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Abstract

For some women, times of reproductive transition represent times of high risk for the onset or exacerbation of depressive symptoms. In order to maintain emotional stability, the female brain must adapt to fluctuations in hormones that affect neurotransmitter functioning. Difficulty with this adaptation, along with stresses related to social role transitions, may confer heightened vulnerability to depression. In this review, we summarize data regarding the course, expression and risks of depression and related symptoms during puberty and menarche, the luteal phase of the menstrual cycle, the perinatal period and perimenopause. We note treatment strategies that have been found to be effective for depressive symptoms during specific phases of the female reproductive cycle.

Keywords

depression menarche perimenopause postpartum pregnancy premenstrual dysphoric disorder puberty

Sex and gender influence the prevalence, expression, course and response to treatment of depressive disorders. Sex influences vulnerability to depression partly through hormonal and genetic effects on the developing fetal brain [1]. Posited gender influences on depression include cultural gender roles, differential stressors and differing cognitive styles [2].

For some women, times of reproductive transition pose a high risk for the onset or exacerbation of depressive or dysphoric symptoms. Sex hormones modulate neurotransmitter systems that regulate mood [3]. The female brain relies on mechanisms to adapt to hormonal flux, such as rapid upregulation and downregulation of neurotransmitter receptors [4]. Insufficient adaptive mechanisms could render some women vulnerable to dysphoria during times of hormonal change. Since times of hormonal change are often times of social role change, the unique social stressors associated with reproductive transitions can further increase vulnerability to depression.

In this review, we highlight clinically relevant data regarding depressive and dysphoric symptoms related to women's reproductive cycle events: puberty and menarche, the menstrual cycle, the perinatal period and perimenopause. These data can inform interventions that are tailored to each reproductive stage [5]. Since this review is intended as a literature update, data are included and summarized based on clinical relevance, with no specific methodologic inclusion criteria.

Puberty & menarche

Effects on depression

During adolescence, marked gender differences emerge in terms of vulnerability to depression. Prior to puberty, the prevalence of depression is somewhat higher in boys; after puberty, the prevalence markedly increases in girls relative to boys [6]. Among adolescent girls, pubertal stage predicts the emergence of depression better than age [7]. The incidence and persistence of depressive symptoms increase across pubertal stages in girls, but not in boys [8].

In addition to posited hormonal influences, factors that increase vulnerability to depression in pubertal girls include: body dissatisfaction, sexual abuse, cognitive styles and coping strategies, and early puberty onset.

Body dissatisfaction

Bodily changes that result from puberty in girls may move them away from a culturally ascribed ‘thin ideal’. As a result, pubertal girls tend to express more body dissatisfaction than boys, with pubertal boys more often pleased with the changes occurring in their bodies. Body dissatisfaction is a significant influence on the emergence of depression among adolescent girls [9].

Sexual abuse

Sexual abuse is more prevalent in girls than boys. It is a major risk factor for the emergence of depression in adolescent girls [10].

Cognitive styles & coping strategies

On average, boys and girls tend to develop different styles of thinking regarding stressful life events. More girls than boys are inclined to ruminate on problems, to believe that negative events are their fault and to believe that negative events will always happen to them. More boys than girls take an active problem-solving approach to stress. The cognitive styles that predominate in girls correlate with the likelihood of developing depressive disorders [11].

Early puberty onset

Among girls, early onset of puberty and menarche is associated with increased rates of depressive symptoms [12,13]. Mediating factors may include increased peer pressure, early sexual activity and increased body dissatisfaction in girls who mature early [14]. In addition, parental conflict and other stressors in the family environment may heighten the risk (independently or interactively) for both early-onset puberty and depression [15].

Assessment & treatment

A comprehensive assessment of adolescent girls whose depressive symptoms began during perimenarche includes asking about contributory factors, such as sexual abuse, body dissatisfaction, early sexual activity, peer pressure and family conflicts. Ascertaining a girl's usual approach to stressful situations may help to identify her cognitive style and coping strategies. The presence of these contributory factors can inform treatment. For example, psychotherapy could be focused on developing effective problem-solving skills, navigating family conflict, resisting peer pressure, recovering from sexual trauma and/or improving self-esteem and body image. Targeted psychotherapy is a first-line treatment for depression in adolescent girls, owing to data suggesting an increased risk of suicide in adolescents who take antidepressant medications [5].

