SUMMARY: A 6.6-year-old female presented to endocrinology with precocious puberty for evaluation and management. Workup was initiated, and a diagnosis of central precocious puberty was confirmed. A decision was made to initiate pubertal blockade using gonadotropin-releasing hormone agonist (GnRHa) therapy with depot leuprolide acetate injections every 3 months. The patient received the first depot leuprolide acetate injection in the right ventrogluteal area. Six hours following the injection, the patient was reported to be inconsolable in pain, which was localized to the right hip site of the earlier injection and associated with a refusal to ambulate. The pain and discomfort continued to progress over the next 24 h despite an alternating regimen of Tylenol and ibuprofen prompting admission to the emergency department. Vital signs demonstrated a low-grade fever and elevated C-reactive protein. An ultrasound of the right hip demonstrated fluid accumulation within the joint. Over the next week, the patient was unable to walk independently and required assistance for activities of daily living. By 2 weeks after the injection, the pain began to remit, and the patient resumed activities of daily living. Following consultation with allergy, a decision was made to continue GnRHa suppressive therapy with an alternative analog (Triptodur). The patient tolerated subsequent treatment without reaction. LEARNING POINTS: Although gonadotropin-releasing hormone agonists (GnRHa) have a generally good safety profile, there is a history of both local and systemic hypersensitivity reactions associated with their use. Despite the long-acting formulation of depot leuprolide acetate, the systemic reaction in this case appears to be self-limited. Discontinuation of therapy or a change to an alternative formulation of GnRHa analog should be considered based on the need for therapy versus the potential risk of rechallenge.

Girls with either hypo- or hypergonadotropic hypogonadism need treatment with estrogens to initiate puberty and maintain a normal hormonal milieu. The focus of this review is hormone replacement treatment in girls with hypogonadism, to initiate and progress through puberty, and to maintain a healthy hormonal milieu in women. It also addresses what is known in the literature regarding estrogen levels in girls and women, instructive cases, practical tables for reference and application, and thoughts on future directions in this area. It represents a thorough literature review with author opinions and recommendations. Girls with normal ovarian function begin puberty on average at 10.5 years old, although there is variation according to ethnicity and degree of excess weight gain. The aim of estrogen therapy to initiate puberty is to mimic normal onset and rate of progression. On the basis of the currently available literature, when a diagnosis of hypogonadism is established, we recommend initiating treatment between age 11 and 12 years of age, with dose increases approximately every 6 months until adult levels are reached. In some situations, treatment may be delayed to allow time for diagnosis or permit more time for linear growth, or address unique risks found in girls treated for various cancers or blood disorders. When adult dosing is reached, progestins are also used to protect uterine health. This can be combined sequentially, allowing regular menstruation, or combined continuously when menstrual bleeding is not preferred. Treatment is continued until the average age of menopause, again with various considerations for longer or shorter duration on the basis of risk-benefit ratios. Transdermal estrogens are considered the most physiologic replacement and theoretically might have fewer associated risks. We review what is known about risks and outcomes and areas for future research.

Girls with either hypo- or hypergonadotropic hypogonadism need treatment with estrogens to initiate puberty and maintain a normal hormonal milieu. The focus of this review is hormone replacement treatment in girls with hypogonadism, to initiate and progress through puberty, and to maintain a healthy hormonal milieu in women. It also addresses what is known in the literature regarding estrogen levels in girls and women, instructive cases, practical tables for reference and application, and thoughts on future directions in this area. It represents a thorough literature review with author opinions and recommendations. Girls with normal ovarian function begin puberty on average at 10.5 years old, although there is variation according to ethnicity and degree of excess weight gain. The aim of estrogen therapy to initiate puberty is to mimic normal onset and rate of progression. On the basis of the currently available literature, when a diagnosis of hypogonadism is established, we recommend initiating treatment between age 11 and 12 years of age, with dose increases approximately every 6 months until adult levels are reached. In some situations, treatment may be delayed to allow time for diagnosis or permit more time for linear growth, or address unique risks found in girls treated for various cancers or blood disorders. When adult dosing is reached, progestins are also used to protect uterine health. This can be combined sequentially, allowing regular menstruation, or combined continuously when menstrual bleeding is not preferred. Treatment is continued until the average age of menopause, again with various considerations for longer or shorter duration on the basis of risk-benefit ratios. Transdermal estrogens are considered the most physiologic replacement and theoretically might have fewer associated risks. We review what is known about risks and outcomes and areas for future research.

Abstract Background Elevated stearoyl-CoA desaturase activity has been described in obese states, with an increased desaturation index (DI) suggesting enhanced lipogenesis. Differences in the DI among various phenotypes of abnormal adiposity have not been studied. Abnormal accumulation of subcutaneous adipose tissue occurs in rare adipose disorders (RADs) including Dercum's disease (DD), multiple symmetric lipomatosis (MSL), and familial multiple lipomatosis (FML). Examining the DI in subcutaneous fat of people with DD, MSL and FML may provide information on adipose tissue fatty acid metabolism in these disorders. The aims of this pilot study were: 1) to determine if differences in adipose tissue DIs are present among RADs, and 2) to determine if the DIs correlate to clinical or biochemical parameters. Methods Subcutaneous adipose tissue was obtained from human participants with DD (n = 6), MSL (n = 5), FML (n = 8) and obese Controls (n = 6). Fatty acid composition was determined by gas chromatography/mass spectrometry. The DIs (palmitoleic/palmitic, oleic/stearic, vaccenic/stearic ratios) were calculated from the gas chromatogram peak intensities. SCD1 gene expression was determined. Spearman's correlations between the DIs and available clinical or biochemical data were performed. Results In DD subjects, the vaccenic/stearic index was lower (p < 0.05) in comparison to Controls. Percent of total of the saturated fatty acid myristic acid was higher in DD compared with Controls and FML. Percent of monounsaturated vaccenic acid in DD trended lower when compared with Controls, and was decreased in comparison to FML. In MSL, total percent of the polyunsaturated fatty acids was significantly lower than in the Control group (p < 0.05). In the total cohort of subjects, the palmitoleic/palmitic and oleic/stearic DIs positively correlated with age, BMI, and percent body fat. Conclusions The positive associations between the DIs and measures of adiposity (BMI and percent body fat) support increased desaturase activity in obesity. The lower vaccenic/stearic DI in DD SAT compared with Controls suggests presence of other factors involved in fat accumulation in addition to lifestyle. Other mechanisms driving fat accumulation in DD such as inflammation or lymphatic dysfunction should be investigated.

Summary

An 11-year-old girl with past medical history of septic shock and multi-organ failure at age 5 presented to her primary care doctor with concern for pallor of the lips. Laboratory studies demonstrated low free thyroxine (T4) and normal thyroid-stimulating hormone (TSH). A referral to endocrinology was made where the patient was evaluated, and laboratory evaluation was repeated. The patient was asymptomatic and clinically euthyroid with a height consistent with her mid-parental height and was in mid- to late-puberty. The repeated laboratory evaluation demonstrated a pattern suggestive of primary hypothyroidism with low free T4 and an elevated TSH. However, the magnitude of elevation of TSH was less than expected, given the degree of lowering of free T4; therefore, central hypothyroidism was considered. Workup was initiated, and laboratory studies and MRI imaging confirmed an underlying diagnosis of panhypopituitarism in the setting of pituitary stalk interruption syndrome.

Learning points

Pituitary stalk interruption syndrome is a rare but important cause of panhypopituitarism. Central hypothyroidism should be suspected in patients with low free thyroxine with an inappropriate degree of elevation of thyroid-stimulating hormone. Workup of central hypothyroidism should include multi-pituitary hormone assessment, and, if evident, MRI imaging should be done. Adrenal insufficiency should be suspected in a hypotensive, critically ill patient who is failing to improve on standard-of-care therapy.

Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-Lalpha expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44.

