Sex Hormones & the Female Brain: A Focus on Mood Disorders

Female sex hormones can have effects on the brain both during hormonal transition periods and across a woman’s lifespan, including short-term shifts during the menstrual cycle.^1,2 A 2021 review, published in Neuroendocrinology, showed an overall reduction in grey matter and region-specific decreases in brain areas during puberty and the menstrual cycle, during pre- and post-pregnancy, as well as during perimenopause and menopause, where the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. These changes in brain volume were significantly correlated with estradiol, testosterone, progesterone, and luteinizing hormone levels in some of the studies included in the review, but directionality remains inconclusive between studies. The comprehensive results indicate that sex hormones play an important role in brain plasticity during female hormonal transition periods, and, most notably, are not restricted to developmental periods.²Fluctuations in female hormones are highly expressed in brain areas important for emotional processing and may predispose women to mood disorders,² as they interact with neurotransmitters such as serotonin, dopamine, GABA, and glutamate.³ 

In the following video, IFM educator Wendy Warner, MD, discusses the link between imbalanced hormones and mood disorders, which is taught in IFM's Hormone Advanced Practice Module (APM).

(Video Time: 3 minutes) Dr. Wendy Warner is board certified in gynecology and holistic integrative medicine and is a certified functional medicine practitioner. Her practice, Medicine in Balance, is a collaborative holistic medical practice in suburban Philadelphia.

Depression is disproportionately reported by women (almost twice as often as by men) during reproductive age.⁴ For example, the worldwide annual prevalence of depression in 2010 for females and males was 5.5 and 3.2%, respectively. In the US, women had an approximately two-fold higher risk of depression than men, with 21.3% of women and 12.9% of men experiencing major depressive episodes during their lifetimes. Some researchers speculate that a potential mechanism accounting for this difference, in part, may include covariation between estrogen levels and the incidence peak of female depression.⁴

This difference between sexes is most prominent during the reproductive years.³ The overall heightened risk for depression in women can begin as early as puberty³ due to fluctuating estradiol levels.⁵ While some women may experience depression during pregnancy,³ researchers speculate that pregnancy may sometimes offer a form of protection against depression. The peripartum period is considered high risk for mood instability in women with a history of major depressive disorder (MDD) and bipolar disorder (BD).^6,7 A 2021 review by Yu et al focused on triggering factors related to postpartum disorder (PPD) such as reproductive hormones, stress hormones, and inflammation, suggesting that progesterone levels, which progressively increase throughout pregnancy and drop rapidly after delivery, may be correlated with PPD. The authors also suggest that a low prenatal allopregnanolone (a progesterone derivative) may predict PPD.⁸ 

The severity of mood fluctuations throughout a woman’s lifespan ranges from reports of low mood, irritability, impulsivity, and fear to severe suicidal behavior.³ A subgroup of women suffer from clinical levels of premenstrual mood changes called premenstrual dysphoric disorder (PMDD), which includes symptoms like anxiety, irritability, and depressed mood.³ Premenstrual exacerbations (PME) of ongoing mood disorders are well studied; a 2021 review estimates that in women with mood disorders, approximately 60% report PME, while some women with bipolar disorder also show symptom exacerbations around ovulation.² During perimenopause, women enter a vulnerable period for developing a depressive illness, with women who begin the menopausal transition early having a more significant risk of first onset depression.³

While there is evidence of the beneficial effect of hormone therapy on cognitive and affective function,⁹ hormone replacement therapy (HRT) can elicit significant side effects and is not the only treatment option. While HRT is an extremely common intervention, it has its own health risks and may not address the underlying causes of hormonal imbalance. The functional medicine approach is to look upstream at the wide variety of ways that the hypothalamic, pituitary, adrenal, thyroid, and gonadal (HPATG) axis modulates health. By applying dietary modifications, nutraceutical supplementation, and other lifestyle changes as a frontline treatment, the need for HRT can often be minimized or avoided.

