Hormones 101 | Vitalte

Hormone Therapy Explained: The Science, the History, and the Truth

Hormone science really took off in the late 1800s and early 1900s, when researchers realized that certain organs were secreting “internal secretions” into the bloodstream that could act at a distance.

Experiments like removing and transplanting animal testes, ovaries, and thyroids showed dramatic changes in growth, metabolism, and behavior, leading to the concept of “hormones” as chemical messengers rather than just nerve signals. By the mid-20th century we could isolate, synthesize, and mass-produce hormones like insulin, thyroid hormone, cortisol, estrogen, and testosterone, opening the door to modern endocrinology, contraception, menopausal therapy, and later hormone optimization/“replacement” medicine.

The WHI Legacy: Fear, Misinterpretation, and Updated Evidence

The Women’s Health Initiative (WHI), launched in the 1990s, was meant to test whether conjugated equine estrogens plus medroxyprogesterone acetate (Prempro) prevented chronic disease in older postmenopausal women.

The early 2002 report highlighted increased risks of breast cancer, stroke, and blood clots and the trial arm was stopped early. Those topline headlines were blasted everywhere, but they over-generalized from one older, higher-risk population on one specific horse-estrogen/synthetic progestin regimen to “all hormones are dangerous for all women.” Prescriptions collapsed, many symptomatic women were taken off therapy, and fear spread to men’s hormones by association.

Two decades of re-analysis now show the picture is far more nuanced: age at initiation, time since menopause, route of administration, and hormone type (bioidentical vs non-bioidentical) matter a lot, and for many appropriately selected patients the benefits can outweigh the risks.

That’s where today’s tailwinds come from: updated position statements from major societies, better data on individualized and bioidentical regimens, regulatory pathways that recognize physiologic replacement rather than “anti-aging gimmickry,” and legal/med-mal frameworks that now acknowledge that undertreating hypoestrogenism or hypogonadism can also harm patients—not just over-treating.

What Happens to Our Hormones as We Age?

Think of your body like a high-performance car.
Your food, sleep, and exercise are the gasoline — the fuel you burn every day to function, work, and play. But gas alone doesn’t keep a car running well. To truly perform, the engine needs something even more important:

Hormones are the “oil” in your engine.

They keep the entire system running smoothly by helping every chemical message in your body arrive clearly, completely, and with the full intended power. When your hormone levels are healthy, the body communicates with precision — your energy flows, your mind stays sharp, your metabolism works efficiently, and your relationships benefit.

But just like a car’s oil thins out over time, your natural hormone levels decline as you age. For most people, this begins quietly in the early 30s. The causes differ —

• the stress of raising multiple children
• demanding jobs and long seasons of pressure
• poor sleep, processed foods, chronic inflammation
• environmental toxins and endocrine disruptors

The fact is this: men and women today have significantly lower hormone levels than people did just 30 years ago, and the symptoms show up everywhere — low energy, reduced motivation, unreliable libido, mood instability, slower recovery, weight gain, and declining cognitive sharpness.

Modern medical science has changed the game. We now understand how to restore hormones to healthy physiological levels, safely and effectively, allowing the body to perform the way it was designed to.

VitalTE is pushing the drug development envelope to provide patients, providers and payors an answer that is decades over due. An HRT solution that provides more effective symptom relief, at a safer dose, in a more convenient delivery mechanism.

Testosterone – Key Physiologic Functions

1. Androgenic effects – sexual development & function

Drives development and maintenance of male sexual characteristics and reproductive tissues (penis, testes, prostate).

Supports libido and erectile function in hypogonadal men; treatment is recommended to restore secondary sex characteristics and relieve symptoms.

Source:

1. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline hypogonadism. https://pubmed.ncbi.nlm.nih.gov/29562364/

2. Anabolic effects – muscle mass, strength, and physical function

Testosterone stimulates muscle protein synthesis and increases lean mass and strength; this has been shown in trials of older hypogonadal or low-normal men receiving physiologic testosterone.

Meta-analyses show significant increases in lean body mass and decreases in fat mass with testosterone therapy.

