bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum LH concentrations in hypogonadal men during transdermal testosterone replacement through scrotal skin: further evidence that ageing enhances testosterone negative feedback
Authors: Winters Stephen J. , Atkinson Linda
Published: November 2003

OBJECTIVE

The present study was designed to explore further the mechanism for the decline in androgen production as men age by studying the influence of ageing on testosterone negative feedback control of gonadotrophin secretion.

DESIGN

Circulating testosterone, dihydrotestosterone, oestradiol, SHBG and LH concentrations were measured during long‐term treatment of men with primary hypogonadism using transdermal testosterone via scrotal skin.

PATIENTS

Results were compared in 12 hypogonadal men below age 40 years (34 ± 1.1 years; mean ± SEM), 13 middle‐aged men, aged 51 ± 2.2 years, and 10 men age 64 years or older (68 ± 1.4 years).

RESULTS

During the course of therapy, circulating LH levels were suppressed 48% (F = 2.42, P = 0.018) from 19.8 ± 6.0 IU/l at baseline to 10 ± 7.7 IU/l during month 15 in elderly men. By contrast, LH levels were unchanged (F = 0.31; P = 0.97) in young men (20.3 ± 7.4 IU/l at baseline and 17.7 ± 14.9 IU/l during treatment month 15). Intermediate results were observed in middle‐aged men in whom LH levels declined slightly (F = 1.34; P = 0.24). Transdermal testosterone treatment produced similar circulating testosterone levels (F = 1.49; P = 0.24) and oestradiol levels (F = 0.60; P = 0.42) in elderly and young men. Mean plasma DHT levels were approximately 20% higher (F = 9.91; P = 0.01) during treatment in elderly men (overall mean values of 8.03 ± 0.37 nmol/l) than in young men (6.68 ± 0.08 nmol/l). When total DHT was adjusted for higher plasma SHBG levels in elderly men, the free DHT index during treatment was similar (F = 0.23; P = 0.64) in both groups.

CONCLUSIONS

These data provide further evidence that the set point for androgen negative feedback control of gonadotrophin secretion in men is altered by ageing. Taken together with previous findings, these results provide a potential explanation for the unchanged or slightly increased plasma LH levels and reduced testosterone production characteristic of elderly men. Accordingly, ageing‐associated Leydig cell insufficiency leads to a decline in testosterone production, but circulating LH levels do not rise appropriately because the set‐point for negative feedback is decreased.
Mortality and morbidity in transsexual subjects treated with cross‐sex hormones
Authors: Van Kesteren Paul J. M. , Asscheman Henk , Megens Jos A. J. , Gooren Louis J. G.
Published: November 2003

OBJECTIVE

The optimum steroid hormone treatment regimes for transsexual subjects has not yet been established. We have investigated the mortality and morbidity figures in a large group of transsexual subjects receiving cross‐sex hormone treatment.

DESIGN

A retrospective, descriptive study in a university teaching hospital.

SUBJECTS

Eight hundred and sixteen male‐to‐female (M  →  F) and 293 female‐to‐male (F  →  M) transsexuals.

INTERVENTIONS

Subjects had been treated with cross‐sex hormones for a total of 10 152 patient‐years.

OUTCOME MEASURES

Standardized mortality and incidence ratios were calculated from the general Dutch population (age‐ and gender‐adjusted) and were also compared to side effects of cross‐sex hormones in transsexuals reported in the literature.

RESULTS

In both the M  →  F and F  →  M transsexuals, total mortality was not higher than in the general population and, largely, the observed mortality could not be related to hormone treatment. Venous thromboembolism was the major complication in M  →  F transsexuals treated with oral oestrogens and anti‐androgens, but fewer cases were observed since the introduction of transdermal oestradiol in the treatment of transsexuals over 40 years of age. No cases of breast carcinoma but one case of prostatic carcinoma were encountered in our population. No serious morbidity was observed which could be related to androgen treatment in the F  →  M transsexuals.

CONCLUSION

Mortality in male‐to‐female and female‐to‐male transsexuals is not increased during cross‐sex hormone treatment. Transdermal oestradiol administration is recommended in male‐to‐female transsexuals, particularly in the population over 40 years in whom a high incidence of venous thromboembolism was observed with oral oestrogens. It seems that in view of the deep psychological needs of transsexuals to undergo sex reassignment, our treatment schedule of cross‐sex hormone administration is acceptably safe.
Final height in non‐growth hormone deficient children treated with growth hormone
Authors: Bernasconi S. , Street M. E. , Volta C. , Mazzardo G. , The Italian Multicentre Study Group
Published: November 2003

OBJECTIVE

To evaluate the final height of non‐growth hormone deficient (N‐GHD) children treated with growth hormone (GH).

DESIGN

Multicentre retrospective study.

PATIENTS

71 (54M/17F) N‐GHD children (peak GH after pharmacological stimulation >14–24 mU/l) who had been treated for 4.19 ± 0.14 years with GH (0.69 ± 0.02 IU/kg/week).

MEASUREMENTS

Height (H) and height velocity (HV) expressed as standard deviation score (SDS) for chronological age (CA) and bone age (BA), BA/CA ratio, and predicted adult height (PAHSDS) were evaluated before and during treatment, and at each pubertal stage. Target height (TH), and final height (FH) were also calculated, and expressed as SDS.

RESULTS

In the whole group, HSDS for CA increased significantly after the first year on GH, and remained significantly increased for 4 years. This did not occur to HSDS for BA, owing to a significant increase in BA/CA after the first year of therapy. In addition, this increase coincided with stages 4 and 5 of puberty. HVSDS for CA and BA also increased significantly after the first year of treatment, and remained significantly elevated for 4 years. PAHSDS did not change significantly during treatment. FHSDS (−1.69 ± 0.07) was similar to PAHSDS (−1.6 ± 0.12) and target height (THSDS) (−1.46 ± 0.08). FHSDS was ≥THSDS in 36.6% of the patients, and ≥initial PAHSDS in 34.5%. Male patients were subdivided into 2 groups (A and B). Patients in Group A (n = 26) started treatment at puberty, while group B (n = 28) consisted of subjects who started therapy during prepubertal years. Height, height velocity and predicted adult height showed the same pattern as in the whole group, in each subgroup. BA/CA advanced significantly in group A after the second year on GH and in group B, after at least 3 years of therapy. FHSDS, THSDS, and PAHSDS were similar in both groups (−1.7 ± 0.13, −1.29 ± 0.2 and −1.39 ± 0.15 in group A and −1.48 ± 0.11, −1.85 ± 0.15 and −1.36 ± 0.12 in group B, respectively). However, in group B (prepubertal), FHSDS was ≥initial PAHSDS in 60% of the patients and ≥THSDS in 40.7%, while in group A (pubertal), FHSDS was ≥initial PAHSDS only in 22.7% of the patients and ≥THSDS in 34.6%. FHSDS was found to be correlated with THSDS, PAHSDS at the onset of treatment, and after 1 year of treatment. The age at the beginning of puberty, and the duration of puberty were appropriate in all groups.

CONCLUSIONS

GH treatment was effective in increasing height velocity of short non‐GH‐deficient children, but final height was not definitely improved with respect to initial predicted adult height.
Pituitary dysfunction in recently post‐menopausal women
Authors: Lyons Anthony , Ng Connie , Fielding Katherine , Hosking David , Selby Colin , Lawson Nigel ,   on behalf of the Nottingham EPIC Study Group
Published: November 2003

OBJECTIVE

Some recently post‐menopausal women have lower than expected FSH concentrations, raising the possibility of subclinical hypothalamo–pituitary impairment. We have therefore performed pituitary stimulation tests in a group of recently post‐menopausal women recruited to a bone loss prevention study.

DESIGN

Prospective study of health volunteers.

SETTING

Outpatient, teaching hospital in Nottingham UK.

SUBJECTS

Forty‐seven women selected from a cohort of 428 healthy volunteers to an osteoporosis prevention study all within 10 years of the menopause.

MAIN OUTCOME MEASURES

Response of the pituitary to formal stimulation tests and its relationship to bone mineral density.

RESULTS

A significantly attenuated response to pituitary stimulation was found in a group of otherwise healthy women with an FSH considered to be inappropriately low for the level of circulating oestradiol. The impaired responses were significant not only for FSH as expected but also to LH and prolactin at 1 hour after injection of GnRH and TRH (area under the curve, FSH P = 0.01, LH P = 0.001, prolactin P < 0.0001). TSH secretion was not significantly impaired. Baseline cortisol, growth hormone and thyroxine (T4) were normal in both control and test subjects. The test group was both heavier and taller, with a higher lean body mass, a higher body mass index and a greater total body fat than the controls. Bone mineral density showed no significant differences between the groups. Test subjects also had a higher free oestradiol index (P < 0.001) which correlated strongly (r = 0.534, P = 0.00026) with baseline FSH levels and possibly reflects a greater tissue exposure to biologically active hormone. Oestrone concentrations were, however, no different between the groups.

