Perimenopause, menopause and the brain

The menopause is when menstruation ceases owing to a reduction in hormone production from the ovaries. It is an indication that the ovaries are failing and no longer producing the hormones they have done throughout the reproductive years. The perimenopause represents a variable timeframe before the menopause when the hormones that are produced by the ovaries (oestradiol, progesterone and testosterone) can be highly fluctuant and responsible for many physical and psychological symptoms.

The average age of the menopause in the UK is 51, and perimenopausal symptoms are commonly seen during the transition towards this in the mid-to-late 40s, although they can occur much earlier. Patients may also experience an iatrogenic menopause, where ovaries may be surgically removed or their function affected by medical treatment such as chemotherapy, leading to a lack of hormone production.

The psychological symptoms that could be attributed to a typical menopause include anxiety, low mood, paranoia, anhedonia, irritability, dissociation, insomnia and feelings of low self-worth. These symptoms come about because of the impact of hormonal changes on the brain. Psychological symptoms associated with menopause may be sufficiently severe to reach ‘caseness’ for a mental disorder or may exacerbate underlying pre-existing mental disorders.

Oestradiol, progesterone and testosterone are important hormones in brain function, oestradiol most notably so. Oestradiol has a role in the modulation of serotonin, and serotonergic pathways are thought to be involved in the neurobiological basis of depression.^{Reference Herson and Kulkarni1} When oestradiol levels fluctuate during the perimenopause and menopause, destabilising effects on mood can therefore occur.^{Reference Douma, Husband, O'Donnell, Barwin and Woodend2} Other neurotransmitter pathways, including dehydroepiandrosterone sulfate and gamma-aminobutyric acid (GABA),^{Reference Herson and Kulkarni1} are also affected by the menopause and thought to be linked to changes in mood.

In addition to oestradiol, total and free testosterone levels decline with age, often beginning in the mid reproductive years. There is evidence that transdermal testosterone therapy gives a meaningful improvement in psychological well-being^{Reference Davis3} as well as in the treatment of hypoactive sexual desire disorder.^{Reference Islam, Bell, Green, Page and Davis4}

Progesterone receptors are also found within the brain, and reduced levels of progesterone, although not seen to have a consistent impact on psychological well-being, can have an impact on menopausal symptomology which would otherwise lead to an increase in psychological distress. An example of this is progesterone replacement improving insomnia; progesterone is converted to allopregnanolone in the brain, which leads to downstream GABAergic effects resulting in improvement in sleep.^{Reference Mikin5} Improved sleep can in turn enhance emotional resilience.

Pre-existing severe mental illness and the perimenopause

Fluctuations of hormone levels and the eventual decline in oestrogen levels during the perimenopause represent a risk factor for new-onset psychological symptoms (including anxiety, low mood and brain fog, which are commonly experienced in the normal course of menopause,^{Reference Monteleone, Mascagni, Giannini, Genazzani and Simoncini6} and first episodes of mental illness, including depressive episodes^{Reference Freeman, Sammel, Lin and Nelson7} and psychotic episodes^{Reference Fisher, Ortiz and Powers8} among others).

Oestradiol is a potent neurosteroid and tends to be ‘neuroprotective’:^{Reference Kulkarni9} stages of life where oestradiol is relatively low (premenstrually, postpartum, peri- and postmenopause) are associated with increases in depressive^{Reference Soares and Zitek10} and psychotic^{Reference Brzezinski-Sinai and Brzezinski11} episodes in women.

In this paper, we largely consider what happens to patients with pre-existing chronic mental illness who may be at risk of a relapse in symptoms^{Reference Worsley, Davis, Gavrilidis, Gibbs, Lee and Burger12} or develop a need for higher doses of medication or new-onset treatment resistance.^{Reference Gonzalez-Rodriguez, Catalan, Penades, Ruiz Cortes, Torra and Seeman13} It is worth noting that some patients with mental illness seem to have a particularly hormonal signature to their relapse pattern (e.g. episodes of illness at hormonal events such as menarche, and premenstrually, perinatally and with some forms of hormonal contraception). This group of patients in particular are at risk of a decline in their mental health with the perimenopause.^{Reference Herson and Kulkarni1,Reference Studd and Nappi14}

Depression

Patients with a pre-existing depressive disorder are at risk of relapse in the perimenopausal period^{Reference Worsley, Davis, Gavrilidis, Gibbs, Lee and Burger12} and may find that antidepressants which had previously helped are no longer effective,^{Reference Worsley, Davis, Gavrilidis, Gibbs, Lee and Burger12} or that a much higher dose is required to have the same effect.^{Reference Grigoriadis, Kennedy and Bagby16} There may also be a slightly different quality to the symptoms compared with premenopausal depressive episodes, the nuance of which is distinguished by the MENO-D questionnaire (Box 1)^{Reference Kulkarni, Gavrilidis, Hudaib, Bleeker, Worsley and Gurvich17} and summarised in Table 1.

Box 1 Prompt questions for MENO-D.

See www.maprc.org.au/sites/www.maprc.org.au/files/MENO-D_0.pdf for question responses and scoring details.

1. 1 Over the last 2 weeks have you noticed reduced energy levels?

2. 2 Over the last 2 weeks have you experienced increased paranoid thinking?

3. 3 Over the last 2 weeks have you felt more irritable?

4. 4 Over the last 2 weeks has your self-esteem been lowered?

5. 5 Over the last 2 weeks have you withdrawn socially?

6. 6 Over the last 2 weeks have you experienced heightened levels of anxiety?

7. 7 Over the last 2 weeks have you experienced physical symptoms?

8. 8 Over the last 2 weeks have you experienced sleep disturbance?

9. 9 Have you gained weight (in comparison to pre-menopause weight)?

10. 10 Over the past 2 weeks have you experienced a decreased libido?

11. 11 Over the last 2 weeks have you noticed any memory related difficulties?

12. 12 Over the past 2 weeks have you experienced problems concentrating?

Table 1 Comparison of presentation of perimenopausal depression with depressive episodes not associated with menopause

In England and Wales, the highest rates of suicide in women are seen in the 45–49-year-old age group (7.8 per 100 000 in 2021).¹⁸ Similar trends are seen in data from Australia; this has been examined and may be related to symptoms associated with perimenopause.^{Reference Kulkarni19} A recent review by the Healthcare Safety Investigation Branch in response to a death by suicide of a perimenopausal woman has identified the management of perimenopausal symptoms in mental health services as a particular concern and tasked the Royal College of Psychiatrists with improving this.²⁰

Physical health risks associated with menopause

As levels of oestradiol, progesterone and testosterone decline during the perimenopause and into the menopause, we see an increase in a number of health risks. Postmenopausal patients are at increased risk of osteoporosis, cardiovascular disease, diabetes and cognitive decline. This is before mentioning the impact of perimenopausal and menopausal symptoms that can lead to a decline in overall well-being and difficulty in maintaining a healthy lifestyle, which both indirectly contribute to poorer physical health.^{Reference Langer35}

Physical health risks associated with severe mental illness

People living with mental illness are recognised as having reduced life expectancy in comparison with the general population and are seen to have worse levels of physical health, especially with respect to the cardiovascular system.^{Reference Doherty and Gaughran36}

Mental illnesses also complicate strategies for the prevention and management of medical illnesses. There are a variety of factors that are seen to affect the health inequalities that those with mental illness face, including poverty and social isolation, access to healthcare, genetics, treatment side-effects and lifestyle choices.^{Reference Walker, McGee and Druss37}

Physical health implications of HRT

HRT has faced a plethora of negative press coverage over the past 20 years. The Women's Health Institute randomised controlled trial³⁸ is understood to have led to a decline in HRT prescriptions, as clinicians felt a significant level of uncertainty about the risk/benefit ratio of prescribing HRT. However, more reassuring outcomes following re-analysis of the data mean that the benefits of HRT can be more readily appreciated without concern about causing harm if appropriate HRT is prescribed.

