Impact of Estradiol Addback

Impact of Estradiol Addback on Somatostatin Rebound in Older Men

Repletion of testosterone (T) in older men drives Growth Hormone secretion after its aromatization to estradiol (E2) by potentiating endogenous GH drive.

Study Overview

• Status: Completed
• Conditions: Normal Healthy Volunteers
• Intervention / Treatment: Drug: Degarelix; Drug: Anastrozole; Drug: Testosterone; Drug: Estrogen patch

Detailed Description

Systemic concentrations of Te, E2, GH, Insulin-like Growth Factor-I and IGFBP-3 decline in healthy aging men. Relative sex-steroid deprivation accentuates GH and IGF-I depletion, since Te stimulates GH and IGF-I production in older men, hypogonadal males of all ages, and patients undergoing (genotypic female-to-male) gender reassignment. Tamoxifen blocks this effect of Te, suggesting involvement of E2 in GH's stimulation in men. E2 per se stimulates GH secretion in women. Because Te is converted to E2 by aromatization in the body, we postulate that E2 is the active moiety in men also. Moreover, we hypothesize that the decline of E2 in older men contributes to the fall in GH output. This has never been tested. From a clinical vantage, understanding the mechanistic basis of Te's drive of the somatotropic axis is especially relevant in boys with pubertal failure, adults with primary hypogonadism and men with aging-related hypoandrogenemia. In relation to aging in the male, testosterone and E2 bioavailabilities fall by 35-50% in the eighth compared with third decade of life. From a medical perspective, aging is accompanied by progressive osteopenia, sarcopenia and intra-abdominal obesity. These adverse outcomes are remediable by short-term replacement with Te and/or recombinant GH, thus linking GH/Te/E2 availability with key body-compositional features.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion:

• 60 healthy men (ages 60 to 80 y);
• BMI 18-30 kg/m2
• Community dwelling; and voluntarily consenting

Exclusion:

• Recent use of psychotropic or neuroactive drugs (within five biological half-live);
• Obesity (outside weight range above);
• Laboratory test results not deemed physician acceptable, cholesterol >250, triglycerides > 300, BUN >30 or creatinine > 1.5 mg/dL, liver functions tests twice upper limit of normal, electrolyte abnormality, anemia; hemoglobin <12.0 gm/dL
• Drug or alcohol abuse, psychosis, depression, mania or severe anxiety;
• Acute or chronic organ-system disease;
• Endocrinopathy, other than primary thyroidal failure receiving replacement; untreated osteoporosis
• 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 peanut oil (used in some injectable Te preparations)
• Unwillingness to provide written informed consent.
• PSA > 4.0 ng/mL
• History or suspicion of prostatic disease (elevated PSA, indeterminate nodule or mass, obstructive uropathy.
• History of 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, congential QT prolongation, and medications used to treat cardiac arrhythmias
• Gynecomastia > 2 cm, untreated
• Untreated gallbladder disease
• History of smoking greater than one ppd.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Degarelix/Te/placebo/ placebo; Degarelix 80 mg (given as two s.c. injections of 60 mg) once [called day 1]; Te enanthate 100 mg i.m. given on day 1, 8 and 15; Oral placebo once daily x 22 days; and no patch beginning on day 1 and changed every 3 days through day 22.	Drug: Degarelix; Drug: Testosterone
EXPERIMENTAL: degarelix/Te/anastrozole/ placebo; degarelix 80 mg (given as two s.c. injections of 60 mg) once [called day 1]; Te enanthate 100 mg i.m. given on day 1, 8 and 15; Oral anastrozole 2.0 mg once daily x 22 days; and no patch beginning on day 1 and changed every 3 days through day 22.	Drug: Degarelix; Drug: Anastrozole; Drug: Testosterone
EXPERIMENTAL: degarelix/Te/ anastrozole/E2 patch; degarelix 80 mg (given as two s.c. injections of 60 mg) once [called day 1]; Te enanthate 100 mg i.m. given on day 1, 8 and 15; Oral anastrozole 2.0 mg once daily x 22 days; and an E2 patch calibrated to deliver 0.05 mg/day E2 beginning on day 1 and changed every 3 days through day 22.	Drug: Degarelix; Drug: Anastrozole; Drug: Testosterone; Drug: Estrogen patch
EXPERIMENTAL: degarelix/ placebo/placebo/no patch; degarelix 80 mg (given as two s.c. injections of 60 mg) once [called day 1]; placebo i.m. given on day 1, 8 and 15; Oral placebo once daily x 22 days; and no patch beginning on day 1 and changed every 3 days through day 22.	Drug: Degarelix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BioStatistical Analysis	The primary analytical outcome is the summed mass of GH secreted in pulses over the 15 h of overnight blood sampling. The outcome measure is relevant, since sex-steroid hormones and regulatory peptides uniquely control GH secretory-burst mass.	Subjects will undergo 15-h overnight (2200 - 1300 h) fasting, 10-min blood sampling

Collaborators and Investigators

• Sponsor: Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (ACTUAL): September 30, 2016
• Study Completion (ACTUAL): December 30, 2018

Study Registration Dates

• First Submitted: May 22, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (ESTIMATE): May 27, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Androgens; Testosterone; Anastrozole; Estrogens
• Other Study ID Numbers: 13-000047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO