention to “premenstrual
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tension” through his case series published in 1931.1 He described women who experienced “tension” in conjunction with a variety of emotional symptoms and worsening of their concurrent medical conditions, during the few days prior to
menstruation. He posited a connection between “ovarian function…and other organic
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symptoms.” In their classic paper, Greene and Dalton argued for the term
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“premenstrual syndrome” because they felt candidate symptoms prior to the onset of menses were far more extensive than “tension” and could vary from mild to severe.2 As one fast forwards to current times, a lack of clarity continues with regard to the definition of premenstrual disorders although expert societies have coalesced in support of a framework that describes various premenstrual conditions. 3 This expert review
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Definitions
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provides an update on premenstrual conditions and their management.
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Premenstrual symptom severity varies from normative, mild premenstrual molimina, to severe and disabling symptoms. The American Psychiatric Association published criteria for a severe clinical syndrome, premenstrual dysphoric disorder (PMDD), in its Diagnostic and Statistical Manual 5 (see Table 1).4 This category describes women who have at least five, predominantly affective symptoms, in association with functional impairment. However, there are also women who experience distress and impairment but are either subthreshold for PMDD or have predominantly physical symptoms who
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are best considered to suffer from premenstrual syndrome (PMS). In this instance, criteria put forth by the International Society for Premenstrual Disorders (ISPMD) and the Royal College of Obstetricians and Gynaecologists, are helpful (see Table 2).
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These criteria are based upon the literature and opinion of experts who worked together over the past 10 years to harmonize definitions and subcategorize premenstrual
disorders. The criteria for PMS do not stipulate a minimum number of symptoms nor
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any particular symptom. The criteria for PMDD are more stringent than those for PMS and reflect the most severe end of the spectrum for premenstrual disorders. This also
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means a greater number of women are likely to meet criteria for PMS than PMDD (see below). However, PMS and PMDD criteria share features such as symptom expression during the luteal phase of the cycle with a symptom-free period, as well as functional impairment in association with the condition.3 Problems with recall bias5 led to
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recommendations that a menstrual calendar should prospectively document the timing, duration and severity of symptom expression. The ISPMD group also articulated “variant premenstrual disorders” such as premenstrual exacerbation of another medical
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condition and progestin-induced disorders, which likely have biological bases that differ from core premenstrual disorders.3 The framework devised by the ISPMD is useful in
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guiding treatment decisions.6 In this review, we use the term PMS to refer to both PMS and PMDD, unless the finding is specific to PMDD.
Many different emotional and physical symptoms are reported by women in the premenstrual period although the frequency of a handful of symptoms stands out. In a study that included a large community and a clinical cohort of women who prospectively
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recorded symptoms, the most problematic complaints were: bloating, mood swings, lethargy, irritability, breast-tenderness, anxiety/tension and fear of being rejected.7 Symptoms were the most severe the day before and first day of menses. DSM 5 criteria
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for PMDD reflects these findings, with the exception that physical complaints are
clustered into one item. A diagnosis of PMS can be made in the absence of severe emotional symptoms if the physical manifestations are sufficiently problematic to cause
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functional impairment.
Epidemiology
Community-based studies that could provide estimates of PMDD and PMS are difficult to conduct because retrospective reports of symptom timing, the most efficient manner
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of querying large groups of women, frequently differ from prospectively gathered data.5 Of the few available surveys that relied on concurrent collection of symptom reports in community populations, the point prevalence of PMS in menstruating women was
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between 20% and 30% 8, 9 while rates of PMDD ranged from 1.2%-6.4%.9-11 Retrospective data show that both PMS and PMDD are present in women across the
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globe.12
Risk Factors
Retrospective surveys from the United States show that PMS is more prevalent in whites than African American Women, similar to other psychiatric diseases that may be
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influenced by cultural differences.13, 14 Risk does not differ among various premenopausal age groups.15 Dietary factors are shown to moderate the risk of PMS, although this may reflect the confounding influence of positive health habits in general.
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High intake of thiamine, riboflavin, non-heme iron, and possibly zinc protect against, while high potassium intake may increase the risk of PMS.16 There is also evidence that adiposity and metabolic syndrome increase risk of PMS, particularly if women are
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over 27.5 kg/m2.17, 18 Other factors associated with the development of PMS include use of nicotine cigarettes17 and early sexual abuse and trauma.19, 20 It is also clear that
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comorbidity between depressive and/or anxiety disorders and PMS is high, although it is not clear whether these conditions predispose toward PMS, or whether PMS increases the likelihood of other conditions.21 PMS appears to be familial with concordance rates that are higher among monozygotic than dizygotic twins.22, 23 However, familial risk
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Etiopathology
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differs for PMS and common mood and anxiety disorders.22
Since PMS does not occur prior to menarche, in pregnancy or postmenopausal,
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exposure to changing levels of gonadal steroids is obligatory. While research has not supported a simple excess or deficit of a hormone, it appears that a woman’s response to hormonal changes can lead to symptom expression.24 A leading theory suggests that some women may have a pathological response to either withdrawal from25 or exposure to26 the progesterone metabolite, and gamma amino butyric acid (GABA) agonist, allopregnanolone. It is notable that blockage of allopregnanolone production
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reduces premenstrual symptoms 27, 28 and some serotonin reuptake inhibitors (SRIs), which are effective treatments for premenstrual disorders (see below), also effect
hormones would be beneficial per this theory.
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allopregnanolone levels.29 Treatments that eliminate cyclic changes in ovarian
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The classic and alternative but compelling view on the pathophysiology of premenstrual disorders suggests that the deficit lies in functioning of the serotonin system and
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especially, the serotonin transporter.30 The neurotransmitter serotonin is implicated in the pathophysiology of mood and anxiety disorders as well as PMS. Sex steroids and their receptors are abundant in many brain regions that regulate emotions and behavior, such as the amygdala, and they modulate serotonin transmission.31-33 In humans,
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premenstrual symptoms can be elicited by the depletion of serotonin’s precursor, tryptophan34 and by a serotonin receptor antagonist.35 An abundance of work also shows that indices of serotonergic transmission are dysregulated in women with PMS
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(cf. Yonkers et al36 for a review).
Direct exploration of brain functioning in women with and without premenstrual disorders have produced promising findings (cf Hantsoo et. Al. 37 and Comasco et al. 38). Sections of the frontal cortex exert “top-down” control on areas of the brain that receive and integrate emotional and physical input, such as the amygdala. Under appropriate hormonal conditions, differences in circuitry may lead women with PMS to have greater difficulty exerting sufficient top down control than women without premenstrual
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disorders;39, 40 this can lead to the expression of emotional symptoms, impulsivity and impaired executive function.41 Thus, treatments that stabilize emotional symptoms and
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impulsivity can be beneficial.
Evidence Based Treatments
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Treatments for PMS and PMDD fall into 4 main categories: 1) non-pharmacological approaches such as diet, exercise and psychotherapy; 2) psychotropic treatment; 3)
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hormonal agonists and antagonists; 4) vitamins and botanicals.
Non-Pharmacological Approaches: Many of these recommendations reflect positive
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health habits. Exercise, which stabilizes mood, may be helpful for mood and physical symptoms that occur premenstrually 42 but the evidence in support of this is minimal.6 There is stronger evidence, including a randomized clinical trial, that a complex
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carbohydrate diet during the luteal phase may help women with PMS presumably because this increases the amount of serotonin that is available centrally.43 Cognitive
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behavioral therapy (CBT) may be of benefit to women with PMS in that it can help women manage emotional symptoms. The most rigorous trial compared CBT to fluoxetine and found no difference between groups or additive effects of both CBT and fluoxetine. At follow-up, response to CBT was better maintained than fluoxetine but attrition was high (nearly 50%).44
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Serotonin Reuptake Inhibitors: The evidence supporting the efficacy of SRIs, administered either throughout the menstrual cycle or only during the second half of the menstrual cycle,45 is strong.46 Most studies followed criteria for PMDD although this
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class of agents is also helpful for women who are subthreshold for PMDD.47 SRI’s have a rapid onset of action for PMDD.48 An interesting implication from this is that different
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mechanisms may underly the efficacy of SRIs for PMDD compared with depression.
