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Throughout life, a woman's levels of sex hormones, including progesterone and oestrogen, naturally fluctuate. Most steroid hormone synthesis in women occurs in the brain, adipose tissue, and peripheral glands. This process involves intracellular receptors that enter the nucleus and undergo conformational changes. Oestrogen and progesterone then bind to steroid receptors via the classical route, thereby controlling gene expression. Additionally, sex steroid receptors are found outside the nucleus in the endoplasmic reticulum, the mitochondria, and the plasma membrane. These receptors initiate numerous signalling cascades that operate through non-classical pathways.
Neurosteroids, also known as neuroactive steroids, are steroid hormones that affect the neurological system. Neurones and glial cells in the central and peripheral nervous systems may synthesise them from scratch or do so peripherally before passing over the blood-brain barrier. Given that steroid hormones pass the blood-brain barrier, measuring their plasma levels will be crucial for understanding how the brain functions, even if it has been demonstrated that levels of these hormones in peripheral blood differ from those in cerebrospinal fluid. These hormones' impact on the central nervous system may be divided into activational and organisational. Through classical and non-classical routes, activational effects transiently alter brain activity in a particular environment. Examples of these pathways include glutamatergic, GABAergic, serotonergic, and dopaminergic synapses. The ability of chemicals, such as sex hormones, to permanently change the nervous system's organisation through several mechanisms, including myelination, neural pruning, apoptosis, and dendritic spine remodelling, is known as an organisational impact.
How neurosteroids modulate synaptic plasticity through long-term potentiation (LTP) is a prime illustration of these effects. Events that result in a sustained increase in synaptic strength and are correlated with memory and learning processes are referred to as this neuromodulation process. Oestrogen produces alterations in plasticity and improves cognitive processes in the hippocampus. This region is crucial for the consolidation of information from short-term memory to long-term memory and for spatial memory, where LTP is shown. Neurosteroids govern several brain regions involved in the modulation of mood, behaviour, and cognition by their organisational and activational effects in the central nervous system (CNS).
Consequently, women's greater vulnerability to mood disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression is linked to endogenous sexual hormone variations during various reproductive periods of a woman's life. Furthermore, endogenous oestrogen and progesterone levels may impact several cognitive functions, including fear extinction, emotion perception, decision-making, and memory consolidation. For instance, during the menstrual cycle, women with high levels of estradiol and progesterone exhibit enhanced verbal abilities and decreased visual-spatial abilities; conversely, when these levels are low, the reverse is seen. Additionally, in non-human primates after ovariectomies, low levels of progesterone and estradiol cause deficiencies in spatial memory that may be corrected by periodic low-dose oestrogen therapy. Low-dose oestrogen therapy is in line with current research that suggests neurosteroids may be a practical treatment approach for neurodegenerative diseases like Parkinson's, Alzheimer's, and multiple sclerosis, as well as mental conditions like schizophrenia and depression.
Therefore, this blog suggests that women's health will be enhanced throughout their lifetimes, and neurocognitive dysfunctions will be avoided if sex steroids are balanced hormonally according to the various life stages.
THE IMPORTANCE OF HORMONAL BALANCE AND THE ACTIONS OF STEROID HORMONES IN WOMEN'S BRAINS
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Hormonal Production Throughout a Woman's Life
The Ovarian Continuum:
The ovary's ability to function decreases with age. Women enter the perimenopausal period about four years before menopause, during which they experience a range of symptoms, including headaches, sleep disorders, mood swings, anxiety, depressive symptoms, cognitive decline, hot flashes, and, in later stages, vaginal dryness and bone fractures. The ovaries release more oestrogen during this time owing to gonadotropin stimulation, which causes endometrial development and might result in excessive bleeding and irregular periods.
About two years following menopause, hormone levels will stabilise and show little to no variation. FSH levels will stay high during this time, while estradiol and progesterone levels will remain low. An increased frequency of neurodegenerative disorders like Alzheimer's disease has been linked to a reduction in steroid hormones and cognitive deficits. The impact of ageing on the reproductive axis, especially at the central nervous system level, should be considered. The hypothalamus GnRH neurones regulate the menstrual cycle's cyclicity, which undergoes functional and anatomical changes as we age. Because of this, it is impossible to fully separate the aging processes in the neurological system from the aging phenomena of the endocrine system.
Actions of hormones in the female brain: Classical and Non-classical Pathways of Estradiol and Progesterone Action
Progesterone
Through progesterone response elements (PREs) located within the promoter region of target genes, progesterone diffuses into the cell. It binds to its receptors (PRα and PRβ) in the classical route, regulating transcription. Progesterone functions via the non-classical route, as do several neuroactive metabolites, including dihydroprogesterone (DHP) and allopregnanolone. Membrane receptors, including PRα, PRβ, PQMR, and PGMR1, are involved in this process. Progesterone acts through these receptors to activate various signalling cascades, second messengers, ion influx and efflux, protein kinase A (PKA), and transcription of many genes.
Progesterone exhibits neuroprotective effects in the central nervous system (CNS) through conventional and non-classical routes. These effects increase cell survival and anti-apoptotic mechanisms, bioenergetic system control, and, more frequently than oestrogen, promoting neural cell proliferation. The combination of oestrogen and progesterone is not synergistic and, when administered simultaneously, results in a lower response than either hormone administered alone or in sequence. It is important to emphasise this even though both hormones are potent regulators of cell survival, bioenergetic systems, and neurogenesis.