Functional Medicine Clinical Considerations for Balancing Hormones

NUTRITIONAL INTERVENTIONS 

Research suggests that specific nutrients, dietary patterns, and overall nutrition may play either beneficial or detrimental roles in hormonal balance. Understanding potential nutrition-hormone relationships, including hormone signaling sensitivity, is a key part of the functional medicine approach to hormonal dysfunction. At the most basic level, consumption of anti-inflammatory foods—specifically fruits and vegetables—may help alleviate symptoms of many chronic conditions associated with increased inflammation.^10-13

Determining the underlying cause of a hormonal imbalance or dysfunction may be challenging, depending on the individual patient and presentation. Understanding cellular sensitivity to hormonal signaling and what may be influencing any impaired signal reception is an important consideration for a subsequent intervention. Cellular sensitivity is the S in IFM’s “PTSD” mnemonic, which is used in the general assessment of hormone dysfunction and helps determine if the dysfunction is related to hormone production, hormone transport, signaling sensitivity, or to an issue with detoxification. This approach also helps identify points of leverage where physicians can apply individualized interventions to help restore hormonal balance.

Two enzymes, aromatase and 5-alpha reductase, affect the conversion of testosterone to estrogen and the conversion of testosterone to dihydrotestosterone, respectively. Modulating these enzymes can therefore have a significant impact on the levels of testosterone and estrogens circulating in the body. A variety of factors affect those enzymes, and IFM has created patient handouts that list foods, herbs, and nutrients that have been shown to modulate these hormone levels. In the IFM Clinical Practice Toolkit, these are titled “Maintaining Healthy Testosterone Levels” and “Aromatase Inhibitors.”

EXERCISE INTERVENTIONS

High estradiol is associated with mood dysfunction in women, and exercise may address this imbalance.¹⁴ A 2015 systematic review and meta-analysis based on randomized controlled trials conducted among healthy women demonstrates a significant decrease in total and free circulating estradiol concentrations induced by physical activity. This finding confirms the associations reported in observational studies, independent of menopausal status. The study concludes that overall, physical activity induces a decrease in circulating sex hormones.¹⁴

Hormone homeostasis and levels of physical activity are also factors known to modulate hippocampal plasticity and lead to strengthening (long-term potentiation) or weakening (long-term depression) of synapses.¹⁵ Physical activity is a potent modulator of hypothalamic-pituitary-adrenal axis (HPA) activity and circulating sex hormone concentrations. A 2020 study on the interplay between hormones on hippocampal plasticity across the lifespan suggests that:

• Exercise modulates systemic and local levels of stress hormones, sex hormones, and metabolic hormones.
• Exercise-induced hormonal changes modulate hippocampal neuroplasticity.
• Exercise benefits hormonal balance and neuroplasticity throughout the lifespan.¹⁵

A small 2022 randomized clinical trial suggests that aerobic exercise, along with a balanced diet, may modulate sex hormone levels and improve homeostasis balance in obese postmenopausal women.¹⁶ In this study, 40 women were distributed into two equal groups: the experimental group that received aerobic training three times per week for 12 weeks along with a balanced diet and the control group that received a balanced diet only. Both groups demonstrated a significant difference in sex hormones (i.e., a substantial decrease in estradiol, total testosterone, and free testosterone and a substantial increase in sex hormone–binding globulin).¹⁶ Another recent randomized controlled trial suggests that aerobic exercise, combined with the MIND diet, may improve cognitive and functional levels and substitute sex-hormone deficiency in postmenopausal women, which affects the longevity of brain health.¹⁷ The results of this study showed a highly statistically significant reduction in weight, BMI, and serum levels of estradiol, total testosterone, and free testosterone, as well as an increase in sex hormone–binding globulin (SHBG) in the experimental group (p <0.01) compared to the control group (p <0.05).¹⁷

Learn how to re-establish hormonal balance in IFM’s Hormone Advanced Practice Module (APM). This functional medicine Advanced Practice Module will clarify exactly how to approach hormonal dysregulation, with discussions on the most important evaluations to make and integrative treatment approaches to apply. IFM’s faculty team supplies clinicians with the foundational background, insight, and in-depth clinical thinking to confidently assess and treat patients who present with hormonal dysfunction. Learn more: