Contributions to Hypertension With Androgen Deprivation Therapy

Study Overview
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Brief Summary
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This study plans to learn more about contributors to high blood pressure in men who undergo androgen deprivation therapy (ADT) to treat prostate cancer. Prostate cancer is the most common non-skin cancer in men, affecting approximately 1 in 8 American men and its primary treatment is through the use of ADT. However, ADT increases the likelihood of developing heart disease including high blood pressure. This study will determine if dysfunction of the nervous system and/or kidneys occurs in men undergoing ADT, as these systems play a significant role in control of blood pressure. The results from this study will help us understand the ways in which ADT contributes to heart disease and help us develop therapies to prevent heart disease in prostate cancer survivors.

Official Title
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Autonomic and Renal Contributions to Hypertension With Androgen Deprivation Therapy

Conditions
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Androgen Deprivation Therapy, Prostate Cancer, Hypertension, Autonomic Dysfunction, Renal Disease

Intervention / Treatment
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* Drug: Gonadotropin-Releasing Hormone Agonist
* Drug: Androgen receptor inhibitor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -age 40+ years; resting blood pressure <140/90 mmHg; fasted blood glucose <126 mg/dL; testosterone ≥400 ng/dL; sedentary to recreationally active; nonsmokers; healthy as determined by medical history, physical exam, blood and urine chemistries and resting and exercise ECG during a physician supervised graded exercise treadmill test OR recent diagnosis of non-metastatic prostate cancer with plans to undergo androgen deprivation therapy; PSA <4.00 ng/dL if in the non-cancer group; Gleason Score ≤7 if in the prostate cancer group; no use of medications that might influence cardiovascular function (e.g., antihypertensives, lipid-lowering medications); willing and able to be on GnRHagonist and AR inhibitor; not taking antioxidant vitamins, corticosteroids, or anti-inflammatory medications, or willing to stop use for four weeks prior to the start of the study; not using exogenous sex hormones for at least one year Exclusion Criteria: -acute liver disease; chronic kidney disease, serum creatinine >1.3 mg/dL, macroalbuminuria >300 mg/g of proteinuria pre-existing or active cardiac, renal or hepatic disease, epilepsy or other seizure disorder; diabetes, active or chronic infection, disease that affects the nervous system; Gleason Score ≥8; thyroid dysfunction, defined as ultrasensitive TSH <0.5 or >5.0 mU/L, volunteers with abnormal TSH values will be re-considered for participation after follow-up evaluation by the PCP with initiation or adjustment of thyroid hormone replacement; tobacco use within the previous 12 months

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prostate Cancer<br>Men undergoing androgen deprivation therapy via gonadotropin releasing hormone agonist plus androgen receptor inhibitor for the treatment of prostate cancer | Drug: Gonadotropin-Releasing Hormone Agonist<br>* 8 weeks of GnRH agonist<br>* Other names: Goserelin;Drug: Androgen receptor inhibitor<br>* 2 weeks of AR Inhibitor<br>* Other names: Enzalutamide;|
| Active Comparator: Healthy + ADT<br>Healthy men undergoing gonadal suppression via gonadotropin releasing hormone agonist plus androgen receptor inhibitor for 9 weeks | Drug: Gonadotropin-Releasing Hormone Agonist<br>* 8 weeks of GnRH agonist<br>* Other names: Goserelin;Drug: Androgen receptor inhibitor<br>* 2 weeks of AR Inhibitor<br>* Other names: Enzalutamide;|
| Placebo Comparator: Healthy + Placebo<br>Healthy men undergoing placebo for 9 weeks. | Drug: Placebo<br>* Placebo tablet and injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cardiovagal Baroreflex Sensitivity | The change in cardiovagal baroreflex sensitivity will be assessed the modified Oxford procedure | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in blood pressure reactivity to the cold pressor test | The change in blood pressure will be assessed from quiet rest to sympathetic activation using the cold pressor test | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in exercise pressor reflex | The change in blood pressure will be assessed from quiet rest to isometric handgrip exercise | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in ambulatory blood pressure variability | Ambulatory blood pressure variability will be determined from 24-hour ambulatory blood pressure monitoring. | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in beat-to-beat blood pressure variability | Beat-to-beat blood pressure variability will be using finger photoplethysmography measured in the laboratory. | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in renal vascular resistance | Renal blood flow will be determined using ultrasound and blood pressure will be determined using finger photoplethysmography. These measures will be used to estimate renal vascular resistance. | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in Renal dysfunction biomarkers | Neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM)-1, interleukin (IL)-18, and vanin-1 will be quantified in urine using commercially available assay kits. Concentrations will be normalized to urinary flow rate. | Before and after 9 weeks of androgen deprivation therapy or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sympathetic baroreflex sensitivity | Changes in muscle sympathetic nerve activity in response to changes in blood pressure will be assessed using the modified Oxford procedure | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in Sympathetic reactivity | The change in muscle sympathetic nerve activity will be assessed from quiet rest to sympathetic activation using the cold pressor test. | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in glomerular filtration rate | Glomerular filtration rate and renal plasma flow will be calculated by iohexol (Omnipaque 300, GE Healthcare) clearance technique. Plasma and urine iohexol and p-aminohippurate clearance will be measured on a High-Performance Liquid Chromatography (HPLC, Waters, Milford, MA). | Before and after 9 weeks of androgen deprivation therapy or placebo | 
| Change in renal plasma flow | Renal plasma flow will be calculated by p-aminohippurate (Basic Pharma) clearance techniques. Plasma and urine p-aminohippurate clearance will be measured on a High-Performance Liquid Chromatography (HPLC, Waters, Milford, MA). | Before and after 9 weeks of androgen deprivation therapy or placebo |