Part 1 of this series re-evaluated the WHI and NHS studies on MHT, while Part 2 explored its role in supporting cognitive function, cardiovascular health, bone strength, and skin integrity. Building on these insights, this section delves into how MHT influences metabolism and glucose regulation, immune function, mood, sleep, and sexual health—highlighting the latest research on how hormone optimization contributes to overall well-being and resilience.
Metabolism & Glucose Regulation
The Research
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Estrogen plays a crucial role in enhancing insulin sensitivity, which is the body’s ability to effectively use insulin to regulate blood sugar levels. It does this by promoting glucose uptake into muscle cells, helping the body convert sugar into energy. Estrogen supports lipid metabolism (the way the body processes fats) and regulates pancreatic beta-cell function, which is essential for the production and release of insulin to help control blood sugar levels. By influencing GLUT4—a key glucose transporter found in fat and muscle tissues—estrogen helps improve how glucose is absorbed and used by the body. Additionally, it can help reduce the accumulation of visceral fat (fat around internal organs) by regulating how fat cells develop, ultimately lowering the risk of type 2 diabetes.
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Progesterone contributes to metabolic balance by regulating cortisol—the body’s primary stress hormone. Elevated cortisol levels, especially when chronic, can lead to weight gain, particularly around the abdomen (known as central adiposity). Progesterone helps modulate the hypothalamic-pituitary-adrenal (HPA) axis, which controls the body’s stress response, thereby reducing cortisol-related fat accumulation. Moreover, progesterone may influence the secretion of adiponectin, a hormone produced by fat cells that enhances insulin sensitivity and supports glucose and fat metabolism. Higher levels of adiponectin are associated with better blood sugar control and a lower risk of metabolic disorders.
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Testosterone supports lean muscle mass development, which naturally increases the basal metabolic rate—the amount of energy the body uses at rest. More muscle means better glucose uptake into muscle cells, improving insulin sensitivity and helping regulate blood sugar levels. Testosterone also enhances mitochondrial function (the energy centers of cells) and promotes the breakdown of fatty acids (the building blocks of fat) for energy, reducing overall fat accumulation, particularly visceral fat. Additionally, testosterone helps regulate hormones like leptin (which controls hunger) and adiponectin (which influences fat metabolism and insulin sensitivity), both of which are critical for maintaining a healthy metabolic balance.
The Mixed Results
- Observational studies suggest MHT users have a lower incidence of metabolic syndrome, characterized by a combination of abdominal obesity, hypertension, dyslipidemia, and insulin resistance. However, randomized trials show varied results influenced by MHT formulation, dosage, and pre-existing metabolic risks. Differences may also depend on individual lifestyle factors, such as physical activity levels, diet, and genetic predispositions, which significantly impact metabolic outcomes.
Immune Regulation & Inflammation
The Research
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Estrogen plays a crucial role in modulating the immune system by influencing the production of cytokines—molecules that help regulate immune responses. It promotes the production of anti-inflammatory cytokines like IL-10 (interleukin-10), which act as signaling molecules to calm the immune response and reduce chronic inflammation. These cytokines function like messengers, instructing the immune system to reduce its activity and prevent unnecessary tissue damage. At the same time, estrogen suppresses the secretion of pro-inflammatory markers such as TNF-α (tumor necrosis factor-alpha) and IL-6 (interleukin-6), which are associated with chronic inflammatory diseases like arthritis and cardiovascular conditions.
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In addition to its effects on cytokines, estrogen enhances the function of macrophages—immune cells responsible for detecting and eliminating harmful pathogens. This action supports tissue repair and strengthens overall immune surveillance. Estrogen also influences the maturation of B-cells, which are essential for producing antibodies that help the body fight infections. This contributes to stronger defenses against infections and offers protection against age-related diseases linked to declining immune function. By balancing immune signals, supporting pathogen elimination, and promoting antibody production, estrogen plays a key role in maintaining immune health and reducing inflammation.
- Progesterone also contributes to immune regulation by suppressing T-cell activation, which helps prevent excessive immune responses that can lead to inflammation. It promotes the development of regulatory T-cells (Tregs)—a special type of immune cell that maintains immune tolerance, ensuring the body doesn’t mistakenly attack its own healthy tissues. Progesterone also reduces the maturation of dendritic cells, which are responsible for presenting antigens (foreign substances) to the immune system. By limiting this process, progesterone helps minimize unnecessary immune activation, potentially reducing the risk of autoimmune flare-ups in conditions like rheumatoid arthritis.
- Testosterone’s role in immune function is complex and appears to differ between men and women. In men, testosterone is generally considered immunosuppressive, potentially leading to a reduced immune response. In women, however, the effects are less clear. Some studies suggest that higher testosterone levels in women may be associated with lower levels of certain antibodies, such as Immunoglobulin A (IgA), especially in those who are sexually active. This indicates that testosterone could modulate immune responses in women, but the exact mechanisms and implications require further research.
Ongoing Debate
- While some research suggests that MHT may help reduce chronic inflammation and promote better immune regulation, other studies have raised concerns. Specifically, synthetic progestins (artificial forms of progesterone) may trigger pro-inflammatory responses in certain individuals. Elevated levels of inflammatory markers like C-reactive protein (CRP)—a key indicator of inflammation—have been observed in some MHT users. As discussed previously, this continues to suggest that the type, dosage, and formulation of MHT can influence inflammatory risks. Personalized approaches that consider individual health factors are essential for minimizing potential immune-related side effects.
