STRESS AND THE MENSTRUAL-CYCLE - RELEVANCE OF CYCLE QUALITY IN THE SHORT-TERM AND LONG-TERM RESPONSE TO A 5-DAY ENDOTOXIN CHALLENGE DURING THE FOLLICULAR PHASE IN THE RHESUS-MONKEY

The notion that stress activates central and peripheral pathways to in hibit the menstrual cycle is well accepted, but the initial processes through which this occurs have not been investigated. This study uses a relevant nonhuman primate model to document the cyclic endocrine eff ects imposed by a moderate short-term stress episode in the follicular phase. The stress paradigm is a B-day inflammatory/immune-like challe nge produced by the administration of bacterial endotoxin [lipopolysac charide (LPS)], which, through the release of endogenous cytokines and other mediators, induces a physiopathological response similar to a b acterial infection. LPS was administered iv twice daily for 5 days sta rting on days 2-8 of the follicular phase. The stress challenge result ed in a significant lengthening of the follicular phase in all monkeys . Two distinct groups were observed. In group 1 (n = 5), the mean (+/- SE) length of the follicular phase in the LPS-treated cycle was signif icantly increased, from 10.2 +/- 0.2 in control cycle 2 to 30.8 +/- 4. 3 days (except in one monkey that had a 4-month amenorrheic interval). In group 2 (n = 5), the length of the follicular phase significantly increased but not to exceed the duration of the LPS treatment (9.7 +/- 1.1 vs. 13.6 +/- 1.2). Estradiol concentrations decreased significant ly after LPS in group 1 (34.8 +/- 5.5 vs. 16.2 +/- 6.5 pg/mL) and rema ined suppressed after the challenge. In group 2, estradiol levels rema ined stationary throughout the 5-day LPS treatment (26.0 +/- 6.5 vs. 2 5.6 +/- 3.9). Compared with control values at a similar stage of the f ollicular phase, most LH and FSH values during LPS treatment were high er than controls. Estradiol and gonadotropin surges were delayed by LP S treatment for a varying length of time according to each grp. Signif icant differences in integrated luteal progesterone concentrations cha racterized control cycles of groups 1 and 2 (group 1: 36.5 +/- 1.5, gr oup 2: 47.5 +/- 2.6). In group 1, there were no further effects of LPS on luteal progesterone during the treatment and two post-LPS cycles. In contrast, in group 2, integrated luteal progesterone concentrations were significantly decreased in post-LPS cycle 1 (to 36.0 +/- 4.4). C ortisol significantly increased at hour 3 after each morning LPS injec tion but the amplitude of the response decreased over the 5-day period . Progesterone increased significantly by hour 3 after the first LPS i njection but remained unchanged after subsequent LPS administration. O ur data demonstrate that a 5-day inflammatory-like episode during the follicular phase can delay folliculogenesis and that damage to this pr ocess is intensified in individuals who already demonstrate a subtle c yclic degradation, in the form of decreased progesterone secretion in the luteal phases preceding the stress episode. Long-term endocrine ef fects, in the form of decreased luteal secretory activity in the first poststress cycle, are observed in normally cycling individuals, sugge sting that inadequacy of the luteal phase may represent the first stag e in the damage that a stress episode can inflict upon the normal mens trual cycle.