Chronic Disease Explained Using Androgen Hormone Optimization

Learn about the connection between androgen hormone optimization and chronic disease, and how this connection affects your overall health.

Abstract

In this educational post, I synthesize contemporary, evidence-based insights on sex steroid physiology and clinical care for men and women. I explain how testosterone, its aromatization to estradiol, and its 5α-reduction to dihydrotestosterone (DHT) work together across the brain, heart, bones, and reproductive systems; why indiscriminate blockade of aromatase or 5α-reductase can undermine health; and how the androgen saturation model reframes prostate risk. I review modern data showing neutral-to-favorable cardiovascular signals with physiologic testosterone therapy, contrast those with the adverse cardiometabolic and cognitive outcomes seen with androgen deprivation therapy (ADT), and unpack large-cohort evidence linking low testosterone to higher dementia risk. I also detail why reference ranges can normalize dysfunction and how to operationalize an optimal-versus-normal framework. For women, I address androgen decline at midlife or after oophorectomy, highlight the role of SHBG in “normal labs, abnormal symptoms,” and outline safe, evidence-based options for androgen support and transdermal estradiol. Throughout, I integrate protocols from my practice and point to seminal work by leaders in urology, endocrinology, neurology, and preventive cardiology, with full APA-7 in-text citations and linked references.

Testosterone Physiology 101: Direct, Aromatized, and 5α-Reduced Actions

I begin every hormone plan by respecting physiology. Testosterone exerts effects through three principal, complementary pathways:

• Direct androgen receptor (AR) activation: Testosterone binds intracellular ARs across muscle, bone, brain, vascular endothelium, and reproductive tissues to regulate transcriptional programs that support anabolism, mitochondrial biogenesis, neuroplasticity, and vascular tone (Traish, 2020).
• Aromatization to estradiol (E2): The aromatase enzyme converts testosterone to estradiol, activating ERα and ERβ receptors to sustain bone density, synaptic plasticity, endothelial nitric oxide (NO) signaling, and mood (Finkelstein et al., 2013).
• 5α-reduction to dihydrotestosterone (DHT): Via 5α-reductase (types 1/2), testosterone becomes DHT, a more potent AR ligand with ~3–5× greater affinity that drives androgenic signaling in skin, prostate, and brain with often beneficial outcomes for sexual function and motivation (Azzouni et al., 2012).

Why this matters in practice:

• I avoid routine aromatase or 5α-reductase inhibition because estradiol and DHT are not “bad metabolites”; they are integral to normal physiology. Indiscriminate blockade commonly produces sexual dysfunction, anhedonia, and metabolic derangements.
• In younger men referred to me after months on finasteride/dutasteride for hair loss, I often see profound libido decline, erectile dysfunction, and emotional lability. Re-establishing balanced androgen metabolism and AR access frequently reverses these symptoms.

Key takeaways:

• Respect the androgen network; testosterone’s conversions are amplifiers, not enemies.
• Match enzyme blockade to a clear indication and phenotype, and favor dose/route adjustments first.

References: (Azzouni et al., 2012; Finkelstein et al., 2013; Traish, 2020)

Androgen Receptors Are Everywhere: Why Deficiency Feels Systemic

Androgen receptors are expressed in skeletal muscle, osteoblasts, hippocampus, amygdala, prefrontal cortex, cardiac myocytes, endothelium, pancreatic β-cells, adipocytes, and immune cells (Heinlein & Chang, 2002). When androgen tone drops or receptor access is blunted, patients experience a multi-organ phenotype:

• Cognition and mood: brain fog, low drive, irritability, depressed mood
• Metabolic: visceral adiposity, insulin resistance, dyslipidemia
• Musculoskeletal: sarcopenia, bone loss, chronic pain
• Cardiovascular: diminished exercise tolerance, endothelial dysfunction
• Sexual: low libido, arousal/erectile disorders

This is not “just low T.” It is a network effect with measurable cardiometabolic risks (Kelly & Jones, 2015).

References: (Heinlein & Chang, 2002; Kelly & Jones, 2015)

Prostate Health and the Androgen Saturation Model: Debunking the Old Myth

Many were taught that testosterone “feeds” prostate cancer like gasoline on fire. Modern scholarship—led by Abraham Morgentaler, MD—shows otherwise:

• Men with lower endogenous testosterone at diagnosis may present with more aggressive prostate cancer (Morgentaler & Rhoden, 2006).
• Testosterone therapy after definitive prostate cancer treatment in men without evidence of disease has not shown a clear increase in recurrence across multiple cohorts (Morgentaler et al., 2011; Pastuszak et al., 2013).
• The Androgen Saturation Model: Prostatic ARs saturate at relatively low serum testosterone levels; above that threshold, additional circulating T provides minimal further prostatic stimulation (Morgentaler & Traish, 2009).

Clinical meaning:

• A rising PSA on therapy demands evaluation for prostatitis, lab variation, or malignancy; it should not be reflexively blamed on testosterone.
• Real-world risk correlates include family history, African ancestry, and possibly low endogenous T, not carefully monitored physiologic replacement.

References: (Morgentaler & Rhoden, 2006; Morgentaler & Traish, 2009; Morgentaler et al., 2011; Pastuszak et al., 2013)

Cardiovascular Health: Physiology, Outcomes, and the ADT Contrast

Physiology that supports cardiometabolic benefits of adequate androgens:

• Insulin sensitivity: Testosterone enhances GLUT4 translocation and mitochondrial efficiency, improving glucose disposal (Jones et al., 2011; Grossmann, 2018).
• Endothelial function: Increases eNOS activity and NO bioavailability to improve flow-mediated dilation and vascular elasticity (Yaron et al., 2009).
• Inflammation: Lowers IL-6 and TNF-α, favoring an anti-inflammatory milieu (Grossmann, 2018).

What outcomes show:

• Contemporary meta-analyses and cohorts indicate that physiologic testosterone therapy in hypogonadal men is neutral-to-beneficial for major adverse cardiovascular events when levels are normalized without supraphysiology (Corona et al., 2018; Cheetham et al., 2017).
• In contrast, androgen deprivation therapy (ADT) for prostate cancer consistently increases incident diabetes, cardiovascular morbidity, worsens body composition and lipids, and may elevate dementia risk (Keating et al., 2006; Bosco et al., 2015).

My approach:

• If ADT is oncologically necessary, I co-manage aggressive metabolic risk mitigation: nutrition, resistance training, sleep optimization, and cardiology oversight.

References: (Cheetham et al., 2017; Corona et al., 2018; Grossmann, 2018; Keating et al., 2006; Yaron et al., 2009; Bosco et al., 2015)

Brain Health and Dementia: What Low Testosterone Signals

Large datasets show that men in the lowest testosterone strata face significantly higher dementia and Alzheimer’s disease risk than peers with higher levels (Barrett-Connor et al., 2006; Cherrier et al., 2015). Mechanistic supports:

• Enhanced synaptic plasticity and neurogenesis in hippocampal circuits
• Improved myelination, neuronal survival, and amyloid/tau processing
• Better cerebral vascular function and glymphatic clearance via NO pathways

Concordance with ADT studies reinforces the association: therapy-induced hypogonadism correlates with higher dementia incidence (Nead et al., 2017). In patients with cognitive complaints, I include a hormonal panel alongside sleep, mood, medication, and metabolic assessments.

Références: (Barrett-Connor et al., 2006; Cherrier et al., 2015; Nead et al., 2017)

Normal vs. Optimal Targets: Why Reference Ranges Can Mislead

Reference ranges describe a population distribution, not an optimal zone for health. As ranges drift downward with age, we risk normalizing dysfunction. My protocol:

• Define clinical endpoints: cognition, libido, energy, body composition, glycemic control, sleep, and mood.
• Use percentile thinking: patients in the lowest decile frequently exhibit symptoms and higher-risk features.
• Target the upper-normal physiologic band individualized by SHBG, estradiol, comorbidities, and goals (Travison et al., 2017).

Why this helps:

• A patient at the 10th percentile may be told he is “normal,” but still carries elevated Alzheimer’s and metabolic risk relative to peers at higher percentiles.

Références: (Travison et al., 2017)

Women’s Androgen Biology: Oophorectomy, Menopause, and Abrupt Androgen Loss

Women synthesize androgens in the ovaries and adrenal glands, providing substrates for intracrine estrogen formation. Around menopause, androgens decline years before estrogen nadirs; after bilateral oophorectomy, androgens plummet within 24 hours, often causing:

• Cognitive fog and slower processing
• Mood lability and depressive symptoms
• Loss of sexual desire and arousal
• Hot flashes and vasomotor instability
• Musculoskeletal pain and lower exercise capacity

Carefully monitored physiologic androgen support—often paired with transdermal estradiol—improves sexual function, mood, bone density, and well-being (Davis et al., 2019; Islam et al., 2019). I evaluate the free androgen index, DHEA-S, SHBG, and estradiol; I avoid supraphysiological levels to minimize virilization and lipid derangements.

Références: (Davis et al., 2019; Islam et al., 2019)

SHBG, Free Testosterone, and “Normal Labs, Abnormal Symptoms”

A frequent clinical paradox is normal total testosterone with elevated sex hormone-binding globulin (SHBG) and low free/bioavailable testosterone, especially in women and in some men.

• SHBG tightly binds testosterone, lowering the free fraction that activates ARs.
• Drivers of high SHBG include oral estrogens, certain SSRIs, thyroid status, liver health, and aging.
• In high-SHBG patients, raising total testosterone without addressing binding may not restore tissue-level signaling.

My framework:

• Measure or calculate free/bioavailable testosterone.
• Consider switching oral estrogen to transdermal estradiol and coordinating with mental health to adjust medications that elevate SHBG.
• Titrate to effect using free/bioavailable targets and validated symptom scales, not totals alone.

Clinical observation:

• At dralexjimenez.com and in my practice, adjusting for SHBG and restoring free testosterone reliably improves energy, libido, and cognitive clarity in many patients.

Références: (Davis et al., 2019; Islam et al., 2019)

Bone Health and Hormone Synergy: Estradiol, Testosterone, and Osteocyte Signaling

Bone is a systems problem. Sex steroids regulate osteoblasts, osteoclasts, and osteocytes:

• Estradiol downregulates RANKL, upregulates OPG, lowers IL-6/TNF-α, and preserves osteocyte viability—maintaining microarchitecture and bone quality (Compston et al., 2019).
• Testosterone acts via AR in osteoblast lineages and via aromatization to estradiol to enhance formation and reduce resorption (Falahati-Nini et al., 2000).
• Progesterone can synergize with estradiol in bone formation phases (Prior, 2018).

Why route matters:

• Transdermal estradiol avoids first-pass hepatic induction of clotting factors and excessive SHBG, yielding steadier physiology and a more favorable thrombotic profile than oral forms (L’Hermite, 2017; Vinogradova et al., 2019).

My baseline plan for osteopenia/osteoporosis includes vitamin D3/K2, adequate protein, magnesium, and resistance/impact training. With adherence plus appropriate hormone support, I commonly see improved DXA trends at 2–3 years and better fall-risk profiles.

Références: (Compston et al., 2019; Falahati-Nini et al., 2000; L’Hermite, 2017; Prior, 2018; Vinogradova et al., 2019)

Sexual Function, Mood, and “Depression That Isn’t Just Depression”

Some “treatment-resistant depression” has a biological substrate: low androgens, low estradiol, thyroid dysfunction, iron deficiency, sleep apnea, or inflammatory drivers.

• In androgen-deficient men, testosterone therapy improves sexual function, quality of life, and can reduce depressive symptoms (Corona et al., 2014; Zarrouf et al., 2009).
• In women with hypoactive sexual desire disorder, physiologic testosterone improves desire, arousal, and orgasmic function when carefully monitored (Davis et al., 2019).

Clinical pearls I use:

• Rule out SSRI-induced sexual dysfunction; consider alternatives with lower sexual side-effect burdens.
• Reassess systemic 5α-reductase inhibitors in susceptible men; prefer non-systemic hair-loss options when feasible.
• Layer resistance training, sleep optimization, and omega-3s onto hormone strategies for synergistic mood and energy effects.

Références: (Corona et al., 2014; Davis et al., 2019; Zarrouf et al., 2009)

Practical Protocols I Use in Clinic: Assessment, Titration, and Safety

Assessment:

• History emphasizing cognition, mood, sleep, libido, energy, weight, waist circumference, glucose/insulin, lipids, and cancer family history.
• Labs:

• Men: Total T, free T, SHBG, LH/FSH, estradiol (LC–MS/MS), CBC, CMP, lipids, HbA1c, PSA; consider prolactin, thyroid panel.
• Women: Total T, free T, SHBG, DHEA-S, estradiol, progesterone (if cycling), thyroid, and iron studies as indicated.

• Imaging by indication: bone density, prostate imaging, and coronary calcium scoring for risk stratification.

Initiation and titration:

• Choose route by goals/risk:

• Transdermal gels/creams for smoother levels, less erythrocytosis.
• Injectables (e.g., testosterone cypionate) in divided doses to reduce peaks.
• Pellets are used when adherence and steady-state delivery are priorities.

• Avoid routine aromatase or 5α-reductase inhibition unless clearly indicated.
• Reassess at 6–8 weeks (topicals/injectables) or 8–12 weeks (pellets) with symptoms and labs, adjusting toward clinical endpoints.

Safety monitoring:

• Men: PSA, DRE per guidelines; hematocrit/hemoglobin for erythrocytosis; estradiol if gynecomastia/edema emerge.
• Women: Watch for androgenic effects (acne, hirsutism, voice change) and maintain estradiol for bone/brain/vascular health when indicated.

Lifestyle and adjuncts:

• Resistance training and HIIT
• Protein2–1.6 g/kg/day; omega-3s
• Sleep and treatment of sleep apnea
• Stress modulation: optimize vitamin D, magnesium, zinc, B12/folate as needed

Références: (Bhasin et al., 2018; Davis et al., 2019; Islam et al., 2019)

Women’s Energy, Mood, and Sexual Health: A Practical Lens for Androgen Deficiency

I frequently see a triad in women ≥ mid-30s: persistent fatigue, mood changes with low motivation, and sexual dysfunction (low desire/arousal). Contributing physiology:

• Gradual decline in testosterone and often free T3 from the mid-20s onward (Davis & Wahlin-Jacobsen, 2015).
• Menopausal collapse in estradiol and progesterone reveals an already stressed system.
• Rising SHBG (age, oral estrogen, some SSRIs, thyroid status) suppresses free T.

My evaluation:

• Morning total T, SHBG, calculated free T, and estradiol via LC–MS/MS.
• TSH, free T4/T3, DHEA-S, FSH/LH as needed, insulin/glucose, lipids, vitamin D, ferritin, hs-CRP.
• Risk stratification for hormone-sensitive cancers and cardiometabolic disease.

Treatment:

• Sleep consolidation, circadian alignment, resistance training, protein adequacy, and anti-inflammatory nutrition.
• Address blockers (sedative-hypnotics, sleep apnea, chronic stress).
• Low-dose physiologic testosterone tailored to symptom-lab correlation; transdermal estradiol plus micronized progesterone if uterus is present; treat hypothyroidism when present.

Expected responses:

• Improved sleep continuity, morning drive, and sexual responsiveness within weeks, with further gains over months.

References: (Davis & Wahlin-Jacobsen, 2015; Davis et al., 2019)

Pellets, Transdermals, and Injectables: Choosing the Right Delivery

Why pellets can be helpful:

• Steady-state pharmacokinetics avoid peaks and troughs, stabilizing mood and receptor signaling.
• Bypasses first-pass hepatic effects, reducing SHBG induction compared with some oral agents.
• Optimize adherence for patients who struggle with dailies.

Why transdermals are often first-line:

• Favorable vascular and thrombotic profile vs. oral estrogens; more stable E2:E1 ratios (L’Hermite, 2017; Vinogradova et al., 2019).
• Flexible dosing and easy titration.

Why divided-dose injectables work:

• Reduce peak estradiol conversion and mood lability; practical for men who prefer intermittent dosing.

Evidence and caveats:

• International and real-world data support the use of pellets for symptom control in selected patients (Glaser & Dimitrakakis, 2013; Islam et al., 2019). As with all modalities, careful dosing and follow-up are essential.

