Clinical trial NCT02271282: Estradiol-Receptor Blockade in Older Men and Women
Official title: Pilot Study of Estradiol-Receptor Blockade in Older Men and Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Normal Healthy Volunteers
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2014-10-22
Enrollment: 40
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Summed mass of growth hormone over 10 hours
timeFrame: Participants will be followed for an average of 2 months with growth hormone measurements occuring 10 days after initiating study medication administration.
Secondary outcomes:
measure: Growth hormone responsiveness over last 2h
timeFrame: Participants will be followed for an average of 2 months with growth hormone measurements occuring 10 days after initiating study medication administration
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Johannes Veldhuis, MD
role: PRINCIPAL_INVESTIGATOR
References: