What are the causes of reduced testosterone levels?

Causes of Reduced Testosterone Levels

Reduced testosterone levels in men result from either primary testicular dysfunction, secondary hypothalamic-pituitary axis impairment, or functional hypogonadism driven by obesity and metabolic comorbidities—with obesity being the most common reversible cause in clinical practice. 1

Primary (Hypergonadotropic) Hypogonadism

Primary hypogonadism results from direct testicular dysfunction with elevated LH/FSH levels 1:

Common Causes

• Klinefelter syndrome (47,XXY) - the most frequent genetic cause of primary hypogonadism 1
• Orchitis - particularly mumps orchitis, chemotherapy, and radiation therapy 1
• Testicular trauma or torsion 1
• Bilateral cryptorchidism (uncorrected) 1

Uncommon Causes

• Rare chromosomal abnormalities (XX male, 47 XYY, 48 XXYY syndrome) 1
• Myotonic dystrophy types I and II 1
• Sickle cell disease 1
• Defects of testosterone biosynthesis 1
• Bilateral congenital anorchia 1

Secondary (Hypogonadotropic) Hypogonadism

Secondary hypogonadism results from hypothalamic-pituitary axis impairment with low or inappropriately normal LH/FSH levels 1:

Congenital/Developmental

• Idiopathic hypogonadotropic hypogonadism (IHH) including Kallmann syndrome (with anosmia) and normosmic IHH 1
• Combined pituitary hormone deficiency 1
• Prader-Willi syndrome 1

Structural/Localized Problems

• Pituitary adenomas (micro/macroadenomas) - prolactinomas are particularly common 1
• Traumatic brain injury 1
• Pituitary or cranial irradiation 1
• Surgical hypophysectomy 1
• Hypothalamic tumors 1
• Inflammatory conditions: lymphocytic hypophysitis, sarcoidosis, Wegener's granulomatosis 1
• Langerhans' histiocytosis 1

Drug-Induced

• Opiates - suppress GnRH secretion 1
• Anabolic steroids and exogenous testosterone - suppress the HPG axis through negative feedback 1, 2
• GnRH agonists or antagonists 1
• Glucocorticoids 1
• Estrogens and progestogens (including cyproterone acetate) 1
• Hyperprolactinemia-inducing medications 1

Functional Hypogonadism

Functional hypogonadism represents borderline low testosterone secondary to reversible systemic conditions without organic HPG axis pathology—this is the most common presentation in clinical practice. 3

Obesity and Metabolic Disorders

• Obesity causes reduced testosterone through two mechanisms: decreased sex hormone-binding globulin (SHBG) and increased aromatization of testosterone to estradiol in adipose tissue, leading to estradiol-mediated negative feedback on pituitary LH secretion 1
• Type 2 diabetes mellitus - mean testosterone levels are lower in men with diabetes compared to age-matched controls, though obesity is a major confounder 1
• Metabolic syndrome 3, 4
• The relationship between obesity/metabolic disorders and low testosterone is bidirectional and multifactorial 3

Critical distinction: In obesity, proportionately reduced testosterone and SHBG with normal LH/FSH represents "pseudo-hypogonadism" rather than true pathological hypogonadism 5. Free testosterone may remain normal despite low total testosterone when SHBG is reduced 1.

Chronic Systemic Diseases

• HIV infection - particularly with protease inhibitors (>5% develop new-onset diabetes) and nucleoside reverse transcriptase inhibitors 1
• Chronic organ failure (renal, hepatic, cardiac) 1
• Chronic inflammatory arthritis 1
• Obstructive sleep apnea 1

Other Systemic Conditions

• Aging - total and free testosterone decline with age while SHBG rises 1, 6
• Cushing syndrome (glucocorticoid excess) 1
• Acute and critical illness 1
• Eating disorders 1
• Excessive endurance exercise 1
• Depression 3

Diagnostic Approach

When evaluating low total testosterone, measure morning (8-10 AM) free testosterone by equilibrium dialysis and SHBG to distinguish true hypogonadism from pseudo-hypogonadism of obesity. 1

• If testosterone is subnormal on repeat testing, measure LH and FSH to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 1
• For secondary hypogonadism, evaluate for pituitary dysfunction: prolactin, iron saturation, pituitary function testing, and MRI of sella turcica 1
• In men with diabetes or obesity who have total testosterone near the lower limit, check SHBG as it is often low and associated with lower testosterone levels 1

Key Clinical Pitfalls

The most common error is treating functional hypogonadism with testosterone replacement rather than addressing the underlying reversible condition. 5, 3

• Weight loss substantially reverses obesity-related testosterone reductions and is more effective than testosterone treatment for non-specific symptoms 5
• Testosterone therapy in young men desiring fertility suppresses spermatogenesis through negative feedback—alternative agents (intranasal testosterone, selective estrogen modulators, aromatase inhibitors, or hCG) should be considered 2
• In functional hypogonadism, first-line therapy is lifestyle modification: caloric restriction, resistance training, 7-9 hours sleep nightly, and optimization of comorbidities (diabetes, sleep apnea, depression) 3
• Testosterone replacement in older men with hypogonadism has been associated with increased coronary artery plaque volume and cardiovascular events in some studies 1