A great deal of poor testosterone prescribing traces back to one shortcut: treating a number instead of a person. Before you can decide whether a man in front of you has testosterone deficiency, you need a working model of how his body produces testosterone, why the value on the lab report moves around so much, and what conditions push the number without touching the underlying gland. Build the model first. The prescribing decisions in later parts depend entirely on it.
The Axis in Plain Terms
The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulses roughly every 60 to 90 minutes. Those pulses instruct the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH travels to the Leydig cells of the testis and drives testosterone synthesis. FSH acts on the Sertoli cells and, together with the very high intratesticular testosterone concentration that Leydig cells generate locally, supports spermatogenesis. Testosterone and its aromatized product estradiol then feed back on both the hypothalamus and the pituitary to restrain further GnRH and LH release.
- 1Hypothalamus releases GnRH in pulses
- 2Pituitary releases LH and FSH
- 3LH drives Leydig cell testosterone synthesis
- 4FSH + intratesticular testosterone support spermatogenesis
- 5Testosterone and estradiol feed back to suppress GnRH/LH
Exogenous testosterone enters at the feedback step — which is exactly why it suppresses LH, FSH, intratesticular testosterone, and sperm production.
Exogenous testosterone does not add to the system; it replaces the signal that runs it. When you prescribe testosterone, LH and FSH fall, Leydig cell output falls, intratesticular testosterone concentration falls dramatically, and spermatogenesis is suppressed. This is not a rare adverse effect — it is the predictable pharmacology. Every man of reproductive age must be counseled on this before the first dose.
Why the Number Moves
Total testosterone follows a diurnal rhythm, peaking in the early morning and declining across the day. The amplitude of that rhythm is larger in younger men and blunts with age, but it is present enough at every age that a mid-afternoon draw can produce a spuriously low value in a man with entirely normal physiology. Testosterone is also secreted in pulses tracking LH pulsatility, so two draws an hour apart in the same man can differ meaningfully. Acute illness, poor sleep, recent heavy exertion, and a non-fasting state all lower measured values.
A low afternoon testosterone in a tired 44-year-old is not a diagnosis. It is a reason to repeat the test correctly.
SHBG: The Number Behind the Number
Most circulating testosterone is bound. Roughly 44 to 65 percent is tightly bound to sex hormone-binding globulin (SHBG), most of the remainder is weakly bound to albumin, and only about 0.5 to 3 percent circulates free. Because total testosterone measures all three pools, anything that changes SHBG changes the total without necessarily changing the biologically available fraction.
| SHBG is increased by | SHBG is decreased by |
|---|---|
| Aging | Obesity and insulin resistance |
| Hyperthyroidism | Type 2 diabetes |
| Cirrhosis and hepatitis | Nephrotic syndrome |
| Anticonvulsants | Glucocorticoids |
| Estrogens (including oral) | Androgens and anabolic steroids |
| HIV disease | Hypothyroidism |
| Weight loss | Acromegaly |
Obtain SHBG and calculate free testosterone when the total testosterone is borderline (roughly 200 to 400 ng/dL), when symptoms and total testosterone disagree, or when a condition on either column above is present. Calculated free testosterone using a validated equation is preferred to most direct analog immunoassays, which perform poorly. Equilibrium dialysis is the reference standard when available.
Guideline consensus across the Endocrine Society and AUA; assay-method recommendations are supported by comparative assay validation studies rather than outcome trials.
Age-Related Decline Versus Organic Hypogonadism
Total testosterone declines gradually with age, on the order of 1 to 2 percent per year after roughly age 30 to 40 in longitudinal cohorts. That decline is real, but it is not the same entity as classical hypogonadism from testicular failure or pituitary disease. Much of the observed age-associated decline is mediated by accumulating comorbidity — visceral adiposity, sleep apnea, metabolic syndrome, chronic opioid or glucocorticoid use — rather than by chronologic age itself. This distinction drives the entire evaluation in Part II: a substantial fraction of men referred for 'low T' have a reversible contributor that, when addressed, meaningfully raises their testosterone without any prescription.
The number that wasn't the problem
A 47-year-old man presents asking for testosterone. He reports fatigue, low motivation, reduced libido, and difficulty losing weight over the past two years. He works night shifts, sleeps five to six hours, and has gained 35 pounds since his last physical. BMI is 36. He brings a testosterone level of 238 ng/dL drawn at 3:40 p.m. at a walk-in clinic. He also reports loud snoring and daytime somnolence; his partner has witnessed apneic episodes.
Do you have enough information to diagnose testosterone deficiency, and what would you do next?