A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency.

AIMS: To determine the effectiveness of different doses of r-hGH therapy during puberty in children with growth hormone deficiency (GHD). METHODS: Randomized controlled trial of different doses of r-hGH therapy administered during puberty in 49 children with GHD. The patients were allocated randomly using a random number table to one of two groups: group 1 (15 IU/m(2)/week) or group 2 (30 IU/m(2)/week). Patients were included if they had received r-hGH daily at a dose of 15 IU/m(2)/week (0.7 mg/m(2)/day) for at least 1 year before randomization. RESULTS: Height increase standard deviation scores (SDS) were similar between the two groups (group 1: 1.1; group 2: 1.2; p = 0.81). CONCLUSION: A higher dose of r-hGH administered during puberty does not appear to have a significant effect on final height of children with GH deficiency. Altering pubertal tempo or intensifying prepubertal r-hGH therapy may be a more promising approach to improving final height in children with GH deficiency.

Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR)54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.

Hypoglycaemia and Russell-Silver syndrome.

AIM: To determine both the incidence and aetiology of chronic hypoglycaemia in symptomatic children with Russell-Silver syndrome (RSS) during the first four years of life. STUDY DESIGN: Twenty-four children with RSS under the age of 4 years, who had either clinical symptoms of hypoglycaemia or previous evidence of biochemically documented hypoglycaemia, were admitted to hospital for 48 hours to perform a 24-h cortisol/glucose profile and a diagnostic fast in those who did not develop spontaneous hypoglycaemia. A dietary assessment was also performed. Glucose profile was assessed in 20 children and cortisol profile in 16; combined glucose and cortisol profile in 15 children. Eight children had a diagnostic fast. Mean chronological age at time of assessment was 2.2 +/- 0.8 years (range 1.1-3.9 years). RESULTS: Ten of 24 children had previously been documented as having hypoglycaemia. Seven of 12 patients were growth hormone (GH) insufficient after a glucagon test. Their feeding pattern was described as 'poor and picky eaters' in all, seven requiring nasogastric tube feeding. The mean spontaneous energy intake (n = 8) was 56 +/- 19.6 kcal/kg/day (range 38-90). Nocturnal sweating was the commonest symptom (23.96%), followed by irritability (11.46%), tantrums (7.29%), pallor and shakiness (3.13%). The glucose profile in seven children showed hypoglycaemia but only four were symptomatic. None of the children was cortisol deficient. The mean period of fasting was 11.8 +/- 4 hours (range 3-18 h). No metabolic/hormonal abnormality, with the exception of GH insufficiency, was detected at the time of hypoglycaemia. CONCLUSION: Children with RSS are prone to develop spontaneous hypoglycaemia especially if they are not fed both frequently and regularly. The most likely explanation is accelerated starvation and/or GH insufficiency. We suggest guidelines to minimise hypoglycaemia in these children.

Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group of Pubertal development in Chronic Renal Failure.

