Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome

Although prior studies suggest reduced androgen levels in women with acquired immune deficiency syndrome wasting, little is known regarding the regulation of adrenal and ovarian androgen secretion in such patients. We investigated ovarian and adrenal function in 13 human immunodeficiency virus-infected women with acquired immune deficiency syndrome wasting and 21 age- and body mass index-matched healthy control subjects studied in the early follicular phase. Subjects received hCG (5000 U, im) on d 1 and Cosyntropin (0.25 mg, i.v.) on d 3 after dexamethasone (1 mg, orally, at 2400 h) pretreatment on d 2. At baseline, human immunodeficiency virus-infected subjects demonstrated significantly reduced T [18 +/- 2 vs. 25 +/- 2 ng/dl (0.6 +/- 0.1 vs. 0.9 +/- 0.1 nmol/liter); P = 0.02], free T [1.5 +/- 0.1 vs. 2.4 +/- 0.2 pg/ml (5.3 +/- 0.5 vs. 8.3 +/- 0.6 pmol/liter); P = 0.001], androstenedione [119 +/- 6 vs. 162 +/- 14 ng/dl (4.16 +/- 0.20 vs. 5.66 +/- 0.48 nmol/liter); P = 0.02], and dehydroepiandrosterone sulfate [0.96 +/- 0.17 vs. 1.55 +/- 0.19 microg/ml (2.6 +/- 0.5 vs. 4.2 +/- 0.5 micromol/liter); P = 0.047] levels compared with the control subjects. T [8 +/- 2 vs. 6 +/- 2 ng/dl (0.3 +/- 0.1 vs. 0.2 +/- 0.1 nmol/liter); P = 0.48], free T [0.5 +/- 0.2 vs. 0.4 +/- 0.1 pg/ml (1.7 +/- 0.7 vs. 1.5 +/- 0.5 pmol/liter); P = 0.85], 17 hydroxyprogesterone [0.5 +/- 0.2 vs. 0.7 +/- 0.2 microg/liter (1.6 +/- 0.6 vs. 2.0 +/- 0.6 nmol/liter); P = 0.63], and androstenedione [-1 +/- 12 vs. 8 +/- 11 ng/dl (-0.03 +/- 0.42 vs. 0.28 +/- 0.39 nmol/liter), P = 0.61] responses to hCG were not different between the groups. Cortisol responses were increased and dehydroepiandrosterone sulfate responses were decreased in the human immunodeficiency virus-infected vs. control subjects after ACTH stimulation. The ratio of DHEA to cortisol was significantly decreased at 60 (71 +/- 11 vs. 107 +/- 10; P = 0.02) and 90 (63 +/- 8 vs. 102 +/- 9; P = 0.004) min post-ACTH in the human immunodeficiency virus-infected patients compared with control subjects. Baseline urinary free cortisol levels were not different between the groups [36 +/- 9 vs. 36 +/- 5 microg/24 h (99 +/- 26 vs. 100 +/- 13 nmol/d)]. The DHEA to cortisol ratio correlated with the CD4 count (r = 0.67; P = 0.01). These data demonstrate significant shunting of adrenal steroid metabolism away from androgenic pathways and toward cortisol production in human immunodeficiency virus-infected women with the wasting syndrome. In contrast, our data suggest intact ovarian androgen responsivity to hCG stimulation. Further studies of the mechanism of adrenal steroid shunting and the efficacy of androgen replacement in human immunodeficiency virus-infected women are necessary.     

Amiodarone-induced thyrotoxicosis: left ventricular dysfunction is associated with increased mortality

OBJECTIVE: Amiodarone-induced thyrotoxicosis (AIT) is a challenging management problem, since patients treated with amiodarone invariably have underlying heart disease. Consequently, thyrotoxicosis can significantly contribute to increased morbidity and mortality. The aim of this study was to compare the clinical outcome and hormone profiles of patients with AIT (n = 60) with those with Graves' thyrotoxicosis (n = 49) and toxic multinodular goitre (MNG, n = 40). DESIGN: A retrospective study of patients with AIT in a single institution was conducted. METHODS: Data from patients with AIT over 12 years were collected. RESULTS: Mean TSH levels were significantly suppressed in all three groups. However, there was no intergroup significant difference. Free thyroxine (T4) levels were significantly higher in AIT (45.6 +/- 3.5 pmol/l) and Graves' disease (44.6 +/- 4.0 pmol/l) compared with toxic MNG (31.5 +/- 5.1 pmol/l, P < 0.05). In contrast, free triiodothyronine (T3) levels were only significantly higher in Graves' disease (14.7 +/- 1.5 pmol/l, P = 0.002) compared with AIT (8.6 +/- 0.7 pmol/l) and toxic MNG (7.4 +/- 0.5 pmol/l). Six deaths occurred in the patients with AIT (10.0%, P < 0.01) and no deaths occurred in the other groups. Amiodarone treatment (P = 0.002) was the most significant predictor of death, whereas free T4, free T3 and age did not affect outcome. Within the amiodarone-treated group severe left ventricular dysfunction (P = 0.0001) was significantly associated with death. CONCLUSIONS: (i) AIT differs from other forms of thyrotoxicosis, and (ii) severe left ventricular dysfunction is associated with increased mortality in AIT.     

Treatment of hyperthyroidism associated with thyrotropin-secreting pituitary adenomas with iopanoic acid

TSH-secreting tumors comprise less than 2% of all pituitary adenomas. All patients present with hyperthyroidism with a detectable TSH level, and a majority have macroadenomas. Oral cholecystographic agents (e.g. iopanoic acid) potently inhibit the activation of T(4) to the more potent T(3). They have been used successfully to treat primary thyroidal hyperthyroidism and thyroxine overdose. However, they have not been employed in the treatment of central hyperthyroidism. We report, herein, the first two patients with thyrotropinomas, in whom iopanoic acid (Telepaque) has been used perioperatively to safely and rapidly achieve euthyroidism. In case 1, free T(3) index improved from a value of 634 to 175 (normal range 78-162) after 3 d of therapy with iopanoic acid. In case 2, free T(3) by dialysis improved from 697 pg/dl (10.7 pmol/liter) to 195 pg/dl (3.0 pmol/liter) (normal range 210-440 pg/dl; 3.2-6.7 pmol/liter) after 7 d of therapy with iopanoic acid.     

Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography

OBJECTIVE: Current thinking is that amiodarone-induced thyrotoxicosis (AIT) might be either iodine-induced thyrotoxicosis in latent hyperthyroidism (Type 1) or destructive thyroiditis (Type 2), and also that colour-flow Doppler sonography (CFDS) of the thyroid and serum interleukin 6 (IL-6) are tools that can classify AIT and direct treatment. To assess the validity of this thinking, our objective was to determine whether CFDS and IL-6 identified AIT subgroups with distinct features. DESIGN: Retrospective case-note audit of all patients presenting with AIT to the Endocrine Department of a UK teaching hospital over a 3-year period. To assess proportions of Type 1 vs. Type 2 AIT and to compare and contrast their clinical features. PATIENTS: 37 patients were identified with AIT (mean age 65, range 20-86 years). In 30 patients in whom AIT persisted, 25 underwent CFDS. RESULTS: In 25 patients who underwent CFDS, 10 (40%) were classified as Type 1, 10 (40%) as Type 2 and 5 (20%) as indeterminate type. In the patients classified by CFDS in whom AIT persisted, 40% of Type 1 patients were male vs. 90% of Type 2 patients. Also, free T4 tended to be lower in patients presenting with Type 1 AIT (52.1 +/- 7.5 pmol/l) compared to Type 2 (74.8 +/- 8.1 pmol/l, P = 0.08), free T3 was lower (8.8 +/- 0.9 vs. 15.6 +/- 3.0 pmol/l, P = 0.03) and the cumulative amiodarone dose was lower (66 +/- 20 vs. 186 +/- 28 g, P = 0.002). We used less prednisolone to achieve euthyroidism in patients with Type 1 AIT whereas carbimazole doses were not different and the time to euthyroidism was the same in both groups (81 +/- 21 vs. 88 +/- 13 days). IL-6 was raised in two patients with Type 1 and in one patient with Type 2 AIT. CONCLUSIONS: CFDS could characterize two distinct subtypes in patients with AIT. Conversely, IL-6 seemed to be an unhelpful test in this context.     

