One promising but understudied area in the field of testosterone (T) therapy is its effect on metabolism and the development of type II diabetes. Metabolomics is a powerful research tool that can detect very early signs of metabolic derangement that may lead to metabolic disease. In this observational study, investigators aim to apply metabolomics in order to better understand how T therapy influences metabolism. In a clinical population of outpatient men with T deficiency investigators will perform comprehensive clinical evaluations and also obtain blood for metabolomics. This will be done once prior to T therapy and again after 4-6 months of T therapy. Investigators hypothesize that they can detect metabolic derangements in men with T deficiency and that these derangements will improve with T therapy.

One promising but understudied area in the field of T therapy is its effect on insulin resistance (IR) and the development of type II diabetes and cardiometabolic disease. Although several clinical studies suggest T therapy improves metabolic parameters and may prevent disease progression, a mechanism for understanding this process is lacking. Investigators propose to use metabolomics to shed light on how metabolic function changes with T therapy.

Metabolomics is an established investigative tool that measures hundreds of unique chemical markers (metabolites) involved in normal and diseased cellular processes from a blood sample. Previous studies using the Metabolite Profiling Platform at the Broad Institute of Harvard/Massachusetts Institute of Technology applied tandem liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to large, population-based cohorts. These studies identified and validated highly sensitive signatures of IR that successfully predicted occult risk for type II diabetes in clinically normal men. Investigators now plan to apply metabolomics to a clinical population in order to obtain a new perspective on the biochemical metabolic changes that occur based on a man's testosterone status. Investigators plan to study men with symptomatic testosterone deficiency identified at Men's Health Boston (MHB), an outpatient men's health clinic.

In a pilot study involving 32 blood samples, investigators have already identified a specific metabolomic signature in men undergoing androgen deprivation therapy for prostate cancer. Based on these preliminary results and other recent studies, investigators hypothesize that they can detect metabolic derangements in men with T deficiency and that these derangements will respond to changes in T levels. Investigators will address this hypothesis though the following specific aims:

Aim 1: To characterize metabolite profiles and evaluate metabolic dysfunction in T deficient men

To accomplish this aim investigators will study T deficient men presenting to MHB. In addition to metabolite profiling, these men will undergo a comprehensive clinical evaluation at MHB including:

• Complete History and Physical exam
• Assessment of symptoms of T deficiency and sexual function using validated and other questionnaires
• Comprehensive hormonal and metabolic laboratory evaluation
• Body composition (including visceral and subcutaneous adiposity) by dual x-ray absorptiometry (DXA) Investigators will build a reference dataset relating metabolite profiles with metabolic risk factors in a clinical population of T deficient men. This will include data on the relationship between metabolite profiles and sexual and other symptoms of T deficiency. Investigators will also compare concentrations of select metabolites between T deficient men and matched eugonadal controls previously studied in the Framingham cohort.

Aim 2: To determine how T therapy influences metabolite profiles and IR

1. To identify metabolites that change in response to raising serum T
2. To determine how changes in metabolite profiles relate to changes in IR
3. To determine how response in terms of sexual function symptoms of low T relate to response in metabolite profiles and IR.

Metabolite profiles will be obtained and clinical evaluation performed (described above under Aim1) at baseline and again after 6 months of therapy. Investigators will study interactions between changes in sexual function and serum T, IR, body composition and metabolite profiles (with particular attention to established metabolite markers of IR).

Inclusion Criteria:

• Symptomatic testosterone deficiency
• Intend to undergo testosterone therapy at Men's Health Boston
• Total testosterone <350ng/dL or free testosterone <1.5ng/dL

Exclusion Criteria:

• Type 1 diabetes
• Use of exogenous testosterone or clomiphene citrate
• Known karyotype abnormalities
• Seizure disorders
• Malignancy

Testosterone deficient men who intend to undergo testosterone therapy at an outpatient men's health clinic.