The Complex Interrelationships of Menstrual Cyclicity and Anxiety Disorders

The ocurrence and severity of anxiety disorders have been correlated with fluctuations in female sex steroid levels in both epidemiological and experimental studies.^1-5 Female reproductive hormones play a role not only in the development and course of anxiety disorders but also in treatment response.^1,2,6-12 This article focuses on the premenstrual exacerbation of anxiety disorders and briefly reviews the biological pathways and physiological mechanisms thought to contribute to the expression of different anxiety disorder subtypes. Female steroid hormone influences on pharmacological properties of psychoactive drugs used to treat anxiety disorders are also addressed, because these may contribute to treatment response in women who experience premenstrual exacerbation of these disorders.

Pathways and mechanisms
Estrogen and progesterone(Drug information on progesterone) are female sex steroids that control fertility through the menstrual cycle. Estrogen levels are low during the early part of the cycle, peak just before ovulation, and then gradually rise in the early luteal phase before falling a few days before menstruation. Progesterone levels remain low throughout the follicular phase, significantly increase after ovulation to peak in the mid luteal phase, and then sharply decrease a few days before menses. The hormonal fluctuations, particularly the relatively quick withdrawal of sex steroids at the end of the luteal phase, produce diverse physiological effects including effects on the CNS to which some women are particularly sensitive. These women may experience premenstrual dysphoric disorder (PMDD) and/or premenstrual exacerbation of an underlying psychiatric disorder.^13,14

Sex steroids affect mood and anxiety by mediating changes in neurotransmitter systems in a diverse array of brain regions (mostly by enhancing neuroamine activity). Sex steroids cross the blood-brain barrier and act through both genomic and rapid nongenomic mechanisms; they may also be synthesized within the brain.^15,16 Areas of the brain implicated in anxiety disorders—including the amygdala, hippocampus, central gray matter, basal ganglia, and various cortical areas—are targets of female sex steroids and contain specific steroid receptors.^4,15,17,18 CNS activities of noradrenaline, dopamine(Drug information on dopamine), serotonin (5-HT), and g-aminobutyric acid (GABA), which are implicated in the pathophysiology of anxiety, are all affected by female sex ste- roids.^{2,6-8,12,15,16,19-25} Overall, estrogens(Drug information on estrogens) exert an agonistic effect on both 5-HT and noradrenaline activities by increasing their synthesis and release, inhibiting their reuptake, and slowing their degradation.^2,5,26

Progesterone acts as an allosteric modulator of GABA, with its anxiolytic effects attributed to the metabolite, allopregnanolone, on the GABA-benzodiazepine receptor complex (GBRC).^{2,16,21,25,27} A rapid withdrawal of progesterone, not absolute levels of progestins, appears to be implicated in behavioral premenstrual symptoms, possibly also via GABA-A receptors.²⁵ Animal models of withdrawal from exogenous progesterone administration have demonstrated plasticity of GABA-A receptor expression in brain areas implicated in anxiety, such as the amygdala and periaqueductal gray matter.²⁵

Overall, cyclical fluctuations in sex steroids may substantially influence the clinical course and symptom severity of anxiety disorders, but systematic data examining this issue are limited.^1-3 Existing data are conflicting because of methodological inconsistencies among studies.

Anxiety disorder subtypes Generalized anxiety disorder
Premenstrual worsening is frequently reported by women with general anxiety disorder (GAD); one study reported a prevalence of 52%.³ The mechanisms by which some women experience premenstrual worsening of GAD, however, are not known. Limited evidence suggests that GAD is associated with decreased serum levels of pregnanolone sulfate,¹² but changes in neurosteroid levels in women who experience premenstrual exacerbation of GAD have not, to our knowledge, been examined. Benzodiazepines are more likely to be prescribed for women with GAD than for men, and while these compounds demonstrate good efficacy in GAD treatment,^1,28,29 a significant influence of the menstrual-cycle phase in treatment response has been observed.¹

Panic disorder
A large number of studies suggest that the serotonergic, noradrenergic, and GABAergic systems all play an important role in the pathophysiology of panic disorder (PD).^30-33 Studies point to decreased numbers and/or subsensitivity of a₂-adrenergic receptors,^31,32 decreased binding and/or sensitivity of GABA-A receptors, and/or decreased brain GABA levels in PD.³⁰ Other physiological systems may also contribute to the pathophysiology of PD. Some studies report significantly increased basal cortisol levels in patients with PD,³⁴ but a more robust finding is the increased adrenocorticotropic hormone (ACTH) and cortisol responses to hypothalamic-pituitary-adrenal (HPA) axis challenges.^35,36 Serotonergic antidepressants are first-line treatment for PD,^30,33 but benzodiazepines also display high efficacy in both short- and long-term treatment of PD.³⁰

There is evidence suggesting a prominent role of progesterone in the risk of PD and in the occurrence of panic attacks in women, possibly as a result of the anxiolytic effects of allopregnanolone at the level of the GABA-A receptor complex. A recent study found that a polymorphism in the progesterone receptor gene was associated with PD in women but not in men.³⁷ Experimentally induced panic attacks have been shown to decrease GABAergic tone via decreased levels of allopregnanolone and pregnanolone, as measured in blood, in patients with PD but not in control subjects.²¹ Furthermore, enhancement of endogenous GABA exerts anxiolytic effects in experimentally induced panic.³⁰ Administration of a synthetic progesterone before a panic challenge decreased panic and anxiety responses to a panicogenic agent in female patients with PD.³⁸

If further confirmed, these results may support a potential therapeutic value for sex steroid treatments.³⁸ There is less data on spontaneous panic attacks in premenstrual exacerbation of PD, however, and this may be important because it has been suggested that anticipatory anxiety activates different physiological systems than those activated by the panic attack itself.^33,39,40 Progesterone's role in PD may also be mediated through effects on the b-adrenergic system.^16,38