Clinical trial NCT01378299
Conditions: Hypogonadism
Keywords: testosterone
Sponsor: VA Office of Research and Development
Start date: 2011-10-01; Completion date: 2017-11-07
Enrollment: 105 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Testosterone (T) replacement prevents bone loss and relieves symptoms associated with androgen deficiency in male patients with hypogonadism, but at the expense of an increase in prostate-related adverse events and in the hematocrit values above the normal which may lead to bad circulatory outcomes. Most of the effects of T on the male skeleton are mediated by its conversion to estradiol (E2) by the enzyme aromatase. Genetic variations in the aromatase (CYP19A1) gene result in enzymes with variable activity and variable levels of E2 and T. This project is designed to determine if genetic variations in the CYP19A1 gene will result in differences in the skeletal response and incidence of side effects from T treatment in patients with low T. A large number of male Veterans are on T. Results from this project will help identify patients who would benefit from the therapy from those at risk for side effects, and would definitely have an impact in the future care of these patients and male patients in general once genetic profiling becomes part of the standard of care.

Detailed description:
Estrogen has been gaining recognition as the primary hormone that regulates the male skeleton. Estrogen in males is mainly derived from the conversion of testosterone to estradiol by the enzyme aromatase. Polymorphisms of the aromatase gene (CYP19A1) have been reported to result in variable enzyme activity resulting in variable hormonal profile and differences in bone mineral density (BMD) among the variants. These polymorphisms were also found to influence changes in BMD in response to hormone therapy in postmenopausal women and bone loss from aromatase inhibitors in women with breast cancer. It is possible that these same polymorphisms will also influence skeletal response to testosterone therapy in hypogonadal males given testosterone.

Among the side effects described for testosterone therapy, prostate-related events and an increase in hematocrit represent as the more common and the potentially more serious side effects. However, these side effects do not affect everybody, suggesting that a certain subgroup of patients is predisposed to these side effects. Because polymorphisms in the CYP19A1 gene result differences in activity among variants leading in variable substrate and product accumulation, the investigators hypothesize that these polymorphisms will influence the skeletal response and perhaps susceptibility to side effects from testosterone therapy. Thus the objectives of this proposal are: (1) To evaluate the influence of polymorphisms in the CYP19A1 gene on the skeletal response to testosterone in male patients with low testosterone, (2) To evaluate the influence of polymorphisms in the CYP19A1 gene on the susceptibility to side effects from testosterone therapy, (3) To evaluate the changes in functional activity of the aromatase enzyme in clinically significant CYP19A1 gene polymorphisms. The investigators propose to treat 105 patients with testosterone cypionate 200 mg IM every 2 weeks for an 18-month treatment period. The investigators will do serial measurements of BMD by dual energy X-ray absorptiometry, markers of bone turnover, hematocrit, prostate-specific antigen (PSA), prostate volume and hormonal assays. Changes in BMD and markers of bone turnover with testosterone treatment will be compared among the different CYP19A1 genotypes. The investigators will also compare changes in hematocrit, PSA and prostate volume among the different CYP19A1 genotypes. Changes in functional activity among the variants will be evaluated by CYP19 gene expression studies on the adipose tissues obtained from periumbilical fat biopsies, and by changes the in estradiol to testosterone ratio, a surrogate marker for aromatase activity. The investigators anticipate that variants with increase in activity will have relatively higher estradiol levels than less active variants resulting in greater increments in BMD. Meanwhile, less active variants will have relatively higher levels of testosterone than other variants and have greater increments in hematocrit. On the other hand, variants associated with higher estradiol to testosterone ratio will experience greater increases in PSA and prostate volume with therapy.

The incidence of testosterone deficiency goes up with aging and the presence of co-morbid conditions making male hypogonadism one of the common problems among patients attending the VA clinics who, are for the most part, elderly with various co-morbid conditions. Indeed, a large number of VA patients are already taking testosterone for hypogonadism, some of them primarily to prevent further bone loss. It is possible that some of these patients do not derive benefit from the drug while subjecting them to potential serious side effects. Results from this proposal will identify the genetic profiles of favorable responders from poor responders or those who might be more prone to serious side effects, thus, may impact the future care of male Veterans and hypogonadal patients in general, once genetic profiling becomes part of the standard of care.

Arms: arm 1: All patients who qualify for the study will receive testosterone cypionate
Interventions: intervention 1: Testosterone Cypionate
Intervention descriptions: intervention 1: Testosterone cypionate was administered at 200 mg by intramuscular injection every 2 weeks.

DEPo-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble 17 (beta)-cyclopentylpropionate ester of the androgenic hormone testosterone.

Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble in vegetable oils. The chemical name for testosterone cypionate is androst-4-en-3-one,17-(3-cyclopentyl-1oxopropoxy)-, (178)-. Its molecular formula is CvH400a, and the molecular weight of 412.61.

Protocol documents: