Astressin B, a Corticotropin-Releasing Hormone Receptor Antagonist, Accelerates the Return to Normal Luteal Function after an Inflammatory-Like Stress Challenge in the Rhesus Monkey

Endocrinology, Feb 2007

Xiao, Ennian, Xia-Zhang, Linna, Vulliemoz, Nicolas, Rivier, Jean, Ferin, Michel

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Astressin B, a Corticotropin-Releasing Hormone Receptor Antagonist, Accelerates the Return to Normal Luteal Function after an Inflammatory-Like Stress Challenge in the Rhesus Monkey

Endocrinology Astressin B, a Corticotropin-Releasing Hormone Receptor Antagonist, Accelerates the Return to Normal Luteal Function after an Inflammatory-Like Stress Challenge in the Rhesus Monkey Ennian Xiao 0 Linna Xia-Zhang 0 Nicolas Vulliemoz 0 Jean Rivier 0 Michel Ferin 0 0 Department of Obstetrics and Gynecology (E.X. , L.X.-Z., N.V., M.F.) , College of Physicians and Surgeons, Columbia University , New York, New York 10032; and The Salk Institute (J.R.), La Jolla, California 92186 , USA Endogenous release of CRH in stress has been associated with a dysfunctional reproductive endocrine axis. In the rhesus monkey, an inflammatory-like stress challenge in the luteal phase decreases luteal secretory function. Here, we tested the effectiveness of astressin B, a nonspecific CRH receptor antagonist, in constraining the deleterious impact of a 10-d lipopolysaccharide (LPS) challenge on the menstrual cycle. Two protocols were carried out in nine animals. In the first, the animals, after showing two normal consecutive control cycles, were injected daily for 10 days with LPS (75-125 g/d) during the luteal phase of the cycle. The animals were followed through the two postchallenge cycles. The second protocol, carried out in the following year, was identical with protocol 1, except that the animals were treated with astressin B (0.45 mg/kg) 1 h before each daily LPS challenge during the - STRitaErSyS-aAdNreDnalT(HHEPAre)suaxltiasnatraecktinvoawtedn thoypdoistrhuaplatmpiucl-spaittiulegonadotropin release and reproductive function ( 1 ). Administration of CRH, a principal neuroendocrine regulator of the HPA axis, has been shown to acutely inhibit GnRH/LH secretion in the rodent and primate ( 2–5 ), providing evidence that a decrease in LH pulse frequency is primarily related to an inhibitory effect of CRH on the hypothalamic GnRH pulse generator. Similar evidence has been obtained in the sheep, where CRH release into the hypophyseal portal circulation coincides with the suppression of GnRH and LH pulsatile release in response to endotoxin administration ( 6, 7 ), although under certain conditions, stressors may in this species also exert a subtle influence on pituitary response to GnRH ( 8 ) We have previously shown that administration of a CRH antagonist prevents the acute inhibition of pulsatile LH release that follows an immune/inflammatory stress-like challenge after central administration of IL1- ( 9 ). Decrease of endogenous CRH activity by a CRH antagonist or by Alprazolam, a benzodiazepine derivative, also prevents the acute GnRH/LH decrease that follows insulin-induced hypoglycemia in the monkey and rodent ( 10 –12 ) and intermittent foot shocks or restraint in the rodent First Published Online November 2, 2006 Abbreviations: CV, Coefficient(s) of variation; HPA, hypothalamicpituitary-adrenal; LPS, lipopolysaccharide. Endocrinology is published monthly by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community. luteal phase. Blood samples were obtained daily to document cyclic hormones levels. The LPS challenge significantly decreased luteal progesterone and LH release during the challenge cycle. Inhibition of luteal progesterone extended to the two successive postchallenge cycles. Astressin B treatment prevented luteal LH but not luteal progesterone decrease during the treatment cycle and restored normal progesterone secretion during the two posttreatment cycles. We conclude that the deleterious impact of a short-term inflammatory stress challenge on luteal function is far longer than the stress period itself. Systemic administration of astressin B accelerates the return to normal luteal function, presumably by restoring normal neuroendocrine regulation of gonadotropin secretion. (Endocrinology 148: 841– 848, 2007) ( 13–15 ). These data demonstrate a pivotal role of CRH in mediating the acute suppressive effects of stressful stimuli on pulsatile GnRH/LH