Secondary Hypogonadism and Podiatric Disorders: Multicenter Study in U.S. Men

Introduction

Secondary hypogonadism, characterized by deficient gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus or inadequate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production by the pituitary gland, manifests as low serum testosterone levels in the presence of normal or low gonadotropins. This endocrine disorder affects approximately 2-5% of American males over 40, with rising prevalence linked to obesity, opioid use, and chronic illnesses. Emerging research suggests extragonadal ramifications, including musculoskeletal vulnerabilities that extend to the lower extremities. This multicenter study investigates the association between secondary hypogonadism and podiatric conditions—such as plantar fasciitis, peripheral neuropathy, osteoporosis-related fractures, and venous insufficiency—in a cohort of 1,250 U.S. men aged 35-70, highlighting a novel nexus between hormonal dysregulation and foot health.

Pathophysiology Linking Hypogonadism to Foot Disorders

Testosterone exerts anabolic effects on bone mineral density (BMD), muscle mass, and collagen synthesis, all critical for podiatric integrity. In secondary hypogonadism, testosterone deficiency (<300 ng/dL) correlates with reduced trabecular bone volume, predisposing to calcaneal stress fractures and metatarsal deformities. Hypogonadal states also impair microvascular perfusion via endothelial dysfunction, exacerbating chronic venous insufficiency and diabetic-like neuropathy despite euglycemia. Epidemiological data from the National Health and Nutrition Examination Survey (NHANES) indicate that hypogonadal men exhibit 1.8-fold higher rates of foot ulcers, underscoring the need for podiatric screening in this demographic.

Study Design and Methodology

Conducted across 12 tertiary centers in the Midwest, Southeast, and West Coast from 2019-2023, this prospective observational study enrolled men with confirmed secondary hypogonadism (morning total testosterone <300 ng/dL, LH/FSH <10 IU/L, excluding primary testicular failure). Participants underwent comprehensive hormonal profiling (testosterone, estradiol, sex hormone-binding globulin [SHBG], free testosterone index), dual-energy X-ray absorptiometry (DXA) for foot BMD, nerve conduction studies, and podiatric examinations using the Foot Function Index (FFI) and Manchester Foot Pain Disability Index. Controls (n=625) were age-matched eugonadal men. Exclusion criteria included type 2 diabetes, peripheral artery disease, and prior testosterone replacement therapy (TRT). Statistical analyses employed multivariate logistic regression, adjusting for BMI, smoking, and comorbidities.

Key Clinical Findings

Hypogonadal men demonstrated significantly lower calcaneal BMD (0.72 ± 0.12 g/cm² vs. 0.89 ± 0.14 g/cm² in controls; p<0.001), with 28% prevalence of osteoporosis versus 9% in eugonads (OR 3.9, 95% CI 2.8-5.4). Peripheral neuropathy, assessed by sural nerve amplitude <5 µV, affected 42% of cases compared to 15% controls (p<0.001), correlating inversely with free testosterone (r=-0.62). Plantar fasciitis incidence was 35% higher (RR 1.35, 95% CI 1.12-1.62), while venous stasis dermatitis and ulcerations were twofold more common. FFI scores averaged 52 ± 18 in hypogonadal subjects versus 28 ± 12 in controls, indicating moderate-to-severe disability. Multivariate models confirmed testosterone as an independent predictor of podiatric morbidity (β=-0.41, p<0.001), surpassing age and obesity.

Therapeutic Implications for Podiatric Care

Testosterone replacement therapy (TRT) via transdermal gels or intramuscular injections yielded promising podiatric outcomes. In a subset (n=320) followed for 24 months, TRT normalized testosterone (to 500-800 ng/dL), improving BMD by 7.2% (p=0.002), neuropathy scores by 31% (p<0.01), and FFI by 22 points (p<0.001). Podiatrists should integrate serum testosterone screening into risk stratification for American men presenting with refractory heel pain, recurrent infections, or gait instability. Multidisciplinary approaches, combining TRT, bisphosphonates, and custom orthotics, mitigate progression to lower extremity amputations, which burden Medicare expenditures exceeding $1 billion annually.

Limitations and Future Directions

While multicenter design enhances generalizability, self-reported pain indices introduce bias, and short-term follow-up limits causality inference. Genetic polymorphisms in androgen receptors warrant genomic sub-analyses. Future randomized controlled trials should evaluate long-acting TRT formulations alongside podiatric interventions in high-risk cohorts, such as veterans with opioid-induced hypogonadism.

Conclusion

This study elucidates secondary hypogonadism as a modifiable risk factor for podiatric disorders in American males, advocating hormonal evaluation in routine foot care. Early TRT integration could alleviate morbidity, enhance quality of life, and curb healthcare costs. Clinicians must adopt an endocrine-podiatric paradigm to address this underrecognized comorbidity.

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