Women, Estrogen, and Mitochondria: Sex Differences That May Affect Your Hormones, Energy, and Longevity

Mitochondria play a pivotal role in many aspects of women's health, including hormone balance, cell function, and feeling like you are fully charged with power. Women have about 35 trillion cells in the body and mitochondria are the organelles inside of cells that produce energy through chemical reactions, leading to the designation as the remarkable power source of the cell. Thus, mitochondria are a cornerstone aspect of each of the cells of our body—they act as a power factory that fuels trillions of chemical reactions each second. When your mitochondria are functioning well, your cells feel fully powered and you have the energy you need to accomplish the activities of daily living. 

Sadly, many women over 40 find that they do not have mitochondria that are functioning well. The relationship between mitochondria and your hormones is bidirectional: mitochondria are important for making steroid hormones like estrogen and testosterone, but estrogen and testosterone also modulate the activity of your mitochondria.¹ As estrogen and sometimes testosterone levels start to falter in women over 40 who are going through perimenopause, or in the postpartum period, women may experience mitochondrial impairment. Increasingly, ovarian aging is thought to be a problem with your mitochondria.²

When your mitochondria become less functional, in your ovaries and in other cells of your body, you age faster. Estrogen plays a key role in the brain during reproductive years, and fluctuating then low estrogen in perimenopause and menopause puts many women at greater risk of adverse brain changes that may herald a greater risk of Alzheimer’s disease and other conditions of brain aging. Falling estrogen and mitochondrial dysfunction may be one of the most important root causes at the heart of the two-fold greater risk women have of developing Alzheimer’s disease.

As you age over 40, the brain’s capacity to generate the fuel it needs for optimal function wanes in about 80 percent of women. Estrogen is the key factor that maintains glucose metabolism at a healthy level to properly power the brain and other cells of the body. Overall, estrogen supports not just brain metabolism but also synaptic plasticity and cognitive function. Many cognitive benefits have been found associated with bioidentical hormone therapy, and we believe the benefits are linked to estrogen’s neuroprotective effects, either from direct brain effects or indirectly by enhancing cardiometabolic health, or both.³ Unfortunately, the salient effects of estrogen on the brain have shown some mixed data, particularly when given as hormone therapy to older women over the age of 60. More research is needed in order to provide more definitive guidance to menopausal women regarding the influence of bioidentical hormone therapy on the risk of Alzheimer’s disease.

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As estrogen falters, you must ask yourself several critical questions:

• Are my mitochondria functioning correctly or are they underpowering my cells?
• Is my estrogen level dropping, potentially putting my brain at increased risk of decreased glucose uptake and cognitive decline?
• Am I a good candidate to replace my declining estrogen?
  

We will be exploring these questions and answers in subsequent blogs and my upcoming book.

The Mitochondria’s Job Description

Besides the interconnectedness of estrogen, mitochondria have many jobs with regard to cell function, maintenance, survival, and health. 

Mitochondria are the main source of energy inside of your 35 trillion cells and also generate reactive oxygen species within the cell.

Here are the highlights of the mitochondria job description.

• Mitochondria produce energy through chemical reactions. Mitochondria break down nutrients like glucose, fats, and proteins to create adenosine triphosphate (ATP), which is the energy currency for most cellular reactions.
• Mitochondria support pregnancy. During pregnancy, mitochondria provide energy for the development of the embryo.
• Mitochondria support insulin secretion. In beta cells of the pancreas, mitochondria play a role in the secretion of insulin in response to glucose.
• In men, mitochondria support sperm movement. Mitochondria in sperm cells produce energy to help the sperm move.
• Mitochondria contain their own DNA, which can affect processes across all 12 chromosomes in the nucleus.
• Estrogen has many influences on mitochondrial activity, binds to estrogen receptors in mitochondria, and can influence production of brain-derived neurotrophic factor and sirtuin 3 (SIRT3) pathways.⁴
• Mitochondrial influence longevity and health span. When mitochondria are not functioning properly, cells can become underpowered and lead to organ dysfunction and disease.

Sex Differences in Mitochondria

We are aware of many biological or sex differences in mitochondria size, origin, and function.