Premenstrual dysphoric disorders

Types of premenstrual dysphoric disorders

Many women experience physical, psychological and/or behavioral changes related to their menstrual cycles. In approximately 1–8% of women of reproductive age, these changes meet the diagnostic criteria for premenstrual dysphoric disorder (PMDD) [16 –18]. By definition, women with PMDD experience at least five of 11 specific symptoms, beginning during the last week of the postovulatory phase of the menstrual cycle, remitting at, or shortly after, the onset of menses, and causing functional impairment. At least one symptom must be mood-related (e.g., depression, anxiety, irritability or mood lability) [19]. Among these mood symptoms, irritability is the most common [20,21]. Other symptoms can include reduced energy, difficulty concentrating, changes in sleep and/or appetite, feeling overwhelmed, joint or muscle pain, breast tenderness or swelling and abdominal bloating. Approximately 12–18% of women of reproductive age experience premenstrual dysphoric symptoms that cause distress and/or impairment, but have fewer than five discrete symptoms [22,23].

A related problem is premenstrual exacerbation (PME) of depression during the late luteal phase of the menstrual cycle. Women experiencing PME have symptoms that meet diagnostic criteria for recurrent major depression, but with a clinically significant increase in severity and likelihood of symptom recurrence during the postovulatory part of the menstrual cycle [24].

Although it is not understood why some women are vulnerable to premenstrual dysphoric symptoms, indirect evidence supports the hypothesis that some women's nervous systems are sensitive to cyclic changes in gonadal hormones [25]. Estrogen and progesterone influence the functioning of neurotransmitters, such as serotonin and γ-aminobutyric acid (GABA), that play a key role in mood states. A number of studies have found that women with PMDD have serotonergic and GABA-ergic abnormalities in the symptomatic luteal phase of their cycles, but not in the asymptomatic follicular phase [26]. Genetic variations in estrogen receptors that may underlie differential neurotransmitter and neuropeptide sensitivity are being explored [27].

Assessment of premenstrual dysphoric symptoms

Charting daily variations in symptoms for at least two menstrual cycles helps elucidate whether symptoms are linked to the menstrual cycle, and, if so, their pattern and severity. Scheduling two evaluation sessions, one premenstrual and one after menses onset, allows the clinician to compare symptoms and mental status examination at different cycle phases. For women already taking antidepressant medication, checking pre- and post-menstrual serum levels can help to determine whether pharmacokinetics differ substantially at different cycle phases [28]. In some women, hormonal influences on pharmacokinetics result in cyclically subtherapeutic medication levels that can be confused with PME.

Treatment & intervention

Since women may experience a wide variety of premenstrual symptoms, and exhibit marked individual differences in treatment responsiveness, a multifaceted treatment approach is often indicated. Interventions with some demonstrated efficacy are summarized in this section.

Antidepressant medication

For many women, a key component of treatment is a serotonergic antidepressant [29]. Among these, fluoxetine, paroxetine and sertraline are approved by the US FDA for the treatment of PMDD. Other antidepressants with serotonergic activity, including citalopram, clomipramine, escitalopram, fluvoxamine, nefazodone and venlafaxine, have been demonstrated to be superior to placebo for treating premenstrual dysphoric symptoms [30 –33]. By contrast, antidepressants with little to no serotonergic activity, such as buproprion, maproptiline and desipramine, have been found to be no more effective than placebo in treating PMDD [34 –36].

For premenstrual symptoms, antidepressants can be administered in a variety of dosing patterns, as summarized in Table 1. Choice of dosing regimen depends on patient preferences and tolerability of side effects.

Table 1.

Dosing strategies for premenstrual psychiatric symptoms.

Dosing strategy	Description
Continuous dosing	Medication is administered everyday throughout the menstrual cycle
Luteal-phase dosing	Medication is started at ovulation, on approximately day 14 of a 28-day period, and stopped 1–2 days after menstrual bleeding begins
Symptom-onset dosing	Medication is started as soon as premenstrual symptoms are noticed, and stopped 1–2 days after menstrual bleeding begins
Luteal-phase boosting	A higher dose is started at ovulation, on approximately day 14 of a 28-day period, and lowered 1–2 days after menstrual bleeding begins

Continuous dosing involves administering the antidepressant daily, at a consistent dose. Women with comorbid mood or anxiety disorders, those who have irregular menstrual cycles or difficulty keeping track of their cycles, and patients subject to adverse effects from abrupt medication discontinuation may benefit from continuous dosing.

