RESUMO
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.
Assuntos
Cromanos/administração & dosagem , Intolerância à Glucose/tratamento farmacológico , Glucose/administração & dosagem , Hipoglicemiantes/administração & dosagem , Ilhotas Pancreáticas/metabolismo , Tiazóis/administração & dosagem , Tiazolidinedionas , Administração Oral , Adulto , Animais , Método Duplo-Cego , Feminino , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Cobaias , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , TroglitazonaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/genética , Resistência à Insulina , Insulina/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adulto , Glicemia/análise , Índice de Massa Corporal , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Testosterona/sangueRESUMO
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.
RESUMO
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.
Assuntos
Doenças da Glândula Tireoide/sangue , Tireotropina/sangue , Adulto , Idoso , Feminino , Humanos , Hipertireoidismo/sangue , Hipotireoidismo/sangue , Hipotireoidismo/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/terapia , Hormônios Tireóideos/uso terapêuticoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Intolerância à Glucose/epidemiologia , Síndrome do Ovário Policístico/complicações , Adulto , Análise de Variância , Glicemia/metabolismo , Chicago/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Feminino , Seguimentos , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Síndrome do Ovário Policístico/sangue , Prevalência , Análise de Regressão , Testosterona/sangueRESUMO
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.
Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Negro ou Afro-Americano , População Negra , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Família , Feminino , Hispânico ou Latino , Humanos , Sistemas de Informação , Insulina/sangue , Insulina/farmacologia , Japão/etnologia , Lipídeos/sangue , Masculino , Núcleo Familiar , Linhagem , Fenótipo , População BrancaRESUMO
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.
Assuntos
Insulina/metabolismo , Síndrome do Ovário Policístico/genética , Adolescente , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Insulina/farmacologia , Secreção de Insulina , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismoRESUMO
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)
Assuntos
Hidroxiprogesteronas/sangue , Hiperandrogenismo/sangue , Nafarelina , Doenças Ovarianas/sangue , 17-alfa-Hidroxipregnenolona/sangue , 17-alfa-Hidroxiprogesterona , Adolescente , Adulto , Androstenodiona/sangue , Dexametasona/farmacologia , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Testosterona/sangueRESUMO
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.
Assuntos
Hormônios/administração & dosagem , Leuprolida/administração & dosagem , Nafarelina/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Humanos , Hormônio Luteinizante/sangue , Masculino , Caracteres Sexuais , Testosterona/sangueRESUMO
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.
Assuntos
3-Hidroxiesteroide Desidrogenases/deficiência , Glândulas Suprarrenais/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Hirsutismo/metabolismo , Nafarelina/farmacologia , Ovário/metabolismo , Esteroides/biossíntese , 17-alfa-Hidroxipregnenolona/sangue , 17-alfa-Hidroxiprogesterona , Adolescente , Adulto , Desidroepiandrosterona/sangue , Feminino , Hirsutismo/enzimologia , Humanos , Hidroxiprogesteronas/sangue , Cinética , Ovário/efeitos dos fármacos , Testosterona/sangueRESUMO
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.
Assuntos
Hipoglicemiantes/uso terapêutico , Insulina/fisiologia , Metformina/uso terapêutico , Ovário/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Esteroides/biossíntese , Adulto , Androgênios/sangue , Feminino , Glucose/fisiologia , Teste de Tolerância a Glucose , Gonadotropinas/sangue , Humanos , Insulina/metabolismo , Secreção de Insulina , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologiaRESUMO
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.
Assuntos
Gonadotropinas/sangue , Hipogonadismo/diagnóstico , Hipófise/fisiologia , Puberdade Tardia/diagnóstico , Testículo/fisiologia , Testosterona/sangue , Adolescente , Adulto , Diagnóstico Diferencial , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/farmacologia , Gonadotropinas/metabolismo , Humanos , Hipogonadismo/sangue , Hormônio Luteinizante/sangue , Masculino , Nafarelina , Projetos Piloto , Puberdade Tardia/sangue , Sono/fisiologia , Testículo/efeitos dos fármacos , Testosterona/metabolismoRESUMO
Previous studies have shown that hyperinsulinism is associated with hyperandrogenism in patients with the polycystic ovary syndrome, a form of functional ovarian hyperandrogenism (FOH). Although many studies have documented insulin resistance and hyperinsulinemia in polycystic ovary syndrome, the relative roles of insulin secretion and clearance in the pathogenesis of the hyperinsulinism remain uncertain. In this study, using individually derived C-peptide kinetic parameters, insulin secretion rates were calculated directly from plasma C-peptide concentrations in 10 patients with FOH and 7 weight-matched control subjects. All subjects were studied during a 24-h period when they ate a standardized diet consisting of 3 mixed meals. On a separate occasion, insulin sensitivity was calculated during a hyperinsulinemic euglycemic clamp. Although glucose concentrations in both groups were within the normal range, the FOH group had higher basal (P < 0.01) and 24-h insulin (P < 0.04) concentrations. The increased insulin concentrations reflected both a reduced clearance (P < 0.02) and an increased secretion of insulin. Basal insulin secretion rates were significantly increased (P < 0.04) in the FOH patients. By contrast, their incremental insulin secretory response to meals was markedly reduced. This reduction in the postprandial responses resulted from a reduction in the relative amplitude of meal-related (P < 0.007) secretory pulses, rather than from a reduction in the number of pulses present. Insulin sensitivity was also lower in those with FOH. Thus, women with FOH have significantly higher basal insulin secretory rates and attenuated secretory responses to meals. These secretory patterns resemble those of noninsulin-dependent diabetes mellitus more than they do those of simple obesity.
