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

NCT01763541 | Withdrawn Early Phase 1 DMC

• 1 other identifier: 2012P002337
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertension

Keywords

Natriuretic Peptides

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (20)

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

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

• Aldosterone levels in men with testosterone on low-salt diet

  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

  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

  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

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

Study Arms (2)

Testosterone

OTHER

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; Drug: Anastrozole

Estradiol

OTHER

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

Interventions

leuprolide acetate DRUG

Given to both arms to induce hypogonadism

Also known as: Lupron Depot 3.75 mg and 7.5 mg

Estradiol; Testosterone

Anastrozole DRUG

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

Also known as: Arimidex

Testosterone

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Hypertension

Interventions

Leuprolide; Anastrozole

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Karen Miller, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Neuroendocrine Research Program in Women's Health

Study Record Dates

• First Submitted: November 13, 2012
• First Posted: January 9, 2013
• Study Start: June 1, 2014
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: October 19, 2017

Record last verified: 2017-10

Locations

US (1)