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 organisational and activational.
- Organisational 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.
Finding #1
Thus, estrogen and progesterone have an effect on memory, mood, cognition, and behaviour.
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.
Finding #2
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 - Organisational 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.
Finding #3
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 behaviour,
- mood,
- 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.
Finding #4
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 gynaecologic 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.
Finding #5
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 utilise 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
Utilising 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 behaviour. 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.
Reference
Website – https://www.factsaboutfertility.org/hormonal-balance-and-the-female-brain-a-review/