What is the best course of treatment for a patient with low testosterone and low Sex Hormone-Binding Globulin (SHBG) levels?

Management of Low Testosterone with Low SHBG

In men with low total testosterone and low SHBG, measure morning free testosterone by equilibrium dialysis to determine if true hypogonadism exists—if free testosterone is normal, this represents the pseudo-hypogonadism of obesity and weight loss is the primary treatment, not testosterone replacement. 1, 2

Diagnostic Algorithm

Initial Biochemical Assessment

• Confirm low total testosterone with a repeat morning (8-10 AM) measurement on a separate day, as diagnosis requires persistent low levels (<300 ng/dL) 1, 3
• Measure free testosterone by equilibrium dialysis (the gold standard assay) along with SHBG to understand binding dynamics 1, 4
• Obtain serum LH and FSH to distinguish primary versus secondary hypogonadism 4, 3

Understanding Low SHBG Context

Low SHBG is primarily driven by obesity and metabolic conditions, not testicular failure 1:

• Obesity is the most common cause of reduced SHBG through insulin resistance and metabolic syndrome 1, 2
• Type 2 diabetes mellitus and insulin resistance directly suppress SHBG production 1, 2
• Hypothyroidism reduces SHBG (check TSH) 1
• Medications including glucocorticoids, growth hormone, and anabolic steroids lower SHBG 1

Critical Distinction: True vs. Pseudo-Hypogonadism

If free testosterone is normal despite low total testosterone and low SHBG, this represents pseudo-hypogonadism of obesity, not pathological hypogonadism 2:

• The proportionate reduction in both testosterone and SHBG with normal LH/FSH confirms a eugonadal state 2
• This condition is reversible with weight loss and does not require testosterone replacement 2
• Obesity causes increased aromatization of testosterone to estradiol in adipose tissue, with subsequent estradiol-mediated negative feedback suppressing pituitary LH secretion in some cases 1

If free testosterone is also frankly low, this represents true hypogonadism requiring treatment 1, 3

Treatment Decision Framework

When Free Testosterone is Normal (Pseudo-Hypogonadism)

Do NOT initiate testosterone replacement therapy 2:

• Weight reduction is the primary intervention and substantially reverses testosterone reductions 2
• Optimize management of obesity-related comorbidities: type 2 diabetes, obstructive sleep apnea, depression 2
• Rationalize concomitant medications that may suppress testosterone or SHBG 2
• Testosterone treatment is less effective than diet and lifestyle intervention for reversible conditions 2
• Unwarranted testosterone treatment leads to adverse effects including infertility, elevated hematocrit, prothrombotic state, and testosterone dependence 2

When Free Testosterone is Low (True Hypogonadism)

Initiate testosterone replacement therapy only if both biochemical deficiency AND hypogonadal symptoms are present 4, 3:

Specific Symptoms to Assess

Sexual symptoms (most specific) 1:

• Reduced libido
• Erectile dysfunction
• Decreased spontaneous/morning erections

Physical symptoms 1:

• Decreased vigorous activity
• Reduced muscle mass and strength
• Hot flashes
• Gynecomastia

Psychological symptoms 1:

• Low mood/mood deflection
• Decreased motivation
• Fatigue

Contraindications to Testosterone Therapy

Absolute contraindications 3:

• Breast or prostate cancer
• Palpable prostate nodule or PSA >4 ng/mL (or >3 ng/mL in high-risk men)
• Hematocrit >50%
• Untreated severe obstructive sleep apnea
• Severe lower urinary tract symptoms (IPSS >19)
• Uncontrolled or poorly controlled heart failure

Fertility Considerations

For men wishing to preserve fertility, use selective estrogen receptor modulators (SERMs) like clomiphene citrate rather than testosterone replacement 4:

• Testosterone replacement suppresses the HPG axis and causes infertility 4
• SERMs stimulate endogenous testosterone production while maintaining spermatogenesis 4

Monitoring Protocol

Initial Phase (First Year)

• Follow-up at 1-2 months to assess efficacy and consider dose adjustments 4
• Subsequent visits at 3-6 month intervals for the first year 4

At Each Visit Assess

• Symptomatic response to treatment 4
• Voiding symptoms and sleep apnea symptoms 4
• Digital rectal examination 4
• Serum testosterone levels (aim for mid-normal range) 3
• PSA levels 4
• Hematocrit or hemoglobin 4

Common Pitfalls to Avoid

• Never treat based on total testosterone alone when SHBG is low—always measure free testosterone to avoid misdiagnosing pseudo-hypogonadism as true hypogonadism 1, 2
• Avoid testosterone testing during acute illness, as this transiently suppresses testosterone levels 1
• Do not use screening questionnaires to diagnose testosterone deficiency, as they lack specificity 1
• Never initiate testosterone in obese men without first attempting weight loss, as this is the most effective intervention for pseudo-hypogonadism 2