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Investigating the connection among thyroid function, sensitivity to thyroid hormones, and metabolic syndrome in euthyroid children and adolescents affected by type 1 diabetes
Journal of Pediatric Endocrinology and Metabolism
Abstract
Objectives
A connection between thyroid hormones (THs) and diverse metabolic pathways has been reported. We evaluated thyroid function and tissue sensitivity to THs in children and adolescents with T1D in comparison to euthyroid controls. Additionally, we investigate whether a relationship exists between sensitivity indices and metabolic parameters.
Methods
A retrospective analysis was conducted on 80 pediatric patients diagnosed with T1D. Clinical parameters, TSH, FT3, FT4, and the presence of MS were documented. Additionally, indices of peripheral sensitivity (FT3/FT4 ratio) and central sensitivity (TSH index, TSHI; TSH T4 resistance index, TT4RI; TSH T3 resistance index, TT3RI) were assessed. Thirty healthy subjects were considered as controls.
Results
The overall prevalence of MS was 7.27 %, with MS identified in 8 out of 80 (10 %) T1D subjects; none of the controls manifested MS (p<0.01). No significant differences were observed in indexes of tissue sensitivity to THs between subjects with or without MS (all p>0.05). Correlations between THs and indexes of THs tissue sensitivity and metabolic parameters in controls and T1D patients were noted.
Conclusions
This study affirms a heightened prevalence of MS in children with T1D compared to controls and underscores the potential role of THs in maintaining metabolic equilibrium.
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Background:
Reduced central sensitivity to thyroid hormones (TH) has been observed in euthyroid adults with reduced renal function. This topic is unexplored in young people with overweight or obesity (OW/OB).
Objective:
To evaluate the association between sensitivity to TH and mild reduced estimated glomerular filtration rate (MReGFR) in euthyroid children and adolescents with OW/OB.
Methods:
Data of 788 euthyroid children and adolescents with OW/OB (aged 6-16 years), recruited from seven Italian centers for the care of OW/OB, were evaluated. Peripheral sensitivity to TH was estimated through the FT3/FT4 ratio, while central sensitivity was assessed by estimating TSH index (TSHI), Thyrotroph T4 Resistance Index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI), Parametric Thyroid Feedback Quantile-based Index (PTFQI). MReGFR was defined by an eGFR value ≥60 and ≤90 mL/min/1.73 m2.
Results:
Subjects with MReGFR had significantly lower levels of FT3/FT4 ratio (0.43±0.09 vs 0.44±0.10; p=0.028) and higher levels of TSH (2.89±1.00 vs 2.68±0.99; p=0.019), TSH Index (2.95±0.45 vs 2.85±0.55; p=0.031), TFQI [1.00 (0.98-1.00) vs 1.00 (0.97-1.00); p=0.046] and PTFQI (0.66±0.17 vs 0.60±0.23; p=0.006) compared with individuals with normal eGFR. Odds ratio of MReGFR raised of 1.2-3.2-fold for each increase of 1 mIU/L in TSH, 1 unit in TSHI, and PTFQI, but not for FT3/FT4 ratio.
Conclusion:
MReGFR is associated with reduced indices of central sensitivity to TH in euthyroid children and adolescents with OW/OB. This preliminary observation should be confirmed in prospective studies.
Specific learning disorders (SLDs) are the most frequently diagnosed developmental disorders in childhood. Different neurocognitive patterns have been found in patients with overweight and obesity, but no data on childhood obesity and SLDs have been reported. To increase our understanding of the relationship between neuropsychological developmental and obesity, we assessed the prevalence of SLD in a pediatric population with obesity. We retrospectively included 380 children and adolescents with obesity. For all participants, auxological, metabolic, demographic features, relationship and social skills, anamnestic data on pregnancy and the perinatal period, stages of development and family medical history were reviewed. SLD was defined according to the DSM-5 criteria. A group of 101 controls of normal weight was included. The overall prevalence of SLD was 10.8%, and SLD was more prevalent in patients with obesity (p < 0.001), with male predominance (p = 0.01). SGA was associated with SLD (p = 0.02). Speech retardation (p < 0.001), limited relationships with peers (p < 0.001) and didactic support (p < 0.001) were noted in the SLD group compared to the group without SLD. A higher prevalence of family history of neuropsychiatric disorders was observed in the SLD group (p = 0.04). A higher fasting glucose level was detected in patients with obesity and SLD compared to subjects without SLD (p = 0.01). An association between obesity and SLD could not be excluded, and an overlap of pathogenic factors for both conditions should be considered.
Background
Thyroid hormones (TH) play multiple effects on glucose metabolism. Some recent studies carried out in adult patients suggested an association between altered sensitivity to TH and type 2 diabetes, obesity, and metabolic syndrome. No studies are currently available on the presence of altered sensitivity to the action of TH in youths with prediabetes.
Objective
To evaluate the relationship between sensitivity to TH and impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or glycosylated hemoglobin (HbA1c) ≥ 5.7% in youths with overweight/obesity (OW/OB).
Materials and methods
This cross-sectional study included 805 Caucasian youths with OW or OB (aged 6-18 years) recruited at seven Italian centers for the care of OW/OB. Individuals with TH out of the normal range of TH in each center were excluded. The fT3/fT4 ratio was evaluated to assess peripheral sensitivity, while TSH index (TSHI), Thyrotroph T4 Resistance Index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI) and Parametric TFQI were calculated to assess central sensitivity.
Results
Youths with IGT (n =72) showed higher levels of TSH (3.08 ± 0.98 vs 2.68 ± 0.98 mIU/L, P =0.001), TSHI (3.06 ± 0.51 vs 2.85 ± 0.53, P =0.001), TT4RI (46.00 ± 17.87 vs 38.65 ± 16.27, P <0.0001), TFQI [1.00 (0.97-1.00) vs 1.00 (0.99-1.00)], P=0.034), PTFQI (0.67 ± 0.20 vs 0.60 ± 0.22, P =0.007) compared to youths without IGT (n =733), independently of centers and age. No differences were observed for fT3/fT4-ratio. The others phenotypes of prediabetes were not associated with altered sensitivity to TH. Odds ratio of IGT raised of 1-7-fold for each increase of 1 mIU/L in TSH (P =0.010), 1 unit in TSH Index (P =0.004), TT4RI (P =0.003) or PTFQI (P =0.018), independently of centers, age, and prepubertal stage.
Conclusion
IGT was associated with a reduced central sensitivity to TH in youths with OW/OB. Our finding suggests that IGT phenotype, known to be associated with an altered cardiometabolic risk profile, might also be associated with an impaired TH homeostasis in youths with OW/OB.
PurposeTo estimate the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and to evaluate the associations between thyroid parameters, MAFLD and liver fibrosis in euthyroid patients with newly diagnosed type 2 diabetes mellitus (T2DM).Methods
Overall, 776 patients with newly diagnosed T2DM and 120 subjects without diabetes were included. All the participants were euthyroid, and were categorized as non-MAFLD and MAFLD. Demographic information, biochemical parameters, and serum thyroid hormones were collected. The thyroid hormone sensitivity indices were calculated. MAFLD was defined according to abdominal ultrasound and clinical manifestations. Noninvasive fibrosis indices were calculated to identify advanced liver fibrosis.ResultsThe prevalence of MAFLD was significantly higher in patients with T2DM than in subjects without diabetes. Levels of free triiodothyronine (FT3) and FT3 to free thyroxine (FT4) ratio were significantly higher in subjects with MAFLD. In patients with T2DM, levels of thyroid stimulating hormone (TSH), Thyroid feedback quantile-based index (TFQIFT3) calculated using FT3 and TSH, thyrotroph T3 resistance index (TT3RI) and thyrotroph T4 resistance index (TT4RI) were significantly higher in subjects with MAFLD. The prevalence of MAFLD increased with the rise of FT3, FT3/FT4, TSH, and sensitivity to thyroid hormone indices (TFQIFT3, TT3RI, and TT4RI). But significant correlations were not found between thyroid hormones, sensitivity to thyroid hormones and MAFLD, after adjustment for BMI and HOMA-IR. The incidence of advanced fibrosis tended to increase as the rise of TSH and sensitivity to thyroid hormone indices (TFQIFT3, TT3RI, TT4RI, and TSHI).ConclusionMAFLD was prevalent in euthyroid patients with newly diagnosed T2DM. Higher normal FT3, TSH and impaired sensitivity to thyroid hormones are associated with increased incidence of MAFLD, being dependent on other metabolic factors.
PurposeAn alteration of central and peripheral sensitivity to thyroid hormones (THs) seems to be associated with an increased risk of prediabetes in adulthood. Aims of this study was to evaluate the relationship between the sensitivity to THs, the severity of overweight and the glyco-metabolic alterations in prepubertal euthyroid children with obesity.Methods
Prepubertal subjects with simple obesity and matched controls were recruited from three Italian pediatric endocrinology centers and underwent clinical and biochemical evaluations. HOMA-IR, HOMA-β, insulinogenic index, Matsuda index were evaluated in children with obesity. Indexes of peripheral sensitivity (FT3/FT4 ratio) and central sensitivity (TSH index, TSHI; TSH T4 resistance index, TT4RI; Thyroid Feedback Quantile-based Index, TFQI; Parametric TFQI, PTFQI) to thyroid hormones were calculated in both groups.ResultsEighty prepubertal children with obesity (Group 1; mean age 7.60 ± 1.51 years) and 28 healthy normal-weight controls (Group 2) were recruited. BMI and leptin were higher in group 1 than in group 2. The FT3/FT4 ratio correlated negatively with HOMA-β (r = −0.29; p = 0.01) and was significantly positively associated with BMI (p = 0.03), IR (p = 0.03) and fasting blood glucose (p = 0.04) in group 1. TT4RI, TSHI, PTFQI, TFQI, were significantly negatively associated with Matsuda-index, IGI and BMI in group 1.Conclusion
Central and peripheral sensitivity to thyroid hormones is significantly affected by the severity of overweight and the presence of IR. Altered tissue sensitivity to THs in the prepubertal children with obesity could be implicated in the pathogenesis of glucose metabolism impairment.
Background
This study aimed to evaluate the relationship between thyroid-related hormones and vascular complications in type 2 diabetes mellitus (T2DM) patients with euthyroidism.
Methods
We enrolled 849 patients with T2DM after screening out the ineligible. Multivariate logistic regression was used to analyze the relationship between fT3, fT4, the fT3/fT4 ratio, thyroid-stimulating hormone, and diabetic vascular complications. Spearman correlation analysis was used to determine the correlation between thyroid-related hormones and vascular complications.
Results
In this cross-sectional study of T2DM, 538 patients with carotid atherosclerosis (CA) and 299 patients with diabetic peripheral neuropathy (DPN). The prevalence of DPN was negatively correlated with fT3 and the fT3/fT4 ratio but positively correlated with fT4 (all P<0.01). At the same time, the odds ratio for DPN decreased with increasing fT3 (T1: reference; T2: OR: 0.689, 95%CI: 0.477, 0.993; T3: OR: 0.426, 95% CI: 0.286, 0.633, all P<0.05) and fT3/fT4 ratio (T1: reference; T2: OR: 0.528, 95% CI: 0.365, 0.763; T3: OR: 0.413, 95% CI: 0.278, 0.613, all P<0.001). In terms of sensitivity and specificity, fT4 was found to be 39.5% and 71.4% accurate, respectively, with a 95% CI of 0.531-0.611.
Conclusions
We found a negative correlation between fT3 and fT3/fT4 ratio and the number of individuals with DPN, and a positive correlation between fT4 and the prevalence of DPN.
Thyroid function plays a crucial role in nervous system integrity and metabolic homeostasis. We evaluated the pattern of TSH, FT4 and FT3 release in children with neuromotor impairment (NI) in relationship with metabolic syndrome (MS). We enrolled 55 patients with NI and 30 controls. Clinical parameters, thyroid function and MS presence were recorded. Principal component analysis (PCA), cluster analysis, and logistic regression models were performed. MS was detected in 54.5% of patients. Four clusters were identified: the first one included only controls and, contrasting with cluster 4, was exclusively characterized by children with disability and MS. This latter showed increased FT4 and FT3 and decreased TSH levels. Cluster 2, characterized by disability without MS showed high FT4 and FT3, whereas cluster 3 with low FT4 and FT3 mainly included disability (90%) and showed prevalent MS (57%). The association between TSH and NI is represented by a U-shape structure. The TSH, FT3 and FT4 release patterns may reflect thyrotropic adaptation, allostatic response and compensatory mechanisms. These mechanisms, found in both MS and disability, show that the odds of having a condition of NI with or without MS increase as the TSH values deviate, in both directions, from a value of 2.5 mLU/mL.
PurposeThe hormonal thyroid changes related to obesity, even when in the euthyroid state, may contribute to the unfavorable cardio-metabolic profile of obese patients. In this retrospective study, we aim to investigate the biochemical thyroid changes and the association between serum TSH, FT4, FT3 and cardio-metabolic risk factors in euthyroid obese youths.Methods
Four hundred ninety-one Caucasian euthyroid obese children and adolescents aged 9.93 ± 2.90 years were recruited. Each patient underwent clinical and auxological examination and laboratory workup including an OGTT and the measurement of thyroid function and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio, total cholesterol to HDL ratio, atherogenic index of plasma, insulinogenic index, area under the glucose and insulin curves were calculated.ResultsWe found that TSH was positively correlated with BMI-SDS values and significantly associated with hypercholesterolemia and hyperinsulinemia; FT4 resulted negatively correlated with BMI-SDS; FT3 was positively correlated with BMI-SDS and the area under the curve of insulin and negatively correlated with HDL. FT3 and FT4 resulted significantly associated with severe obesity. In addition, children with high-normal TSH values showed higher triglyceride to high-density lipoprotein cholesterol ratio values than those with normal TSH levels.Conclusions
Our data showed that thyroid hormones could influence obesity, lipid and glycemic parameters in euthyroid youths. These findings could carry implications regarding optimal TSH levels in obese children and confirm the importance of evaluating the thyroid function as possible adjunctive cardio-metabolic risk factor related to obesity.
Background:
Metabolic syndrome (MS) is closely linked to obesity; however, not all individuals with obesity will develop obesity-related complications and a metabolically healthy obesity (MHO) group is also described.
Objective:
To perform a multivariate analysis (MVA) of the anthropometric and biochemical data in pediatric patients with obesity to reveal a "phenotype" predictive for MS.
Methods:
We analyzed 528 children with obesity (OB) and 119 normal-weight pediatric patients (NW). Adiposity indices were recorded, and MS was detected. MVA was performed.
Results:
Analysis of the structure of correlation of the variables showed that the variables of waist circumference (WC), body mass index (BMI), and estimated fat mass (eFM) were positively correlated with each other as a whole. In addition, the variables of the triglycerides (TG), triglyceride-glucose (TyG) index, and visceral adiposity index were positively correlated with each other as a whole, although none were correlated with the variables of BMI z-score, waist-to-height ratio, WC, eFM, or weight. The variables that related to insulin resistance (IR) and dyslipidemia were crucial for the early stratification of patients at risk of MS.
Conclusions:
Independently of body weight, IR, dyslipidemia, hypertriglyceridemia, and fat distribution seem to be the strongest MS risk factors. The early detection of and intervention in these modifiable risk factors are useful to protect children's health.
Thyroid dysfunction increases the prevalence of metabolic syndrome. However, the link between thyroid hormones and metabolic syndrome remains debatable, and the effect of sex on their relationship is not completely understood. To elucidate the relationship of thyroid hormones with metabolic syndrome and its components according to sex in euthyroid individuals in South Korea. Adult participants who underwent thyroid tests at our institution between January 2015 and December 2018 and had thyroid-stimulating hormone (TSH; 0.270-4.200 μIU/mL) and free thyroxine (FT4; 0.93-1.70 ng/dL) levels in the normal range were included. After correcting for age and body mass index, multiple linear regression was performed to assess the association of TSH and FT4 with metabolic syndrome and its components, and logistic regression was performed to estimate the risk of developing metabolic syndrome and its components according to different thyroid hormone quartiles. We included 12,478 men and 7,575 women in this study. The prevalence of metabolic syndrome was 9.68%. In men, TSH was positively associated with blood pressure and triglycerides, and the odds ratio for high blood pressure and hypertriglyceridemia was approximately 1.3 times higher in the fourth quartile than in the first quartile. FT4 associated positively with waist circumference, and a high odds ratio for abdominal obesity in the fourth quartile was observed in both men (odds ratio [OR], 1.239; 95% confidence interval [CI], 1.045-1.470) and women (OR, 1.302; 95% CI, 1.029-1.649). A negative association was found between FT4 and triglycerides, and concurrently, the odds ratios for hypertriglyceridemia were lower in the fourth quartile in both men (OR, 0.692; 95% CI, 0.619-0.774) and women (OR: 0.641; 95% CI: 0.512-0.803). In addition, a higher odds ratio for high blood pressure was observed in the fourth quartiles of FT4 and TSH in women. However, there was no association between TSH and FT4 levels and the onset of metabolic syndrome in either of the sexes. Serum TSH and FT4 levels were associated with different metabolic syndrome components in men and women, but there was no association with the onset of metabolic syndrome.
Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.
Free triiodothyronine/free thyroxine (FT3/FT4) ratio is considered as an index of the activities of iodothyronine deiodinase types 1 and 2 (DIO1 and DIO2, respectively) and is reportedly associated with insulin resistance in euthyroid adults. Euthyroid women with polycystic ovary syndrome accompanied with insulin resistance have lesser deiodinase activities. Correspondingly, the serum insulin level in a fasted condition positively correlates with the FT3/FT4 ratio, and insulin depletion decreases the DIO2 activity in mice. Selected genetic variants in DIO1 are also associated with insulin resistance measures. Therefore, if insulin positively regulates DIO1 and DIO2, the FT3/FT4 ratio should decrease under impaired insulin action, and the casual insulin level and FT3/FT4 ratio should be negatively correlated. To evaluate this hypothesis, we conducted a single-center retrospective study between 2018 and 2021. All participants visited the selected hospitals monthly for type 2 diabetes mellitus treatment and casual plasma glucose and HbA1c level measurements. Furthermore, their casual serum insulin levels were measured annually. Meanwhile, we excluded patients treated with insulin injection. Ultimately, we evaluated 71 patients, which all exhibited euthyroid conditions. The FT3/FT4 ratio was independently associated with thyroid-stimulating hormone, casual plasma glucose, and casual insulin levels. In terms of the regression coefficients of the univariate linear regression analysis, the FT3/FT4 ratio negatively correlated with the casual serum insulin levels. Therefore, the risk of FT3/FT4 ratio underestimation should be considered when diagnosing Graves’ disease, which is often accompanied with insulin resistance.
Objective
The present study examined the relationship between thyroid function status and the prevalence of metabolic syndrome in a Chinese population.
Methods
Cross-sectional data were obtained from the Thyroid Disease, Iodine Nutrition and Diabetes Epidemiology (TIDE) Survey. A total of 62,408 subjects aged ≥18 years were enrolled. Differences in metabolic indicators and the prevalence of metabolic syndrome according to sex and thyroid function status were compared. Logistic regression was used to analyze the influence of thyroid function on metabolic syndrome and its components.
Results
The prevalence of metabolic syndrome was generally higher in men than women. Overt hyperthyroidism and subclinical hypothyroidism had a significant effect on metabolism in men. Body mass index (BMI), waist circumference, and triglycerides (TGs) were significantly lower in men in the overt hyperthyroidism group, and BMI, waist circumference, systolic blood pressure (SBP) and TGs were higher in men in the subclinical hypothyroidism group than men in the normal group. Overt and subclinical hypothyroidism had significant impacts on metabolic components in women. BMI, waist circumference, TGs, SBP and DBP in the subclinical and overt hypothyroidism groups were significantly higher than the euthyroid group in women. The relative risk of abdominal obesity and hypertriglyceridemia was increased in women with hypothyroidism. Thyroid dysfunction had different effects on metabolic syndrome and its components before and after menopause.
Conclusion
Thyroid function had important effects on the prevalence of metabolic syndrome. Women with hypothyroidism, especially post-menopausal women, had a higher risk of metabolic syndrome than men.
Background
The presence of metabolic syndrome among diabetes patients is frequent and is associated with an increased incidence of chronic complications and mortality. Despite several studies have been conducted, there is no overall estimation on the prevalence of metabolic syndrome among type 1 diabetic patients. Therefore, this study aimed to estimate the pooled prevalence of metabolic syndrome among patients with type 1 diabetes mellitus.
Methods
Medline via PubMed, CINAHL, ScienceDirect, Ovid, Google Scholar, ResearchGate and African Journals Online were searched by limiting publication period from January 2005 to October 2020. Data were extracted with a standardized format prepared in Microsoft Excel and exported to Stata 16.0 for analyses. The I ² statistic was used to check heterogeneity across the included studies. DerSimonian and Laird random-effects model was applied to estimate pooled prevalence and 95% confidence interval across studies. Funnel plot symmetry, Begg’s test and Egger’s regression test were used to determine the presence of publication bias. Subgroup and sensitivity analysis as well as meta-regression were conducted to explore the potential sources of heterogeneity. The study protocol is registered on PROSPERO with reference number: CRD42020213435.
Results
In this meta-analysis, a total of 27 studies with 45,811 study participants were included. The pooled prevalence of metabolic syndrome was 23.7% with substantial heterogeneity (I ² = 98.2%; P < 0.001). Geographical-based subgroup analysis revealed that the highest prevalence was observed in Australia (27.3%). As per meta-analysis of 17 studies, the pooled prevalence of metabolic syndrome in female type 1 diabetes patients (25.9%) was slightly higher than male T1DM patients (22.5%).
Conclusion
Nearly a quarter of the type 1 diabetes mellitus patients were affected by metabolic syndrome. Therefore, more attention should be paid to the prevention and control of the epidemic and for the reduction of the morbidity and mortality associated with metabolic syndrome among type 1 diabetes mellitus patients.
Introduction:
Insulin resistance (IR) is a key and early pathogenetic mechanism of cardiometabolic diseases with huge potential if being early detected and mitigated, for lowering the burden of the diseases. Available data are conflicting to what extent adult thyroid dysfunction is associated with IR. Therefore, we aimed to investigate the association and to identify which thyroid parameters are predictors of IR.
Material and methods:
After undergoing basic anthropometric and biochemical studies including thyroid hormones, oral glucose tolerance test (OGTT) and insulin, 1425 middle-aged individuals were divided into three groups according to the thyroid parameters: overt hypothyroidism (OH), subclinical hypothyroidism (SH) and euthyroidism (EU).
Results:
The homeostasis model assessment of IR (HOMA-IR), fasting insulin and 2-hour glucose levels of OGTT showed a steady, yet insignificant, increase from EU through SH to OH. The strongest noted correlations were those of insulin levels with free triiodothyronine/free thyroxine (FT3/FT4) ratio (r = 0.206, p < 0.001) and FT3 (r = 0.205, p < 0.001). Also in the case of HOMA-IR, the only statistically significant correlations were observed with FT3 (r = 0.181, p < 0.001) and the FT3/FT4 ratio (r = 0.165, p < 0.001). Among other thyroid hormones, linear logistic regression proved the FT3/FT4 ratio as the only significant predictor of HOMA-IR (linear coefficient = 5.26, p = 0.027) and insulin levels (linear coefficient = 18.01, p = 0.023), respectively. Thyroid-stimulating hormone was not associated with IR in either correlation or regression analysis.
Conclusions:
The FT3/FT4 ratio should be more emphasised in the diagnosis and treatment of thyroid disorders. Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio, potentially leading to a decrease in insulin resistance, and thus a risk of the cardiometabolic diseases.
Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.
Obesity in childhood is the main determinant of whole body reduced insulin sensitivity. This association has been demonstrated in multiple adult and pediatric cohorts. The mechanistic link explaining this association is the pattern of lipid partitioning in the face of excess calories and energy surplus. A tight relation exists between typical lipid deposition patterns, specifically within the skeletal muscle and liver, as well as the intra-abdominal compartment and whole body insulin sensitivity. The impact of lipid deposition within insulin responsive tissues such as the liver and skeletal muscle relates to the ability of fatty acid derivates to inhibit elements of the insulin signal transduction pathway. Strengthening the relation of obesity and reduced insulin sensitivity are the observations that weight gain reduces insulin sensitivity while weight loss increases it. This manifests as the appearance of cardiovascular risk factor clustering with weight gain and its recovery in the face of weight loss. Both obesity per se, via the adipocytokine profile it induces, and low insulin sensitivity, are independent determinants of the adverse metabolic phenotype characteristic of the metabolic syndrome.
OBJECTIVE Diabetes prevalence and incidence increase among individuals with hypothyroidism but also among those with hyperthyroxinemia, which seems contradictory. Both high free thyroxine (fT4) and high thyroid-stimulating hormone (TSH) are present in the resistance to thyroid hormone syndrome. A mild acquired resistance to thyroid hormone might occur in the general population and be associated with diabetes. We aimed to analyze the association of resistance to thyroid hormone indices (the Thyroid Feedback Quantile-based Index [TFQI], proposed in this work, and the previously used Thyrotroph T4 Resistance Index and TSH Index) with diabetes.
RESEARCH DESIGN AND METHODS We calculated the aforementioned resistance to thyroid hormone indices based on a U.S. representative sample of 5,129 individuals ≥20 years of age participating in the 2007–2008 National Health and Nutrition Examination Survey (NHANES). Also, to approximate TFQI, a U.S.-referenced Parametric TFQI (PTFQI) can be calculated with the spreadsheet formula =NORM.DIST(fT4_cell_in_pmol_per_L,10.075,2.155,TRUE)+NORM.DIST(LN(TSH_cell_in_mIU_per_L),0.4654,0.7744,TRUE)−1. Outcomes of interest were glycohemoglobin ≥6.5%, diabetes medication, diabetes-related deaths (diabetes as contributing cause of death), and additionally, in a fasting subsample, diabetes and metabolic syndrome. Logistic and Poisson regressions were adjusted for sex, age, and race/ethnicity.
RESULTS Odd ratios for the fourth versus the first quartile of TFQI were 1.73 (95% CI 1.32, 2.27) (Ptrend = 0.002) for positive glycohemoglobin and 1.66 (95% CI 1.31, 2.10) (Ptrend = 0.001) for medication. Diabetes-related death rate ratio for TFQI being above versus below the median was 4.81 (95% CI 1.01, 22.94) (Ptrend = 0.015). Further adjustment for BMI and restriction to normothyroid individuals yielded similar results. Per 1 SD in TFQI, odds increased 1.13 (95% CI 1.02, 1.25) for diabetes and 1.16 (95% CI 1.02, 1.31) for metabolic syndrome. The other resistance to thyroid hormone indices showed similar associations for diabetes-related deaths and metabolic syndrome.
CONCLUSIONS Higher values in resistance to thyroid hormone indices are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality. Resistance to thyroid hormone may reflect energy balance problems driving type 2 diabetes. These indices may facilitate monitoring treatments focused on energy balance.
The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.
Objective:
This study was performed to evaluate the effects of metabolic parameters and thyroid dysfunction on the development of non-alcoholic fatty liver disease (NAFLD).
Methods:
The current study evaluated a total of 115 patients, 75 female and 40 male. Physical examination and anthropometric measurements were applied to all participants. Hypothyroidism was considered at a thyroid stimulating hormone level ≥ 4.1 mIU/L. Patients with euthyroidism and patients with hypothyroidism were compared. Abdominal ultrasonography was used to diagnose non-alcoholic fatty liver disease. The participants were further compared with regard to the presence of non-alcoholic fatty liver disease. Logistic regression modeling was performed to identify the relationship between non-alcoholic fatty liver disease and independent variables, such as metabolic parameters and insulin resistance.
Results:
Non-alcoholic fatty liver disease was identified in 69 patients. The mean waist circumference, body mass index, fasting plasma insulin, HOMA-IR (p<0.001) and FT3/FT4 ratio (p=0.01) values were significantly higher in the patients with NAFLD compared to those without it. Multivariate regression analysis revealed that FT3/FT4 ratio, waist circumference and insulin resistance were independent risk factors for non-alcoholic fatty liver disease.
Conclusion:
Insulin resistance, enlarged waist circumference, elevated body mass index, higher FT3/FT4 ratio and hypertriglyceridemia are independent risk factors for NADLF, whereas hypothyroidism is not directly related to the condition.
The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.
There have been recent advances in understanding of the local control of thyroid activity and metabolism, including deiodinase activity and thyroid hormone membrane transport. The goal of this review is to increase the understanding of the clinical relevance of cellular
deiodinase activity. The physiologic significance of types 1, 2 and 3 deiodinase (D1, D2 and D3, respectively) on the intracellular production of T3 are discussed along with the importance and significance of the production of reverse T3. The difference in the pituitary and peripheral activity
of these deidoidinases under a wide range of common physiologic conditions results in different intracellular T3 levels in the pituitary and peripheral tissues, resulting in the inability to detect low tissue levels of thyroid hormone in peripheral tissues with TSH testing. This review demonstrates
that extreme caution should be used in relying on TSH or serum thyroid levels to rule out hypothyroidism in the presence of a wide range of conditions, including physiologic and emotional stress, depression, dieting, obesity, leptin insulin resistance, diabetes, chronic fatigue syndrome, fibromyalgia,
inflammation, autoimmune disease, or systemic illness, as TSH levels will often be normal despite the presence of significant hypothyroidism. The review discusses the significant clinical benefits of thyroid replacement in such conditions despite having normal TSH levels and the superiority
of T3 replacement instead of standard T4 therapy.
Metabolic syndrome (MetS) is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of MetS exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define MetS that are also linked to the syndrome have been identified. In this review, we critically consider existing definitions and evolving information, and conclude that there is still a need to develop uniform criteria to define MetS, so as to enable comparisons between different studies and to better identify patients at risk. As the application of the MetS model has not been fully validated in children and adolescents as yet, and because of its alarmingly increasing prevalence in this population, we suggest that diagnosis, prevention and treatment in this age group should better focus on established risk factors rather than the diagnosis of MetS.
Short-term experimental diabetes mellitus (DM) produces a significant decrease in serum thyroid hormones, a decreased or normal serum thyroid-stimulating hormone (TSH) and a reduction in hepatic and renal T4-5'-deiodination. However, little is known about the effects of chronic diabetes mellitus on the pituitary-thyroid axis function. We evaluated the changes induced by very short-term (6 days), short-term (15 days) and chronic (6 months) streptozotocin-induced diabetes mellitus in 3-month old female Dutch-Miranda rat serum T4, serum TSH and T4-5'-deiodinase activity in the thyroid and pituitary glands. Serum hormones were determined by specific radioimmunoassays. Iodothyronine-5'-deiodinase activities were assayed in the thyroid and pituitary microsomal fractions using 2 microM T4 as substrate. Mean serum T4 was significantly decreased from 3.3 to 2.0 micrograms/dl 6 days after diabetes mellitus induction, and from 2.2 to 1.5 micrograms/dl after 15 days of DM, with no significant changes in serum TSH, indicating a decreased pituitary TSH responsiveness to the diminished suppression by T4, even though pituitary T4-5'-deiodinase activity was unchanged. Thyroid T4-5'-deiodinase was unchanged after 6 days of diabetes mellitus, but was significantly increased from 20.6 to 37.0 pmol T3/mg protein after 15 days. Six months after diabetes mellitus induction, both serum T4 and thyroid T4-5'-deiodinase returned to normal ranges and serum TSH was unchanged, although pituitary T4-5'-deiodinase was now significantly decreased from 2.7 to 1.7 pmol T3/mg protein. These findings indicate that some kind of adaptation to chronic insulinopenia may occur at the thyroid level, but this does not seem to be true for the pituitary.
Introduction:
To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population.
Methods:
A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum-free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Chinese-referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio.
Results:
Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079-1.262, p < .001), TT4RI (OR = 1.115, 95% CI: 1.031-1.206, p = .006), TFQI (OR = 1.196, 95% CI: 1.106-1.294, p < .001), PTFQI (OR = 1.194, 95% CI: 1.104-1.292, p < .001), and lower values of FT3/FT4 ratio (OR = 0.914, 95% CI: 0.845-0.990, p = .026) were associated with MetS. Increased levels of TFQI and PTFQI were associated with abdominal obesity, hypertriglyceridemia, and hypertension. Increased levels of TSHI and TT4RI were associated with hypertriglyceridemia, abdominal obesity, low high-density lipoprotein cholesterol. Reduced levels of FT3/FT4 ratio were associated with hyperglycemia, hypertension, and hypertriglyceridemia. The levels of TSHI, TFQI, and PTFQI were negatively related to SMA and positively related to VAT, SAT, and TAT (all p < .05).
Conclusions:
Reduced thyroid hormone sensitivity was associated with MetS and its components. Impaired thyroid hormone sensitivity might affect the distribution of adipose tissue and muscle.
Background
Recently, reduced sensitivity to thyroid hormone as a more common finding in the general population and its possible association with metabolic parameters has been the focus of attention. We evaluated the cross-sectional association of thyroid hormone sensitivity with diabetes, metabolic syndrome (MetS), and its components.
Methods
The study included a Tehranian representative sample of 5124 subjects aged ≥20 years participating in the Tehran Thyroid Study (2008-2011). Body weight, waist circumference and blood pressure were measured, and serum concentrations of lipids and lipoproteins, fasting blood glucose (FBG), insulin, free T4 (fT4) and TSH were assayed. Thyroid hormone resistance was calculated by thyroid feedback quantile-based index (TFQI) and Iranian-referenced parametric TFQI (PTFQI) and compared with two other indices of TT4RI and TSHI.
Results
TFQI was significantly associated with high BP metabolic syndrome criterion (OR=1.14, 95% CI: 1.06, 1.23) and DM (OR=1.16, 95% CI: 1.04, 1. 30, p=0.009) in euthyroid subjects after adjusting for age, sex, smoking, physical activity, BMI, and HOMA-IR. TFQI was not associated with new-onset diabetes contrary to known diabetes in subgroup analysis. The results were similar for PTFQI. TSHI (OR=1.22, 95% CI: 1.08, 1.38, P=0.001) and TT4RI (OR=1.08, 95% CI: 1.01, 1.16, P<0.001) were associated only with high BP in euthyroid subjects.
Conclusion
The new TFQI index seems to be the indicator of reduced sensitivity to thyroid hormone most suitable to associate its population variations with diabetes and hypertension in euthyroid subjects; however, interpretation for diabetes should be concerned with cautions, necessitating future studies.
Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and viceversa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic beta cells and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients and this association can have important repercussions on the outcome of both these disorders. Therefore, we offer recommendations for the diagnosis, management and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.
Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults.
Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults.
Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis.
TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria.
At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.01-1.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.03-1.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.0-5.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6-7.5).
Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome.
The objective of the study was to quantify insulin resistance in type 1 diabetes patients by estimated glucose disposal rate (eGDR), according to the presence or absence of the metabolic syndrome, and its relationship with chronic complications.
This was a cross-sectional study in 91 patients with type 1 immune-mediated diabetes managed at an outpatient endocrinology clinic. All participants were Caucasians aged 18 yr or older with type 1 diabetes duration of more than 6 months who had completed the study protocol.
Twenty-nine patients met metabolic syndrome criteria, yielding a prevalence of 31.9%. Although no differences in insulin requirements were found between diabetic patients with and without metabolic syndrome, lower eGDR levels, indicating greater insulin resistance, were observed in metabolic syndrome patients compared with those without (6.19 +/- 1.5 mg/kg(-1) x min(-1) vs. 9.93 +/- 1.6 mg/kg(-1) x min(-1)) (P < 0.001). An eGDR level less than 8.77 mg/kg(-1) x min(-1) showed 100% sensitivity and 85.2% specificity for metabolic syndrome diagnosis. All patients with diabetes complications had eGDR values below 8.16 mg/kg(-1) x min(-1). eGDR level was significantly lower in patients with diabetic retinopathy (5.97 +/- 1.2 mg/kg(-1) x min(-1)), diabetic neuropathy (5.06 +/- 0.4 mg/kg(-1) x min(-1)), or diabetic nephropathy (5.79 +/- 1.5 mg/kg(-1) x min(-1)) compared with those without (9.38 +/- 2.0 mg/kg(-1) x min(-1), P < 0.001; 9.26 +/- 2.0 mg/kg(-1) x min(-1), P < 0.001; and 9.19 +/- 2.2 mg/kg(-1) x min(-1), P < 0.001).
Insulin resistance is common in type 1 diabetes patients and is associated with microvascular complications. eGDR, as an insulin resistance marker, provides more useful information than other classical variables such as insulin requirements.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Mixed longitudinal data on the physical changes at puberty in 228 normal boys are presented together with normal standards for stages of genital and pubic hair development.The genitalia began to develop between the ages 9½ years and 13½ years in 95% of boys (mean = 11.6 ± 0.09) and reached maturity at ages varying between 13 and 17 (mean = 14.9 ± 1.10). The age at which pubic hair first appeared was not accurately determined, but its development through the later stages was studied. It reached the equivalent of an adult female distribution at a mean age of 15.2 ± 0.01 years.On average the genitalia reached the adult stage 3.0 years after they first began to develop; but some boys completed this development in as little as 1.8 years while others took as much as 4.7 years. Some boys complete the whole process in less time than others take to go from Stage G2 to Stage G3. The genitalia begin to develop before pubic hair is visible in photographs in practically all boys.The 41 boys in whom it could be studied reached their maximum rate of growth (peak height velocity) at a mean age of 14.1 ± 0.14 years.Very few boys (about 5%) reached peak height velocity before their genitalia were in Stage 4 and over 20% did not do so until their genitalia were adult. Peak height velocity is reached, on the average, nearly 2 years later in boys than in girls, but the boys' genitalia begin to develop only about 6 months later than the girls' breasts. Pubic hair appears about 1½ years later in boys than in girls.
Mixed longitudinal data on the physical changes at puberty in 192 normal girls are presented, together with pictorial standards for stages of breast and pubic hair development. The first sign of puberty (i.e. either breast or pubic hair development) appeared between the ages of 8.5 years and 13 years in 95% of girls, and the breasts reached the mature stage between 11.8 and 18.9 years. The mean ages at which the intermediate stages of breast and pubic hair development were reached are given; all had standard deviations of approximately 1 year. The mean age at peak height velocity (i.e. the maximum rate of growth in stature) was 12.14 ± ±0.14 (SD =0.88) and the mean age at menarche was 13.47 ± 0.10 (SD = 1.02). The limits of normal variation in the length of time which girls take to pass from one stage of breast or pubic hair development to another are given. The interval from the first sign of puberty to complete maturity varied from 1.5 years to over 6 years. The bud stage of breast development persisted for between 6 months and 2 years before further change took place. The mean interval from the beginning of breast development to menarche was 2.3 ± 0.1 years, but the range observed was 6 months to 5 years 9 months. The mean interval from the beginning of breast development to peak height velocity was 1.01 ±0.12 years (SD = 0.77). The limits of normal variation in the relation between breast and pubic hair development, the adolescent growth spurt, and menarche are described. Peak height velocity was reached very early in puberty by about 25% of girls, and in all cases it preceded menarche. 90% of girls had menstruated before their breasts reached the mature stage. Pubic hair was seen before breast development had begun in about a third of all girls. The use of these data in making a clinical distinction between normal and abnormal puberty is discussed, together with their relevance to the study of the neuro-endocrine mechanisms by which puberty is controlled.