How to manage low free testosterone levels affecting libido and orgasm strength in men with normal or high total testosterone levels?

Management of Low Free Testosterone with Normal/High Total Testosterone Affecting Libido and Orgasm

Measure morning free testosterone by equilibrium dialysis on two separate occasions along with sex hormone-binding globulin (SHBG) levels, and if free testosterone is confirmed frankly low despite normal total testosterone, initiate testosterone replacement therapy after completing a hypogonadism workup. 1, 2

Diagnostic Algorithm

Confirm the biochemical diagnosis systematically:

• Obtain morning (8-10 AM) free testosterone by equilibrium dialysis on at least two separate assessments, as this is the gold standard method and assay variability is significant 1, 2
• Measure SHBG levels simultaneously, since low SHBG (common in obesity) can result in normal total testosterone despite truly low free testosterone due to increased aromatization of testosterone to estradiol in adipose tissue 1, 2
• If free testosterone is confirmed low on repeat testing, measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish primary testicular failure from secondary pituitary-hypothalamic hypogonadism 1
• Check serum prolactin if testosterone is low with concurrent low/normal LH levels to rule out hyperprolactinemia 2, 3
• If secondary hypogonadism is identified (low testosterone with low LH/FSH), measure serum prolactin, iron saturation, perform pituitary function testing, and obtain MRI of the sella turcica to identify underlying pituitary or hypothalamic pathology 1

Understanding the Mechanism

The dissociation between total and free testosterone occurs through specific pathophysiologic mechanisms:

• In obesity, low SHBG concentrations frequently cause normal total testosterone with normal free testosterone levels in many men 1, 2
• However, a subset of men with obesity will have frankly low free testosterone due to increased aromatization of testosterone to estradiol in adipose tissue, causing estradiol-mediated negative feedback that suppresses pituitary LH secretion 1, 2
• Men with low-normal total testosterone (301 ng/dL or greater) but low free testosterone may have low bioavailable testosterone not reflected in total testosterone values, and these men respond well to testosterone replacement therapy for sexual symptoms 4

Treatment Decision-Making

Testosterone replacement therapy is indicated when specific criteria are met:

• Free testosterone by equilibrium dialysis must be frankly low on at least 2 separate morning assessments 1, 2
• Complete the hypogonadism workup to rule out etiologies unrelated to obesity or other reversible causes 1, 2
• Confirm presence of hypogonadal symptoms including decreased libido, reduced energy, impaired orgasmic function, or erectile dysfunction 1, 2, 5
• Total morning testosterone should be less than 300 ng/dL if using total testosterone as an additional criterion 2

Clinical evidence supports testosterone replacement in this population:

• Testosterone replacement improves libido in 30-97% of hypogonadal men depending on baseline testosterone levels, with men having total testosterone 201-300 ng/dL showing 96.6% improvement in libido 4
• Meta-analyses demonstrate that testosterone therapy improves orgasmic function in hypogonadal men 5
• Sexual activity, hypogonadal symptoms, and sexual desire improve significantly with testosterone replacement therapy over 24 months in men with confirmed hypogonadism and low libido 6
• Testosterone replacement improves erectile function response to PDE5 inhibitors in hypogonadal men and those with low-normal testosterone 2, 7

Testosterone Replacement Method Selection

Choose transdermal testosterone preparations as first-line therapy:

• Transdermal testosterone gel or patches produce stable day-to-day testosterone levels and are most convenient for patients 1, 2, 3
• Gels dry quickly when applied but can transfer to others via prolonged skin contact; absorption can be variable in some patients 1
• Patches minimize transfer issues but may cause skin irritation and adherence problems 1

Alternative delivery methods have specific advantages:

• Intramuscular testosterone injections avoid daily administration and are advantageous in patients with reduced disease-management skills or resources, but cause fluctuating testosterone levels 1, 2
• Implantable testosterone pellets provide long-term delivery but require a procedure for implantation 1
• Injectable options generally cost less than transdermal preparations 1

Monitoring Protocol

Follow a structured monitoring schedule:

• Test testosterone levels 2-3 months after treatment initiation and after any dose adjustment, targeting normalization of free testosterone levels 1, 3
• Once stable levels are achieved, monitor every 6-12 months 3
• For patients receiving testosterone injections, measure levels midway between injections 3

Critical Pitfalls to Avoid

Do not rely on total testosterone alone in men with obesity or metabolic syndrome, as up to 50% of men with low total testosterone will have normal free testosterone due to low SHBG, preventing unnecessary endocrine investigation. 1, 2

Do not initiate testosterone replacement without confirming low free testosterone on two separate occasions, as single measurements are unreliable due to assay variability. 1, 2

Do not prescribe testosterone replacement for men desiring fertility without first considering gonadotropin therapy (hCG initially, followed by FSH addition), as testosterone replacement suppresses spermatogenesis. 2

Recognize that erectile dysfunction alone does not improve reliably with testosterone replacement unless overt hypogonadism is present; testosterone primarily improves libido and orgasmic function rather than erectile mechanics. 5, 7, 6