Estradiol-Receptor Blockade in Older Men and Women

NCT02271282 | Completed Phase 1

• 1 other identifier: 14-004704
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Repletion of testosterone (Te) in older men drives GH secretion after its aromatization to estradiol (E2), which acts via the estrogen receptor (ER). Conversely, we postulate that estrogen deprivation in postmenopausal women attenuates growth hormone (GH) secretion and insulin-like growth factor-1 (IGF-I) production, thus favoring development of metabolic syndrome in men treated with toremifene, a new estrogen antagonist used adjunctively in prostatic cancer

Conditions

Normal Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• Summed mass of growth hormone over 10 hours

  Subjects will be given toremifene/placebo on Day 1 to take for 10 days. For one night between Days 8-12, from date of randomization, subjects will undergo a 12-h overnight (2200-1000h) fasting, every 10-min blood sampling. The primary analytical outcome is the summed mass of growth hormone (ie. mean/min/max) secreted in pulses over the first 10h of overnight blood samples. Pulsatile growth hormone is relevant, since sex-steroid hormones and regulatory peptides uniquely control growth hormone secretory-burst mass

  Participants will be followed for an average of 2 months with growth hormone measurements occuring 10 days after initiating study medication administration.

Secondary Outcomes (1)

• Growth hormone responsiveness over last 2h

  Participants will be followed for an average of 2 months with growth hormone measurements occuring 10 days after initiating study medication administration

Study Arms (2)

Oral Toremifene/Oral Placebo

EXPERIMENTAL

Oral toremifene will be given once on Day 1 and continue daily x10 days. A single combined IV injection of growth hormone releasing hormone (GHRH)/ghrelin (both doses 0.3mcg/kg) will be given on the overnight visit. After at least 3 weeks, subjects will return to receive oral placebo on Day 1 and continue daily x10 days. A single combined IV injection of GHRH/ghrelin (both doses 0.3mcg/kg) will be given on the overnight visit.

Drug: Toremifene; Drug: Placebo; Drug: GHRH/Ghrelin combined Injection

Oral Placebo/Oral Toremifene

EXPERIMENTAL

Oral placebo will be given once on Day 1 and continue daily x10 days. A single combined IV injection of GHRH/ghrelin (both doses 0.3mcg/kg) will be given on the overnight visit. After at least 3 weeks, subjects will return to receive oral toremifene on Day 1 and continue daily x10 days. A single combined IV injection of GHRH/ghrelin (both doses 0.3mcg/kg) will be given on the overnight visit.

Drug: Toremifene; Drug: Placebo; Drug: GHRH/Ghrelin combined Injection

Interventions

Toremifene DRUG

Oral Placebo/Oral Toremifene; Oral Toremifene/Oral Placebo

Placebo DRUG

Oral Placebo/Oral Toremifene; Oral Toremifene/Oral Placebo

GHRH/Ghrelin combined Injection DRUG

Oral Placebo/Oral Toremifene; Oral Toremifene/Oral Placebo

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• healthy women and men (ages 50 to 80 y); women will be post-menopausal (clinically defined by E2 \< 50 pg/mL, FSH \> 30Iu/L)
• BMI 18-35 kg/m2
• community dwelling; and voluntarily consenting

You may not qualify if:

• recent use of psychotropic or neuroactive drugs (within five biological half-live);
• obesity (outside weight range above);
• Laboratory test results not deemed physician acceptable, viz potassium \<3.5 mEq/L, magnesium \<1.5 mEq/L, triglycerides \> 300, BUN \>30 or creatinine \> 1.5 mg/dL, liver functions tests twice upper limit of normal, anemia (hemoglobin must meet Blood Bank requirements - Hgb ≥ 12.5 g/dL)
• drug or alcohol abuse, psychosis, depression, mania or severe anxiety;
• acute or chronic organ-system disease, including renal failure (creatinine \> 1.5 mg/dL)
• endocrinopathy, other than primary thyroidal failure receiving replacement
• nightshift work or recent transmeridian travel (exceeding 3 time zones within 7 days of admission),
• acute weight change (loss or gain of \> 2 kg in 6 weeks);
• allergy to toremifene
• unwillingness to provide written informed consent.
• PSA \> 4.0 ng/mL in men
• History or suspicion of prostatic disease (elevated PSA, indeterminate nodule or mass, obstructive uropathy, or breast cancer),
• Other carcinoma (excluding localized basal cell carcinoma removed or surgically treated with no recurrence).
• History of thrombotic arterial disease (stroke, TIA, MI, angina) or deep vein thrombophlebitis.
• History of CHF, cardiac arrhythmias, congenital QT prolongation, and medications used to treat cardiac arrhythmias or other strong CYP3A4 inhibitors.

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Interventions

Toremifene

Intervention Hierarchy (Ancestors)

Tamoxifen; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Johannes Veldhuis, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 17, 2014
• First Posted: October 22, 2014
• Study Start: December 1, 2014
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: September 14, 2016

Record last verified: 2016-09

Locations

US (1)