• Mitochondrial genes. Studies indicate that women have higher levels of genes involved in mitochondrial biogenesis (creation) and maintenance, while males have higher expression of genes related to energy production through mitochondrial activity.⁵
• Sex hormones regulate mitochondrial function. Estrogen and testosterone are thought to play a significant role in regulating mitochondrial function and can contribute to these observed sex differences⁶, since women tend to have higher estrogen levels compared to men until menopause, and men tend to have higher testosterone levels than women throughout the lifespan.
• Mitochondrial number and shape. In the heart, female cardiac mitochondria outnumber than male cardiac mitochondria, at least in mice.⁷ Male cardiac mitochondria are smaller, more fragmented, and more circular than female cardiac mitochondria.⁸
• Mitochondrial function. In blood, women have higher mitochondrial complexes I, I+II, and IV, uncoupled respiration, and electron transport system (ETS) capacity than males—the clinical relevance is not yet clear.⁹
• The source of mitochondrial DNA. Mitochondrial DNA is almost exclusively inherited from the mother, which may lead to sex differences in metabolic regulation.¹⁰
• Mitochondrial antioxidant defenses. In the heart, female cardiomyocytes have a higher capacity for antioxidant defenses than male cardiomyocytes, which may help buffer against oxidative stress though this has not yet been proven.¹¹
• Mitochondrial calcium retention. Female cardiac mitochondria have a greater capacity for retaining calcium than male cardiomyocytes.¹²
• Mitochondria and autoimmunity. In an emerging area, mitochondrial dysfunction may be linked to impaired T cell function in the immune system and poor quality control, and may ultimately decrease tolerance and increase risk of autoimmunity.¹³
• Mitochondrial size in older individuals. In one study, women had larger mitochondria before training, but men had larger mitochondria after training.¹⁴

While there are certain differences in mitochondrial function that have been identified between men and women, the deeper implications of these differences are not yet clear.

The Mitochondrial Aging Hypothesis

In scientific circles, there is a hypothesis that as mitochondria age, the result is increased DNA damage to mitochondria, leading to more reactive oxygen species and worsening function of mitochondria in terms of their job description. This can be manifest as signs of aging.¹⁵ The “mitochondrial aging hypothesis” has been applied to brain aging, particularly in women over the age of 40, and may in part explain the increased risk of Alzheimer’s disease seen in women compared to men. The mitochondrial aging hypothesis posits that as you get older and particularly as estrogen declines in women, quality control in mitochondria diminishes.¹⁶ The net result is increased reactive oxygen species, which may promote problems like beta-sheet aggregation, apoptosis, and/or cell cycle arrest producing neurofibrillary tangles and other hallmarks of Alzheimer’s disease.

The low estrogen state that occurs in women in the late stages of perimenopause and menopause is associated with diminished mitochondrial function and power. You may feel it as fatigue, particularly after a workout. Declining estrogen may increase a woman’s vulnerability to accelerated aging as a result of mitochondrial dysfunction, brain degeneration, and cognitive decline. Unfortunately, this area has been largely ignored by medical researchers until more recently—we need more investigation into the underlying mechanisms that affect the aging female brain so that we can help women improve mitochondrial function with lifestyle medicine, perhaps supplements, and in order to be able to counsel women appropriately about whether bioidentical hormone therapy may be a safe choice.

Footnotes

¹Lejri I, et al. Mitochondria, Estrogen and Female Brain Aging. Front Aging Neurosci. 2018 Apr 27;10:124. doi: 10.3389/fnagi.2018.00124. PMID: 29755342; PMCID: PMC5934418. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934418/pdf/fnagi-10-00124.pdf

²Kasapoğlu I, Seli E. Mitochondrial Dysfunction and Ovarian Aging. Endocrinology. 2020 Feb 1;161(2):bqaa001. doi: 10.1210/endocr/bqaa001. PMID: 31927571. https://pubmed.ncbi.nlm.nih.gov/31927571/

³Briceno Silva G, et al. Influence of the Onset of Menopause on the Risk of Developing Alzheimer's Disease. Cureus. 2024 Sep 10;16(9):e69124. doi: 10.7759/cureus.69124. PMID: 39262936; PMCID: PMC11387275. https://pubmed.ncbi.nlm.nih.gov/39262936/

⁴Lejri I, Grimm A, Eckert A. Mitochondria, Estrogen and Female Brain Aging. Front Aging Neurosci. 2018 Apr 27;10:124. doi: 10.3389/fnagi.2018.00124. PMID: 29755342; PMCID: PMC5934418. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934418/pdf/fnagi-10-00124.pdf

⁵Li N, et al. The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes. bioRxiv [Preprint]. 2023 Dec 9:2023.12.08.570893. doi: 10.1101/2023.12.08.570893. Update in: Proc Natl Acad Sci U S A. 2024 Jun 11;121(24):e2321267121. doi: 10.1073/pnas.2321267121. PMID: 38106076; PMCID: PMC10723445. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10723445/pdf/nihpp-2023.12.08.570893v1.pdf