release. It is also possible that CRH may also directly modulate ovarian steroidogenesis because CRH and its receptors have been detected in the rodent and nonhuman primate ovary ( 16, 17 ). A more chronic immune/inflammatory-like stress episode, like that produced by short-term IL-1 or endotoxin [lipopolysaccharide (LPS)] administration, has also been shown to disrupt the reproductive cycle in the rat, ewe, and monkey ( 18 –21 ). In the monkey, a 5-d LPS challenge during the luteal phase invariably resulted in reduced secretory luteal function, as evidenced by diminished progesterone secretion (22). In the human, luteal inadequacy has often been described in situations where stress is suspected or present and in general may represent an initial response of the reproductive axis to stressors or energy-related demands ( 1, 21, 23–27 ). Because an inadequate luteal phase may in some patients also impact on fertility ( 28, 29 ), it is of clinical significance to test the effectiveness of a CRH receptor antagonist in preventing stress stimuli to induce this type of cyclic dysfunction. Here, we have investigated in a nonhuman primate model whether peripheral administration of astressin B, a long-lasting nonselective CRH receptor antagonist (30) previously reported to revert stressor-induced HPA secretory responses and anxiogenic-like responses ( 31– 33 ), can prevent the deleterious effect of LPS on luteal function. Materials and Methods Data analysis Study animals Nine adult female rhesus monkeys (Macaca mulatta) were used in the study. The animals (body weight, 6 – 8.5 kg) were housed within a temperature- and light-controlled room (lights on, 0800 –2000 h) and fed twice a day with Purina monkey chow supplemented daily with fruits and vegetables. Menstruations were checked by daily vaginal swabbing and unsedated animals had been habituated previously to daily venipuncture. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Columbia University, and the research was conducted in accord with the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act. All animals participated in an active enrichment program provided by the staff of Veterinary Medicine and supervised by the Institutional Animal Care and Use Committee. Experimental protocols The experiments were conducted between September and March of successive years. The protocols, each started in September, compared the effects on the menstrual cycle of a 10-d LPS challenge administered during the luteal phase in the absence (protocol 1) or presence (protocol 2) of a CRH receptor antagonist (astressin B). Daily blood samples for hormonal measurements were obtained throughout the protocols. During the LPS challenge, an additional sample was taken 3 h after the daily LPS injection. Each animal participated in both protocols. Only animals which exhibited two consecutive normal ovulatory menstrual cycles (labeled control cycles 1 and 2), as determined by length of each cycle phase and by integrated luteal progesterone levels (area under the curve during the entire luteal phase) of 40 ng/ml or above ( 21 ), were used in the experimental protocols. Each protocol consisted of two normal control cycles, a challenge cycle, and two postchallenge cycles. In protocol 1, monkeys were injected iv once daily with LPS (75–125 g/d; W Escherichia coli 055:B5; Sigma, St. Louis, MO) for 10 d starting on d 2 or 3 of the luteal phase. The initial LPS dose was 75 g/d. If an individual did not respond by showing a decrease in luteal progesterone, the dose was later increased to 100 or 125 g after two intervening normal cycles. In protocol 2, taking place during the following year, the monkeys were injected once daily with LPS (at the dose found to be the minimal effective dose in protocol 1) for 10 d starting on d 2 or 3 of the luteal phase, as well as with astressin B, a nonspecific CRH receptor antagonist (0.45 mg/kg; synthesized in Dr. J. Rivier’s laboratory). There were two subgroups: in group 1 (n 4), astressin B was dissolved in dimethyl sulfoxide (20 mg/ml), then diluted with sesame oil to 2 mg/ml and injected once sc 1 h before LPS administration; and in group 2 (n 5), astressin B was dissolved in sterile water (2 mg/ml) and divided into two aliquots injected im 1 h before LPS administration and 5 h later. In view of the indistinguishable response in these two astressin subgroups, the data were pooled. Because protocols 1 and 2 could not be