Mood, Mental Health & Sleep
The Research
- Estrogen modulates serotonin and dopamine pathways, stabilizing mood and reducing the risk of depression. It enhances cognitive flexibility, emotional resilience, and the synthesis of serotonin by increasing the expression of tryptophan hydroxylase—a key enzyme in serotonin production. Estrogen also influences synaptic plasticity in the prefrontal cortex and hippocampus, contributing to emotional regulation and memory processing. Additionally, estrogen helps regulate the activity of an enzyme called monoamine oxidase, which is responsible for breaking down serotonin—a key hormone that influences mood, sleep, and emotional well-being. By reducing the breakdown of serotonin, estrogen helps maintain higher levels of this “feel-good” hormone in the brain, supporting better mood stability and emotional resilience.
- Progesterone supports restful sleep by interacting with GABA receptors—part of the brain’s calming system that helps slow down nerve activity, promoting relaxation and sleepiness. Its byproducts, like allopregnanolone, are especially powerful in enhancing this calming effect, helping to deepen sleep stages and reduce the time it takes to fall asleep. These soothing effects of progesterone are particularly noticeable during the luteal phase of the menstrual cycle (the second half, after ovulation) and in perimenopausal women, who often experience sleep disturbances due to fluctuating hormone levels.
- Testosterone contributes to emotional resilience and motivation by influencing the brain’s dopamine system, which plays a key role in feelings of reward, pleasure, and drive. Research suggests that testosterone therapy can help reduce depressive symptoms in postmenopausal women by enhancing sensitivity to rewarding experiences and promoting neuroplasticity—the brain’s ability to adapt and form new connections—in regions that regulate mood, like the amygdala and prefrontal cortex. Additionally, testosterone helps regulate the hypothalamic-pituitary-adrenal (HPA) axis, which controls the body’s response to stress. By lowering cortisol (the primary stress hormone), testosterone can help reduce feelings of stress and anxiety, further supporting emotional well-being.
Conflicting Evidence
- While MHT can improve mood and mental health, some formulations—particularly those involving synthetic progestins—may exacerbate anxiety or depressive symptoms. This effect is potentially due to harmful changes in neurotransmitter pathways (brain chemical signaling) or receptor sensitivity (how responsive brain receptors are), particularly in women with a predisposition to mood disorders.
Libido & Sexual Function
The Research
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Estrogen plays an essential role in maintaining vaginal tissue health, elasticity, and natural lubrication, which helps reduce symptoms of vaginal atrophy—a condition common during menopause that causes thinning, dryness, and inflammation of the vaginal walls. Estrogen stimulates the production of substances like mucopolysaccharides and hyaluronic acid, which help keep the vaginal tissues hydrated and flexible, improving comfort during intercourse. Additionally, estrogen supports the strength and resilience of the vaginal epithelium (the outer layer of tissue), helping to maintain a healthy pH balance and reduce the risk of infections by strengthening the tissue structure.
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Progesterone contributes to hormonal balance and indirectly supports sexual well-being. It helps regulate the body’s stress response by lowering cortisol levels—a hormone that, when elevated, can suppress sexual desire. By reducing stress levels, progesterone may help enhance libido. Additionally, progesterone contributes to a stable mood and emotional well-being, both of which are essential for maintaining a positive and satisfying sexual experience.
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Testosterone is a key hormone in supporting sexual desire, arousal, and responsiveness. It influences dopamine pathways in the brain, which are closely tied to feelings of motivation and reward, including sexual desire. Testosterone also boosts genital blood flow, enhancing sexual sensation and improving responsiveness during intimacy. Clinical studies have shown that testosterone therapy can increase libido, improve sexual satisfaction, and raise the frequency of sexual activity in postmenopausal women, underlining its important role in maintaining sexual vitality.
Conflicting Evidence:
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While bioidentical estrogen therapies, such as transdermal 17β-estradiol, are generally well-tolerated, some women may still experience side effects like headaches, nausea, and breast tenderness, particularly during the adjustment phase or with incorrect dosing. Progesterone is usually well-tolerated, but some may experience side effects such as mood changes, fatigue, foggy headedness or decreased libido, emphasizing the need for personalized dosing and monitoring. Testosterone therapy is effective for treating hypoactive sexual desire disorder (HSDD) but carries uncertainties regarding optimal dosing and individual responses. Higher doses may lead to side effects like acne, hair loss, or voice changes, requiring careful monitoring to minimize risks.
Conclusion
Menopausal Hormone Therapy (MHT) can support women’s health by promoting metabolic balance, immune regulation, emotional well-being, sleep quality, and sexual vitality. However, outcomes depend on hormone type, dosage, and individual health profiles.
While MHT offers benefits, it also carries potential risks, particularly with oral estrogen and synthetic progestin, as outlined in Part 1. Risks are considered lower with low-dose, transdermal, or vaginal formulations, and research suggests these options may even reduce the likelihood of conditions like endometrial and ovarian cancer. Using the lowest effective dose and considering non-oral options can help minimize risks.
Bioidentical hormones are frequently marketed as a safer option compared to traditional hormone therapies; however, current large-scale research and long-term safety data are limited. Existing evidence is not sufficient to confirm their superior safety or effectiveness. Major medical bodies, including the American College of Obstetricians and Gynecologists (ACOG), express caution regarding compounded bioidentical hormone therapy, citing concerns about safety, effectiveness, and quality control.
While clinical experiences may sometimes outpace available research, current scientific evidence does not substantiate claims of increased safety. Therefore, it is crucial for women to engage in informed discussions with their healthcare providers to personalize hormone therapy decisions, carefully considering potential benefits alongside known and unknown risks.
I consider hormones to be just one component of a broader health strategy. Achieving optimal health during menopause often requires a comprehensive, integrative approach. Part 4 of this series will explore natural and lifestyle-based strategies—including nutrition, exercise, stress management, and complementary therapies—offering additional options for women seeking to enhance their health during and after menopause.
References
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