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1. Comparison of the reproductive cycles in rodents and humans
In the rodent, the estrous cycle is short and the pre-ovulatory LH surge is brief, timed by the
light cycle and dependent on the brain (Simpkins, 2000; Goldman et al., 2007). The brain plays a
deterministic role in the LH surge in rodents. Every afternoon during a critical period, a brain signal
for LH secretion occurs that is driven by the increased activity of noradrenergic neurons (Wise et
al., 1997). As such, selective blockage of this increased activity in noradrenergic neurons during this
brief period blocks the pre-ovulatory LH surge (Ordog et al., 1998).
The human menstrual cycle is long, exhibits protracted pre-ovulatory LH surge and ends with
menses due to the death of the corpus luteum and the resulting decline in estrogens and progestins.
The driving force for the pre-ovulatory LH surge in women is ovarian estrogen secretion (Ordog et
al., 1998; Simpkins, 2000). The role of brain regulation of GnRH is that the pre-ovulatory LH surge
is permissive in women and other primates. Indeed, the entire menstrual cycle can be recapitulated in
Rhesus monkeys in which the source of GnRH has been destroyed, by exogenous administration of
pulses of GnRH (Pohl & Knobil, 1982; Ordog et al., 1998). In contrast to the observations in rodents,
inhibitors of NE neurotransmission do not affect the pre-ovulatory LH surge in women or other
primates (Knobil, 1974; Weiss et al., 1977).
2. Comparison of reproductive ageing in rodents and humans
Reproductive ageing in rodents and women is distinctively different. In female Sprague-Dawley
rats, reproductive senescence is a result of a breakdown of the brain regulation of the LH surge,
while the ovaries are functional very late into life. The decline in reproductive function is primarily a
result of the inability of brain NE neurons to transmit the estrogen signal to GnRH neurons (Wise et
al., 1997). The inability to stimulate a pre-ovulatory LH surge results in the maintenance of ovarian
follicles and the persistent secretion of estrogens. Sequentially, the increased secretion of estrogens
causes a persistent state of hyperprolactinaemia (Welsch et al., 1970; Sarkar et al., 1982; O’Connor
et al., 2000). Thus in the Sprague-Dawley rat, reproductive senescence is characterized by persistent
hyperestrogenaemia and hyperprolactinaemia with low concentrations of LH and follicle-stimulating
hormone (FSH) (Simpkins, 2000).
Advancing age in the female Sprague-Dawley rat is associated with increasing numbers
of days spent in estrus with eventual entry into a constant estrous state associated with elevated
estrogen and prolactin concentrations and a high incidence of mammary tumours. Other rat strains
(such as Fischer 344) are more likely to show age-related increases in the number of days spent in
diestrus followed by a constant diestrus or pseudopregnant-like condition. This reproductive state
is associated with the development of a number of corpora lutea that are stimulated to secrete progesterone
by prolactin. Rats in this reproductive state show a much lower incidence of mammary
tumours.
In women, reproductive ageing is characterized by exhaustion of ovarian follicles and the resulting
menopause (Taylor, 1998). During menopause, the ability to induce a pre-ovulatory LH surge is
normal, but estrogens, the driving force for the cycle, are absent. The menopause is characterized by
low concentrations of estrogen and high concentrations of LH and FSH, while prolactin concentrations
are usually unchanged or slightly reduced secondary to decreased estrogen (Simpkins, 2000).
The major differences between the parameters of reproductive senescence in female Sprague-Dawley
rats, female Fischer 344 rats and women are summarized in Table A2.
3. Similarities with reproductive pathologies in women
Polycystic ovarian syndrome (PCOS) is an anovulatory state in women that is characterized by
the presence of a cystic ovary associated with elevated concentrations of LH, increased production
of estrogen, elevated concentrations of androgens and marked hirsutism. It is associated with obesity,
ATRAZINE 37–138 JMPR 2007