Sex Differences in Biological Systems and the Conundrum of Menopause: Potential Commonalities in Post-Menopausal Disease Mechanisms
Abstract
:1. Introduction
2. Biological Sex Differences and Function
3. Menopause
4. Why Menopause?
5. The Consequences of Menopause
5.1. Osteoporosis
5.2. Dementia
5.3. Cardiovascular Disease
5.4. Obesity
5.5. Osteoarthritis
- (1)
- One may assume that in the pre-menopausal state, the potential risk for the various post-menopausal conditions must serve a purpose in that they arose and have been retained in the genome or epigenome. If retained for a purpose, then most likely the purpose is associated with reproduction advantages. Thus, all of the post-menopausal conditions could be related to various aspects of reproduction. If that is the case, then why do only a subset of females develop OP, dementia, OA or cardiovascular disease, and, thus, would those with such post-menopausal risks not be selected for over millennia and a higher percentage of females have most or all of the conditions?
- (2)
- Is the fact that most females do not express all of the post-menopausal conditions indicated above due to adverse outcomes if the risks of all are evident in the pre-menopausal states of individuals? In fact, as a large percentage of females in developed countries now have chronic obesity in the decades prior to menopause, has this altered risk for other post-menopausal conditions compared to during evolutionary history? Therefore, could some of the post-menopausal conditions be conditions of more recent life, with them not being a “risk” when these conditions arose?
- (3)
- Thanks to the extensive evidence regarding bone loss under various conditions, the post-menopausal condition of OP may be used as a focal point for discussion of alternative explanations for post-menopausal conditions. Some of the most relevant pieces of evidence are outlined below in point form:
- (A)
- Astronauts in microgravity lose bone at a variable rate and from the lower extremities > the upper [141,142]. As most astronauts have been males, this means that when removed from a 1 g environment, males can lose bone, but the rate is quite variable, similar to post-menopausal females with OP (~75% of OP patients on Earth).
- (B)
- Young skeletally mature males and females subjected to prolonged bedrest under controlled conditions lose bone at a variable rate [67]. Thus, the failure to experience bone ground reaction forces (GRFs) in the presence of a 1 g environment leads to the loss of bone and this is an example of the “use it or lose it” principle [65,143,144]. As both males and females lose bone at a variable rate, both males and females exhibit variation in bone loss when a 1 g environment is lost or GRFs are not engaged, but only a subset of females develop OP after menopause. Thus, the bone cell targets in OP can be dysregulated by both the loss of mechanical engagement and after menopause. Does that imply separate regulatory systems?
- (C)
- Related to (B), only a subset of females develop osteoporosis after going through menopause or after being subjected to ovariectomy and the loss of ovarian sex hormones. The rate of bone loss is variable in different individuals and may have secondary consequences [145], and not all sites/locations lose bone equally. From bedrest outcomes, it can be assumed that females who do not develop OP after menopause likely also have the potential for variable bone loss if removed from GRFs and, potentially, when exposed to microgravity. Thus, the subset of females developing OP must have a defect in a regulatory system that can override the mechanisms behind the mechanical stimulation (i.e., GRFs in a 1 g environment), and variable bone loss is somehow intrinsic to the end stage target cells (i.e., bone cells) but not a putative regulatory system. Furthermore, as the loss of mechanical stimulation and/or a microgravity environment appears to lead to more bone loss in lower extremities and this is not the case in OP, the putative regulatory system regulated by sex hormones such as estrogen and estrogen receptors is likely not dependent on a mechanical stimulus. Furthermore, it may also not be dependent on a mechanical stimulus for those males who develop OP (~25% of the cases), as they also are physically active and subjected to ground reaction forces even when they have the disease.
- (D)
- The loss of ovarian sex hormones associated with menopause likely does not lead to reversion to a state that existed prior to puberty. This conclusion is based on the fact that after puberty, skeletal maturity is established and thus a biological set point is entrenched. Secondly, puberty is associated with extensive epigenetic modifications [2,3,4], and thus such modifications and any others occurring due to life experiences are not reversed by menopause and, after ~35 years of menstrual cycles, only interrupted by pregnancies. The pre-puberty years are associated with growth and maturation, while puberty is associated with biological modifications associated with sex hormone elevations and in females the preparation for reproductive success. This scenario raises the possibility that the risk of OP and potentially other post-menopausal conditions/diseases arise as a consequence of puberty, possibly linked to variations in the targeting of epigenetic modifications associated with puberty and sex hormone receptor activities.
- (4)
- If one takes the contrarian view that many or most of the post-menopausal conditions have a common underlying mechanistic feature related to hormones and hormone action, what could this be? First, all of the affected tissues or systems are vascularized and innervated except for articular cartilage. While cartilage is neither and is central to OA, the articulating joints function as organ systems. Furthermore, there are different sub-types of OA and cartilage may just be the “weak link” due to the fact that it is devoid of vascularity and innervation [118].
6. What Potential Mechanisms Would Allow for the Development of Tissue-Specific Alterations in the Microvasculature and Innervation?
7. The Challenge of Understanding Conditions Associated with Menopause from Those of Aging
8. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hart, D.A. Sex Differences in Biological Systems and the Conundrum of Menopause: Potential Commonalities in Post-Menopausal Disease Mechanisms. Int. J. Mol. Sci. 2022, 23, 4119. https://doi.org/10.3390/ijms23084119
Hart DA. Sex Differences in Biological Systems and the Conundrum of Menopause: Potential Commonalities in Post-Menopausal Disease Mechanisms. International Journal of Molecular Sciences. 2022; 23(8):4119. https://doi.org/10.3390/ijms23084119
Chicago/Turabian StyleHart, David A. 2022. "Sex Differences in Biological Systems and the Conundrum of Menopause: Potential Commonalities in Post-Menopausal Disease Mechanisms" International Journal of Molecular Sciences 23, no. 8: 4119. https://doi.org/10.3390/ijms23084119