CYP19A1 Gene and Pharmacogenetics of Response to Testosterone Therapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01378299
Recruitment Status : Active, not recruiting
First Posted : June 22, 2011
Last Update Posted : June 1, 2017
Baylor College of Medicine
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Hypogonadism Drug: Testosterone Cypionate Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: CYP19A1 Gene and Pharmacogenetics of Response
Actual Study Start Date : October 1, 2011
Actual Primary Completion Date : November 7, 2016
Estimated Study Completion Date : October 31, 2017

Arm Intervention/treatment
Experimental: Arm 1: Testosterone Cypionate
All patients who qualify for the study will receive testosterone cypionate
Drug: Testosterone Cypionate

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 mole

Other Name: depo testosterone

Primary Outcome Measures :
  1. Bone mineral density [ Time Frame: 18 mos ]
    Changes in bone mineral density from baseline

Secondary Outcome Measures :
  1. PSA [ Time Frame: 18 mos ]
    changes in PSA from baseline

  2. hematocrit [ Time Frame: 18 mos ]
    changes in hematocrit from baseline

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Male Veterans with low total testosterone (<300 ng/dl) as defined by the Endocrine Society, who are between 40-75 years of age.
Accepts Healthy Volunteers:   Yes

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01378299

United States, New Mexico
New Mexico VA Health Care System, Albuquerque, NM
Albuquerque, New Mexico, United States, 87108-5153
United States, Texas
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, United States, 77030
Sponsors and Collaborators
VA Office of Research and Development
Baylor College of Medicine
Principal Investigator: Reina C Villareal, MD New Mexico VA Health Care System, Albuquerque, NM

Responsible Party: VA Office of Research and Development Identifier: NCT01378299     History of Changes
Other Study ID Numbers: SPLC-001-10S
First Posted: June 22, 2011    Key Record Dates
Last Update Posted: June 1, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

People who ensure quality from the institutions where the research is being done, federal and other regulatory agencies will have access to all of the research data such as Food and Drug Administration (FDA) and Data Monitoring Committee (DMC). The purpose of collecting information covered under 38 U.S.C. 7332 is to conduct scientific research and no personnel involved in this study will identify, directly or indirectly, any individual patient or subject in any report of such research.

The only research data that will leave the MEDVA MC will be emailed to the FDA and Data Monitoring Committee, and will include only data on subjects who developed side effects including heart attacks, strokes, high hematocrit, high PSA, psychiatric problems and other adverse events, and the results of their tests. None of the 18 HIPAA identifiers will be included.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

Additional relevant MeSH terms:
Gonadal Disorders
Endocrine System Diseases
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents