Fundamentals of OA. An initiative of Osteoarthritis and Cartilage. Obesity and metabolic factors in OA.

OBJECTIVE: Obesity was once considered a risk factor for knee osteoarthritis (OA) primarily for biomechanical reasons. Here we provide an additional perspective by discussing how obesity also increases OA risk by altering metabolism and inflammation. DESIGN: This narrative review is presented in four sections: 1) metabolic syndrome and OA, 2) metabolic biomarkers of OA, 3) evidence for dysregulated chondrocyte metabolism in OA, and 4) metabolic inflammation: joint tissue mediators and mechanisms. RESULTS: Metabolic syndrome and its components are strongly associated with OA. However, evidence for a causal relationship is context dependent, varying by joint, gender, diagnostic criteria, and demographics, with additional environmental and genetic interactions yet to be fully defined. Importantly, some aspects of the etiology of obesity-induced OA appear to be distinct between men and women, especially regarding the role of adipose tissue. Metabolomic analyses of serum and synovial fluid have identified potential diagnostic biomarkers of knee OA and prognostic biomarkers of disease progression. Connecting these biomarkers to cellular pathophysiology will require future in vivo studies of joint tissue metabolism. Such studies will help reveal when a metabolic process or a metabolite itself is a causal factor in disease progression. Current evidence points towards impaired chondrocyte metabolic homeostasis and metabolic-immune dysregulation as likely factors connecting obesity to the increased risk of OA. CONCLUSIONS: A deeper understanding of how obesity alters metabolic and inflammatory pathways in synovial joint tissues is expected to provide new therapeutic targets and an improved definition of "metabolic" and "obesity" OA phenotypes.

Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Do DSM-5 Section II personality disorders and Section III personality trait domains reflect the same genetic and environmental risk factors?

BACKGROUND: DSM-5 includes two conceptualizations of personality disorders (PDs). The classification in Section II is identical to the one found in DSM-IV, and includes 10 categorical PDs. The Alternative Model (Section III) includes criteria for dimensional measures of maladaptive personality traits organized into five domains. The degree to which the two conceptualizations reflect the same etiological factors is not known. METHODS: We use data from a large population-based sample of adult twins from the Norwegian Institute of Public Health Twin Panel on interview-based DSM-IV PDs and a short self-report inventory that indexes the five domains of the DSM-5 Alternative Model plus a domain explicitly targeting compulsivity. Schizotypal, Paranoid, Antisocial, Borderline, Avoidant, and Obsessive-compulsive PDs were assessed at the same time as the maladaptive personality traits and 10 years previously. Schizoid, Histrionic, Narcissistic, and Dependent PDs were only assessed at the first interview. Biometric models were used to estimate overlap in genetic and environmental risk factors. RESULTS: When measured concurrently, there was 100% genetic overlap between the maladaptive trait domains and Paranoid, Schizotypal, Antisocial, Borderline, and Avoidant PDs. For OCPD, 43% of the genetic variance was shared with the domains. Genetic correlations between the individual domains and PDs ranged from +0.21 to +0.91. CONCLUSION: The pathological personality trait domains, which are part of the Alternative Model for classification of PDs in DSM-5 Section III, appears to tap, at an aggregate level, the same genetic risk factors as the DSM-5 Section II classification for most of the PDs.

The evolution of fecundity is associated with female body size but not female-biased sexual size dimorphism among frogs.

Sexual size dimorphism (SSD) is one of the most common ways in which males and females differ. Male-biased SSD (when males are larger) is often attributed to sexual selection favouring large males. When females are larger (female-biased SSD), it is often argued that natural selection favouring increased fecundity (i.e. larger clutches or eggs) has coevolved with larger female body size. Using comparative phylogenetic and multispecies regression model selection approaches, we test the hypothesis that among-species variation in female fecundity is associated with the evolution of female-biased SSD. We also ask whether the hypothesized relationship between SSD and fecundity is relaxed upon the evolution of parental care. Our results suggest a strong relationship between the evolution of fecundity and body size, but we find no significant relationship between fecundity and SSD. Similarly, there does not appear to be a relationship between fecundity and the presence or absence of parental care among species. Thus, although female body size and fecundity coevolve, selection for increased fecundity as an explanation for female-biased SSD is inconsistent with our analyses. We caution that a relationship between female body size and fecundity is insufficient evidence for fecundity selection driving the evolution of female-biased SSD.

Towards an evidence-based process for the clinical interpretation of copy number variation.

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Clinical laboratory implementation of cytogenomic microarrays.

Examination of the whole genome for copy number alterations by microarray is now routinely done in many laboratories. The field of cytogenetics has evolved to adapt this technology, and the current phase of transition has resulted in the need for standardization in methodologies and interpretation of data. This review will outline some of the changes addressed in the field over the last several years and briefly discuss some of the trends in data processing, analysis and interpretation.

Genetic and environmental influences on internalizing psychopathology vary as a function of economic status.

BACKGROUND: Different theories of the link between socio-economic status (SES) and mental illness have been postulated. In particular, two theories of this association, social causation and social selection, differ in the implied causal pathway. The authors employ behavior genetic modeling to consider evidence for both social selection and social causation in the relationship between income variation and internalizing disorders. METHOD: Behavior genetic modeling was used to estimate the presence of gene-environment interaction (GxE, social causation) in the presence of gene-environment correlation (rGE, social selection). Participants were members of a sample of 719 twin pairs from the Midlife in the United States study. Four internalizing (INT) syndromes were assessed: major depression (MD); generalized anxiety disorder (GAD); panic attacks (PA); neuroticism (N). SES was measured with total family household income. RESULTS: One factor best accounted for the variance shared between MD, GAD, PA and N. The etiology of variation in INT changed from high to low levels of income, with unique environmental factors playing a larger role in INT variation at lower levels of income. Across levels of income, rGE between income and INT was modest (low income ra=0.39 to high income ra=0.54), implying a selection process operating through genetic effects linking lower income with INT psychopathology. CONCLUSIONS: Findings support social causation by suggesting that low income contributes significantly to environmental variation in INT. Modest support was found for social selection, but should be extended using longitudinal designs. Effective interventions for internalizing psychopathology may differ depending on income.

Contrasting prototypes and dimensions in the classification of personality pathology: evidence that dimensions, but not prototypes, are robust.

BACKGROUND: DSM-5 may mark the shift from a categorical classification of personality pathology to a dimensional system. Although dimensional and categorical conceptualizations of personality pathology are often viewed as competing, it is possible to develop categories (prototypes) from combinations of dimensions. Robust prototypes could bridge dimensions and categories within a single classification system. METHOD: To explore prototype structure and robustness, we used finite mixture modeling to identify empirically derived personality pathology prototypes within a large sample (n=8690) of individuals from four settings (clinical, college, community, and military), assessed using a dimensional measure of normal and abnormal personality traits, the Schedule for Nonadaptive and Adaptive Personality (SNAP). We then examined patterns of convergent and discriminant external validity for prototypes. Finally, we investigated the robustness of the dimensional structure of personality pathology. RESULTS: The resulting prototypes were meaningful (externally valid) but non-robust (sample dependent). By contrast, factor analysis revealed that the dimensional structures underlying specific traits were highly robust across samples. CONCLUSIONS: We interpret these results as further evidence of the fundamentally dimensional nature of an empirically based classification of personality pathology.

U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements.

BACKGROUND: Chromosomal rearrangements resulting in an interstitial inverted duplication with concomitant terminal deletion were first described for the short arm of chromosome 8 in 1976. Since then, this type of alteration has been identified and characterised for most chromosome arms. Three mechanisms are commonly proposed to explain the origin of this type of rearrangement. All three mechanisms involve formation of a dicentric chromosome that then breaks in a subsequent meiotic division to produce a monocentric duplicated and deleted chromosome. However, the events leading to the formation of the dicentric chromosome differ between the mechanisms. In one mechanism, either parent carries a paracentric inversion. This results in formation of a loop during meiotic pairing with a recombination event occurring in the loop. In the second mechanism, inverted low copy repeats in the same chromosome arm allow partial folding of one homologue onto itself with a recombination event between the inverted repeats. The third mechanism involves a pre-meiotic double-strand break with subsequent fusion, or U-type exchange, between the sister chromatids. The first two mechanisms require a single copy region to exist between the duplicated and deleted regions on the derivative chromosome, and therefore high resolution analysis of the rearrangement can be used to distinguish between these mechanisms. METHODS AND RESULTS: Using G-banded chromosome analysis, fluorescence in situ hybridisation (FISH) and array comparative genomic hybridisation (CGH), we describe 17 new cases of inverted duplication with terminal deletion of 2q, 4p, 5p, 6q, 8p, 9p, 10q, 13q, 15q, 18p, 18q, and 22q. CONCLUSIONS: These new cases, combined with previously described cases, demonstrate that U-type exchange is the most frequent mechanism for this rearrangement and can be observed on most, or perhaps all, chromosome arms.

Externalizing disorders: cluster 5 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: The extant major psychiatric classifications DSM-IV and ICD-10 are purportedly atheoretical and largely descriptive. Although this achieves good reliability, the validity of a medical diagnosis is greatly enhanced by an understanding of the etiology. In an attempt to group mental disorders on the basis of etiology, five clusters have been proposed. We consider the validity of the fifth cluster, externalizing disorders, within this proposal. METHOD: We reviewed the literature in relation to 11 validating criteria proposed by the Study Group of the DSM-V Task Force, in terms of the extent to which these criteria support the idea of a coherent externalizing spectrum of disorders. RESULTS: This cluster distinguishes itself by the central role of disinhibitory personality in mental disorders spread throughout sections of the current classifications, including substance dependence, antisocial personality disorder and conduct disorder. Shared biomarkers, co-morbidity and course offer additional evidence for a valid cluster of externalizing disorders. CONCLUSION: Externalizing disorders meet many of the salient criteria proposed by the Study Group of the DSM-V Task Force to suggest a classification cluster.

Peroxisome synthesis in the absence of preexisting peroxisomes.

Zellweger syndrome and related diseases are caused by defective import of peroxisomal matrix proteins. In all previously reported Zellweger syndrome cell lines the defect could be assigned to the matrix protein import pathway since peroxisome membranes were present, and import of integral peroxisomal membrane proteins was normal. However, we report here a Zellweger syndrome patient (PBD061) with an unusual cellular phenotype, an inability to import peroxisomal membrane proteins. We also identified human PEX16, a novel integral peroxisomal membrane protein, and found that PBD061 had inactivating mutations in the PEX16 gene. Previous studies have suggested that peroxisomes arise from preexisting peroxisomes but we find that expression of PEX16 restores the formation of new peroxisomes in PBD061 cells. Peroxisome synthesis and peroxisomal membrane protein import could be detected within 2-3 h of PEX16 injection and was followed by matrix protein import. These results demonstrate that peroxisomes do not necessarily arise from division of preexisting peroxisomes. We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes.

Inhibitors of COPI and COPII do not block PEX3-mediated peroxisome synthesis.

In humans, defects in peroxisome biogenesis are the cause of lethal diseases typified by Zellweger syndrome. Here, we show that inactivating mutations in human PEX3 cause Zellweger syndrome, abrogate peroxisome membrane synthesis, and result in reduced abundance of peroxisomal membrane proteins (PMPs) and/or mislocalization of PMPs to the mitochondria. Previous studies have suggested that PEX3 may traffic through the ER en route to the peroxisome, that the COPI inhibitor, brefeldin A, leads to accumulation of PEX3 in the ER, and that PEX3 overexpression alters the morphology of the ER. However, we were unable to detect PEX3 in the ER at early times after expression. Furthermore, we find that inhibition of COPI function by brefeldin A has no effect on trafficking of PEX3 to peroxisomes and does not inhibit PEX3-mediated peroxisome biogenesis. We also find that inhibition of COPII-dependent membrane traffic by a dominant negative SAR1 mutant fails to block PEX3 transport to peroxisomes and PEX3-mediated peroxisome synthesis. Based on these results, we propose that PEX3 targeting to peroxisomes and PEX3-mediated peroxisome membrane synthesis may occur independently of COPI- and COPII-dependent membrane traffic.

PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.

Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.

Comparison of targeted and whole genome analysis of postnatal specimens using a commercially available array based comparative genomic hybridisation (aCGH) microarray platform.

PURPOSE: The University of Utah Comparative Genomic Hybridization Microarray Laboratory was one of the first US laboratories to offer comparative genomic hybridisation (CGH) microarray testing using a commercial platform in a clinical setting. Results for 1076 patients (1598 chips) are presented. METHODS: The Spectral Genomics/PerkinElmer Constitutional Chip (targeted array), SpectralChip 2600 (whole genome array) and a "Combo" chip (both arrays run simultaneously) were the tests offered. Abnormal results were confirmed by an alternative method, most often fluorescence in situ hybridisation. RESULTS: In 669 cases with known normal cytogenetics, an abnormal detection rate of 10.8% was observed, (5.3%, 12.2% and 14.1% for the Constitutional Chip, SpectralChip 2600 and Combo assay, respectively). Known copy number variants and single clone abnormalities are not included in these rates. Single clone abnormalities are reported separately. For 1076 total cases, we report an average abnormal rate of 16.9% (8.7%, 23.7% and 18.6% for the three assays). This rate includes characterisation of some abnormalities previously identified by cytogenetics. CONCLUSIONS: CGH microarray provides a likely aetiology for the clinical phenotype in many cytogenetically normal cases, and a whole genome array generally identifies copy number changes more effectively than a targeted chip alone.

Expansion in size of a terminal deletion: a paradigm shift for parental follow-up studies.

BACKGROUND: Parental studies are often necessary subsequent to the identification of a chromosome abnormality. The recommended studies are based on assumptions about how chromosome rearrangements occur. One such assumption is that deletion size is stable through generations. RESULTS: We have identified a family where a small subtelomeric deletion in a phenotypically and cytogenetically normal mother expanded nearly 10-fold into a clinically consequential and cytogenetically visible deletion in her affected daughter. CONCLUSION: Traditional parental follow-up studies would have not identified this expansion, but would have rather classified the deletion in the daughter as either de novo or benign. Only by sizing the deletion by array comparative genomic hybridisation in both the mother and the daughter was the expansion recognised. Previous assumptions about chromosome behaviour suggest that this phenomenon may have been easily missed in other cases of chromosomal deletions. Therefore, this case illustrates the need for more comprehensive analyses of parental chromosome structure when characterising an abnormality in a child.

Inflammatory pain-induced signaling events following a conditional deletion of the N-methyl-D-aspartate receptor in spinal cord dorsal horn.

The N-methyl-d-aspartate (NMDA) receptor in the spinal cord dorsal horn (SCDH) is one of the mechanisms involved in central sensitization during chronic pain. Previously, this laboratory created a spatio-temporal knockout (KO) of the N-methyl-d-aspartate receptor I (NR1) subunit in the mouse SCDH. The NR1 KO completely blocks NR1 gene and subsequent NMDA receptor expression and function in SCDH neurons. In the NR1 KO mice, the mechanical and cold allodynia induced at 24 h after complete Freund's adjuvant (CFA) was reduced. However, the protective effects of KO were transient and were not seen at 48 h after CFA. These observations suggest the presence of NMDA-independent pathways that contribute to CFA-induced pain. CFA induces the activation of several signaling cascades in the SCDH, including protein kinase C (PKC)gamma and extracellular signal-regulated kinases (ERK1/2). The phosphorylation of PKCgamma and ERK1/2 was inhibited in the SCDH of NR1 KO mice up to 48 h after CFA treatment, suggesting that these pathways are NMDA receptor-dependent. Interestingly, neuronal cyclooxygenase (COX) -2 expression and microglial p38 phosphorylation were induced in the SCDH of the NR1 KO at 48 h after CFA. Our findings provide evidence that inflammatory reactions are responsible for the recurrence of pain after NR1 KO in the SCDH.

Squamous cell carcinoma of the vulva in a young woman with Crohn's disease.

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. Because Crohn's disease is transmural it may form fistulas to adjacent structures, including the perineum and vulva. CASE: A 28-year-old white female with a history of Crohn's disease presented with a non-healing vulvar fistula. Biopsy revealed squamous cell carcinoma. CONCLUSION: Young women may develop squamous cell carcinoma associated with fistulae of Crohn's disease.

The association between personality disorders with alcohol use and misuse: A population-based twin study.

BACKGROUND: A clearer understanding of the etiological overlap between DSM-IV personality disorders (PDs) and alcohol use (AU) and alcohol use disorder (AUD) is needed. To our knowledge, no study has modeled the association between all 10 DSM-IV PDs and lifetime AU and AUD. The aim of the present study is to identify which PDs are most strongly associated with the phenotypic, genetic, and environmental risks of lifetime AU and AUD, and to determine if these associations are stable across time. METHODS: Participants were Norwegian twins assessed at two waves. At Wave 1, 2801 twins were assessed for all 10 DSM-IV PD criteria, lifetime AU, and DSM-IV AUD criteria. At Wave 2, six of the 10 PDs were again assessed along with AU and AUD among 2393 twins. Univariate and multiple logistic regressions were run. Significant predictors were further analyzed using bivariate twin Cholesky decompositions. RESULTS: Borderline and antisocial PD criteria were the strongest predictors of AU and AUD across the two waves. Despite moderate phenotypic and genetic correlations, genetic variation in these PD criteria explained only 4% and 3% of the risks in AU, and 5% to 10% of the risks in AUD criteria, respectively. At Wave 2, these estimates increased to 8% and 23% for AU, and 17% and 33% for AUD. CONCLUSIONS: Among a large Norwegian twin sample, borderline and antisocial PD criteria were the strongest predictors of the phenotypic and genotypic liability to AU and AUD. This effect remained consistent across time.

Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay.

A chemiluminescence-based GH assay with 30- to 100-fold increased sensitivity recently disclosed combined basal and pulsatile GH secretion in men. However, how age, sex steroid hormones, and obesity singly and jointly influence the basal vs. pulsatile modes of GH release is not known. We used the foregoing assay (detection threshold, 0.002-0.005 microgram/L) and high sensitivity and specificity (> or = 90% each) deconvolution analysis to quantitate basal and pulsatile GH secretion from 24-h serum GH concentration profiles in 26 healthy lean and obese men, whose ages spanned 18-63 yr and whose percentage body fat ranged from 12-47%. Concentrations of serum insulin-like growth factor I (IGF-I), IGF-I-binding protein-1 (IGFBP-1), and IGFBP-3 were related to specific measures of basal or pulsatile GH release. We observed that mean (24-h) serum GH concentrations embraced a 140-fold range from 0.013-1.8 micrograms/L and were related negatively to age (r = -0.50; P < 0.01), percentage body fat (r = -0.620; P < 0.01), and their interaction (r = -0.610; P < 0.01). In contrast, testosterone was a robustly positive statistical determinant of mean serum GH values (r = 0.628; P = 0.0006). Stepwise multivariate regression analysis disclosed that percentage body fat alone and jointly with the serum testosterone concentration controlled, respectively, 38% and 50% of the total variability in GH levels (P = 0.0013 and P = 0.0008). As assessed by deconvolution analysis, GH secretory burst mass was negatively related to percentage body fat (r = -0.621; P < 0.01) and positively to serum testosterone (r = 0.529; P = 0.0054). The calculated half-life of GH correlated positively with serum estradiol (r = 0.447; P = 0.032), and negatively with percentage body fat (r = -0.437; P = 0.048). Basal GH secretion rates were negatively related to serum estradiol (r = -0.485; P = 0.016). In contrast, GH secretory burst frequency and duration were unrelated to age, percentage body fat, or sex steroids. The fraction of total GH secreted in bursts was negatively correlated with the body mass index (r = -0.540; P < 0.01). Serum IGF-I concentrations were positively related to total pulsatile GH secretion (r = 0.690; P = 0.0011) and negatively to age (r = -0.597; P = 0.007) and percentage body fat (r = -0.611; P = 0.009).(ABSTRACT TRUNCATED AT 400 WORDS)

Alterations in luteinizing hormone secretory activity in women with insulin-dependent diabetes mellitus and secondary amenorrhea.

To investigate hypothalamic and/or pituitary abnormalities in women with poorly controlled insulin-dependent diabetes mellitus (IDDM) and secondary amenorrhea, we measured serum LH every 10 min for 24 h and for 2 additional h after the administration of exogenous GnRH in 8 women with IDDM and amenorrhea and compared these to data from 15 eumenorrheic nondiabetic women. LH pulses were characterized by the pulse detection algorithm Cluster, and secretory episodes were evaluated using the multiple parameter deconvolution procedure Deconv. Cluster analysis revealed fewer LH pulses per 24 h (14.3 +/- 1.2 vs. 19.9 +/- 0.6; P < 0.001; mean +/- SEM), a greater peak width (63 +/- 4.9 vs. 44 +/- 2.2 min; P < 0.01), and greater peak area (136 +/- 17 vs. 89 +/- 13 IU/L.min; P < 0.01) in the diabetic women. Analysis with Deconv revealed fewer LH secretory episodes per 24 h in the diabetic women (14.4 +/- 0.9 vs. 20.4 +/- 0.5; P < 0.001) and no statistical difference in LH half-lives. The IDDM women responded to a 10-micrograms GnRH bolus with LH pulses of larger total (51 +/- 15.9 vs. 15 +/- 1.4 IU/L; P < 0.01) and incremental (29 +/- 7.6 vs. 9 +/- 1.2; P < 0.001) amplitude. In summary, we observed that amenorrheic diabetic women have fewer LH pulses/secretory episodes than normal women. However, they respond well to exogenous GnRH, suggesting that compromise of the GnRH pulse generator, rather than pituitary dysfunction, is responsible for their menstrual dysfunction.