By Dr. Allison Smith, ZRT Laboratory
The testicles of a man in his 20s contribute approximately 5–10 mg of testosterone per 24-hour day, yielding total testosterone levels in venous blood of roughly 300–1200 ng/dL at the diurnal morning peak. Testosterone, whether endogenous or given exogenously, negatively feeds back on the hypothalamus, limiting GnRH and thus LH and FSH from the pituitary. A man taking supraphysiological doses of testosterone can expect very low or undetectable levels of LH and FSH in the serum.
What happens when the prescription dose overshoots the patient’s optimal dose? Certainly, LH and FSH practically disappear. Additionally, there can be a return of all or some of the original hypogonadal symptoms — which could be due to down-regulation of the tissue receptors. This is something seen quite frequently in the lab, especially with doses of topical testosterone gels over 50 mg per day. An interesting area of current research is androgen receptor sensitivity measured by a genetic finding (CAG repeat polymorphism), the increasing degree of which is negatively correlated to testosterone tissue uptake.
Understanding Andropause and Late Onset Hypogonadism
Andropause can have different presentations for each individual patient. Late onset hypogonadism (LOH) is a form of secondary hypogonadism appearing in men over 40, with estimated prevalence climbing as high as 30% in men over 70. There is a higher prevalence in men with type II diabetes and sleep apnoea. The key symptoms are sexual, and the clinical sign is low total and free testosterone in the serum — both are needed for diagnosis of LOH.
Symptoms of Low Testosterone
Sexual symptoms:
- Frequency of morning erections (<1 per month)
- Sexual thoughts (<2–3 times a month)
- Erectile function suitable for intercourse (almost never)
Psychological symptoms:
- Sadness
- Low energy
- Fatigue
Physical symptoms:
- Inability to walk more than 1 km
- Decreased flexibility — can’t bend or kneel
- Not able to engage in vigorous activity
Most men with age-related low testosterone levels are asymptomatic. Common drug therapies and nutritional deficiencies like low vitamin D are associated with lower levels of free testosterone. Adrenal and thyroid functions are altered by stress, and changes in cortisol, T3, T4, LH, FSH, SHBG and prolactin may be the beginning of where low free and total testosterone levels turn into noticeable symptoms.
To establish a full hormonal baseline — including testosterone, estradiol, DHEA, cortisol and SHBG — our Comprehensive Male Saliva Hormone Profile (LCMS) measures the free, bioavailable fraction of key male hormones using gold-standard LCMS analysis — the most clinically relevant method for assessing and monitoring topical testosterone therapy.
The U-Shaped Curve: Why More Is Not Always Better
Recent studies have shown that dosing with supraphysiological amounts of topical testosterone may actually increase the risk of cardiovascular events in elderly men, rather than preventing them as seen endogenously when testosterone levels are replete.
Why are prescriptions being written at doses higher than normal physiological production? Larger-than-physiologic doses of topical testosterone are often needed to see total testosterone in serum studies rise — and when dosing is started too high, it can be confusing to follow the symptom picture. For instance, if the starting prescription is 50 mg and the patient’s optimal zone (the bottom of the U) is 10–20 mg, even if the patient initially improves, mood and sexual symptoms will eventually return. Starting at low doses and increasing them over time will help create a patient’s own U-shaped curve and prevent diminishing returns.
What to Check When Numbers Look Good But Symptoms Remain
When a man on TRT still has symptoms despite apparently normal testosterone levels, the following markers should be assessed:
- Estradiol levels. Testosterone converts to estradiol via aromatase, which exists in nearly all body tissues including fat, gonads, blood vessels, brain and skin. If estradiol is rising with testosterone therapy, an aromatase inhibitor may be required.
- SHBG levels. Testosterone circulates bound to SHBG at a high percentage. If SHBG is becoming elevated, free testosterone will decrease and symptoms usually appear.
- DHT levels. Testosterone metabolises to DHT at the tissue level via 5-alpha reductase. Elevation in DHT is correlated with an increase in erythrocytosis — also assess haematocrit.
- DHEA-S levels. Low androgen symptoms may be attributable to low levels of this largely adrenal androgen.
- Thyroid function. Symptoms often overlap significantly with symptoms of low testosterone.
- Diurnal free cortisol. To assess for physiological stress response which may be playing a role in symptom development.
Because cortisol dysregulation is one of the most common confounders in male hormone symptoms, our Adrenal Function Saliva Test Kit (LCMS) measures cortisol at four time points across the day alongside DHEA-S — helping to identify whether adrenal dysfunction is contributing to persistent symptoms despite TRT.
For men whose symptoms overlap with thyroid dysfunction — fatigue, low energy, weight changes, mood disturbance — our Thyroid Test Kit (with Specialist Doctor Report) measures TSH, Free T4, Free T3 and TPO antibodies, with a full specialist interpretation included.
Treat the Lab or Treat the Person?
Is there a risk associated with NOT treating a low testosterone level in the asymptomatic man? The answer is arguably yes — though this does not necessarily mean giving everyone testosterone when it is low in the serum. Imbalances in estradiol, free testosterone and DHEA can profoundly affect a man’s cardiovascular risk profile. Lower testosterone levels are associated with incidence of atrial fibrillation, type 2 diabetes, obesity and peripheral artery disease.
The symptoms of low testosterone are shared with other conditions — and this can be a major pitfall for patients and clinicians alike. In these cases, correcting a low serum testosterone to normal levels through testosterone prescription will not make the symptoms improve. Sorting all of this out can be a huge challenge, but is often a solvable problem by digging further into the sex hormones and remembering the U-shaped curve.
Originally by Dr. Allison Smith, ZRT Laboratory. Reproduced with permission. Last reviewed: May 2026.