Causes of Low Testosterone (Hypogonadism)
Low testosterone (hypogonadism) can result from a wide range of conditions affecting either testicular function (primary hypogonadism) or the hypothalamic-pituitary axis (secondary hypogonadism), with significant impacts on morbidity, mortality, and quality of life. 1, 2
Primary Classification of Hypogonadism
Primary Hypogonadism (Testicular Dysfunction)
- Common causes:
- Aging
- Testicular trauma or injury
- Orchitis (testicular inflammation)
- Cryptorchidism (undescended testes)
- Klinefelter syndrome
- Radiation/chemotherapy
- Orchidectomy (surgical removal of testes)
Secondary Hypogonadism (Hypothalamic-Pituitary Dysfunction)
- Common causes:
- Obesity and metabolic syndrome
- Type 2 diabetes mellitus
- Chronic systemic diseases
- Pituitary tumors
- Medications
- Hyperprolactinemia
- Chronic stress
- Aging (combined mechanism)
Detailed Causes by Category
Genetic and Congenital Disorders
- Rare chromosomal abnormalities (XX male, 47 XYY, 48 XXYY syndrome)
- Down syndrome (21 Trisomy)
- Noonan syndrome
- Myotonic dystrophy
- Kallmann syndrome
- Prader-Willi syndrome
- Disorders of sex development (gonadal dysgenesis)
- Aromatase deficiency
- Kennedy disease (spinal and bulbar muscular atrophy)
- Androgen insensitivity syndromes
- 5α-reductase type II deficiency 1
Acquired Testicular Disorders
- Orchitis (mumps, other viral infections)
- Testicular trauma
- Testicular torsion
- Bilateral congenital anorchia
- Uncorrected cryptorchidism
- Varicocele
- Sickle cell disease
- Adrenoleukodystrophy
- Radiation/chemotherapy damage 1
Hypothalamic-Pituitary Disorders
- Pituitary tumors (micro/macroadenomas)
- Hypothalamic tumors
- Traumatic brain injury
- Pituitary stalk diseases
- Surgical hypophysectomy
- Pituitary or cranial irradiation
- Inflammatory conditions (hypophysitis, sarcoidosis, granulomatosis)
- Langerhans' histiocytosis
- Hyperprolactinemia 1
Systemic Diseases and Conditions
- Type 2 diabetes mellitus/metabolic syndrome
- Obesity (particularly visceral adiposity)
- HIV infection
- Chronic organ failure (kidney, liver, heart)
- Chronic inflammatory arthritis
- Cushing syndrome (glucocorticoid excess)
- Eating disorders
- Malnutrition
- Chronic illness
- Critical illness
- Celiac disease 1, 3, 4
Lifestyle and Environmental Factors
- Aging (progressive decline)
- Chronic stress (elevated cortisol)
- Sleep deprivation/poor sleep quality
- Excessive alcohol consumption
- Endurance exercise (extreme)
- Nutritional deficiencies (zinc, magnesium, vitamin D)
- Low polyphenol intake
- Oxidative stress 5, 6
Medication and Drug-Related Causes
- Opiates
- GnRH agonists or antagonists
- Glucocorticoids
- Estrogens
- Anabolic steroids
- Progestogens (including cyproterone acetate)
- Hyperprolactinemia-inducing drugs
- Antiandrogens (flutamide, bicalutamide, nilutamide)
- 5α-reductase inhibitors (finasteride, dutasteride)
- Estrogen receptor blockers
- Aromatase inhibitors 1, 7
Age-Related Hypogonadism
Age-related testosterone decline (late-onset hypogonadism) typically results from a combination of:
- Primary testicular failure
- Hypothalamic-pituitary axis dysfunction
- Increased sex hormone-binding globulin (SHBG) levels
- Comorbid conditions that accumulate with age 1, 5
Clinical Manifestations
Low testosterone can manifest as:
- Sexual symptoms (reduced libido, erectile dysfunction, decreased morning erections)
- Physical symptoms (decreased energy, reduced muscle mass, increased fat mass, decreased bone density)
- Psychological symptoms (depressed mood, fatigue, decreased motivation, cognitive difficulties) 1, 2, 8
Factors Affecting SHBG Levels
SHBG levels affect bioavailable testosterone and can be altered by:
- Factors increasing SHBG: Aging, anticonvulsants, estrogens, thyroid hormone, hyperthyroidism, hepatic disease, smoking, HIV/AIDS
- Factors decreasing SHBG: Obesity, hypothyroidism, acromegaly, Cushing's disease, insulin resistance, nonalcoholic fatty liver disease, nephrotic syndrome 1
Clinical Pearls
- Always distinguish between primary and secondary hypogonadism through appropriate hormonal testing (testosterone, LH, FSH)
- Consider functional hypogonadism when no organic cause is identified
- Address modifiable risk factors (obesity, metabolic syndrome, sleep disorders) before considering testosterone replacement
- Measure morning testosterone levels on at least two separate occasions for diagnosis
- Avoid testosterone testing during acute illness when levels may be transiently suppressed 1, 2, 8