PMD category
Symptom characteristics
Core PMD
Occur in ovulatory cycles
Type not specified—may be somatic and/or psychological
Number not specified
Absent after menstruation and before ovulation
Recur in the luteal phase of the cycle
Prospectively rated for two cycles
Cause significant impairment (work, school, hobbies, interpersonal relationships, distress)
Variant PMD
PMD due to nonovulatory ovarian activity
Symptoms arise from ovarian activity other than those of ovulation (rare)
Premenstrual exacerbation
Symptoms of an underlying psychological or somatic disorder significantly worsen premenstrually
Progestogen-induced PMD
Symptoms result from exogenous progestogen administration
PMD with absent menstruation
Symptoms arise from continued ovarian activity though menstruation is suppressed/eliminated
10.4.3.1 Core Premenstrual Disorders
Core PMD is characterized by:
Symptoms occur in ovulatory cycles.
Symptoms are not specified—somatic and/or psychological.
Number of symptoms not specified.
Symptoms are absent after menstruation and before ovulation (i.e., there is no underlying disorder).
Symptoms must recur in the luteal phase.
Symptoms must be prospectively rated for a minimum of 2 menstrual cycles.
Symptoms must cause significant distress and/or impairment in work, school, social, and interpersonal roles.
See DSM-5 [1] for the diagnostic criteria for premenstrual dysphoric disorder (PMDD).
10.4.3.2 Variant Premenstrual Disorders
Variant PMD includes four subtypes (Table 10.1) [2]:
Premenstrual exacerbation (of an underlying psychological or somatic disorder).
PMD with absent menstruation, which occurs in women whose ovarian cyclicity is maintained but menstruation has been suppressed or eliminated by: (1) hysterectomy (with ovarian conservation), (2) endometrial ablation, or (3) endometrial suppression with intrauterine progestogen-containing contraceptive systems.
Progestogen-induced PMD (from exogenous progestogen administration).
PMD due to nonovulatory ovarian activity—this classification is poorly defined, and there are no clear mechanisms by which this occurs.
10.5 Etiology and Pathogenesis
10.5.1 What Are Some of the Pathogenetic Theories of Premenstrual Disorder?
There is no known exact cause of PMDs and the etiology is assumed to be multifactorial. Fluctuations in sex steroids are presumed to be involved in the pathogenesis of symptoms of PMD due to the appearance of symptoms during the luteal phase; the absence of symptoms with ovulation suppression, in anovulatory cycles, and after ovariectomy; and the induction of premenstrual symptoms by exogenous hormone administration in susceptible women [3]. Studies have consistently not demonstrated abnormalities in follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, or progesterone levels in women with PMDs compared to control women.
PMD is thought to involve altered serotonin activity, which could influence mood, aggression, and modulation of sex-steroid-driven behavior. Evidences for this etiological theory include: (1) effectiveness of serotonin-enhancing treatment such as selective serotonin reuptake inhibitors, (2) provocation of premenstrual symptoms with decrease in serotonin transmission, and (3) altered indices of serotonergic transmission in women with PMDs.
Allopregnanolone is a metabolite of progesterone that is a positive modulator of the gamma-aminobutyric acid (GABA) inhibitory neurotransmitter system. PMD may involve altered allopregnanolone or GABA levels during the luteal phase and possible reduced sensitivity of the GABAA receptor to allopregnanolone (and its anxiolytic effects) during the luteal phase.
Neuroimaging studies have suggested altered brain neurocircuitry in women with PMDs with abnormal patterns of activation or excitability in the dorsolateral prefrontal cortex and cerebellum, decreased top-down control, and dysregulation in working memory neural circuitry compared with healthy controls. There have also been reports of increased reactivity to negative or emotional social stimuli during the luteal phase and an increased acoustic startle response in women with PMD.
Other systems that have been theorized to be involved include calcium, altered circadian rhythms, noradrenergic neurotransmission, beta-endorphins, and brain-derived neurotrophic factor.
10.5.1.1 Risk Factors
Previous major depressive disorder has been reported as a risk factor in several studies. Some studies also report previous postpartum depression.
Possible other risk factors include interpersonal trauma history, current stress, and seasonal changes.
Heritability for premenstrual symptoms ranges between 30 and 80 %.
10.5.1.2 Onset Characteristics
Onset of moderate to severe premenstrual symptoms can occur at any point after menarche.
Prevalence of PMD and severity of symptoms may vary from adolescence through perimenopause, but this has not been well studied.
Premenstrual disorders occur in multiple cultures. Some cultures report a preponderance of somatic symptoms compared to emotional symptoms. Seeking treatment is influenced by cultural factors.
10.5.1.3 Working Model
Premenstrual symptoms occur during ovulatory cycles and likely involve a differential sensitivity to exposure and/or withdrawal of circulating ovarian sex steroids. Levels of ovarian sex steroids are generally normal in women with PMDs. Both abnormalities in serotonergic transmission and reduced sensitivity of the GABAA receptor during the luteal phase to allopregnanolone are likely etiological factors. It has been postulated that the serotonin reuptake inhibitor antidepressants may be effective both by increasing serotonin synaptic availability as well as increasing the availability of allopregnanolone [4]. It also has been postulated that the rapid action of antidepressants in PMD may involve the interaction of serotonin and estrogen receptors and response. The evidence for these theories is largely indirect (peripheral, not central nervous system [CNS], levels) to date.
Suppression of ovulation will precisely eliminate symptoms in women with core PMD. However, gonadotropin-releasing hormone (GnRH) analogues eliminate all ovarian sex steroids markedly, so the efficacy is not conclusively the result of suppression of ovulatory progesterone or its metabolites. Anecdotally, “add-back” estrogen (without the normally required) progestogen appears to maintain symptom suppression in many women. Administration of progestogen during hormone replacement can frequently result in the generation or regeneration of “PMS-like” symptoms (progestogen-induced PMD; see Table 10.1).
