Estradiol-Receptor Blockade in Older Men and Women
Estradiol-Receptor Blockade in Older Men and Women
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
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.
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.