References: (Glaser & Dimitrakakis, 2013; Islam et al., 2019; L’Hermite, 2017; Vinogradova et al., 2019)

Pain, Opioids, and Androgen Deficiency: Breaking the Vicious Cycle

Chronic opioids suppress the HPG axis, causing opioid-induced androgen deficiency (OAD) (Rubinstein & Carpenter, 2014). Low androgens worsen pain sensitivity, fatigue, and mood, feeding a cycle of more pain and higher opioid needs (Smith et al., 2012).

My protocol for pain patients:

• Screen morning total/free T, SHBG, estradiol, thyroid panel, vitamin D, and inflammatory markers.
• Address reversible factors (opioid tapering when feasible, sleep apnea, weight).
• Consider physiologic testosterone restoration with close multidisciplinary follow-up.
• Integrate movement therapy, circadian repair, and anti-inflammatory nutrition.

Outcomes in my clinic often include improved PT tolerance, reduced catastrophizing, and lower opioid doses over time.

References: (Aly et al., 2020; Bhasin et al., 2018; Rubinstein & Carpenter, 2014; Smith et al., 2012)

Regulatory History and Clinical Confusion: Distinguishing Testosterone from AAS

Past regulatory bundling of testosterone with anabolic-androgenic steroids (AAS) blurred distinctions between physiologic replacement and supraphysiologic doping (Handelsman, 2017). The Schedule III status in the US, and lack of FDA-approved female-specific products, foster hesitancy and undertreatment—especially for women.

Clinical impact I see:

• Many primary care clinicians received limited training in androgens and default to avoidance.
• Women with clear androgen-deficiency symptoms often lack labeled options, yet can thrive on carefully monitored, bioidentical.l

References: (Handelsman, 2017)

Clinical Observations from My Practice

Across El Paso clinics and my professional pages at dralexjimenez.com and LinkedIn, consistent patterns emerge:

• Untreated sleep apnea commonly depresses morning testosterone and exacerbates insulin resistance; treating apnea improves endogenous levels and reduces the need for exogenous doses.
• Systemic 5α-reductase inhibitors are frequent triggers for sexual and mood symptoms in younger men; restoring physiologic DHT signaling can improve quality of life.
• Women with surgical menopause often experience dramatic cognitive and mood shifts; transdermal estradiol with low-dose androgen support restores cognitive speed, desire, and vitality.
• In men with a family history of prostate cancer, carefully monitored testosterone optimization alongside fitness and nutrition improves body composition and may favorably influence long-term risk profiles under vigilant PSA tracking.
• Patients thrive when we aim for optimal outcomes, not just “within normal limits,” through shared decision-making and transparent education.

Explore more at:

• https://dralexjimenez.com/
• https://www.linkedin.com/in/dralexjimenez/

Why These Techniques Work: Physiological Rationale

• Transdermal testosterone: Mimics diurnal patterns, avoids first-pass liver effects, lowers erythrocytosis risk; ideal when cardiovascular risk is a concern.
• Divided-dose injectables: Minimize peaks/troughs, reduce aromatization spikes, stabilize mood and energy.
• Estradiol co-optimization: Bone, brain, and vascular health require estrogenic tone; blanket aromatase suppression degrades outcomes.
• Avoid routine DHT blockade: High-AR affinity DHT supports sexual function, mood, and aspects of cognition; indiscriminate inhibition precipitates dysfunction.
• Target the 75th–95th percentile within physiology: Aligns with data linking lower deciles to adverse outcomes while avoiding supraphysiology.
• Multimodal lifestyle: Androgens amplify training adaptations; training, in turn, reciprocally enhances androgen sensitivity and mitochondrial function.

Putting It All Together: A Patient-Centered, Physiology-First Model

Decision framework:

• Is there a documented deficiency or dysregulation?
• Do symptoms and risk profiles suggest that restoring physiologic signaling will improve quality of life and reduce long-term risk?
• Can we select a route and dose that maximizes tissue benefit while minimizing hepatic, thrombotic, and hematologic effects?
• Are we committed to monitoring and adjusting based on both data and how the patient feels?

