Premenstrual dysphoric disorder: How to alleviate her suffering
Accurate diagnosis, tailored treatments can greatly improve women’s quality of life
Approximately 75% of women experience a premenstrual change in emotional or physical symptoms commonly referred to as premenstrual syndrome (PMS). These symptoms—including increased irritability, tension, depressed mood, and somatic complaints such as breast tenderness and bloating—often are mild to moderate and cause minimal distress.1 However, approximately 3% to 9% of women experience moderate to severe premenstrual mood symptoms that meet criteria for premenstrual dysphoric disorder (PMDD).2
PMDD includes depressed or labile mood, anxiety, irritability, anger, insomnia, difficulty concentrating, and other symptoms that occur exclusively during the 2 weeks before menses and cause significant deterioration in daily functioning. Women with PMDD use general and mental health services more often than women without the condition.3 They may experience impairment in marital and parental relationships as severe as that experienced by women with recurrent or chronic major depression.2
PMDD often responds to treatment. Unfortunately, many women with PMDD do not seek treatment, and up to 90% may go undiagnosed.4 In this article, we review the prevalence, etiology, diagnosis, and treatment of PMDD.
A complex disorder
A distinguishing characteristic of PMDD is the timing of symptom onset. In women with PMDD, mood symptoms occur only during the luteal phase of the menstrual cycle (ovulation until onset of menses) and resolve after menstruation onset. Women with PMDD report normal mood and functioning during the follicular phase of the menstrual cycle (first day of the menstrual cycle until ovulation).
Although PMS and PMDD criteria share affective and somatic symptoms, more symptoms are required for a PMDD diagnosis, and symptoms often are more severe.5 As defined in DSM-IV-TR (Table),6 PMDD has a broader range of symptoms than PMS and includes symptoms not included in the American College of Obstetrics and Gynecology criteria for PMS,7 such as impaired concentration, appetite, and sleep (hypersomnia or insomnia); and mood lability. PMDD symptoms must occur only during the 2 weeks preceding menses, although on average symptoms last 6 days and severity usually peaks in the 2 days before menses.1 The prevalence of subthreshold PMDD is fairly common; approximately 19% of women will meet some—but not all—DSM-IV-TR criteria for PMDD.3
In a revision proposed for DSM-5, PMDD would be included as a mood disorder, which represents a significant change from DSM-IV-TR, where it is listed in the appendix as “research criteria.”8 In addition, in oral contraceptive users, a PMDD diagnosis should not be made unless the premenstrual symptoms are reported to be present and as severe when the woman is not taking the oral contraceptive.8
Comorbidity with other axis I disorders such as major depressive disorder (MDD), bipolar disorder (BD), and anxiety disorders is high.9-11 Women with an MDD history have the highest correlation with PMDD,9 and worsening premenstrual mood symptoms are more common in women with BD.12 Payne et al11 found that premenstrual symptoms were reported by twice as many women diagnosed with mood disorders (68%) than women without a psychiatric diagnosis (34%). Moreover, 38% to 46% of women with PMDD have comorbid seasonal affective disorder, and 11% to 38% report a comorbid anxiety disorder.12 Women with PMDD and a history of MDD have lower cortisol concentrations than non-PMDD women.10 Although interventions for PMDD and a comorbid axis I disorder may be similar, it is important to consider both when planning treatment.
Abuse, trauma, and PMDD. An association between PMS/PMDD and a history of sexual and physical abuse is well-documented.13 Studies have reported abuse histories among almost 60% of women with PMDD,14 although studies comparing abuse and trauma in PMDD vs non-PMDD women have been small. A recent study found that trauma and posttraumatic stress disorder are independently associated with PMDD and premenstrual symptoms.15
Evidence suggests that a history of abuse is associated with specific biological sequelae in PMDD women, particularly with respect to hypothalamic-pituitary-thyroid axis measures and noradrenergic activity.16-18 Women with PMDD and a history of sexual abuse show:
- markedly elevated triiodothyronine (T3) concentrations (the more biologically potent thyroid hormone) that appear to result from increased conversion of thyroxine (T4) to T316
- lower circulating plasma norepinephrine concentrations17
- greater resting and stress-induced heart rates and systolic blood pressure compared with non-abused PMDD women, an effect that is eliminated by clonidine (an α-2 adrenergic receptor agonist).18
One study showed that PMDD women with abuse histories had higher blood pressure measurements at rest and during stress and exhibited greater vascular tone than non-abused women; these effects were not seen in non-PMDD women with similar abuse histories.14 This body of evidence is consistent with the concept that PMDD is a stress-related disorder,19 and that a history of abuse is prevalent and may identify a clinically distinct subgroup of PMDD women with respect to thyroid axis and adrenergic physiology. Screening PMDD patients for abuse histories may help manage the disorder.
