Dorothy I. Shulman

Adrenal insufficiency: still a cause of morbidity and death in childhood.

Adrenal insufficiency is relatively rare in childhood and adolescence. Signs and symptoms may be nonspecific; therefore, the diagnosis may not be suspected early in the course. If unrecognized, adrenal insufficiency may present with life-threatening cardiovascular collapse. Adrenal crisis continues to occur in children with known primary or secondary adrenal insufficiency during intercurrent illness because of failure to increase glucocorticoid dosage. In this article, current knowledge of the incidence, diagnosis, and treatment of adrenal insufficiency in children and factors precipitating adrenal crisis are summarized. Suggestions for prevention of adrenal crisis in patients at risk are provided for health care professionals and families.

Effects of short-term growth hormone therapy in rats undergoing 75% small intestinal resection.

Thirty 250-g male rats underwent 75% small intestinal resection and received s.c. injections of water [short gut (SG)—control], human growth hormone (hGH) at 0.1 mg/kg/dose [SG-low-dose (LD) GH], or hGH at 1.0 mg/kg/dose [SG-high-dose (HD) GH] every other day for 28 days. Ten additional rats underwent sham operation and received water injections (sham control). After 28 days, SG-control and SG-LDGH rats weighed significantly less than the sham control group; the mean weight of the SG-HDGH group was not different from other groups. Weight per centimeter of the distal ileum was greater in all SG groups compared to the sham control group, and was greater in the SG-HDGH than in the SG-control group. Mean mucosal height of the distal ileum was greater in both SG groups receiving GH than in sham controls. No differences in ileal mucosal DNA content or ileal insulin-like growth factor-1 (IGF-1) content were identified between groups. Mucosal sucrase activity was not increased in hGH-treated rats. Serum calcium and phosphorus concentrations were higher in SG-HDGH rats than in SG-control animals. HDGH increased body weight, distal ileal weight/cm, and mucosal height in rats undergoing 75% small bowel resection. A trend toward normalization of serum calcium, phosphorus, and plasma IGF-1 concentrations was also observed. Further longer-term studies are indicated to learn if GH has a beneficial effect upon gut growth and function in the SG syndrome.

Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development.

Although treatment of children and adolescents who have disorders of growth and adolescent development with aromatase inhibitors is increasingly common, data for or against their use are extremely limited. Precocious puberty, short stature, and gynecomastia are conditions for which inhibition of the enzyme aromatase might prove beneficial to reduce clinical signs of estrogenization and/or estrogen-mediated skeletal maturation. In this report, we summarize the published data regarding the use of aromatase inhibitors in these conditions, and review known and potential benefits, safety concerns, and shortcomings of the available information.

Bicalutamide and Third-Generation Aromatase Inhibitors in Testotoxicosis

Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization.

Hypothalamic-pituitary dysfunction in primary empty sella syndrome in childhood

In a series of 37 consecutive CT scans performed in children referred to our pediatric endocrine unit, an empty (eight) or partially empty (one) sella turcica was found in nine (24%) patients with short stature or delay in sexual maturation, precocious puberty, or hypoparathyroidism. The size and contour of the sella were abnormal in only three patients. Five of the nine children had evidence of decreased growth hormone secretion as determined by subnormal GH secretory responses to provocative tests (peak GH concentration less than 7 ng/ml) or assessment of endogenous 24-hour GH secretion (mean 24-hour GH concentration less than 3 ng/ml). Two children had multiple pituitary hormone deficiencies. Although primary empty sella syndrome was often associated with hypothalamic-pituitary dysfunction in this series, the prevalence of an empty sella in normal children is unknown. Further identification and evaluation of children with empty sella may provide new information regarding the cause of pituitary dysfunction in childhood.

Evaluation of growth hormone secretion: provocative testing vs endogenous 24-hour growth hormone profile.

