Claudio N. Soares, MD, PhD

[[{"type":"media","view_mode":"media_crop","fid":"15695","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_1429663829078","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"783","media_crop_rotate":"0","media_crop_scale_h":"133","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Being a woman is a risk factor for 

. Female gender has been consistently identified as an independent predictor of sleep problems, including excessive daytime sleepiness, difficulty in initiating or maintaining sleep, and nighttime awakenings.

 More women appear to suffer from sleep disturbances than men, even when other factors, such as age, comorbid medical illnesses (eg, chronic pain), and 

 (eg, depression, anxiety), are taken into account.

This brief review addresses what is currently known about sleep problems in women. The main focus is on sleep issues that are particularly relevant to reproductive stages in a woman’s life cycle and therefore potentially linked to reproductive and/or hormonal factors. As such, some strategies for management that are specific to women will also be reviewed.

Menstrual cycle–related sleep disturbances

Sleep problems may emerge along with mild to moderate premenstrual symptoms or dysmenorrhea or may even accompany a more severe and disabling form of premenstrual disturbance-

. Polysomnographic data suggest that women with dysmenorrhea experience less efficient sleep and more wakefulness than women without painful menstrual cycles.

 On the other hand, changes in sleep architecture have not been systematically documented during the premenstrual phase of the menstrual cycle despite numerous (but subjective) reports of sleep disruption, hypersomnia, and insomnia.

Menstrual cycle–related sleep disturbances could be driven, at least in part, by changes in progesterone, prolactin, and melatonin dynamics. A recent 

 across the menstrual cycle included controls and women suffering from PMDD. The findings revealed high progesterone levels and elevated core body temperature in both groups during the luteal phase compared with the follicular phase of their menstrual cycles.

 Those with PMDD and insomnia, however, showed decreased melatonin secretion and increased slow wave sleep during luteal phases. These findings reinforce the hypothesis of an altered homeostatic regulation of the sleep-wake cycle in PMDD caused by changes in the 

Improvement of sleep disturbances in women with premenstrual syndrome (PMS) or PMDD is commonly related to symptomatic relief-management of cramping, edema, or painful symptoms with diuretics and anti-inflammatory medications or antidepressants for depressed mood, anxiety, and irritability. In some cases, the use of continuous oral contraceptives is recommended for PMS/PMDD; the effects of oral contraceptives on sleep do not seem to be detrimental but need to be further investigated.

It is important to highlight that some women might not experience isolated premenstrual problems; instead, they might present with a premenstrual exacerbation of an underlying psychiatric condition such as anxiety, depression, or bipolar disorder. Their complaints might, in fact, represent an exacerbation of sleep disturbances that are commonly associated with these underlying conditions. If well characterized, premenstrual exacerbation often requires a different treatment strategy, such as dose optimization of current therapies (eg, 

, benzodiazepines, atypical antipsychotics) or an add-on treatment during the most symptomatic, bothersome period (eg, 7 to 10 days before the onset of menses).

Sleep might be disrupted substantially and accompanied by significant physiological changes during pregnancy. Reports of sleep disturbances during pregnancy range from 15% to 80%, depending on the population studied and the time of assessment. Most women attribute their disrupted sleep during the first trimester to physical discomfort caused by nausea and vomiting as well as to stressors related to other factors (poor psychosocial support, unplanned pregnancy, etc). As pregnancy progresses through the second and third trimesters, there are increased awakenings and more fatigue, leg cramps, and shortness of breath.

Changes in sex hormones may contribute to the occurrence of 

 during pregnancy. Snoring occurs more often, possibly because of changes in progesterone levels and upper airway resistance. Some pregnancies are also accompanied by sleep apnea and restless legs syndrome. Although frank obstructive sleep apnea is not common, its management is important given the potential implications for maternal and fetal health.

Upper airway resistance increases throughout pregnancy and may contribute to frequent arousals and subsequent daytime sleepiness. Restless legs syndrome is quite common in pregnancy and may be partially related to lower folate levels and iron deficiency-iron depletion occurs with fetal development, and standard iron supplementation during pregnancy is often insufficient. Nutritional supplements should thus be considered for symptomatic or at-risk individuals.

 has been associated with poor obstetric and perinatal outcomes, including longer labors and higher incidences of cesarean deliveries and postpartum mood disorders.

 Overall, women in the postpartum period seem to experience lower sleep efficiency, with shorter latency to rapid eye movement sleep (characteristic of depression) and reduced total sleep time. Although it is expected that most awakenings and changes in sleep-wake ratios are related to the newborn’s feeding and direct care, other factors may play a role, including changes in melatonin and progesterone levels and increased irritability and mood swings (postnatal blues). Early detection, monitoring, and effective interventions (if needed) to alleviate mood and anxiety symptoms during pregnancy seem imperative to diminish the risk of postpartum mood and sleep disturbances.

Clinicians and patients are frequently puzzled by the complex interactions between sleep problems, aging, and menopause-related hormonal changes. Quite often it is difficult to determine whether sleep problems result from a primary disorder or are secondary to the emergence of hot flashes or depression. Perceived sleep problems (ie, decline in sleep quality) are commonly associated with depression, anxiety, or vasomotor symptoms. Objective sleep measures (polysomnographic studies) may also indicate a primary sleep disorder, such as obstructive sleep apnea or restless legs syndrome. In other words, sleep disturbances during the midlife years are quite frequently multifactorial.

 more than doubles (from 6.5% to 16%) among women transitioning into midlife. Several factors may contribute to this phenomenon; reduced progesterone levels may be a factor-progesterone is a known respiratory stimulant and upper airway dilator. Increased body weight may also be an important factor, although an increased risk of obstructive sleep apnea has been observed independently of body weight. 

 may also affect sleep in midlife women and appears to occur more frequently in women with vasomotor symptoms. In addition, fluctuations in estrogen and progesterone levels may alter GABA (Î³-aminobutyric acid) function and play a role in menopause-related insomnia, given GABA’s central role in sleep initiation and maintenance.

 during midlife has been associated with improvements in perceived sleep quality and self-reported sleeping problems; objective measures of sleep, however, have shown more modest results, with a reduction in sleep fragmentation, wakefulness, and arousals.

 Non-hormonal strategies, such as eszopiclone and 

, have been successful in improving insomnia in perimenopausal and early postmenopausal women.

 It is interesting to note that the use of a sleeping aid led to a reduction in the number of perceived nighttime hot flashes but not daytime hot flashes.

Other interventions such as quetiapine, when used to manage mood disorders, also have a positive effect on sleep and quality of life in symptomatic menopausal women.

Sleep problems may have a good response to nonpharmacological interventions, such as 

 and cognitive-behavioral therapies. Sleep hygiene measures include changes in daily routine (diet, exercise, and caffeine and alcohol consumption) as well as environmental changes to minimize the effects of noise, light, and room temperature. Cognitive-behavioral therapies for insomnia are effective when used alone or in combination with sleep aids.

Sleep problems are more common in women throughout the life cycle and, in some cases, are associated with or exacerbated by reproductive-related events. Underlying primary disorders, such as obstructive sleep apnea and restless legs syndrome, and psychiatric disorders, such as depression and anxiety, should always be investigated and ruled out. Quite often, concurrent treatment strategies are needed. For example, hormone therapy for the alleviation of hot flashes in symptomatic menopausal women in combination with antidepressants, hypnotics, or behavioral strategies may reduce the number and intensity of nocturnal hot flashes and improve sleep. A multiprofessional approach is recommended, particularly when sleep problems are accompanied by poorer quality of life and psychosocial impairment.

This article was acquisitioned and reviewed by Dr Karl Doghramji, Psychiatric Times Section Editor for Sleep Disorders. Dr Doghramji is Professor of Psychiatry, Neurology, and Medicine, and Medical Director of the Jefferson Sleep Disorders Center at Thomas Jefferson University in Philadelphia.

Dr Soares is Researcher and Consultant and Former Professor in the department of psychiatry and behavioural neurosciences at McMaster University in Hamilton, Ontario. He reports no conflicts of interest concerning the subject matter of this article.

 Klink ME, Quan SF, Kaltenborn WT, Lebowitz MD. Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia. 

 Soares CN. Insomnia in women: an overlooked epidemic? 

 Baker FC, Driver HS, Rogers GG, et al. High nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea. 

 Shechter A, LespÃ©rance P, Ng Ying Kin NM, Boivin DB. Nocturnal polysomnographic sleep across the menstrual cycle in premenstrual dysphoric disorder. 

Freeman EW, Halbreich U, Grubb GS, et al. An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome. 

 Lee KA, Gay CL. Sleep in late pregnancy predicts length of labor and type of delivery. 

 Saletu B, BrandstÃ¤tter N, Metka M, et al. Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression. 

 Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. 

 Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. 

 Dorsey CM, Lee KA, Scharf MB. Effect of zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study. 

 Soares CN, Joffe H, Rubens R, et al. Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. 

 Frey BN, Haber E, Mendes GC, et al. Effects of quetiapine extended release on sleep and quality of life in midlife women with major depressive disorder. 

 Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. 

Articles

This brief review addresses what is currently known about sleep problems in women. The main focus is on sleep issues that are particularly relevant to reproductive stages in a woman’s life cycle and therefore potentially linked to reproductive and/or hormonal factors.

Characteristics of Sleep Disorders in Women

The ocurrence and severity of anxiety disorders have been correlated with fluctuations in female sex steroid levels in both epidemiological and experimental studies.

 Female reproductive hormones play a role not only in the development and course of anxiety disorders but also in treatment response.

 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.




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.



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.

 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.

 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.

 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.



Progesterone acts as an allosteric modulator of GABA, with its anxiolytic effects attributed to the metabolite, allopregnanolone, on the GABA-benzodiazepine receptor complex (GBRC).

 A rapid withdrawal of progesterone, not absolute levels of progestins, appears to be implicated in behavioral premenstrual symptoms, possibly also via GABA-A receptors.

 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.



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.

 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%.

 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,

 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,

 a significant influence of the menstrual-cycle phase in treatment response has been observed.


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).

 Studies point to decreased numbers and/or subsensitivity of a

 decreased binding and/or sensitivity of GABA-A receptors, and/or decreased brain GABA levels in PD.

 Other physiological systems may also contribute to the pathophysiology of PD. Some studies report significantly increased basal cortisol levels in patients with PD,

 but a more robust finding is the increased adrenocorticotropic hormone (ACTH) and cortisol responses to hypothalamic-pituitary-adrenal (HPA) axis challenges.

 Serotonergic antidepressants are first-line treatment for PD,

 but benzodiazepines also display high efficacy in both short- and long-term treatment of PD.



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.

 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.

 Furthermore, enhancement of endogenous GABA exerts anxiolytic effects in experimentally induced panic.

 Administration of a synthetic progesterone before a panic challenge decreased panic and anxiety responses to a panicogenic agent in female patients with PD.

 

If further confirmed, these results may support a potential therapeutic value for sex steroid treatments.

 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.

 Progesterone's role in PD may also be mediated through effects on the b-adrenergic system.

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.

 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.



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.

 This suggests that in some women with PD, the reactivity to carbon dioxide and/or the suffocation alarm threshold may be impaired.


The impact of female reproductive hormones on the course and severity of social anxiety disorder (SAD) has yet to be investigated.

 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 a

 and decreased dopamine binding and dopamine reuptake sites in the striatum.

 No abnormalities in HPA axis function have been identified in SAD.

 Serotonergic dysfunction (particularly in females with social phobia) was reported in one study.

 Serotonergic medications are first-line treatment for patients with social phobia,

 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.

 Information on other steroids in SAD is lacking.




Clinical studies suggest that there are serotonergic mechanisms in obsessive-compulsive disorder (OCD), especially in women.

 However, increased dopamine neurotransmission has also been implicated.

 Recent retrospective studies have found that almost half of a sample of women with OCD reported experiencing premenstrual worsening of OCD symptoms.

 Findings from another study, with a greater percentage of women of reproductive age, showed that 20% of those with OCD reported premenstrual exacerbation.

 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.

 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,

 and serotonergic antagonism on dopamine neurotransmission (causing increased dopamine activity and consequent exacerbation of OCD).

 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.

 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.



 
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.

 A hyperreactive HPA axis, with exaggerated cortisol responses to stressors, is characteristic of PTSD.

 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.

 Another study reported low cerebrospinal fluid allopregnanolone levels in women of reproductive age with PTSD.



Serotonergic antidepressants are the treatment of choice because they show efficacy in both PTSD and comorbid disorders.

 Benzodiazepines should be used with caution in PTSD but may be effective as adjunctive therapy to SSRIs.


Information on physiological changes across the menstrual cycle in the absence of drug therapy is lacking,

 so it is not surprising that research on changes in drug action across the menstrual cycle is scarce as well.

 Sex differences in the pharmacodynamics and pharmacokinetics of a number of drugs have been described

 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.

 Interactions between psychoactive drugs and cyclical fluctuations in anxiety disorders might be expected because of the similar neural pathways activated,

 and may be particularly critical for psychoactive drugs with a narrow therapeutic index.


