Progesterone Amplifies Estrogen-stimulated Growth Hormone Secretion in Older Women

The systemic availability and orderly secretion patterns of GH and sex steroids decline in
healthy aging men and women. The combined changes have substantial clinical implications to
aging-related physical frailty, diminished aerobic capacity, sarcopenia, osteopenia, visceral
adiposity, glucose intolerance, and reduced psychosocial wellbeing. Whereas androgen is
considered the main trophic (anabolic) sex steroid, recent data demonstrate that certain
tissues respond principally to GH and testosterone-derived estradiol, Estrogen (E2) (e.g.
bone, brain, liver and pituitary). In principle, frailty may thus be associated with dual GH
and sex-steroid deficiencies. Additionally, young, but not older healthy women secrete
significant amounts of progesterone for approximately 14 days during the luteal phase of
every menstrual cycle. When GH levels rise nearly two fold, the investigators hypothesize
that progesterone potentiates the GH response to E2. This hypothesis arises from scattered
indirect studies often using synthetic progestins with partial androgen agonism, instead of
progesterone per se.

Because there is no basis for estimating statistical power for this novel paradigm, 40 women,
10 each in 4 groups, will be studied. The pilot data will be used to calculate statistical
power for a definitive R01-based investigation of gender-specific distinctions in
estrogen-regulated pituitary-hormone secretion.

Inclusion Criteria:

- women ages 50 to 80

- postmenopausal as defined by: any combination of the following

- Hormonally postmenopausal for 1 year

- Lh greater than 15 IU/L, FSH greater than 30 IU/L

- Total hysterectomy with oophorectomy greater than one year

- Hysterectomy with ovaries preserved with hormone levels: Lh > 15 IU/L, FSH > 30
IU/L

- Following laboratory results with normal range, unless PI approves out of range
values.

- BMI 18 to 35

Exclusion Criteria:

- structural hypothalamo-pituitary-gonadal disease

- endocrinopathy (diseases involving the following organs pituitary, thyroid, adrenals,
ovaries, testes and pancreas), other than primary thyroid failure receiving
replacement

- recent (within 2 weeks) estrogen, progestin, anabolic steroid or glucocorticoid use

- clinically significant ECG abnormality as determined by study team physicians

- obstructive uropathy

- history of a stroke

- history of MI or angina

- acute or chronic systemic disease

- recent transmeridian travel (traversing more than 3 time zones within 7 days of
admission)

- current night shift work

- concurrent use of neuropsychiatric medications

- alcohol or drug abuse, current and within 2 years

- history of depression, psychosis, or mania

- weight gain or loss (2 kg or more in 3 weeks)

- BMI > 35 kg/m2

- anemia, hemoglobin less than 12.5 g/dl

- abnormal hepatorenal function, creatinine outside normal range, ALT greater than two
times normal range

- biochemical and chemistry lab results out of physician acceptable range

- history of deep-vein thrombophlebitis

- history of Congestive Heart Failure, cardiac arrhythmias, and medications used to
treat cardiac arrhythmias

- known allergy to estradiol valerate, castor oil or sesame oil

- history of smoking within the last 2 years

- untreated gall bladder disease

- lack of voluntary, written informed consent

- history of carcinoma excluding localized basal cell or squamous cell, including women
with known, suspected or history of breast cancer

- not clinically postmenopausal

- women with allergies to nuts will not be enrolled in the study.