CYP19A1 (Cytochrome P450 Family 19 Subfamily A Member 1) Gene and Pharmacogenetics of Response to Testosterone Therapy
| Status: | Completed |
|---|---|
| Conditions: | Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 40 - 75 |
| Updated: | 3/7/2019 |
| Start Date: | October 1, 2011 |
| End Date: | November 7, 2017 |
CYP19A1 Gene and Pharmacogenetics of Response
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.
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.
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.
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.
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.
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