Luteal-phase dosing involves initiating treatment at the time of ovulation (approximately day 14 of a 28-day cycle) and discontinuing 1–2 days after menses begins. A meta-analysis of 29 serotonergic antidepressant treatment studies demonstrated that intermittent dosing was significantly more effective than placebo for premenstrual symptom reduction, but was somewhat less effective than continuous dosing [37]. A luteal-phase dosing strategy is suitable for women with regular menstrual cycles who are able to adhere to the on/off timing, have no symptoms during the follicular phase and are concerned regarding medication side effects.

Symptom-onset dosing involves beginning medication as soon as premenstrual symptoms are noticed and stopping medication within 3 days of menses onset [38]. A study comparing symptom-onset and luteal-phase dosing of escitalopram for PMDD found significant improvement using either dosing strategy, although women with severe PMDD were less likely to improve with symptom-onset dosing [39].

Luteal-phase boosting involves increasing the antidepressant dose during the luteal phase and decreasing to a lower dose at onset of menses. Limited data suggest that this dosing strategy is effective for women with PME [40].

Approximately 40% of women with PMDD do not respond to serotonergic medications [41]. Nonresponders and partial responders require a more comprehensive approach, using one or more of the interventions described below.

Anxiolytic medication

Anxiolytic medications are not FDA-approved for the treatment of PMDD. Studies of the efficacy of benzodiazepines for PMDD symptoms show mixed results [42 –44]. Buspirone, a nonbenzodiazepine anxiolytic agent, may be effective for alleviating PMDD symptoms, but data are limited [45,46]. In clinical practice, benzodiazepines may be used during the evaluation phase to alleviate anxiety while charting symptoms, for temporary relief while initiating longer-term treatment, or as needed for occasional breakthrough symptoms.

Hormonal intervention

Oral contraceptive pills have variable effects on premenstrual mood, with most women experiencing no change, and more women experiencing worsening than improvement [47]. One exception is drospirenone/ethinyl estradiol, administered as 24 days of active pills followed by a 4-day drug-free interval, the only oral contraceptive agent FDA-approved for treating PMDD [48]. Pilot data suggests that this agent may also be effective as an adjunct to antidepressants for premenstrual exacerbation of depression [49]. Gonadotropin-releasing hormone (GnRH) agonists are also effective [50]. These medications cause a ‘chemical menopause’ and are generally used only for temporary relief in severe cases, although ongoing research is investigating ways to ‘add back’ estrogen and progesterone in order to improve safety without causing symptom recurrence [51]. Hysterectomy with oophorectomy is effective, and can be considered in women with GnRH-responsive symptoms who have an additional indication for the surgery [52,53].

Herbal therapy

In a randomized, double-blind, placebo-controlled trial, vitex agnus castus (chasteberry) extract significantly decreased anger, irritability, headache and breast fullness compared with placebo [54]. When compared with fluoxetine in a randomized, single-blind trial, chasteberry was equally effective overall, but fluoxetine was more effective for emotional symptoms while chasteberry was more effective for physical symptoms [55].

Nonpharmacologic interventions

Nonpharmacologic approaches can help to ameliorate premenstrual dysphoric symptoms, with or without adjunctive medication. These include cognitive-behavioral therapy [56], aerobic exercise [57] and calcium supplementation [58]. Promising pilot data suggest that further study of phototherapy and biofeedback is warranted [59].

Perinatal depression

Description & prevalence of perinatal mood changes

Approximately 9.4–12.7% of pregnant women develop a major depressive episode during pregnancy [60]. Untreated depressive symptoms during pregnancy are associated with an increased risk of preterm birth [61] and enduring changes in infant temperament and subsequent stress response in offspring [62].

Three distinct but overlapping types of postpartum mood disturbances are ‘blues’, depression and psychoses. Postpartum ‘blues’ is a normal mood change experienced by approximately 50% of women within the first few weeks after delivery, characterized by pronounced emotional reactivity but not a sustained, predominant depressed mood [63]. Postpartum major depression is experienced by up to 21.9% of perinatal women within the first year after giving birth [60]. Postpartum depression may reduce breastfeeding [64], impair parenting capability in conjunction with other risk factors [65], and adversely affect children's cognitive, emotional and behavioral development [66,67]. Postpartum psychotic symptoms arise in approximately one in 1000 women giving birth, but in up to 35% of women with bipolar diatheses [68]. Postpartum psychotic symptoms are most often part of a mood episode, whether manic, depressive or mixed [69]. Onset is usually within the first 3 weeks after delivery, often beginning within the first 3 days [70]. Compared with nonpostpartum psychotic mood episodes, there is more disorientation and mood lability in postpartum episodes [71 –73]. Difficulty with neuronal adaptation to abrupt hormonal change is posited to contribute to vulnerability to each of these postpartum mood states [74]. Other posited contributory factors to postpartum depression include heightened postpartum inflammatory responses and hypothalamic–pituitary–adrenal axis dysregulation [75,76]. Psychosocial risk factors may also be influential, such as difficulty adjusting to unrealistically high personal and social expectations regarding motherhood [77].

Treatment of perinatal depression

When considering pharmacotherapy for perinatal psychiatric symptoms, the risks of untreated symptoms must be weighed against the risks of medication. Relapse rates are high for women with major depression who discontinue medication while pregnant [78]. Risks of medication can be reduced by choosing agents that have been relatively well studied in human pregnancy and have not been associated with major neonatal or pregnancy complications. Emerging data are also suggesting dosing strategies during pregnancy that can minimize risks, such as using pharmacokinetic measures to titrate dosing, or using partial dose tapers near the end of pregnancy to reduce the risk of neonatal withdrawal [79].

Interpersonal psychotherapy has been found to be effective for treating and preventing perinatal depression, particularly in women having difficulty navigating perinatal role transitions [80]. If maternal psychiatric symptoms have impaired the mother–infant relationship, mother–infant psychotherapy may be helpful [81].

Perimenopause & depression

Impact of perimenopause on depression

The transition to menopause is a time of heightened risk of depressive symptoms. It is estimated that there is at least a twofold increase in new-onset depressive symptoms and major depressive episodes during perimenopause [82]. The risk of developing depressive symptoms is especially high when levels of sex hormones fluctuate most [83]. There are some data suggesting that women with histories of PMDD and/or postpartum depressive symptoms may be more vulnerable to perimenopausal depression [84,85].

Factors that may contribute to depressive symptoms in perimenopausal women include:

Stress: perimenopausal women have greater physiologic reactivity to stress than premenopausal women [86]. Unanticipated stress, uncontrollable stress and stressors that adversely affect self-esteem are especially likely to contribute to perimenopausal depression [87]. Frequent midlife stressors include career problems, deaths and serious illnesses of significant others, as well as parenting, marital tensions and role changes [88];

Hot flashes: women who experience hot flashes are significantly more likely to develop depressive symptoms. While some have posited a ‘domino effect’ (i.e., physical discomfort and/or resultant sleep deprivation leading directly to depression), most studies have found that hot flashes and depressive symptoms are correlated, but without one causing the other [89];

Other health problems: women who experience chronic medical problems, such as migraines, diabetes and fibromyalgia, may be more vulnerable to perimenopausal depression, especially if they experience role limitations owing to health problems [90,91];

Personal and cultural attitudes: attitudes regarding menopause, and the role of older women in a given culture, may influence the likelihood that a woman will become depressed in the transition to menopause [92].

Assessment of perimenopausal women for depression

Untreated depression can increase medical morbidity after menopause, including risks from cardiovascular disease [93], diabetes [94] and osteoporosis [95]. The high prevalence and risks of untreated symptoms suggest that universal screening for depression is warranted among perimenopausal women in primary-care settings [96]. This can be accomplished with validated self-report questionnaires, such as the nine-item Patient Health Questionnaire (PHQ-9) [97]. The PHQ-9 facilitates the diagnosis of major and minor depression, rates symptom severity and can be used to track response to treatment.

