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Late-Onset Hypogonadism (Testosterone Deficiency) – Diagnosis and Therapy

Definitions

Late-onset hypogonadism (term used by the EAU guideline) or testosterone deficiency (AUA guideline) is a disease of the older male with symptoms of testosterone deficiency and a testosterone serum concentration below the reference range, leading to potentially harmful effects on numerous organ systems. Obsolete but synonymous terms are (partial) androgen deficiency in the aging male (PADAM or ADAM).

Epidemiology and Pathophysiology of Testosterone Deficiency

Hypothalamic-pituitary-testosterone axis:

From the age of 40, there is a physiological decrease of serum testosterone by 1% per year. As sex hormone-binding globulin (SHBG) increases concomitantly, bioavailable testosterone (free and albumin-bound) decreases even more. Counter-regulation causes an increase in LH, and the rhythm of LH release is flattened.

Hypothalamic-pituitary-adrenal axis:

Decrease in the adrenal androgens like dehydroepiandrosterone (DHEA).

Metabolic syndrome:

Metabolic syndrome is a cluster of conditions that increase the cardiovascular risk: abdominal obesity, high serum triglycerides, low serum HDL cholesterol, arterial hypertension, and increased insulin resistance. Numerous studies have found an association of metabolic syndrome with hypogonadism (Wespes et al., 2013):

• Obesity and leptin concentration are substantial risk factors for hypogonadism and vice versa.
• Castration or antiandrogens increase the risk of metabolic syndrome.
• Substitution of testosterone improves several parameters of the metabolic syndrome.
• It is still unclear whether the metabolic syndrome causes hypogonadism or vice versa.

Epidemiology of Low Testosterone:

The prevalence of lower-than-normal testosterone is 20% in men over 60, 30% over 70 and 50% over 80 years of age. The prevalence rate is even higher, if free testosterone is also considered (Harman et al., 2001). Testosterone deficiency is more common in older men, obesity, comorbidity, and poor general health (Wu et al., 2008).

Signs and Symptoms

Symptoms are nonspecific, and the association with (borderline) decreased testosterone concentrations is not clear:

• Sexuality: decreased libido is an early symptom, followed by erectile dysfunction.
• Psychological changes: early symptoms are lethargy and sleep disturbances, followed by depression and reduced mental performance.
• Decreased hair growth and aging skin.
• Osteoporosis, decreasing muscle strength
• Increasing abdominal fat storage and metabolic syndrome.

Diagnosis of Testosterone Deficiency

Laboratory tests:

Measure testosterone and FSH in the morning as a search test. Normal values exclude relevant hypogonadism; pathological values of these two hormones detect 99% of the above-mentioned disorders. The lower standard value for testosterone is 12 nmol/l (3 ng/ml).

Further hormone tests:

If testosterone or FSH are abnormal, the laboratory tests are repeated and SHBG, LH, TSH and prolactin are also ordered. The other pituitary axes are tested in case of decreased pituitary hormones or increased prolactin. The SHGB can be used to calculate the free androgen index (FAI) or free testosterone, helping in the evaluation of borderline low testosterone levels.

Free testosterone:

1–3% of testosterone in the blood is present unbound, more than 97% is bound to binding proteins such as SHBG and albumin. According to Vermeulen's formula, the concentration of testosterone, SHBG, and albumin can be used to calculate free testosterone, and the normal value is above 0.25 nmol/l. Free testosterone is considered more clinically relevant than the FAI (Vermeulen et al., 1999).

Free androgen index (FAI):

Bioactive testosterone can be judged with the combined determination of SHBG and total testosterone and the calculation of the free androgen index:

FAI = ( Testosterone (nmol/l) × 100 ) \ SHBG (nmol/l)

The standard value of FAI for men is 30–150, and values below 30 indicate a relative testosterone deficiency. The FAI is considered less reliable than the calculated determination of free testosterone.

Diagnosis of the metabolic syndrome:

Measurement of body weight, abdominal circumference, and blood pressure. Relevant systemic diseases are detected by determining blood count, HbA_1C, CRP, liver enzymes, and creatinine.

