Exacerbation of common medical and mental health disorders at specific phases of the menstrual cycle is a prevalent phenomenon. Although the precise cause is unclear, studies implicate complex interactions between the immune and neuroendocrine systems. The menstrual cycle also is a trigger for the onset of depressive disorders, including premenstrual dysphoric disorder, a disorder specific to the luteal phase of the menstrual cycle, and depression associated with the transition to menopause. This article discusses common mental health problems exacerbated by the menstrual cycle, with a particular focus on premenstrual dysphoric disorder and perimenopausal depression. Throughout the reproductive lifespan, routine screening and assessment for the presence of common psychiatric disorders are critical for accurate diagnosis and provision of effective treatment. Management options include referral or consultation with a primary care provider or psychiatrist; treatment options for premenstrual dysphoric disorder and perimenopausal depression include pharmacotherapy with antidepressant agents and/or psychotherapy. Hormones may be helpful.
Exacerbation of various medical and mental health conditions at specific phases of the menstrual cycle, particularly during the luteal and menstrual phases, is a common phenomenon ( Table 1 ). Approximately 50% of migraines in women are menstrually related, catamenial epilepsy affects 10-70% of women with epilepsy, and premenstrual exacerbation of asthma has been reported in up to 40% of asthmatic women. Prexisting mental health disorders with premenstrual exacerbation include anxiety, and bipolar, psychotic, and eating disorders ( Table 2 ). Lifetime prevalence rates for anxiety disorder are estimated at 30%. Generalized anxiety disorder (GAD) in women has a total lifetime prevalence rate of 7% with rates as high as 10% after age 45 years. In primary care settings, GAD is the most common anxiety disorder and the second most common psychiatric disorder after depression. The menstrual cycle appears to trigger the onset of premenstrual dysphoric disorder (PMDD), a mood disorder specific to the luteal phase of the menstrual cycle that affects up to 6% of premenopausal women, and depression associated with the transition to menopause. Although up to 50% of women may experience depressive symptoms during the menopausal transition, most are not diagnosed with depression.
| Condition |
|---|
| Acne |
| Acute appendicitis |
| Acute intermittent porphyria |
| Aphthous ulcers |
| Asthma |
| Diabetes |
| Endocrine allergy and anaphylaxis |
| Epilepsy |
| Erythema multiforme |
| Glaucoma |
| Hereditary angioedema |
| Irritable bowel syndrome |
| Migraines |
| Multiple sclerosis |
| Paroxysmal supraventricular tachycardia |
| Rheumatoid arthritis |
| Uticaria |
| Disorder |
|---|
| Anxiety |
| Bipolar disorder |
| Eating disorders |
| Menopausal transition-related depression |
| Premenstrual dysphoric disorder (PMDD) |
Obstetrician-gynecologists often serve as a woman’s primary health care provider during the reproductive and menopausal years and are therefore in a unique position to recognize the presence of disorders exacerbated or triggered by the menstrual cycle or transition to menopause. We describe the phenomenon of disease triggered or exacerbated by the menstrual cycle, examine potential underlying mechanisms to explain menstrual cycle-related effects, identify psychiatric disorders commonly exacerbated by the menstrual cycle with a particular focus on PMDD and depression associated with the transition to menopause, discuss the role of the obstetrician-gynecologist in identifying predictable patterns of symptom deterioration of psychiatric disorders exacerbated by the menstrual cycle, and review management options for psychiatric disorders exacerbated by the menstrual cycle.
Examining etiologic factors in menstrual cycle disease exacerbation
The precise cause and underlying mechanisms of menstrual cycle-related disease exacerbation are not clearly understood. Complex interactions between fluctuating and declining levels of ovarian hormones during the menstrual cycle have been associated with the immune and neuroendocrine systems. In some women with migraines, the sudden decline in levels of estrogen during the menstrual cycle appears to trigger migraine onset ; after menopause, when estrogen levels are low with little fluctuation, migraines tend to improve. Eighty percent of pregnant women with migraines without aura report no migraines during the third trimester; nearly all (94%) report return of migraines after delivery. Sudden estrogen withdrawal, in 98 women who received gonadotropin-releasing hormone as part of in vitro fertilization, was associated with migraines in 28 (28.6%) women, of whom 23 (82%) reported debilitating severity. Treatment for menstrual migraine treatment included therapy given shortly after the migraine begins as well as short-term preventive therapies with triptans (serotonin receptor agonists), nonsteroidal antiinflammatory drugs, and estrogen supplements given typically 2 days before menses and up to 3 days after the onset of menstruation. Long-term preventive therapy is recommended for recurrent migraines or a concomitant medical condition that could respond to migraine therapy. For those with migraines while taking low-dose 21-day cycle 20 or 30 μg oral contraceptives (OCs), the addition of estrogen during the placebo week may alleviate menstrual migraine. Continuous OCs for 11 weeks to suppress ovulation and menses may also prevent the onset of menstrual migraine.