Sources:

1. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms, https://journals.physiology.org/doi/full/10.1152/ajpendo.00362.2001

2. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2265.2005.02339.x

3. Bone biology – cortical growth, density, and fracture risk

Testosterone contributes to cortical bone size and strength, especially during puberty, while much of adult male trabecular bone and anti-resorptive control is actually estradiol-driven (see E2 section), but T still plays a role in bone formation.

Observational and interventional data link low testosterone to reduced bone mineral density and increased fracture risk; testosterone replacement can improve BMD in hypogonadal men.

Sources:

1. Testosterone and Male Bone Health: A Puzzle of Interactions, https://academic.oup.com/jcem/article-abstract/110/7/e2121/8090450?redirectedFrom=fulltext

2. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2265.2005.02339.x

4. Hematopoiesis – red blood cell production

Testosterone stimulates erythropoiesis, partly via increased erythropoietin and direct effects on bone marrow.

Clinical trials consistently show hematocrit and hemoglobin increases with testosterone therapy, which is why guidelines emphasize monitoring for erythrocytosis.

Sources:

1. Testosterone and the aging male: To treat or not to treat?, https://www.sciencedirect.com/science/article/abs/pii/S0378512210000125

2. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline, https://academic.oup.com/jcem/article/103/5/1715/4939465

5. Neurocognitive and mood effects

Testosterone deficiency is associated with depressed mood, reduced vitality, and cognitive slowing; some trials show modest improvements in mood, sexual desire, and certain cognitive domains with replacement, especially when baseline T is clearly low.

Mechanistically, T and its metabolites modulate dopaminergic and serotonergic pathways and influence hippocampal structure and function.

Sources:

1. Effect of Testosterone Supplementation on Functional Mobility, Cognition, and Other Parameters in Older Men, https://jamanetwork.com/journals/jama/fullarticle/1149440

2. Revisiting the role of testosterone: Are we missing something?, https://pmc.ncbi.nlm.nih.gov/articles/PMC5434832/

6. Metabolic and cardiovascular regulation

Low testosterone is strongly associated (epidemiologically) with visceral obesity, insulin resistance, metabolic syndrome, and type 2 diabetes.

Interventional data suggest testosterone therapy can reduce fat mass and improve insulin sensitivity in hypogonadal men, though cardiovascular outcome data remain nuanced and formulation-specific. Wiley Online Library+1

A 2024 review highlights complementary metabolic benefits of testosterone and estradiol in men, with estradiol more dominant for anti-resorptive bone effects, and both steroids influencing adipose tissue and glucose homeostasis. JC International

Sources:

1. Testosterone and the aging male: To treat or not to treat?, https://www.sciencedirect.com/science/article/abs/pii/S0378512210000125

2. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2265.2005.02339.x

3. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations, https://www.jci.org/articles/view/180073

Estradiol – Key Physiologic Functions in Men

Critical point: Most estradiol in men (≥80%) comes from aromatization of testosterone in peripheral tissues.

(Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men, https://www.nejm.org/doi/full/10.1056/NEJMoa1206168)

1. Bone health – dominant regulator of bone resorption in men

Multiple human models (genetic aromatase deficiency, aromatase inhibition, and controlled suppression trials) show that estradiol is the primary sex steroid preventing bone resorption in adult men; testosterone plays a complementary role in bone formation and size. PubMed+2JC International+2

Aromatase-deficient men (very low E2) have markedly low bone mass and unfused epiphyses, despite high testosterone, underscoring estradiol’s central role. PMC

Trials of aromatase inhibitors in older men show that raising testosterone but lowering estradiol leads to decreased BMD, again confirming estradiol’s critical importance. Oxford Academic+1

Source:

1. Estrogens and bone health in men. https://pubmed.ncbi.nlm.nih.gov/11730247/

2. Sexual function, libido, and erectile physiology

Estradiol is not just a female hormone; it is essential in men for libido, erectile function, and spermatogenesis, with estrogen receptors and aromatase present in brain, penis, and testes. PMC

Clinical and observational studies show that very low estradiol (e.g., with aggressive aromatase inhibition) is associated with reduced sexual desire, impaired erectile rigidity, and worsened sexual function scores, even when testosterone is relatively high. PubMed+2Nature+2

