CYP19A1 (Cytochrome P450 Family 19 Subfamily A Member 1) Gene and Pharmacogenetics of Response to Testosterone Therapy

Phase 1

Completed

Conditions: Hypogonadism

Interventions: Drug: Testosterone Cypionate

Registration Number: NCT01378299

Lead Sponsor: VA Office of Research and Development

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 105

Inclusion Criteria

Male Veterans with low total testosterone (<300 ng/dl) as defined by the Endocrine Society, who are between 40-75 years of age.
These patients must be ambulatory; and be willing and able to provide written informed consent.

Exclusion Criteria

history of prostate cancer, breast cancer
history of testicular disease
untreated sleep apnea
any ongoing illness that, in the opinion of the investigator, could prevent the subject from completing the study
patients with a hematocrit of more than 50% (2010 Endocrine Society Guidelines)
prostate-related findings of a palpable prostate nodule on exam, a serum PSA of 4.0 ng/ml or more, International Prostate Symptom Score >8(9), urinary postvoid residual by ultrasound of >149 ml, or an abnormal transrectal ultrasound
patients who are on androgen replacement therapy, selective androgen receptor modulator, or finasteride
patients currently on medications that affects bone metabolism such as:
- estrogen
- the selective estrogen receptor modulator (SERM) as raloxifene
- use of bisphosphonates (i.e. risedronate, alendronate, zoledronic acid and pamidronate)
- within two years of study entry
- aromatase inhibitors
- GnRH analogs
- glucocorticoids of at least 5 mg daily for one month or more
- anabolic steroids
- dilantin
- warfarin
patients with diseases known to interfere with bone metabolism as hyperparathyroidism, untreated hyperthyroidism, osteomalacia, chronic liver disease, renal failure, hypercortisolism, malabsorption and immobilization
those with current alcohol use of more than 3 drinks per day (62).
history of documented coronary artery disease at high risk for recurrence
Subjects with osteoporosis or a BMD T-score of -2.5 in the lumbar spine, total femur or femoral neck as well as those patients with a history of osteoporosis-related fractures (spine, hip or wrist) or vertebral deformities on lateral spine radiographs deemed as fragility fractures by the team principal investigator.
history of documented coronary artery disease at high risk for recurrence, history of deep vein thrombosis and cerebrovascular event.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1: Testosterone Cypionate	Testosterone Cypionate	All patients who qualify for the study will receive testosterone cypionate

Primary Outcome Measures

Name	Time	Method
Percent Change in Bone Mineral Density (BMD) According to the rs1062033 Polymorphism in the CYP19A1 Gene	baseline to 18 months	Percent change in bone mineral density from baseline to 18 months.
Percent Change in Bone Mineral Density (BMD) According to rs700518 Polymorphism in the CYP19A1 Gene	form baseline to 18 months	Percent change in bone mineral density from baseline to 18 months

Secondary Outcome Measures

Name	Time	Method
Percent Change in Bone Mineral Density According the Presence of Diabetes Mellitus	Baseline to 18 months	Percent change in bone mineral density from baseline to 18 months
Percent Change in Hematocrit According to re1062033 Polymorphism of the CYP19A1 Gene	Baseline to 18 months	Percent change in hematocrit from baseline to 18 months
Percent Change in Bone Turnover Markers According to the rs700518 Polymorphism of the CYP19A1 Gene	Baseline to 18 months	Percent change in bone turnover from baseline to 18 months.
Percent Change in Bone Mineral Density According to Body Mass Index (BMI)	baseline to 18 months	Percent changes in bone mineral density from baseline
Percent Change in Prostate-specific Antigen (PSA) According to the rs700518 Polymorphism of the CYP19A1 Gene	From baseline to 18 months	Percent change in PSA from baseline to 18 months
Percent Change in Prostate-specific Antigen (PSA) According to the rs1062033 Polymorphism of the CYP19A1 Gene	from baseline to 18 months	Percent change in PSA from baseline at 18 months
Percent Change in Hematocrit According to the Genotype of the 700518 Polymorphism of the CYP19A1gene	baseline to 18 months	Percent change in hematocrit from baseline to 18 months
Percent Change in Aromatase Gene Activity From the Buffy Coat According to the 700518 Polymorphism of the CYP19A1 Gene	Baseline to 6 months	Percent change in gene expression from baseline to 18 months
Percent Change in Bone Turnover Markers According to the rs1062033 Polymorphism of the CYP19A1 Gene	Baseline to 18 months	Percent change in bone turnover markers
Percent Change in Bone Turnover Markers According the Presence of Diabetes Mellitus	Baseline to 18 months	Percent change in bone turnover markers from baseline to 18 months.

Trial Locations

Locations (2): Michael E. DeBakey VA Medical Center, Houston, TX
🇺🇸
Houston, Texas, United States
New Mexico VA Health Care System, Albuquerque, NM
🇺🇸
Albuquerque, New Mexico, United States