The many effects of reproductive hormones on the brain

Published 25 May 2021

The aim of a well attended Campus meeting organised by the SIG Reproductive Endocrinology in May was to present the latest findings on how sex hormones from various organs influence the brain, not vice versa – and to emphasise that there’s a psychological as well as physical effect in women.

What was apparent by the end of this Campus meeting was that more attention must be given to addressing not only the physical but also the psychological effect of hormones in women; and that improved screening, targeted therapies such as antidepressants and new classes of drugs have the potential to relieve their symptoms – or even cure them.

The first part of the meeting provided a comprehensive update on the basics of how hormones - neuropeptides, AMH and hormonal contraceptives - affect the brain, and may even trigger depression and suicidal thoughts as a result of menstrual cycle syndromes.

Richard Anderson from the University of Edinburgh presented evidence on the key role that the so-called KNDy neurons expressing kisspeptin play in stimulating GnRH and LH, with elevated/fast secretion of these gonadotrophins a feature in PCOS patients. Therapeutic applications based on partial GnRH suppression may become available for PCOS and other conditions using NK3 receptor antagonists, and large clinical trials are under way. NK3 therapies have been associated in trials with a ‘remarkable’ reduction in menopausal hot flushes, which are linked to GnRH pulses, according to Anderson.

LH over-secretion and reduced fertility characteristics akin to PCOS have also been linked to AMH overexposure, which Joop Laven from Erasmus University in the Netherlands said leads to ‘aberrant wiring of the midbrain’. High AMH levels have consequences too for PCOS offspring – Laven presented findings showing the hormone impairs aromatase activity in the placenta with LH levels higher in PCOS daughters (and in sons) compared with controls. A possible clinical approach, he suggested, was that PCOS patients delay pregnancy to when ‘embryo yields may be higher and aneuploidy lower’.

Inger Sundstrom-Poromaa from Uppsala University Hospital in Sweden cited ‘overwhelming evidence’ from RCTs for selective serotonin reuptake inhibitors (SSRIs) as a first line therapy for premenstrual dysphoric disorder (PMDD). She also highlighted the pros and cons of other treatments: low dose hormonal contraceptives, GnRH agonists (which alleviate symptoms but have side effects unacceptable to many), progesterone, which Sundstrom-Poromaa concluded is ineffective, and a future novel treatment ulipristal acetate (UA) shown to be effective in curing PMDD symptoms (50% UA group vs 22% placebo) but which can’t currently be prescribed following an EMA review.(1)

Despite a 60-year history and widespread worldwide use, the contraceptive pill’s impact on brain structure via hormone suppression remains underexplored. The 160 Campus participants attending online from 48 countries heard how more (and better designed) longitudinal studies are still needed to establish associations (as suggested in current literature) between the range of progestogens used and brain effects - eg, increased working memory and depression.

During the second half of the meeting, on common fertility-related endocrine conditions, several presenters made lively cases for better treatments. Psychiatrist Vibe Frokjaer from Copenhagen University, Denmark, provided an update on sex hormone fluctuations, mental distress and associations with ART. Research by her and colleagues into women following GnRH agonist and GnRH antagonist protocols for ART suggests that mental distress during treatment is not causally linked to hypogonadism per se or to the choice of protocol.(2) Instead, estrogen sensitivity, brain-based mechanisms and neuroticism appear to play a role, and this needs to be translated into prevention/treatment, she said.

In a presentation on estradiol deficiency, Lawrence Nelson from the Mary Elizabeth Conover Foundation in the US outlined the ‘dramatic consequences’ of low levels (eg, memory loss and anxiety) and appealed to ESHRE members for wider support of physiologic HRT (with transdermal patches) so women, notably POI patients, get ‘the hormone they were meant to have’.(3) Aled Rees, from Cardiff University in Wales, urged clinicians to screen PCOS patients in light of evidence of higher prevalence of emotional distress among these women, and for researchers to adjust for obesity in order to determine its role vs PCOS in psychological symptoms; and an update was given on endometriosis treatments including preliminary findings for publication next year on the role of virtual reality in alleviating chronic pelvic pain.

Campus organiser Cornelis Lambalk said there were many areas still to explore in the field of hormones and the brain, but the ambition is to cover these in a follow-up event next year.

1. Comasco E, Kopp Kallner H, Bixo M, et al. Ulipristal acetate for treatment of premenstrual dysphoric disorder: A proof-of-concept randomized controlled trial. Am J Psychiatr 2020: 178: 256-265.
2. Stenbæk D, Toftager M, Hjordt L, et al. Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology. Hum Reprod 2015; 30; 103-110.
3. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019; 364;

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