bluuebunny/crossref_metadata_2025 huggingface dataset:
Administration of recombinant human growth hormone on alternate days is sufficient to increase whole body protein synthesis and lipolysis in growth hormone deficient adults
Authors: Lucidi Paola , Laureti Stefano , Santoni Stefania , Lauteri Marco , Busciantella‐Ricci  , Angeletti Gabriella , Santeusanio Fausto , De Feo Pierpaolo
Published: March 2003

OBJECTIVE

At present, the duration of the effect of recombinant human growth hormone (rhGH) on the rates of protein synthesis and lipolysis in GH deficient (GHD) adults is unknown. This study was designed to establish the frequency of rhGH administration necessary to provide the beneficial metabolic effects of the hormone in GHD adults.

DESIGN AND PATIENTS

Two different studies (A and B) were performed in two groups of five GHD men. In study A, whole body protein and lipid kinetics was determined in the basal state (Bas), 12 (GH12h) and 36 (GH36h) h after the last of seven injections of rhGH (3.3 μg/kg), given at bedtime on alternate days. In study B, the same parameters were determined in the basal state (Bas), 60 (GH60h) and 84 (GH84h) h after the last of seven injections of rhGH (3.3 μg/kg), given at bedtime at 3 day intervals.

MEASUREMENTS

The rates of protein metabolism were estimated by infusing [1–13C]leucine, and those of lipolysis by infusing [1,1,2,3,3‐D5]glycerol.

RESULTS

Leucine oxidation decreased (P < 0.01) by approximately 30% after GH12h and GH36h but did not change after GH60h and GH84h. Non‐oxidative leucine disposal increased after GH12h and GH36h by approximately 13% (P < 0.05) whereas it did not change after GH60h and GH84h. Glycerol appearance increased (P < 0.01) by approximately 45% after GH12h and GH36h but did not change after GH60h and GH84h.

CONCLUSIONS

The effects on protein and lipid metabolism following the injection of rhGH last longer than 36 and less than 60 h. In fact, rhGH administration on alternate days induced a sustained increase in the rates of protein synthesis and lipolysis of GHD adults, whereas a longer interval of administration (3 days) had no effect by 60 h.
Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine
Authors: Donnelly Peter , White Christopher
Published: March 2003

OBJECTIVE

Primary hypothyroidism can cause disturbances in normal gonadal function. The aim of this study was to investigate the relationship in men between hypogonadism and primary hypothyroidism and the extent to which free and total testosterone levels rose after introduction of replacement thyroxine.

DESIGN

Paired study of patients in a hypothyroid and thyroxine treated state.

PATIENTS

Ten men with primary hypothyroidism.

MEASUREMENTS

Free and total testosterone, gonadotrophin and prolactin levels before and after thyroxine replacement therapy.

RESULTS

Low free testosterone levels (161 ± 62 pmol/l) demonstrated at the time the men were hypothyroid rose significantly with the commencement of thyroxine replacement (315 ± 141 pmol/l; P < 0.001). Gonadotrophin levels were not elevated consistent with hypogonadotrophic hypogonadism. Hyperprolactinaemia, which can occur in primary hypothyroidism and cause hypogonadotrophic hypogonadism, was not present in the majority of these patients. However a reduction in prolactin level was evident with thyroxine replacement and a rise in free testosterone levels.

CONCLUSION

This suggests an effect of hypothyroidism on gonadotrophin secretion at the level of the hypothalamus‐pituitary, either directly or through modulation of prolactin secretion. Low free testosterone may also be a contributing factor to some of the symptoms and signs of hypothyroidism in men.
Relapse of hirsutism following long‐term successful treatment with oestrogen–progestogen combination
Authors: Kokaly Waleed , McKenna T. Joseph
Published: March 2003

OBJECTIVE

While several forms of treatment have been reported to be successful in relieving hirsutism over periods of 6–12 months, there is little if any information on the long‐term outcome of hirsutism following the withdrawal of successful treatment. The combination of ethinyl oestradiol, 35 μg, and cyproterone acetate, 2 mg (EE‐CA) for 21 days followed by 7 days without treatment is widely used in a cyclical manner in the treatment of hirsutism. The present study was undertaken to evaluate the outcome of withdrawal of long‐term successful treatment of hirsutism with EE‐CA.

DESIGN, PATIENTS AND MEASUREMENT

In this retrospective study the clinical records of 57 patients with idiopathic hirsutism or polycystic ovary syndrome who had been treated with EE‐CA were reviewed. The degree of hirsutism had been assessed by the Ferriman and Gallwey scoring system (FG). The testosterone/sex hormone binding globulin ratio (T/SHBG), was derived prior to and following the introduction of treatment with EE‐CA.

RESULTS

Fifty‐two of the 57 patients achieved a satisfactory clinical response. In the group of patients who were satisfied with the outcome of treatment, FG decreased from 12.9 ± 3.6 to 5.5 ± 2.5 and T/SHBG ratio decreased from 11.3 ± 9.5 to 1 ± 0.8 (reference range: 1–5.2). The duration of treatment prior to its withdrawal in this group was 28.2 ± 13.7 months. The five patients who were not satisfied with the response abandoned treatment after 16 ± 2.8 months; the pretreatment FG was 16.2 ± 8.3, while the T/SHBG decreased from 6.1 ± 3.1 to 1.1 ± 0.6 in these patients. Subsequent follow‐up data, after withdrawal of treatment, were available on 34 of these 52 patients. Twenty‐eight of the 34 patients exhibited relapse of hirsutism after 6.15 ± 2.8 months. Six patients did not relapse during a follow‐up period of 18.8 ± 7.8 months. The six patients who did not relapse were treated for a significantly longer period than the group who relapsed, 40 ± 6.9 and 26.1 ± 8.3 months, respectively, P < 0.01. However, the groups did not differ significantly when examined for pretreatment FG, 11.5 ± 3.8 and 13.2 ± 3.6 and pretreatment T/SHBG 8.9 ± 5 and 13.4 ± 11.9.

CONCLUSION

These data indicate that ethinyl oestradiol and cyproterone acetate achieved a satisfactory clinical outcome in the treatment of hirsutism in 90% of patients. However, on withdrawal of treatment after a mean duration of over 2 years, relapse occurred in 80% of these patients after a mean of 6 months. If it is assumed that the successfully treated patients lost to follow‐up all maintained long‐term remission, the relapse rate is still an unsatisfactory 65% at 6 months. These are disappointing results which indicate for the first time that successful outcome requires that treatment be maintained for several years. Patients embarking upon treatment for hirsutism should be advised that maintenance of reduced hair growth requires long‐term treatment, probably for at least 3–4 years.
One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults
Authors: Beentjes John A. M. , van Gorkom Britta A. P. , Sluiter Wim J. , de Vries Elisabeth G. E. , Kleibeuker Jan H. , Dullaart Robin P. F.
Published: March 2003

OBJECTIVE Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo‐controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate.

PATIENTS AND DESIGN Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n=5), high dose GH therapy (2U daily, n=5) or placebo (n= 6) during 6 months. Thereafter, all patients were treated with 2U of GH daily during a 6‐months open extension period.

MEASUREMENTS Plasma Insulin‐like growth hormone I (IGF‐I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5‐bromo‐2′‐deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period.

RESULTS IGF‐I rose from 8.9±6.7 to 34.6 ±20.0 nmol/l after 6 months in 8 GH treated patients (P <0.01 from baseline; P<0.01 from change with placebo). In the extension study, plasma IGF‐I was also increased in the patients who previously received placebo (P<0.02, n=5). LI was evaluable in 14 biopsies at baseline, in 16 after 6 months and in 14 after 12 months. Overall crypt LI did not change in 8 GH treated patients after 6 months (P< 0.40 from baseline; P>0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n= 5, P>0.40) and in those who continued GH replacement (n=9, P>0.60; P>0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling.

CONCLUSIONS Six to 12 months of GH replacement therapy, aimed to increase plasma IGF‐l into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.
Cardiovascular disease in women with polycystic ovary syndrome at long‐term follow‐up: a retrospective cohort study
Authors: Wild Sarah , Pierpoint Tracey , McKeigue Paul , Jacobs Howard
Published: March 2003

OBJECTIVE

Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle‐aged women previously diagnosed with PCOS and age‐matched control women.

DESIGN

A retrospective cohort study of women diagnosed with PCOS in the United Kingdom before 1979.

PATIENTS

Seventy cohort members died before 31 March 1999. Morbidity data were collected from 319 women with PCOS and 1060 age‐matched control women. Sixty‐one women with PCOS and 63 control women attended a clinical examination.

MEASUREMENTS

Data were collected from death certificates, general practitioners' records and questionnaires with measurement of cardiovascular risk factors in a subsample of questionnaire respondents.

RESULTS

All‐cause and cardiovascular mortality in the cohort were similar to women in the general population (standardized mortality ratios (95% CI): 93 (72–117) and 78 (45–124), respectively). Women with PCOS had higher levels of several cardiovascular risk factors: diabetes (P = 0.002) hypertension (P = 0.04), hypercholesterolaemia (P < 0.001), hypertriglyceridaemia (P = 0.02) and increased waist:hip ratio (P = 0.004). After adjustment for BMI, odds ratios (OR) were 2.2 (0.9–5.2) for diabetes, 1.4 (0.9–2.0) for hypertension and 3.2 (1.7–6.0) for hypercholesterolaemia. A history of coronary heart disease (CHD) was not significantly more common in women with PCOS (crude OR (95%CI) 1.5 (0.7–2.9)) but the crude OR for cerebrovascular disease was 2.8 (1.1–7.1).

CONCLUSION

At long‐term follow‐up, a history of nonfatal cerebrovascular disease and cardiovascular risk factors including diabetes are more prevalent among women with polycystic ovary syndrome. Morbidity and mortality from of coronary heart disease among women with polycystic ovary syndrome is not as high as previously predicted. This finding challenges our understanding of the aetiology of coronary heart disease in women.
Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo‐controlled feasability study for male contraception
Authors: Kamischke Axel , Plöger Daniela , Venherm Stefan , Von Eckardstein Sigrid , Von Eckardstein Arnold , Nieschlag Eberhard
Published: March 2003

OBJECTIVE

Approaches to hormonal male contraception are based on injectable testosterone esters alone or in combination with gestagens or GnRH analogs but the short half‐life of clinically used testosterone esters have long hindered further development. This study was designed to prove the efficacy of the long‐acting testosterone undecanoate ester (TU) alone or in combination with oral levonorgestrel (LNG) in a phase II clinical trial.

DESIGN AND SUBJECTS

Twenty‐eight healthy men were randomized to receive injections of 1000 mg TU every 6 weeks in combination with daily oral LNG (250 μg) or daily oral placebo treatment over a period of 24 weeks, followed by a control period of 28 weeks.

MEASUREMENTS

During the course of the study semen analysis, reproductive hormone analysis, analysis of clinical chemistry and lipid parameters, well‐being and sexual function, sonography of scrotal contents and prostate were performed.

RESULTS

Marked suppression of gonadotrophins in both treatment groups resulted in azoospermia in 8/14 and 7/14 volunteers and severe oligozoospermia (< 3 × 1012/l) in 4/14 and 7/14 in the placebo and gestagen treated groups, respectively. Time to induction of azoospermia (mean ± SEM) was not significantly different between the placebo (week 19.5 ± 2.2) and LNG groups (week 15.4 ± 2.2). During the whole treatment period mean testosterone serum concentrations remained within normal limits. Although not significant, it was evident that volunteers who became azoospermic had a better suppression of gonadotrophins and lower SHBG levels during treatment compared to non‐azoospermic volunteers. Despite better gonadotrophin suppression in the LNG group no significant differences compared to placebo could be observed in the extent and kinetics of suppression of spermatogenesis, thus not demonstrating a major beneficial effect of LNG in the combination with injectable TU. Treatment led in both groups to a decrease of HDL and Lp(a) which was more pronounced in the LNG group (P > 0.05).

CONCLUSION

Treatment with 1000 mg testosterone undecanoate injected at 6 weekly intervals or in combination with levonorgestrel showed suppression of spermatogenesis comparable to weekly injections of 200 mg testosterone enanthate. Because of its long half‐life and in the absence of severe side‐effects, testosterone undecanoate can be considered as first choice testosterone ester in further studies of hormonal male contraception.
Alterations of the 11p15 imprinted region and the IGFs system in a case of recurrent non‐islet‐cell tumour hypoglycaemia (NICTH).
Authors: Bertherat Jérôme , Logié Armelle , Gicquel Christine , Mourriéras Florence , Luton Jean Pierre , Le Bouc Yves
Published: March 2003

BACKGROUND AND OBJECTIVE

Non‐islet‐cell tumour hypoglycaemia (NICTH) is a rare disorder and has been explained by oversecretion of non mature IGF‐II and dysregulation of the IGFs sytem. The mechanisms responsible for tumoural IGF‐II overexpression in NICTH have been rarely studied. We report an extensive study of IGF‐II and IGFBPs as well as chromosome 11p15 gene expression regulation in a case of a pleural fibrosarcoma in a 63‐year‐old patient presenting with NICTH.

METHODS AND RESULTS

Abnormal high molecular weight precusor forms of IGF‐II were present in the patient's serum and were associated with dramatic alterations in the circulating levels of IGF‐I, IGF‐II and their binding proteins, as well as an inhibition of the somatotroph axis. These alterations returned to normal following complete surgical removal of the tumour. No structural change in chromosome 11p15 region was apparent in the tumour. However, dysregulation of this imprinted region was demonstrated, leading to the loss of imprinting of the IGF‐II gene associated with high IGF‐II expression, and by contrast decreased level of expression of H19 and p57KIP2 genes. Recurrence of the tumour four years latter was not associated with hypoglycaemia or changes in the levels of circulating IGFs or IGFBPs, despite IGF‐II overexpression by the tumour. This suggests that a large tumour volume is required to reach high enough levels to cause changes in the levels of circulating IGFs and IGFBPs, and to cause hypoglycaemia.

CONCLUSION

These results suggest that a dysregulation of gene expression and imprinting of chromosome 11p15 region is associated with tumour growth and IGF‐II overexpression in non‐islet‐cell tumour hypoglycaemia.
Inhibins A and B are regulated differentially in the early post‐partum period
Authors: Burger  , Mamers  , Groome
Published: March 2003

BACKGROUND

The early postpartum period is characterized endocrinologically by a rapid fall in the levels of oestradiol (E2) and immunoreactive inhibin, and a delayed rise in serum follicle stimulating hormone (FSH). No description is currently available of changes in serum inhibins A and B.

OBJECTIVES

The present study aimed to examine the levels of inhibin A and B during the early weeks of postpartum lactational amenorrhoea, to determine whether there was evidence for differential regulation of the two hormones at a time when no dominant follicle was developing in the ovary.

SUBJECTS AND METHODS

Serum samples were available from 12 subjects aged 29–38 in whom postpartum levels of FSH, immunoreactive inhibin, E2 and prolactin had been examined previously. Samples for hormone assays had been obtained prior to delivery, daily for the 3–5 days postpartum, and weekly thereafter. Inhibins A and B were measured by specific ELISA assays, and results were calculated as 10 day averages for samples obtained on days 1–10, 11–20, 21–30, etc. postpartum. Normal hormone concentrations for reference were obtained from volunteers, also aged 29–38, sampled on days 3–5 of a normal menstrual cycle.

RESULTS

Inhibin A in the predelivery sample ranged from 62 to 1243 ng/l, geometric mean 592. Concentrations fell rapidly postpartum and reached a nadir in the low follicular phase range between days 5 and 37 postdelivery, mean 13.6 days. The concentrations of both inhibin B and FSH rose 14–27 days postpartum from their initially low postdelivery levels, to reach the normal follicular phase range. These increases in concentration were significantly correlated in all individual subjects.

CONCLUSIONS

The secretion of inhibin A and B is regulated differentially during the early stages of lactational amenorrhoea, just as it is in the late luteal phase of the normal menstrual cycle. Whilst inhibin A falls postpartum, reflecting cessation of placental function, and remains low until ovulatory cycles are resumed, FSH and inhibin B rise after a delay of two weeks or more. It is postulated that the rise of inhibin B is the result of secretion from a cohort of small follicles stimulated by rising FSH levels.
Plasma concentrations of tumor necrosis factor‐α (TNF‐α) and soluble TNF receptors in patients with bulimia nervosa
Authors: Nakai Yoshikatsu , Hamagaki Seiji , Takagi Ryuro , Taniguchi Ataru , Kurimoto Fumihiko
Published: March 2003

BACKGROUND

Tumor necrosis factor‐α (TNF‐α) is a cytokine with numerous immunological and metabolic activities. In addition, TNF‐α can stimulate a variety of physiological, neuroendocrine and behavioural responses of the central nervous system. In experimental animals, TNF‐α induces changes in physiological and behavioural parameters which have also been observed in eating disorders. The biological activities of TNF‐α are mediated by two structurally related, but functionally distinct receptors, TNF‐RI and TNF‐RII. Since injection of TNF‐α results in increased shedding of TNF‐α receptors, it is likely that TNF‐α release is reflected by soluble TNF‐receptors (sTNF‐Rs) levels.

AIMS

We studied plasma concentrations of TNF‐α and two sTNF‐Rs (sTNF‐RI and sTNF‐RII) in female patients with bulimia nervosa.

DESIGN AND PATIENTS

Twenty female patients with bulimia nervosa (BN) and 20 age‐matched normal women (N) were studied.

MEASUREMENTS

Plasma TNF‐α concentrations were measured by enzyme immunoassay kit and plasma concentrations of sTNF‐RI and sTNF‐RII were measured by enzyme‐linked immunosorbent assay.

RESULTS

Plasma TNF‐α concentrations in BN were significantly higher than those in N (4.7 ± 0.5 ng/l vs. 1.6 ± 0.1 ng/l; P < 0.01). Although no significant difference was observed in plasma sTNF‐RI concentrations between the two groups, plasma sTNF‐RII concentrations in BN were significantly higher than those in N (2080.0 ± 107.5 ng/l vs. 1569.5 ± 84.0 ng/l; P < 0.01). Plasma TNF‐α concentrations were significantly related to plasma sTNF‐RI concentrations (r = 0.511, P < 0.05) and to plasma sTNF‐RII concentrations (r = 0.532, P < 0.05) in bulimic patients. However, plasma TNF‐α concentrations were not related to body fat mass or to bulimic behaviours in these patients.

CONCLUSIONS

Our present findings suggest that the adipose tissue may not be the immediate source of TNF‐α in bulimic patients but the increase in plasma TNF‐α in these patients may be derived from the central nervous system sources. The elevated sTNF‐RII may reflect different shedding kinetics compared with sTNF‐RI in bulimic patients.
Goitre prevalence and thyroid abnormalities at ultrasonography: a comparative epidemiological study in two regions with slightly different iodine status
Authors: Knudsen Nils , Bülow Inge , Jørgensen Torben , Laurberg Peter , Ovesen Lars , Perrild Hans
Published: March 2003

OBJECTIVE

The association between severe iodine deficiency and endemic goitre is well established, but little information is available on the relation between milder degrees of iodine deficiency and goitre prevalence.

SUBJECTS

In a comparative epidemiological study performed in two regions in Denmark, we examined 4649 subjects from the general population, women aged 18–65 years and men aged 60–65 years.

METHODS

Ultrasonography and palpation of the thyroid was performed in all participants. Iodine excretion was measured in casual urine samples. Previous thyroid disease was detected by questionnaires, personal interviews and tracing of records.

RESULTS

The median iodine excretion was 61 μg/l (mild iodine deficiency (ID)) and 45 μg/l (moderate ID) in the two regions. Median thyroid volume at ultrasonography was 11.9 ml (mild ID) and 13.6 ml (moderate ID), P < 0.001, and thyroid enlargement was found in 15.0% (mild ID) and 22.6% (moderate ID), P < 0.001. Goitre prevalence increased in both regions with age to the age group 40–45 years, but not after that age. Subjects who had moved from the moderate ID to the mild ID area had the same prevalence of thyroid enlargement as the subjects staying permanently in the mild ID area. Thyroid nodules at ultrasonography were found in 30% in both regions, but nodules were larger and more often palpable in the moderate ID area. Palpable goitre was found in 9.8% (mild ID) and 14.6% (moderate ID), P < 0.001. The greatest regional difference in thyroid abnormalities was found among men.

CONCLUSION

Marked differences in the prevalence of thyroid abnormalities were found in these regions with modest differences in iodine excretion.
The diagnosis of growth hormone deficiency (GHD) in successfully treated acromegalic patients
Authors: Murray R. D. , Peacey S. R. , Rahim A. , Toogood A. A. , Thorner M. O. , Shalet S. M.
Published: March 2003

Due to persistent qualitative abnormali‐ties in GH secretion following treatment, and lack of a sensitive marker of GHD in mid‐adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin‐induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo–pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients.

Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B).

All patients underwent 20 min blood sampling to provide a 24‐h GH profile. Serum IGF‐I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30‐min intervals thereafter for 180 min. At the final visit hexarelin 1·5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15‐min intervals from − 30 to 180 min.

All patients in group A showed an increment in serum GH following hexarelin (ΔGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24‐h GH > 0·5 mU/l. In group B only 4/11 achieved a ΔGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a ΔGHHEX < 2 mU/l were also demonstrated to have a mean 24‐h GH of < 0·5 mU/l and serum IGF‐I SDS < + 0·5. All four patients in Group B who achieved a ΔGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine.

Despite loss of the GH response to arginine, the ΔGHHEX is retained in a proportion of those patients in whom ‘safe’ GH levels were achieved following irradiation. From the putative mechanisms of action of these provocative agents a plausible explanation would be that the GHRH axis is more resilient than endogenous somatostatin‐secreting neurones to radiation‐induced damage. Furthermore, GH secretagogues may have a role, in combination with serum IGF‐I levels, in the diagnosis of GH deficiency in treated acromegaly.
A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene
Authors: Söderlund D. , Canto P. , De La Chesnaye E. , Ulloa‐Aguirre A. , Méndez J. P.
Published: March 2003

BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH‐R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH‐R gene in three families with isolated hypogonadotrophic hypogonadism.

PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included.

MEASUREMENTS DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene.

RESULTS A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH‐R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH‐R gene.

CONCLUSIONS This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH‐R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH‐R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect.
Absence of mutations in the growth hormone (GH)‐releasing hormone receptor gene in GH‐secreting pituitary adenomas
Authors: Salvatori Roberto , Thakker Rajesh V. , Lopes M. Beatriz , Fan Xiaoguang , Eswara Jairam R. , Ellison David , Lees Peter , Harding Brian , Yang Inmyung , Levine Michael A.
Published: March 2003

GH‐releasing hormone (GHRH) is a potent stimulator of somatotroph cell proliferation and GH secretion. GHRH acts via binding to a G‐protein coupled receptor (GPCR) (GHRH‐R), that activates adenylyl cyclase (AC) and increases growth and function of somatotroph cells. Indeed, a subset (30–40%) of somatotrophic adenomas contain somatic mutations of the GNAS1 gene that encodes the alpha subunit of the G‐protein (Gsα) that stimulates AC. As activating mutations of other GPCRs cause development of endocrine tumours, we hypothesized that somatic activating mutations of the GHRH‐R might provide the molecular basis for somatotroph cell proliferation in a subset of human GH‐secreting pituitary adenomas.

We analysed genomic DNA isolated from 26 somatotrophinomas, 17 of which lacked activating mutations in the GNAS1 gene. We individually amplified via polymerase chain reaction all 13 coding exons and the exon‐intron boundaries of the GHRH‐R gene. We used denaturing gradient gel electrophoresis to search for abnormalities in exons 1 through 11. Abnormally migrating bands were subjected to direct sequencing. Exons 12 and 13, encoding for the intracellular C‐terminal domain, were subjected to direct sequencing.

Mutations were not detected in any of the tumours, but a rare polymorphism in codon 225 corresponding to the third transmembrane domain (V225I) was discovered.

GHRH‐R mutations are absent or rare in somatotrophinomas, and other mechanisms must explain the somatotroph cell proliferation in the adenomas that lack activating mutations in the GNAS1 gene.
Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO‐QOL) after different treatments
Authors: Terwee C. B. , Dekker F. W. , Mourits M.P. , Gerding M. N. , Baldeschi L. , Kalmann R. , Prummel M. F. , Wiersinga W. M.
Published: March 2003

The Graves' ophthalmopathy quality of life questionnaire (GO‐QOL) is the first instrument available to measure health‐related quality of life (HRQL) of patients with Graves' ophthalmopathy. The main objective of this study was to define a minimal clinically important difference (MCID) in score on the GO‐QOL that can be considered an important improvement in HRQL by examining changes in GO‐QOL scores in patients who subjectively report improvement from their treatment. A secondary objective was to test the longitudinal validity of the GO‐QOL, using prespecified hypotheses about expected treatment effects.

A prospective cohort study.

We included 164 patients who were scheduled for radiotherapy (23), orbital decompression (10 for sight loss, 38 for exophthalmos), eye muscle surgery (31), eyelid lengthening (43) or blepharoplasty (19).

Patients completed the GO‐QOL and three general HRQL questionnaires, before and three or six months after treatment, depending on the performed procedure. Clinical characteristics were collected from the medical records. Mean changes in GO‐QOL scores and effect sizes were calculated after different treatments, and in subgroups of responders and nonresponders according to clinical characteristics and according to the patients themselves.

A clinical response to treatment was associated with a change in GO‐QOL scores of approximately 10–20 points after major treatments (radiotherapy or decompression), and with a change of approximately 3–10 points after minor surgery (eye muscle surgery, eyelid lengthening, blepharoplasty). Changes in GO‐QOL scores of about 6–10 points were considered important improvements by the patients themselves. The direction and amount of change in GO‐QOL scores after different treatments were in accordance with our prespecified hypotheses about treatment effects. Effect sizes in the GO‐QOL subscales were generally higher than effect sizes of the general HRQL subscales, supporting the longitudinal validity of the GO‐QOL.

As a general guideline, one could consider a mean change of at least 6 points on one or both subscales an important change in daily functioning for patients. For more invasive therapies, a change of at least 10 points is recommended as a minimal clinically important difference.
The islet amyloid polypeptide (amylin) gene S20G mutation in Chinese subjects: Evidence for associations with type 2 diabetes and cholesterol levels
Authors: Lee S. C. , Hashim Y. , Li J. K. Y. , Ko G. T. C. , Critchley J. A. J. H. , Cockram C. S. , Chan J. C. N.
Published: March 2003

BACKGROUND and OBJECTIVES There has been evidence that the S20G mutation in the islet amyloid polypeptide (amylin) gene may be associated with type 2 diabetes. In the present study, we investigated the distribution of the mutation in Hong Kong Chinese, and examined whether there was evidence for associations between the mutation and type 2 diabetes and/or metabolic profiles.

SUBJECTS and METHODS This study involved 227 early and 235 late‐onset (defined as onset age ≤ 40 and > 40 years, respectively) type 2 diabetic patients, as well as 126 nondiabetic subjects. The mutation was detected using a PCR‐RFLP method.

RESULTS We identified six (2·6%) and one (0·4%) patients heterozygous for the mutation from the early and late‐onset groups, respectively (P = 0·05). None of the nondiabetic subjects had the mutation. Insulin deficiency and poor glycaemic control were not common findings amongst carriers of the mutation. In the early onset group, the patients with the mutation had lower plasma levels of total (4·3 ± 0·9 mmol/l vs. 5·3 ± 1·1 mmol/l, P = 0·02) and low density lipoprotein (LDL)‐cholesterol (2·3 ± 0·7 mmol/l vs. 3·2 ± 0·9 mmol/l, P = 0·01) than those without the mutation.

CONCLUSIONS Our data suggest that the islet amyloid polypeptide gene mutation might be associated with early occurrence of type 2 diabetes and lower plasma levels of total and low density lipoprotein‐cholesterol in the Chinese population.
Increased insulin sensitivity in young, growth hormone deficient children
Authors: Husbands Sandra , Ong Ken K. L. , Gilbert Jan , Wass John A. H. , Dunger David B.
Published: March 2003

OBJECTIVE Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children.

DESIGN AND PATIENTS Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety‐one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GH ≥ 20 IU/l).

MEASUREMENTS The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity.

RESULTS GH deficient children were more insulin sensitive than GH sufficient children (P = 0·004) and had lower glucose nadirs post‐insulin (P = 0·005). Subgroup analysis revealed that these differences were greater in younger (< 12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P < 0·05) compared to nonprimed tests.

CONCLUSIONS Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.
Detection of a recurring mutation in the human growth hormone‐releasing hormone receptor gene
Authors: Salvatori Roberto , Aguiar‐Oliveira Manuel H. , Monte Luciana V. B. , Hedges Lora , Santos Norma L. , Pereira Rossana M. C. , Phillips John A.
Published: March 2003

objective Mutations in the gene encoding for the GH‐releasing hormone receptor (GHRHR) have been recently described in patients with familial isolated GH deficiency (IGHD) type IB. To date, all reported mutations have been found in kindreds sharing common ancestors. The only exception is a T to A transversion which causes a substitution of histidine for leucine in codon 144 (L144H) and creates a DraIII restriction site. This mutation was described in two families with different ethnic background residing in two different continents (Europe and North America).

design We searched for GHRHR mutations in a new family with IGHD from a third continent (South America) and found the affected individuals to be homozygous for the same L144H change. We performed linkage analysis with intra‐ and para‐genic polymorphisms to determine if the three families carrying the L144H allele are related.

results Linkage analysis studies demonstrated that one of the three families does not share the same para‐ and intragenic GHRHR polymorphisms with the other two.

conclusions The L144H mutation has arisen at least twice and should be considered for initial genetic analysis in patients with familial IGHD in whom the a GHRHR mutation is suspected.
Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan
Authors: Gleeson Helena K. , Souza Anita H. O. , Gill Matthew S. , Wieringa Gilbert E. , De A. Barretto Elenilde S. , Barretto‐Filho J. A. S. , Shalet Stephen M. , Aguiar‐Oliveira Manuel H. , Clayton Peter E.
Published: March 2003

objective Growth hormone deficiency (GHD) is associated with adverse changes in lipid profile. However, changes in lipids through life in a homogeneous group of GHD subjects have not been defined.

patients and measurements We examined lipid levels in a group of untreated severely GHD patients with a mutation in the GHRH receptor gene from a rural community in North‐east Brazil. Lipid profiles in 15 GHD subjects [eight children and adolescents (one male), age (median [range]) 13·2 (5·4–19·9) years; seven adults (one male), age 47 (33–66) years] were compared with those in 29 indigenous controls from the same extended kindred [17 children and adolescents (six male), age 10·2 (5·3–18·4) years; 12 adults (eight male), age 54·5 (33–80) years]. All GHD subjects had a peak GH response of < 0·5 ng/ml in response to an insulin tolerance test and extremely reduced IGF‐1 levels (median 5·5 ng/ml). Data were compared between cohorts and with an age‐ and sex‐matched white American reference population.

results Abnormalities were confined to plasma total cholesterol (TC) and low‐density lipoprotein cholesterol (LDL‐C) levels. More GHD children had levels of plasma TC and LDL‐C above the 95th percentile for our reference population (3/8 and 4/7, respectively) compared to controls (0/17 and 1/15, respectively) (P < 0·05). In the adults, median TC and LDL‐C levels were higher in the GHD than controls (P < 0·05) (6·3 vs. 4·1 mmol/l; 4·4 vs. 2·7 mmol/l, respectively). Median Z‐scores, calculated using values from the reference population, were not different between GHD children and adults for both TC (+0·8 vs.+0·4) and LDL‐C (+1·4 vs.+0·7).

conclusions The lipid profile in children as well as in adults with very severe GHD is adversely modified. There would appear to be no significant worsening of the lipid abnormality with duration of GHD or achievement of adulthood.
Genetics of type 2 diabetes and insulin resistance: knowledge from human studies
Authors: McIntyre E. A. , Walker M.
Published: March 2003

Both type 2 diabetes mellitus (T2DM) and insulin resistance are complex traits in which multiple gene effects and metabolic and environmental factors combine to contribute to the overall pathogenesis of these conditions. This complexity has complicated the search for susceptibility genes and has led to different but complementary approaches being used for the detection of gene effects. These include the study of monogenic cases of insulin resistance and T2DM, association studies of candidate genes and genome‐wide scans. The peroxisome proliferator‐activated receptor gamma (PPARγ) and calpain‐10 (CAPN10) genes have recently been identified as T2DM susceptibility genes, and the lessons learnt from these studies are helping to shape future strategies to search for additional susceptibility genes in T2DM and insulin resistance.
Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism
Authors: Seifarth C. , Trenkel S. , Schobel H. , Hahn E. G. , Hensen J.
Published: March 2003

objective Antihypertensive drugs influence the neurohumoral cardiovascular system and the concentration of hormones involved in blood pressure regulation. Little is known, however, about the extent to which various antihypertensive drugs influence cardiovascular hormone concentrations and thus disturb the differential diagnosis of hypertension in clinical practice. In this study we compare the impact of different antihypertensive medicaments on the renin–angiotensin–aldosterone system in patients with essential hypertension who are screened for primary aldosteronism.

design and subjects We analysed serum aldoster‐one (SAC) and plasma renin concentration (PRC) in 37 normotensive controls, 144 hypertensive patients with essential hypertension, and 19 patients with primary aldosteronism. Patients were on different treatment regimens such as single drug or combination therapy with β‐blockers, angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II subtype 1 (AT1) receptor antagonists, calcium channel blockers, spironolactone and no treatment.

results In patients with essential hypertension, β‐blocker therapy (n = 47) led to a highly significant suppression of renin, whereas serum levels of aldosterone were not significantly altered. ACE inhibitors and AT1 receptor antagonists (n = 55) decreased aldosterone levels only to a minor extent. Calcium channel blockers (n = 23) had no significant influence on SAC or PRC. In patients with primary aldosteronism treated with spironolactone (n = 8), renin escaped suppression and reached very high levels.

conclusion β‐blockers and aldosterone antagonists have the strongest impact on the renin–angiotensin system. The decrease in renin concentration by β‐blockers leads to an increase in the ratio of aldosterone to renin, and thus to false‐positive results in patients with essential hypertension. Calcium channel blockers, and probably also ACE inhibitors and AT1 receptor antagonists alone or in combination, may be continued during screening for primary aldosteronism by determination of renin and aldosterone concentration.
A signal peptide mutation of the arginine vasopressin gene in monozygotic twins
Authors: Boson Wolfanga L. , Sarubi Juliana C. , D’Alva Catarina B. , Friedman Eitan , Faria Daniela , De Marco Luiz , Wajchenberg Bernardo
Published: March 2003

Familial neurohypophysial diabetes insipidus (FNDI) is a rare autosomal dominant syndrome stemming from the absence of arginine vasopressin (AVP). More than thirty‐five different germline mutations in the arginine vasopressin‐neurophysin II gene have been reported. These mutations are either in the signal peptide or scattered throughout the neurophysin II domain. A missense mutation altering alanine at position −1 to either valine or threonine in the signal peptide domain has previously been found in ten unrelated families. In the present report, Brazilian female monozygotic twins with clinically typical central DI in whom biochemical and molecular characterization were carried out are described. Direct mutational analysis by sequencing of the vasopressin gene in germline DNA revealed a heterozygous missense mutation (G→A) at nucleotide 279, predicting the substitution of alanine by threonine at position −1 of the signal peptide moiety. In summary, we present an extremely rare case of familial central diabetes insipidus in monozygotic Brazilian twins with a seemingly common missense mutation in the AVP gene.
Diagnosis of growth hormone deficiency after pituitary surgery: the combined acipimox/GH‐releasing hormone test
Authors: Van Dam P. Sytze , Dieguez Carlos , Cordido Fernando , De Vries Wouter R. , Veldhuyzen Bernard F. E. , Van Thiel E. , F. Casanueva Felipe , Koppeschaar Hans P. F.
Published: March 2003

objective Reduction of plasma free fatty acids leads to enhanced GH response after stimulation by GH‐releasing hormone (GHRH). We studied the clinical usefulness of combined administration of acipimox and GHRH for the diagnosis of GH deficiency.

design We evaluated 35 patients [mean age 53·0 years; mean body mass index (BMI) 26·7 kg/m2] after pituitary surgery. We compared GH responses after acipimox and GHRH with the GH response during an insulin tolerance test (ITT) and, in a subgroup of 12 patients, with the GHRH/arginine test. The acipimox/GHRH test was additionally performed in 21 control subjects (mean age 53·8 years; mean BMI 24·7 kg/m2).

results In the patients, the mean (± SEM) peak GH was almost four‐fold higher after acipimox/GHRH (6·94 ± 1·07 µg/l, range 0·46–23·1; P < 0·001) and after GHRH/arginine (8·32 ± 1·23 µg/l, range 1·1–49·2; P < 0·001) than after ITT (1·84 ± 0·46 µg/l, range 0·01–11·9). According to the ITT, 29 patients were severely GH deficient (peak GH < 3·0 µg/l). Peak GH levels after acipimox/GHRH in controls ranged from 7·5 to 78·4 µg/l (mean 29·3 ± 3·5). GH peak values during the acipimox/GHRH test were significantly correlated with values from the ITT (r = 0·63, P < 0·01) and GHRH/arginine test (r = 0·87, P < 0·001). Areas under the curve were also correlated. According to generally accepted cut‐off peak GH levels for the ITT and GHRH/arginine test, a GH peak exceeding 11·2 µg/l excludes severe GH deficiency after acipimox/GHRH. Our control data indicate that the cut‐off level is lower at older age.

conclusions The acipimox/GHRH test leads to GH responses similar to those of the GHRH/arginine test, and to higher peak GH values if compared with the ITT. The acipimox/GHRH test is a potential additional tool to detect GH deficiency in patients with pituitary disease, in particular in patients with a perturbation of fatty acid metabolism.