Low testosterone—why do men lose strength, and how can they regain it without hormones?

Aim of the study: Testosterone deficiency is defined as a total testosterone level <300 ng/dL confirmed on two early morning lab draws. Testosterone therapy has historically been offered to men with symptomatic testosterone deficiency in the form of injections, gels, or pellets.

Results: However, this medication is expensive and requires patients to administer injections themselves. Over-the-counter herbal supplements and designer steroids remain available, although they have not been studied extensively and are associated with potential for abuse as well as increased liver and cardiovascular risks. This review aims to discuss existing alternatives to traditional testosterone therapy, including the effectiveness, safety, and side effects of these options. The authors suggest that the SERM clomiphene citrate (CC) holds the greatest promise as a non-testosterone treatment option for testosterone deficiency.

Aim of the study: Pathologic hypogonadism occurs when serum testosterone is significantly and persistently reduced by irreversible organic (structural, genetic) disorders of the hypothalamic-pituitary-testicular axis. Men with pathologic hypogonadism require lifelong testosterone replacement.

Results: Herein we demonstrate how clinically significant weight loss substantially reverses obesity-related reductions in serum testosterone and ameliorates nonspecific symptoms resembling, but not due to, androgen deficiency. The important reversible steps include weight reduction and optimizing management of type 2 diabetes mellitus, obstructive sleep apnea, depression, and other obesity-related comorbidities, as well as rationalizing concomitant drug regimens. In the absence of pathological hypogonadism, testosterone treatment is less effective than a diet and lifestyle intervention at correcting the reversible conditions responsible for the nonspecific symptoms and associated reduced serum testosterone concentrations observed in men with obesity. As such, testosterone treatment is not indicated, and unwarranted off-label testosterone treatment can lead to adverse effects such as infertility, elevated hematocrit requiring venesection, a prothrombotic state, and testosterone dependence.

Aim of the study: The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex.

Results: Lifestyle measures are the cornerstone of management, as they can potentially improve symptoms of androgen deficiency regardless of their effect on testosterone levels. In selected patients, bariatric surgery can reverse obesity-induced hypogonadism. If these measures fail to relieve symptoms and normalize testosterone levels, testosterone replacement therapy could be started in appropriately selected men. Aromatase inhibitors and selective estrogen receptor modulators are not recommended because there is no consistent evidence from clinical trials.

Aim of the study: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. To review the metabolic impact of late-onset hypogonadism.

Results: Obesity is one of the strongest modifiable risk factors for late-onset hypogonadism, and coexisting diabetes leads to further hypothalamic-pituitary-testicular axis suppression. This suppression is functional and therefore potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that suppression of the hypothalamic-pituitary-testicular axis is mediated by dysregulation of pro-inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the idea that excess estradiol is a major contributor to suppression of the hypothalamic-pituitary-testicular axis. Instead, deficient relative estradiol signaling may contribute to metabolic dysregulation in men with diabesity.

Aim of the study: Obesity, which is increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and is one of the strongest predictors of receiving testosterone treatment.

Results: Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition, even in addition to diet alone. However, larger, longer-term RCTs designed to assess outcomes that matter to patients and potential risks are needed. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated nonclassical hypogonadism. Lifestyle measures or, where indicated, bariatric surgery to achieve weight loss, and optimization of comorbidities remain first-line approaches.

Aim of the study: Over the past decade, there have been concerns about the safety of testosterone therapy (TTh) in hypogonadal men. Several concerns have centered on the use of TTh and its potential link to cardiovascular (CV) events, prostate cancer, and benign prostatic hyperplasia (BPH).

Results: The majority of patients treated with TTh today are treated off-label. Low serum testosterone levels have been associated with increased CV events. Currently, the evidence is inconclusive as to whether TTh increases the risk of CV events. There is no evidence linking TTh to the development of prostate cancer or worsening of BPH symptoms. Finally, lifestyle modification, such as losing weight and improving sleep, can improve serum testosterone levels in hypogonadal men. Clinicians prescribing testosterone should be aware of the current controversies associated with TTh. Current literature does not suggest that TTh carries significant risks of prostate cancer, worsening BPH symptoms, or CV events. However, more studies, including randomized placebo-controlled trials, are needed. Finally, patients should be appropriately counseled about the indications for TTh and the benefits of lifestyle modification before starting TTh.

Aim of the study: Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide are increasingly used to treat obesity and type 2 diabetes in men of reproductive age, but practical guidance for counseling men planning fatherhood remains limited. This structured narrative review distinguishes endocrine, semen, sexual-function, and clinical fertility outcomes.

Results: Evidence on paternal preconception exposure is insufficient, and pregnancy-related label precautions do not by themselves establish risk from paternal exposure. No eligible controlled tirzepatide-specific study assessing semen or clinical fertility outcomes was identified by this search. These therapies should be used for established metabolic indications, not as male infertility treatments. The proposed framework is author-developed, evidence-informed, non-validated, and intended for individualized counseling and prospective evaluation.