Assuntos
Androgênios/sangue , Hiperinsulinismo/etiologia , Hiperinsulinismo/fisiopatologia , Ilhotas Pancreáticas/fisiopatologia , Doenças Ovarianas/complicações , Adulto , Glicemia/análise , Peptídeo C/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Hiperinsulinismo/sangue , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Concentração OsmolarRESUMO
We have previously demonstrated that a single dose of the GnRH agonist nafarelin stimulates both gonadotropin and sex steroid secretion in adult men and women. In order to define the maturational steps involved in this response, we tested the effect of nafarelin on LH, FSH, testosterone (T), and estradiol (E2) secretion over 24 h in four groups of males: prepubertal (P1; n = 4), early pubertal (P2; n = 8), and midpubertal boys (P3; n = 4) with variations in the timing of puberty, and normal young adult males (P4; n = 10). Nafarelin stimulated rapid gonadotropin release in all groups, but the pattern of LH response varied. In prepubertal and pubertal boys, LH levels peaked 3-4 h after nafarelin and declined by 50% or more at 24 h post nafarelin. By contrast, adults reached an initial LH peak at 1 h, and LH secretion was sustained with levels 24 h post nafarelin equivalent to those during the early response phase. Nafarelin stimulated T secretion in all groups, but the response was greatest in groups P3 and P4; the maximal incremental rise (delta) in T was 1.2 +/- 0.5, 4.4 +/- 1.0, 18.8 +/- 5.4, and 15.3 +/- 1.4 nmol/L in P1, P2, P3, and P4 males, respectively (analysis of variance: F = 14.4, P < 0.001). E2 concentrations increased much more in adults than in the other groups post nafarelin: delta E2 was 5.5 +/- 1.1, 22.1 +/- 14.7, 83.9 +/- 47.5, and 323.8 +/- 14.7 pmol/L in the P1, P2, P3, and P4 groups, respectively (F = 71.1, P < 0.001). Similarly, the delta E2/delta T ratio was significantly greater in adult males than in less mature males. This developmental pattern of response to nafarelin suggests that male pubertal maturation involves increase of the gonadotrope LH readily releasable and reserve pools. The dissociation of E2 from T responses to nafarelin during puberty suggests that aromatase activity does not fully mature in males until puberty is complete. These findings indicate that a single dose of the GnRH agonist nafarelin is a promising means of assessing the maturation of the pituitary-gonadal axis in males.
Assuntos
Estradiol/metabolismo , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Nafarelina/farmacologia , Puberdade/fisiologia , Testosterona/metabolismo , Adolescente , Adulto , Envelhecimento/fisiologia , Humanos , Cinética , MasculinoRESUMO
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.
Assuntos
Cromanos/farmacologia , Fibrinólise/efeitos dos fármacos , Resistência à Insulina/fisiologia , Insulina/sangue , Síndrome do Ovário Policístico/tratamento farmacológico , Tiazóis/farmacologia , Tiazolidinedionas , Adulto , Androgênios/sangue , Feminino , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Gonadotropinas/sangue , Humanos , Leuprolida/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , TroglitazonaRESUMO
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.
Assuntos
Doenças das Glândulas Suprarrenais/congênito , Doenças das Glândulas Suprarrenais/complicações , Hiperandrogenismo/etiologia , Sistemas Neurossecretores/fisiologia , Doenças Ovarianas/etiologia , Virilismo/fisiopatologia , Adolescente , Doenças das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/congênito , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Criança , Dexametasona/farmacologia , Feminino , Humanos , Hidrolases/deficiência , Hiperandrogenismo/metabolismo , Hiperandrogenismo/fisiopatologia , Hormônio Luteinizante/metabolismo , Nafarelina/farmacologia , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Doenças Ovarianas/fisiopatologia , Caracteres Sexuais , Testosterona/metabolismo , Virilismo/metabolismoRESUMO
This article summarizes the relationship between insulin and androgen excess, with a focus on what is known regarding two related issues in polycystic ovary syndrome: (1) defects in insulin secretion in PCOS and their role in the development of glucose intolerance in this population; and (2) pharmacologic interventions designed to attenuate hyperinsulinemia and its sequelae in PCOS.
Assuntos
Hiperinsulinismo/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Feminino , Intolerância à Glucose/etiologia , Humanos , Hiperinsulinismo/etiologia , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Secreção de Insulina , Metformina/uso terapêutico , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/fisiopatologiaRESUMO
We have found that women with typical polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to a 100-micrograms test dose of the gonadotropin-releasing hormone agonist nafarelin without evidence of hindered estrogen secretion. To understand the basis of this response, we computed the apparent efficiency of the steps in steroid biosynthesis from the pattern of plasma steroids in response to nafarelin. The proximate cause appears to be excessive 17 alpha-hydroxylase activity and high, yet partially down-regulated, 17,20-lyase activity in the delta 4-pathway. These results suggest that this pattern of steroid secretion results from abnormal regulation (dysregulation) of these activities, possibly involving the enzyme cytochrome P450c17. To determine the usefulness of nafarelin testing for the diagnosis of ovarian hyperandrogenism, we then prospectively studied 40 hyperandrogenic women. The plasma 17-PROG response to nafarelin was supranormal in 58% of the women. The responses of 17-PROG to nafarelin and free testosterone to dexamethasone correlated well and were concordant in approximately 85% of cases. Baseline serum luteinizing hormone concentration was elevated in only 48% of cases. To understand ovarian structure-function relationships, we studied another 20 consecutive hyperandrogenic women. Among seven women with polycystic ovaries, five had an elevated LH level, and four of these five (80%) had an elevated 17-PROG response to nafarelin. Conversely, about half of patients with the PCOS-like disorder of ovarian function did not have polycystic ovaries. Ovarian stromal area, but not LH levels, correlated significantly (r = 0.45) with the 17-PROG response to nafarelin. Thus, both stromal hyperplasia and dysregulation of steroidogenesis seem to be manifestations of abnormal intraovarian regulation of cell growth and function. We conclude that a PCOS-like disorder of ovarian function in response to nafarelin testing is found in approximately half of hyperandrogenic women. The pathogenetic implication of our results is that abnormal intraovarian modulation of LH action seems to be a major factor in ovarian hyperandrogenism. The diagnostic implication of our data is that ovarian androgen excess will often be missed by use of common diagnostic criteria for PCOS.
Assuntos
Androgênios/metabolismo , Nafarelina , Síndrome do Ovário Policístico/diagnóstico , Androgênios/biossíntese , Animais , Dexametasona , Feminino , Humanos , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/metabolismoRESUMO
OBJECTIVE: To determine whether a mutation in the GnRH receptor gene is responsible for polycystic ovary syndrome (PCOS). DESIGN: Molecular analysis of human genomic DNA. SETTING: Academic research environment. PATIENT(S): Eighty patients with PCOS. INTERVENTION(S): Extraction and polymerase chain reaction (PCR) analysis of genomic DNA, confirmation of PCR products by ethidium bromide staining of agarose gels after electrophoresis, denaturing gradient gel electrophoresis of PCR products, and photography. MAIN OUTCOME MEASURE(S): Mutations in the GnRH receptor of women with PCOS. RESULT(S): Denaturing gradient gel electrophoresis revealed no mutations in the exonic sequence encoding the open reading frame of the GnRH receptor. CONCLUSION(S): A mutation in the GnRH receptor gene is unlikely to be the underlying cause of PCOS in most patients. The molecular basis of this disorder remains unknown.
Assuntos
Análise Mutacional de DNA , Síndrome do Ovário Policístico/genética , Receptores LHRH/genética , Adolescente , Adulto , Éxons , Feminino , Humanos , Fases de Leitura Aberta , Reação em Cadeia da Polimerase/métodosRESUMO
Women with polycystic ovary syndrome (PCOS) are at increased risk of developing diabetes mellitus type 2. Insulin resistance plays a key role in the predisposition to diabetes in PCOS; however, defects in insulin secretion also appear to contribute to its development. Since diabetes mellitus is not a universal consequence in PCOS, however, it is important to develop means to identify those women who are at highest risk. In this way, it may become possible to delay or even prevent the onset of diabetes mellitus in later life. Identification of genetic factors and use of pharmacological agents may allow early identification of those women with PCOS who are at greatest risk for development of diabetes mellitus type 2.