Recombinant human thyrotropin as adjuvant in the treatment of multinodular goiters with radioiodine

The use of 131I in the treatment of multinodular goiters (MNG) is well established. We evaluated the effect of 30 microCi 131I (1.11 GBq) in 18 patients with MNG with the aid of two injections of 0.1 mg recombinant human TSH (rhTSH), given on d 1 and 2. A dose of 30 microCi 131I was given on d 3. TSH, T3, free T4, and thyroglobulin were measured on d 1, 2, 3, 5, 10, 30, 60, 90, and 180, and antithyroid antibodies were measured on d 1, 30, 90, and 180. Twenty-four-hour 131I uptake measured 1-3 months before rhTSH increased from 12.3 +/- 6.2 to 53.5 +/- 10.9% (P < 0.0001), free T4 from 1.3 +/- 0.2 to peak 3.2 +/- 1.1 ng/dl levels (P < 0.0001), T3 from 113.9 +/- 35.0 to peak 332.2 +/- 123.0 ng/dl levels (P < 0.0001), TSH from 0.76 +/- 0.71 to peak 18.9 +/- 5. 3 mU/liter levels (P < 0.0001), and thyroglobulin from 280.9 +/- 370.0 to peak 1838.5 +/- 1360.7 ng/dl levels (P = 0.001). Painful thyroiditis (33%) and mild thyrotoxicosis (39%) constituted minor side effects. There were no changes in echocardiographic parameters, done before and after rhTSH administration, on d 3. Hypothyroidism developed in 65%. Mean goiter size, measured by computed tomography, decreased from 97.9 +/- 45.4 to 65.5 +/- 47.3 ml (P < 0.0001; reduction: 39 +/- 19%) after 6 months. We conclude that rhTSH is a safe and efficient therapeutic tool in the treatment of MNG allowing the use of outpatient therapeutic 131I doses.     

Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life

CONTEXT: Newborns with ambiguous genitalia or males with nonpalpable gonads usually require an early assessment of the presence and functional state of testicular tissue. OBJECTIVE: Our objective was to characterize the precise ontogeny of the serum patterns of gonadotropins, testosterone, anti-Müllerian hormone (AMH), and inhibins in normal newborn boys. DESIGN: We conducted a cross-sectional and longitudinal study. SUBJECTS: Serum samples were obtained in 57 boys and 13 girls on d 2 of life. A second sample was obtained on d 7, 10, 15, 20, and 30 (boys) and on d 30 (girls). MAIN OUTCOME MEASURES: Serum levels of gonadotropins, testosterone, AMH, and inhibins were measured. RESULTS: In males, LH and FSH were undetectable or very low on d 2. By d 7, LH increased to 3.94 +/- 3.19 IU/liter (mean +/- sd) and FSH to 2.04 +/- 1.67 IU/liter. LH/FSH ratios were 0.40 +/- 0.11 (d 2) and 2.02 +/- 0.20 (d 30). AMH rose from 371 +/- 168 pmol/liter (d 2) to 699 +/- 245 pmol/liter (d 30), and inhibin B rose from 214 +/- 86 ng/liter (d 2) to 361 +/- 93 ng/liter (d 30). The inhibin alpha-subunit precursor (pro-alphaC) remained stable during the first month of life. Testosterone levels were 66 +/- 42 ng/dl (d 2), 82 +/- 24 ng/dl (d 20), and 210 +/- 130 ng/dl (d 30). A sexual dimorphism was observed in AMH and inhibin B (lower in girls on d 2 and 30), in LH/FSH ratio (lower in girls on d 30) and in testosterone (lower in girls on d 30). CONCLUSIONS: Sertoli cell markers AMH and inhibin B are the earliest useful markers indicating the existence of normal testicular tissue.     

Glucocorticoid response in amiodarone-induced thyrotoxicosis resulting from destructive thyroiditis is predicted by thyroid volume and serum free thyroid hormone concentrations

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders. OBJECTIVE: The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively. SETTING: This study was conducted at university centers. PATIENTS: Sixty-six untreated patients with type 2 AIT were enrolled in the study. INTERVENTION: All patients were treated with prednisone (initial dose, 0.5 mg/kg.d) as long as needed to restore euthyroidism, defined as cure of AIT. MAIN OUTCOME MEASURE: The main outcome measure was cure time. RESULTS: The median cure time was 30 d (95% confidence interval, 23-37 d). Serum free T4 concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T3 concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95-0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77-0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (相似文献   

Dynamics of serum cortisol levels after transsphenoidal surgery in a cohort of patients with Cushing's disease

Transsphenoidal pituitary surgery is the treatment of choice for Cushing's disease (CD). Despite the widespread acceptance of this procedure, there is no agreement regarding the definition of successful treatment. We prospectively studied postoperative serum cortisol dynamics in 41 patients with CD (including a total of 45 surgeries). The mean postoperative follow-up period was 4.8 yr. Remission was defined as clinical and laboratory signs of adrenal insufficiency, glucocorticoid dependence, and serum cortisol suppression on overnight oral 1-mg dexamethasone suppression test. Serum cortisol was measured preoperatively and postoperatively at 6, 12, and 24 h (28 surgeries) and at 10-12 d (45 surgeries). No statistical difference was detected in mean preoperative and 6-h postoperative cortisol levels between surgically induced remission patients [22.1 +/- 7.73 microg/dl (610 +/- 213.3 nmol/liter) and 25.2 +/- 19 microg/dl (695.2 +/- 524.4 nmol/liter)] and surgical failure patients [23.6 +/- 6.95 micro g/dl (651.4 +/- 161.8 nmol/liter) and 37.5 +/- 18.1 microg/dl (1035 +/- 499.6 nmol/liter); P = 0.50 and P = 0.17]. At 12 and 24 h after surgery, the difference was significant (P = 0.009 and P < 0.0001). Mean cortisol levels were 12.44 +/- 13.3 microg/dl (343.3 +/- 367.1 nmol/liter) and 4.72 +/- 6.72 microg/dl (130.3 +/- 185.5 nmol/liter) in the remission group and 26.3 +/- 7.06 microg/dl (725.9 +/- 194.8 nmol/liter) and 23.5 +/- 6.86 microg/dl (648.6 +/- 189.3 nmol/liter) in the failure group (P = 0.009; P < 0.0001). At 10-12 d after the procedure, the difference was also significant (P < 0.0001): cortisol levels were 2.52 +/- 3.32 microg/dl (69.5 +/- 91.6 nmol/liter) in the remission group and 24.9 +/- 13.3 microg/dl (687.2 +/- 367.1 nmol/liter) in the failure group. In conclusion, in the immediate postoperative period of transsphenoidal surgery, remission of CD is not necessarily defined by undetectable serum cortisol. During the first 10-12 d after surgery, cortisol nadir correctly classified the remission [cortisol, 7.0 microg/dl (193.2 nmol/liter) or less] and the failure groups [cortisol, 8.0 microg/dl (220.8 nmol/liter) or more]. Glucocorticoid should be administered only after laboratory and/or clinical evidence of adrenal insufficiency.     

Novel interactions of adiponectin with the endocrine system and inflammatory parameters

Several markers of chronic immune activation have been found in association with obesity and insulin resistance. We aimed to study the interaction of adiponectin with chronic inflammation and known components of the insulin resistance syndrome. Insulin sensitivity (minimal model analysis) and plasma soluble fractions of TNF-alpha receptor 1 (sTNFR1) and 2 (sTNFR2), adrenal and thyroid function, and adiponectin were evaluated in 68 apparently healthy subjects. An additional group of type 2 diabetic patients (n = 19) similarly studied, except for insulin sensitivity, were also included in the analysis. As reported by others, serum adiponectin concentrations were higher in women than in men (13.55 +/- 9.79 vs. 8.64 +/- 7.83 mg/liter; P = 0.018). They were also higher in healthy subjects compared with diabetic patients (10.35 +/- 8.48 vs. 7.41 +/- 8.31 mg/liter; P = 0.021). As expected also, circulating adiponectin was significantly associated with waist to hip ratio (r = -0.28; P = 0.013), diastolic blood pressure (r = -0.25; P = 0.027), fasting plasma high-density lipoprotein cholesterol (r = 0.35; P = 0.001), triglycerides (r = -0.37; P = 0.001), and insulin sensitivity (r = 0.30; P = 0.011). Additionally, subjects in the higher quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 microg/liter; P = 0.012), a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 microg/liter; P = 0.055), higher concentration of serum morning cortisol (16.86 vs. 13.52 microg/dl; P = 0.027), and higher serum free T(4) levels (1.31 vs. 1.20 ng/dl; P = 0.038). Multiple regression analysis models were constructed to predict adiponectin concentrations. Predictive variables in these models included insulin sensitivity, waist to hip ratio and free T(4), contributing to 17%, 10%, and 8% of adiponectin variance, respectively, These findings suggest that circulating adiponectin differentially modulates insulin action and that thyroid-axis, inflammatory cytokines, and the adrenal cortex might intervene in this modulation.     

Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes

Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG (cFT). Hypogonadism was defined as low FT or cFT. The mean age was 54.7 +/- 1.1 yr, mean body mass index (BMI) was 33.4 +/- 0.8 kg/m(2), and mean HbA1c was 8.4 +/- 0.2%. The mean T was 12.19 +/- 0.50 nmol/liter (351.7 +/- 14.4 ng/dl), SHBG was 27.89 +/- 1.65 nmol/liter, and FT was 0.250 +/- 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels (3.15 +/- 0.26 vs. 3.91 +/- 0.24 mIU/ml for LH and 4.25 +/- 0.45 vs. 5.53 +/- 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation of BMI with FT (r = -0.382; P < 0.01) and T (r = -0.327; P < 0.01). SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age (r = 0.538; P < 0.001) and T (r = 0.574; P < 0.001). FT correlated strongly with cFT (r = 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r = 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.     

