What is hypogonadism?

What is Hypogonadism?

Hypogonadism is a clinical syndrome characterized by low serum testosterone levels occurring in association with specific symptoms including diminished libido, erectile dysfunction, reduced muscle mass and strength, decreased bone density, increased body fat, diminished energy and vitality, depressed mood, and impaired cognition. 1

Definition and Pathophysiology

Hypogonadism represents a clinical condition requiring both biochemical evidence of testosterone deficiency and the presence of characteristic symptoms—neither alone is sufficient for diagnosis. 2, 1 The syndrome results from insufficient secretion of testosterone, which is the primary male sex hormone responsible for development and maintenance of male sex organs, secondary sex characteristics (facial and body hair, deepening of voice, muscle mass), bone density, and sexual function. 3

Types of Hypogonadism

The classification of hypogonadism is critical because it determines treatment approach and fertility potential:

Primary (Hypergonadotropic) Hypogonadism

• Caused by testicular failure, resulting in low testosterone with elevated gonadotropin levels (FSH and LH above normal range). 2, 3
• Congenital causes include Klinefelter's syndrome, cryptorchidism, bilateral torsion, vanishing testis syndrome, and Leydig cell aplasia. 2, 3
• Acquired causes include testicular trauma, orchitis, orchiectomy, chemotherapy, radiation damage, and toxic damage from alcohol or heavy metals. 2, 3
• Treatment limitation: These patients can only receive testosterone therapy, which permanently compromises fertility by suppressing the hypothalamic-pituitary-gonadal (HPG) axis. 2

Secondary (Hypogonadotropic) Hypogonadism

• Results from hypothalamic or pituitary dysfunction, characterized by low testosterone with low or low-normal gonadotropin levels (FSH, LH). 2, 3, 4
• Congenital causes include idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, and gonadotropin or LHRH deficiency. 2
• Acquired causes include pituitary tumors, traumatic brain injury, pituitary-hypothalamic injury from radiation, and certain medications. 2, 3
• Treatment advantage: These patients can potentially achieve both fertility restoration and normal testosterone levels with gonadotropin therapy (hCG plus FSH). 2

Functional Hypogonadism

• Diagnosed when low testosterone occurs without organic alterations in the HPG axis, often as a consequence of comorbidities such as obesity, metabolic syndrome, or diabetes. 1
• Commonly reversible with weight loss through low-calorie diets and increased physical activity, which can normalize testosterone levels and gonadotropins. 2

Compensated Hypogonadism

• Characterized by normal testosterone levels with elevated luteinizing hormone production, representing a subclinical state where the pituitary is working harder to maintain normal testosterone. 1

Late-Onset Hypogonadism (LOH)

• Also called age-related male hypogonadism or andropause, this encompasses adult-onset conditions of both organic and functional origins. 2
• Unlike classical hypogonadism, LOH often occurs without identifiable causes and increases with age. 2
• Important caveat: Safety and efficacy of testosterone therapy in "age-related hypogonadism" have not been established by FDA standards. 3

Clinical Manifestations

Sexual Symptoms (Most Specific)

• Diminished libido is the key symptom most specific for hypogonadism. 2, 1, 5
• Erectile dysfunction frequently accompanies hypogonadism, though it has multiple potential causes. 2, 1, 5

Physical Symptoms

• Reduced muscle mass and strength with increased body fat and altered body composition. 2, 1, 5
• Diminished bone density leading to osteoporosis risk. 2, 1, 5
• Anemia may develop due to reduced erythropoiesis. 2, 1

Psychological Symptoms

• Diminished energy, sense of vitality, or sense of well-being are common but non-specific complaints. 2, 1
• Increased fatigue and reduced physical activity. 2, 1, 6
• Depressed mood and impaired cognition. 2, 1, 7

Critical pitfall: These symptoms are highly non-specific and screening questionnaires lack specificity for systematic screening—diagnosis requires both persistent symptoms AND confirmed biochemical testosterone deficiency. 2, 1

Diagnostic Requirements

Diagnosis mandates both clinical symptoms AND biochemical confirmation—neither alone is sufficient. 2, 1

Biochemical Testing

• Two separate morning total testosterone measurements (drawn between 8-10 AM) below 300 ng/dL are required to establish hypogonadism. 2, 1
• Testosterone testing should be avoided during acute illness, as illness can temporarily suppress testosterone levels. 2
• Free testosterone measurement by equilibrium dialysis should be obtained in men with obesity or when total testosterone is borderline. 1
• LH and FSH levels must be measured to distinguish primary from secondary hypogonadism, which has critical treatment implications. 1, 3

Clinical Assessment

• History taking should evaluate for pituitary disorders, surgical history, comorbidities (obesity, metabolic syndrome, diabetes), medications affecting the HPG axis, and fertility concerns. 2
• Physical examination should include BMI, waist circumference, and assessment for signs of androgen deficiency. 2
• Drug-induced causes must be excluded, including opiates, GnRH agonists/antagonists, glucocorticoids, estrogens, and anabolic steroids. 1

Associated Comorbidities

Hypogonadism is strongly linked with metabolic syndrome, type 2 diabetes, obesity, erectile dysfunction, and osteoporosis. 5, 7 Functional hypogonadism commonly correlates with obesity and metabolic disorders, and weight loss can reverse obesity-associated secondary hypogonadism. 2

Treatment Implications

Treatment of hypogonadism with testosterone supplementation may result in clinical benefits including improved libido, sexual function, bone density, muscle mass, body composition, mood, and erythropoiesis. 2, 7 However, testosterone therapy is absolutely contraindicated in men seeking fertility preservation, as it suppresses spermatogenesis and causes azoospermia. 2, 1 For secondary hypogonadism patients desiring fertility, gonadotropin therapy (hCG plus FSH) is mandatory. 2, 1

Important limitation: The condition is often underdiagnosed in clinical practice, and approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation. 5, 8