Shulman, D. I. and Bercu, B. B. (University of South Florida College of Medicine, All Childrens Hospital, Florida, USA). Evaluation of growth hormone secretion: provocative testing vs endogenous 24‐hour growth hormone profile. Acta Paediatr Scand [Suppl] 337:61, 1987.

Non-nutritive sucking does not increase blood levels of gastrin, motilin, insulin and insulin-like growth factor 1 in premature infants receiving enteral feedings.

Non‐nutritive sucking in premature infants accelerates weight gain for unclear reasons. The effects of non‐nutritive sucking on enteral hormone secretion may augment digestion and/or absorption of nutrients. Blood concentrations of gastrin, motilin, insulin and insulin‐like growth factor‐1 were measured before and 72 h after the initiation of nasogastric feedings in 21 premature infants randomly assigned to either a non‐nutritive suckling or control group. Gastrin and motilin concentrations increased significantly after feedings in all infants (mean ± SEM) (gastrin, 4 ± 4 to 73 ± 9 pg/ml, p<0.01; motilin, 141 ± 5 to 181 ± 3 pg/ml, p<0.01) Pre‐ and post‐feed insulin concentrations were greater in the non‐nutritive sucking group receiving bolus feeds than in control infants who were bolusfed (P<0.01). Non‐nutritive sucking in premature infants does not appear to alter blood concentrations of motilin, gastrin, insulin or insuline‐like growth factor‐1 three days after initiation of feedings. If changes in the secretion of these hormones are induced by non‐nutritive sucking, they may be at a local paracrine level.

Results of a Second Year of Therapy with the 12-Month Histrelin Implant for the Treatment of Central Precocious Puberty

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from  mIU/mL at 12 months to  mIU/mL at 24 months (< .0001) in naïve subjects, and from  mIU/mL at 12 months to  mIU/mL at 24 months () in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

Watery diarrhea, hypokalemia, achlorhydria syndrome in an infant: effect of the long-acting somatostatin analogue SMS 201-995 on the disease and linear growth

An 8-week-old infant presented with vomiting and failure to thrive due to small bowel obstruction caused by a diffusely enlarged pancreas. Surgical bypass of the obstruction was followed by secretory diarrhea, hypokalemia, and dehydration. Plasma vasoactive intestinal peptide (VIP) (823pg/ml), pancreatic polypeptide (4,500 pg/ml), and neurotensin (680 pg/ml) concentrations were markedly elevated. No neoplastic process was identified. Therapy with the long-acting somatostatin analogue SMS 201-995 was followed by decline in VIP concentrations (900 to 200-300 pg/ml), decrease in stool frequency, and normalization of serum electrolytes. During 12 months of somatostatin analogue therapy, length and weight progressed along the 3rd percentile on the Tanner growth chart.

Natural history of idiopathic diabetes insipidus

OBJECTIVE To determine what percentage of diabetes insipidus (DI) in childhood is idiopathic and to assess the natural history of idiopathic DI. STUDY DESIGN We conducted a retrospective chart review of 105 patients with DI who were born or had DI diagnosed between 1980-1989 at 3 medical centers. A second cohort of 30 patients from 6 medical centers in whom idiopathic DI was diagnosed after 1990 was evaluated retrospectively for subsequent etiologic diagnoses and additional hypothalamic/pituitary deficiencies and prospectively for quality of life. RESULTS In the first cohort, 11% of patients had idiopathic DI. In the second cohort, additional hypothalamic/pituitary hormone deficiencies developed in 33%, and 37% received an etiologic diagnosis for DI. Health-related quality of life for all the patients with idiopathic DI was comparable with the healthy reference population. CONCLUSIONS Only a small percentage of patients with DI will remain idiopathic after first examination. Other hormone deficiencies will develop later in one-third of those patients, and slightly more than one-third of those patients will have an etiology for the DI diagnosed. Long-term surveillance is important because tumors have been diagnosed as long as 21 years after the onset of DI. Quality of life for these patients is as good as the reference population.