Acromegaly with 'normal' growth hormone levels

Trends in Endocrinology & Metabolism, 2000

Annals of Saudi Medicine, 2002

A Elamin, A Tuvemo, Growth Hormone Treatment in Children and Adolescents. 2002; 22(1-2): 47-55 The use of growth hormone (GH) in clinical endocrine practice is in an ever-expanding state, because the beneficial effects of GH in a variety of clinical conditions are increasingly appreciated. Although GH has been used to treat GH-deficient patients for more than 40 years, practical guidelines for GH therapy in children and adolescents have not been available until recently. 1-3 In the past, human GH was extracted from cadaver pituitaries in a tedious procedure and was available in limited quantities. In 1985, however, clinical data indicated that pituitary-derived GH was the likely source of contaminated material (prions), which was responsible for the development of a slowly progressive and fatal neurological disorder known as Creutzfeldt-Jacob disease. 4 Consequently, production and distribution of pituitary GH for therapy were discontinued. Biosynthetic GH of recombinant DNA origin with an amino acid sequence identical to that of human GH became available for prescription in the US and Europe in 1986 and is produced commercially now by several laboratories. Current GH preparations contain minimal impurities, are apparently safe, and are available in unlimited supply. These characteristics, in combination with recent scientific enthusiasm, have prompted its use in several conditions for some of which neither efficacy nor safety has been proven. Concurrently, this unprecedented surge in the use of GH in clinical medicine has raised great concerns about the ethical and economical issues of such therapy. 5 The controversy over the absolute and relative indications of GH treatment in clinical endocrine practice will not resolve until more data become available and clear evidence-based recommendations could be made. However, according to the code of safe clinical practice, GH should only be prescribed by endocrinologists and experienced physicians, and GH therapy should be taken seriously. In addition to the high cost, GH injections are painful and serious side effects, although uncommon, do occur. The present article reviews the available evidence in the medical literature regarding the safety and efficacy of GH treatment in children and adolescents, and summarizes the clinical practice guidelines in relation to its approved and experimental uses. Biosynthesis and Genetic Influence Human GH is a 191 amino-acid polypeptide hormone synthesized and secreted by the somatotropes of the anterior pituitary gland. Its larger precursor peptide, pre-somatropin, is also secreted but has no physiologic action. The GH, which is expressed by the fetal pituitary, has little or no physiological actions in the fetus until late in pregnancy due to the lack of functional GH receptors on fetal tissues. During pregnancy, pituitary GH expression in the mother is suppressed and human chorionic somatotropin (hCS), a GH variant expressed by the placenta becomes the predominant GH in the mother by the 20th week of gestation. This placental growth hormone acts in the mother to stimulate the production of insulin-like growth factors and modulate intermediary metabolism, resulting in an increase in the availability of glucose and amino acids to the fetus. However, despite its potent somatogenic activity, the hCS is not released into the fetal circulation and most of the intrauterine growth is influenced by the human placental lactogen (hPL). 6 The human GH and placental hPL gene family, which consists of two GH and three PL genes, is important in the regulation of maternal and fetal metabolism and the growth and development of the fetus. The GH gene (GH-1) is the first in a cluster of five closely related genes on the long arm of chromosome 17 (q22-24). The four other genes have more than 90% sequence identity with GH-1 gene. They consist of the CS1 and CS2 genes, which encode for hCS, a placental GH gene (HG-2), and a partially disabled pseudo-gene (CSP). When the fetal genome lacks the CS1 and CS2 genes, the hCS production is diminished, but fetal growth and postpartum lactation are not affected. 7 The GH-1 gene is expressed in pituitary somatotropes under the control of two hypothalamic hormones. Growth hormone-releasing hormone (GHRH) stimulates and somatostatin inhibits GH release. Alternating secretion of

The Journal of Clinical Endocrinology & Metabolism, 2001

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.

Pituitary, 2010

Growth hormone (GH) measurements are routinely used for important treatment decisions in patients with acromegaly, yet their reliability is affected by numerous factors including assay precision and variability, sampling intensity, and hormone pulsatility. The day-today variation in GH in acromegaly has not been studied. This study quantified the magnitude of day-today GH variability in patients with acromegaly by performing an analysis of previously obtained plasma GH profiles. The analysis was performed at the Michigan Clinical Research Unit at the University of Michigan. A total of nine 48 h Q10 min GH profiles obtained in nine patients with active acromegaly were examined. The study was planned after data collection and analysis was conducted using Altman-Bland methods. Day 1 vs. Day 2 values were examined. 95% confidence intervals of the D2 vs. D1 ratios were calculated on all individual subject data as well as on a single 0800 h GH sample and composite mean data for 2-, 5-, 9-, and 24-h sampling protocols. Confidence interval range was 0.66-1.50 for the 0800 h sample and was similar for all sampling protocols except somewhat more narrow for the 24-h sampling (0.75-1.32). Daily variations in GH levels introduce an additional confounding element when using a single GH level or even daily GH curves to assess a patient's GH milieu. It may have an impact on result interpretation and subsequent treatment decisions especially when GH results are considered borderline.

European Journal of Endocrinology, 2002

Objective: To compare baseline characteristics in adult patients with growth hormone (GH) deficiency (GHD) who had previously been treated for Cushing's disease or acromegaly with data from patients with GHD of other aetiologies. To study the effects of GH therapy in those patients who had completed at least 6 months of GH replacement. Design: Data from a large outcomes research database (KIMS (Pharmacia International Metabolic Database)). Methods: 135 patients were identified with previous Cushing's disease, 40 had had acromegaly, and 1392 had GHD of other aetiologies. The number of additional hormone deficiencies, and the mean age of the patients were similar in the three groups. Similar proportions of patients in each group were treated using surgery, but radiotherapy was used more often in patients with acromegaly than those with other diagnoses. Results: At baseline, the prevalence of diabetes mellitus and hypertension were significantly higher in the group treated for Cushing's disease, and the prevalence of stroke was significantly higher in the group treated for acromegaly. The incidence of coronary heart disease and claudication were similar in all three groups. Patients treated for Cushing's disease had lower bone mineral density and suffered fractures more often than other GHD adults. Body mass index, waist-hip ratio, serum concentrations of lipids and standard deviation scores of serum concentrations of insulin-like-growth factor-I were similar in the three groups. The dose of GH administered was comparable in the three groups and the effects of GH replacement on waist circumference, blood pressure and quality of life were also similar across the groups. The numbers and types of adverse events reported were not different between the groups. Conclusions: These data suggest that the characteristics of patients in these diagnostic groups depend on the primary disease which resulted in GHD, and that the clinical expression of GHD does not differ between the groups. Patients with previous hypercortisolism showed more long-term effects of their disease, such as diabetes mellitus, hypertension and fractures. A benefit from GH replacement was evident in patients previously treated for acromegaly and Cushing's disease particularly in relation to quality of life.