Testosterone: Physiology, Hypogonadism, and Replacement Therapy

Introduction

Testosterone is the primary male sex hormone produced by Leydig cells in the testes. It is essential for development of male reproductive organs, secondary sexual characteristics, bone density, muscle mass, erythropoiesis, libido, and overall well-being. Testosterone production is regulated by the hypothalamic-pituitary-gonadal (HPG) axis.

Testosterone Physiology

Production and Regulation

Component	Hormone	Function
Hypothalamus	GnRH (gonadotropin-releasing hormone)	Stimulates pituitary to release LH and FSH
Anterior pituitary	LH (luteinizing hormone)	Stimulates Leydig cells in testes to produce testosterone
Anterior pituitary	FSH (follicle-stimulating hormone)	Stimulates Sertoli cells for spermatogenesis
Testes (Leydig cells)	Testosterone	Male sexual development, anabolic effects, negative feedback on HPG axis
Sertoli cells	Inhibin B	Negative feedback on FSH
Adipose tissue	Aromatase	Converts testosterone to estradiol (negative feedback)

Testosterone Forms and Transport

Form	Percentage	Bound To	Bioavailability
Free testosterone	1-2%	Unbound	Biologically active
Albumin-bound	30-40%	Albumin (low affinity)	Readily dissociates (“bioavailable”)
SHBG-bound	60-70%	Sex hormone-binding globulin (high affinity)	Not bioavailable

Normal Testosterone Levels

Age	Total Testosterone (ng/dL)	Free Testosterone (ng/dL)
20-30	400-1,000	9-30
30-40	350-900	8-25
40-50	300-850	7-22
50-60	250-750	6-18
60-70	200-650	5-15
70+	150-600	4-12

Hypogonadism

Classification

Type	Location of Defect	Testosterone	LH/FSH	Sperm Production
Primary (hypergonadotropic)	Testes	Low	High (compensatory)	Low or absent
Secondary (hypogonadotropic)	Pituitary or hypothalamus	Low	Low or inappropriately normal	Low or absent
Late-onset (age-related)	Mixed	Low-normal to low	Normal to slightly elevated	Variable

Primary Hypogonadism

Cause	Mechanism	Features
Klinefelter syndrome (XXY)	Extra X chromosome; testicular dysgenesis	Small firm testes, gynecomastia, tall stature, learning disability, azoospermia
Cryptorchidism (undescended testicles)	Impaired testicular development at higher temperature	Unilateral or bilateral; earlier repair improves outcomes
Chemotherapy (alkylating agents)	Gonadotoxic to Leydig cells and germ cells	Dose-dependent; some recovery possible
Radiation therapy	Scrotal radiation damages testicular tissue	Usually permanent
Orchitis (mumps)	Viral destruction of testicular tissue	Usually unilateral; bilateral in 15%
Testicular trauma/torsion	Direct damage or ischemia	Variable; may be partial
Anabolic steroid abuse	Exogenous testosterone suppresses endogenous production	Reversible after discontinuation (may take months)
Aging	Leydig cell dysfunction, reduced testicular perfusion	Gradual decline of 0.5-2% per year after age 30
Hemochromatosis	Iron deposition in Leydig cells	Associated with other endocrine dysfunction
Autoimmune orchitis	Anti-Leydig cell antibodies	Rare; associated with polyglandular autoimmune syndromes
Myotonic dystrophy	Testicular atrophy	Multisystem disorder

Secondary Hypogonadism

Cause	Mechanism	Reversible
Pituitary tumor (prolactinoma, non-functioning)	Mass effect on gonadotrophs or hyperprolactinemia suppressing GnRH	Yes (surgery, dopamine agonist)
Other sellar masses (craniopharyngioma, cysts)	Mass effect	Yes (surgery)
Hemochromatosis	Iron deposition in gonadotrophs	No (iron removal prevents progression)
Severe illness (critical illness, burns, MI)	Functional suppression of HPG axis	Yes (resolves with recovery)
Sleep apnea	Disrupted HPG axis via hypoxia and inflammation	Yes (CPAP treatment)
Obesity	Aromatization of T to estradiol; leptin resistance; inflammatory cytokines	Yes (weight loss)
Diabetes mellitus	Insulin resistance impairs HPG axis	Yes (glycemic control)
Cushing syndrome (endogenous or exogenous glucocorticoids)	Suppression of GnRH and LH	Yes (treat Cushing; taper steroids)
Hyperprolactinemia	Suppresses GnRH	Yes (dopamine agonist)
Opioids	Suppress GnRH via mu-receptor activation	Yes (taper or switch opioids)
Anabolic steroid withdrawal	Suppressed HPG axis	Yes (time; may take months-years)
GnRH deficiency (Kallmann syndrome)	Congenital GnRH deficiency	No (requires gonadotropin therapy for fertility)
Idiopathic	Unknown cause	Variable

