The FACTS 2021 CME Conference
Fertility Awareness – Expanding Care for Women’s Health

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May 10, 2021

National Women’s Health Week

Hormonal Balance and the Female Brain: A Review


By Kaitlyn McOsker


Editor’s Note: Each year, Mother’s Day marks the beginning of National Women’s Health Week, a time to focus on prevention as well as behaviors women can incorporate to enhance their health and well-being. For National Women’s Health Week, Kaitlyn McOsker summarized a 2018 article[i] by Del Río et al published in Frontiers in Public Health titled, “Steroid Hormones and their Action in Women’s Brains: The Importance of Hormonal Balance.” The article explains the significance of the natural fluctuations of estrogen and progesterone and describes their vital role in mood, cognition, memory, and overall mental health. 


Estrogen and progesterone are vital hormones for overall female health and well-being. From menarche to menopause, the natural fluctuation of estrogen and progesterone affects not only the reproductive organs but also the brain. When these hormones act in the brain, they are referred to as “neurosteroid” hormones. The neurosteroid hormones have two main effects, classified broadly as organizational and activational. Organizational effects are permanent alterations of nervous system structure, including myelination and strengthening of synapses. Activational effects are non-permanent alterations on brain activity through their interaction with neurotransmitters.

Thus, estrogen and progesterone have an effect on memory, mood, cognition, and behavior.

A woman’s mental health can be dramatically affected by alterations in the natural fluctuation of hormones, including changes caused by exogenous hormones. The 2018 article by Del Río et al provides a review of steroid hormone production in the female body and their role in the female nervous system.

The ‘Ovarian Continuum’

The natural fluctuation of hormones throughout the menstrual cycle is important for normal reproductive function and balance of brain chemistry. The ‘ovarian continuum’ refers to the different types of ovarian activity throughout a woman’s life. For example, cycles in which no apparent ovarian activity is present occur during childhood and menopause, when sex hormone levels are low. Women may also experience anovulatory cycles throughout their reproductive years, such as during puberty and breastfeeding, where estrogen levels are suppressed and not high enough to induce the luteinizing hormone (LH) surge that stimulates ovulation. Variations in estrogen, progesterone, LH, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), prolactin, and thyroid hormones all play a role in the ovarian continuum and ovulatory capacity, thus also affecting the brain.

Therefore, variations in hormone levels, either naturally or due to hormonal imbalance, can lead to changes in brain chemistry.

Estrogen, Progesterone, and the Female Brain: Organizational Effects

The direct effect of estrogen and progesterone in the brain plays an important role in the permanent structure of the nervous system. In the brain, these hormones act via classical and non-classical pathways. For both hormones, the classical pathway involves diffusion of the hormone into cells, binding to receptors, and then entering the nucleus where they directly affect transcription of DNA. The non-classical pathways involve hormones binding to membrane receptors and activating signaling cascades.

Estrogen and progesterone exert a neuroprotective effect via activation of anti-apoptotic pathways, expression of enzymes that reduce free radicals, regulation of glucose uptake, and induction of neural cell proliferation. Progesterone also plays a role in the regulation of glial cells and myelin production in the central and peripheral nervous systems. However, the central takeaway is that estrogen and progesterone are not synergistic – when given simultaneously, there is an overall lower response in the brain as compared to being given alone or in a natural sequence. Thus, the natural fluctuation in the menstrual cycle is imperative for a proper neuroprotective balance.

Estrogen and Progesterone on Neurotransmitters: Activational Effects

Estrogen and progesterone also affect brain levels of various neurotransmitters, including glutamate, gamma-Aminobutyric acid (GABA), serotonin, and dopamine. Estrogen increases the release of glutamate, the main excitatory neurotransmitter in the brain, and increases N-methyl-d-aspartate (NMDA) receptor synthesis and expression. This enhances neuronal excitability and has been shown to improve learning, memory, and other cognitive functions. Estrogen decreases the release of GABA, the main inhibitory neurotransmitter in the brain, promoting increased glutamate and dopamine transmission.

