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

Gonadal Steroid Regulation of the Natriuretic Peptide System

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 Overview

• Status: Withdrawn
• Conditions: Hypertension
• Intervention / Treatment: Drug: leuprolide acetate; Drug: Anastrozole

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Testosterone; To determine the effect of testosterone on the NP responses to acute and chronic salt loading. One testosterone patch (Androderm 5 mg) applied to each male subject each day for 14 days. Intervention: Leuprolide acetate and anastrozole	Drug: leuprolide acetate; Given to both arms to induce hypogonadism; Other Names: Lupron Depot 3.75 mg and 7.5 mg; Drug: Anastrozole; Given to men to prevent conversion of administered testosterone to estradiol.; Other Names: Arimidex
Other: Estradiol; To determine the effect of estradiol on the NP responses to acute and chronic salt loading. Two estradiol patches (Vivelle Dot 0.1mg) will be applied to each female subject twice-a-week for 2 weeks. Intervention: leuprolide acetate	Drug: leuprolide acetate; Given to both arms to induce hypogonadism; Other Names: Lupron Depot 3.75 mg and 7.5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	At day 7 of week of testosterone administration with low-salt diet
NP levels in men with testosterone patch and high-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)	At day 7 of week of testosterone administration with high-salt diet
NP levels in women with estradiol 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)	At day 7 of week of estradiol administration with low-salt diet
NP levels in women with estradiol patch and high-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)	At day 7 of week of estradiol administration with high-salt diet
NP levels in men with placebo 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)	At day 7 of week of placebo administration with low-salt diet
NP levels in men with placebo patch and high-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)	At day 7 of week of placebo administration with high-salt diet
NP levels in women with placebo 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)	At day 7 of week of placebo administration with low-salt diet
NP levels in women with placebo patch and high-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)	At day 7 of week of placebo administration with high-salt diet

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Renin Activity (PRA) levels in women on estradiol on low-salt diet	Plasma Renin Activity (PRA)	At day 7 of week of estradiol administration on low-salt diet
Aldosterone levels in men with testosterone on low-salt diet	Aldosterone	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)	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)	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)	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		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		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		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		At days 6 and 7 of week of placebo administration on high-salt diet
Aldosterone levels in men on testosterone on high-salt diet		At days 6 and 7 of week of testosterone administration on high-salt diet
Aldosterone levels in men on placebo on high-salt diet		At days 6 and 7 of week of placebo administration on high-salt diet
Aldosterone levels in men on placebo on low-salt diet		At day 7 of week of placebo administration on low-salt diet
Aldosterone levels in women on estradiol on high-salt diet		At days 6 and 7 of week of estradiol administration on high-salt diet
Aldosterone levels in women on estradiol on low-salt diet		At day 7 of week of estradiol administration on low-salt diet
Aldosterone levels in women on placebo on high-salt diet		At days 6 and 7 of week of placebo administration on high-salt diet
Aldosterone levels in women on placebo on low-salt diet		At day 7 of week of placebo administration on low-salt diet
Urinary sodium concentration in women on estradiol on high-salt diet		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		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		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		0, 60, and 120 minute of saline infusion on morning of day 7 of placebo administration on high-salt diet

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Karen Miller, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: November 13, 2012
• First Submitted That Met QC Criteria: January 4, 2013
• First Posted (Estimate): January 9, 2013

Study Record Updates

• Last Update Posted (Actual): October 19, 2017
• Last Update Submitted That Met QC Criteria: October 17, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Natriuretic Peptides
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide; Anastrozole
• Other Study ID Numbers: 2012P002337