By appropriate HRT, we mean body-identical HRT, which we know has no venous thromboembolic risk^{Reference Simon39} and causes no significant increase in breast cancer risk^{Reference Abenhaim, Suissa, Azoulay, Spence, Czuzoj-Shulman and Tulandi40} and is the gold-standard HRT that should be considered as first line therapy. In summary, body-identical HRT comprises transdermal oestradiol, in a patch, gel or spray, alongside micronised progesterone capsules for people who have a womb and require endometrial protection. An alternate means of providing endometrial protection is a Mirena coil. Further adjuncts include vaginal hormone preparations for genitourinary symptoms of menopause, which can indirectly affect psychological well-being,^{Reference Newson, Kirby, Stillwell, Hackett, Ball and Lewis41} and transdermal testosterone, as a cream or gel, which is currently not licensed for use in women in the UK but can have a pivotal role in menopausal symptom management. Body-identical HRT is generally safe as it quite simply replaces the missing reproductive hormones, while improving symptoms as well as future health.^{Reference Gordon, Rubinow, Eisenlohr-Moul, Xia, Schmidt and Girdler42}

November 2015 saw the National Institute for Health and Care Excellence publish guidance on the diagnosis and management of menopause.⁴³ The British Menopause Society has issued a consensus statement on HRT,^{Reference Hamoda, Panay, Pedder, Arya and Savvas44} and there is also guidance from the International Menopause Society published in 2016.^{Reference Baber, Panay and Denton45} A simple prescribing guide summarising these guidelines and available evidence has been written by Newson Health Menopause Society in 2022.⁴⁶

HRT can improve symptomatology of the perimenopause and menopause, which in itself can offer huge improvement in quality of life. There is also evidence that it can reduce risk of osteoporosis and cardiovascular disease, colon cancer, type II diabetes and cognitive decline.^{Reference Langer35,Reference Langer, Hodis, Lobo and Allison47}

HRT as a potential adjunct to psychotropic medication

HRT can be used to restore the declining levels of hormones in the perimenopause. Psychiatrists regularly assess and treat hypothyroidism, recognising it as an endocrinological condition with important psychological sequelae sometimes causing or at best exacerbating mental illness. The hormonal decline with perimenopause is more prevalent than hypothyroidism, and it is imperative that it is considered and managed alongside treatment plans for mental illness.

In new-onset low mood associated with the perimenopause, HRT (oestradiol and progestogen if needed) is the first line of treatment, and there is no evidence that antidepressants are beneficial.⁴³ Current guidelines are to treat perimenopausal depression as any other depressive episode. However, it is known that peri- and postmenopausal people do not respond to selective serotonin reuptake inhibitors as effectively as other demographics,^{Reference Grigoriadis, Kennedy and Bagby16} and rates of discontinuation due to adverse events are significant.^{Reference Wu, Tseng, Wu, Li, Chen and Kuo48} There is limited evidence that desvenlafaxine is slightly efficacious in treating major depressive disorder in post- and perimenopausal patients, but other antidepressants have not been effectively scrutinised in this population.^{Reference Herson and Kulkarni1} Oestradiol therapy has been shown to be beneficial in the treatment of perimenopausal depression both as a standalone agent and with even greater effect when combined with antidepressants.^{Reference Herson and Kulkarni1}

As discussed above, there is a strong correlation between vasomotor symptoms and anxiety symptoms. Venlafaxine is licensed for the treatment of vasomotor symptoms in the perimenopause, but HRT has been shown to be more effective.^{Reference Khan, Kapoor, Faubion and Kling49}

Throughout reproductive life, oestradiol is thought to raise the threshold of vulnerability to developing psychotic symptoms by being protective against schizophrenia;^{Reference Kulkarni9} psychotic symptoms have been shown to be most severe in the premenstrual phase of the cycle when oestradiol levels are low.^{Reference Riecher-Rossler, Hafner, Stumbaum, Maurer and Schmidt50} There have been case reports of new-onset perimenopausal psychosis failing to respond to antipsychotics but responding to HRT (oestradiol and progestogen) either as a sole agent^{Reference Bergemann, Abu-Tair and Strowitzki51} or as an adjunct to antipsychotics.^{Reference Lindamer, Lohr, Harris and Jeste52}

In premenopausal patients with chronic schizophrenia, transdermal oestradiol improves psychotic^{Reference Kulkarni, Gavrilidis, Wang, Worsley, Fitzgerald and Gurvich53} and depressive^{Reference Lascurain, Camunas-Palacin, Thomas, Breadon, Gavrilidis and Hudaib54} symptoms. A community study of postmenopausal women with psychotic illnesses found that those on HRT had fewer negative symptoms and needed lower doses of antipsychotics compared with women who had never received hormone therapy.^{Reference Lindamer, Buse, Lohr and Jeste55} A hypothesis with face validity is that using HRT to treat perimenopausal symptoms will optimise quality of life (e.g. improving sleep and reducing psychological distress and physical symptoms) and is likely to reduce the risk of relapse in schizophrenia.

There has been very little research into the role of HRT in the management of bipolar affective disorder through the perimenopause, but a small study found that perimenopausal women with a pre-existing diagnosis of bipolar affective disorder who did not use HRT had significant worsening of their symptoms of bipolar affective disorder compared with those who used HRT.^{Reference Freeman, Wosnitzer Smith, Freeman, McElroy, Kmetz and Wright22}

Hyperprolactinaemia with antipsychotics: an iatrogenic exacerbation of menopause?

Patients with chronic illnesses treated by antipsychotic medication (and to a lesser extent antidepressants) often have iatrogenic hyperprolactinaemia. Prolactin suppresses the hypothalamic secretion of gonadotrophin-releasing hormone, which leads to a suppression of follicle-stimulating hormone (FSH) and luteinising hormone and downstream suppression of sex hormones (oestradiol, progesterone and testosterone). This iatrogenic hypo-oestrogenic state may be exacerbated by the decline in oestradiol secondary to menopause (Fig. 1). It can also be hard to assess whether a patient with oligomenorrheoa is perimenopausal or not when prolactin is already high. Although measuring hormones to diagnose menopause is not usually recommended,⁴³ in this scenario measuring FSH may be helpful, as raised FSH will give evidence that the patient may be perimenopausal as well as hyperprolactinaemic.

Fig. 1 Interactions of psychotropic medication and hormonal events on the hypothalamopituitary–gonadal axis. The − symbol indicates inhibitory action; the + symbol indicates stimulation. FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinising hormone.

However, whatever the cause, a patient with new oligomenorrhoea will have low oestradiol levels and, as discussed below, this has negative implications for longer term physical health and so is worth treating, whether through adjustments to psychotropics or consideration of oestrogen as an adjunct. For this reason, it is particularly important to discuss menstrual cycles with patients on antipsychotics and/or approaching menopause and to work to optimise oestrogen levels in order to safeguard future physical and mental health.

About the authors

Sophie Behrman, BA, BM, BCh, MRCPsych, is a consultant general adult psychiatrist working in a community mental health team in Oxford, employed by Oxford Health NHS Foundation Trust, UK. She is also an Honorary Clinical Research Fellow of the Oxford University Department of Psychiatry. Clair Crockett, BSc Hons, MBChB, DRCOG, MRCGP, DFSRH, is a general practitioner with a special interest in menopause employed by Newson Health Menopause and Wellbeing Centre, Stratford-upon-Avon, UK.