Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma.

Background: Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods: This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results: Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (ß coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and ß coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively). Conclusions and relevance: In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Health-related quality of life following FDG-PET/CT for cytological indeterminate thyroid nodules.

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules. Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done. Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FDG-PET/CT scan. Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05). Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology.

[18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial.

PURPOSE: To assess the impact of an [18F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. METHODS: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT and were randomised to an [18F]FDG-PET/CT-driven or diagnostic surgery group. In the [18F]FDG-PET/CT-driven group, management was based on the [18F]FDG-PET/CT result: when the index nodule was visually [18F]FDG-positive, diagnostic surgery was advised; when [18F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. RESULTS: Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [18F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [18F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2-40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [18F]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively. CONCLUSION: An [18F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. TRIAL REGISTRATION NUMBER: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544 .

Bone Mineral Density in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma: A Longitudinal Follow-Up Study.

Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [ß-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers ß-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Long-Term Effects of Radioiodine Treatment on Female Fertility in Survivors of Childhood Differentiated Thyroid Carcinoma.

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) µg/L vs. 1.6 (IQR 0.6-3.1) µg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.

Biochemically Silent Sympathetic Paraganglioma, Pheochromocytoma, or Metastatic Disease in SDHD Mutation Carriers.

CONTEXT: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range. PARTICIPANTS: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years. CONCLUSIONS: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions.

Psychosocial development in survivors of childhood differentiated thyroid carcinoma: a cross-sectional study.

OBJECTIVE: The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC. DESIGN AND METHODS: Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used. RESULTS: We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales. CONCLUSIONS: Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.

Diastolic Dysfunction is Common in Survivors of Pediatric Differentiated Thyroid Carcinoma.

INTRODUCTION: Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers. METHODS: In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis ≤18 years and follow-up ≥5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e') less than 2 SD of mean age-adjusted reference data. RESULTS: The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was near normal. Diastolic dysfunction was present in 14 asymptomatic survivors (21.2%). Overall, diastolic function of survivors was lower compared with controls (e'mean 14.5 versus 15.8 cm/s, P = 0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed. CONCLUSION: While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac aging.

Long-Term Quality of Life in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma.

Context: Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer-specific HRQoL in survivors only. Design: Survivors diagnosed between 1970 and 2013 at age ≤18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer-specific HRQoL questionnaire. Results: Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer-specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL. Conclusions: Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration.

Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study.

INTRODUCTION: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands. PATIENTS AND METHODS: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis ≤18 y) treated in The Netherlands between 1970 and 2013 were assessed using medical records. RESULTS: We identified 170 patients. Overall survival was 99.4% after a median follow-up of 13.5 years (range 0.3-44.7 y). Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 years (range 5.8-18.9 y). At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 GBq (range 0.74-35.15 GBq). Life-long postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (odds ratio 2.00, 95% confidence interval 0.78-5.17, P = .152). CONCLUSIONS: Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of life-long postoperative complications. Adverse effects may be reduced by the centralization of care, which is crucial for children with DTC.

Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome.

The present study tests the hypothesis that specific endocrine, metabolic, and anthropometric features distinguish obese women with polycystic ovary syndrome (PCOS) who resume ovulation in response to calorie restriction and weight loss from those who do not. Fifteen obese (body mass index 39 +/- 7 kg/m(2)) hyperandrogenemic oligoovulatory patients undertook a very low calorie diet (VLCD), wherein each lost > or =10% of body weight over a mean of 6.25 mo. Body fat distribution was quantitated by magnetic resonance imaging. Hormones were measured in the morning at baseline, after 1 wk of VLCD, and after 10% weight loss. To monitor LH release, blood was sampled for 24 h at 10-min intervals before intervention and after 7 days of VLCD. Responders were defined a priori as individuals exhibiting two or more ovulatory cycles in the course of intervention, as corroborated by serum progesterone concentrations > or =18 nmol/l followed by vaginal bleeding. At baseline, responders had a higher sex hormone-binding globulin (SHBG) concentration but were otherwise indistinguishable from nonresponders. Body weight, the size of body fat depots, and plasma insulin levels declined to a similar extent in responders and nonresponders. Also, SHBG increased, and the free testosterone index decreased comparably. However, responders exhibited a significant decline of circulating estradiol concentrations (from 191 +/- 82 to 158 +/- 77 pmol/l, means +/- SD, P = 0.037) and a concurrent increase in LH secretion (from 104 +/- 42 to 140 +/- 5 U.l(-1).day(-1), P = 0.006) in response to 7 days of VLCD, whereas neither parameter changed significantly in nonresponders. We infer that evidence of retention of estradiol-dependent negative feedback on LH secretion may forecast follicle maturation and ovulation in obese patients with PCOS under dietary restriction.

