Growth hormone plus childhood low-dose estrogen in Turner's syndrome.

BACKGROUND: Short stature and ovarian failure are characteristic features of Turner's syndrome. Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome, a randomized, placebo-controlled trial is needed to document whether such treatment increases adult height. Furthermore, it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit. We examined the independent and combined effects of growth hormone and early, ultra-low-dose estrogen on adult height in girls with Turner's syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 149 girls, 5.0 to 12.5 years of age, to four groups: double placebo (placebo injection plus childhood oral placebo, 39 patients), estrogen alone (placebo injection plus childhood oral low-dose estrogen, 40), growth hormone alone (growth hormone injection plus childhood oral placebo, 35), and growth hormone-estrogen (growth hormone injection plus childhood oral low-dose estrogen, 35). The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week. The doses of ethinyl estradiol (or placebo) were adjusted for chronologic age and pubertal status. At the first visit after the age of 12.0 years, patients in all treatment groups received escalating doses of ethinyl estradiol. Growth hormone injections were terminated when adult height was reached. RESULTS: The mean standard-deviation scores for adult height, attained at an average age of 17.0±1.0 years, after an average study period of 7.2±2.5 years were -2.81±0.85, -3.39±0.74, -2.29±1.10, and -2.10±1.02 for the double-placebo, estrogen-alone, growth hormone-alone, and growth hormone-estrogen groups, respectively (P<0.001). The overall effect of growth hormone treatment (vs. placebo) on adult height was a 0.78±0.13 increase in the height standard-deviation score (5.0 cm) (P<0.001); adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group, by 0.32±0.17 standard-deviation score (2.1 cm) (P=0.059), suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone. CONCLUSIONS: Our study shows that growth hormone treatment increases adult height in patients with Turner's syndrome. In addition, the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement. (Funded by the National Institute of Child Health and Human Development and Eli Lilly; ClinicalTrials.gov number, NCT00001221.).

Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance.

OBJECTIVE: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. DESIGN AND METHODS: Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. RESULTS: Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. CONCLUSIONS: Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome.

CONTEXT: McCune-Albright syndrome (MAS) is caused by mutations in GNAS (most often R201C or R201H) leading to constitutive cAMP signaling and multiple endocrine dysfunctions, including morphological and functional thyroid involvement. OBJECTIVE: The objective of the study was to characterize the clinical and molecular features of the MAS-associated thyroid disease in a large cohort of patients. DESIGN: This was a retrospective analysis. SETTING: The study was conducted at the National Institutes of Health Clinical Center. PATIENTS: The study included 100 consecutive MAS patients. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Functional and morphological evaluation of the thyroid was measured. Ex vivo experiments were performed on MAS thyroid samples to study the effects of the GNAS mutations on the 5'-deiodinases. Reconstitution experiments in HEK-293 cells were performed to study the effects of GNAS mutations on the type-2 5'-deiodinase. RESULTS: Fifty-four patients had abnormal thyroid ultrasound findings. This group, compared with patients without abnormal findings, had higher T(3) to T(4) ratio, indicating an elevated 5'-deiodinase activity. Thyroid samples from MAS subjects, compared with normal tissue, showed a significant increase in both type 1 (D1) and type 2 (D2) 5'-deiodinase activity (D1 control 5.9 +/- 4.5 vs. MAS 41.7 +/- 26.8 fmol/min.mg, P < 0.001; D2 control 28.3 +/- 13.8 vs. MAS 153.1 +/- 43.7 fmol/min.mg, P < 0.001). Compared with cells transfected with the wild-type R201 allele, the basal transcriptional activity of the D2 promoter was significantly increased in both mutants (C and H) (R 10733 +/- 2855, vs. C 18548 +/- 4514, vs. H 19032 +/- 4410 RLU +/- SD, P < 0.001). CONCLUSION: Thyroid pathology is a common occurrence in MAS. Consistent with the molecular etiology of the disease, the shift in T(3) to T(4) ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.

Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome.

UNLABELLED: Most lesions in FD and their attendant functional disability occur within the first decade; 90% of lesions are present by 15 years, and the median age when assistive devices are needed is 7 years. These findings have implications for prognosis and determining the timing and type of therapy. INTRODUCTION: Fibrous dysplasia of bone (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Variable amounts of skeletal involvement and disability occur. The age at which lesions are established, the pace at which the disease progresses, if (or when) the disease plateaus, and how these parameters relate to the onset of disability are unknown. To answer these questions, we performed a retrospective analysis of a group of subjects with FD. MATERIALS AND METHODS: One hundred nine subjects with a spectrum of FD were studied for up to 32 years. Disease progression was assessed in serial (99)Tc-MDP bone scans by determining the location and extent of FD lesions using a validated bone scan scoring tool. Physical function and the need for ambulatory aids were assessed. RESULTS: Ninety percent of the total body disease skeletal burden was established by age 15. Disease was established in a region-specific pattern; in the craniofacial region, 90% of the lesions were present by 3.4 yr, in the extremities, 90% were present by 13.7 yr, and in the axial skeleton, 90% were present by 15.5 yr. Twenty-five of 103 subjects eventually needed ambulatory aids. The median age at which assistance was needed was 7 yr (range, 1-43 yr). The median bone scan score for subjects needing assistance was 64.3 (range, 18.6-75) compared with 23.1 (range, 0.5-63.5) in the unassisted subjects (p < 0.0001). Among subjects needing assistance with ambulation, 92% showed this need by 17 yr. CONCLUSIONS: The majority of skeletal lesions and the associated functional disability occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. Likewise, therapeutic interventions must be tailored to where the patient is in the natural history of the disease (i.e., progressive disease [young] versus established disease [older subjects]). These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.

Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study.

CONTEXT: Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness. OBJECTIVE: Our objective was to assess the effectiveness of the potent, third-generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. DESIGN: Subjects were evaluated at baseline and every 6 months for 12-36 months while on treatment with letrozole 1.5-2.0 mg/m(2).d. SETTING: This was an open-label therapeutic trial at a single clinical center. PATIENTS: Patients included nine girls aged 3-8 yr with MAS and/or gonadotropin-independent puberty. MAIN OUTCOME MEASURES: Measures included rates of linear growth, bone age advance, mean ovarian volume, estradiol, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin, alkaline phosphatase, urinary hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptides. RESULTS: Girls had decreased rates of growth (P < or = 0.01) and bone age advance (P < or = 0.004) and cessation or slowing in their rates of bleeding over 12-36 months of therapy. Mean ovarian volume, estradiol, and indices of bone metabolism fell after 6 months (P < or = 0.05) but tended to rise by 24-36 months. Uterine volumes did not change. One girl had a ruptured ovarian cyst after 2 yr of treatment. CONCLUSIONS: This preliminary study suggests that letrozole may be effective therapy in some girls with MAS and/or gonadotropin-independent precocious puberty. Possible adverse effects include ovarian enlargement and cyst formation.

Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation.

OBJECTIVE: Fibrous dysplasia (FD) of bone may occur solely as a skeletal condition or it may occur in association with extraskeletal manifestations, including growth hormone (GH) excess. Uncertainty exists as to the management of FD involving the optic nerves. In an effort to clarify management, the authors studied a large population of patients. METHODS: One hundred four patients underwent an evaluation that included review of records, endocrine testing, cranial computed tomography, and neuro-ophthalmological examination. RESULTS: Ninety-one of 104 patients had craniofacial FD; complete records were available for 87 patients (174 nerves). Seventeen percent of the optic nerves were less than 50% encased, 22% were 50 to 99% encased, and 61% were 100% encased. Twelve percent of the nerves that were 100% encased showed evidence of optic neuropathy, but 88% did not. The group with optic neuropathy was not older than the group without. Patients with GH excess were significantly more likely to have nerves that were 100% encased (relative risk, 4.1; 95% confidence interval, 1.5-11.1; P = 0.0017) and to have optic neuropathy (relative risk, 3.8; 95% confidence interval, 2.0-7.1; P = 0.0019). Six prophylactic optic nerve decompressions were performed; in five patients, vision was stable after surgery, and one patient was blind after surgery. Thirteen interventional optic nerve decompression procedures were performed; six of the 13 patients showed some improvement and seven of the 13 showed no improvement or worsened vision. CONCLUSION: The vast majority of optic nerves encased with FD do not exhibit symptoms of optic neuropathy and seem to be stable over time. GH excess is associated with increased risk of nerve encasement and optic neuropathy. Patients with craniofacial FD should be screened for GH excess, and optic nerve decompression should be performed only when there is objective evidence of progressive optic neuropathy.

Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases.

PURPOSE: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall syndrome (PHS), have a more benign course. METHODS: Thirty-seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems. RESULTS: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH. CONCLUSIONS: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.

Lack of efficacy of fadrozole in treating precocious puberty in girls with the McCune-Albright syndrome.

We administered the aromatase inhibitor fadrozole to 16 girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome. The girls' ages ranged from 3.2-9.7 yr, and their bone ages ranged from 5.75-14.25 yr. After baseline evaluations, fadrozole was started at a dose of 240 microg/kg.d (equivalent to the dose recommended for therapy of estrogen-dependent breast cancer) for 12-21 months and increased to 480 microg/kg.d for an additional 12 months in 10 girls. During treatment, seven girls had evidence of central precocious puberty; hence, the GnRH agonist deslorelin (4 microg/kg.d sc) was added to their regimen. One girl was on a long-acting GnRH agonist from the start of treatment. Patients were evaluated at 2-6-month intervals throughout treatment. After the first 6-12 months of treatment, fadrozole showed some benefits in 10 girls, including decrease in frequency of menses and/or rates of linear growth and bone maturation; however, fadrozole had no significant benefit in the group as a whole. The seven girls with evidence of central precocious puberty had no slowing in the progression of their puberty during the combined fadrozole and GnRH analog treatment. Adverse effects of fadrozole included inhibition of cortisol and aldosterone biosynthesis at the dose of 480 microg/kg.d, without clinical evidence of adrenal insufficiency. In addition, three patients complained of nonspecific abdominal pain during fadrozole treatment. In one patient, this resolved with a reduction in dose from 480 to 240 microg/kg.d; in two patients, it resolved spontaneously. One girl had muscle weakness and constipation on the 480 microg/kg.d. This resolved after discontinuation of the drug. We conclude that fadrozole is not sufficiently potent to block estrogen synthesis in most girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome and may impair the adrenocortical stress response.

Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of the disease is postzygotic activating mutations of the GNAS1 gene product, G(s)alpha. The term gsp oncogene has been assigned to these mutations due to their association with certain neoplasms. The aim of this study was to estimate the prevalence of GH excess in MAS, characterize the clinical and endocrine manifestations, and describe the response to treatment. Fifty-eight patients with MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test, and underwent a TRH test, serial GH sampling from 2000-0800 h, and magnetic resonance imaging of the sella. We found that vision and hearing deficits were more common in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of interest, patients with a history of precocious puberty and GH excess who had reached skeletal maturity achieved normal adult height despite a history of early epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH, 11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%) patients. All patients with elevated IGF-I levels were treated with cabergoline (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with cabergoline, serum IGF-I decreased, but not to the normal range. In the eight patients treated with LAO alone, IGF-I decreased, and, in four, returned to the normal range. The remaining 4 patients were treated with a combination of cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I decreased further, but did not enter the normal range. GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to LAO.