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.

 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.

 Gonadal hormones may affect bioavailability through changes in absorption rates, necessitating luteal-phase increases of some medications in certain women.


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.

 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.

-Glycoprotein levels are decreased by estrogen, resulting in highest levels during menses.

 Most anxiolytic medications are moderately to highly protein bound. More specifically, the binding of SSRIs is mostly to a

-glycoprotein, and some antidepressants (particularly tricyclic antidepressants) have a relatively narrow therapeutic index, putting women at an increased risk for adverse effects or toxicity.



Hepatic metabolism Sex differences in hepatic metabolism of a number of drugs have been reported.

 Peak rates at mid cycle cause lower blood levels of drugs in the luteal phase and higher drug levels in the follicular phase.

 There is no evidence that benzodiazepine metabolism is altered across the menstrual cycle.

 The estrogenic component of oral contraceptive pills is known to increase conjugation activity.



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,

 and it is responsible for hydroxylation of steroid hormones.

 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).

 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.


Women have lower renal clearance rates and concomitant increases in plasma levels of some but not all anxiolytic medications,

 possibly due to lower glomerular filtration rates, although limited evidence suggests no change in glomerular filtration rates across the menstrual cycle.

 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.

 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.



Limited evidence suggests that clinical effects of buspirone are not affected by sex.

 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.

 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 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.

 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.

 Furthermore, drugs that increase hepatic enzyme induction may increase metabolism of contraceptives and cause failure of their contraceptive action.

 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,

 possibly due to progesterone's effects on the GBRC amplifying the pharmacological effects of diazepam.

 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.

 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.


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.

 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.

 Kinrys G, Wygant LE. Anxiety disorders in women: does gender matter to treatment? [in Portuguese]. 

 Pigott TA. Gender differences in the epidemiology and treatment of anxiety disorders. 

 Hsiao MC, Hsiao CC, Liu CY. Premenstrual symptoms and premenstrual exacerbation in patients with psychiatric disorders. 

 Weinstock LS. Gender differences in the presentation and management of social anxiety disorder. 

 Seeman MV. Psychopathology in women and men: focus on female hormones. 

 Frackiewicz EJ, Sramek JJ, Cutler NR. Gender differences in depression and antidepressant pharmacokinetics and adverse events. 

 Fernandez-Guasti A, Agrati D, Reyes R, Ferreira A. Ovarian steroids counteract serotonergic drugs actions in an animal model of obsessive-compulsive disorder. 

 Barnes C, Mitchell P. Considerations in the management of bipolar disorder in women. 

 Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. 

 Schnoll SH, Weaver MF. Pharmacology: gender-specific considerations in the use of psychoactive medications. In: Wetherington CL, Roman AB, eds. 

Drug Addiction Research and the Health of Women

. Rockville, Md: National Institute on Drug Abuse; 1998:223-228.


 Yonkers KA, Kando JC, Cole JO, Blumenthal S. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. 

 Kendall DA, Stancel GM, Enna SJ. The influence of sex hormones on antidepressant-induced alterations in neurotransmitter receptor binding. 

 Rubinow DR, Hoban MC, Grover GN, et al. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. 

 Soares CN, Cohen LS, Otto MW, Harlow BL. Characteristics of women with premenstrual dysphoric disorder (PMDD) who did or did not report history of depression: a preliminary report from the Harvard Study of Moods and Cycles. 

 Genazzani AR, Stomati M, Morittu A, et al. Progesterone, progestagens and the central nervous system. 

 Eser D, Romeo E, Baghai TC, et al. Neuroactive steroids as modulators of depression and anxiety. 

 Matthew SJ, Coplan JD, Gorman JM. Neurobiological mechanisms of social anxiety disorder. 

 Nemeroff CB, Bremner JD, Foa EB, et al. Posttraumatic stress disorder: a state-of-the-science review. 

 Denys D, Zohar J, Westerberg HG. The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. 

 Morris ME, Lee JJ, Predko LM. Gender differences in the membrane transport of endogenous and exogenous compounds. 

 Ströhle A, Romeo E, di Michele F, et al. Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. 

 Bicikova M, Tallova J, Hill M, et al. Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. 

 Brambilla F, Biggio G, Pisu MG, et al. Neurosteroid secretion in panic disorder. 

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.

Claudio N. Soares, MD, PhD

Articles

Characteristics of Sleep Disorders in Women

The Complex Interrelationships of Menstrual Cyclicity and Anxiety Disorders