Sources:

1. The role of estradiol in male reproductive function, https://pmc.ncbi.nlm.nih.gov/articles/PMC4854098/

2. Gonadal steroids and body composition, strength, and sexual function in men, https://pubmed.ncbi.nlm.nih.gov/24024838/

3. Neurocognitive and mood effects

Estradiol has neuroprotective and neuromodulatory roles: it enhances synaptic plasticity, mitochondrial function, and modulates monoamine systems (serotonin, dopamine, GABA), which collectively influence mood and cognition.

Low estradiol in men (from aromatase inhibition or severe hypogonadism) is associated with worsened mood, fatigue, and cognitive complaints, although high-quality RCT data are more limited than for bone. PMC+1

Sources:

1. Estradiol and Age-Related Bone Loss in Men https://journals.physiology.org/doi/full/10.1152/physrev.00051.2017

2. Revisiting the role of testosterone: Are we missing something? https://pmc.ncbi.nlm.nih.gov/articles/PMC5434832/

4. Cardiometabolic function

Estradiol helps regulate lipid metabolism, endothelial function, and vascular inflammation. Reviews on sex steroids highlight that estrogens generally improve lipid profiles and vascular reactivity, and that low E2 is associated with higher cardiovascular risk markers in both sexes.

In men, estradiol (derived from T) contributes to healthy fat distribution and insulin sensitivity; estradiol deficiency shifts toward increased visceral fat and adverse metabolic phenotype. JC International+1

Source:

1. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations, https://www.jci.org/articles/view/180073

5. Joint, connective tissue, and pain modulation

Estrogens modulate collagen turnover, cartilage metabolism, and inflammatory signaling, contributing to joint comfort and mobility.

Clinical evidence from women and men suggests that estrogen deficiency (surgical menopause, aromatase inhibition, natural decline) is associated with arthralgia and musculoskeletal pain, and that restoring or preserving E2 levels often improves symptoms.

Sources:

1. Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications, https://www.mdpi.com/1422-0067/22/4/1568

2. Aromatase inhibitors in male: A literature review, https://www.sciencedirect.com/science/article/pii/S2603924922000386

6. Immune modulation & inflammation

Estrogens broadly exert anti-inflammatory effects, including modulation of NF-κB and cytokine profiles, affecting autoimmune risk and tissue repair. MDPI

This immune-modulating role overlaps with cardiometabolic and musculoskeletal benefits, particularly in the context of chronic low-grade inflammation associated with aging and obesity. JC International+1

Sources:

1. Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications, https://www.mdpi.com/1422-0067/22/4/1568

2. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations https://www.jci.org/articles/view/180073

How Testosterone and Estradiol Work Together

Aromatization & shared pathways

80% of male estradiol is produced by aromatization of testosterone, mainly in adipose tissue, bone, and brain.

Finkelstein’s controlled suppression study in NEJM showed:

Androgen deficiency → loss of lean mass, reduced muscle size and strength.

Estrogen deficiency → increased fat mass and substantial contributions to declines in sexual function.

Take-home: many of “testosterone’s” clinical effects in men (especially on bone, fat, and sexual function) are actually co-mediated or even dominated by estradiol generated from testosterone.

Source:

1 Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men, https://www.nejm.org/doi/full/10.1056/NEJMoa1206168

Clinical consequences of blocking aromatization (real-world caution with AIs)

Aromatase inhibitors in men raise testosterone but lower estradiol; studies consistently show:

↓ BMD or negative bone effects.
Potential worsening of joint pain and adverse metabolic changes in some settings.

This is why many experts caution against routine or aggressive estradiol suppression in men on testosterone therapy unless there’s a specific indication.

Sources:

1. Effects of Aromatase Inhibition on Bone Mineral Density and Bone Turnover in Older Men with Low Testosterone Levels, https://academic.oup.com/jcem/article-abstract/94/12/4785/2596582

2. Aromatase inhibitors in male: A literature review, https://www.sciencedirect.com/science/article/pii/S2603924922000386