Mental health in the peri- and postmenopause

Menopause is a natural event, which is defined by the final menstrual period and is preceded by many years of “menopausal transition” associated with marked hormonal changes. Although this is a physiological process, it may have a negative impact on women’s physical and mental health. Nowadays, with a life expectancy of around 80 years in many societies, women spend more than one third of their lives in peri-and postmenopause.¹ Historically, we are thus faced with a new challenge.

What is menopause?

“Menopause” refers to the last menstrual period, “perimenopause” (“menopausal transition” or “climacteric”) to the period with irregular menstrual cycles prior to menopause through to a year after the last period, “postmenopause” to the years following the final menstrual period. The mean age of menopause is 49 years with a wide variation. Menopausal transition with menstrual cycle irregularities and hormonal changes already starts 5–8 years earlier.² During these years the ovarian production of estrogens and progesterone decreases, often with strong fluctuations of blood levels, to stop permanently with menopause.

Common symptoms

Common symptoms are hot flushes and night sweats, which affect about 80% of women, insomnia, difficulties concentrating (brain fog), vaginal dryness, dyspareunia, decreased libido, anxiety, and depression.^1,3 The symptoms can continue for years and massively influence the quality of life and work performance.

Exploring the influence of menopause on mental health

Research exploring the nexus between menopause and mental health grapples with several hurdles. Older studies often lack precise differentiation between menopause, perimenopause, and postmenopause or had no longitudinal design to explore increase in incidence.¹ Interpretation of data is difficult, as mental changes in this period can arise from the loss or rather the fluctuations of sex hormones, more indirectly from vegetative and sleeping problems (domino theory), from psychosocial stressors, or from an interaction of all these factors.

The role of estrogens in mental health

Estrogens play a pivotal role for mental health. Particularly 17-β-estradiol, the estrogen most active in the brain, has neuroprotective as well aspsychoprotective properties and modulates neurotransmitter systems, including serotonin, norepinephrine, dopamine, glutamate, and acetylcholine.¹ Clinically it may enhance affective symptoms and cognitive functioning, mitigate stress sensitivity, aggressive and suicidal behavior, and have antipsychotic properties.¹

Menopause and mood disorders

There seems to be a two- to four-fold increase of depressive symptoms and even major depressive disorders during menopausal transition. Depressive symptoms have been shown to correlate with hormonal fluctuations, implying that estrogen fluctuations might act as triggers. A history of prior depression emerged as a consistent risk factor for perimenopausal depression. Hormone replacement might be protective.¹

Menopause and schizophrenic psychoses

As we have shown women develop schizophrenic psychoses approximately 4–5 years later than men, with a second peak of onsets after age 40. And women in this age group have more severe symptoms and illness coursescompared to men.⁴With the «estrogen protection hypothesis» we postulated that 17-β-estradiol protects against psychosis, and its loss unveils vulnerability.⁵

Estrogen replacement

Intervention studies

While hormone replacement therapy (HRT) has traditionally been associated with managing menopausal symptoms,⁶ it also seems to ameliorate depressive symptoms and major depressive disorders, especially if onset is during perimenopause.^1,6–9 It probably works via stabilizing fluctuating estrogen levels.⁹ There are also studies at odds, but many of those studies were small, started with estrogens long after menopause or used less potent forms of estrogen.¹⁰

In women with schizophrenic psychoses, the addition of estrogens to standard antipsychotics may reduce psychotic and depressive symptoms and potentially also cognitive decline.¹¹ Unfortunately, most studies on psychoses have been performed in young women, although the greatest effects would be expected in peri- and postmenopause.

Critical reappraisal of estrogen replacement

Estrogen replacement in peri- and postmenopause has been challenged by several studies, especially the Women’s Health Initiative (WHI) study, because of suspected side effects. However, this study was criticized for methodological flaws, particularly the high age of the women studied, the prophylactic application, and the use of synthetic hormones.^1,12 A reanalysis of data could not confirm the first findings, but rather showed benefits when estrogen replacement was started early in a so-called “window of opportunity”.¹³

If applied in the best mode it obviously can reduce not only menopausal symptoms and osteoporosis, but also depression, cognitive decline, coronary heart disease, and all-cause mortality.^{1,6–9,12,13}

Certainly, contraindications must be considered.^{1,6–8,12–14} However, in case of therapeutic use potential side effects must be compared to the side effects of psychotropics. It goes without saying that estrogens should only be substituted in close cooperation of psychiatrist and gynecologist, based on an individual risk-benefit assessment and with close monitoring. The final decision must always be taken by well-informed women themselves.

Unfortunately, after the first false alarms based on misinterpretations of the WHI data, professionals and patients now “overestimate the risks and contraindications and underestimate the impact of menopausal symptoms on a woman’s quality of life”.⁸

Implications for research

More research on indications and contraindications of estrogen replacement for women with mental disorders is urgently needed, especially also on the relative risks of hormones compared to psychotropics or on the best augmentation strategies.

Implications for prophylaxis and therapy

Hormone replacement during perimenopause is a so far underestimated therapeutic option for patients with mentaldisorders. Especially depression with onset in perimenopause might be treated with estradiol. More severe cases also need antidepressants.¹

In schizophrenic psychoses, estradiol may serve as an adjunct to antipsychotic medications, potentially permitting a reduction in antipsychotic dosage and its side effects. Menopausal hormone therapy is not officially approved for the treatment of depression in Europe or the USA. But it should be considered to alleviate low mood according to the guidelines of several national and international societies especially in perimenausal women with vasomotor symptoms.^6–8

Clinicians might prescribe it based on individual indications such as menopausal symptoms or prophylaxis of osteoporosis. Psychiatrists should have sufficient knowledge to advise their patients and cooperate with gynecologists. To this end they should know the best mode of hormone replacement, i.e., natural 17-β-estradiol applied transdermally (patches or gel). Progestogens must be added for endometrial protection in women with uterus. Here, “body identical” micronized progestogens seem to have the least side effects.^1,6,12,14

SERMs

Alternatives such as selective estrogen receptor modulators (SERMs) might also ameliorate symptoms in postmenopausal women with schizophrenia or depression.^1,15 However, results so far are inconsistent.

Psychopharmacotherapy

Psychopharmacotherapy in peri- and postmenopausal women should align with established guidelines. Estradiol can be used in a first step or added for augmentation. Special requirements for women should always be considered, such as gender differences in pharmacodynamics and pharmacokinetics or the interaction of medication with sex hormones.¹

Selective serotonin reuptake inhibitors (SSRIs) can ameliorate both depression and hot flashes. Their augmentation with estrogens seems especially effective.¹ Women with schizophrenia need higher antipsychotic doses in the postmenopause, probably due to estrogen withdrawal.¹

Psychotherapy

For women, this phase of life is often burdened with numerous psychosocial stressors. Aging might be realized quite harshly; health problems might arise. Sexual and relational problems might occur. Children might leave the house. And women might feel the need to reevaluate their expectations for life. Gender-specific socialization, gender roles, and gender role stereotypes as well as low self-esteem have often prevented women from pursuing their goals. With all the role changes occurring, they might for the first time realize this. Old suppressed role conflicts might get virulent and must be worked on in psychotherapy. Empowerment and the development of self-confidence are essential.^1,16

Psychotherapy in this age group should also pay attention to women’s subjective experience of the menopause, including their physical complaints, their fears and beliefs regarding menopause and the experienced changes, as well as their femininity and sexuality.¹⁶ Cognitice behavioral therapy (CBT) has been recommended and adapted for menopause.^8,17

Other therapeutic approaches

Education about menopause can empower women. Alternative medicine, though increasingly popular, so far lacks substantial evidence and confersits own risks.¹ Women might suffer from manifold physical problems, which should be carefully diagnosed and treated. Often, we see complex interactions between aging, hormonal, and psychosocial changes in women of this age group. Thus, integrating biological and psychosocial treatments tailored to individual needs is vital.

Conclusions

Menopause is a physiological event accompanied by massive hormonal and other biological alterations and often also manifold psychosocial changes. All these changes can obviously interact and trigger or aggravate mental problems and disorders, especially in vulnerable, predisposed women.¹⁸

Clinicians should not only use specific psychotherapeutic and psychosocial interventions as well as tailored psychopharmacotherapy, but also consider estrogen therapy. The latter should be prescribed based on individual risk-benefit assessments in close cooperation between psychiatrists, general practitioners, gynecologists, and - most importantly - the well-informed woman herself.

As we continue to unravel the complexities of perimenopausal mental health, additional research is imperative to refine treatment strategies and ensure optimal care for women in this critical phase of life.

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