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Phthalate exposure impairs testis development and function; however, whether phthalates affect nonreproductive functions is not well understood. To investigate this, C57BL/6J mice were fed 1-500 mg di-n-butyl phthalate (DBP) in corn oil, or vehicle only, daily from 4 to 14 days, after which tissues were collected (prepubertal study). Another group was fed 1-500 mg/kg·d DBP from 4 to 21 days and then maintained untreated until 8 weeks for determination of adult consequences of prepubertal exposure. Bones were assessed by microcomputed tomography and dual-energy X-ray absorptiometry and T by RIA. DBP exposure decreased prepubertal femur length, marrow volume, and mean moment of inertia. Adult animals exposed prepubertally to low DBP doses had lower bone mineral content and bone mineral density and less lean tissue mass than vehicle-treated animals. Altered dynamics of the emerging Leydig population were found in 14-day-old animals fed 100-500 mg/kg·d DBP. Adult mice had variable testicular T and serum T and LH concentrations after prepubertal exposure and a dose-dependent reduction in cytochrome p450, family 11, subfamily A, polypeptide 1. Insulin-like 3 was detected in Sertoli cells of adult mice administered the highest dose of 500 mg/kg·d DBP prepubertally, a finding supported by the induction of insulin-like 3 expression in TM4 cells exposed to 50 μM, but not 5 μM, DBP. We propose that low-dose DBP exposure is detrimental to bone but that normal bone mineral density/bone mineral content after high-dose DBP exposure reflects changes in testicular somatic cells that confer protection to bones. These findings will fuel concerns that low-dose DBP exposure impacts health beyond the reproductive axis.
Outcome-dependent sampling (ODS) study designs are commonly implemented with rare diseases or when prospective studies are infeasible. In longitudinal data settings, when a repeatedly measured binary response is rare, an ODS design can be highly efficient for maximizing statistical information subject to resource limitations that prohibit covariate ascertainment of all observations. This manuscript details an ODS design where individual observations are sampled with probabilities determined by an inexpensive, time-varying auxiliary variable that is related but is not equal to the response. With the goal of validly estimating marginal model parameters based on the resulting biased sample, we propose a semi-parametric, sequential offsetted logistic regressions (SOLR) approach. The SOLR strategy first estimates the relationship between the auxiliary variable and the response and covariate data by using an offsetted logistic regression analysis where the offset is used to adjust for the biased design. Results from the auxiliary variable model are then combined with the known or estimated sampling probabilities to formulate a second offset that is used to correct for the biased design in the ultimate target model relating the longitudinal binary response to covariates. Because the target model offset is estimated with SOLR, we detail asymptotic standard error estimates that account for uncertainty associated with the auxiliary variable model. Motivated by an analysis of the BioCycle Study (Gaskins et al., Effect of daily fiber intake on reproductive function: the BioCycle Study. American Journal of Clinical Nutrition 2009; 90(4): 1061-1069) that aims to describe the relationship between reproductive health (determined by luteinizing hormone levels) and fiber consumption, we examine properties of SOLR estimators and compare them with other common approaches.
Copyright © 2011 John Wiley & Sons, Ltd.
The luteinizing hormone/choriogonadotropin hormone receptor (LH/CG R) signals to regulate ovulation, corpus luteum formation, and fetal survival during pregnancy. Agonist binding to the LH/CG R is poorly reversible, emphasizing the importance of a cellular mechanism to temper signaling by a potentially persistently active receptor. Like other G protein-coupled receptors (GPCRs), signaling by this receptor is modulated by its binding of an arrestin. We have identified ADP ribosylation factor 6 (ARF6) as a protein whose activation state is regulated by the LH/CG R and which functions to regulate the availability of plasma membrane-docked arrestin 2 to this receptor. We hypothesize that ARF6 might also serve GPCRs other than the LH/CG R to regulate the availability of arrestin 2 for receptor desensitization.
OBJECTIVE - Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are clinically overlapping stress associated disorders. Neuroendocrine perturbations have been noted in both syndromes, and they are more common in women, suggesting abnormalities of gonadal steroid hormones. We tested the hypothesis that women with FM and CFS manifest abnormalities of the hypothalamic-pituitary-gonadal (HPG) hormonal axis.
METHODS - We examined the secretory characteristics of estradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH), including a detailed analysis of LH in premenopausal women with FM (n = 9) or CFS (n = 8) during the follicular phase of the menstrual cycle compared to matched healthy controls. Blood was collected from an indwelling intravenous catheter every 10 min. over a 12 h period. LH was assayed from every sample; pulses of LH were identified by a pulse-detection program. FSH and progesterone were assayed from a pool of hourly samples for the 12 h period and estradiol from samples pooled over four 3 h time periods.
RESULTS - There were no significant differences in FSH, progesterone, or estradiol levels in patients versus controls. There were no significant differences in pulsatile secretion of LH.
CONCLUSION - There is no indication of abnormal gonadotropin secretion or gonadal steroid levels in this small, but systematic, study of HPG axis function in patients with FM and CFS.
Desensitization of guanine nucleotide binding protein-coupled receptors is a ubiquitous phenomenon characterized by declining effector activity upon persistent agonist stimulation. The luteinizing hormone/choriogonadotropin receptor (LH/CGR) in ovarian follicles exhibits desensitization of effector adenylyl cyclase activity in response to the mid-cycle surge of LH. We have previously shown that uncoupling of the agonist-activated LH/CGR from the stimulatory G protein (G(s)) is dependent on GTP and attributable to binding of beta-arrestin present in adenylyl cyclase-rich follicular membrane fraction to the third intracellular (3i) loop of the receptor. Here, we report that LH/CGR-dependent desensitization is mimicked by ADP ribosylation factor nucleotide-binding site opener, a guanine nucleotide exchange factor of the small G proteins ADP ribosylation factors (Arfs) 1 and 6, and blocked by synthetic N-terminal Arf6 peptide, suggesting that the GTP-dependent step of LH/CGR desensitization is receptor-dependent Arf6 activation. Arf activation by GTP and ADP ribosylation factor nucelotide-binding site opener promotes the release of docked beta-arrestin from the membrane, making beta-arrestin available for LH/CGR; Arf6 but not Arf1 peptides block beta-arrestin release from the membrane. Thus, LH/CGR appears to activate two membrane delimited signaling cascades via two types of G proteins: heterotrimeric G(s) and small G protein Arf6. Arf6 activation releases docked beta-arrestin necessary for receptor desensitization, providing a feedback mechanism for receptor self-regulation.
This research investigated whether ergot alkaloids associated with endophyte-infected tall fescue could alter plasma concentrations of pituitary hormones that regulate biological processes related to cattle performance. Seven Angus yearling steers received single i.v. injections of ergotamine tartrate, ergonovine maleate, or saline vehicle in a simple cross-over design. Each steer was given a different compound each week. Blood samples were collected at 15-min intervals for 45 min before and 240 min after treatments to assess plasma concentrations of prolactin, growth hormone, and LH. Respiratory rates were measured hourly to ascertain a systemic effect. Ambient temperature averaged 34 degrees C during data collection. Treatment x time was a significant source of variation for respiration rate and plasma concentrations of each hormone evaluated. Respiration rates were higher for ergonovine than for saline (P < .02) and ergotamine (P < .07) 30 min after treatment, but they were higher (P < .05) for ergotamine than for ergonovine and saline by 210 min after treatment. Both alkaloids transiently elevated (P < .01) plasma growth hormone concentrations compared with before alkaloid treatment and after saline treatment. Ergotamine reduced (P < .01) plasma concentrations of prolactin and LH throughout the 120-min period after treatment compared with concentrations before ergotamine treatment and after saline treatment. Ergonovine lowered (P < .01) prolactin concentrations for a shorter time than ergotamine and did not affect mean LH concentrations. Results indicated that ergot alkaloids implicated as contributing agents to fescue toxicosis can alter plasma concentrations of pituitary hormones important to cattle production.
