Impact of Endogenous E2 on SSI and GH Rebound

Systemic concentrations of testosterone (Te), estradiol (E2), GH, IGF-I and IGFBP-3 decline in healthy aging individuals (1-3). Sex-steroid deprivation accentuates GH and IGF-I depletion, since Te and E2 stimulate GH and IGF-I production in older adults, hypogonadal patients of all ages, and patients undergoing gender reassignment (1,2,4). Tamoxifen blocks the effect of Te, suggesting involvement of E2 in GH's stimulation in men (5). E2 also stimulates GH secretion in women, putatively via the nuclear estrogen receptor (ER-alpha) (1,2,6,7). Because Te, E2 and GH fall with menopause, and Te is converted to E2 by aromatization in the body (8-10), we postulate that diminished Te concentrations, Te→E2 concentrations and low E2 mediate low GH output in older women. What remains unknown is whether the low E2 levels in postmenopausal women retain GH-stimulating effects. To test this notion would require blocking: (i) aromatase-enzyme activity, which mediates E2 synthesis from Te, and/or (ii) estrogen receptor-alpha, which transduces most of E2's stimulation of the GH axis.

Inclusion:

• 60 healthy post-menopausal women (ages 55 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-lives);
• 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 function tests exceeding twice upper limit of normal, electrolyte abnormality, anemia;
• Drug or alcohol abuse, psychosis, depression, mania or severe anxiety;
• Systemic inflammatory disease;
• Endocrinopathy, other than primary thyroidal failure receiving replacement;
• Nightshift work or recent transmeridian travel (exceeding 3 time zones within 7 days of CRU admission);
• Acute weight change (loss or gain of > 2 kg in 6 weeks);
• Systemic illness
• Unwillingness to provide written informed consent.
• Allergy to anastrozole or fulvestrant (treatment drugs).
• History or suspicion of breast cancer.
• 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, congenital QT prolongation, and medications used to treat cardiac arrhythmias.
• Pre-menopausal status as determined by screening hormone measurements.