Santiago Molina, M.A., BOMA-USA Teacher Trainer/Supervisor
A Summary of the paper of the same title published in Frontiers: Available HERE
Extensive research has shown that sex hormones, particularly estrogen and progesterone, impact women's lives in a significant way. From menarche to menopause, and through all the stages in between, women experience dramatic fluctuations in the levels of sex hormones. These fluctuations are part of the ovarian continuum - the various types of ovarian activity that a woman can present throughout her lifetime - and they affect the body as a whole, including the central nervous system (CNS).
Steroid hormones, also known as “neurosteroids” or “neuroactive steroids” because they have an effect in the CNS and/or the PNS (peripheral nervous system), are produced in peripheral glands, in adipose tissue, and in the brain (by neurons and glial cells). Both in the CNS and in peripheral tissues, estrogen and progesterone act via the classical pathway by binding to steroid intracellular receptors that find their way into the nucleus, where they regulate gene expression; and via non-classical pathways, as sex steroid receptors can be found outside the nucleus, including mitochondria, the endoplasmic reticulum, and the plasma membrane, where they activate different signaling cascades and exert their actions. Through these mechanisms, neurosteroids have significant effects on neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Furthermore, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities.
We classify the effects of these hormones on the CNS as either activational or organizational. The activational effects modify neural activity in specific and non-permanent ways (i.e. modulating neurotransmitter synapses). Organizational effects permanently alter the structure of the nervous system through mechanisms such as: myelination, neural pruning, apoptosis (programmed cell death), and dendritic spine remodeling. A good example of these effects is the role that neurosteroids have in modulating the synaptic plasticity of long-term potentiation (LTP), via the above-mentioned mechanisms. This process refers to events that produce an increase in synaptic strength, which persists in time and plays an important role in memory and learning in the hippocampus, where estrogen has been shown to improve cognitive functions.
Through the mentioned mechanisms, neurosteroids regulate different brain areas involved in mood, behavior, and cognition. Therefore, the fluctuation of sex hormones during specific reproductive stages of a woman's life correlates with an increased susceptibility to develop mood disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. Endogenous estrogen and progesterone levels also may affect different cognitive processes such as decision-making, emotion recognition, consolidation of emotional memory, and fear extinction. For example, women show improved verbal abilities and decreased visual-spatial abilities when estradiol and progesterone levels are high and the opposite occurs when estradiol and progesterone levels are low. These differences can be partially explained via the role that neurosteroids play in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thereby influencing neuronal plasticity. This makes them worthy of further studies that may make use of them to treat different disorders of the CNS, as recent studies have shown that neurosteroids could be effective in treating psychiatric disorders, such as schizophrenia, depression, and also against neurodegenerative disorders, such as Alzheimer's, Parkinson's, and multiple sclerosis.
In the same way that endogenous steroids influence CNS functionality, steroid hormones administered exogenously also exert their actions on the brain. Two of the most common ways in which hormones are administered to women exogenously are: 1) hormonal therapy during menopause and 2) hormonal contraceptives. When facing a need for the administration of exogenous hormones, consideration should be given to the stage of life each woman finds herself in since exogenous hormones will have different effects on the brain depending on the stage. For example, when treating adolescents, special consideration must be given to the temporal plasticity window of their developing brain, since it is a period when exogenous hormones may produce both activational and organizational changes in the brain that may have long-term effects. At the other extreme, women who are over 10 years past menopause must take precaution when initiating hormone replacement therapy (HRT), since they have been shown to have negative effects on the CNS, increasing the risk of pathologies such as Alzheimer’s disease or stroke.
However, it is important to consider that there are many situations when HRT and the administration of exogenous hormones is beneficial. For example, cases such as anorexia nervosa will require, as part of the treatment, the administration of hormones. Similarly, as women age, steroidal hormones decline and this could have negative consequences, such as hot flashes, osteoporosis, a decrease in libido, and depressive mood. Thus, special consideration for these individuals needs to be addressed. Also, the type estrogen and progesterone administered and the timeliness of their administration is of great importance. Regarding the type of estrogen and progesterone, certain progestins (lab-made progesterone), as medroxyprogesterone acetate, have some negative effects on myelination and their influence on mood and cognitive capacity have been shown to be deleterious, both in experimental and clinical trials (see full-version paper references). Considering the time of administration, it must be emphasized that the combination of estrogen and progesterone is not synergistic. Therefore, the simulteous combined administration leads to detrimental results when compared to either hormone administered alone or in sequence. Thus, when exogenous steroid therapy is indicated, healthcare providers should at least consider the stage of life, the state of the ovarian continuum that the patient finds herself in, the types of estrogen and progesterone administered, and finally, the timeliness and sequence of their administration must be precisely taken into account.
Finally, some questions to consider in future investigations include:
i. In terms of the ovarian continuum, what patterns of ovarian activity will have negative effects on the nervous system and what patterns will have positive effects?
ii. Should the effects of oral contraception (OCs) on the CNS be considered as adverse? Could they have positive effects?
iii. Is there a different effect on the brain when OCs are taken during adolescence? What is the effect of emergency contraception on the adolescent brain?
iv. To what degree should HT formulations be guided by physiological patterns of exposure (i.e., cyclical vs. continuous)?
In summary, the activity exerted by steroid hormones on the nervous system emphasizes the notion that achieving hormonal balance is a useful tool in seeking the well-being of women. Healthcare providers, as well as the general population, should be aware of this knowledge.
The figure shows areas of the brain regulated by steroid hormones (Top), and some of the effects found when a normal or abnormal balance between estrogen and progesterone is present (Bottom) PFC, prefrontal cortex.