Melvin M. Grumbach

Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency

During childhood and young adulthood, the skeleton accrues virtually all the bone mineral it will ever have.1 Since the aging process is associated with bone loss, the more bone mass one gains in the formative years, the less likely it is that increased bone resorption and decreased bone formation will result in osteoporosis. Hence, the failure to achieve optimal peak bone mass is a pathogenetic mechanism in osteoporosis. The sex steroids are critically important in helping to establish peak bone mass for both sexes. Girls with estrogen deficiency do not achieve optimal peak bone mass.2–4 Similarly, achievement of peak .xa0.xa0.

Growth and Growth Hormone

Abstract Human growth hormone (HGH) deficiency was documented by radioimmunoassay in 35 patients — 16 with isolated HGH, 7 HGH and TSH, 4 HGH and ACTH, and 8 HGH, TSH and ACTH deficiencies. Of 15 p...

Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback

Summary A syndrome associated with juvenile hypothyroidism is described, the cardinal feature of which is sexual development beyond that consistent with the bone age and other indices of maturity. The 3 girls described in this paper had precocious menstruation, galactorrhea, absence of public hair, and enlargement of the sella turcica. One patient was excessively pigmented. These abnormal signs disappeared promptly when the hypothyroid state was alleviated. Serial x-rays of the skull after treatment with thyroid was instituted revealed an initial period of further enlargement and demineralization of the pituitary fossa followed by a decrease in its size toward normal. A normal menarche later ensued in 2 of the girls when the level of maturity had progressed appropriately. The implications of the close similarity between the findings in this syndrome and in patients with pituitary tumors are discussed. A primary target gland deficiency is suggested as the etiologic factor in at least some patients with chromophobe adenomas. It is postulated that the mechanism for the development of menorrhagia, galactorrhea, and pigmentation in these patients was an overlapping secretion of gonadotropin, mammotropic hormone, and (in 1 case) melanocyte-stimulating hormone along with the presumed high level of thyroid-stimulating hormone. A similar overlap in pituitary hormones occurs in experimental pituitary tumors induced by single target gland deficiencies and in certain clinical endocrine disorders. This lack of specificity in the pituitary feedback mechanism, so strikingly demonstrated in the present syndrome, is suggested as the mechanism responsible for a number of phenomena commonly observed in clinical endocrine disorders.

Growth Hormone Treatment for Short Stature

Fifteen short but otherwise normal children, 4.3 to 15.5 years old, with heights greater than 3 S.D. below the mean value for age, growth rates less than or equal to 5.0 cm per year, and normal serum levels of immunoreactive growth hormone in response to provocative stimuli (peak greater than or equal to 10 ng per milliliter) were treated with intramuscular injections of pituitary growth hormone (0.1 U per kilogram) three times weekly for six months, as were 14 children with documented growth hormone deficiency. In all the latter children growth rate increased by more tan 2.0 cm per year during treatment. In 6 of the 14 short normal children who remained prepubertal, growth rate also increased, by 2.2 to 4.2 cm per year during treatment; four of these children had normal base-line serum somatomedin C concentrations. In both short normal children and children with growth hormone deficiency, the increment in serum somatomedin C concentrations after 4 or 10 daily injections of growth hormone correlated with bone age but not with later growth or growth hormone levels. Among the short normal children, those who responded to growth hormone were younger and had a greater delay in bone age and a slower pretreatment growth rate than the nonresponders. These observations suggest that a dose of growth hormone comparable to that used for the treatment of hypopituitarism increases growth rate in some short normal children.

Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effect of treatment in 42 patients

Forty-two cases of craniopharyngioma in children reviewed. Only 9.5% had sought medical attention because of symptoms suggesting hormonal deficit; however, growth retardation was present in 53% and growth hormone deficiency was documented in 72% before treatment. Multiple hypothalamic-pituitary hormone deficiencies were present in all patients after treatment. Eleven percent had normal skull radiographs at presentation; pneumonencephalograms and computed tomographic brain scans were abnormal on every occasion on which they were performed. Recurrence and mortality rates as well as the neurologic outcome of survivors were similar in children treated by radical excision and those treated by limited excision plus radiotherapy. The neurologic prognosis was poorest in those children who had limited excision or drainage without radiotherapy. Additional hypothalamic-pituitary dysfunction following treatment was less common in children who had limited excision plus radiotherapy than in children who had either limited excision or attempted total removal. Unless gross total tumor excision can be readily achieved, limited excision by transsphenoidal microsurgery or craniotomy plus radiotherapy appears to be the treatment of choice for craniopharyngioma in childhood.

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement.nnAdvances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex.nnAdditional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ).nnThree traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … nnAddress correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

Delayed onset of hypopituitarism: Sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors†‡

Four children with short stature who received irradiation to the head in conventional doses had clinical and laboratory evidence of hypothalamic-pituitary hormone deficiencies several years later. Growth hormone was deficient in all. One patient also had evidence of TSH, ACTH, and gonadotropin deficiency. Basal prolactin levels and prolactin response to synthetic TRF were normal in all patients tested. Treatment with human growth hormone significantly increased growth rate. We suggest that children should have the hypothalamic-pituitary area shielded from irradiation. Periodic measurements of hypothalamic-pituitary function should be performed in children who have had irradiation to the head, in order to detect and treat hormonal deficiencies before growth and development are seriously compromised.

Pediatric Endocrinology Update: An Overview

The goals of this presentation are to review the essential roles of aromatase, estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due to mutations in the aromatase gene (CYP19) and estrogen resistance due to disruptive mutations in the estrogen receptor gene have no effect on normal male sexual maturation in puberty. However, they lead to absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, continued growth into adulthood and very tall adult stature in both sexes. Gonadotropin and androgen levels are elevated in patients with either estrogen deficiency (aromatase deficiency) or estrogen resistance (estrogen receptor mutation). Glucose intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal integrity is compromised. Increased bone turnover, reduced bone mineral density and osteoporosis develop in both sexes. Sexual orientation is appropriate in males and females. In females, aromatase deficiency in the ovary causes pubertal virilization and multicystic ovaries because of elevated gonadotropins and androgens. Simultaneously, secondary sexual maturation fails to occur. Placental aromatase deficiency results in virilization of the mother and her female fetus because of the accumulation of potent androgens which are not converted to estrogens. The male fetus has normal genitalia. In conclusion, estrogens are essential for normal female secondary sexual maturation, bone maturation, epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral mass. Estrogens also influence insulin sensitivity and lipid homeostasis. However, estrogens do not appear to be essential for fetal survival, placental growth, or female sexual differentiation.

Amino acid and alpha-keto acid-induced hyperinsulinism in the leucine-sensitive type of infantile and childhood hypoglycemia.

Summary 1. Studies on 2 patients with leucine-induced “idiopathic” hypoglycemia showed that l -isoleucine also caused a striking fall in the concentration of blood glucose. d -leucine, l -valine, l -alanine, dl -threonine, and l -glycine did not have a significant effect. 2. The α-keto acid analogue of leucine, α-ketoisocaproic acid, induced hypoglycemia when injected intravenously but not its metabolite isovaleric acid. Its action was less effective orally. Pyruvic acid and α-ketoisovaleric acid failed to elicit a similar response. 3. No evidence of a defect in amino acid or α-keto acid metabolism was found, nor of a direct effect of leucine on glycolysis in whole blood. 4. It was shown that leucine caused increased peripheral utilization of glucose, suggesting an insulin-like action. Direct determinations of plasma insulin indicated a sharp rise in circulating insulin following the administration of leucine. 5. It is concluded that l -leucine, l -isoleucine, and their keto acid analogues induce an increase in the concentration of plasma insulin irrespective of the blood glucose level, an effect which may be attributed to their direct action on the mechanism of insulin secretion.

Sulfated Mucopolysaccharides of Urine and Organs in Gargoylism (Hurler's Syndrome) II. Additional Studies.

Summary 1) Further examples of quantity and types of urinary excretion of sulfated mucopolysaccharides in Hurlers syndrome have been studied in 9 cases. All excreted both ChS-B as the major component and heparitin sulfate as a minor constituent. 2) In one case, excretion of mucopolysaccharides dropped after prednisone administration. 3) From various organs of 5 autopsy cases, the 2 polysaccharides were isolated. 4) Livers of 4 cases contained between 1.2 and 6.7% of total mucopolysaccharides (on fat-free dry wt). In 3 of these, 90% was heparitin sulfate, but from all of these, also some ChS-B was obtained. One liver had approximately equal quantities of the 2 polysaccharides. 5) In one case, spleen, brain and kidney of the same individual also yielded both polysaccharides, but in proportions remarkably different from those of liver. Brain of 2 additional cases also yielded the 2 mucopolysaccharides. One of these contained 85% of ChS-B. The brain of a normal child did not yield any chondroitin sulfate, but hyaluronate and heparitin sulfate.