performed randomly and to exclude the possibility that animals became unresponsive to a repeated challenge, we tested the inhibitory effect of an additional LPS challenge on luteal progesterone secretion in two monkeys in the year after completion of protocols 1 and 2. Hormone measurements Daily blood samples were centrifuged, and sera were kept at 20 C until assay. Estradiol, progesterone, and cortisol were measured by chemiluminescent immunoassays (Immulite System, Diagnostic Products Corporation, Los Angeles, CA). Assay sensitivity was 20 pg/ml for estradiol, 0.2 ng/ml for progesterone, and 0.2 g/dl for cortisol. Interassay coefficients of variation (CV) were 10.5% for estradiol, 7.9% for progesterone, and 6.3% for cortisol. Monkey LH and FSH were measured in a recombinant cynomolgus RIA (reagents provided by Dr. A. F. Parlow; Pituitary Hormones and Antisera Center, Los Angeles Medical Center, Torrance, CA) as described previously ( 34 ). LH and FSH assay sensitivity (at 95% binding) was 0.06 and 0.045 ng/ml, respectively; intraassay CVs were 7.9 and 5.0%; and interassay CV were 13.1 and 6.1%. Individual samples from the two protocols were measured in the same assay. Mean ( se) length of the follicular and luteal phase and integrated luteal progesterone levels (area under the curve during the entire luteal phase) were calculated for each menstrual cycle in all protocols. Day 1 of the luteal phase was designated as the day after the LH peak. To evaluate the effect of the LPS challenge on the luteal phase and a possible protective effect of astressin B, integrated progesterone levels were compared in the control, treatment, and posttreatment cycles within each protocol by one-way ANOVA, followed by the Newman-Keuls multiple comparison test. To compare effects of the LPS challenge alone and after treatment with astressin B, integrated progesterone secretion during the challenge/treatment cycles were calculated as a percentage of the mean of two control cycles and analyzed with the Mann-Whitney ranking test. Mean ( se) daily LH and FSH concentrations during the luteal phase of challenge/treatment and postchallenge/treatment cycles were compared with those in the two control cycles by one-way ANOVA, followed by the Newman-Keuls multiple comparison test. Daily changes in the mean cortisol response to LPS were analyzed by ANOVA. Statistical analysis was performed using PRISM (GraphPad, San Diego, CA). Results Corpus luteum secretory function A 10-d LPS challenge during the luteal phase significantly inhibited corpus luteum function, as evidenced by decreased progesterone secretion; mean ( se) integrated progesterone levels decreased by 41.8 5.8% of control cycles (P 0.001) (Fig. 1A). Inhibition of luteal progesterone extended to the two successive postchallenge cycles; mean progesterone in seven monkeys decreased by 42.3 8.0% of controls in postchallenge cycle 1 and by 32.8 11.5% in postchallenge cycle 2 (P 0.001). The other two monkeys became amenorrheic. Treatment with astressin B did not prevent the inhibitory effect of LPS on luteal progesterone during the treatment cycle; progesterone decreased by 31.7 7.8% of control cycles (P 0.05), and levels were not significantly different from those in the LPS-alone group (Fig. 1B). However, astressin B treatment restored mean integrated progesterone in the posttreatment cycles to the level of control cycles in eight of nine animals. Astressin B also restored cyclicity in one of the two monkeys that had become amenorrheic after LPS alone. A similar 10-d LPS challenge given to two monkeys in the third year after completion of protocols 1 and 2 produced a similar decrease in luteal progesterone during the challenge and postchallenge cycles as that seen in protocol 1 (data not shown), suggesting that there was no increasing body tolerance to LPS within the confines of these experimental protocols. Gonadotropin secretion Overall luteal LH secretion was significantly inhibited during the LPS challenge; mean ( se) LH levels decreased by 25% of control cycles (P 0.05). Luteal LH concentrations in the two postchallenge cycles were also lower but not significantly so (15 and 16% of control, P 0.078 and 0.057 in cycles 1 and 2, respectively) (Fig. 1C). Treatment with astressin B prevented the LPS-induced LH decreases in the LPS challenge cycle and in the two posttreatment cycles and restored LH to levels not significantly different from controls (Fig. 1D). Figure 2 shows mean daily LH (Fig. 2, A and B) and FSH (Fig. 2, C and D) levels from the day of the LH peak to menstruation. When calculated from d 4 post-LH peak to d 11 (a period when all nine animals were under the LPS challenge), daily LH levels were also significantly lower in the LPS challenge cycle than in controls (P 0.05) (Fig. 2A), whereas they were not significantly different from control after astressin B administration (Fig. 2B). LPS exerted no effects on overall or daily FSH concentrations during the luteal phase (Fig. 2, C and D). Menstrual cyclicity Compared with control cycles, there were no effects of the LPS challenge on length of the luteal phase (except in one monkey in which it was shortened to 7 d; this animal subsequently became amenorrheic), nor on the length of the follicular and luteal phases in the two postchallenge cycles in the seven monkeys that maintained ovulatory cycles. No changes in follicular and luteal phase length were observed in the astressin or posttreatment cycles (except in one monkey that again became amenorrheic). Pre-LH surge estradiol peaks were not different from controls in all challenge and treatment cycles (Table 1). Figure 3 illustrates estradiol, progesterone, and gonadotropin profiles throughout the two protocols in an individual monkey. Cortisol response As expected, LPS stimulated cortisol release; 3 h after LPS, cortisol significantly increased from 28.8 2.5 to 73.5 8.9 g/dl on d 1 of LPS injection (P 0.05). Although a significant cortisol increase after each daily LPS injection occurred, this response became blunted over time, and by d 6, the cortisol increase (to 41.9 2.8 g/dl) was significantly smaller than on d 1 (P 0.05) (Fig. 4A). Treatment with astressin B failed to prevent the stimulation of cortisol by LPS; the cortisol increase 3 h after LPS astressin B was similar to that after LPS alone (from 27.4 2.9 to 64.6 4.8 on d 1), and the cortisol response also became blunted with time (to 36.7 1.7 on d 7; P 0.05 vs. d 1) (Fig. 4B). Overall mean cortisol responses are shown in Table 2. Animal response Both the daily and overall LPS doses used here were decisively lower than doses reported in a previous publication ( 22 ). As a result, fewer symptoms were noted. Most animals, particularly on the first day of LPS, delayed meal eating time until later in the day. No overall decreased feeding was observed, and body weight remained constant in all animals. Astressin B treatment did not prevent the eating delay on the first day of the LPS challenge. The data provide two important findings. The first is that a 10-d inflammatory-like stress challenge during the luteal phase in the nonhuman primate not only inhibits LH and luteal secretory function during the challenge cycle but also extends this inhibitory effect on progesterone secretion through the two subsequent challenge-free luteal phases. The second demonstrates that treatment with astressin B, a nonselective CRH receptor antagonist, prevents this inhibitory neuroendocrine effect of the inflammatory challenge on LH secretion and accelerates recovery to a normal menstrual cycle. Our data show that LH and progesterone levels are significantly decreased during the luteal phase of the LPS challenge cycle compared with control cycles. Because LH has an obligatory role in the production of progesterone by the primate corpus luteum ( 35 ), the significant decrease in progesterone may in great part be related to diminished LH release throughout the luteal phase. LPS or IL-1 administration has been shown previously to acutely decrease pulsatile LH release in the rat ( 36, 37 ), sheep (6), and monkey ( 9, 38 ), most probably the result of a central suppression of the GnRH pulse generator ( 6, 39, 40 ). Significantly, cotreatment with astressin B restores normal daily LH levels during the 10-d LPS challenge, clearly indicating that the neuroendocrine effect of LPS on GnRH/LH release reflects its impact on central CRH. However, notwithstanding its effectiveness in restoring LH, astressin B was unable to prevent the decrease in progesterone during the luteal phase of the LPS challenge cycle. The reason for this is not clear, but it is possible that the persistent LH-independent progesterone decrease reflects direct actions of LPS-induced cytokines on the ovary ( 1, 36, 41 ). The persistence of low progesterone levels in the presence of astressin B, however, appears to