Study of the Effect of Testosterone and Estradiol on NP Responses to Acute and Chronic Salt Loading

Early Phase 1WithdrawnNCT01763541

Massachusetts General Hospital

Overview

There is gender dimorphism in cardiovascular risk, with men at higher risk than women. However, the fundamental basis for the protective effect of female sex remains unclear. Recent data implicate the natriuretic peptide (NP) system as an important determinant of blood pressure. Also, NP levels are twice as high in women of reproductive age than in men, and gonadal steroids are important determinants of circulating NPs. These are the marked, but poorly understood differences in the NP status between men and women. The investigators hypothesize that gonadal steroids regulate NP release, specifically that testosterone inhibits and estrogen activates the NP axis, leading to differences in both resting NP levels and dynamic responses of the NP, RAAS, and kidneys to acute and chronic salt loading. Understanding the basis for gender differences in NP function should provide important insights regarding mechanisms underlying hypertension in men versus women.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Conditions

Hypertension

Interventions

leuprolide acetateDRUG

Given to both arms to induce hypogonadism

AnastrozoleDRUG

Given to men to prevent conversion of administered testosterone to estradiol.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * 18-40 years old * no history of hypertension * normal BMI * Male: normal testosterone and free testosterone levels * Female: regular menses, negative pregnancy test, no sex steroid therapy \>/=3 mos Exclusion Criteria: * on hypertensives, diuretics, or insulin * with diabetes mellitus * estimated creatinine clearance \<60 ml/min * prior cardiovascular, liver or renal disease * history of hormonally-responsive cancer * elevated liver function test (LFTs) * atrial fibrillation * abnormal sodium or potassium levels * taking medications that directly impact the endocrine system (exogenous hormones, steroids, etc.) * taking medications that indirectly impact the endocrine system (SSRIs, opioids, finasteride, etc.) * with untreated hyper- or hypothyroidism * smoker * psychiatric history * Women: not willing to abstain from getting pregnant during the course of the study, with abnormal menstrual cycle, or who have osteoporosis * Men: with polycythemia

Locations (1)

Massachusetts General Hospital

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

NP levels in men with testosterone patch and low-salt diet

B-type natriuretic peptide (BNP), Atrial natriuretic peptide (ANP), amino-terminal brain natiuretic peptide (N-BNP), amino-terminal atrial natiuretic peptide (N-ANP), cyclic guanosine monophosphate (cGMP)

Time frame: At day 7 of week of testosterone administration with low-salt diet

NP levels in men with testosterone patch and high-salt diet

Time frame: At day 7 of week of testosterone administration with high-salt diet

NP levels in women with estradiol patch and low-salt diet

Time frame: At day 7 of week of estradiol administration with low-salt diet

NP levels in women with estradiol patch and high-salt diet

Time frame: At day 7 of week of estradiol administration with high-salt diet

NP levels in men with placebo patch and low-salt diet

Time frame: At day 7 of week of placebo administration with low-salt diet

NP levels in men with placebo patch and high-salt diet

Data from ClinicalTrials.gov

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Secondary Outcomes

Plasma Renin Activity (PRA) levels in women on estradiol on low-salt diet

Plasma Renin Activity (PRA)

Time frame: At day 7 of week of estradiol administration on low-salt diet

Aldosterone levels in men with testosterone on low-salt diet

Aldosterone

Time frame: At day 7 of week of testosterone administration on low-salt diet

Plasma Renin Activity (PRA) levels in women on estradiol on high-salt diet

Plasma Renin Activity (PRA)

Time frame: At days 6 and 7 of week of estradiol administration on high-salt diet

Plasma Renin Activity (PRA) levels in women on placebo on low-salt diet

Plasma Renin Activity (PRA)

Time frame: At day 7 of week of placebo administration on low-salt diet

Plasma Renin Activity (PRA) levels in women on placebo on high-salt diet

Plasma Renin Activity (PRA)

Time frame: At days 6 and 7 of week of placebo administration on high-salt diet

Plasma Renin Activity (PRA) levels in men on testosterone on low-salt diet

Time frame: At day 7 of week of testosterone administration on low-salt diet

Plasma Renin Activity (PRA) levels in men on testosterone on high-salt diet

Time frame: At days 6 and 7 of week of testosterone administration on high-salt diet

Plasma Renin Activity (PRA) levels in men on placebo on low-salt diet

Time frame: At day 7 of week of placebo administration on low-salt diet

Plasma Renin Activity (PRA) levels in men on placebo on high-salt diet

Time frame: At days 6 and 7 of week of placebo administration on high-salt diet

Aldosterone levels in men on testosterone on high-salt diet

Time frame: At days 6 and 7 of week of testosterone administration on high-salt diet

Aldosterone levels in men on placebo on high-salt diet

Time frame: At days 6 and 7 of week of placebo administration on high-salt diet

Aldosterone levels in men on placebo on low-salt diet

Time frame: At day 7 of week of placebo administration on low-salt diet

Aldosterone levels in women on estradiol on high-salt diet

Time frame: At days 6 and 7 of week of estradiol administration on high-salt diet

Aldosterone levels in women on estradiol on low-salt diet

Time frame: At day 7 of week of estradiol administration on low-salt diet

Aldosterone levels in women on placebo on high-salt diet

Time frame: At days 6 and 7 of week of placebo administration on high-salt diet

Aldosterone levels in women on placebo on low-salt diet

Time frame: At day 7 of week of placebo administration on low-salt diet

Urinary sodium concentration in women on estradiol on high-salt diet

Time frame: 0, 60, and 120 minute of saline infusion on morning of day 7 of estradiol administration on high-salt diet

Urinary sodium concentration in women on placebo on high-salt diet

Time frame: 0, 60, and 120 minute of saline infusion on morning of day 7 of placebo administration on high-salt diet

Urinary sodium concentration in men on testosterone on high-salt diet

Time frame: 0, 60, and 120 minute of saline infusion on morning of day 7 of testosterone administration on high-salt diet

Urinary sodium concentration in men on placebo on high-salt diet

Time frame: 0, 60, and 120 minute of saline infusion on morning of day 7 of placebo administration on high-salt diet