Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model.

To address whether gonadotropin-releasing hormone (GnRH) regulates its own expression and the expression of its receptor in the hypothalamus and ovary, we treated five groups of prepubertal/peripubertal female rats from postnatal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 microgram/day, or a placebo. We compared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ovary and uterus. Onset of puberty was determined by vaginal opening, and expression levels of GnRH and GnRH-receptor were determined using either quantitative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 microgram/day) inhibited while TRIP (10 and 100 microgram/day) stimulated serum gonadotropins (P<0.05). The expression of GnRH in the preoptic area did not show significant differences among the treatment groups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 microgram/day). GnRH mRNA could not be detected in the uterus by either real-time PCR or competetive RT-PCR. The GnRH-receptor expression in the hypothalamus (preoptic area and mediobasal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimulated by TRIP (10 microgram/day) but inhibited by CET (100 microgram/day). In contrast, in the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 microgram/day) and CET (100 microgram/day). Interestingly, the GnRH-receptor was even expressed in the uterus where it was strongly stimulated by both CET and TRIP in a dose-related manner. This shows that in addition to their different pituitary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also demonstrates an organ-specific regulation of GnRH and GnRH-receptor gene expression which is likely part of a local autoregulatory system. We conclude that the ovarian and uterine effects of GnRH analogs must be considered in addition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.

Assessing the relationship between quality of care and the characteristics of health care organizations.

In the past two decades, relationships among health plans, medical groups, and providers have grown more complex and the number of clinical management strategies has increased. In this context, determining the independent effect of a particular organizational strategy on quality of care has become more difficult. The authors review some of the issues a researcher must address when studying the relationship between organizational characteristics and quality of care. They offer criteria for selecting a research question, list organizational characteristics that may influence quality, and suggest sampling and study design techniques to reduce confounding. Since this type of research often requires a health care organization as collaborator, the authors discuss strategies for developing research partnerships and collecting data from the partner organization. Finally, they offer suggestions for translating research into policy.

Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model.

GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by desensitization of pituitary GnRH receptors. Little has been published about the use of GnRH antagonists such as cetrorelix to control the onset of puberty and whether they are potentially advantageous compared with GnRH agonists. We conducted two multigroup experiments (12 and 10 d, respectively) treating prepubertal/peripubertal female rats with either the GnRH agonist triptorelin or buserelin and compared them with rats treated with the GnRH antagonist cetrorelix and controls to assess the effects on pubertal progress and serum hormones. In the second experiment, the effects of buserelin and cetrorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and the alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by delayed vaginal opening, lower ovarian weights, and lower serum estradiol levels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin experiment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subunit were stimulated by buserelin but not by cetrorelix. Even though all three of these GnRH analogues inhibited gonadal development and delayed the onset of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effects. We conclude from this female rat model that cetrorelix may offer advantages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.

Reconciling quality measurement with financial risk adjustment in health plans.

BACKGROUND: Initiatives to improve quality measurement (QM) and to create systems for financial risk adjustment (RA) have developed in response to concerns about price competition's threat to quality and stimulation of risk selection. QM is designed to help purchasers identify best plans, to aid plans in their selection of providers, to facilitate quality improvement by plans and providers, and to assist patients faced with choices among plans and providers. The goal of RA is to eliminate incentives for plans and providers to avoid sick, high-cost patients in favor of healthy, low-cost patients. CONFLICTS BETWEEN QM AND RA: For QM it is often necessary to identify all patients with a particular condition, and many quality measures involve intervening on patients early in the course of their disease. Identifying patients through utilization decisions (for example, identifying patients with depression through receipt of an antidepressant prescription) may bias QM. For RA, the focus is on the highest-cost patients, and patient capture through resource utilization is more likely to be appropriate. DISCUSSION: Achieving QM and RA depends on improving information systems and patient identification processes and developing standard definitions for important variables. QM and RA could both be improved, and the conflicts between them reduced, if they were based more on detailed clinical data, if consensus definitions of quality of care for specific diagnoses could be achieved, if the number of QM measures that target acute and chronic care (versus preventive care) were increased, and if information systems were enhanced.

Activation of gene expression of the gamma-aminobutyric acid rather than the glutamatergic system in the preoptic area during the preovulatory gonadotropin surge of the rat.

There is increasing evidence that in the rat prior to and during the preovulatory LH surge, release rates of GABA in the preoptic area (POA) are decreased while no such changes occurred in the mediobasal hypothalamus (MBH). In addition, GnRH release appears to be facilitated by an increased preoptic excitation of glutamate (GLU). To investigate whether such changes of secretory activity of intrahypothalamic GABA or GLU neurons are associated with altered gene expression of biosynthetic enzymes or transporter proteins characteristic for either neuronal system, we determined mRNA levels of the two forms of the GABA-synthesizing enzyme glutamate decarboxylase (GAD65 and GAD67), the glutamate-synthesizing enzyme glutaminase (GLS), the GABA transporter type 1 (GAT-1) and the glutamate-aspartate transporter type 1 (GLAST). Competitive RT-PCRs using mutant cRNAs as internal standards were conducted with mRNA extracted from microdissected tissue of POA and MBH from diestrous, proestrous, and estrous rats. Proestrous animals were subgrouped according to their endocrine status as follows: 'prior to', on the 'ascending' or on the 'descending' limb of the LH peak, and 'after the LH surge (post)'. During the preovulatory LH surge, mRNA concentrations of GAD67 and GAT-1 in the POA were significantly increased compared to those observed on diestrous (2.8-fold for GAD67 and 2.5-fold for GAT-1, p < 0.01), while in the MBH the amount of both mRNAs remained constant. The expression levels of GAD65, GLS and GLAST were without any changes in the POA as well as in the MBH. These findings support the hypothesis that in rats induction of the preovulatory LH surge is controlled at the level of GnRH perikarya, and suggest that altered activities of intrapreoptic GABA neurons at both transcriptional and secretory levels are pivotal for the preovulatory activation of GnRH neurons.

Population choice and variable selection in the estimation and application of risk models.

This paper shows that risk adjustment models based on demographic and employment variables are not easily transferable from one population to the next, and that administrative variables are not useful in predicting medical expenditures. We found statistically significant differences between models built on populations of employees from a single employer enrolled in two different health plans, and between models built on populations of enrollees from a single health plan employed at two different companies. Employment-based variables (e.g., length of employment) had little predictive power in any of these risk models. We conclude that policymakers should be careful in applying risk models across populations, and that future versions of risk models for use within large employers need not include employment-based variables.

Reduction of luteinzing hormone secretion induced by long-term feed restriction in male rats is associated with increased expression of GABA-synthesizing enzymes without alterations of GnRH gene expression.

In rats, fasting or restriction of feed intake impairs the activity of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator which results in reduced luteinizing hormone (LH) secretion. It is still unknown which neurotransmitters are involved in this phenomenon. However, it is known that increased GABA concentrations in the hypothalamus reduce GnRH biosynthesis and release. Therefore, we examined whether 17 days of feed restriction in male rats affected the hypothalamic gene expression of GnRH and the GABA-synthesizing enzymes glutaminase (GLS) and glutamic acid decarboxylase-which exists in two forms, GAD67 and GAD65-in the mammalian brain. Furthermore, the expression of the GnRH receptor (GnRH-R) and the GABA transporter 1 (GAT-1) were investigated. Feed restriction resulted in a 75% reduction in body weight (b.w.) compared to rats fed ad libitum. Serum concentrations of LH and testosterone in the feed restricted group were significantly reduced to approximately 15% of that of rats fed ad libitum, while the FSH concentration remained unchanged. In the mediobasal hypothalamus (MBH) where GnRH is released into the portal vessels, mRNA levels of GAD67 and GLS were increased twofold compared to rats fed ad libitum while no changes were observed in the preoptic area of the hypothalamus (POA) where GnRH is biosynthesised. Neither the expression of preoptic GnRH mRNA nor the expression of GAD65 and of GnRH-R mRNA in both hypothalamic structures was affected by feed restriction. In the anterior pituitary, a significant reduction of the expression of GnRH-R, LH-beta and the alpha subunit was observed in the feed restricted rats, whereas FSH-beta mRNA levels remained constant. Thus, feed restriction selectively increased the expression of GABA-synthesizing enzymes in the MBH but did not modify GnRH expression in the POA. However, the reduced expression of the LH-beta- and alpha-subunit and of the GnRH-R in the anterior pituitary indicates that pulsatile GnRH release may have been attenuated or even abolished. We suggest, that enhanced expression of GABA-synthesizing enzymes reflects increased GABAergic neurotransmission and thereby reducing GnRH release from the MBH.

Managed care and children: an overview.

This article lays the foundation for the other articles in this journal issue, which examine the effect of managed health care arrangements on a particular population: children. Although managed care has been used to finance and deliver health care services for decades, the meaning of this term often has been unclear to health care consumers and practitioners because new forms of managed care have evolved rapidly. The one consistent and unifying concept across all managed care arrangements is that enrollees obtain care from a network of participating health care providers who contract with the managed care organization and abide by the organization's rules. The uncertainty of what managed care is has made it difficult to measure the effect of these arrangements on health service delivery and health outcomes, especially in the pediatric population, where the development of outcome and quality measures lags behind that for adults. The incentives posed by managed care suggest both potential advantages and disadvantages to these arrangements for children. On the positive side, managed care enrollment may offer a "medical home" for primary care services to children who otherwise would obtain only episodic care; improve the coordination of health care services; and encourage more preventive health services. On the negative side, under capitated reimbursement, health plans have an incentive to enroll only healthy children with the lowest expected health care expenditures, and providers have an incentive to offer fewer services than may be appropriate. Managed care also may limit enrollees' choice of providers, particularly for specialty care. Despite the paucity of information about the effect of managed care on the delivery of pediatric health services and on child health outcomes, children are disproportionately being enrolled in managed care plans.

Medicare and managed care.

Medicare offers nearly universal, but limited, coverage for the elderly. The vast majority of beneficiaries therefore obtain supplemental coverage, or they enroll in HMOs to gain extra benefits at substantially lower or zero cost. This is possible because of reduced utilization and costs, as well as favorable selection of lower-risk enrollees into HMOs. Competition from HMOs may lower local fee-for-service costs as well. Quality and satisfaction measures are quite balanced, with some results showing better HMO performance and some worse. The absence of adequate risk-adjusted payments to HMOs, however, gives them little incentive to develop high-quality programs for the sickest enrollees.

The costs and outcomes of restricting public access to poison control centers. Results from a natural experiment.

OBJECTIVES: The authors examined the costs and outcomes resulting from a natural experiment during which direct public access to poison control centers was restricted and then restored. METHODS: Both societal and health care purchaser perspectives were used. Probability data were obtained from a natural experiment during which public callers from a large county in California were electronically blocked from directly accessing the poison control center. Callers were referred to 911, which had direct access to the poison control center, if they thought they had a poisoning emergency. We conducted telephone interviews of: (a) persons who attempted to call the poison control center for a child's poisoning exposure but who did not have direct access (n = 270) and (b) persons who called the poison control center after direct access was restored (n = 279). Cost data were obtained from primary data collection and from other sources. The outcome measure was the appropriateness of the treatment location (at home or at a health care facility). Caller-reported outcomes were also examined. RESULTS: The average additional cost per blocked call was $10.89 from a societal perspective, or $33.14 from a health care purchaser perspective. Fourteen percent of callers with restricted access were treated at an inappropriate location, compared with only 2% of callers with direct poison control center access. Also, 14% did not obtain any professional advice after they attempted to call the poison control center, although 66% of these cases involved potentially toxic substances. Results were robust across a range of sensitivity analyses. CONCLUSION: Restricting direct public access to poison control centers created additional costs to society, the health care sector, and callers.