For a discussion of the etiology of PMDD, see Box 1.
DSM-IV-TR research criteria for PMDD
Source: Reference 6
Reproductive hormones in PMDD etiology
Although questions remain about the pathogenesis of premenstrual dysphoric disorder (PMDD), literature documents the role of gonadal steroids (estrogen and progesterone) in the etiology of premenstrual syndrome (PMS)/PMDD and suggests that women with PMDD are differentially sensitive to the normal physiologic fluctuations of gonadal hormones throughout the menstrual cycle.a
The first half of the menstrual cycle—the follicular phase—begins with increasing levels of follicular stimulating hormone (FSH) leading to maturity of the ovarian follicle. Once the follicle is ripe, the luteal phase of the menstrual cycle begins with a surge in luteinizing hormone (LH), which results in ovulation of the mature follicle, followed by increased secretion of progesterone, followed by increased estrogen secretion. The system is regulated via negative feedback, and high levels of progesterone decrease gonadotropin-releasing hormone (GnRH) pulse frequency, which leads to decreased secretion of FSH and LH, and subsequent decline of estrogen and progesterone. If the ovarian follicle is not fertilized, menstruation begins and FSH levels rise again, initiating the follicular phase of the menstrual cycle.
Fluctuations in reproductive steroid levels have been implicated in the etiology of PMDD from studies showing that oophorectomy and ovulation inhibitors (GnRH agonists) relieve symptoms.b Some researchers proposed that symptoms are related to the drop of progesterone in the late luteal phase; however, many women have symptoms that start at ovulation or during the early luteal phase before the fall in progesterone concentrations.c PMS symptoms may occur independently of the mid-to-late luteal phase.d Because production of gonadal steroids does not differ between women with or without PMS or PMDD,e it may be that follicular or periovulatory changes in levels of estradiol or progesterone secretion trigger symptoms of PMDD in susceptible women, while women without PMDD appear to be immune to these effects of gonadal steroids. This idea is supported by a study showing that pharmacologic induction of a hypogonadal state eliminates symptoms in most women with severe PMS, while “adding back” estrogen or progesterone within the context of hypogonadism elicits return of PMS symptoms in those with PMS but not in controls.a
Abnormalities in serotonin levels also may contribute to PMDD.f In 1 study, a serotonin receptor antagonist precipitated return of symptoms within 24 hours of administration in women with PMDD but not in controls.g PMDD symptoms also can be evoked by depleting the serotonin precursor tryptophan.h When women with PMDD received paroxetine at different phases of their menstrual cycle, they showed fluctuations in serotonergic function across their cycles; these fluctuations were not seen in controls.i Other neurotransmitters implicated in PMDD include γ-aminobutyric acid (GABA),j glutamate,k lower levels of cortisol and beta-endorphins,l and an abnormal stress response.m
Other studies have focused on differing concentrations of luteal phase hormonesn and gene associations. Two studies suggested that PMDD is heritableo,p and other studies have looked at the association between specific psychological traits that are more prominent in PMDD and single nucleotide polymorphisms in the estrogen receptor alpha gene.q,r
Thyroid hormones also may play a role in the etiology of PMS/PMDD. Thyroid function tests have shown greater variability in women with PMS vs controls,s although this variability appears to be limited to women with a sexual abuse history.t Other studies have evaluated hormones regulated across the circadian and sleep-wake cycles, including melatonin, cortisol, thyroid-stimulating hormone, and prolactin, which suggests that although levels of these hormones may not differ between women with PMDD and controls, the timing of their excretion may vary.s Additionally, women with PMDD are characterized by prefrontal brain asymmetry on electroencephalography that also is evident in patients with major depressive disorder.u
There also may be dysregulation of allopregnanolone (ALLO) in women with PMDD.v,w ALLO is a metabolite of progesterone that is a neurosteroid produced in the brain as well as in the ovary and adrenals.v It produces anxiolytic effects by acting as a modulator of GABA receptors.x In PMDD, ALLO levels may influence the severity of premenstrual symptoms.w
- Schmidt PJ, Nieman LK, Danaceau MA, et al. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338(4):209-216.
- Muse KN, Cetel NS, Futterman LA, et al. The premenstrual syndrome. Effects of “medical ovariectomy.” N Engl J Med. 1984;311(21):1345-1349.
- Yonkers KA, O’Brien PM, Eriksson E. Premenstrual syndrome. Lancet. 2008;371(9619):1200-1210.
- Schmidt PJ, Nieman LK, Grover GN, et al. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med. 1991;324(17):1174-1179.
- Rubinow DR, Schmidt PJ. The neuroendocrinology of menstrual cycle mood disorders. Ann N Y Acad Sci. 1995;771:648-659.
- Steiner M, Pearlstein T. Premenstrual dysphoria and the serotonin system: pathophysiology and treatment. J Clin Psychiatry. 2000;61(suppl 12):17-21.
- Roca CA, Schmidt PJ, Smith MJ, et al. Effects of metergoline on symptoms in women with premenstrual dysphoric disorder. Am J Psychiatry. 2002;159(11):1876-1881.
- Menkes DB, Coates DC, Fawcett JP. Acute tryptophan depletion aggravates premenstrual syndrome. J Affect Disord. 1994;32(1):37-44.
- Inoue Y, Terao T, Iwata N, et al. Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests. Psychopharmacology (Berl). 2007;190(2):213-219.
- Epperson CN, Haga K, Mason GF, et al. Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry. 2002;59(9):851-858.
- Batra NA, Seres-Mailo J, Hanstock C, et al. Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder. Biol Psychiatry. 2008;63(12):1178-1184.
- Straneva PA, Maixner W, Light KC, et al. Menstrual cycle, beta-endorphins, and pain sensitivity in premenstrual dysphoric disorder. Health Psychol. 2002;21(4):358-367.
- Epperson CN, Pittman B, Czarkowski KA, et al. Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder. Neuropsychopharmacology. 2007;32(10):2190-2198.
- Thys-Jacobs S, McMahon D, Bilezikian JP. Differences in free estradiol and sex hormone-binding globulin in women with and without premenstrual dysphoric disorder. J Clin Endocrinol Metab. 2008;93(1):96-102.
- Payne JL, Klein SR, Zamoiski RB, et al. Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees. Arch Womens Ment Health. 2009;12(1):27-34.
- Kendler KS, Karkowski LM, Corey LA, et al. Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry. 1998;155(9):1234-1240.
- Miller A, Vo H, Huo L, et al. Estrogen receptor alpha (ESR-1) associations with psychological traits in women with PMDD and controls. J Psychiatr Res. 2010;44(12):788-794.
- Huo L, Straub RE, Roca C, et al. Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biol Psychiatry. 2007;62(8):925-933.
- Girdler SS, Pedersen CA, Light KC. Thyroid axis function during the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology. 1995;20(4):395-403.
- Girdler SS, Thompson KS, Light KC, et al. Historical sexual abuse and current thyroid axis profiles in women with premenstrual dysphoric disorder. Psychosom Med. 2004;66(3):403-410.
- Accortt EE, Stewart JL, Coan JA, et al. Prefrontal brain asymmetry and pre-menstrual dysphoric disorder symptomatology. J Affect Disord. 2011;128(1-2):178-183.
- Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6(6):2311-2322.
- Girdler SS, Straneva PA, Light KC, et al. Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry. 2001;49(9):788-797.
- Brot MD, Akwa Y, Purdy RH, et al. The anxiolytic-like effects of the neurosteroid allopregnanolone: interactions with GABA(A) receptors. Eur J Pharmacol. 1997;325(1):1-7.