Low testosterone, or testosterone deficiency, is a condition that can impact men's health, with diagnosis relying on a combination of symptoms and blood tests, and treatment involving various approaches to restore hormone levels [1].

Testosterone is a crucial hormone in men, playing a vital role in various bodily functions, including reproduction, metabolism, and red blood cell production [8]. When testosterone levels fall below the normal range, a condition known as testosterone deficiency (TD) or hypogonadism can occur. This condition can manifest with a range of symptoms and may require medical intervention to restore hormone balance [1].

Diagnosing Low Testosterone Levels

Diagnosing testosterone deficiency typically involves a two-pronged approach: assessing a man's symptoms and conducting laboratory blood tests [1]. Common diagnostic criteria include total testosterone (TT) levels at or below 300 ng/dL accompanied by symptoms. For men with borderline low testosterone (TT between 300-400 ng/dL), objective signs such as low bone density or elevated HbA1c (a measure of blood sugar) may also indicate a deficiency [1].

It is important to note that symptoms of low testosterone can sometimes overlap with other health conditions. For instance, thyroid function tests (TFTs), which measure thyroid stimulating hormone (TSH) and circulating thyroid hormones, are frequently used to diagnose and monitor thyroid disorders [6]. TSH, secreted by the pituitary gland, is a key indicator for primary thyroid dysfunction [6]. Insufficient thyroid hormones, known as hypothyroidism, can be primary (thyroid gland issue) or secondary (pituitary gland or hypothalamus issue) [7]. Rare conditions, such as TSH-secreting pituitary adenomas, can also lead to hormonal imbalances [5]. Therefore, a comprehensive evaluation by a healthcare provider is essential to ensure an accurate diagnosis and rule out other potential causes of symptoms.

Clomiphene Citrate: An Off-Label Option

Clomiphene citrate (CC) is an established treatment option for men with low testosterone, although it is often used off-label for this purpose, as testosterone replacement therapy (TRT) is the only FDA-approved treatment for male hypogonadism [1, 4]. A retrospective study analyzed men diagnosed with low or borderline low testosterone who were treated with CC. The initial dosing typically involved 25 mg every other day (QOD), with the possibility of increasing to 50 mg QOD if testosterone levels remained low [1].

Treatment response for CC therapy was defined as achieving a total testosterone level of at least 400 ng/dL while on treatment, along with an increase in total testosterone of 200 ng/dL or more from baseline levels [1]. This approach aims to stimulate the body's natural testosterone production rather than directly replacing the hormone.

Testosterone Replacement Therapy: Approved Treatment

Testosterone Replacement Therapy (TRT) is the only treatment specifically approved by the FDA for male hypogonadism [4]. Various forms of TRT exist, including testosterone undecanoate (TU) [3]. A large retrospective study compared clinical outcomes and potential adverse effects between patients receiving clomiphene citrate and those on testosterone replacement therapy. The study investigated new diagnoses of conditions such as fractures, osteoporosis, polycythemia, thrombosis, hypertension, pulmonary embolism, coronary artery disease, and cerebrovascular accidents in over 2500 matched individuals in each treatment group [4].

Weighing the Benefits and Risks of Treatment

The decision to pursue testosterone therapy involves considering potential benefits and risks, which have been the subject of ongoing research:

Mortality and Metabolic Health: A study involving men with adult-onset testosterone deficiency found that mortality was lower in those treated with testosterone undecanoate (TU) compared to untreated men over nearly nine years of follow-up [3]. Untreated men experienced a worsening of metabolic syndrome features, while men on TU showed improvements in these metabolic risk factors [3].
Cardiovascular Health and Atrial Fibrillation: The relationship between testosterone therapy and atrial fibrillation (AF) has been a debated topic. However, a review of contemporary scientific evidence suggests that testosterone deficiency itself may contribute to the incidence of AF, and testosterone therapy does not appear to increase the incidence of AF. While some studies have suggested a link, a closer examination indicates potential confounding factors, and a larger body of evidence points to no increased risk from testosterone therapy [2].
Hypertension: Research indicates an inverse association between serum testosterone levels and the incidence of hypertension in men aged 40 and older. Hypertensive men in this age group were found to have significantly lower serum testosterone levels than those with normal blood pressure [8].

While TRT is generally considered safe when appropriately monitored, the comparative study mentioned earlier investigated a range of potential adverse effects, including cardiovascular events and blood disorders, in patients receiving either TRT or clomiphene citrate [4]. It is crucial for patients to discuss these potential outcomes thoroughly with their healthcare provider.

The Broader Picture: Other Hormonal Considerations

Symptoms often associated with low testosterone, such as fatigue, weight changes, or mood disturbances, can also be indicative of other hormonal imbalances. For example, conditions affecting the thyroid gland, such as hypothyroidism (insufficient thyroid hormones) or hyperthyroidism (excessive thyroid hormones), can present with similar non-specific symptoms [7, 5]. The pituitary gland, which regulates both testosterone and thyroid hormone production, can also be the source of issues [5, 6, 7]. Therefore, a thorough diagnostic process is vital to identify the correct underlying cause of symptoms and ensure appropriate treatment. Patients experiencing symptoms suggestive of hormonal imbalance should consult a healthcare professional for accurate diagnosis and personalized management.

Sources

Predictors of clomiphene citrate response in the treatment of men with testosterone deficiency. https://pubmed.ncbi.nlm.nih.gov/42251758/
Does Testosterone Therapy Increase Risk of Atrial Fibrillation? Appraisal of the Contemporary Scientific and Clinical Evidence. https://pubmed.ncbi.nlm.nih.gov/42402865/
The association between age and mortality in men with adult-onset testosterone deficiency is altered by testosterone therapy. https://pubmed.ncbi.nlm.nih.gov/42391314/
Testosterone Versus Clomiphene Treatment of Hypogonadism: A Retrospective Analysis in US Veterans. https://pubmed.ncbi.nlm.nih.gov/42015850/
Thyrotropin/growth hormone co-secreting pituitary adenoma with pancytopenia: a case report. https://pubmed.ncbi.nlm.nih.gov/42323692/
Thyroid function tests: Thyroid disease: assessment and management: Evidence review C. https://pubmed.ncbi.nlm.nih.gov/35129920/
Management of hypothyroidism: Thyroid disease: assessment and management: Evidence review E. https://pubmed.ncbi.nlm.nih.gov/35129923/
The Serum Testosterone Level in Male Patients Is Inversely Associated With Hypertension Incidence. https://pubmed.ncbi.nlm.nih.gov/42533705/

This article summarises published research for a general audience. It is not medical advice — talk to a qualified clinician about your own situation. Need help finding one? Browse doctors.