Researchers have published results of what they say is “the first well-powered study” investigating how menopausal hormone therapy (MHT) affects the risk of psychosis relapse in women of menopausal age with schizophrenia spectrum disorders (“schizophrenia,” in this story). Their results suggest that MHT does meaningfully decrease relapse risk if the therapy is taken between the ages 40 and 55, but possibly not after.  

The study sheds light on how MHT affects relapse risk in menopausal women with schizophrenia, but more broadly serves as a reminder of how schizophrenia in women differs in important ways, in terms of disease course, compared with men.

An international team co-led by Bodyl A. Brand Ph.D. and Heidi Taipale, Ph.D. at universities, respectively, in the Netherlands and Finland, note in their paper appearing in the American Journal of Psychiatry that when initially diagnosed, “women with schizophrenia or schizoaffective disorder on average show a less severe clinical picture than men.” This, they add, “has led to the suggestion that women with schizophrenia have a less significant disease burden” than men. For some of those who hold this view, the sex difference has been hypothesized to be the result of protective effects exerted by the female sex hormone estrogen.  

Data indicates that 10 years after an initial psychotic episode, women and men have “similar functional outcomes” and similar rates of hospital readmissions, according to the team, which included Iris E. Sommer, M.D., Ph.D., a 2007 BBRF Independent Investigator and 2005 BBRF Young Investigator. This does not mean, however, that women and men experience symptoms of schizophrenia in the same pattern or have similar experiences over the long course of the illness.  

After age 45, “women show a remarkable decline in [schizophrenia] outcome, with notably higher frequency of psychosis relapses” compared not only with younger women but also compared with males of the same age with schizophrenia.  “The observed worsening of outcome in women around the menopausal transition could reflect the loss of cellular and molecular protective functions of estrogens,” the team says. Indeed, past research indicates estrogens can act as antioxidants, as boosters of neuroplasticity, and can facilitate neurotransmission.  

Importantly, several periods in a woman’s life that are associated with estrogen decline are also ones in which symptoms of schizophrenia tend to intensify, the team says. These intervals include the premenstrual phase of the menstrual cycle as well as the period following childbirth. In most women, the time of most profound estrogen decline occurs during “perimenopause,” or the period around menopause, beginning when they are in their 40s. The transition to menopause typically begins in women around the age of 50, after a cessation of menstrual cycles for 12 months. Estrogen levels never recover.    

The researchers were motivated to learn more about the impact of hormonal therapy on psychosis relapse (defined in the study as readmission to hospital) in part because increasing antipsychotic drug dosage after age 45 to manage worsening symptoms “does not seem to yield the desired effect” in many cases.

In the early 2000s, MHT, which has been available since the 1960s, became controversial and broadly unpopular following publication of research indicating it had adverse impacts on rates of heart disease, stroke, and breast cancer. According to the team, later studies showed that MHT when initiated within 10 years after menopause is in fact associated with reduced mortality from all causes and reduced risks of heart disease, osteoporosis, and diabetes.  

Given the association between estrogen decline and the worsening of schizophrenia outcomes in women, it made sense to the researchers to conduct a study making use of comprehensive medical databases capturing health events in people admitted to hospital in Finland. “The potential benefits of estrogen augmentation have never been systematically investigated within a population of women with schizophrenia of menopausal age.” Finland’s national health records made such a study possible.  

The Finland records for the period 1972–2014 included 30,785 women diagnosed with schizophrenia spectrum disorders and admitted to hospital. Of these, 3,488, who were between the ages of 40 and 62 between 1995 and 2017, received menopausal hormonal therapy. The study cohort was composed of women who started MHT during or within 10 years of the menopausal transition.  

Finland drug prescription registers made it possible to determine which of various forms of MHT women of the study cohort received—involving the administration of estrogen alone or estrogen and progestogen combined. They were analyzed according to age, in groups that began receiving the therapy at 40-49, 50-55, and 56-62. The effectiveness of different formulations of the therapy was also assessed.

Of the 3,488 women who received MHT between ages 40 and 62, precise determination of their age at initiation of the therapy was possible in 63%. Most of the women (71%) used MHT for more than 1 year and 54% had only one period of use; 53% of the women had at least one hospitalization for psychosis during the period of follow-up (from initiation of MHT until 1995 or death, whichever came first).  

Overall, the team reported, use of any MHT was associated with a 16% decreased risk of psychosis relapse. Reduced relapse risk was observed in those beginning the therapy between ages 40 and 49 and between 50 and 55, but not 56 to 62.

Estrogen-only formulations as well as fixed and combined formulations were associated with similar decreases in relapse risk, ranging between 14% and 21%. Oral formulations were associated with decreased relapse risk, but not formulations administered via skin patches (transdermal). There may not have been enough data on the latter to support a strong conclusion. Further comparisons of formulations with different estrogenic or progestogenic compounds indicated “slight differences in effectiveness” in relapse risk reduction. More research is needed to determine if specific formulations are most effective, the team said.  

As for why risk reduction was not seen in women beginning MHT after age 55, the team speculated that this could be due to the depletion of cellular receptors for estrogen which occurs naturally due to normal estrogen deprivation following menopause.  

At menopausal age, antipsychotic effectiveness decreases and relapse risk increases, while higher doses do not effectively prevent relapse, the team summarized. “The current study provides evidence that … augmentation [of estrogen] with MHT may provide a better strategy for relapse prevention,” and might also have other health benefits including reduction in overall mortality as well as risk for diabetes, osteoporosis, dementia, heart disease, and possibly also colon cancer risk, according to the researchers.

“MHT is not without risks,” they noted. “Before starting any type of MHT, careful assessment of personal and family history, including that of venous thromboembolism [blood clots in the veins] is essential.”