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Hormone Agonists and Antagonists: Even though combined oral contraceptives are commonly used as treatments for PMS, evidence in support of their efficacy is remarkably sparse. Rigorous clinical trials,49, 50 established that a combination oral contraceptive comprised of 3 mgs of the progestin drospirenone and 20 micrograms of
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ethinyl estradiol (Yaz®), taken for 24 days of a 28-day cycle is efficacious for PMDD. This oral contraceptive is approved to treat PMDD in women who desire contraception, however FDA warnings of risk for blood clots in drospirenone-containing birth control
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pills, should be considered. The shortened hormone free interval may be pivotal to the efficacy since a standard 21 day active treatment phase with these steroids was not
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effective51 while a second oral contraceptive, continuous daily levonorgestrel 90 micrograms/ethinyl estradiol 20 micrograms was helpful in a pivotal trial. 52 However, subsequent trials of daily levonorgestrel were less supportive53 and it may be the combination of the type of hormones and platform for administration that are responsible for efficacy. At this point, it is difficult to say that other oral contraceptives are effective for PMDD or PMS.
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The data in support of estrogen, either administered orally as ethynyl estradiol or via
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patch or implant is of poor quality; estrogen can also provoke symptoms in some women and can cause side effects.54 Similarly, progesterone has been advocated as a
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treatment for PMS but research in support of this treatment is of low quality.55
Gonadotropin-releasing hormones (GnRH) agonists, used in a continuous manner,
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suppress ovarian release of estrogen and ovulation leading to an improvement of PMS symptoms.56-58 Typical treatment in studies and practice is a monthly injection of leuprolide acetate 3.75 milligrams. The resulting hypoestrogenic state produces common adverse effects such as vaginitis, vasomotor symptoms and decrease in bone
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density. For this reason, and its high costs, GnRH agonist are usually reserved for
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severe cases of PMS, or as third line agents behind SSRI’s and oral contraceptives.
Surgery: Refractory symptoms may require surgical intervention of total hysterectomy
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with bilateral salpingo-ophorectomy to eliminate menstrual cyclicity. To ensure a patient would benefit from such a definitive treatment, GnRH agonists should be used to produce a similar effect to assess the benefit and tolerance of a hypoestrogenic state.
Complementary Medicines: The most frequently studied complementary medicines for PMS include Vitamin B-6 (pyridoxine), Vitex Agnus Castus (Chasteberry), St. Johns
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Wort, Gingko Biloba and Evening Primrose Oil. Vitamin B-6 has received the greatest amount of attention and has been the focus of 13 trials. A Cochrane quantitative review showed benefit of B-6 in doses up to 100 mgs per day but cautions that the quality of
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most studies was low.59 Peripheral neuropathy can occur with doses of 200 mgs/day or
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higher raising safety concerns.
Vitex Agnus Castus extract has been used to treat PMS in doses of 20-40 mgs/day,
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although preparations and amounts vary among studies. The compound binds to the dopamine-2 receptor, opioid receptor and β-estrogen receptor. The European Medicines Agency registered it as “well-established” use for PMS and a recent metaanalysis showed it was more effective than placebo in 17 trials.60 However, studies
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supporting its efficacy were generally of low quality and available preparations vary in quality and quantity of the extract. 6
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The Chinese plant Ginkgo biloba L. is primarily known for its antioxidant properties, but
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some data suggest it can treat several mental health disorders and improve memory. Its effect on stress and depressive symptoms and anti-inflammatory properties may be the basis for its effect. One placebo-controlled RCT administered Ginkgo three times per day to 85 women with PMS from the luteal phase through the beginning of menses.61 Physical and psychological effects were significantly reduced by the end of the first cycle of treatment.61
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Hypericum perforatum (St. John’s Wort) may alleviate PMS symptoms via its effects on neuromodulator synthesis. Common symptoms such as bloating, food cravings, headache and fatigue were significantly decreased with daily 900 milligram tablets in a
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double-blinded placebo-controlled randomized clinical trial consisting of 36 women.62
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Mood and physical symptoms involving pain remained unaffected.62
Calcium also influences neuromodulation and has been thus become a therapeutic
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target for PMS. Studies show low calcium in women with PMS and the possibility that women with PMS may have secondary hyperparathyroidism.63 Trials with supplemental calcium in dosages as low as 500 milligram daily in women who experience moderatesevere PMS have shown significant decrease in symptoms.64, 65 However, calcium
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treatment showed a smaller effect size than fluoxetine in one small study.66
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Management Recommendations
The first step in management of PMS is to accurately establish a diagnosis. This
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requires a careful medical, gynecological, and psychiatric history that would include information on diet and exercise. Laboratory tests, such as gonadal steroid levels, are not useful. Thyroid indices can be obtained if the clinician suspects thyroid dysfunction but this would not lead to expression of cyclical symptoms. Mood and anxiety disorders may underlie premenstrual complaints in many women and clinicians may be able to identify them with careful questioning. However, retrospective report of symptom offset with the beginning of menses may be inaccurate and diagnostic certainty is enhanced
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with a menstrual calendar. The prospective calendar of symptoms a patient keeps should include at least one, but ideally two menstrual cycles because some women have cycle-to-cycle variability. This recommendation should be balanced by the
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distress a woman is experiencing, which may preclude a delay in treatment initiation. Clinicians may devise a tailored calendar for their patient based upon what she
endorses as problematic symptoms. Symptoms should be assigned a severity score
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(eg. 1-5) each day. Alternatively, there are established calendars such as the Daily
(COPE)68 that patients may use.
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Record of Severity of Problems (DRSP) 67 or the Calendar of Premenstrual Experiences
After completion of menstrual calendars, women may show: 1) symptoms that began in
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the premenstrual phase and offset at the beginning of menses or shortly thereafter (PMS or PMDD); 2) ongoing symptoms that worsen during the premenstrual phase (premenstrual worsening of another condition); 3) continuous or sporadic symptoms not
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related to a phase of the menstrual cycle (neither PMS nor PMDD). Recommendations
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outlined below depend upon the results of such an evaluation.
Premenstrual symptoms limited to the premenstrual phase (PMS or PMDD) The Royal College of Obstetricians & Gynaecologists have published guidelines that are endorsed by the National Institute for Health Care Excellence (NICE) in the United Kingdom. First line treatments, per that guideline, include exercise, vitamin B-6 (100 mgs), CBT, oral contraceptives and intermittent or continuous SSRIs.6 If a woman has
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mild symptoms, a very short duration of symptoms or does not want to undergo treatment with an oral contraceptive or SRI, it is reasonable to commence treatment with diet (complex carbohydrates during the late luteal phase), exercise, 100 mgs B-6
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and calcium (1000 mgs daily). Women who do not want medication could also try a course of CBT that is typically delivered in about 12 sessions. Women who have
moderate to severe symptoms that lead to functional impairment or women who do not
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respond to these interventions are candidates for oral contraceptives or SRI treatment. The contraceptive with the strongest efficacy data for PMS and PMDD is a
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drosperinone/estrogen preparation with a shortened hormone free interval (24 on and 4 days off).69 Women who desire contraception are appropriate for this option. Women who are on another oral contraceptive and have premenstrual mood and anxiety symptoms may benefit from switch to a drosperinone/estradiol preparation with a
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shortened hormone-free interval or the addition of an SRI.70
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Women in the moderate to severe group who do not need contraception are candidates for treatment with a SRI. Patients with regular cycles who can predict the onset of
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symptoms, can try initiating medication at symptom onset48 or after ovulation.71 Women who have difficulty predicting the onset of symptoms or ovulation, or who have not fully responded to intermittent SRI treatment should consider daily treatment. Some evidence suggests that women who have severe physical symptoms may have a superior response to daily treatment rather than intermittent SRI treatment.46 Women who have not responded to drospirenone/estradiol should also consider an SRI.6 An SRI should be continued at least one and ideally two months. If a woman does not
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respond to an SRI at a recommended dose or if she is unable to tolerate it, another SRI
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may be tried before deciding that this class of medications is ineffective.
