Decrease in gonadotropin-releasing hormone (GnRH) pulse frequency with aging in postmenopausal women

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 des igned to-determine the effect of age on GnRH pulse frequency in women in th e absence of gonadal feedback using gonadotropin free alpha-subunit (FAS) a nd LH as neuroendocrine markers of endogenous GnRH secretion. All studies w ere performed in healthy, euthyroid postmenopausal women (PMW) during dayti me hours. The impact of sampling interval and duration on assessment of pul se 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. Eac h 5-min series was then reduced to simulate a 10-min series and then a 15-m in series for pulse analysis, and the effect of 8 h compared with 12 h of s ampling was determined. To define the changes in the frequency and amplitud e of pulsatile hormone secretion with aging, 11 younger (45-55 yr) and 11 o lder (70-80 yr) PMW were then studied over 8 h at a 6-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 progre ssively 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, t he 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. 5 1.3 +/- 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 young er and older PMW, respectively) despite no differences in estrone or estrad iol levels. The older PMW also demonstrated a slower FAS pulse frequency co mpared with their younger counterparts, as reflected in an increased FAS IP I (52.6 +/- 3.1 and 70.6 +/- 5.9 min; P < 0.002). The difference in IPIs be tween 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 pu lse 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 F AS as the primary marker of GnRH pulse generator activity indicate that GnR H pulse frequency in younger PMW is faster than previously reported, but no t 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 pu lse frequency with age provides evidence of age-related changes in the hypo thalamic component of the reproductive axis that are independent of changes in gonadal function.