Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women

OBJECTIVE: Our aim was to determine the effect of aging on the hypothalamic-pituitary-gonadal axis function. STUDY DESIGN: We studied 9 women aged 25 to 40 years with well-defined idiopathic premature ovarian failure and compared them with 8 women aged 51 to 70 years who had age- appropriate menopause. All women underwent 24 hours of frequent blood sampling every 10 minutes before and after replacement with transdermal estradiol targeted to achieve serum concentrations of approximately 100 pg/ml. RESULTS: In the absence of estrogen exposure, women with premature ovarian failure demonstrated a greater 24-hour mean luteinizing hormone concentration compared with that in the older women with age-appropriate menopause (32.3 ± 4.3 mlU/ml vs 19.2 ± 2.4 mlU/ml, p = 0.0001). Despite the lesser luteinizing hormone serum levels in the older group, the luteinizing hormone pulse frequency per 24 hours was similar (22.1 ± 3.0 pulses per 24 hours in prematurely menopausal women vs 21.9 ± 2.5 pulses per 24 hours in the older postmenopausal women, p = 0.94). When exposed to estrogen, mean luteinizing hormone concentrations decreased to 11.6 ± 2.7 mlU/ml in prematurely menopausal women versus 4.4 ± 1.0 mlU/ml in older postmenopausal women, p = 0.017. Both groups had suppressed mean luteinizing hormone secretion compared with their paired, non-estradiol-exposed studies, p = 0.0001. Frequency of luteinizing hormone pulsations was reduced to 16.5 ± 3.5 pulses per 24 hours in prematurely menopausal women exposed to estradiol (p < 0.0058, compared with non-estradiol-exposed women). Further reduction was observed in older postmenopausal women (11.5 ± 1.1 pulses per 24 hours, p = 0.0001, compared with nonestradiol exposure, and p = 0.0125, vs prematurely menopausal, estradiol-exposed women). Pulse amplitude was suppressed in both prematurely menopausal women (5.6 ± 0.5 mlU/ml to 2.3 ± 0.5 mlU/ml, p = 0.0001) and older postmenopausal women (3.6 ± 0.4 mlU/ml to 2.3 ± 0.6 mlU/ml p = 0.04) in the presence of estradiol. Although luteinizing hormone pulse amplitudes were greater in the women with premature menopause in the absence of estradiol (p = 0.0028) compared with those in older postmenopausal women, pulse amplitudes became similar in the presence of estradiol. Parallel changes in mean follicle-stimulating hormone were observed. Women with premature ovarian failure had a mean follicle- stimulating hormone level of 71.1 ± 9.4 mlU/ml that was suppressed to 18.0 ± 4.1 mlU/ml after estradiol exposure (p = 0.0001); values in older postmenopausal women were 45.9 ± 6.0 and 10.3 ± 2.0, respectively (p = 0.0001). Although the women with premature ovarian failure secreted more follicle-stimulating hormone in the absence and presence of estradiol, only the former situation was statistically significant (p = 0.0008 and p = 0.23, respectively). CONCLUSIONS: These data suggest that there is an age-related decrease in gonadotropin secretion that may be hypothalamic or pituitary in origin. There is less luteinizing hormone secreted in women older than age 50. There is greater suppression of luteinizing hormone and follicle- stimulating hormone secretion by estradiol in aged women. Thus these data indicate that postmenopausal hormone changes involve central hypothalamic- pituitary alterations, as well as ovarian changes.