Study of the Effect of Testosterone and Estradiol on NP Responses to Acute and Chronic Salt Loading - Full Text View

Purpose

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.

Condition	Intervention	Phase
Hypertension	Drug: leuprolide acetate Drug: Anastrozole	Phase 0

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Basic Science
Official Title:	Gonadal Steroid Regulation of the Natriuretic Peptide System

Resource links provided by NLM:

MedlinePlus related topics: Dietary Sodium High Blood Pressure

Drug Information available for: Estradiol Testosterone propionate Methyltestosterone Testosterone cypionate Testosterone Estradiol cypionate Testosterone enanthate Estradiol valerate Estradiol acetate Estradiol hemihydrate Leuprolide acetate Anastrozole

U.S. FDA Resources

Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:

NP levels in men with testosterone patch and low-salt diet [ Time Frame: At day 7 of week of testosterone administration with low-salt diet ] [ Designated as safety issue: No ]
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)
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 ] [ Designated as safety issue: No ]
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)
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 ] [ Designated as safety issue: No ]
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)
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 ] [ Designated as safety issue: No ]
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)
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 ] [ Designated as safety issue: No ]
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)
NP levels in men with placebo patch and high-salt diet [ Time Frame: At day 7 of week of placebo administration with high-salt diet ] [ Designated as safety issue: No ]
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)
NP levels in women with placebo patch and low-salt diet [ Time Frame: At day 7 of week of placebo administration with low-salt diet ] [ Designated as safety issue: No ]
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)
NP levels in women with placebo patch and high-salt diet [ Time Frame: At day 7 of week of placebo administration with high-salt diet ] [ Designated as safety issue: No ]
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)

Secondary Outcome Measures:

Plasma Renin Activity (PRA) levels in women on estradiol on low-salt diet [ Time Frame: At day 7 of week of estradiol administration on low-salt diet ] [ Designated as safety issue: No ]
Plasma Renin Activity (PRA)
Aldosterone levels in men with testosterone on low-salt diet [ Time Frame: At day 7 of week of testosterone administration on low-salt diet ] [ Designated as safety issue: No ]
Aldosterone
Plasma Renin Activity (PRA) 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 ] [ Designated as safety issue: No ]
Plasma Renin Activity (PRA)
Plasma Renin Activity (PRA) levels in women on placebo on low-salt diet [ Time Frame: At day 7 of week of placebo administration on low-salt diet ] [ Designated as safety issue: No ]
Plasma Renin Activity (PRA)
Plasma Renin Activity (PRA) 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 ] [ Designated as safety issue: No ]
Plasma Renin Activity (PRA)
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Aldosterone levels in men on placebo on low-salt diet [ Time Frame: At day 7 of week of placebo administration on low-salt diet ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Aldosterone levels in women on estradiol on low-salt diet [ Time Frame: At day 7 of week of estradiol administration on low-salt diet ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Aldosterone levels in women on placebo on low-salt diet [ Time Frame: At day 7 of week of placebo administration on low-salt diet ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]

Estimated Enrollment:	250
Study Start Date:	January 2013
Estimated Study Completion Date:	January 2018
Estimated Primary Completion Date:	June 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: Lupron Depot 3.75 mg and 7.5 mg Drug: Anastrozole Given to men to prevent conversion of administered testosterone to estradiol. Other Name: Arimidex
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 Name: Lupron Depot 3.75 mg and 7.5 mg

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01763541

Contacts

Contact: Anu V Gerweck, NP	617-724-1837	avgerweck@partners.org
Contact: Melissa G Landa, BA	617-724-0785	mlanda3@partners.org

Locations

United States, Massachusetts
Massachusetts General Hospital	Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Anu V Gerweck, NP 617-724-1837 avgerweck@partners.org
Contact: Melissa G Landa, BA 617-724-0785 mlanda3@partners.org
Principal Investigator: Karen Miller, MD

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

Principal Investigator:

Karen Miller, MD

Massachusetts General Hospital

More Information

No publications provided

Responsible Party:	Karen Klahr Miller, MD, Director, Neuroendocrine Research Program in Women's Health, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT01763541 History of Changes
Other Study ID Numbers:	2012P002337
Study First Received:	November 13, 2012
Last Updated:	January 4, 2013
Health Authority:	United States: Data and Safety Monitoring Board United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:

Natriuretic Peptides

Additional relevant MeSH terms:

Hypertension
Vascular Diseases
Cardiovascular Diseases
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Methyltestosterone
Estradiol
Polyestradiol phosphate
Leuprolide
Anastrozole
Estradiol valerate
Estradiol 3-benzoate
Estradiol 17 beta-cypionate

Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Anabolic Agents
Estrogens
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Fertility Agents, Female
Fertility Agents

ClinicalTrials.gov processed this record on May 19, 2013