CONCLUSIONS

Serum FSH concentrations are not invariably elevated in recently post‐menopausal women and use of FSH as a determinant for post‐menopausal status in clinical trials should be used with caution. Notwithstanding their higher free oestradiol index, women found to have an abnormally low basal FSH had evidence of poor prolactin, FSH and LH but not TSH responses to pituitary stimulation. This may represent either a degree of subclinical pituitary failure or a variant of normal. The low levels of gonadotrophin activity did not affect bone mineral density.
Bone mineral density in Turner's syndrome—a longitudinal study
Authors: Shaw N. J. , Rehan V. K. , Husain S. , Marshall T. , Smith C. S.
Published: November 2003

OBJECTIVE

Osteoporosis is a recognized problem in adult women with Turner's syndrome, the aetiology of which is unclear. The aim of this study was to examine bone mineralization longitudinally in a group of girls with Turner's syndrome and to study the effect of different treatments on bone mineral density.

DESIGN

A prospective observational study.

PATIENTS

Eighteen girls with Turner's syndrome aged 4–17 years attending a paediatric endocrine clinic.

MEASUREMENTS

Bone mineral density of the lumbar spine was assessed using dual energy X‐ray absorptiometry at several time points over a 2.5‐year period.

RESULTS

Only one girl had evidence of a significant reduction in bone density when comparisons were made with control data related to body weight and pubertal status. No advantage was found for any form of treatment in optimizing bone mineralization.

CONCLUSIONS

As there is little evidence of reduced bone mineral density in girls with Turner's syndrome there is no justification for an early introduction of oestrogen replacement during the prepubertal years.
Urinary growth hormone: a screening test for growth hormone sufficiency
Authors: Butt Debra A. , Sochett Etienne B.
Published: November 2003

OBJECTIVES

The majority of short statured children referred for serum GH testing prove to be GH sufficient. The purpose of our study was to evaluate urinary growth hormone (uGH) as a screening test for GH sufficiency.

PATIENTS

We studied (i) short statured children previously diagnosed as GH sufficient (n = 44) or GH deficient (n = 41) (peak serum GH ≥8 μg/l or <8 μg/l, respectively); (ii) short children undergoing serum GH stimulation tests (n = 23, test group); (iii) normal statured children (n = 45, control group).

DESIGN

Three separate overnight urine collections were obtained in all groups. GH injections in GH deficient subjects were discontinued 4 days prior to urine collection.

MEASUREMENTS

uGH concentrations were measured using a chemiluminescence immunoassay. Overnight uGH was expressed in several ways (overnight excretion and overnight excretion corrected for body surface area, time and creatinine). Receiver operator curves (ROC) were constructed from the data obtained in the GH sufficient and deficient subjects. Sensitivity and specificity were then determined for various urinary cut‐offs. These cutoffs were validated in turn in the test group by comparison of the predicted with the observed GH status.

RESULTS

The GH deficient group had the lowest GH output with respect to overnight uGH, overnight uGH/m2, overnight uGH/h and overnight uGH/creatinine when compared with the GH sufficient and control groups (P = 0.0001). Overnight uGH/m2 data gave the greatest area under the ROC curve. At 100% specificity (no GH deficient subjects), it had the highest sensitivity, 63.6% (49.2–78.0% CI) at a cut‐off of 2.3 ng/m2 (63.6% of GH sufficient subjects had uGH levels >2.3 ng/m2). When this and other cut‐offs were applied to the test group, we found consistency between the observed and predicted numbers of GH sufficient and deficient subjects.

CONCLUSIONS

We conclude that urinary GH is a useful test for the diagnosis of GH sufficiency as defined by serum criteria and can be used to reduce significantly the number of serum stimulation tests.
Anti‐GAD65 autoantibody in Taiwanese patients with insulin‐dependent diabetes mellitus: effect of HLA on anti‐GAD65 positivity and clinical characteristics
Authors: Chuang Lee‐Ming , Lin Chun‐Yin , Wu Huey‐Peir , Tsai Wen‐Yu , Tai Tong‐Yuan , Lin Boniface J.
Published: November 2003

OBJECTIVE

Anti‐GAD65 antibody has been studied widely in patients with insulin‐dependent diabetes mellitus (IDDM) in many different populations. However, the prevalence of GAD65 autoantibody has not been assessed in Taiwanese patients with IDDM. We therefore characterized GAD65 antibody and investigated the effect of HLA‐DR phenotypes on GAD65 autoimmunity and other clinical characteristics in Taiwanese subjects with IDDM.