Adiponectin is an insulin sensitizing fat cell (FC) hormone whose levels are related to adipose tissue (AT) mass and depot distribution. We hypothesized that the nature of AT expansion (hypertrophy vs. hyperplasia) contributes to obesity-related reductions in serum adiponectin and that this effect is influenced by the regional distribution of AT to subcutaneous (S) and visceral (V) depots. Thirteen obese subjects provided paired AT biopsies. Serum total and high molecular weight (HMW) adiponectin levels were determined by ELISA. Secretion was quantified following 24-h explant culture. FC size, number, % large, and % small FC were determined by microscopic analysis. Secretion of total adiponectin was highest by SAT (P = 0.008) and correlated more strongly with serum adiponectin (total: P = 0.015, r = 0.77; HMW: P = 0.005, r = 0.83) than did secretion by VAT (P = 0.05, r = 0.66 for both). FC size was greatest in SAT and correlated negatively with both serum (total: P = 0.01, r = -0.74; HMW: P = 0.03, r = -0.69) and secreted (total: P = 0.05, r = -0.72; HMW: P = 0.02, r = -0.87) adiponectin. The % small FC in SAT correlated positively with both serum (total: P = 0.006, r = 0.87; HMW: P = 0.009, r = 0.79) and secreted (total: P = 0.03, r = 0.75; HMW: P = 0.01, r = 0.92) adiponectin. VAT FC size correlated negatively with serum HMW adiponectin (P = 0.01, r = -0.76) but not with any measure of secretion. VAT had the greatest % small FC, which related positively to serum HMW (P = 0.004, r = 0.81) and to secreted total adiponectin (P = 0.02, r = 0.78). These studies indicate that differences in fat cell size and depot distribution of AT expansion are important influences on adiponectin in obesity.

Type 2 Diabetes (T2D) is associated with impaired vascularization of adipose tissue (AT) . IL8, GROα and IL15 are pro-angiogenic myokines, secreted at elevated levels by T2D myotubes. We explored the direct impact of these myokines on AT vascularization. AT explants from subjects with T2D and without diabetes (non-diabetic, ND) were treated with rIL8, rGROα and rIL15 in concentrations equal to those in conditioned media (CM) from T2D and ND myotubes, and sprout formation evaluated. Endothelial cells (EC) were isolated from T2D and ND-AT, treated with rGROα and tube formation evaluated. Finally, we investigated the involvement of MMP-2 and -9 in vascularization. ND and T2D concentrations of IL8 or IL15   caused similar stimulation of sprout formation in ND- and T2D-AT. GROα exerted a similar effect in ND-AT. When T2D-AT explants were exposed to GROα, sprout formation in response to T2D concentrations was reduced compared to ND. Exposure of EC from T2D-AT to GROα at T2D concentrations resulted in reduced tube formation. Reduced responses to GROα in T2D-AT and EC were also seen for secretion of MMP-2 and -9. The data indicate that skeletal muscle can potentially regulate AT vascularization, with T2D-AT having impairments in sensitivity to GROα, while responding normally to IL8 and IL15.

Objectives

The Bethesda system for reporting cytopathology (TBSRTC) has been widely adopted in the management of thyroid nodules. Based on the limited pediatric data available, the implied malignancy risk for each of the categories may be significantly different in pediatrics vs. adults, especially in the indeterminate categories (Bethesda Class III or IV). We report the diagnostic utility of fine needle aspiration (FNA) biopsy at our institution based on the Bethesda system and the risk of malignancy in each category.

Methods

We retrospectively reviewed all patients who underwent a thyroid FNA at our tertiary pediatric hospital from 12/1/2002 to 11/30/2018. FNA results were classified according to TBSRTC. Patient demographics, cytology, histopathology, radiological and clinical follow-ups were examined.

Results

A total of 171 patients were included with 203 cytological samples. Average age at initial FNA was 14.7 years (range 6.9-18.6 years). The numbers of nodules reported for Bethesda categories I-VI were 29, 106, 22, 14, 6 and 26, respectively, and the rate of malignancy was: 13.8, 4.7, 22.7, 35.7, 83.3 and 100%, respectively. Use of ultrasound guidance reduced the non-diagnostic rate from 38.1 to 11.5%. Introduction of on-site adequacy testing further reduced the non-diagnostic rate to 6.5% since 2014.

Conclusions

The risk of malignancy for thyroid nodules in this pediatric cohort is higher than reported in adults. However, rates described here are much closer to adult ranges than previously published pediatric cohorts. The addition of adequacy testing improved the non-diagnostic rate of FNA procedures performed with ultrasound guidance.