To elucidate the endocrine mechanisms underlying the pubertal growth failure observed in patients with chronic renal failure (CRF), we used deconvolution analysis to estimate the rates of GH secretion and elimination in nighttime plasma GH profiles of peripubertal boys with CRF and after renal transplantation (Tx). Forty-three boys with advanced CRF (conservative treatment with glomerular filtration rate < 25 mL/min.1.73 m2 or dialysis; CT/D group), 38 boys after Tx, and 40 healthy control boys were studied. The estimated plasma GH half-life (mean +/- SEM) was significantly higher (P < 0.05) in CRF (25 +/- 1.8 min) than in Tx patients (21 +/- 1.6 min) and controls (20 +/- 0.5 min). In the pre- and early pubertal CT/D boys, the calculated GH secretion rate was low normal or reduced when expressed in absolute numbers or normalized per unit distribution volume or body surface. In late puberty, whereas body surface-corrected GH secretion was double the prepubertal value in normal boys (389 +/- 56 vs. 868 +/- 113 micrograms/m2.11 h; P < 0.01), it did not differ significantly from the prepubertal rate in CT/D boys (281 +/- 59 vs. 389 +/- 56 micrograms/m2.11 h). GH hyposecretion resulted from a decrease in the mass of GH released within each burst, whereas burst frequency was unchanged. In the Tx group, GH secretion rates were significantly reduced in the prepubertal (221 +/- 39 micrograms/m2.11 h; P < 0.05) and late pubertal period (266 +/- 64 micrograms/m2.11 h; P < 0.01). The mass of hormone secreted per burst was significantly reduced at each pubertal stage, whereas GH secretory burst frequency tended to be increased (significant in prepubertal group, P < 0.05). The GH secretion rate was positively correlated with plasma testosterone levels (r = 0.58; P < 0.0001) in controls, but not in CT/D or Tx patients. GH secretion rates were lower than expected at each level of plasma testosterone in both patient groups except CT/D boys with plasma testosterone below 0.9 nmol/L. In the Tx group, GH secretion rate was positively correlated with relative height (r = 0.31; P < 0.05). The dosage of corticosteroids administered for immunosuppression was negatively correlated with GH burst mass (r = -0.42; P < 0.01) and GH secretion rate (r = -0.29; P = 0.08) and positively correlated with GH burst frequency (r = 0.49; P < 0.01). We conclude that in peripubertal boys with CRF, a state of GH hyposecretion is associated with an increase in the apparent plasma half-life of GH.(ABSTRACT TRUNCATED AT 400 WORDS)

Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging.

OBJECTIVE: To quantify the extent of hypothalamic damage after surgery for craniopharyngioma using magnetic resonance imaging (MRI) and to relate the findings to changes in body mass index (BMI). PATIENTS: Sixty-three survivors (36 males, 27 females) of childhood cramopharyngioma were treated surgically between 1973 and early 1994. METHODS: Cranial MRI was performed at a structured follow-up assessment 1.5-19.2 yr after the initial surgery. Hypothalamic damage was scored as 0 (no visible damage), 1 (intermediate), or 2 (severe). RESULTS: After surgery there was an increase in BMI standard deviation (SD) from diagnosis to study assessment in all but 7 patients. However, patients with MRI scores of 2 (n = 17) had a significantly greater increase in median BMI SD score at follow-up (+5.5 SD score), compared with +2.5 SD score and +1.1 SD score for patients with MRI scores of 1 or 0, respectively. Of the 17 cases with MRI scores of 2, 10 had a history of extreme weight loss or weight gain at presentation; preoperative neuroimaging demonstrated extensive hypothalamic infiltration by tumor in these cases. CONCLUSION: MRI gives sufficient anatomical definition to allow assessment of the extent of hypothalamic damage and, thereby, prediction of the patients most at risk for severe post-operative weight gain.

Postoperative whole abdomino-pelvic irradiation for patients with high risk endometrial cancer.

Forty-seven patients with endometrial cancer, surgical Stage I through IV, received adjuvant whole abdomino-pelvic irradiation with a nodal and vaginal boost between August 1981 through December 1986. The median age was 66.5 years (range 37-86 years). Twenty-two patients were Stages I-II, 14 Stage III, and eleven patients Stage IV. Thirty-four patients (79%) had positive peritoneal cytology, 29 patients (62%) had deep myometrial involvement, 27 patients (58%) had high grade lesions, 18 patients (40%) had either serous-papillary or adenosquamous histologic variants, and ten patients (22%) had residual disease of up to 2 cm. remaining after operation, mostly in the form of nodal disease. Twenty-four patients (51%) had two or more life time laparotomies. Mean follow-up was 40.5 mo. (range 17-85 mo.). The 5-year actuarial survival was 68% and the 5-year relapse-free survival (RFS) was 77%. The 5 year relapse-free survival for Stages I/II, III, and IV were 85%, 78%, and 53%, respectively. The 5 year relapse-free survival for grades 1/2 was 100% and for grades 3/4 was 60%. (p value of 0.0017). Acute toxicity has been modest, and particularly evident in thinner patients (weight below 115 lbs.). Chronic toxicity of significance has been limited to one patient with a conservatively managed bowel obstruction. These results are very encouraging and suggest benefit to the use of more aggressive adjuvant irradiation.

Adjuvant whole abdominopelvic irradiation for high risk endometrial carcinoma.

Fifty-six patients with surgical Stage III or IV endometrial carcinoma, or earlier stage disease with two or more risk factors for peritoneal recurrence, were given postoperative whole abdomino-pelvic irradiation (WAPI) with nodal and vaginal boosts between November 1981 and May 1989. Mean age at diagnosis was 63 years. Twenty-seven patients were surgical Stage I-II, 17 Stage III, and 12 Stage IV. Thirty-seven (66%) had deep myometrial involvement, 34 (61%) had positive peritoneal cytology, 31 (55%) had high grade lesions, 20 (36%) had either serous-papillary or adenosquamous histologic variants, and 13 (23%) had up to 2 cm residual disease remaining after surgery. Mean overall follow-up was 45 months. The 7-year actuarial survival was 63.8% with a 7-year disease-free survival (DFS) of 60.9%. By surgical stage, the 7-year DSF was 77.1% for Stage I-II, 57.8% for Stage III, and 25.0% for Stage IV (p = 0.006). The 7-year DSF was 79.8% for those with lesions of Broder's grade 1 or 2, and 46.9% for grades 3 or 4 (p = 0.001). Multivariate analysis demonstrated that of all covariates considered, only surgical stage and histologic grade had prognostic significance for survival and disease-free survival. Acute toxicity has been common but mild; chronic toxicity has been almost entirely subclinical with the exception of three cases of moderate to severe bowel toxicity. These results suggest that post-operative WAPI is a safe and efficacious treatment alternative for patients with surgical Stage I through III high-risk endometrial carcinoma.

An evaluation of hormonal changes at puberty in man.

The pulsatile nature of the secretion of gonadotrophins, sex steroids and growth hormone are important in both the onset and maintenance of sexual maturation. The night-time is intimately related to the endocrine events which result in puberty, such that hormone measurements during the daytime have little meaning. This relationship between the night-time and gonadal function is not restricted to puberty but continues in adult life; the onset of the preovulatory LH surge occurs in the early hours of the morning. Girls seem more sensitive to small changes in GnRH concentrations than boys, which is why the physical signs of puberty appear slightly earlier in them. Low levels of oestradiol appear to assist growth hormone secretion, whereas higher levels of testosterone are required for the same effect. This probably explains the sex differences in the timing of the pubertal growth spurts.

Growth and growth hormone secretion.

Growth hormone pulse amplitude is intimately connected with growth in childhood. Its effects are most clear in middle childhood, although the influence of adrenal androgens is probably also important. In infancy, nutrition plays an important part and, in the adolescent growth spurt, the synergism with sex steroids is important. Detailed attention needs now to be focussed on the mechanisms by which growth hormone is secreted and has its action; these include the effects of GHRH, somatostatin, insulin and IGF-I.

Treatment of growth delay in boys with isolated growth hormone deficiency.

We report our experience in treating growth delay in boys with isolated growth hormone deficiency (IGHD) receiving biosynthetic human growth hormone. The study was performed in 15 boys with IGHD receiving GH. At the chronological age of 13.1 (1.1) years (SD), 13 were prepubertal, two were in early puberty and there was a mean bone age delay of 2.5 (1.4) years. A growth spurt was induced by either depot testosterone or oxandrolone. There was an increase in growth rate from 5.7 (1.6) cm/year, occurring the year before anabolic or sex steroid therapy, to 8.1 (1.2) cm/year during treatment (p < 0.05), followed by 7.3 (1.9) cm/year the year after the cessation of treatment (p < 0.05). There was no significant change in height SD score for bone age, which was -0.69 (0.97) at the commencement of anabolic or sex steroid therapy and -0.53 (0.84) at the end of treatment. Before the induced growth spurt, there was equal body proportion between sitting height and subischial leg length, which had no significant change following androgen treatment. Spontaneous progress in pubertal development was achieved by all patients with an increase in testicular volume from a mean of 2.9 (2-8) to 6.1 (4-10) ml. The pattern of growth presented by patients treated with oxandrolone or those with testosterone was similar. Our data suggest that growth delay and delayed puberty, in patients with IGHD during concomitant growth hormone therapy, can be treated without deterioration in height prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Why is the retention of gonadotrophin secretion common in children with panhypopituitarism due to septo-optic dysplasia?

Septo-optic dysplasia (De Morsier syndrome) is a developmental anomaly of mid-line brain structures and includes optic nerve hypoplasia, absence of the septum pellucidum and hypothalamo-pituitary abnormalities. We describe seven patients (four female, three male) who had at least two out of the three features necessary for the diagnosis of septo-optic dysplasia. Four patients had hypopituitarism and yet normal gonadotrophin secretion: one of these also had anti-diuretic hormone insufficiency; three had isolated GH deficiency and yet had premature puberty, with the onset of puberty at least a year earlier than would have been expected for their bone age. In any progressive and evolving anterior pituitary lesion it is extremely unusual to lose corticotrophin-releasing hormone/ACTH and TRH/TSH secretion and yet to retain gonadotrophin secretion. GnRH neurons develop in the nasal mucosa and migrate to the hypothalamus in early fetal life. We hypothesise that the arrival of GnRH neurons in the hypothalamus after the development of a midline hypothalamic defect may explain these phenomena. Progress in spontaneous/premature puberty in children with De Morsier syndrome may have important implications for management. The combination of GH deficiency and premature puberty may allow an apparently normal growth rate but with an inappropriately advanced bone age resulting in impaired final stature. GnRH analogues may be a therapeutic option. In conclusion, some patients with De Morsier syndrome appear to retain the ability to secrete gonadotrophins in the face of loss of other hypothalamic releasing factors. The migration of GnRH neurons after the development of the midline defect may be an explanation.

Vulvovaginoplasty in gynecologic oncology.

Eight patients from M.D. Anderson Hospital underwent Williams' vulvovaginoplasty for sexual rehabilitation following pelvic exenteration. In 7 of the 8 patients the functional results were excellent, and none of the patients experienced morbidity. This surgical procedure is less extensive than other reconstructive methods and skin grafting or mechanical dilatation are rarely required.

Retroperitoneal endometriosis causing unilateral hip pain.

BACKGROUND: The usual symptoms of endometriosis are secondary dysmenorrhea, dyspareunia, and infertility, but when located in the retroperitoneal space, it might have atypical symptoms that delay diagnosis and postpone therapy. CASE: A young nulligravida presented with secondary dysmenorrhea and concurrent cyclic hip pain. Recent laparoscopy was reportedly normal. Computed tomography (CT)-directed percutaneous needle biopsy of a retroperitoneal mass showed endometriosis. Laparotomy with retroperitoneal dissection removed the endometriosis, and operative arthroscopy released strictured hip tendons improving her hip pain and limp. CONCLUSION: Retroperitoneal endometriosis presenting as hip pain was diagnosed by CT-guided percutaneous needle biopsy permitting removal by a multidisciplinary surgical approach.

The evolution of polycystic ovaries in a girl with hypogonadotropic hypogonadism before puberty and during puberty induced with pulsatile gonadotropin-releasing hormone.

We describe a girl of 12.7 years who had GnRH deficiency after surgery and radiotherapy for a craniopharyngioma at age 5 years. She had large cystic ovaries with a small uterus in the absence of spontaneous gonadotropin pulsatility. Puberty was induced by low-dose pulsatile GnRH treatment over a 1.5-year period. In the perimenarcheal period, ovarian morphology became typical of PCO with abnormal diurnal pulsatile gonadotropin secretion. These data suggest that PCO is primarily a disorder of the ovary and that the observed gonadotropin abnormalities are secondary to the ovarian lesion.

Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted?

Seventy-five children treated for craniopharyngioma between 1973 and 1994 were studied to demonstrate which pre- and intraoperative factors were indicative of a poor outcome as defined by a quantitative assessment of morbidity. This involved a retrospective review of 65 patients and a prospective study of 10 patients focused on clinical details and cranial imaging and a follow-up "study assessment" of 66 survivors performed over the last 2 years. As part of the assessment, 63 patients underwent magnetic resonance imaging with a three-dimensional volume acquisition sequence 1.5 to 19.2 years after initial surgery. Predictors of high morbidity included severe hydrocephalus, intraoperative adverse events, and young age ( < or = 5 years) at presentation. Predictors of increased hypothalamic morbidity included symptoms of hypothalamic disturbance already established at diagnosis, greater height ( > or = 3.5 cm) of the tumor in the midline, and attempts to remove adherent tumor from the region of the hypothalamus at operation. Large tumor size, young age, and severe hydrocephalus were predictors of tumor recurrence, whereas complete tumor resection (as determined by postoperative neuroimaging) and radiotherapy given electively after subtotal excision were less likely to be associated with recurrent disease. Based on these findings, the authors propose an individualized, more flexible treatment approach whereby surgical strategies may be modified to provide long-term tumor control with the lowest morbidity.

Body composition in early onset eating disorders.

BACKGROUND: Body mass index (BMI) or equivalent weight for height indices are the most widely used measures of body composition in early onset and adolescent eating disorders. Although of value as screening instruments the limitation in disease states is their inability to discriminate fat and fat-free components of body weight. OBJECTIVE: To compare height-adjusted fat and fat-free components of body composition in children and young adolescents with different types of eating disorders with those of age matched reference children. DESIGN: Weight, height, triceps and subscapular skinfold thickness were measured in 172 children (aged 7-16 y) with eating disorders receiving specialist treatment. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using Slaughter's and Deurenberg's equations and normalisation for height. Using data from 157 normal children, representative of the UK 1990 growth reference data, reference curves for FMI and FFMI+/-2 s.d. were derived. Results for patient groups were superimposed on these reference curves. RESULTS: FMI and FFMI were both reduced in eating disorders associated with malnutrition, including anorexia nervosa (AN). AN subjects did not differ from other subjects with comparable degrees of malnutrition. Children with eating disorders of normal weight, such as bulimia nervosa and selective eating, did not differ significantly from reference children in their relative FM and FFM. CONCLUSIONS: FM and FFM merit independent consideration in disorders of malnutrition in children, rather than expressing data as percentage body fat or percentage BMI. The implications of loss of FFM on growth and development merit further investigation.

Disorders of pubertal development.

Puberty is the period of life during which reproductive capability is acquired. It is characterized clinically by the acquisition of secondary sexual characteristics associated with a growth spurt, and on average takes 3-4 years. Early maturation is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys. Delayed puberty is defined when there are no signs of puberty at the age of 13.4 years in girls and 14 years in boys (2 SD above the mean of chronological age for the onset of puberty). There are many forms of premature sexual maturation: gonadotrophin-dependent (central, or 'idiopathic' or 'true' precocious puberty) and gonadotrophin-independent precocious puberty (McCune-Albright syndrome in girls, testotoxicosis in boys); isolated premature thelarche (in the forms of classical, atypical and variant); premature adrenarche (characterized by the production of significant quantities of androgens between 5 and 8 years of age); premature menarche. The differential diagnosis of delayed puberty is between constitutional delay of growth and puberty, pubertal delay secondary to chronic disease and hypogonadotrophic hypogonadism.

Premature thelarche: clinical follow-up and indication for treatment.

Not only is the diagnosis of isolated premature thelarche difficult to distinguish from other variants of premature sexual maturation, but within the subgroups of isolated premature thelarche, there are probably at least two subgroups: "classical" and "atypical". We do not appreciate how potential treatment could affect each group, although it seems likely that those in the "classical" group would not have an indication for treatment. The longer-term follow-up of large numbers of patients is essential if we are to understand the long-term sequelae of this condition.

Body mass index and hypothalamic morphology on MRI in children with congenital midline cerebral abnormalities.

Obesity is common in children with congenital midline defects of the brain, due to various endocrine reasons: hypothyroidism, growth hormone deficiency and inappropriate cortisol replacement. However, obesity occurs more often in the absence of an endocrinopathy. We reviewed 31 patients (10 females, 21 males) with midline intracranial defects (holoprosencephaly, absence of septum pellucidum, absence of corpus callosum, optic nerve hypoplasia) and correlated the morphology of the hypothalamus with body mass index (BMI), as BMI SDS. Endocrinopathies were present in 16 out of the 31 patients. We conclude that there was a trend of increasing mean BMI SDS with increasing hypothalamic abnormality, although this was not statistically significant.