Estradiol-Receptor Blockade in Older Men and Women

Mayo Clinic

Status and phase: Completed; Phase 1

Conditions: Normal Healthy Volunteers

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

Study type: Interventional

Funder types: Other

Identifiers

NCT02271282

14-004704

Details and patient eligibility

About

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

Full description

Systemic concentrations of Te, E2, GH, IGF-I and insulin growth factor binding protein 3 (IGFBP-3) decline in healthy aging men and women. 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. The estrogen-receptor antagonist, tamoxifen, blocks this effect of Te, suggesting involvement of E2 in GH's stimulation at least in young men. E2 alone stimulates GH secretion in young and older women. Because Te is converted to E2 by aromatization in the body, we postulate that E2 is the active moiety in both men and women. Moreover, we hypothesize that the decline of E2 in older men and women contributes to the fall in GH output. These basic concepts will be tested here.

Enrollment: 40 patients

Sex: All

Ages: 50 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion:

1. 40 healthy women and men (ages 50 to 80 y); women will be post-menopausal (clinically defined by E2 < 50 pg/mL, FSH > 30Iu/L)
2. BMI 18-35 kg/m2
3. community dwelling; and voluntarily consenting

Exclusion:

1. recent use of psychotropic or neuroactive drugs (within five biological half-live);
2. obesity (outside weight range above);
3. 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)
4. drug or alcohol abuse, psychosis, depression, mania or severe anxiety;
5. acute or chronic organ-system disease, including renal failure (creatinine > 1.5 mg/dL)
6. endocrinopathy, other than primary thyroidal failure receiving replacement
7. nightshift work or recent transmeridian travel (exceeding 3 time zones within 7 days of admission),
8. acute weight change (loss or gain of > 2 kg in 6 weeks);
9. allergy to toremifene
10. unwillingness to provide written informed consent.
11. PSA > 4.0 ng/mL in men
12. History or suspicion of prostatic disease (elevated PSA, indeterminate nodule or mass, obstructive uropathy, or breast cancer),
13. Other carcinoma (excluding localized basal cell carcinoma removed or surgically treated with no recurrence).
14. History of thrombotic arterial disease (stroke, TIA, MI, angina) or deep vein thrombophlebitis.
15. History of CHF, cardiac arrhythmias, congenital QT prolongation, and medications used to treat cardiac arrhythmias or other strong CYP3A4 inhibitors.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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40 participants in 2 patient groups

Oral Toremifene/Oral Placebo

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Toremifene

Drug: GHRH/Ghrelin combined Injection

Oral Placebo/Oral Toremifene

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Toremifene

Drug: GHRH/Ghrelin combined Injection