Progesterone also has a neuroprotective impact on glial cells, where myelination plays a specific function in regulation. Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system produce myelin. One oligodendrocyte in the CNS can extend up to 40 processes onto many neighbouring axons; as a result, it affects the electrical activity of many axons. From oligodendrocyte progenitor cells (OPC), which move toward unmyelinated axons, oligodendrocytes can multiply. Once there, they mature and produce processes that can eventually create the myelin sheath. Progesterone stimulates these processes by increasing intracellular signalling, oligodendrocyte progenitor proliferation, and transcription of essential elements in myelin formation pathways, including myelin basic protein and 2', 3'-cyclic nucleotide-3'-phosphodiesterase.
Moreover, allopregnanolone functions as a solid positive GABA-A receptor allosteric modulator. Through an autocrine/paracrine loop, this modulation causes OPC to proliferate. Thus, progesterone and its metabolites play a crucial role in fostering cellular development and oligodendrocyte activity in the central nervous system.
Estradiol
Oestrogens diffuse into target cells by the traditional estrogenic route, activating ER α and β to create dimers. The activated receptors enter the nucleus and attach to DNA's oestrogen response elements (ERE). Research has demonstrated that ERα and ERβ are also found in mitochondria, where they bind to DNA found in the mitochondria. Gene transcription occurs both at the nuclear and mitochondrial levels due to ERE activation. Oestrogens function through several receptors (ERα, ERβ, GPER, and GqmER) situated in the plasma membrane in the non-classical route. Oestrogen activates many signalling cascades via these receptors, including phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinases (MAPK), second messengers, ion influx, and efflux. Lastly, additional ways to promote genomic transcription by inducing non-classical pathways exist.
Impact of Exogenous Synthetic Steroid Hormone Administration on Behaviour, Emotions, and Cognitive Functions.
Exogenous Synthetic Steroid Administration: Contraceptives:
Millions of women use hormonal contraceptives regularly; they frequently begin using them while they are young when sex hormones have significant organisational effects on the development of the brain. Hormonal contraception comes in three primary formulations: progestin-only, multiphasic, and monophasic combinations. These can be given orally, intramuscularly (IM) injections, subcutaneous implants, or via medicated IUDs. Combined hormonal contraceptive tablets combine progestin with one of two forms of oestrogens: mestranol, also known as 3-methyl ethinyl estradiol, which is less frequently used than ethinyl estradiol. The fact that adolescents are going through a period of neuronal plasticity, in which hormone levels can alter neurones and influence the structural and architectural functioning of the brain, helps to explain why exogenous hormones have a more significant impact on mood and suicidal thoughts in this age group.
Furthermore, levonorgestrel (LNG) injection during the follicular phase of monkeys can block ovulation, as evidenced by the significant suppression of estradiol and the increase in cycle duration from 32 to 52 days (at levels like those reported in emergency contraception). Research conducted on women who had undergone sterilisation also showed that when LNG is given during the early or late follicular phase, it usually inhibits ovulation or causes short luteal phases (LH) but not at the LH peak. Depending on the stage of the cycle during which it is given, this interference with the balance of endogenous oestrogen and progesterone, in addition to a potential direct effect on brain cells, may have an impact on mood in women taking emergency contraception.
Menopausal Hormone Therapy: Exogenous Synthetic Steroid Administration
Although the average lifespan has grown from 50 to 80, women's menopause ages are mostly set. Because of this, a more significant proportion of women will have postmenopausal symptoms for more than one-third of their lifetimes. As a result, the effects of declining oestrogen levels on several facets of women's health are pertinent. Hormone therapy (HT) regimens have been created to treat symptoms and prevent disorders associated with the fall in hormone secretion in women who are perimenopausal or in the early stages of postmenopause. HT can be given as an unopposed estrogen-only medication, a continuously mixed formulation (oestrogen + progesterone), or a sequentially combined formulation.
These days, the genitourinary syndrome of menopause/vulvovaginal atrophy, hypoestrogenism, prevention of bone loss, and vasomotor symptoms are among the FDA-approved indications for HT. Furthermore, decreased levels of steroidal hormones are linked to depression and cognitive decline; however, these effects can be reversed with appropriate HT. On the other hand, HT prescription could be linked to an increased risk of heart disease, stroke, venous thromboembolism, and malignancies that are sensitive to oestrogen. It is, therefore, appropriate to take this into account when providing menopausal women with counselling.
Along with their neurotrophic effects, oestrogens also increase the number of dendritic spine formations in the PFC, hippocampus, and amygdala. Functional magnetic resonance studies together have demonstrated that in comparison to non-users of HT, postmenopausal women on HT have higher activation, more considerable volume, and increased cerebral blood flow to the hippocampus—a region known to be impaired in major depressive illness.
The date of commencement, the type of progestin and oestrogen used, the mode of administration (oral vs. transdermal), and the treatment plan (continuous vs. sequential) will all affect the pleiotropic effects of HT.
The proportion of estrogenic forms supplied during menopause varies from premenopause regarding the type of oestrogens and progestins. At the beginning, the ratio of estradiol (E2) to estrone (E1) is around five times higher. Later, E1 is the main form of oestrogen during menopause and postmenopause. Thus, E2 must be given in HT to replicate premenopausal physiology. The transdermal use of E2 has shown a consistently positive impact on women's mood during their perimenopausal stage. Conversely, the administration of HT in continuous conjugated equine estrogens (CEEs) (0.625 mg/d), rich in E1, does not show positive results concerning mood.
To your health,
Nwabekee.
REFERENCE
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 Health, 6.
Good work!
Educational!!!