Steroids in adult men with type 1 diabetes: a tendency to hypogonadism.

OBJECTIVE: To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. RESULTS: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. CONCLUSIONS: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Low amplitude and disorderly spontaneous growth hormone release in obese women with or without polycystic ovary syndrome.

Obesity is associated with considerably reduced plasma GH concentrations, which may contribute to anovulation in (obese) women with polycystic ovary disease (PCOS). This clinical investigation was undertaken to establish whether the GH release process is deranged in obese women with PCOS and, if so, whether the observed anomalies are features of the syndrome or a sequel of body fat accretion. To this end we sampled 24-h plasma GH concentration profiles at 10-min intervals in 15 obese PCOS patients [mean age, 29 yr (range, 20-38); percent body fat, 47 +/- 5.2%], 15 equally obese controls with regular menstrual cycles [age, 34 yr (range, 20-44); percent body fat, 48 +/- 4.9%], and 15 healthy age-matched lean controls [age, 34 yr (range, 21-45); percent body fat, 29 +/- 9.0%]. Compared with lean controls, obese PCOS patients exhibited a greater than 60% reduction in basal and a greater than 75% reduction in pulsatile and total daily GH secretion due to a 2.7-fold attenuation of burst mass and a lesser (1.4-fold) slowing of GH pulse frequency. The mean +/- SEM number of statistically significant GH peaks was 13.9 +/- 1.2/24 h, the endogenous GH half-life was 14.1 +/- 0.4 min, basal GH secretion was 5.0 +/- 0.7 mU/liter.24 h, and total secretion was 61.4 +/- 9.6 mU/liter.24 h in obese women with PCOS. None of these parameters differed from those in the body mass index-matched controls. The approximate entropy ratio was significantly increased in obese women (both PCOS and controls), indicating greater irregularity of the GH release process. Total GH secretion in patients and the two control groups correlated strongly and negatively with percent body fat (r = -0.775; P < 10(-8)). Serum concentrations of IGF-I and IGF-binding protein-3 were higher in patients with PCOS than in obese controls (P = 0.03 and P = 0.02, respectively), but the IGF-1/IGF-binding protein-3 ratio was equivalent in all three study groups. In conclusion, the profoundly reduced and irregular GH release in obese women with PCOS appears to be a corollary of body fat accretion and not of the syndrome per se.

Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS.

We hypothesized that short-term calorie restriction would blunt luteinizing hormone (LH) hypersecretion in obese women with polycystic ovary syndrome (PCOS) and thereby ameliorate the anovulatory endocrine milieu. To test this hypothesis, 15 obese patients with PCOS and nine age- and body mass index-matched healthy women underwent 24-h blood sampling to quantitate plasma LH, leptin, and insulin levels. PCOS subjects were prescribed a very low caloric liquid diet (4.2 MJ/day) for 7 days and were then resampled. Basal and pulsatile LH secretion was threefold higher in PCOS subjects, but plasma insulin and leptin levels were not different in the calorie-replete state. Contrary to expectation, calorie restriction enhanced basal and pulsatile LH secretion even further. As expected, plasma glucose, insulin, and leptin concentrations decreased by 18, 75, and 50%, respectively. Serum total testosterone concentration fell by 23%, whereas serum estrone, estradiol, sex hormone-binding globulin (SHBG), and androstenedione concentrations remained unchanged. Enhanced LH secretion in the presence of normal metabolic and hormonal adaptations to calorie restriction points to anomalous feedback control of pituitary LH release in PCOS.