Establishment of reference intervals for markers of fetal thyroid status in amniotic fluid

Fetal goiter can arise as a result of fetal hyper or hypothyroidism. Although this condition is rare, it can be life threatening. Detection of fetal goiter in utero is possible with the aid of ultrasound, but proper prenatal treatment depends on knowledge of hormonal status. Amniotic fluid (AF) sampling is less technically demanding and poses fewer risks to the fetus than cordocentesis for fetal serum sampling, but well-established reference ranges for AF thyroid studies are not available in the literature. We have established reference intervals for AF (TSH), total T(4) (tT(4)), and free T(4) using stored AF samples. The reference intervals were: TSH (n = 127), less than 0.1-0.5 mU/liter, with a median of 0.1 mU/liter; tT(4) (n = 129), 2.3-3.9 microg/dl (30-50 nmol/liter), with a median of 3.3 microg/dl (4 nmol/liter); and free T(4) (n = 119) less than 0.4-0.7 ng/dl (5-9 pmol/liter), with a median of 0.4 ng/dl (5 pmol/liter). These intervals represent the largest study done to date on third trimester AF using automated immunoassays. A literature search of fetal goiter revealed a number of cases of hypothyroidism. Seven cases reported AF TSH concentrations (range, 1.1-28.9 mU/liter) and four reported AF tT(4) concentrations [range, 0.98-1.25 micro g/ml (13-16 nmol/liter)], all of which fell outside our reference intervals. These data support the use of AF to diagnose fetal hypothyroidism, reducing the need to resort to a riskier procedure such as cordocentesis.     

Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy

Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/- 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass index. Moreover, after metformin therapy, hyperandrogenemia and hyperinsulinemia were normalized, and glucose utilization improved [obese before: total T, 0.9 +/- 0.15 ng/ml; fasting insulin, 22.2 +/- 12.1 U/liter; glucose utilization, 2.15 +/- 0.5 mg/kg.min; obese after: total T, 0.5 +/- 0.2 ng/ml; fasting insulin, 11.6 +/- 6 U/liter; glucose utilization, 4.7 +/- 1.4 mg/kg.min 9P < 0.003, P < 0.006, and P < 0.002, respectively); nonobese before: total T, 1 +/- 0.5 ng/ml; fasting insulin, 15.5 +/- 7.6 U/liter; glucose utilization, 3.4 +/- 0.7 mg/kg.min; nonobese after: total T, 0.8 +/- 0.5 ng/ml; fasting insulin, 9 +/- 3.8 U/liter; glucose utilization, 6 +/- 1.7 mg/kg.min (P < 0.04, P < 0.02, and P < 0.0008, respectively)]. In conclusion, our data clearly demonstrate that women with polycystic ovary syndrome, obese and nonobese, have elevated endothelin-1 levels compared with the age-matched control group. In addition, 6 months of metformin therapy reduces endothelin-1 levels and improves their hormonal and metabolic profile.     

Luteal phase deficiency in recreational runners: evidence for a hypometabolic state

Exercising women with amenorrhea exhibit a hypometabolic state. The purpose of this study was to evaluate the relationship of luteal phase deficient (LPD) menstrual cycles to metabolic hormones, including thyroid, insulin, human GH (hGH), leptin, and IGF-I and its binding protein levels in recreational runners. Menstrual cycle status was determined for three consecutive cycles in sedentary and moderately active women. Menstrual status was defined as ovulatory or LPD. Subjects were either sedentary (n = 10) or moderately active (n = 20) and were matched for age (27.7 +/- 1.2 yr), body mass (60.2 +/- 3.3 kg), menstrual cycle length (28.4 +/- 0.9 d), and reproductive age (14.4 +/- 1.2 yr). Daily urine samples for the determination of estrone conjugates, pregnanediol 3-glucuronide, and urinary levels of LH were collected. Blood was collected on a single day during the follicular phase (d 2-6) of each menstrual cycle for analysis of TSH, insulin, total T3, total T4, free T4, leptin, hGH, IGF-I, and IGF binding protein (IGFBP)-1 and IGFBP-3. Among the 10 sedentary subjects, 28 of 31 menstrual cycles were categorized as ovulatory (SedOvul). Among the 20 exercising subjects, 24 menstrual cycles were included in the ovulatory category (ExOvul), and 21 menstrual cycles were included in the LPD category (ExLPD). TSH, total T4, and free T4 levels were not significantly different among the three categories of cycles. Total T3 was suppressed (P = 0.035) in the ExLPD (1.63 +/- 0.07 nmol/liter) and the ExOvul categories of cycles (1.75 +/- 0.8 nmol/liter) compared with the SedOvul category of cycles (2.15 +/- 0.1 nmol/liter). Leptin levels were lower (P < 0.001) in both the ExOvul (5.2 +/- 0.4 microg/liter) and the ExLPD categories of cycles (5.1 +/- 0.4 microg/liter) when compared with the SedOvul category of cycles (13.7 +/- 1.7 microg/liter). Insulin was lower (P = 0.009) only in the ExLPD category of cycles (31.9 +/- 2.8 pmol/liter) compared with the SedOvul (60.4 +/- 8.3 pmol/liter) and ExOvul (61.8 +/- 10.4 pmol/liter) categories of cycles. IGF-I, IGFBP-1, IGFBP-3, IGF-I/IGFBP-1, IGF-I/IGFBP-3, and hGH were comparable among the different categories of cycles. These data suggest that exercising women with LPD menstrual cycles exhibit hormonal alterations consistent with a hypometabolic state that is similar to that observed in amenorrheic athletes and other energy-deprived states, although not as comprehensive. These alterations may represent a metabolic adaptation to an intermittent short-term negative energy balance.     

Fibroblast growth factor-23 in patients with Graves' disease before and after antithyroid therapy: its important role in serum phosphate regulation

OBJECTIVE: Hyperthyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of fibroblast growth factor (FGF)-23 in serum phosphate homeostasis in patients with Graves' disease during the course of treatment for hyperthyroidism. CONTEXT: The study group comprised 56 patients (45 for a cross-sectional study and 11 for a longitudinal study) with Graves' disease. For the cross-sectional study, patients were assigned, on the basis of their serum phosphate level, to a hypophosphatemia group (n = 14), a normophosphatemia group (n = 16), or a hyperphosphatemia group (n = 15). Serum FGF-23, calcium, phosphate, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were compared between the three groups. For the longitudinal study, we assessed changes in these biochemical indices before and after antithyroid treatment. RESULTS: In the cross-sectional study, the serum FGF-23 level was significantly higher (P < 0.05) in the hyperphosphatemia group than in the other groups (61 +/- 36 ng/liter vs. 31 +/- 22 ng/liter and 30 +/- 9 ng/liter). In the longitudinal study, serum levels of FGF-23 decreased significantly (P < 0.05) from a high of 54 +/- 12 ng/liter before treatment to 29 +/- 14 ng/liter after treatment. In contrast, the serum 1,25(OH)(2)D level increased significantly (P < 0.005) from 55 +/- 22 pmol/liter before treatment to 185 +/- 76 pmol/liter 3 months after treatment. Serum FGF-23 levels were positively correlated with serum phosphate levels (P < 0.0001) and negatively correlated with serum 1,25(OH)(2)D levels (P < 0.0001). CONCLUSIONS: The significant positive correlation between serum levels of phosphate and FGF-23 indicates that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.     

Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia

Newborns with high TSH at birth and with normal free T(4) and normal or slightly elevated TSH at the confirmatory examination are considered false positive for congenital hypothyroidism. We evaluated thyroid function, thyroid antibodies, thyroid volume and morphology, thyroperoxidase and TSH receptor genes, and auxological data in 56 false positive children at 16-44 months of age. In these children thyroid function at confirmatory examination was fully normal in 33 (TSH, 0.8-4.9 mU/liter; group I) and nearly normal (borderline elevated TSH, 5.0-11.7 mU/liter) in the other 23 (group II). Compared with 65 control children with normal TSH at birth, false positive children had significantly higher basal serum TSH (mean +/- SD, 4.38 +/- 2.2 vs. 1.4 +/- 0.8 mU/liter; P < 0.01). Subclinical hypothyroidism, indicated by increased basal TSH and/or increased TSH response to TRH, was present in 36% children in group I and 70% in group II. Free T(4) was within the normal range in all children. Compared with the control group, false positive children had significantly higher free T(3) values (4.9 +/- 0.8 vs. 3.7 +/- 1.0 pmol/liter; P < 0.01) and a higher prevalence of antithyroid antibodies (25% vs. 1.5%; P < 0.001). Frequent thyroid morphology abnormalities and frequent thyroperoxidase and TSH receptor gene sequence variations were also observed. In conclusion, newborns classified false positive at congenital hypothyroidism screening have a very high risk of subclinical hypothyroidism in infancy and early childhood.     

The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans

Arterial hypertension is known to be frequently associated with thyroid dysfunction, with a particularly high prevalence in chronic hypothyroidism. However, to our knowledge no comprehensive study addressed causal mechanisms possibly involved in this association. We here report the physiological relationships between blood pressure and neuro-humoral modifications induced by acute hypothyroidism in normotensive subjects. Twelve normotensive patients with previous total thyroidectomy were studied. Ambulatory 24-h blood pressure monitoring was performed, and free T(3), free T(4), TSH, PRA, aldosterone, cortisol, adrenaline, and noradrenaline were assayed 6 wk after oral L-T(4) withdrawal (phase 1) and 2 months after resumption of treatment (phase 2). During the hypothyroid state (TSH, 68.1 +/- 27.7 microIU/ml; mean +/- SD), daytime arterial systolic levels slightly, but significantly, increased (125.5 +/- 9.7 vs. 120.4 +/- 10.8 mm Hg; P < 0.05), and daytime diastolic levels (84.6 +/- 7.9 vs. 76.4 +/- 6.8 mm Hg; P < 0.001), noradrenaline (2954 +/- 1578 vs. 1574 +/- 962 pmol/liter; P < 0.001), and adrenaline (228.4 +/- 160 vs. 111.3 +/- 46.1 pmol/liter; P < 0.05) also increased. PRA remained unchanged (0.49 +/- 0.37 vs. 0.35 +/- 0.21 ng/ml.h; P = NS), whereas both aldosterone (310.3 +/- 151 vs. 156.9 +/- 67.5 pmol/liter; P < 0.005) and cortisol (409.2 +/- 239 vs. 250.9 +/- 113 pmol/liter; P < 0.02) significantly increased. By using univariate logistic regression daytime arterial diastolic values, noradrenaline and aldosterone were found to be significantly related to the hypothyroid state (P < 0.02, P < 0.036, and P < 0.024, respectively). In conclusion, our data show that thyroid hormones participate in the control of systemic arterial blood pressure homeostasis in normotensive subjects. The observed sympathetic and adrenal activation in hypothyroidism, which is reversible with thyroid hormone treatment, may also contribute to the development of arterial hypertension in human hypothyroidism.     

Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies

AIM: Autoimmune gastritis is frequently associated with autoimmune thyroiditis and other organ-specific autoimmune diseases, and may lead to atrophic body gastritis (ABG). We studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of ABG in patients with autoimmune gastritis. METHODS: We studied 233 patients with autoimmune gastritis and 211 control subjects. All patients and control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin, pepsinogen I and II, and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy. RESULTS: In PCA/positive patients, mean (+/-sd) serum ghrelin levels were significantly lower (238 +/- 107 pmol/liter), and mean (+/-sd) serum gastrin levels were significantly higher (81.2 +/- 128.3 ng/ml), with respect to PCA/negative patients (282 +/- 104 pmol/liter and 20.7 +/- 13.3 ng/ml, respectively; P < 0.0001). Serum ghrelin and gastrin levels were inversely correlated (P = 0.004). A total of 40 patients had ABG documented by the gastric biopsy (90% in PCA/positive patients and 10% in PCA/negative patients). The receiver operating characteristic curve analysis revealed that a cutoff value for serum ghrelin of 188 pmol/liter was associated with the highest sensitivity and specificity (97.3 and 100%, respectively) in detecting gastric atrophy and was superior to gastrin (P = 0.012), PCA (P = 0.002), and the pepsinogen I/II ratio (P = 0.016) measurements. CONCLUSIONS: Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG.     

Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome

The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS). Twenty-one Caucasian women with PCOS [mean (+/-SEM) age 27 +/- 0.9 yr and body mass index 36.7 +/- 3.3 kg/m(2)] participated in this prospective, randomized, open-labeled study. All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months. Weight, blood pressure, and fasting blood samples were taken at screening, randomization, and on completion. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA)-IR method [HOMA-IR = (insulin x glucose)/22.5]. The results are expressed as mean +/- SEM. When compared with baseline, treatment with both orlistat [93.5 +/- 11.5 ng/dl (3.24 +/- 0.4 nmol/liter) vs. 114.5 +/- 11.5 ng/dl (3.97 +/- 0.4 nmol/liter), P = 0.039] and metformin [97.2 +/- 11.5 ng/dl (3.37 +/- 0.4 nmol/liter) vs. 120.0 +/- 8.7 ng/dl (4.16 +/- 0.3 nmol/liter), P = 0.048] produced a significant reduction in total testosterone. Treatment with orlistat produced a 4.69% reduction in weight (99.0 +/- 6.0 vs. 94.6 +/- 6.1 kg, P = 0.002), and this reduction was more significant than the reduction produced by metformin (4.69 vs. 1.02%, P = 0.006). There was no significant reduction seen after either treatment group for fasting insulin, HOMA-IR, SHBG, or any of the lipid parameters studied. In this study, orlistat produced a significant reduction in weight and total testosterone. The reduction in total testosterone was similar to that seen after treatment with metformin. Therefore, orlistat may prove to be a useful adjunct in the treatment of PCOS.     

Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease

INTRODUCTION: We describe the use of serum cortisol and ACTH levels on postoperative d 1 and 2 as remission predictors after transsphenoidal surgery for Cushing's disease (CD). METHODS: Morning cortisol and ACTH levels were drawn daily after surgery; glucocorticoids were withheld until evidence of hypocortisolemia. Early remission was defined retrospectively as a subnormal morning cortisol level [< or =140 nmol/liter (< or =5 microg/dl)] on postoperative d 1 or 2 and sustained remission as subsequent eucortisolemia. RESULTS: Of 40 consecutive adults with CD (mean age 39 yr), 80% achieved early remission. Of 39 patients with a minimum follow-up of 14 months (mean 33 months), 31 (79.5%) achieved sustained remission at a mean follow-up of 32 months, including 30 of 31 (97%) with early remission and one of eight (12%) without early remission (P < 0.0001). Sustained remission was achieved in 26 of 28 (93%) patients having their first operation, compared with five of 11 (45%) with a prior unsuccessful operation (P < 0.001). For the 32 patients in early remission vs. the eight in nonremission, mean nadir cortisol levels were 57.6 +/- 33.0 (2.05 +/- 1.2 microg/dl) vs. 631.1 +/- 352.2 nmol/liter (22.9 +/- 12.8 microg/dl) (P < 0.0001), and nadir ACTH levels were 11.9 +/- 6.5 vs. 64.1 +/- 54.6 ng/liter (P < 0.001). Of 31 patients with sustained remission, 100% had subnormal morning cortisol levels, whereas 31% had subnormal ACTH levels (P < 0.0001). CONCLUSIONS: Serum morning cortisol levels on postoperative d 1 and 2 without glucocorticoid replacement provide a safe, simple, and reliable measure of early remission for CD and are predictive of sustained remission. This method allows for consideration of a repeat operation during the same hospitalization in patients with persistent hypercortisolemia.     

Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome

Effects of a polyunsaturated fatty acid (PUFA)-rich diet were investigated in 17 polycystic ovary syndrome (PCOS) patients. After a 3-month habitual diet period, dietary fats were partly replaced with PUFAs for another 3 months. The PUFA-rich diet increased plasma linoleic acid from 28.36 +/- 1.00% to 33.76 +/- 1.08% (P < 0.002) and alpha-linolenic acid from 0.52 +/- 0.03% to 1.06 +/- 0.10% (P < 0.0001). Fasting glucose increased from 76 +/- 3 to 95 +/- 3 mg/dl (4.2 +/- 0.2 to 5.30.2 mmol/liter; P < 0.0001), and the area under the curve for glucose during oral glucose tolerance test increased from 421 +/- 34 to 503 +/- 31 mg/dl (23.4 +/- 1.9 to 27.9 +/- 1.7 mmol/liter; P < 0.001). Plasma insulin did not change either at fasting or during oral glucose tolerance test. Fasting plasma free fatty acids decreased from 0.596 +/- 0.048 to 0.445 +/- 0.058 mg/dl (P = 0.037), and ketone bodies decreased from 9.14 +/- 1.57 to 3.63 +/- 0.62 mg/dl (895 +/- 154 to 356 +/- 61 micromol/liter; P < 0.003). Plasma 15-deoxyprostaglandin J(2) tended to decrease (from 239 +/- 65 to 171 +/- 60 ng/ml; P = 0.053). Plasma testosterone, free testosterone, SHBG, dehydroepiandrosterone sulfate, LH, FSH, and urinary estrogen conjugates did not change. Urinary pregnanediol 3-glucuronide increased from 18.6 +/- 2.2 to 31.0 +/- 5.7 micro g/mg creatinine (P = 0.038). In conclusion, increased dietary PUFA intake can exert significant metabolic and endocrine effects in women with PCOS.