Harry J. Hirsch

Persistent hyperinsulinemic hypoglycemia of infancy: Long-term octreotide treatment without pancreatectomy

Eight patients with persistent hyperinsulinemic hypoglycemia of infancy who were treated with octreotide without pancreatectomy are described. All had severe, early-onset disease that would have required partial pancreatectomy had octreotide not been available. Along with octreotide, frequent feedings and raw cornstarch at night were required by all. Octreotide was given in three or four daily subcutaneous injections in four patients and in a continuous subcutaneous infusion with an insulin infusion pump in four. All had mild, transient gastrointestinal symptoms (vomiting, abdominal distention, steatorrhea) after the start of therapy. Asymptomatic gallstones were found in 1 patient after 1 year of treatment. No other long-term untoward effects were noted, including no detrimental effect on psychomotor development. Growth was not affected in five of six patients treated for more than 6 months. In five patients, octreotide was discontinued after 9 months to 5 1/2 years; patients were given diazoxide instead, two required percutaneous gastrostomy, and one 5 1/2-year-old child required no further treatment. The remaining three patients (aged 5 to 9 months) are still being treated with octreotide. We conclude that, with the use of octreotide, pancreatectomy can be avoided in some patients. Particularly in light of our findings of a high incidence of diabetes years after partial pancreatectomy, and clinical improvement after months to years of octreotide treatment, we believe that aggressive medical therapy, when effective, is preferable to partial pancreatectomy.

Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin.

We treated a two-month-old infant with servere intractable hypoglycemia and nesidioblastosis with continuous glucose infusions (0.75 g per kilogram per hour) via a central venous catheter. Preprandial glucose levels on this regimen were 37+/-2 mg per deciliter (+/-S.E.M.). Basal serum insulin levels were within normal fasting levels for this age group but inappropriately elevated for the blood glucose levels. The beta cells were exquisitely sensitive to infusions of synthetic cyclic somatostatin, with a dose-dependent rise in blood glucose and concomitant suppression of serum insulin levels. There was only minimal suppression of plasma glucagon levels. Single subcutaneous injections of 50 microng of protamine zinc somatostatin raised preprandial blood glucose levels to 83+/-3 mg per deciliter for four to five days although preprandial hormone levels were unchanged. These findings indicate that hypoglycemia of infancy is a hyperinsulin state with abnormal basal regulation of insulin secretion.

Aldose reductase inhibition: studies with alrestatin.

Studies with the aldose reductase inhibitor alrestatin in animal models have suggested that the sorbitol pathway may be of etiologic significance in the pathogenesis of peripheral neuropathy in diabetes. In normal subjects and in highly selected diabetic patients with severe peripheral neuropathy, alrestatin given either intravenously (50 mg/kg body weight) or orally (1 gm q.i.d.) produced no acute toxicity. The serum half-life of alrestatin was approximately 1 hr, and 99% was recovered in the urine within 24 hr. Two diabetic patients receiving alrestatin intravenously reported subjective improvements in clinical symptoms 2 days following the start of infusions. These improvements lasted approximately 3 wk after infusions were discontinued. However, there were no significant objective changes in peripheral nerve condition velocities, or on neurologic examination. In a 30-day oral trial with alrestatin in 4 diabetics, there were no subjective improvements in clinical symptoms nor were there objective improvements on neurologic examination or in peripheral nerve conduction velocities. In this study, peak serum levels of alrestatin were approximately 3 times lower than those obtained on intravenous administration, and it is possible that a high peak serum level is critical to the attainment of adequate tissue drug concentrations. Furthermore, the patients were suffering from severe clinical peripheral neuropathy, which could represent a stage of permanent irreversible nerve damage. Studies with alrestatin in newly diagnosed diabetics with peripheral nerve conduction velocity deficits but without clinical neuropathy might provide a better test of the sorbitol pathway hypothesis.

Primary Testicular Dysfunction Is a Major Contributor to Abnormal Pubertal Development in Males with Prader-Willi Syndrome

BACKGROUND Recent studies challenge the assumption that hypogonadism in Prader-Willi syndrome (PWS) is due only to hypothalamic dysfunction. OBJECTIVES The aims of the study were to characterize sexual development and reproductive hormones in PWS males and investigate the etiology of hypogonadism. METHODS Physical examination and blood sampling were performed on 37 PWS males, ages 4 months to 32 yr. RESULTS All had a history of undescended testes; age at orchiopexy ranged from 2 months to 6 yr. Pubertal signs were variable, but none achieved full genital development. Anti-Mullerian hormone (AMH) levels in PWS boys were near the lower limits of normal, decreasing from 44.4 +/- 17.8 ng/ml (mean +/- sd) in young children to 5.9 +/- 4.7 ng/ml in adolescents, similar to normal males. In contrast, inhibin B was consistently low (27.1 +/- 36.1 pg/ml) or undetectable in all age groups. In adult males, FSH levels were high (20.3 +/- 18.3 IU/liter), LH levels were normal (4.2 +/- 4.3 IU/liter), and testosterone levels were low (1.87 +/- 1.17 ng/ml). Only two adults had severe hypogonadotropic hypogonadism with undetectable levels of LH and FSH and high AMH levels (34.9 and 36.7 ng/ml), unlike the other nine adults with AMH levels 2.6 +/- 2.1 ng/ml. Androstenedione (1.06 +/- 0.30 ng/ml) and DHEAS (281.1 +/- 143.6 microg/dl) in adult PWS were normal. CONCLUSIONS Pubertal development in PWS is characterized by normal adrenarche, variable hypothalamic dysfunction, and hypogonadism due to a unique testicular defect. Primary testicular dysfunction is a major component of hypogonadism in PWS.

The Histrelin Implant: A Novel Treatment for Central Precocious Puberty

Objective. Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) at 3- to 4-week intervals. Although generally effective in suppressing clinical and laboratory parameters of puberty, GnRHa injections are painful, and the need for monthly clinic visits may contribute to poor compliance. Recently, a subcutaneous implant was developed that releases the GnRHa histrelin at an average rate of 65 μg/day. The aims of this study were to determine if a histrelin implant would suppress gonadotropin and estradiol (E2) in girls with CPP for 1 year and to compare the suppression to standard treatment. Methods. We studied 11 girls with CPP to determine if the histrelin implant can maintain long-term gonadotropin suppression. Mean age at diagnosis was 6 years (range: 2–9 years). GnRH (100 μg intravenously) stimulation tests (GnRH-STs) showed peak luteinizing hormone and follicle-stimulating hormone responses of 23 ± 28 (mean ± SD) and 20 ± 25 mIU/mL, respectively. All subjects were initially treated with depot intramuscular GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were followed for 15 months after insertion (group A). For the remaining 5 girls, the implant was removed after 9 months, and a new implant was inserted at the same incision site (group B). GnRH-STs were performed before depot GnRHa treatment, immediately before implant insertion, at the 6- and 9-month visits for each patient and the 12- and 15-month visit for those girls followed for 15 months. Results. In all girls, breast development regressed, growth velocity decreased, and bone-age advancement was slowed. Basal gonadotropins and their responses to GnRH-STs and E2 levels were suppressed. Peak luteinizing hormone and follicle-stimulating hormone responses to GnRH-STs at preinsertion versus 9 months were 1.30 ± 1.34 vs 0.25 ± 0.08 and 1.68 ± 1.08 vs 1.13 ± 0.55 mIU/mL, respectively. Basal and stimulated gonadotropin levels and E2 level remained suppressed in all 6 patients followed for 15 months after implant insertion. Patients and parents reported less pain and discomfort and less interference with school activity and work with the implant compared with standard monthly injections. Conclusions. The histrelin implant consistently suppresses clinical and laboratory parameters of puberty for 1 year and is a promising new technique for treating CPP without the pain and inconvenience of monthly injections.

Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction.

OBJECTIVE The variable hypogonadism in Prader-Willi syndrome (PWS) has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. Our aims were to characterize sexual development and reproductive hormones in PWS females and to investigate the etiology of hypogonadism. DESIGN A cross-sectional study. METHODS Physical examination was performed on 45 PWS females (aged 6 weeks to 32 years) and blood samples were obtained for hormonal analyses. RESULTS Age of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (aged 15-30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea. Anti-Mullerian hormone levels were within the normal range in all age groups. Inhibin B was consistently low or undetectable; only five women had levels in the low-normal range (20-54 pg/ml). LH was normal in most children, but low (<1.0 IU/l) in 9 of 15 adults. FSH was within the normal range for age in most children, but low (<0.5 IU/l) in 10 and high in four adults. Estradiol levels were normal-low and androgen levels were normal in the majority. CONCLUSIONS Pubertal development in PWS females, as in males, is characterized by normal adrenarche, pubertal arrest, and hypogonadism due to variable combinations of a unique primary gonadal defect and hypothalamic dysfunction.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

Objective Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Nesidioblastosis Associated with Insulin-mediated Hypoglycemia in an Adult

Nesidioblastosis, the process of differentiation of pancreatic islets from ductular epithelium, is a well-described cause of insulin-mediated hypoglycemia in neonates and infants, but not in adults. A 58-yr-old woman with characteristic clinical features of fasting hypoglycemia had inappropriately elevated plasma immunoreactive insulin levels during symptomatic episodes of fasting hypoglycemia. Angiography, palpation at laparotomy, and resection of the distal three-quarters of the pancreas provided no evidence of a tumor. Pathologic examination of the resected pancreas revealed the findings of nesidioblastosis, i.e., budding of islets from the wall of ductules, and also increased number and size of islets and abnormal shape and location of islets. An entire spectrum of islet cell abnormalities including nesidioblastosis can cause insulin-mediated hypoglycemia in adults, as it does in neonates and infants.

Time to menarche and final height after histrelin implant treatment for central precocious puberty

OBJECTIVE To compare final height, change in body mass index (BMI), and time from end of treatment until menarche in girls with central precocious puberty treated with the histrelin implant versus depot gonadotropin releasing hormone agonist injections. STUDY DESIGN Chart review, interview, and final height measurements of 2 groups of girls with central precocious puberty; triptorelin depot (TD) group: 23 girls were treated from age 8.4 ± 0.3 with monthly injections of TD, for 26.7 ± 2.5 months; histrelin implant group: 11 girls were treated from age 8.7 ± 0.3 years for 28.4 ± 3.7 months, of whom 9 initially received monthly TD injections for 1.5-39 months. Final height, BMI (pretreatment vs recent), and time between either implant removal or last injection to menarche were compared. RESULTS Time between removal of implant or last injection and menarche was 9.3 ± 1.5 (histrelin implant group) versus 16.1 ± 1.7 (TD group) months (P = .02). Predicted height at implant insertion was 156.8 ± 2.6 cm, and final height was 161.1 ± 2.0 cm (not significant [NS]). Predicted height for TD was 155.2 ± 1.9 cm and final height was 157.9 ± 1.7 cm (NS). Change from onset of treatment to final BMI-SDS for histrelin implant was -0.41 ± 0.3, and for TD was -0.03 ± 0.2 (NS). CONCLUSIONS Menarche occurred sooner after implant removal. There was no difference in final height or BMI outcomes between the 2 treatment modalities.

The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction

BackgroundWe characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults.MethodsReproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16–34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (<10 pg/ml); Group B: central hypogonadism (FSH <0.5 IU/l, INB <10 pg/ml); Group C: partial gonadal & central dysfunction (FSH 1.5–15 IU/l, INB >20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5–15 IU/l, INB < 10 pg/ml.ResultsThere were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P = 0.04). Significant differences between the groups were found in mean testosterone (P = 0.04), AMH (P = 0.003) and pubic hair (P = 0.04) in males and mean LH (P = 0.003) and breast development (P = 0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups.ConclusionsAnalysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.