Serotonin is an important contributor to well-being, playing a role in sleep, sexual behavior, mood, and cognitive functions. Estrogen promotes synthesis, prevents degradation, and inhibits reuptake of serotonin; it also promotes the expression of serotonin receptors. Thus, estrogen plays a large role in the overall mood of women. Furthermore, estrogen increases dopamine synthesis and decreases its degradation and reuptake. It improves working memory, decision making, and pleasure.

In contrast to estrogen, progesterone and its metabolites inhibit glutamate transmission, decreasing glutamate release and glutamate-induced dopamine release; they also decrease glutamate receptor responsivity.

Progesterone enhances GABA transmission and receptor activation, which explains why progesterone metabolites have an anti-anxiety effect and why decreased levels are seen in depression.

The coordinated effect of progesterone following estrogen enhances serotonin synaptic activity. In addition, progesterone following estrogen exposure increases dopamine release in the striatum, which improves sensorimotor function and decreases dopamine in the prefrontal cortex, which modulates emotional responses. The proper response of serotonin and dopamine depends on the coordination of estrogen and progesterone, further emphasizing the importance of the natural fluctuation of these hormones.

Exogenous Hormones and the Brain

Exogenous hormones are often prescribed to treat common gynecologic issues, such as endometriosis or polycystic ovary syndrome (PCOS), and used for birth control and hormone replacement therapy (HRT). If the natural fluctuation of these hormones is important for proper brain function, it is expected that interruption of this rhythm with exogenous hormones will affect a woman’s well-being.

Studies have shown an association between hormonal contraception and a decrease in overall well-being, diagnosis of depression, use of antidepressants, and increase in suicide attempts. This is more significant in adolescents, likely due to increased neural plasticity at this age.

Women who utilize levonorgestrel implants, a form of progestin, are more likely to have mood swings, depression, and irritability. When it comes to HRT in menopause, exogenous hormones may have the opposite effect, as it is no longer disturbing the natural fluctuation, but rather restoring the presence of hormones. HRT has been shown to reduce depressive symptoms and improve memory, attention, and reasoning, due to the influence of estrogen on these synaptic systems. Neurons appear to become insensitive to hormones with longer deprivation, suggesting that, when needed, HRT should start sooner rather than later in the perimenopausal transition.

Application to FABMs

Utilizing fertility awareness-based methods (FABMs) to track menstrual cycles enables women and their physicians to diagnose hormonal deficiencies that may explain changes in mood, cognition, and behavior. FABMs can also help identify conditions with mental health manifestations such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Proper replacement of these hormones will not only support reproductive health but can also treat the root causes of many of these mood disorders and mental health conditions. Further studies could look into the association between common menstrual cycle irregularities, steroid hormone levels, and neurotransmitter levels to assist in diagnosing and treating mood, cognition, and memory problems in women.

Editor’s Note: The central role of steroid hormones in adolescent brain development and behavior is further reviewed in an article by Vigil et al titled, “Endocrine Modulation of the Adolescent Brain: A Review.” It was published in 2011 in the Journal of Pediatric and Adolescent Gynecology. According to the article, the association between steroid hormones and adolescent brain organization is crucial to understand teenage behavior, and to assess and treat anxiety and mood disorders in this population.


[i] Del Río, J. P., Alliende, M. I., Molina, N., Serrano, F. G., Molina, S., & Vigil, P. (2018). Steroid Hormones and their Action in Women’s Brains: The Importance of Hormonal Balance. Frontiers in public health6, 141.

About the Author

Kaitlyn McOsker

Author Bio: Kaitlyn McOsker is a fourth-year medical student at the University of Nevada, Reno School of Medicine. This summer, she will begin residency training in obstetrics and gynecology at Baylor College of Medicine in Houston, Texas. She graduated from the University of Nevada, Reno with a Bachelor of Science in biology. She participated in the FACTS elective in January 2021, where she was first introduced to fertility awareness-based methods. She hopes to learn more about these methods and plans to incorporate them into her training and future practice.

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