The Effects of Aging and Estrogen on the Pituitary

Although it is clear that loss of ovarian function plays a major role in the menopause in
women, there is evidence from animal studies that primary age-related hypothalamic and
pituitary changes may also contribute to reproductive aging. Complete cessation of ovarian
function results in the loss of negative feedback of ovarian steroids and inhibin on the
hypothalamic and pituitary components of the reproductive axis. An increase in serum levels
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) occurs in postmenopausal
women with removal of negative ovarian feedback. However, levels of LH and FSH after
menopause decline steadily as a function of age in most though not all studies.

The current study is designed to determine: 1) whether negative feedback on LH and FSH
occurs at the pituitary; and 2) whether there is an effect of aging on estrogen negative
feedback at the pituitary. Younger and older postmenopausal women underwent a baseline study
and a second identical study after a month of low dose estrogen replacement. The study
protocol consisted of the following: 1) administration of a GnRH antagonist (Nal-Glu at 150
mg/kg that blocks endogenous GnRH so that the dose and interval of pituitary exposure to
GnRH are precisely controlled; 2) beginning 8 hours following GnRH antagonist administration
(at a time when LH had reached its nadir following GnRH receptor blockade), administration
of 4 graded doses of GnRH (25, 75, 250 and 750 ng/kg every 2 hours with 2 hours of blood
draws following each dose). Blood was sampled every 30 min for 4 hours before antagonist
administration, every 30 min for the following 7 hours and then every 10 min until the
completion of the study.

Inclusion Criteria:

- 45-55 or 70-80 years old

- History of natural menopause defined by the absence of menses for at least 12 months
(or history of surgical menopause defined as bilateral oophorectomy) and a FSH level
>26 IU/L

- On no hormonal medication or herbal supplements and/or over the counter menopause
therapy for a minimum of 2 months prior to study

- Normal thyroid stimulating hormone, prolactin, factor V Leiden, and complete blood
count - Normal blood urea nitrogen and creatinine (< 2 times the upper limit of
normal)

- basal metabolic index ≤ 30

- Non-smokers or smoke less than 10 cigarettes/day

Exclusion Criteria:

- Absolute contraindications to the use of physiologic replacement doses of estrogen,
including a negative screening mammogram within the past 24 months

- History of coronary artery disease

- On medications thought to act centrally on the GnRH pulse generator

- Past history of hypersensitivity or allergy to narcotics, vancomycin, muscle
relaxants, aspirin, and/or anaphylactic reaction(s) to other drugs

- Prior history of breast cancer and/or blood clots