rule out a role for the local ovarian CRH system ( 16, 17 ) in our experiment. The present data, to the best of our knowledge, are the first report of endocrine effects extending well beyond a shortterm inflammatory challenge in the primate. Indeed, the inhibitory influence of the LPS challenge on luteal progesterone extends to two consecutive postchallenge menstrual cycles, even though LPS administration was confined to 10 d in the luteal phase of the challenge cycle. The present data are at variance with a previous study of a similar design but in which the LPS challenge lasted only 5 d; in that study, the inhibitory effect of the LPS challenge on progesterone secretion was limited to the challenge cycle, with recovered luteal secretory function during the postchallenge cycles in most animals ( 22 ). That the long-term alteration of the cycle occurred even though the present LPS challenge was one with a significantly lower potency (total dose, 750-1000 vs. 1500 g) producing fewer adverse clinical symptoms suggests that duration of the inflammatory challenge rather than its potency plays a greater role in the persistence of deficient luteal function in the postchallenge cycles. An endocrine explanation for the persistence of inadequate secretory luteal phases eludes us; indeed, this phenomenon occurs in the presence of apparently normal follicular function, as suggested by a normal follicular phase length and by normal estradiol peaks during the two postchallenge cycles, and of normal daily FSH profiles during the luteal-follicular transition periods, which are thought to be predictive markers in the inadequate luteal phase syndrome ( 28, 42, 43 ). We speculate that the persistence of low progesterone levels may reflect persistent lower (although not significantly so) daily luteal LH levels in the postchallenge cycles that may not provide sufficient support to luteal secretory function. The lack of significance in the LH analysis may possibly be related to a decrease in the number of animals due to amenorrhea induced by LPS. Of great interest is our demonstration that astressin B treatment, even one that is confined to the 10 d of the inflammatory challenge, prevents the extended deleterious effects of LPS on luteal progesterone in the postchallenge cycles, thereby accelerating the return to normal luteal function and normal menstrual cyclicity. This outcome clearly reinforces the pivotal role of CRH in inducing these long-term effects and may in part suggest a role of CRH in generally described clinical consequences of a prolonged stress challenge in which there may be a temporary (or long-lasting, such as in the posttraumatic stress disorder) failure of homeostatic mechanisms to turn the response off ( 44 – 46 ). The precise nature of these changes remains to be studied. Cortisol was significantly elevated 3 h after LPS injection throughout the 10-d challenge period, although the peak response decreased progressively with time, showing the organism’s adaptation to the daily challenge. That astressin B blocks the inhibitory effect of LPS on LH secretion without altering the peripheral adrenal response is puzzling and suggests a separate central pathway of astressin B on LH in this experiment. Although CRH antagonists had been shown previously to be effective in preventing the acute activation of the HPA axis by cytokines in the rat and primate ( 9, 47 ), the inability to prevent the cortisol increase in our study possibly indicates an inadequate dose of CRH antagonist for this purpose. It may also be that cytokines, released in response to LPS, stimulate ACTH and cortisol independently of CRH, as suggested in mice (48). In a similar vein, we have previously shown that a vasopressin antagonist can prevent IL-induced LH inhibition, without influencing the cortisol response to the cytokine ( 49 ). Likewise, chronic administration of antalarmin, another CRH receptor antagonist, was reported in the rhesus monkey to restore environmental exploration, a behavior inhibited by the stress of social separation, also without preventing the sympathoadrenal response to the stressor ( 50 ). Our data, taken together with several other reports in the literature, suggest that the inadequate luteal phase syndrome may well represent a general primary response to stressors as well as to negative energy balance in the normal cyclic nonhuman primate ( 1, 22, 23, 34 ) and in women ( 24 –27 ) and