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 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, 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 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.¹Panic 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

 

Retrospective studies have found an increase in anxiety and panic symptoms during the premenstrual phase in a substantial portion of women with PD, while the majority of prospective studies have not been able to document these changes.^1,3,23,41,42 Kaspi and colleagues,⁴³ however, found that retrospective reports of premenstrual exacerbations of PD were confirmed in a subsample studied prospectively. They found a worsening of panic symptoms and an increase in panic frequency in half their sample during the premenstruum.⁴³

Gonadal steroid hormones may influence PD through effects on respiration sensitivity. Panic attacks provoked by the inhalation of 35% car- bon dioxide were more frequent and the anxiety significantly more severe in the early follicular phase than in the mid luteal phase in patients with PD, but no difference was seen in controls.⁴⁴ This suggests that in some women with PD, the reactivity to carbon dioxide and/or the suffocation alarm threshold may be impaired.^23,44 Social anxiety disorder (social phobia)
The impact of female reproductive hormones on the course and severity of social anxiety disorder (SAD) has yet to be investigated.^1,4 To our knowledge, there are no studies to date on possible premenstrual exacerbation of SAD.

Noradrenergic and dopaminergic abnormalities have been consistently observed in social phobia, including dysfunction of a₂-adrenoreceptors²⁴ and decreased dopamine binding and dopamine reuptake sites in the striatum.¹⁷ No abnormalities in HPA axis function have been identified in SAD.¹⁷ Serotonergic dysfunction (particularly in females with social phobia) was reported in one study.⁴⁵ Serotonergic medications are first-line treatment for patients with social phobia,^24,46 and benzodiazepines are also effective.^28,46 Allopregnanolone and dehydroepiandrosterone (DHEA) levels were reportedly normal in patients with SAD, while pregnanolone sulfate levels were significantly lower in male patients with generalized social phobia.^23,47 Information on other steroids in SAD is lacking.

Obsessive-compulsive disorder
Clinical studies suggest that there are serotonergic mechanisms in obsessive-compulsive disorder (OCD), especially in women.^1,48,49 However, increased dopamine neurotransmission has also been implicated.¹⁹ Recent retrospective studies have found that almost half of a sample of women with OCD reported experiencing premenstrual worsening of OCD symptoms.^48,50 Findings from another study, with a greater percentage of women of reproductive age, showed that 20% of those with OCD reported premenstrual exacerbation.⁴⁹ Labad and colleagues⁴⁹ also found that patients with an onset or worsening of OCD postpartum more frequently reported premenstrual exacerbation of this condition, as well as premenstrual mood symptoms and a history of depressive disorders.The authors therefore suggest that there may be a continuum of vulnerability in some female patients with OCD to anxiety and mood symptoms during periods of abrupt hormonal variability, such as the premenstruum and postpartum periods.⁴⁹ Similarly, Vulink and colleagues⁵⁰ found that OCD was comorbid with PMDD but that this association only partially explained premenstrual exacerbation of OCD in their study.

Overall, evidence points to menstrual cycle-related sex steroid influences on the course of OCD in some women, possibly via serotonergic mechanisms,^1,7,48 and serotonergic antagonism on dopamine neurotransmission (causing increased dopamine activity and consequent exacerbation of OCD).^19,50 Treatment studies examining efficacy of semi-intermittent dosing (ie, dosage increases during the late luteal phase) in women with documented premenstrual exacer- bation of OCD symptoms would be particularly beneficial in informing treatment practices.⁴⁸ Furthermore, identification of premenstrual exacerbation of OCD may serve as a predictor of postpartum OCD exacerbation, but prospective verification of this association would be useful.

Posttraumatic stress disorder
Decreased hippocampal volume, and decreased hippocampal blood flow in tandem with increased blood flow to cortical areas in patients with posttraumatic stress disorder (PTSD) have been attributed to stress effects.¹⁸ A hyperreactive HPA axis, with exaggerated cortisol responses to stressors, is characteristic of PTSD.^18,51,52 Rasmusson and colleagues⁵² found that DHEA levels at baseline and in response to ACTH were increased in women with PTSD. Further findings showed normal baseline progesterone levels and normal progesterone levels in response to stress in women with PTSD.⁵² Another study reported low cerebrospinal fluid allopregnanolone levels in women of reproductive age with PTSD.⁵³

Serotonergic antidepressants are the treatment of choice because they show efficacy in both PTSD and comorbid disorders.⁵⁴ Benzodiazepines should be used with caution in PTSD but may be effective as adjunctive therapy to SSRIs.²⁸Effects of Female Sex Steroids
Information on physiological changes across the menstrual cycle in the absence of drug therapy is lacking,⁹ so it is not surprising that research on changes in drug action across the menstrual cycle is scarce as well.^10,29 Sex differences in the pharmacodynamics and pharmacokinetics of a number of drugs have been described^9,20,29 and are probably caused (at least in part) by differences in hormone concentrations, body size and fat composition, liver metabolism, gastric absorption and emptying, and cerebral blood flow.^{1,2,6,9,10,55} Interactions between psychoactive drugs and cyclical fluctuations in anxiety disorders might be expected because of the similar neural pathways activated,^12,22 and may be particularly critical for psychoactive drugs with a narrow therapeutic index.^2,8Absorption
Decreased secretion of gastric acid and progesterone in the luteal phase results in slower gastric emptying and could consequently lower drug levels in the blood; study results, however, have shown conflicting results.^6,8-11 Dilution of drugs via fluid retention in the luteal phase could result in lowered drug levels but the amount of fluid retained would have to be fairly large.^8,11 Gonadal hormones may affect bioavailability through changes in absorption rates, necessitating luteal-phase increases of some medications in certain women.^10,11Distribution
Cyclical, menstrual-related changes in body weight and water metabolism may theoretically alter distribution properties of drugs in some women, although this has not been shown to be clinically relevant.^2,9 Many psychotropic medications (eg, benzodiazepines) are lipophilic and therefore gravitate to adipose tissue, where accumulation may prolong half-life; however, there is no information on whether these parameters vary significantly with menstrual-cycle phase.^2,10,11

 

Protein binding
a₁-Glycoprotein levels are decreased by estrogen, resulting in highest levels during menses.^9,20 Most anxiolytic medications are moderately to highly protein bound. More specifically, the binding of SSRIs is mostly to a₁-glycoprotein, and some antidepressants (particularly tricyclic antidepressants) have a relatively narrow therapeutic index, putting women at an increased risk for adverse effects or toxicity.²

Hepatic metabolism Sex differences in hepatic metabolism of a number of drugs have been reported.^2,11,20 Peak rates at mid cycle cause lower blood levels of drugs in the luteal phase and higher drug levels in the follicular phase.⁸ There is no evidence that benzodiazepine metabolism is altered across the menstrual cycle.¹⁰ The estrogenic component of oral contraceptive pills is known to increase conjugation activity.⁹

Cytochrome P-450 enzyme system The enzyme cytochrome 3A4 (CYP 3A4) is involved in the metabolism of more than 50% of drugs in clinical use,^20,55 and it is responsible for hydroxylation of steroid hormones.⁵⁶ Sex differences have been reported for CYP 3A4 and CYP 2C19, with higher activity levels in women resulting in lowered plasma levels of some antidepressants and other drugs (sertraline, carbamazepine, citalopram, clomipramine, imipramine, diazepam, propranolol).^2,8,20,55 Evidence points to higher clearance rates of nonspecific CYP substrates at ovulation and prolonged clearance during the luteal phase, but the clinical relevance of these observations is unknown.⁹Elimination
Women have lower renal clearance rates and concomitant increases in plasma levels of some but not all anxiolytic medications,⁶ possibly due to lower glomerular filtration rates, although limited evidence suggests no change in glomerular filtration rates across the menstrual cycle.^2,9 There is no information to date on P-glycoprotein changes across the menstrual cycle, but the influence of sex ste- roids on P-glycoprotein is suggested by studies with pregnant animals.²⁰ An increase in vasopressin and aldo- sterone plasma levels, and in renin activity during the luteal phase has been demonstrated but the clinical influence of these findings remains unknown.⁹

Limited evidence suggests that clinical effects of buspirone are not affected by sex.⁵⁷ Sex differences in pharmacological parameters of a number of b-blocking agents (eg, metoprolol, propranolol) have been demonstrated in healthy subjects, suggesting that women may require lower than standard doses of these medications to avoid adverse effects.⁵⁸ Similar studies in women with anxiety disorders are still needed and the effects of menstrual cycle-related hormonal fluctuations on b-blockers remain to be explored.

Oral contraceptives
Oral contraceptives are hepatically metabolized and can interfere with metabolism of a number of drugs, increasing clearance of those metabolized by conjugation and glucuronidation and decreasing clearance of drugs metabolized by oxidation.^4,6 Antidepressants significantly metabolized by the liver are likely to be affected by oral contraceptive use (eg, imipramine). Oral contraceptives also affect disposition and dose requirements of antidepressants.

Women who take oral contraceptives may have higher blood concentrations and longer half-lives of drugs and therefore experience potentially more adverse effects and drug toxicity than men.⁶ Furthermore, drugs that increase hepatic enzyme induction may increase metabolism of contraceptives and cause failure of their contraceptive action.⁴ One study found that users of oral contraceptives who took a standard dose of diazepam were relatively "intoxicated" during menses because of pharmacodynamic changes of this benzodiazepine across the menstrual cycle,^4,11 possibly due to progesterone's effects on the GBRC amplifying the pharmacological effects of diazepam.² Despite these findings, the concomitant use of oral contraceptives and antidepressants appears to be relatively safe.

Overall, there is potential for women to have higher plasma levels of psychoactive drugs than men (especially if taken with oral contraceptives); therefore, women require lower doses and/or semi-intermittent dosing to minimize unwanted adverse effects.^2,6,11,29 Generalizations about pharmacological parameters across the menstrual cycle are not possible. The pharmacodynamics and pharmacokinetics of different psychoactive agents need to be studied across the menstrual cycle; generalization of data derived from one drug can be misleading and should be interpreted cautiously, even for drugs within the same class.¹¹Recommendations for Clinical Practice
A better clinical practice to manage anxiety disorders would include:

• A careful assessment of sex-specific triggers of anxiety.
• A clinical interview performed on 2 consecutive occasions (1 in the luteal phase and 1 in the follicular phase of the menstrual cycle).
• The use of a diary for at least 1 menstrual cycle to prospectively chart anxiety symptoms and help identify temporal associations with hormonal changes or possible comorbid disorders.

Once treatment is initiated, women with anxiety disorders should be evaluated during the course of the menstrual cycle for continuous effectiveness of their medications. Women who exhibit premenstrual exacerbation of anxiety disorders may respond to increased doses immediately preceding or during the luteal phase.^48,59 Progesterone augmentation may be a therapeutic option for women with anxiety disorders who do not respond, or who respond only partially, to standard therapeutic regimens.^2,38

 

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