How to manage a patient with low testosterone and uncontrolled diabetes?

Management of Low Testosterone in Men with Uncontrolled Diabetes

In men with diabetes and symptomatic hypogonadism (decreased libido, erectile dysfunction, fatigue), screen with morning total testosterone and consider testosterone replacement therapy if levels are confirmed below 300 ng/dL on two separate occasions, while simultaneously optimizing diabetes control through lifestyle modification and appropriate antidiabetic medications. 1, 2

Initial Diagnostic Workup

Confirm Hypogonadism

• Measure morning total testosterone on two separate occasions using the same laboratory to confirm levels below 300 ng/dL 2
• Document clinical symptoms: reduced sexual desire, erectile dysfunction, decreased energy, fatigue, reduced muscle mass, or poor concentration 1
• Treatment requires BOTH low laboratory values AND clinical symptoms—laboratory values alone do not justify treatment 2

Determine Type of Hypogonadism

• Measure serum LH and FSH to differentiate primary from secondary hypogonadism 2
• Check serum prolactin if LH is low or normal, as hyperprolactinemia can suppress gonadotropins 2
• If total testosterone is below 150 ng/dL with low/normal LH, consider pituitary MRI to evaluate for non-secreting adenomas 3
• In men with total testosterone near 300 ng/dL, measure sex hormone-binding globulin (SHBG) as it is often low in diabetes and associated with lower testosterone levels 1

Assess Diabetes Control and Metabolic Status

• Measure HbA1c and fasting glucose to quantify degree of hyperglycemia 2
• Obtain lipid panel for cardiovascular risk assessment 2
• Calculate BMI and measure waist circumference, as obesity is a major confounder of low testosterone in diabetes 1, 4

Treatment Strategy: Dual Approach

Priority 1: Optimize Diabetes Control First

Lifestyle modification is foundational and can improve both testosterone levels and glycemic control simultaneously. 4

• Weight loss through caloric restriction improves testosterone levels in obese men with secondary hypogonadism 3
• Regular physical activity provides similar benefits, though testosterone increases are typically modest (1-2 nmol/L) 3
• These interventions address the root cause, as insulin resistance itself contributes to low testosterone 5

Priority 2: Consider Testosterone Replacement Therapy

For symptomatic men with confirmed hypogonadism, testosterone therapy provides substantial benefits beyond lifestyle modification alone. 6, 7

Evidence for Testosterone Therapy in Diabetes

• In men with prediabetes and hypogonadism, long-term testosterone therapy prevented progression to type 2 diabetes in 90% of treated men versus 40% progression in untreated controls over 8 years 6
• A randomized controlled trial (T4DM) demonstrated that testosterone treatment for 2 years reduced the proportion developing type 2 diabetes (12% vs 21% in placebo group, p=0.0007) 7
• Testosterone therapy improved HbA1c by 0.39% in treated men while untreated controls worsened by 0.63% 6
• Mortality was significantly lower in testosterone-treated men (7.4% vs 16.1%, p<0.05) and nonfatal myocardial infarction was reduced (0.4% vs 5.7%, p<0.005) 6

Pre-Treatment Assessment

• Obtain baseline hemoglobin and hematocrit to monitor for polycythemia development 2
• Measure prostate-specific antigen (PSA) before initiating therapy 2
• Perform complete blood count to evaluate for unexplained anemia 2

Testosterone Formulation Selection

• Intramuscular testosterone undecanoate (1000 mg at baseline, 6 weeks, then every 3 months) was used in the highest quality trials 6, 7
• Aim for testosterone levels in the mid-normal range during treatment 3
• Choice should consider pharmacokinetics, treatment burden, and cost 3

Combined Approach: The Optimal Strategy

Combining testosterone replacement therapy with lifestyle modifications provides superior outcomes compared to either intervention alone. 4

• The combined approach better motivates patients to perform physical activity and achieve weight loss 4
• This dual strategy addresses both the consequence (low testosterone) and the cause (insulin resistance, obesity) 4
• Improvements occur in body composition, insulin resistance, glucose profile, and potentially sexual function 4

Monitoring During Treatment

Testosterone Therapy Monitoring

• Measure serum testosterone at each monitoring visit to ensure mid-normal therapeutic range 8
• Check hematocrit every 3-6 months initially, then annually, as testosterone increases red blood cell mass 8
• Safety trigger: hematocrit >54% occurred in 22% of testosterone-treated patients and may be treatment-limiting 7
• Monitor PSA with increases of 0.75 μg/mL or more occurring in 23% of treated patients 7

Metabolic Monitoring

• Measure HbA1c and/or fasting glucose every 6-12 months 8
• Check fasting lipid profile every 6-12 months for cardiovascular risk assessment 8
• Monitor liver function tests given hepatic metabolism of testosterone 8

Critical Safety Considerations

Cardiovascular Risk

• Long-term cardiovascular safety trials have not been conducted 9
• Epidemiologic studies and randomized trials remain inconclusive for major adverse cardiovascular events (MACE) 9
• Some studies report increased cardiovascular risk, though the T4DM trial showed reduced myocardial infarction rates 6, 7
• Inform patients of possible cardiovascular risks when deciding whether to initiate therapy 9

Contraindications and Precautions

• Avoid in men with breast cancer or suspected prostate cancer 9
• Use cautiously in patients with preexisting cardiac, renal, or hepatic disease due to sodium and water retention 9
• Monitor for signs of fluid retention and edema 8
• Discontinue if venous thromboembolic events (DVT, PE) are suspected 9

Polycythemia Management

• Polycythemia is the most common dose-limiting adverse effect 7
• If hematocrit exceeds 54%, consider dose reduction or temporary discontinuation 7
• Regular monitoring is essential to prevent thromboembolic complications 8

Special Considerations for Fertility

• For men wishing to preserve fertility, consider gonadotropin therapy (hCG plus FSH) rather than testosterone, as testosterone suppresses spermatogenesis 3
• Selective estrogen receptor modulators may be considered for men with low/normal LH who desire fertility preservation 3

Clinical Pitfalls to Avoid

• Do not treat based on single testosterone measurement—day-to-day variations require confirmation 8
• Do not treat asymptomatic men with low testosterone, as evidence for benefit is lacking 1, 2
• Do not ignore the role of obesity and insulin resistance—these are modifiable factors that directly impact testosterone levels 4, 5
• Do not assume testosterone therapy alone will adequately control diabetes—comprehensive diabetes management remains essential 4