Trends in diabetes self-management education: where are we coming from and where are we going? A narrative review.

AIMS: To summarize the history, development and efficacy of diabetes self-management education on glycaemic control and mental health in adults and children or adolescents with type 1 diabetes and people with type 2 diabetes. A further aim was to review the status of implementation of diabetes self-management education into routine care and outline current gaps in implementation and research. METHODS: We searched PubMed and Google scholar for German- and English-language articles regarding diabetes self-management education, glycaemic control and mental health, and restricted this search to meta-analyses. RESULTS: Diabetes education has evolved from a compliance- and knowledge-oriented approach to an empowerment- and self-management-oriented approach. Diabetes self-management education seems to have a greater impact on glycaemic outcomes than on mental health outcomes, but the latter are rarely assessed. Technological development and digitalization can provide chances and challenges for diabetes self-management education. Digital solutions show promising results and great potential for improving the efficacy of diabetes self-management education further and providing ongoing support. The implementation of diabetes self-management education into routine clinical care frequently remains a challenge. CONCLUSION: Diabetes self-management education has been acknowledged as an essential part of diabetes therapy; however, current gaps regarding the efficacy of diabetes self-management education on mental health, and the need for education on the use of diabetes technology, are future avenues for research.

The effect of an education programme (MEDIAS 2 BSC) of non-intensive insulin treatment regimens for people with Type 2 diabetes: a randomized, multi-centre trial.

AIMS: A self-management oriented education programme (MEDIAS 2 BSC) for people with Type 2 diabetes who are on a non-intensive insulin treatment regimen was developed. In a randomized, multi-centre trial, the effect of MEDIAS 2 BSC was compared with an established education programme that acted as a control group. METHODS: The primary outcome was the impact of MEDIAS 2 BSC on glycaemic control. Secondary outcomes included the incidence of severe hypoglycaemia, hypoglycaemia unawareness, diabetes-related distress, diabetes knowledge, quality of life and self-care behaviour. RESULTS: In total, 182 participants were randomized to the control group or MEDIAS 2 BSC [median age 64.0 (interquartile range 58.0-68.5) vs. 63.5 (57.0-70.0) years; HbA1c 62.8 ± 12.7 mmol/mol vs. 63.7 ± 14.0 mmol/mol; 7.9% ± 1.2% vs. 8.0% ± 1.3%]. After a 6-month follow-up, there was a mean decrease in HbA1c of 3.5 mmol/mol (0.32%) in the control group and 6.7 mmol/mol (0.61%) in MEDIAS 2 BSC. After adjusting for baseline differences and study centre, the mean difference between the groups was -3.3 mmol/mol [95% confidence interval (CI) -0.54 to -5.90 mmol/mol] [-0.30% (95% CI -0.05 to -0.54)] in favour of MEDIAS 2 BSC (P = 0.018). There were no increases in severe hypoglycaemia or hypoglycaemia unawareness. The education programmes had no significant effects on psychosocial outcome variables. CONCLUSION: MEDIAS 2 BSC was more effective in lowering HbA1c than the control condition. MEDIAS 2 BSC is a safe educational tool that improves glycaemic control without increasing the risk for hypoglycaemia. (Clinical Trials Registry No; NCT 02748239).

How to assess diabetes distress: comparison of the Problem Areas in Diabetes Scale (PAID) and the Diabetes Distress Scale (DDS).

AIMS: To compare the properties of the two most commonly used assessment tools for diabetes distress, the Problem Areas in Diabetes Scale (PAID) and the Diabetes Distress Scale (DDS), in order to discriminate their psychometric capabilities and functions. METHODS: Six hundred and twenty-eight people with diabetes (67% Type 1, 33% Type 2) were cross-sectionally assessed with the PAID, the DDS and further self-report scales regarding coping, quality of life, depressive symptoms and self-care, and medical data were gained. We analysed the PAID and DDS for areas of contentual/psychometric divergence in assessing diabetes distress and compared their associations with criteria of interest. RESULTS: Content analysis: The PAID covers a greater variety of emotional concerns and shows a stronger focus on food-related problems and complications. The DDS is more reflective of physician-related distress and problems concerning diabetes self-management. Psychometric analysis: Exploratory factor analyses revealed four-factor structures of both scales, explaining 60% (PAID) and 67% (DDS) of variance. Confirmatory factor analyses confirmed that single-factor and four-factor models fit the data. Total scales proved high and subscales mostly satisfactory reliability. Associations with criteria of interest: The PAID was significantly more strongly associated with dysfunctional coping styles, quality of life and depressive symptoms. The DDS showed significantly stronger associations with diabetes self-care and metabolic outcomes. CONCLUSION: Our results support both PAID and DDS as good self-report measures of diabetes distress. The observed contentual/psychometric differences suggest that a justified choice with regard to the intended clinical or scientific purpose can improve the acquisition of the required data.

Longitudinal relationship of diabetes-related distress and depressive symptoms: analysing incidence and persistence.

AIM: To investigate the longitudinal bi-directionality of diabetes-related distress and depressive symptoms. METHODS: A total of 509 patients receiving intensified insulin therapy completed the Centre for Epidemiological Studies Depression scale questionnaire for the assessment of depressive symptoms as well as the Problem Areas in Diabetes questionnaire for the assessment of diabetes-related distress at baseline and at 6-month follow-up. Separate logistic and linear regression analyses for incidence and persistence were performed with demographic (age, gender, BMI) and medical (diabetes type, HbA1c , diabetes duration, late complications) control variables. RESULTS: Diabetes-related distress at baseline increased the risk of the incidence of elevated depressive symptoms by 2.56-fold (odds ratio 2.56; 95% CI 1.15-5.72; P = 0.02) when controlling for demographic and medical variables. In addition, diabetes-related distress at baseline doubled the chance of the persistence of elevated depressive symptoms (odds ratio 2.04, 95% CI 1.04-3.99; P = 0.04) when controlling for demographic and medical variables. The chance of having persistent elevated diabetes-related distress was increased 5.94-fold (odds ratio 5.94, 95% CI 2.60-13.59; P < 0.0001) when elevated depressive symptoms were present at baseline. None of the medical variables had an influence on incidence or persistence. CONCLUSIONS: Diabetes-related distress was identified as a risk factor for the incidence and persistence of depressive symptoms. Reducing diabetes-related distress could help to prevent the development of elevated depressive symptoms. Furthermore, depressive symptoms were identified as an amplifier for diabetes-related distress. Diabetes-related distress and depressive symptoms were independent risk factors for each other and should be monitored in routine care to disentangle their influence.

Health care effects and medical benefits of a smartphone-based diabetes self-management application: study protocol for a randomized controlled trial.

BACKGROUND: Diabetes self-management is a mainstay of diabetes care, but the implementation of self-management regimens into daily life is complex and often results in discouragement and distress. Modern approaches such as smartphone-based self-management applications are therefore needed to support people with diabetes. Since reimbursability would increase the availability of such digital applications to people with diabetes, we designed a study that meets all scientific and methodological requirements set by the German Digital Healthcare Act to allow reimbursement for a specific application (mySugr PRO). Here, we report the protocol of this study that aims at evaluating the efficacy of the digital self-management application with regard to patient-reported outcomes and medical benefits. METHODS/DESIGN: This multicenter, open-label, randomized, parallel-group, controlled trial will evaluate the health care effects and medical benefits of mySugr PRO. A total of 466 people with diabetes will be randomly allocated (2:1 randomization) to the interventional group (n = 311) that will use the digital self-management application during the 12-week study period or the control group (n = 155; no usage of the application). Baseline and follow-up examinations will assess diabetes distress as the primary endpoint as well as empowerment, HbA1c, blood glucose data, self-management, general well-being, and treatment satisfaction as secondary endpoints. Statistical analyses will use an intention-to-treat procedure (using multiple imputation for missing values) as well as a per-protocol approach for sensitivity analysis. DISCUSSION: To the best of our knowledge, this study will be one of the largest diabetes-specific evaluations of a digital health application supporting people with diabetes in their diabetes self-management that follow the requirements of the German Digital Healthcare Act. TRIAL REGISTRATION: German Clinical Trial Register DRKS00022923 . Registered on 22 October 2020.

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.

Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion.

Gonadotropin-releasing hormone agonist testing of pituitary-gonadal function.

The development of gonadotropin-releasing hormone (GnRH) agonists has provided a unique means to functionally assess the pituitary-gonadal axis in both males and females. These agonists, when given in a dose sufficient to stimulate the gonadotropes and induce a gonadal steroid response, have provided insights into normal reproductive physiology, hyperandrogenic conditions such as the polycystic ovary syndrome (PCOS), and disorders of pubertal development. This review provides an overview of the use of such agonists as probes of the functional status of the pituitary-gonadal axis in both normal and abnormal reproductive states.

Limitations to the use of a sensitive assay for serum thyrotropin in the assessment of thyroid status.

In the majority of clinical settings, a suppressed serum thyrotropin (s-TSH) level determined by the new sensitive assays is diagnostic of thyrotoxicosis. This has led to its proposed use as a screen for thyroid disease. However, s-TSH may be suppressed in conditions other than thyrotoxicosis. We retrospectively reviewed s-TSH measurements made in a large heterogeneous population to determine in which settings a suppressed value could potentially lead to misdiagnosis. We found that a suppressed s-TSH level was useful in making the diagnosis of autonomous thyroid function and in the assessment of thyroid hormone replacement therapy in patients with primary, but not central, hypothyroidism. Hyperthyroidism caused by either intrinsic thyroid disease or thyroid hormone administration accounted for 83% (111/134) of suppressed values; however, central hypothyroidism, nonthyroidal illness, acute psychiatric illness, or the administration of medication was responsible for this finding in 17% (23/134). While a suppressed s-TSH level is generally excellent in the diagnosis of pituitary suppression by thyroid hormone, in specific clinical settings, a suppressed s-TSH level may be seen in the absence of thyroid hormone excess. The limitations of its use as a first-line screen in those conditions must be recognized.

Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

OBJECTIVE: NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS: A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. RESULTS: Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). CONCLUSIONS: The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.

The GENNID Study. A resource for mapping the genes that cause NIDDM.

OBJECTIVE: To develop a resource, consisting of comprehensive data and lymphoblastoid cell lines, of well-characterized NIDDM families that will be available to the scientific community for genetic studies of NIDDM. RESEARCH DESIGN AND METHODS: Non-Hispanic white, Hispanic, African-American, and Japanese-American multiplex NIDDM families, with a minimum of one affected sib-pair, are being collected by the eight Harold Rifkin Family Acquisition Centers. Detailed family and medical histories are obtained from all participants. Family members with diabetes have fasting blood samples drawn, while nondiabetic family members have an oral glucose tolerance test and, when possible, insulin sensitivity and insulin secretion measurements by frequently sampled intravenous glucose tolerance testing or euglycemic insulin clamp. Lymphoblastoid cell lines are established for all participants. RESULTS: Over 1,400 individuals from approximately 220 families have been studied since the start of the GENNID (Genetics of NIDDM) program in July 1993. The goal is that by July 1997, data from 300 non-Hispanic white families, > 100 Hispanic families, > 100 African-American families, and 15 Japanese-American families will have been collected. CONCLUSIONS: The identification of the genes responsible for NIDDM may now be achievable, but only if sound phenotypic data are linked to genetic material from a large number of well-described multiplex families. The GENNID project of the American Diabetes Association is creating a comprehensive resource that will expedite the identification of the genetic basis of NIDDM.

Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives.

Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders of reproductive age women, is associated with an increased risk of type 2 diabetes mellitus. Defects in both insulin action and insulin secretion contribute to this predisposition to diabetes, but the extent to which these defects are heritable among PCOS families has not been examined. In the present study we used the frequently sampled iv glucose tolerance test to quantitate insulin secretion (AIRg), insulin action (Si), and their product (AIRg x Si) among women with PCOS (n = 33) and their nondiabetic first degree relatives (n = 48). We then quantitated the heritability of these measures from familial correlations estimated within a genetic model. Familial (spousal, rhoMF; parent-offspring, rhoPO; and sibling, rhoSS) correlations were derived for log-transformed body mass index (BMI) as well as for AIRg, Si, and AIRg x Si, the latter three of which were adjusted for BMI. There was no evidence of significant heritability for either lnBMI or lnSi in these families. In contrast, the sibling correlation (rhoSS = 0.74) for lnAIRg was highly significant (chi(2) = 7.65; 1 df; P = 0.006). In addition, the parameter quantitating insulin secretion in relation to insulin sensitivity [i.e. ln(AIRg x Si)] was significant among siblings (rho(SS) = 0.74; chi(2) = 4.32; 1 df; P = 0.04). In summary, the results of the present study indicate that there is an heritable component to beta-cell dysfunction in families of women with PCOS. We conclude that heritability of beta-cell dysfunction is likely to be a significant factor in the predisposition to diabetes in PCOS.

Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism.

Plasma 17-hydroxyprogesterone (17PROG) hyperresponsiveness to GnRH agonist (nafarelin) testing is typical of polycystic ovary syndrome and other functional ovarian hyperandrogenism (FOH) that does not meet customary criteria for the diagnosis of polycystic ovary syndrome. We have postulated that this results from abnormal regulation of androgen secretion. Whether this dysregulation is the result of a normal physiological response to ovarian hyperstimulation or escape from down-regulation of steroidogenesis is unknown. To distinguish between these possibilities, we have analyzed the ovarian steroid responses to nafarelin for the apparent efficiency of the steroidogenic steps and the apparent dose-response relationships between blood LH and steroid levels. We compared normal women (n = 18) with three groups of hyperandrogenic women (n = 15-19/group): patients with 17PROG hyperresponsiveness with or without elevated LH levels (type 1 and type 2 FOH, respectively) and patients with normal 17PROG responses to nafarelin (nafarelin negative). Subjects were pretreated with dexamethasone to suppress coincidental adrenal contributions to plasma steroid levels. The pattern of steroid secretion was similarly abnormal in both types of FOH, with the high LH group having generally more severe abnormalities in the levels of steroid intermediates. Baseline 17PROG and 17-hydroxypregnenolone and the ratio of 17PROG to androstenedione (AD) were increased (P < 0.05). In addition, the apparent slope of the 17PROG response to LH was significantly increased. Baseline levels of both AD and dehydroepiandrosterone and the AD response to nafarelin were increased, yet the ratio of peak minus baseline (delta) AD/delta 17PROG (another index of 17,20-lyase activity) was subnormal in FOH. The apparent slope of the testosterone (T) response to LH was significantly increased, and indexes of aromatase activity [estradiol (E2)/T and delta estradiol/delta T] were significantly decreased. Nafarelin stimulated plasma E2 in all groups to rise along an apparently similar LH-E2 dose-response slope. We interpret these results as indicating that FOH patients have generalized overactivity of thecal steroidogenesis, but nevertheless compensate so as to maintain a normal dose-response relationship between blood levels of LH and E2. FOH patients, whether they have LH excess or not, seen to form excessive 17PROG and incompletely dampen (down-regulate) thecal cell 17PROG, AD, and T secretion in response to LH stimulation. 17PROG hyperresponsiveness to nafarelin seems to be prominent both because it is formed in excess and because 17,20-lyase efficiency is rate limiting. The T elevation seems to arise mainly from overactive steroidogenesis, but also partly from an additional functional decrease in aromatase efficiency, which is secondary to negative feedback by the substrate-driven tendency toward estrogen excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute hormonal responses to the gonadotropin releasing hormone agonist leuprolide: dose-response studies and comparison to nafarelin--a clinical research center study.

The hormonal responses to single subcutaneous injection of the GnRH agonist nafarelin have been shown to have considerable potential as a diagnostic test in a number of settings. Since nafarelin injection is no longer produced, studies were conducted to determine the dosage of leuprolide that would yield equivalent responses. Nafarelin 100 micrograms stimulates LH and FSH for 24 h, releasing about 7-fold more gonadotropin than this dose of natural GnRH, which accounts for its ability to elicit gonadal steroid responses. Normal adult men and women were randomized to receive leuprolide doses of 0.1, 1.0, or 10 micrograms/kg; a study extension evaluated doses up to 20 micrograms/kg in men. The responses of LH, FSH, testosterone, and estradiol were monitored for 24 h, and the data were compared to those previously obtained on nafarelin. Leuprolide dose of 10 micrograms/kg yielded LH responses similar to 1-1.5 micrograms/kg nafarelin. However, this leuprolide dose unexpectedly released less FSH than nafarelin. Nevertheless, the gonadotropin responses were sufficient to elicit equivalent or greater sex steroid responses to leuprolide. These studies also further delineated sex-specific differences in pituitary responsiveness to challenge with GnRH agonists: men had a significantly lower baseline FSH level, greater LH release within the first hour, and lesser secretion of LH and FSH over the 24-h period. These studies indicate that leuprolide in a dosage of 10 micrograms/kg would be expected to be efficacious in testing the pituitary-gonadal axis in men and women.

A new test of combined pituitary-testicular function using the gonadotropin-releasing hormone agonist nafarelin in the differentiation of gonadotropin deficiency from delayed puberty: pilot studies.

There is evidence that the capacity to synthesize gonadotropins is less in teenage boys with gonadotropin deficiency (GD) than in those with constitutional delay of puberty (DP). We hypothesized that this might predispose the latter group to have a greater pituitary-testicular response to the potent long-acting GnRH agonist nafarelin. We evaluated GD patients 14.3-24.0 yr of age (n = 8) and prepubertal DP boys 14.8-17.6 yr of age (n = 3). In most subjects the response to nafarelin was compared to that of frequent nocturnal blood sampling for LH and testosterone levels. All subjects received a single dose of nafarelin (1.0 micrograms/kg, sc), and blood was then sampled at 0.5- to 4.0-h intervals for 24 h. Patients with GD could not be distinguished from those with DP by pubertal staging criteria or by baseline values of LH, FSH, or testosterone. Patients with GD exhibited no rise in plasma LH levels during sleep, in contrast to those with DP. All GD patients had LH and FSH responses distinctly less than those of the DP group between 3-24 h postnafarelin. The peak incremental responses of GD and DP to nafarelin were, respectively: LH, 5.5 +/- 2 3 (+/- SEM and 77.2 +/- 8.6 IU/L (P less than 0.02); FSH, 2.7 +/- 1.2 and 9.4 +/- 0.8 IU/L (P less than 0.005). Testosterone peak responses were lower as well (0.26 +/- 0.2 vs 1.6 +/- 0.5 nmol/L, P = 0.05). This pilot study suggests that the response to a single test dose of nafarelin distinguishes GD from DP in the teenage years as well as does measurement of nocturnal LH levels. The testosterone response to the GnRH agonist adds a new dimension to GnRH testing. Nafarelin also allows assessment of the bioactivity of endogenous gonadotropin, is a more potent stimulus of pituitary-testicular function than endogenous GnRH secretion, and is more cost-effective than nocturnal sampling.

Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome.

Hyperinsulinemia contributes to the ovarian androgen overproduction and glucose intolerance of polycystic ovary syndrome (PCOS). We sought to determine whether metformin would reduce insulin levels in obese, nondiabetic women with PCOS during a period of weight maintenance and thus attenuate the ovarian steroidogenic response to the GnRH agonist leuprolide. All subjects (n = 14) had an oral glucose tolerance test, a GnRH agonist (leuprolide) test, a frequently sampled iv glucose tolerance test, graded and oscillatory glucose infusions, and a dual energy x-ray absorptiometry scan before and after treatment with metformin (850 mg, orally, three times daily for 12 weeks). With weight maintenance (body mass index: pretreatment, 39.0 +/- 7.7 kg/m2, posttreatment, 39.1 +/- 7.9 kg/m2), oral glucose tolerance, insulin sensitivity (Si; 0.87 +/- 0.82 vs. 0.74 +/- 0.63 x 10(-5) min-1/ pmol.L), and the relationship between Si and first phase insulin secretion (AIRg vs. Si) were not improved by metformin. The insulin secretory response to glucose, administered in both graded and oscillatory fashions, was likewise unaltered in response to metformin. Free testosterone levels remained about 2-fold elevated (pretreatment, 26.6 +/- 12.7 pg/mL; posttreatment, 22.4 +/- 9.8 pg/mL). Both basal and stimulated LH and FSH levels were unaffected by metformin. The mean responses to leuprolide of 17-hydroxyprogesterone (pretreatment, 387 +/- 158 ng/dL; posttreatment, 329 +/- 116 ng/dL) as well as those of the other ovarian secretory products (androstenedione, dehydroepiandrosterone, progesterone, and estradiol) were not attenuated by metformin. We conclude that hyperinsulinemia and androgen excess in obese nondiabetic women with PCOS are not improved by the administration of metformin.

Ovarian steroidogenic responses to gonadotropin-releasing hormone agonist testing with nafarelin in hirsute women with adrenal responses to adrenocorticotropin suggestive of 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency.

Nonclassical 3 beta-hydroxy-delta 5-steroid dehydrogenase (3 beta-HSD) deficiency type of congenital adrenal hyperplasia has been hypothesized to occur in as many as 10-40% of hirsute women, based on the adrenal steroidogenic responses to ACTH. However, diagnostic criteria for this "late-onset" 3 beta-HSD deficiency are not clearly established. Among 40 successive hyperandrogenic women undergoing evaluation of adrenal steroidogenic responses to ACTH, 8 had responses suggestive of 3 beta-HSD deficiency. Since 3 beta-HSD is present in both the ovary and adrenal, we attempted to document the defect in the ovary by stimulating their ovarian function with a gonadotropin-releasing hormone agonist test using nafarelin (6-D-[2-naphthyl]alanine-gonadotropin-releasing hormone). The eight hirsute women had steroid responses to ACTH suggestive of 3 beta-HSD deficiency, namely, the values of the delta 5-steroids, 17-hydroxypregnenolone and dehydroepiandrosterone, 30 and 60 min after ACTH in each hirsute woman were greater than 2 SD above the normal mean. Seven of the eight hirsute women had at least one elevated delta 5/delta 4-steroid ratio; however, only three of the hirsute women had two abnormal ratios. Furthermore, the response of the delta 4-steroid androstenedione and the ratio of androstenedione to cortisol after ACTH were significantly increased in the hirsute women, findings not consistent with 3 beta-HSD deficiency. After nafarelin, five and six hirsute patients had elevated values of the delta 4-steroids androstenedione and 17-hydroxyprogesterone, respectively. No patient had an elevated delta 5/delta 4-steroid ratio after nafarelin. Thus, ovarian steroidogenic responses to nafarelin did not support the diagnosis of 3 beta-HSD deficiency. Rather, they are consistent in most cases with polycystic ovary syndrome due to dysregulation of 17-hydroxylase and 17,20-lyase activities. We propose that increased activity of the enzyme P450c17 alpha in the adrenal cortex is responsible for most of what is often termed late-onset 3 beta-HSD deficiency.

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.

Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.