Michael Racine - Academia.edu (original) (raw)

Papers by Michael Racine

Pituitary, 2002

The primary treatment of acromegaly remains transsphenoidal adenomectomy, yet the tissue overgrow... more The primary treatment of acromegaly remains transsphenoidal adenomectomy, yet the tissue overgrowth of acromegaly often progresses following surgery, and responds to radiotherapy only after significant delay. Persistently elevated serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations can be normalized in about half of post-surgery acromegalics using the pharmacologic alternatives presently available, the dopamine agonists (DA) and somatostatin (SST) analogs. Cabergoline, the most efficacious DA, normalizes IGF-I in approximately 37% of patients, whereas the long-acting SST analogs, Octreotide LAR and Lanreotide SR, do so in 66%. Significant tumor shrinkage may be attained with SST analogs in particular, and when necessary, the primary medical treatment of acromegaly may be successfully addressed with this class of drugs. Greatly enhanced efficacy is expected from the GH receptor antagonist pegvisomant, which is nearing market availability and will enable ...

BACKGROUND: FSH concentrations are higher in girls than in boys before puberty. We hypothesized t... more BACKGROUND: FSH concentrations are higher in girls than in boys before puberty. We hypothesized that steroid-mediated changes in FSH-regulatory proteins underlie the sex differences in FSH secretion and pubertal timing. METHODS: FSH-regulatory proteins, LH, FSH and sex steroids were measured in ®ve boys, 10 girls, and ®ve girls with Turner syndrome before and during sex steroid treatment (girls, 0.05 mg/day estradiol; boys, 5 mg/day testosterone) for up to 4 weeks. Blood was obtained every 15 min from 20.00 to 08.00 h before and during sex steroid treatment. RESULTS: The mean FSH concentration was higher in girls than in boys (P = 0.0044). Activin-A concentrations were greater (P < 0.0001) and inhibin-B concentrations lower (P < 0.0001) in girls compared with boys. Steroid treatment (i) suppressed LH/FSH concentrations in all subjects; (ii) increased the mean activin-A concentration in all but the Turner girls (P = 0.001); and (iii) decreased inhibin-B concentrations in boys (...

Pediatric Endocrinology, 2013

Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting fr... more Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection. Setting: The study was conducted at secondary and tertiary referral centers. Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. Interventions: There were no interventions. Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD.

AACE Clinical Case Reports, 2015

Objective: Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant condition associa... more Objective: Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant condition associated with various combinations of endocrine and nonendocrine tumors. Insulinomas are rare endocrine tumors in the pediatric age group and may be associated with MEN-1 in 10% of cases. Malignant insulinomas only constitute 5 to 10% of all the insulinomas and are exceedingly rare in children. There are only 11 cases of malignant insulinoma reported in the literature in the pediatric age group. Methods: We are reporting a 16-year-old adolescent male who presented with symptoms of hypoglycemia for the 4 months prior to referral. Results: He was diagnosed with malignant insulinoma with multiple metastases to liver and was treated with surgical resection followed by octreotide treatment. He had additional findings consistent with the diagnosis of MEN-1, including elevated prolactin levels combined with a 4 to 5 mm pituitary lesion possibly due to prolactinoma and mildly elevated calcium levels with a parathyroid ultrasound demonstrating a parathyroid adenoma on the left side measuring 8 × 6 × 4 mm in diameter. He has been free of symptoms and radiologic findings of recurrence of insulinoma 1-year post surgery. Conclusion: Malignant insulinoma is extremely rare in children, but should be considered in cases of hyperinsulinemic hypoglycemia. MEN-1 should also be considered because insulinoma may be the first finding of MEN-1. Surgical resection is the treatment of choice. Somatostatin analog is a safe and effective treatment in children in cases with metastatic insulinoma when residual tumor is present.

Endocrine, 2003

Although acromegaly remains a disease primarily addressed by pituitary microsurgery, most patient... more Although acromegaly remains a disease primarily addressed by pituitary microsurgery, most patients require secondary treatment for persistent growth hormone (GH) hypersecretion and elevated serum insulin-like growth factor-1 (IGF-1) concentrations following adenomectomy. Persistently abnormal serum GH and IGF-1 can be reduced to normal concentrations in better than half of post-surgery acromegalics using the pharmacologic treatments available at present, the dopamine agonists (DA) and somatostatin (SST) analogs. The long-acting SST analogs octreotide LAR and lanreotide SR have become the mainstay of medical treatment for acromegaly, having largely supplanted DA agents since the introduction of bromocriptine for the suppression of GH secretion in the 1970s. The DA cabergoline may be effective in up to half of patients, however, in particular those patients whose tumors cosecrete prolactin. On the horizon is the GH-receptor antagonist pegvisomant, which is expected to enable the reduc...

Pituitary, 2002

Pediatric Endocrinology, 2003

PEDIATRICS, 2003

Little is known about auxologic, autoimmune, and HLA characteristics specific to children with ea... more Little is known about auxologic, autoimmune, and HLA characteristics specific to children with early-onset diabetes (EOD). HLA subtypes have been shown to play an important part in the determination of islet-cell autoimmunity and in the pace and intensity of the beta-cell destructive process. Our goals were to: 1) outline auxologic, autoimmune, and HLA class II characteristics of children diagnosed with type 1 diabetes before 5 years of age (EOD); 2) evaluate differences between EOD and later-onset or non-age-stratified type 1 diabetes; and 3) investigate the relation between type 1 diabetes-related HLA subtypes and markers of diabetic autoimmunity in EOD. Forty children with EOD were studied. Auxologic and antibody radioimmunoassay data were obtained by retrospective analysis of records. HLA diabetes-related class II alleles were typed by polymerase chain reaction using sequence-specific primers. At diagnosis, the average age of the EOD study patients was 2.6 years, body mass index was 16.9 kg/m2, and weight was 106% of average weight for height. When compared with a matched subgroup of children with later-onset type 1 diabetes, preschoolers did not significantly differ in terms of birth weight or body mass index. The frequency of positive islet cell antibodies 512 and glutamic acid decarboxylase 65 antibodies was significantly less in EOD (28.6% and 31.6%, respectively). There were significant differences in the frequencies of some diabetes-related HLA alleles and haplotypes between the early-onset group and a large non-age-stratified type 1 diabetes group. None of the patients with EOD had either of the protective DRB1*1501 or DQB1*0602 alleles. There was a negative correlation between glutamic acid decarboxylase and the predisposing haplotype DR3/DQ2. Children diagnosed with type 1 diabetes before 5 years of age may have different diabetes-related autoimmune and genetic characteristics from those diagnosed at a later age.

Pediatric Diabetes, 2000

The incidence of type 1 diabetes is increasing most rapidly in children under 5 yrs of age, a gro... more The incidence of type 1 diabetes is increasing most rapidly in children under 5 yrs of age, a group where the disease appears to be more accelerated than traditional type 1 diabetes. Little is known about demographics, and markers of diabetes autoimmunity, in infants and pre-schoolers with type 1 diabetes. We report an analysis of 47 children diagnosed with type 1 diabetes prior to 5 yrs of age compared with a representative cohort (n = 49) diagnosed after 5 yrs of age, and all were followed at Loma Linda University (LLU) Children's Hospital. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the prevalence of diabetes autoimmune markers, ICA512, GAD65 and insulin autoantibodies (IAA) antibodies were measured. Children with early-onset diabetes had a significantly higher incidence of viral illness symptoms (p = 0.005) and diabetic ketoacidosis (DKA; p =0.017) at the time of diagnosis. However, hemoglobin A1C (HbA1c) levels at diagnosis were significantly higher in the later-onset group (p = 0.001). A honeymoon period was reported in 14.8% of children diagnosed before 5 yrs of age compared with 42.1% in those diagnosed over 5 yrs of age (p = 0.038). Islet-cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibody titers were significantly different between early-and later-onset groups. ICA titers were positive in 35.29%, and GAD in 41.38% of the early-onset group versus 70.83 and 71.74% in children with later-onset disease, (p =0.001 and 0.009, respectively). IAA titers, drawn after instituting insulin therapy, were not significantly different between the two groups. GAD and ICA512 antibody results suggest a relative lack of diabetes immune markers in infants and toddlers with new-onset diabetes. This finding, and the apparent shorter pre-clinical phase reflected in the lower HbA1c values, may indicate age-related differences in type 1 diabetes autoimmunity or the existence of non-autoimmune diabetogenic mechanisms in younger children.