In a previous report, we have shown that acute activation of the hypothalamo-pituitary-adrenal (HPA) axis by the cytokine interleukin-1 alpha (IL-1 alpha) in the ovariectomized (OVX) rhesus monkey results in an inhibition of LH secretion. Here, we study whether estradiol (E) replacement therapy, at a level that reproduces E concentrations typical of the late follicular phase, modifies the gonadotropin and cortisol responses to IL-1 alpha administration. For E replacement, two Silastic capsules containing E were implanted sc 5 days before the experiment. The serum E concentration increased from less than 5 in OVX to 103.0 +/- 5.2 pg/ml in OVX and E-replaced monkeys. The experimental protocols were carried out 24 h or more after the LH surge that had been induced by E. In Exp 1, the effects of an intracerebroventricular (icv) infusion of physiological saline (group 1) or IL-1 alpha (2.1 or 4.2 micrograms/30 min; group 2) on LH, FSH, and cortisol were compared. IL-1 alpha administration resulted in a progressive release of LH (to 159.0 +/- 8.3% of baseline at 5 h; P < 0.05, 3-5 h vs. saline). Cortisol decreased in group 1 (84.5 +/- 1.3% by 5 h), but increased after IL-1 alpha (147.3 +/- 12.6%; P < 0.05 vs. saline). In Exp 2, we determined whether the stimulatory effects of IL-1 alpha on LH result from the central activation of CRH release (group 3). Infusion of the CRH antagonist, D-Phe12, Nle21,38, CaMe,Leu37-CRF-(12-41) (240 or 360 micrograms/2 h) prevented the increase in LH seen after IL-1 alpha treatment (67.3 +/- 12.5% at 5 h, NS vs. saline). The CRH antagonist also prevented the increase in cortisol and progesterone induced by IL-1 alpha. In Exp 3, we tested whether the stimulatory effect of IL-1 alpha on LH secretion can be simulated by ACTH infusion (group 4). ACTH-(1-24) (10-micrograms bolus plus 50 micrograms/5 h, iv) induced a progressive increase in LH secretion (to 221.5 +/- 27.8% of baseline by 5 h; P < 0.05, 3-5 h vs. saline). ACTH also stimulated cortisol secretion (to 203.3 +/- 30.7% by 5 h). In Exp 4, we investigated the role of adrenal progesterone in the LH response observed in groups 2 and 4. This increase in LH did not occur after pretreatment with RU486, a progesterone antagonist (5 mg Mifepristone; 77 +/- 24.2% by 5 h; P = NS vs. saline), although the increases in cortisol and progesterone were not prevented.(ABSTRACT TRUNCATED AT 400 WORDS)
Cyclic mares were given daily i.m. injections of 150 mg progesterone (Group P, N = 4), 150 mg progesterone and 10 mg oestradiol-17 beta (Group PE, N = 3), 10 mg oestradiol-17 beta (Group E, N = 3) or cottonseed oil vehicle (Group C, N = 4), from the day after ovulation (Day 1) to Day 28. Blood samples were collected daily, and the ovaries were palpated every 1-2 days. Serum FSH and LH concentrations were measured in all samples, and means determined for 7 consecutive 4-day periods throughout treatment. Comparisons within each steroid treatment group between time periods and comparisons between hormone treatment groups within each time period were made to investigate the way in which these ovarian steroids control cyclic gonadotrophin changes in the mare. The increase in LH during oestrus in Group C mares (controls) appeared to be inhibited by progesterone, resulting in low LH concentrations and failure of preovulatory-sized follicles to ovulate. In Group PE LH concentrations were lower than those in Group P, resulting in suppression of the development of the largest follicle. In Group E, treatment had little effect on FSH and LH concentrations, while follicular development was variable (ovulations on Days 25, 33 and 36). None of the steroid treatments appeared to suppress FSH concentrations directly but FSH concentrations showed a reciprocal relationship with the LH-dependent follicular development.
This study examines the effect of oral estrogen treatment on gonadotropin secretion in three young women with gonadal failure. Each subject was treated with 0.1 mg BID of ethinyl estradiol for four weeks, and the LH and FSH responses to 200 microgram of intravenously administered LHRH were measured basally and weekly during therapy. Significant reduction of basal levels of FSH occurred within one week of treatment, with obliteration of LHRH-mediated FSH responsiveness within two weeks. By contrast, basal levels of LH were significantly reduced by the end of the second week of treatment, and LHRH-mediated LH levels were sustained for three weeks. In one subject an LHRH test was performed every other day for two weeks after cessation of therapy. Return of FSH responsiveness was delayed one week beyond that of LH, which occurred within three days of discontinuation of estrogen. These results indicate that during the early phase of oral estrogen replacement therapy, FSH secretion may be selectively blunted; after discontinuation of treatment, recovery of FSH secretion lags behind recovery of LH.
The effect of the luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6,Pro9-NEth]LHRH (LHRHA), on luteinizing hormone (LH) bioactivity was assessed with a rat interstitial cell assay in four men during a 14-d treatment period. Biologic/immunologic (B/I) ratios were unchanged initially with treatment but by day 12 had fallen to levels lower than basal values. Frequent sampling on day 12 revealed blunted gonadotropin responsiveness to LHRHA and absence of spontaneous LH pulsations. Despite continued administration of LHRHA, human chorionic gonadotropin administration resulted in elevated B/I ratios and testosterone levels. Further characterization of the serum immunoreactive LH by Sephadex chromatography revealed a later elution profile during treatment with LHRHA. Thus, LHRHA appears to act, in part, by modification of the bioactivity of LH in man.