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From the Clinical Research Centers |
Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address correspondence and requests for reprints to: Janet E. Hall, M.D., Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
Increasing evidence suggests that aging is associated with dynamic
changes in the hypothalamic and pituitary components of the
reproductive axis that are independent of changes in gonadal hormone
secretion. This study was designed to determine the effect of age on
GnRH pulse frequency in women in the absence of gonadal feedback using
gonadotropin free 
-subunit (FAS) and LH as neuroendocrine markers of
endogenous GnRH secretion. All studies were performed in healthy,
euthyroid postmenopausal women (PMW) during daytime hours. The impact
of sampling interval and duration on assessment of pulse frequency in
PMW was first examined in 10 women with a mean age of 61.6 ± 8 yr
(mean ± SD), in whom blood was sampled every 5 min
for 12 h. Each 5-min series was then reduced to simulate a 10-min
series and then a 15-min series for pulse analysis, and the
effect of 8 h compared with 12 h of sampling was
determined. To define the changes in the frequency and amplitude of
pulsatile hormone secretion with aging, 11 younger (45–55 yr) and 11
older (70–80 yr) PMW were then studied over 8 h at a 5-min
sampling interval.
In the initial series, the mean interpulse intervals (IPIs) for FAS were 53.8 ± 3.6, 69.2 ± 3.9, and 87.6 ± 7.3 min at sampling intervals of 5, 10, and 15 min, respectively (P < 0.0005). The LH IPI also increased progressively with sampling intervals of 5, 10, and 15 min (54.4 ± 2.5, 70.4 ± 2.3, and 91.1 ± 4.4 min; P < 0.0001). At the 5-min sampling interval, the calculated number of pulses/24 h was not different between a 12-h series compared with an 8-h series for either FAS or LH. In the second series of studies, the older PMW had lower gonadotropin levels (LH, 86.5 ± 8.8 vs. 51.3 ± 7.7 IU/L, P < 0.01; FSH, 171.6 ± 16.9 vs. 108.2 ± 10.5 IU/L, P < 0.005; FAS, 1021.5 ± 147.4 vs. 425.6 ± 89.6 ng/L, P < 0.005, in younger and older PMW, respectively) despite no differences in estrone or estradiol levels. The older PMW also demonstrated a slower FAS pulse frequency compared with their younger counterparts, as reflected in an increased FAS IPI (52.6 ± 3.1 and 70.6 ± 5.9 min; P < 0.002). The difference in IPIs between younger and older PMW was not statistically significant for LH (65.4 ± 5.6 and 71.8 ± 6.6 min for younger and older PMW, respectively). FAS pulse amplitude was decreased in older PMW compared with younger PMW (431.7 ± 66.2 vs. 224.6 ± 81.9 ng/L; P < 0.01), whereas the decrease in LH pulse amplitude with age was of borderline statistical significance (23.2 ± 3.1 vs. 15.9 ± 2.1 IU/L; P = 0.09).
In conclusion: 1) the use of a 5-min sampling interval and measurement of FAS as the primary marker of GnRH pulse generator activity indicate that GnRH pulse frequency in younger PMW is faster than previously reported, but not increased over that seen in the late follicular phase and midcycle surge in women with intact ovarian function; and 2) the marked decrease in FAS pulse frequency with age provides evidence of age-related changes in the hypothalamic component of the reproductive axis that are independent of changes in gonadal function.
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