The Journal of Clinical Endocrinology & Metabolism, 2004

The increase in pituitary GH secretion that occurs during mid-late puberty in boys follows an inc... more The increase in pituitary GH secretion that occurs during mid-late puberty in boys follows an increase in circulating testosterone (T) concentration; the direct mechanism by which this occurs is unknown. We hypothesized that T increases GH secretion during puberty by augmenting hypothalamic output of GHRH. Using constant infusions of a GHRH antagonist, we tested this hypothesis in six early pubertal boys with constitutional delay of growth and adolescence who had a mean chronological age of 14.0 +/- 0.3 yr and mean bone age of 11.4 +/- 0.2 yr. Blood samples were obtained from subjects every 15 min for 24 h during the overnight infusion of normal saline (2000-0600 h) and again during the overnight infusion of GHRH antagonist (0.33 microg/kg/h) the following night. Subjects then received transdermal T (5-mg patch) for 12 h nightly and were studied again after 4 wk of treatment. Serum samples were assayed for GH and total ghrelin; the percent suppression of GH during GHRH antagonist infusion was calculated. Morning serum T rose from 0.44 +/- 0.09 to 4.43 +/- 0.74 microg/liter (P = 0.005). T treatment was associated with a 92.6% increase in mean nocturnal GH secretion area under the curve (830 +/- 177 to 1599 +/- 340 microg/24 h.liter). Infusion of GHRH-antagonist suppressed mean nocturnal GH area under the curve by 29.1% before T treatment (830 +/- 177 to 621 +/- 168 microg/24 h.liter), and by 29.4% after T treatment (1599 +/- 340 to 1182 +/- 249 microg/24 h.liter; P = 0.99). Somatotroph sensitivity to GHRH was tested with 0.1- and 1.0-microg/kg doses of GHRH-44 iv; GH response did not change with regard to T treatment. The mean 24-h concentration of total ghrelin was unchanged with regard to T treatment. In summary, nightly transdermal T administration in six boys with constitutional delay of growth and adolescence increased GH output almost 2-fold, whereas the degree of GH suppressibility by GHRH antagonist remained unchanged. We conclude that the T-associated augmentation of GH secretion during early puberty in boys is unlikely to involve an absolute increase in hypothalamic GHRH output.

The Journal of Clinical Endocrinology & Metabolism, 2008

Context: Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. ... more Context: Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. Objective: The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. Design: This was a descriptive case series of up to 3.5 yr duration. Setting: The study was conducted at a university hospital. Patients: Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. Intervention: The intervention was administration of pegvisomant. Main Outcome Measures: Plasma IGF-I and growth velocity were measured. Results: In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. Conclusions: Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory.

The Journal of Clinical Endocrinology & Metabolism, 2009

Human Reproduction, 2004

BMC Pregnancy and Childbirth, 2008

Background: Pregnancy in Type 1 diabetic patients is a precarious condition, both for mother and ... more Background: Pregnancy in Type 1 diabetic patients is a precarious condition, both for mother and fetus with increased the risk of prematurity and, immediately after delivery with risk of respiratory distress syndrome and hypoglycaemia in newborns. A strict control and monitoring of diabetes throughout pregnancy is important in reducing the impact of the disease on the fetus and newborn. In recent years many new technologies have been introduced to ameliorate diabetes monitoring, where the last is the Real-time Continuous Glucose Monitoring System (RT-CGMS). Methods: In the last three years, 72 h continuous glucose monitoring system (RT-CGMS) (Medtronic, CA) was performed in 18 pregnant women with Type 1 diabetes in two moments of pregnancy: during treatment with betamethasone to prevent respiratory distress and during delivery. In both cases insulin was administered intravenous and the dose was changed on the basis of glycaemia. Results: The results present the use of this new technique during two topics moments of pregnancy of type 1 diabetes patients when is very important intensively to monitor diabetes and to obtain the well being of the fetus. No infant experimented hypoglycaemia or respiratory distress syndrome at the moment and in the first hours after the birth. Conclusion: We wish to stress the importance reducing glycaemia during administration of betamethasone and during labor. It is conceivable that the scarce attention paid to monitoring glucose levels in diabetic mothers during labor in gynaecological world may be due to the difficulty in glucose monitoring with the devices until now available. Hopefully, our anecdotal account may prompt improvements with RT-CGMS, and may lead to a better approach to the problem, thereby changing the prognosis of infants born to diabetic mothers.

Journal of Clinical …, 1999

Pituitary, 2002

Pediatric Endocrinology, 2013

AACE Clinical Case Reports, 2015

Endocrine, 2003

Pituitary, 2002

Pediatric Endocrinology, 2003

PEDIATRICS, 2003

Pediatric Diabetes, 2000

The Journal of Clinical Endocrinology & Metabolism, 2004

The Journal of Clinical Endocrinology & Metabolism, 2008

The Journal of Clinical Endocrinology & Metabolism, 2009

Human Reproduction, 2004

BMC Pregnancy and Childbirth, 2008

Journal of Clinical …, 1999