⁶Cruz-Topete D, et al. Uncovering sex-specific mechanisms of action of testosterone and redox balance. Redox Biol. 2020 Apr;31:101490. doi: 10.1016/j.redox.2020.101490. Epub 2020 Mar 5. PMID: 32169396; PMCID: PMC7212492; Lynch S, et al. Sex Hormone Regulation of Proteins Modulating Mitochondrial Metabolism, Dynamics and Inter-Organellar Cross Talk in Cardiovascular Disease. Front Cell Dev Biol. 2021 Feb 11;8:610516. doi: 10.3389/fcell.2020.610516. PMID: 33644031; PMCID: PMC7905018. https://pubmed.ncbi.nlm.nih.gov/33644031/

⁷Scott SR, et al. Sex as Biological Variable in Cardiac Mitochondrial Bioenergetic Responses to Acute Stress. Int J Mol Sci. 2022 Aug 18;23(16):9312. doi: 10.3390/ijms23169312. PMID: 36012574; PMCID: PMC9409303. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409303/

⁸Khalifa AR, et al. Sex-specific differences in mitochondria biogenesis, morphology, respiratory function, and ROS homeostasis in young mouse heart and brain. Physiol Rep. 2017 Mar;5(6):e13125. doi: 10.14814/phy2.13125. PMID: 28325789; PMCID: PMC5371549. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371549/pdf/PHY2-5-e13125.pdf

⁹Silaidos C, et al. Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain. Biol Sex Differ. 2018 Jul 25;9(1):34. doi: 10.1186/s13293-018-0193-7. PMID: 30045765; PMCID: PMC6060503. https://pubmed.ncbi.nlm.nih.gov/30045765/

¹⁰Demarest TG, McCarthy MM. Sex differences in mitochondrial (dys)function: Implications for neuroprotection. J Bioenerg Biomembr. 2015 Apr;47(1-2):173-88. doi: 10.1007/s10863-014-9583-7. Epub 2014 Oct 8. PMID: 25293493; PMCID: PMC4988325. https://pubmed.ncbi.nlm.nih.gov/25293493/

¹¹Xiang D, et al. Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress. Oxid Med Cell Longev. 2021 Jun 28;2021:5523516. doi: 10.1155/2021/5523516. PMID: 34257804; PMCID: PMC8260319. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260319/pdf/OMCL2021-5523516.pdf

¹²Ventura-Clapier R, et al. Estrogens, Estrogen Receptors Effects on Cardiac and Skeletal Muscle Mitochondria. Front Endocrinol (Lausanne). 2019 Aug 14;10:557. doi: 10.3389/fendo.2019.00557. PMID: 31474941; PMCID: PMC6702264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702264/

¹³Rai P, et al. IRGM1 links mitochondrial quality control to autoimmunity. Nat Immunol 22, no. 3 (2021) 312–321; Marchi S, et al. Mitochondrial control of inflammation. Nat Rev Immunol. 2023 Mar;23(3):159-173. doi: 10.1038/s41577-022-00760-x. Epub 2022 Jul 25. PMID: 35879417; PMCID: PMC9310369. https://pubmed.ncbi.nlm.nih.gov/35879417/; Lin L, Ren R, Xiong Q, Zheng C, Yang B, Wang H. Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases. Autoimmun Rev. 2024 Jun;23(6):103583. doi: 10.1016/j.autrev.2024.103583. Epub 2024 Jul 29. PMID: 39084278. https://pubmed.ncbi.nlm.nih.gov/39084278/

¹⁴Junker A, et al. Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis. FASEB J. 2022 Feb;36(2):e22146. doi: 10.1096/fj.202101628R. PMID: 35073429; PMCID: PMC9885138. https://pubmed.ncbi.nlm.nih.gov/35073429/

¹⁵Russell JK, et al. The Role of Estrogen in Brain and Cognitive Aging. Neurotherapeutics. 2019 Jul;16(3):649-665. doi: 10.1007/s13311-019-00766-9. PMID: 31364065; PMCID: PMC6694379. https://pubmed.ncbi.nlm.nih.gov/31364065/

¹⁶Guo Y, et al. Mitochondrial dysfunction in aging. Ageing Res Rev. 2023 Jul;88:101955. doi: 10.1016/j.arr.2023.101955. Epub 2023 May 15. PMID: 37196864. https://pubmed.ncbi.nlm.nih.gov/37196864/