in turn contribute in some patients to infertility ( 28, 29 ). Data in the nonhuman primate also suggest that individuals with an established inadequate luteal phase syndrome are more prone to further menstrual cycle deterioration in response to stressors; therefore, this syndrome may be viewed as a sign of a stress-sensitive individual ( 21, 51 ). Thus, it is becoming evident that the occurrence of inadequate luteal phases should be considered as part of the symptomatology that precedes the fully established hypothalamic chronic anovulation syndrome ( 52 ). The decrease in LH in the presence of normal FSH secretion, such as found in our study, may reflect a still-marginal effect of the stressor on the frequency of the GnRH pulse generator. It is indeed known that a decrease in GnRH pulse frequency in general favors a higher FSH to LH ratio ( 53 ). This effect may also perhaps explain the persistence of normal follicular phases in the postchallenge cycles of our animals. With a more severe real or perceived stress, a more pronounced decrease in GnRH pulse generator activity may then result in amenorrhea, such as seen in two of our animals, in a manner reminiscent of monkeys undergoing more strenuous exercise training ( 23 ). In women, this is also observed in the functional hypothalamic chronic anovulation syndrome associated with lifestyle changes related to excessive exercise, eating disorders, and/or psychological stress ( 52 ). It is worthwhile to mention that CRH receptor antagonist treatment also helped restore cyclicity in one of the two animals in which the LPS challenge had resulted in amenorrhea. Also of clinical interest is the observation that systemic administration of astressin B, a peptide reportedly unable to cross the blood-brain barrier in the rodent ( 32 ), can restore normal neuroendocrine secretion in the primate. One major difference between the two species may be the location of the primary GnRH site thought to control pulsatile gonadotropin release within the arcuate nucleus of the mediobasal hypothalamus in the primate ( 54 ), an area relatively more accessible from the periphery. Similarly, systemic injections of CRH readily decrease LH levels in the primate ( 4, 55 ), whereas CRH is without effect on LH release in the rodent unless it is injected in the brain ( 2, 56 ). In conclusion, our data illustrate the extended endocrine impact of a short-term inflammatory challenge on cyclic reproductive function and clearly demonstrate the role of CRH in that process because systemic administration of the CRH receptor antagonist astressin B accelerates the return to normal cyclicity, presumably by restoring the normal neuroendocrine regulation of gonadotropin secretion. It should be noted that this beneficial action conferred by the CRH receptor antagonist occurs despite the fact that astressin B does not blunt the peripheral HPA axis response to the stressor. The ability of astressin B to restore a normal luteal phase suggests that this or other CRH antagonists may act as potential therapeutic agents in stress-related endocrine dysfunction, such as in the functional hypothalamic chronic anovulation syndrome or in a persistent inadequate luteal phase syndrome, and be beneficial in the treatment of infertility. Acknowledgments We thank Alinda Barth and Nancy Cotui for help in measuring the steroid hormones. Received August 8, 2006. Accepted October 25, 2006. Address all correspondence and requests for reprints to: Michel Ferin, Department of Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: . This work was supported by National Institutes of Health Grants 5RO1 DK39144 (to M.F.) and PO1 DK26741 (to J.R.). The authors have nothing to disclose. Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. 1. Ferin M 2006 Stress and the reproductive system . In: Neill JD, ed. Knobil and Neill's physiology of reproduction . 3rd ed. San Diego: Elsevier; 2627 - 2696 2. Rivier C , Vale W 1984 Influence of corticotropin-releasing factor on reproductive functions in the rat . Endocrinology 114 : 914 - 921 3. 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Xiao, Ennian, Xia-Zhang, Linna, Vulliemoz, Nicolas, Rivier, Jean, Ferin, Michel. Astressin B, a Corticotropin-Releasing Hormone Receptor Antagonist, Accelerates the Return to Normal Luteal Function after an Inflammatory-Like Stress Challenge in the Rhesus Monkey, Endocrinology, 2007, 841-848, DOI: 10.1210/en.2006-1074