10.6 Specific Diagnostic Aspects
10.6.1 What Diagnostic Tool Is Confirmatory for Diagnosis of a Premenstrual Disorder (PMD)?
Diagnosis is made by clinical interview and review of prospective charting of mood, behavioral, and physical symptoms for two symptomatic menstrual cycles. The prospective charting allows the clinician and patient to confirm the specifics, severity, and timing of the premenstrual symptoms and the assessment of any underlying symptoms during the follicular phase. In some cases, the charting allows the clinician to demonstrate to the patient the noncyclical nature of symptoms, which can lead to an alternative diagnosis and workup. Several rating forms exist for prospective ratings, e.g., Daily Record of Severity of Problems (Fig. 10.1) [5] or the Visual Analogue Scales for Premenstrual Mood Symptoms [6].
Fig. 10.1
Daily Record of Severity of Problems (DRSP) (Used with permission from Endicott et al. [5] Copyright J Endicott, W. Harrison)
Medical disorders that should be considered in the differential diagnosis include dysmenorrhea, endometriosis, polycystic ovary disease, thyroid disorders, adrenal system disorders, hyperprolactinemia, and panhypopituitarism. It is also possible that women on oral contraceptives or other hormones (including hormone replacement therapy [HRT]) have induced premenstrual symptoms. Symptom reassessment following discontinuation of the hormone may be indicated, with discussion about possible need for alternative contraception.
Psychiatric disorders that should be considered in the differential diagnosis include major depressive disorder, persistent depressive disorder (dysthymia), bipolar disorder, panic disorder, generalized anxiety disorder, and personality disorder.
If symptoms are present through the follicular phase and are exacerbated during the luteal phase, the woman is considered to have premenstrual exacerbation of an underlying disorder. Conditions that may exhibit premenstrual exacerbation include mood and anxiety disorders, substance misuse, binge eating, migraines, asthma, epilepsy, irritable bowel syndrome, chronic fatigue syndrome, allergies, and autoimmune disorders. The underlying condition should be treated first, and then patients can chart their symptoms again if they feel premenstrual symptoms are still problematic.
If a core premenstrual disorder is confirmed by prospective charting, treatment options can be discussed. Since there are few predictors of response to treatment type, women should be informed about nonpharmacological strategies, antidepressant medications, and hormonal strategies that suppress ovulation.
10.6.2 Indication Phase
Indications for treatment of premenstrual symptoms are the symptoms causing distress for women or interfering with relationships and role functioning.
Some women prefer to pursue nonpharmacological strategies first. If these strategies are not beneficial, there is an indication for antidepressant medication or a hormonal strategy to suppress ovulation.
10.6.3 Informed Consent Phase
Women with a premenstrual disorder should be informed that there are dietary, herbal, and other nonpharmacological treatment options that can be tried prior to taking psychotropic or hormonal medication. When women choose pharmacological options, since there are no studies predicting treatment response, the choice of antidepressant versus hormonal strategy is generally individually determined.
Side effects with antidepressants include nausea, fatigue, decreased energy, sweating, and decreased libido. Long-term side effects that can be problematic include weight gain, decreased libido, and delayed orgasm. Intermittent dosing may decrease side effect burden, but this has not been systematically studied.
Women who may become pregnant should be counseled about the risks with antidepressants during pregnancy. Tapering and discontinuing the antidepressant (if clinically appropriate) should occur once the pregnancy is confirmed to limit the duration of fetal exposure to the medication. Women planning to conceive should not choose paroxetine as first-line treatment or other antidepressants with minimal safety data.
Women choosing to take an oral contraceptive should be counseled about the usual potential side effects. Oral contraceptive medications containing drospirenone may be differentially more effective for PMD, but they have an increased risk of venous thromboembolism.
Ovulation suppression with estrogen needs uterus protection with a progestogen (systemic or intrauterine). However, the progestogen carries the risk of regeneration of premenstrual symptoms.
GnRH agonists and hysterectomy and bilateral salpingo-oophorectomy need hormone replacement (“add-back”) strategy or medication for bone health.
Benzodiazepines may cause sedation and should not be a first-line option in women with a substance misuse disorder.
Doses of vitamin B6 in excess of 200 mg daily may cause peripheral neuropathy.
10.7 Specific Therapeutic Aspects
10.7.1 Treatment Summary
Premenstrual syndrome is a psychosomatic disorder in that the symptoms involve both mind and body. Treatment includes nonpharmacological strategies, antidepressant medications, and strategies (hormonal or surgical) that suppress/eliminate ovulation.
10.7.2 Problem and Patient Orientation
Women with premenstrual symptoms often report symptoms for several years prior to seeking treatment. It is possible that symptoms increase in severity with age or after giving birth and resuming menses, but these reports need study. It is also possible that premenstrual symptoms become more problematic as women assume multiple roles with a partner, children, and employment. A single woman who is a teacher may find that her premenstrual irritability and lack of patience interfere with her teaching role, but she can manage her life outside of the classroom during those days. A married woman with 3 children at home may find that she can function well at her job during the days prior to menses, but her irritability, anger outbursts, and mood swings become apparent when she gets home at the end of the day and feels pressured to prepare a meal and attend to the needs of her family. Many women with severe premenstrual symptoms report reduced quality of life and significant disruption to their interpersonal relationships during the symptomatic days. A small subset of women has anger outbursts and aggressive actions that can lead to significant negative consequences. Some women with severe premenstrual low mood may spend days in bed and miss social obligations and work responsibilities and may wrestle with hopelessness and suicidal thoughts each month.
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