Age-related changes in pulsatile luteinizing hormone release precede the transition to estrous acyclicity and depend upon estrous cycle history

Aging of the female reproductive system in rats is marked by discrete stages in the disappearance of regular estrous cyclicity. We determined at which point in the transition to acyclicity changes in the LH pulse generator could be detected by comparing pulsatile LH release in ovariectomized young rats to three groups of middle-aged rats that were chronologically matched, yet exhibited different stages of reproductive senescence. Since changes in LH pulse amplitudes can result from hypothalamic and/or pituitary factors, we also assessed pituitary responsiveness to exogenous GnRH. Young rats (2-3.5 months) that had shown regular 4- or 5-day estrous cycles and middle-aged rats (9.5-12 months) that exhibited either regular cycles, irregular cycles, or persistent estrus were bilaterally ovariectomized and used 4 weeks later. Rats were implanted with right atrial cannulae and were bled 2 days later at 5-min intervals for 3 h. To test pituitary responsiveness to GnRH, rats were bled at 10-min intervals for 3 h and received GnRH (25 ng/100 g BW, iv) after the first and second hours. The mean inter-peak interval increased in middle-aged irregularly cycling and persistent estrous rats. The frequency distribution of inter-peak intervals was already significantly different in middle-aged regularly cycling compared to that in young regularly cycling rats. Middle-aged rats displayed fewer short inter-peak intervals and a greater frequency of longer intervals between LH pulses. LH pulse duration increased gradually in parallel with increasing reproductive senescence. Pulse amplitude decreased in all groups of middle-aged rats regardless of their prior reproductive status. Mean LH concentrations were significantly lower in middle-aged than in young regularly cycling rats, and a further significant decline was detected in the middle-aged irregularly cycling and persistent estrous groups. Middle-aged regularly and irregularly cycling rats showed decreased pituitary responsiveness to GnRH compared to young regularly cycling rats, whereas middle-aged persistent estrous rats displayed an intermediate level of pituitary responsiveness to GnRH. These data are the first evidence of changing pulse generator function in middle-aged rats that had previously exhibited no change in the regularity of their estrous cycles. We suggest that such changes may play a role in the age-related transition to acyclicity.