Impact of Estradiol Addback

Mayo Clinic

Status and phase: Completed; Phase 1

Conditions: Normal Healthy Volunteers

Treatments: Drug: Estrogen patch; Drug: Anastrozole; Drug: Testosterone; Drug: Degarelix

Study type: Interventional

Funder types: Other

Identifiers

NCT01862835

13-000047

Details and patient eligibility

About

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

Full 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.

Enrollment: 43 patients

Sex: Male

Ages: 60 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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43 participants in 4 patient groups

Degarelix/Te/placebo/ placebo

Experimental group

Description:

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.

Treatment:

Drug: Degarelix

Drug: Testosterone

degarelix/Te/anastrozole/ placebo

Experimental group

Description:

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.

Treatment:

Drug: Degarelix

Drug: Testosterone

Drug: Anastrozole

degarelix/Te/ anastrozole/E2 patch

Experimental group

Description:

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.

Treatment:

Drug: Degarelix

Drug: Testosterone

Drug: Anastrozole

Drug: Estrogen patch

degarelix/ placebo/placebo/no patch

Experimental group

Description:

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.

Treatment:

Drug: Degarelix