Once a woman has been diagnosed with perimenopausal depression, assessing for contributory factors and protective factors can help guide an effective treatment plan. Relevant factors to assess are shown in Table 2 .

Table 2.

Assessing women with perimenopausal depression: contributory and protective factors.

Factor	Contributory to depression	Protective against depression
Stress	Unpredictable, uncontrollable stress; stressors that lower self-esteem; negative attitude toward aging	Stress management skills; viewing menopause as a normal life transition
General health	Sleep disturbance; pain; comorbid medical conditions	Meeting NIH guidelines for physical activity; healthy diet and eating patterns
Social context	Social isolation; role deprivation (e.g., job loss, experiencing departure of children as a loss)	Strong social support network; employment; more formal education

Treatment & intervention

Effective treatment for perimenopausal depression is usually multifaceted, directed at reducing contributory factors and enhancing protective factors. Interventions can include: antidepressant medication, estrogen therapy, psychotherapy, and exercise and physical activity.

Antidepressant medication

When choosing antidepressant medication for perimenopausal women, it is helpful to select agents that simultaneously treat other symptoms, such as hot flashes or pain, without compounding comorbid medical problems or risking dangerous drug–drug interactions. Antidepressants that have been demonstrated to reduce hot flashes in at least some studies include paroxetine, fluoxetine, citalopram, venlafaxine and desvenlafaxine [98]. Serotonin-norepinephrine reuptake inhibitor antidepressants can reduce chronic pain, but the serotonin-norepinephrine reuptake inhibitor venlafaxine may cause hypertension [99]. Antidepressants that cause sedation or postural hypotension could increase the risk of falls, in turn increasing fracture risk in women with osteoporosis. Selective serotonergic reuptake inhibitor antidepressants may reduce bone density [100], which can be monitored as needed for women at risk of osteoporosis.

Estrogen therapy

Estrogen has antidepressant properties in some women. Although study findings are not consistent, available data suggest that women most likely to benefit from estrogen are:

Women who are perimenopausal, not postmenopausal [101 –103];

Women with minor depression, not major depression [104];

Women with a partial response to antidepressant medication, with estrogen used in order to augment response [104,105].

Caveats regarding the use of estrogen as an antidepressant are that its use for this purpose is not FDA-approved, that the risk:benefit ratio is unclear, and that there are insufficient data on optimal dosing and formulations of estrogen [5].

Psychotherapy

Interpersonal psychotherapy is useful for perimenopausal women whose depression is influenced by problems with role transitions, such as career changes, marital stress and parenting problems [106]. It can help women re-examine and shed constricting roles, adopt new roles and negotiate with others for support.

Cognitive-behavioral therapy is useful for perimenopausal women whose depression is influenced by difficulty managing midlife stressors and/or by negative attitudes toward aging. It can help women learn to counter negative thoughts, solve problems and activate themselves when depressive symptoms lead them to feel unmotivated and isolated [107].

Exercise & physical activity

Physical activity alleviates depressive symptoms, while also promoting general health after menopause [108]. However, physical activity declines after menopause in many women [109]. Clinicians can be effective in encouraging women to increase physical activity levels via the following interventions:

Comprehensive assessment to determine whether there are medical limitations on intensity and type of exercise, and to allay unfounded anxieties regarding medical risks of exercise or vigorous physical activity [110];

Helping women define effective goals for exercise. Research suggests that women whose goals are to increase wellbeing and reduce stress sustain physical activity more effectively than women whose goal is to lose weight [111];

Emphasizing the importance of making time for self-care [112];

Focusing on how women can integrate more physical activity into their daily routines, emphasizing that several small increments of activity throughout the day are as effective as one sustained exercise session [110,112];

Helping women identify physical activities they enjoy [112].

Conclusion

Most women do not develop depressive symptoms during reproductive transitions. However, evidence is accumulating to support the hypothesis that some women have a heightened vulnerability to emotional disturbance at times of rapid hormonal flux. Understanding the influence of these reproductive transitions and incorporating evidence-based treatment modifications geared to each reproductive phase can promote optimal mental health in women.

Future perspective

Research is elucidating how genetic makeup, hormonal exposure and environmental stressors interact to shape sex and gender differences in psychopathology. Studies are exploring the reasons for sexual dimorphism in the brain, which begins during fetal development. Researchers are investigating the implications of this sexual dimorphism for normal behavior and psychopathology, including how small inborn sex differences are shaped and amplified by subsequent hormonal flux, life experiences and cultural gender roles.

Normative data concerning sex differences, gender differences and the influence of reproductive cycle events may facilitate the development of more effective treatments for depression during perimenarche, the luteal phase of the menstrual cycle, pregnancy, the postpartum period and perimenopause. Pharmacokinetic and pharmacogenomic studies are shedding light on how pharmacotherapy could be modified to give optimal therapeutic results for individual women at different stages of the reproductive cycle, while minimizing adverse medication effects. Increased knowledge of the complex interactions between ovarian hormones and the nervous system is guiding the development of targeted hormonal interventions. A deepening understanding of social role change and stressors during reproductive transitions is promoting the development of effective, targeted psychotherapies.

Since heightened risk of depression is a predictable accompaniment of reproductive cycle events for some women, prevention of such risk is possible and essential. Research is underway to better identify girls and women at risk for reproductive-linked depressive episode, and to understand how to protect women's brains at vulnerable times.

Executive summary

Introduction

Times of rapid hormonal flux confer a high risk of development or exacerbation of psychiatric symptoms for a subset of women.

High-risk reproductive transitions include puberty and menarche, the luteal phase of the menstrual cycle, the perinatal period and perimenopause.

Premenstrual dysphoric disorders

Approximately 1–8% of menstruating women experience premenstrual dysphoric disorder (PMDD).

Some women experience a separate but related condition, premenstrual exacerbation (PME) of depression.

PMDD can be treated with serotonergic antidepressant medication, administered as a continuous dose, luteal-phase dose or symptom-onset dose.

PME can be treated with serotonergic antidepressant medication, administered as a continuous dose or luteal-phase boosted dose.

Additional interventions for PMDD include psychotherapy, aerobic exercise, calcium supplementation, drospirenone/ethinyl estradiol and vitex agnus castus.

Perinatal depression

The perinatal period is a time of heightened risk for depression.

This heightened risk may be due to a combination of factors, including failure of the CNS to adapt to abrupt hormonal change, hypothalamic–pituitary–adrenal axis dysregulation, heightened postpartum inflammatory response and psychosocial stressors.

Treatment considerations include weighing the risks of medication against the risks of untreated symptoms, and using prescribing practices that reduce the risks of medications for the woman, her fetus and/or her breastfed infant.

Interpersonal psychotherapy, cognitive-behavioral therapy and mother–infant therapy can be effective for specific types of symptoms and problems.

Perimenopause & depression

Rates of depression increase during perimenopause, especially in women with histories of premenstrual and/or postpartum depression.

The risk of developing perimenopausal depressive symptoms is influenced by midlife stress, general health problems, perimenopausal physical symptoms and cultural attitudes toward aging.

Antidepressant medication can be chosen to reduce other symptoms, such as pain and/or hot flashes, and with care not to increase other midlife health risks, such as fractures and hypertension.

Estrogen supplementation is not generally effective as monotherapy for major depression, but can alleviate symptoms of minor depressive symptoms in some women, and may be an effective adjunct when depressive symptoms respond partially to an antidepressant.

Psychotherapy and aerobic exercise can help to alleviate perimenopausal depressive symptoms.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Depression and Related Disorders during the Female Reproductive Cycle

Abstract

Keywords

Puberty & menarche

Effects on depression

Body dissatisfaction

Sexual abuse

Cognitive styles & coping strategies

Early puberty onset

Assessment & treatment

Premenstrual dysphoric disorders

Types of premenstrual dysphoric disorders

Assessment of premenstrual dysphoric symptoms

Treatment & intervention

Antidepressant medication

Anxiolytic medication

Hormonal intervention

Herbal therapy

Nonpharmacologic interventions

Perinatal depression

Description & prevalence of perinatal mood changes

Treatment of perinatal depression

Perimenopause & depression

Impact of perimenopause on depression

Assessment of perimenopausal women for depression

Treatment & intervention

Antidepressant medication

Estrogen therapy

Psychotherapy

Exercise & physical activity

Conclusion

Future perspective

Footnotes

References