Signs and Symptoms of Hypogonadism

Domain	Symptoms	Signs
Sexual	Decreased libido, ED, decreased nocturnal/morning erections, delayed ejaculation	Testicular atrophy, decreased penile length, decreased testicular consistency
Physical	Fatigue, decreased muscle mass and strength, increased body fat, decreased body hair, gynecomastia, hot flashes	Central obesity, sarcopenia, reduced body hair, gynecomastia, small/testes
Bone	Bone pain, fractures (osteoporosis)	Low bone mineral density on DEXA
Cognitive	Difficulty concentrating, memory decline, “brain fog”
Mood	Depression, irritability, anxiety
Metabolic	Increased abdominal fat, insulin resistance, dyslipidemia	Increased waist circumference
Hematologic	Mild anemia, pallor	Low hemoglobin/hematocrit
Sleep	Sleep disturbance, decreased energy

Diagnosis

Test	Indication	Interpretation
Total testosterone (morning, 8-10 AM) x2	Initial screening for hypogonadism	<300 ng/dL: consistent with hypogonadism; 300-400: borderline; >400: likely normal
Free or bioavailable testosterone	When SHBG abnormalities suspected (obesity, aging, thyroid, liver disease)	Free T <5-9 ng/dL or calculated bioavailable T <70-100 ng/dL suggests deficiency
LH, FSH	Distinguish primary vs secondary	High: primary; Low/normal: secondary
Prolactin	Always with secondary hypogonadism	Elevated suggests prolactinoma; >200 ng/mL virtually diagnostic
Iron studies (ferritin, iron saturation)	If suspect hemochromatosis	Elevated confirms
Pituitary MRI	If low T + low/normal LH + no clear cause	Identifies mass lesions
Semen analysis	If fertility desired	Assess spermatogenesis
Karyotype	If suspect Klinefelter	XXY confirms

Testosterone Replacement Therapy (TRT)

Indications for TRT

Appropriate	Inappropriate (Do NOT Use)
Symptomatic male with low testosterone (<300 ng/dL) + primary or secondary hypogonadism	Normal testosterone
Age-related decline with symptoms and low testosterone (shared decision-making)	Age-related decline without symptoms
HIV with weight loss and low testosterone	To improve athletic performance
Chronic glucocorticoid use with low testosterone	Osteoporosis without hypogonadism (other treatments available)
Pituitary disorders with hypogonadism	To improve energy/mood without proven deficiency
	Low libido without low testosterone
	To treat ED without documented hypogonadism (ED may have other causes)

TRT Formulations

Formulation	Dose Range	Frequency	Advantages	Disadvantages
Intramuscular testosterone cypionate/enanthate	50-200 mg IM	Every 1-4 weeks	Inexpensive, flexible dosing	Peaks and troughs (mood swings), requires injection, higher risk of polycythemia
Intramuscular testosterone undecanoate (Aveed)	750 mg IM (3 mL)	Initial, then at 4 weeks, then every 10 weeks	Consistent levels; fewer injections	Risk of pulmonary oil microembolism (POME) - must observe 30 min post-injection
Transdermal gel 1%/1.62% (AndroGel, Testim, Vogelxo)	25-100 mg daily	Daily	Steady levels; flexible dosing; easy	Transfer risk to others; skin irritation; variable absorption
Transdermal patch (Androderm)	2-4 mg daily	Daily	Steady levels	Skin irritation common (30-60%)
Transdermal solution (Axiron)	30-120 mg applied to axilla	Daily	Less transfer risk	Axillary application
Nasal gel (Natesto)	11 mg per nostril	2-3 times daily	No transfer risk; rapid onset/offset	Requires multiple daily doses; nasal side effects
Buccal tablet (Striant)	30 mg	Twice daily	No transfer risk	Gum/mouth irritation; taste changes
Subcutaneous pellets (Testopel)	200-600 mg (2-6 pellets)	Every 3-6 months	Consistent levels; infrequent dosing	Requires minor procedure; extrusion risk (5%); cannot adjust dose easily
Oral testosterone undecanoate (Jatenzo, Kyzatrex)	158-396 mg BID with fat	Twice daily with food	Oral; no injection	Requires high fat meal; variable absorption; liver effects

TRT Monitoring

Parameter	Monitoring Frequency	Target
Testosterone level	3-6 months after initiation, then annually	Mid-normal range (500-800 ng/dL)
Hematocrit / hemoglobin	Baseline, 3-6 months, then annually	Hct <54% (stop or dose reduce if >54%)
PSA	Baseline, 3-6 months, then annually per prostate cancer screening guidelines	Stable; no significant increase
DRE	Baseline, then annually	No new nodules
Lipid panel	Baseline, then annually	Monitor changes
Bone density (DEXA)	Baseline if osteoporotic risk	Assess need for treatment
Breast exam	Annually	Gynecomastia; male breast cancer
Fertility assessment	If fertility desired	Consider hCG or stop TRT

TRT Contraindications

Absolute	Relative
Prostate cancer (active)	PSA >4 ng/mL (uninvestigated)
Breast cancer (male)	Severe BPH (AUA score >19)
Palpable prostate nodule	Polycythemia (Hct >50%)
Undiagnosed PSA elevation	Obstructive sleep apnea (untreated)
Erythrocytosis (Hct >54%)	Severe heart failure (NYHA class III-IV)
Desire for fertility (gonadotropin therapy preferred)	Lower urinary tract symptoms
Severe untreated sleep apnea

Benefits of TRT

Outcome	Evidence	Time to Effect
Libido/sexual desire	Strong improvement	2-6 weeks
Erectile function	Moderate improvement (40-60%)	3-6 months (may need PDE5i adjunct)
Body composition (increased lean mass, decreased fat)	Moderate	3-6 months
Bone density	Moderate increase (2-5% at lumbar spine)	6-12 months
Mood/energy	Moderate improvement	2-6 weeks
Cognition	Mild improvement (verbal memory)	6-12 weeks
Hemoglobin	Increase by 1-2 g/dL	3-6 months
Insulin sensitivity	Mild improvement	6-12 months

Risks of TRT

Risk	Magnitude	Monitoring / Management
Erythrocytosis (Hct >54%)	10-30% (higher with injectable T)	Phlebotomy; dose reduction; switch to topical
Prostate cancer risk	Not clearly increased (no evidence TRT causes prostate cancer)	PSA monitoring
BPH/LUTS exacerbation	Minimal-moderate (some men worsen)	AUA score monitoring
Reduced HDL cholesterol	10-15% decrease	Lipid panel monitoring
Acne, oily skin	Common (especially with injectable)	Topical treatment; dose adjustment
Gynecomastia	5-10%	If painful/persistent, consider aromatase inhibitor
Testicular atrophy	30-50%	hCG co-administration to maintain size and fertility
Infertility (suppressed spermatogenesis)	50-90%	Avoid if desiring fertility within 12 months
Edema (fluid retention)	5-10%	Diuretics if needed
Sleep apnea exacerbation	5-10%	Consider CPAP if OSA
Acromegaly-like (high-dose abuse)	Rare (with abuse)	Avoid supra-physiologic dosing
Venous thromboembolism	Possible (conflicting evidence)	Screen for VTE risk factors
Cardiovascular events	Controversial (no conclusive increase)	Monitor risk factors
Hepatotoxicity	Oral androgens only	Liver function monitoring
Priapism	Rare	Emergency management

TRT and Fertility

Strategy to Preserve/Improve Fertility	Protocol	Notes
hCG alone	1,000-3,000 IU SQ/IM 2-3x/week	Maintains intratesticular testosterone; may be combined with TRT
hCG + TRT (combination)	TRT + hCG 500-1,000 IU every other day	Preserves testicular size and spermatogenesis
hMG (human menopausal gonadotropin) + hCG	hMG 75-150 IU 3x/week + hCG 1,000-2,000 IU 2x/week	For secondary hypogonadism to induce spermatogenesis
Clomiphene citrate (SERM)	25-50 mg daily or every other day	Stimulates endogenous LH/FSH; option for men who want fertility without TRT
Anastrozole (aromatase inhibitor)	1 mg daily; reduce E2	Off-label; increases T and maintains FSH
Stop TRT	Discontinue TRT; may restart spermatogenesis	May take 6-24 months to recover T production

TRT Alternatives (for Mild Hypogonadism or Suboptimal TRT Candidates)

Alternative	Mechanism	Efficacy	Notes
Clomiphene citrate (Clomid)	SERM; blocks estrogen feedback to increase LH/FSH	50-70% achieve testosterone >400 ng/dL	Off-label; no infertility or testicular atrophy; good for younger men
Enclomiphene (Zurampic, off-label)	Pure SERM; fewer side effects than clomiphene	Similar to clomiphene	Limited availability
Anastrozole (Arimidex)	Aromatase inhibitor; reduces conversion of T to E2	Variable increase in T	Off-label; for men with low T/high E2; bone health concern
hCG monotherapy	Stimulates Leydig cells	Preserves/increases testicular volume	For men who desire fertility
Lifestyle modification	Weight loss, exercise, sleep, stress reduction	30-50% increase from baseline	First-line for mild, age-related decline