Testosterone Therapy for Late-Onset Hypogonadism

Modification of lifestyle:

Many men with hypogonadism have a metabolic syndrome. Weight reduction, optimization of diet, increased physical activity, and strict therapy of diabetes mellitus alone can achieve improvement of hypogonadism and is more beneficial than substitution of testosterone alone (Camacho et al., 2013). The avoidance of alcohol and the sufficient treatment of other concomitant diseases is also relevant.

Testosterone Therapy

Testosterone therapy or supplementation is indicated in cases of proven testosterone deficiency (two measurements) with relevant symptoms such as sexual dysfunction, decreased bone density, refractory metabolic syndrome, type 2 diabetes mellitus, or depression (Snyder et al., 2018) (Grossmann et al., 2017).

Intramuscular injections:

Testosterone undecanoate with intramuscular injections allows safe and long-term testosterone substitution. Side effects due to fluctuations in testosterone concentration are reduced compared to older preparations such as testosterone cypionate and testosterone enanthate. Dosage: Testosterone undecanoate 1000 mg i.m., first injection interval six weeks, then every 10–14 weeks, depending on testosterone concentration, symptoms, and wellbeing.

Oral formulations:

Testosterone undecanoate in 2–3 single doses, the short half-life is disadvantageous. There are considerable pharmacokinetic differences between available preparations (Adriol, Jatenzo). Older oral testosterone preparations are liver-toxic and thus obsolete.

Transdermal testosterone preparations:

Testosterone gels are most often prescribed, occasionally also as patches. The transdermal application in the morning mimics the physiological testosterone fluctuations with low concentrations in the evening. The dosage and adjustment protocols differ between available formulations.

Contraindications for Testosterone Therapy:

• Prostate carcinoma
• Male breast carcinoma
• Severe heart failure
• Hematocrit above 0.54
• Obstructive sleep apnea
• Desire to have children

Side Effects of Testosterone supplementation:

Possible is suppression of LH and FSH production with infertility, breast tenderness or enlargement, increase in hematocrit, and exacerbation of occult prostate carcinoma. Data on cardiovascular safety are unclear; on the one hand, cardiovascular complications from testosterone therapy are conceivable (thrombosis, hypertension, decompensation of heart failure, increase in atherosclerosis); on the other hand, hormone therapy lowers some cardiovascular risk factors. Recent randomized trials with two-year follow-ups have not demonstrated an increased risk (Lincoff et al., 2023).

Monitoring During Testosterone Therapy:

Symptoms of hypogonadism will improve with different speeds: better libido can be expected within a few weeks. Improvement in erectile dysfunction, ejaculation, or vitality will take up to six months. Improvement in bone density will be measurable after six months and increases for up to three years after starting therapy. If testosterone therapy does not meet the treatment expectations, clinicians should discontinue testosterone treatment.

Monitoring of Possible Complications of Testosterone Therapy:

Monitoring includes palpation of the prostate and male breast, PSA, blood count (hematocrit), serum lipids, and liver enzymes every six months for the first two years, then annually.

Other androgen substitution:

There are only insufficient trials to support DHEA or estrogen substitution.

References

Köhn, F.-M. (2004). [diagnosis and therapy of hypogonadism in adult males].
Urologe A, 43(12):1563-81; quiz 1582–3.

J. P. Mulhall, L. W. Trost, R. E. Brannigan, E. G. Kurez, and J. B. Redmon et al., “AUA Guideline: Evaluation and Management of Testosterone Deficiency.” [Online]. Available: https://www.auanet.org/guidelines-and-quality/guidelines/testosterone-deficiency-guideline

A. Salonia, S. Minhas, and C. Bettocchi, “EAU Guidelines: Sexual and Reproductive Health,” 2022. [Online]. Available: https://uroweb.org/guidelines/sexual-and-reproductive-health/.

Trottmann, M., Dickmann, M., Stief, C. G., and Becker, A. J. (2010). [laboratory workup of testosterone].
Urologe A, 49(1):11–15.

Tüttelmann, F.; Gromoll, J. & Kliesch, S. [Genetics of male infertility].
Urologe A, 2008, 47, 1561-2, 1564-7

C. Radmayr, G. Bogaert, H. S. Dogan, and S. Tekgül, “EAU Guidelines: Paediatric Urology.” [Online]. Available: https://uroweb.org/guidelines/paediatric-urology/

  Deutsche Version: Altershypogonadismus