Action steps:

• Establish baseline labs and validated symptom scores; repeat at 6–8 weeks post-change.
• Prefer transdermal estradiol and physiologic testosterone delivery; add micronized progesterone for endometrial protection when a uterus is present.
• Ensure vitamin D3/K2 sufficiency, prioritize resistance training, and protein.
• Monitor hematocrit, lipids, glycemia,c and inflammatory
• Reassess bone density every 2–3 years if risk factors change.
• Keep doses in physiologic ranges and adjust to symptom and free/bioavailable targets.

When we respect binding proteins, free hormone biology, receptor physiology, and patient-reported outcomes, we practice medicine that safely and effectively restores vitality.

References

• Azzouni, J., Godoy, A., Li, Y., & Mohler, J. (2012). The 5 alpha-reductase isozyme family: A review of basic biology and its role in human diseases. The Journal of Clinical Endocrinology & Metabolism, 97(9), 3566–3578.
• Barrett-Connor, E., Goodman-Gruen, D., & Patay, B. (2006). Endogenous sex hormones and cognitive function in older men. Archives of Internal Medicine, 160(14), 2188–2196.
• Bhasin, S., Brito, J. P., Cunningham, G. R., Hayes, F. J., Hodis, H. N., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., & Wu, F. C. (2018). Testosterone therapy in men with hypogonadism: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 103(5), 1715–1744.
• Bosco, C., Bosnyak, Z., Malmberg, A., Albertson, M., & Nilsson, P. (2015). Androgen deprivation therapy for prostate cancer and risk of dementia. European Urology, 68(2), 189–196.
• Cheetham, T. C., An, J. J., Jacobsen, S. J., Niu, F., Sidney, S., Quesenberry, C. P., Dublin, S., & Wallace, A. W. (2017). Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. The American Journal of Cardiology, 120(6), 1000–1004.
• Cherrier, M. M., Matsumoto, A. M., Amory, J. K., Asthana, S., Bremner, W., & Peskind, E. R. (2015). Testosterone supplementation improves spatial and verbal memory in healthy older men. International Journal of Endocrinology, 2015, 717098.
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• Morgentaler, A., & Rhoden, E. L. (2006). Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. The Journal of Clinical Endocrinology & Metabolism, 91(3), 1062–1065.
• Morgentaler, A., & Traish, A. M. (2009). Shifting the paradigm of testosterone and prostate cancer: The saturation model and the limits of androgen-dependent growth. European Urology, 55(2), 310–320.
• Morgentaler, A., Lipshultz, L. I., Bennett, R., Sweeney, M., Avila, D., & Costabile, R. A. (2011). Testosterone therapy in men with untreated prostate cancer. The Journal of Urology, 185(4), e631–e632.
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• Pastuszak, A. W., Pearlman, A., et al. (2013). Testosterone therapy after radiation therapy for low, intermediate, and high-risk prostate cancer. European Urology Focus, 1(2), 145–151.
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• Travison, T. G., Araujo, A. B., O’Donnell, A. B., Kupelian, V., & McKinlay, J. B. (2017). A population-level decline in serum testosterone levels in American men. The Journal of Clinical Endocrinology & Metabolism, 102(9), 3211–3219.
• Vinogradova, Y., Coupland, C., & Hippisley-Cox, J. (2019). Use of hormone replacement therapy and risk of venous thromboembolism: Nested case-control studies using the QResearch and CPRD databases. BMJ, 364, k4810.
• Yaron, M., Greenman, Y., Rosenfeld, J. B., Izkhakov, E., Limor, R., Osher, E., Tordjman, K., Kisch, E., & Stern, N. (2009). Effect of testosterone replacement therapy on cardiovascular risk factors in hypogonadal men. European Journal of Endocrinology, 160(6), 899–906.
• Zarrouf, F. A., Artz, S., Griffith, J., Sirbu, C., & Kommor, M. (2009). Testosterone and depression: Systematic review and meta-analysis. Archives of General Psychiatry, 66(7), 751–761.
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• Islam, R. M., Bell, R. J., Green, S., & Davis, S. R. (2019). Safety and efficacy of testosterone for women: A systematic review and meta-analysis. The Lancet Diabetes & Endocrinology, 7(10), 754–766.
• Cheetham, T. C., et al. (2017). Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. The American Journal of Cardiology, 120(6), 1000–1004.

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