In catamenial epilepsy, menstrual-cycle-linked, low levels of progesterone have been associated with decreased seizure threshold. Seizure frequency has been found to be elevated immediately preceding ovulation, corresponding to a rise in estrogen, as well as immediately preceding menses, corresponding to a rapid reduction in estrogen and progesterone. Catamenial epilepsy may be due in part to a decrease in corpus luteum progesterone-derived GABA (gamma-aminobutyric acid) steroids during menstruation. Changing levels of estrogen and progesterone throughout the cycle may alter the metabolism of anticonvulsant drugs, via release of hepatic monooxygenase enzymes.
Estrogen has been shown to influence the development of B and T cells, as well as the differentiation and homeostasis of antigen-presenting cells. If estrogen acts as an immunomodulator, it may contribute to the higher incidence of autoimmune disease observed in women over men. Estrogen may mediate the expression and responsiveness of androgens, progesterone, prolactin, and gonadotropin-releasing hormone, all of which have been shown to have effects on B cell activities and tumor proliferation. The action of estrogens on inflammatory diseases may be antiinflammatory or proinflammatory depending on multiple factors such as the type of immune stimulus (foreign antigens or autoantigens), specific target organs, the pre- or postmenopausal status of the woman, variability in estrogen receptors, differences in intracellular metabolism of estrogen and variable responses of the immune system.
Estrogen appears to act as a neuromodulator with diverse effects on the central nervous system through its influence on neurotransmitter systems. During the menopausal transition, fluctuating levels of estrogen are thought to result in variable functioning of serotonin, which may contribute in part to depression. Estrogen has been found to regulate various aspects of GABA and dopaminergic transmission, both important in the brain’s response to hormones, by serving as inhibitory and excitatory neurotransmitters. An example of the interaction between mood, neuroactive steroids, and the GABA system is PMDD, in which a cluster of negative mood symptoms and physical symptoms occurs during the luteal phase of the menstrual cycle. The sequential addition of progestins or progesterone to postmenopausal estrogen treatment induces negative mood symptoms in some women, thought to be modulated through the GABA system.
Some women may have an abnormal central nervous system response to normal hormone levels. Schmidt et al showed that in women with normal pituitary-gonadal function and premenstrual syndrome (PMS), symptoms of PMS occurred in response to normal hormonal changes during the menstrual cycle; thus in susceptible women, normal levels of gonadal hormones triggered an abnormal response (ie, worsening mood). Lee et al proposed that autonomic balance appears to shift toward sympathetic bias during the luteal phase of the menstrual cycle, resulting in direct modulation of T-helper cells in the lymphoid system. By modulating the lymphoid system and activating the cortisol pathway, the sympathetic system selectively inhibited T-helper 1 functions while facilitating T-helper 2 responses. This bias toward T-helper 2 immunity during the luteal phase favors maternal tolerance of the embryo and successful implantation and may be an evolutionary adaptation designed to prepare the body for the immunologic and physiologic demands of a successful pregnancy but may also contribute to immune variance seen in systemic lupus or rheumatoid arthritis.
Premenstrual exacerbation of preexisting mental health disorders
Anxiety disorders
A worsening of preexisting anxiety symptoms premensturally has been reported. Breier et al studied 43 menstruating women with agoraphobia and found that half experienced significant premenstrual exacerbation of anxiety symptoms. For panic disorder, premenstrual exacerbation may be associated with an increase in anxiety symptom severity or number of panic attacks. Breier et al reported a higher number of panic attacks in 14 of 43 (33%) women with panic disorder, and Hsiao et al also reported premenstrual exacerbation of panic attack frequency in 30% of patients studied. Two studies of approximately 20 patients each with panic disorder, found no significant change in the frequency of panic attacks between the late luteal and follicular phases of the menstrual cycle. Premenstrual exacerbation of GAD has been reported by Hsiao et al in Chinese patients with chronic depression and coexisting GAD who had higher rates of premenstrual exacerbation, and by McLeod et al with more severe anxiety symptoms in patients with both GAD and PMS, compared with nonaffected controls. Labad et al reported some women with obsessive compulsive disorder (OCD) reported worsening of OCD premenstrually and postpartum and exhibited a greater history of mood symptoms, including premenstrual depression and major depression.
Bipolar disorder
Several studies have reported premenstrual exacerbation of psychiatric symptoms as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) in women who had bipolar disorder diagnosed. Exacerbation has been suggested related to rapid cycling, but a relationship between mood and menstrual cycle in rapid cycle bipolar disorder is not clear. Women with bipolar disorder appear more sensitive to negative life stressors and more vulnerable to depressive episodes during certain phases of the reproductive cycle, such as during the transition to menopause and during the postpartum period. A retrospective study (n = 2524) of women with either major depressive disorder (MDD) or bipolar disorder found 20.9% reported postpartum symptoms and 26.4% reported perimenopausal symptoms. Lifetime rates of mood symptoms were similar between women with MDD and bipolar disorder but significantly correlated in women with MDD (odds ratio [OR], 1.66–1.82) compared with nonaffected women.
Psychotic disorders
Menstrual cycle-related exacerbation of psychotic disorders, including a worsening of psychiatric symptoms and clinical features of schizophrenia, have been reported, and hypothesized to be a concurrence of affective, behavioral, and somatic symptoms related to the premenstrual phase of the cycle. Hsiao et al reported that of 50 female Chinese patients with schizophrenia, 52% had PMS and 20% experienced premenstrual exacerbation (mild in 70%) of schizophrenia symptoms. Harlow et al using Swedish registry data (n = 612,306 women with live births, 1987-2001) found postpartum hospitalization incidences of 0.04% for psychotic and 0.01% for bipolar episodes in women with no previous psychiatric hospitalizations, compared with 9.2% and 4.5%, respectively, for women with any predelivery psychiatric hospitalization. More than 40% of women hospitalized during pregnancy for a psychotic or bipolar episode were rehospitalized during the postpartum period, with 90% of all postpartum psychotic or bipolar episodes occurring within the first 4 weeks’ postpartum. Therefore, it is important to identify women with psychiatric histories early in pregnancy and to collaborate with psychiatrists to avoid the risks of hospitalization for postpartum psychosis or bipolar disorder in these women.
Eating disorders
Changes in appetite and eating behavior are common during the premenstrual phase of the menstrual cycle. Women with bulimia, characterized by binge eating and purging, may be susceptible to increased appetite and cravings during the premenstrual phase. Leon et al did not find evidence of menstrual cycle-related exacerbation of abnormal eating behavior in 45 women who had bulimia diagnosed; however, Gladis and Walsh reported a modest statistically significant premenstrual increase in binge eating, particularly the 5 days preceding the menstrual period, among 15 normal-weight bulimic women. Other investigators have found an exacerbation of bulimic symptoms during the premenstrual phase of the cycle.
To date, no studies have been published examining menstrual cycle-related effects on the incidence and course of anorexia, in part, because amenorrhea is a DSM-IV diagnostic criterion for anorexia. The review by Godart et al of studies assessing the prevalence of mood disorders in patients with eating disorders (bulimia and anorexia) found most limited by the lack of controls and a lack of information about puberty and reproductive events. Estimated overall lifetime prevalence of MDD in anorexic inpatients and outpatients was 40%, double the rate in the general community with a correlation between severity of the eating disorder and severity of depression.
PMDD
PMDD, a severe form of PMS, affects an estimated 3-6% of premenopausal women and is characterized by severe mood symptoms confined to the luteal phase of the menstrual cycle, followed by a symptom-free period after menses begin and before ovulation. By definition, a patient must report at least 1 mood symptom severe enough to interfere with social and/or occupational functioning for at least 2 consecutive cycles to meet DSM-IV diagnostic criteria for PMDD: dysphoria, tension, mood lability, or anger/irritability ( Table 3 ). A history of anxiety or mood disorder is common among women with PMDD. In a prospective cohort study (n = 1488, 4 years), Perkonigg et al found preexisting anxiety disorder associated with 2.5 times higher probability of PMDD developing. Patients with PMDD, 30-70% have a lifetime history of MDD. Those without a lifetime history of depression have an elevated risk of later having an episode of MDD. The onset of PMDD may be related to life stressors or environmental factors, including marital disruption, cigarette smoking, a low level of education, and working outside the home.
