Julio Abucham

Changes in serum thyroid hormones levels and their mechanisms during long‐term growth hormone (GH) replacement therapy in GH deficient children

The effects of GH therapy on thyroid function among previous reports have shown remarkable discrepancies, probably due to differences in hormone assay methods, degree of purification of former pituitary‐derived GH preparations, dosage schedules, diagnostic criteria, patient selection, duration of treatment and study design. These considerations motivated us to investigate whether and how GH replacement therapy changes serum thyroid hormone levels, including the much less studied rT3 levels, in a group of unequivocally GH‐deficient children receiving long‐term recombinant human GH therapy.

Short- and Long-Term Efficacy of Combined Cabergoline and Octreotide Treatment in Controlling IGF-I Levels in Acromegaly

Objective: Nearly 40% of acromegalic patients fail to control GH/IGF-I levels with somatostatin analogues (SA). Dopaminergic agonists (DA) are even less effective, but combination therapy with SA and DA normalizes IGF-I levels in 33–56% of patients not controlled by octreotide alone in short-term studies. This study was designed to evaluate short- and long-term efficacy of cabergoline in controlling IGF-I levels in acromegalic patients receiving octreotide. Design: Open-label, single arm, prospective trial. Nineteen patients (14 females, 29–78 years of age) with high IGF-I on octreotide-LAR (30 mg/month IM) for ≧6 months were enrolled. Study I: Cabergoline (PO) was started at 1.0, increased to 2.0 and 3.5 mg/week, and withdrawn at 6-week intervals. IGF-I, GH, and PRL were measured at baseline and at 6-week intervals. Study II: Responder patients (IGF-I ≤1 ULN) resumed cabergoline at individual lowest effective doses and were evaluated at 6-month intervals for ≧12 months. Study III: Responders were withdrawn from octreotide and hormonally evaluated at 3-month intervals. Methods: Serum IGF-I (IRMA), GH (ICMA) and PRL (ICMA) levels were determined by commercially available kits. Results: Addition of cabergoline to octreotide-LAR normalized IGF-I levels in 7 of 19 patients (37%) during both short- and long-term follow-up (12–27 months, mean: 18 months). Octreotide withdrawal increased IGF-I levels in only 2 of 6 responder patients. Normalization of IGF-I levels by cabergoline was strongly associated with IGF-I ≤2.2 ULNR and/or GH ≤4.0 ng/ml under octreotide treatment. Conclusion: Addition of cabergoline to octreotide was effective in both short- and long-term control of IGF-I in acromegaly, especially in patients with mild/moderately elevated GH/IGF-I levels during octreotide.

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

UNLABELLED Combined Pituitary Hormone Deficiency (CPHD) is a prevalent disease in Neuroendocrinology services. The genetic form of CPHD may originate from mutations in pituitary transcription factor (PTF) genes and the pituitary image in these cases may give a clue of what PTF is most probably mutated: defects in LHX4 are usually associated with ectopic posterior pituitary (EPP); defects in LHX3, PIT1, and PROP1, with normally placed posterior pituitary (NPPP); HESX1 mutations are associated with both. OBJECTIVE To identify mutations in PTF genes in patients with idiopathic hypopituitarism followed in our service, based on the presence or absence of EPP on sellar MRI. METHODS Forty patients with idiopathic hypopituitarism (36 families, 9 consanguineous), followed in the Neuroendocrinology Outpatient Clinic of UNIFESP, Brazil, were submitted to sequencing analyses of PTF genes as follows: LHX3, HESX1, PIT1, and PROP1 were sequenced in patients with NPPP (26/40) and HESX1 and LHX4 in patients with EPP (14/40). RESULTS We identified only PROP1 mutations in 9 out of 26 patients with CPHD and NPPP (35%). Since eight of them came from 4 consanguineous families, the prevalence of PROP1 mutations was higher when only consanguineous families were considered (44%, 4/9). At the end of the study, we decided to sequence PROP1 in patients with EPP, just to confirm that they were not candidates for PROP1 mutations. No patients with EPP had PROP1 or other PTF mutations. CONCLUSIONS Patients with idiopathic CPHD and NPPP, born from consanguineous parents, are the strong candidates for PROP1 mutations. Other developmental gene(s) may be involved in the genesis of idiopathic hypopituitarism associated with EPP.

Hereditary corticosteroid-binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred

objective Abnormal corticosteroid‐binding globulin (CBG) is an extremely rare condition and only three mutations have been described in four families. The molecular basis of an abnormal CBG in a Brazilian family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined.

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

IntroductionAcromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.MethodsWe conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.Findings and conclusionsSuccessful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

Recovery of persistent hypogonadism by clomiphene in males with prolactinomas under dopamine agonist treatment

CONTEXT Persistence of hypogonadism is common in male patients with prolactinomas under dopamine agonist (DA) treatment. Conventional therapy with testosterone causes undesirable fluctuations in serum testosterone levels and inhibition of spermatogenesis. OBJECTIVE To evaluate the use of clomiphene as a treatment for persistent hypogonadism in males with prolactinomas. DESIGN Open label, single-arm, prospective trial. PATIENTS Fourteen adult hypogonadal males (testosterone <300 ng/dl and low/normal LH) with prolactinomas on DA, including seven with high prolactin (range: 29-1255 microg/l; median: 101 microg/l) despite maximal doses of DA. INTERVENTION Clomiphene (50 mg/day orally) for 12 weeks. MEASURES Testosterone, estradiol, LH, FSH, and prolactin were measured before and 10 days, 4, 8, and 12 weeks after clomiphene. Erectile function, sperm analysis, body composition, and metabolic profiles were evaluated before and after clomiphene. RESULTS Ten patients (71%), five hyperprolactinemic and two normoprolactinemic, responded to clomiphene (testosterone >300 ng/dl). Testosterone levels increased from 201+/-22 to 457+/-37 ng/dl, 436+/-52, and 440+/-47 ng/dl at 4, 8, and 12 weeks respectively (0.001<P<0.01). Estradiol increased significantly and peaked at 12 weeks. LH increased from 1.7+/-0.4 to 6.2+/-2.0 IU/l, 4.5+/-0.7, and 4.6+/-0.7 IU/l at 4, 8, and 12 weeks respectively (0.001<P<0.05). FSH levels increased in a similar fashion. Prolactin levels remained unchanged. Erectile function improved (P<0.05) and sperm motility increased (P<0.05) in all six patients with asthenospermia before clomiphene. CONCLUSIONS Clomiphene restores normal testosterone levels and improves sperm motility in most male patients with prolactinomas and persistent hypogonadism under DA therapy. Recovery of gonadal function by clomiphene is independent of prolactin levels.

The impact of sleep on age-related sarcopenia: Possible connections and clinical implications.

Sarcopenia is a geriatric condition that comprises declined skeletal muscle mass, strength and function, leading to the risk of multiple adverse outcomes, including death. Its pathophysiology involves neuroendocrine and inflammatory factors, unfavorable nutritional habits and low physical activity. Sleep may play a role in muscle protein metabolism, although this hypothesis has not been studied extensively. Reductions in duration and quality of sleep and increases in prevalence of circadian rhythm and sleep disorders with age favor proteolysis, modify body composition and increase the risk of insulin resistance, all of which have been associated with sarcopenia. Data on the effects of age-related slow-wave sleep decline, circadian rhythm disruptions and obstructive sleep apnea (OSA) on hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG), somatotropic axes, and glucose metabolism indicate that sleep disorder interventions may affect muscle loss. Recent research associating OSA with the risk of conditions closely related to the sarcopenia process, such as frailty and sleep quality impairment, indirectly suggest that sleep can influence skeletal muscle decline in the elderly. Several protein synthesis and degradation pathways are mediated by growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol and insulin, which act on the cellular and molecular levels to increase or reestablish muscle fiber, strength and function. Age-related sleep problems potentially interfere intracellularly by inhibiting anabolic hormone cascades and enhancing catabolic pathways in the skeletal muscle. Specific physical exercises combined or not with nutritional recommendations are the current treatment options for sarcopenia. Clinical studies testing exogenous administration of anabolic hormones have not yielded adequate safety profiles. Therapeutic approaches targeting sleep disturbances to normalize circadian rhythms and sleep homeostasis may represent a novel strategy to preserve or recover muscle health in older adults. Promising research results regarding the associations between sleep variables and sarcopenia biomarkers and clinical parameters are required to confirm this hypothesis.

Acromegaly and pregnancy: a prospective study

CONTEXT AND OBJECTIVE The interaction between pregnancy and acromegaly has been studied only retrospectively. We used prospective data to assess those interactions. DESIGN Prospective, interventional, multicentric study. PATIENTS TEN PREGNANCIES IN EIGHT ACROMEGALIC PATIENTS WERE INCLUDED ACCORDING TO THE FOLLOWING CRITERIA: previous diagnosis of acromegaly; and active acromegaly before pregnancy. Sellar magnetic resonance image (MRI), GH, and IGF1 measurements were carried out before pregnancy. The exclusion criterion was radiotherapy. INTERVENTION Withdrawal of pharmacological treatment (octreotide and/or cabergoline and/or pegvisomant) following pregnancy diagnosis. MAIN OUTCOME MEASURES Clinical/biochemical evaluations throughout pregnancy/puerperium and sellar MRI after delivery; and GH and IGF1 measurements before pregnancy. GH was measured by an interference-free IFMA assay during pregnancy and IGF1 by measured by Immulite 2000 assay in patients and 64 control pregnancies. RESULTS No tumor growth was observed. Nine deliveries were at term and one at 35 weeks (preeclampsia). All newborns were healthy. Mean IGF1 levels before and during pregnancy were similar, but increased significantly during puerperium. As IGF1 in controls increased after midgestation, the prevalence of controlled IGF1 rose significantly from 2/10 (<20 weeks) to 9/10 (>30 weeks). Diabetes mellitus and hypertension/preeclampsia developed in one patient in each group; both complications were nonsignificantly (P=0.06) associated with IGF1 >1.3 ULN before pregnancy. CONCLUSIONS Acromegaly control usually improved and tumor growth was not stimulated during pregnancy in spite of withdrawal of drug treatment. Drug treatment can be discontinued in most patients. Uncontrolled disease before pregnancy may pose a higher risk for diabetes and hypertension.

The natural history of the R120C PROP1 mutation reveals a wide phenotypic variability in two untreated adult brothers with combined pituitary hormone deficiency

Background: Combined pituitary hormone deficiency (CPHD) corresponds to impaired production of growth hormone (GH) and other anterior pituitary hormones. The genetic form of CPHD may result from mutations in pituitary transcription factor genes, and PROP is the most commonly mutated gene in these cases. Patients with PROP1 mutations may have variable CPHD phenotypes but, because they are usually treated in childhood, the wide phenotypic variability caused by these mutations may not be thoroughly appreciated. Methods: Clinical follow-up and molecular analysis of PROP1 in two adult brothers with CPHD, born from consaguineous parents, and not treated until late adulthood. Results: The homozygous R120C mutation was identified in the brothers. Their clinical follow-up showed a wide phenotypic variability: hypogonadism was severe and prevented pubertal development in both, but their final heights were remarkably different, pointing to different degrees in severity of GH/TSH deficiencies; cortisol deficiency developed late in both, but at least 10 yr apart. Conclusion: The lack of treatment in childhood and adolescence allowed the appreciation of the entire natural history of the CPHD caused by the R120C mutation, and it revealed a remarkable phenotypic variability even in siblings with a very similar genetic background.

GHRP-6 is able to stimulate cortisol and ACTH release in patients with Cushing’s disease: Comparison with DDAVP

It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing’s disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing’s disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing’s disease (8 female, 2 male; age: 36.7±4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2μg/kg iv) and DDAVP (10 μg iv) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean ±SE; basal:15.5±1.7 x peak: 45.1±9.3) and cortisol values (nmol/l, basal: 583.0±90.8 vs peak: 1013.4±194.6). ACTH AUC (pmol/l min−1) and cortisol AUC (nmol/l min−1) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0±1.4 vs peak: 50.5±16.2) and cortisol levels (basal: 572.5±112.7 vs peak: 860.5±102.8. AUC values for ACTH and cortisol were 1627.6±639.8 and 18364.7±5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1±9.3 vs 50.5±16.2; AUC: 1235.4±424.8 vs 1627.6±639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r=0.87, p=0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing’s disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.