Women who do not respond to these first line interventions, may be candidates for
treatment with a GnRH agonist, which will end monthly cycles. Women sometimes
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experience clinical worsening at the initiation of this treatment and subsequently improve. If this is continued for at least six months, supplemental estrogen and
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progestin can be given as add-back therapy in order avoid side effects without any diminished effect of the treatment. Practitioners should aim to use the lowest dose possible of both hormones to provide symptom relief and to produce a withdrawal bleed, otherwise risk a recurrence of symptoms.72 If a woman is unable to tolerate systemic
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progestin, a levonorgestrol intrauterine device (IUD) can also be used with rare side effects, although there has not been a trial on this method. For those who experience PMS symptoms from any addition of progestin, some SRI’s are effective treatment for
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vasomotor symptoms. Tibolone, an androgen and progesterone agonist, was tested with 2.5 milligrams daily as add-back in a randomized clinical trial with thirty patients on
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leuprolide with significant improvement of symptoms vs placebo.73 It is important to use continuous rather than cyclic hormone suppression so to not mimic the hormone changes of the menstrual cycle. If this is successful, and the only method that improved the woman’s symptoms, and if she has completed child-bearing, surgical treatment may be indicated. It is critical that a trial of GnRH agonist treatment be conducted prior to consideration of surgical options.
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Ongoing symptoms that worsen in the premenstruum
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It is not uncommon for women to retrospectively report isolated premenstrual symptoms and then to show symptoms during the follicular phase that are not as severe. In this case, the underlying disorder requires treatment. If the underlying disorder is a chronic
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depressive or anxiety disorder, daily treatment with an SRI may be of benefit. If
premenstrual worsening of symptoms continues despite this treatment, health habits
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should be optimized with diet, exercise and the addition of B-6 and calcium. If that is not sufficient, the dose of SRI may be increased during the luteal phase or it may be combined with a drosperinone/estradiol product. Clinicians should monitor for worsening of mood if the contraceptive is added. GnRH agonists will not substantially
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benefit women with depressive symptoms during the follicular phase. 74
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Continuous or sporadic symptoms
Women who do not have a premenstrual symptom pattern should be managed for their
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underlying condition or referred to another clinician who can manage symptoms.
Conclusion
Premenstrual disorders vary in terms of the severity and timing of symptom onset. Treatments are well studied and include lifestyle changes for women with mild symptoms and use of a SRI or contraceptive with drosperinone/estradiol and shortened 17
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hormone free interval for women with moderate to severe premenstrual symptoms, including PMDD. Only a fraction of women will require use of a GnRH agonist or
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the absence of a GnRH trial that shows benefit.
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surgery. Surgical removal of uterus, tubes and ovaries should not be contemplated in
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TABLE 1: DSM 5 PREMENSTRUAL DYSPHORIC DISORDER* A. In most menstrual cycles, the following symptoms must be present in the final week before the onset of menses, start to improve within a few days after the onset of menses, and become minimal or absent in the week postmenses. At least one of the symptoms must be either (1), (2), (3), or (4) and the individual must experience at least five total symptoms: 1. marked affective lability (e.g., mood swings; feeling suddenly sad or tearful or increased sensitivity to rejection) 2. marked irritability or anger or increased interpersonal conflicts 3. marked depressed mood, feelings of hopelessness, or self-deprecating thoughts 4. marked anxiety, tension, feelings of being “keyed up,” or “on edge” 5. decreased interest in usual activities (e.g., work, school, friends, hobbies) 6. subjective difficulty in concentration 7. lethargy, easy fatigability, or marked lack of energy 8. marked change in appetite, overeating, or specific food cravings 9. hypersomnia or insomnia 10. a sense of being overwhelmed or out of control 11. physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of “bloating,” weight gain B. The symptoms are associated with clinically significant distress or interference with work, school, usual social activities, or relationships. C. The disturbance is not merely an exacerbation of the symptoms of another disorder. D. Criterion A should be confirmed by prospective daily ratings during at least two symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication or other treatment) or another medical condition (e.g., hyperthyroidism). * AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013
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Table 2: Premenstrual Syndrome*
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1) Physical and or emotional symptoms 2) Symptoms are present during the luteal phase and abate as menstruation begins 3) A symptom-free week 4) Symptoms are associated with significant impairment during the luteal phase
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*Definition is based upon the International Society for the Premenstrual Disorder Expert Consensus Group; O'BRIEN PMS, BACKSTROM T, BROWN C, et al. Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Archives of Women's Mental Health 2011;14:13-21.
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