SUBJECTS AND MEASUREMENTS

Two hundred and twenty‐five patients (male 102, female 123) with IDDM were recruited. The diagnostic criteria for IDDM were age of onset before 30 years, presence of diabetic ketoacidosis, and insulin‐dependency within 3 years of onset. We employed a radioligand method to detect GAD65 antibody. HLA‐DR typing was performed by the PCR‐SSO techniques. Plasma C‐peptide and antithyroid microsomal antibody were also measured.

RESULTS

The prevalence of GAD65 antibody according to duration of disease were 50/91 (54.9%), 37/95 (38.9%), 8/24 (33%), and 3/15 (20%) among the groups of duration ≤5, 6–10, 11–15, and >15 years, respectively (p = 0.0011). There were no significant differences between GAD(+) and GAD(−) patients in age of onset (11.5 ± 6.5 and 11.6 ± 13.4 years, respectively), gender distribution (male:female 39:59 and 58:69, respectively) and percentage with residual β cell function (38.8% and 29.1%, respectively). Multiple regression analysis revealed that duration of IDDM correlated inversely with residual β cell function. Earlier onset of IDDM correlated with a loss of β cell function and a HLA‐DR phenotype containing DR3/4, DR3/3 or DR3/9.

CONCLUSIONS

Prevalence of GAD65 autoantibody among Taiwanese subjects with IDDM was negatively correlated with duration of disease. Different determinants in the HLA‐DR locus contributed to the clinical onset of IDDM but not to GAD autoimmunity.
Abnormal melatonin secretion in hypogonadal men: the effect of testosterone treatment
Authors: Luboshitzky Rafael , Wagner Oded , Lavi Shachar , Herer Paula , Lavie Peretz
Published: November 2003

OBJECTIVE

We have recently demonstrated that GnRH deficient male patients have increased nocturnal melatonin secretion, whereas hypergonadotrophic hypogonadal males have decreased melatonin levels. We were interested in determining whether testosterone (T) treatment (when T levels were well matched with pubertal control values) has an effect on melatonin secretory profiles in these patients.

DESIGN

Prospective, controlled.

SUBJECTS

Six male patients with idiopathic hypogonadotrophic hypogonadism (IGD), six males with hypergonadotrophic hypogonadism due to Klinefelter's syndrome (KS) and seven controls. Patients were examined before and during the administration of 250 mg testosterone enanthate/month for four months.

MEASUREMENTS

Serum samples for melatonin levels were obtained every 15 minutes from 1900 to 0700 h in a controlled light‐dark environment. The results of FSH, LH, T and oestradiol (E2) (determined at hourly intervals) and melatonin profiles, were compared with the pre‐treatment values in each group, and with values obtained in the control group.

RESULTS

All 12 patients had low pre‐treatment T levels (1.4 ± 0.7 in IGD and 2.0 ± 0.4 in KS vs. 19.8 ±  2.3 nmol/l in controls) and attained normal levels after four months of T treatment (19.5 ± 7 in IGD and 22.7 ±  3.8 nmol/l in KS). Serum LH, FSH and E2 levels (11 ± 4 IU/l, 24 ± 10 IU/l and 113 ± 12 pmol/l, respectively) were still elevated in KS during T treatment as compared with values in controls (2 ± 1 IU/l, 2 ± 1 IU/l and 67 ± 4 pmol/l, respectively). In IGD, serum LH (0.12 ± 0.1 IU/l) and FSH (0.16 ± 0.2 IU/l) levels during T treatment were suppressed. Pretreatment melatonin levels in IGD were greater than those in age‐matched pubertal controls while in KS, melatonin levels were lower than values in controls. Melatonin levels were equal in all 12 hypogonadal patients and controls when T levels were well matched. Mean (±SD) dark‐time melatonin levels decreased from 286 ± 18 to 157 ± 26 pmol/l in IGD and increased from 92 ± 19 to 183 ± 48 pmol/l in KS (vs 178 ± 59 pmol/l in controls). The integrated melatonin values decreased in IGD (from 184 ± 14 to 102 ± 21 pmol/min. l × 103) and increased in KS (from 64 ± 13 to 123 ± 40, vs. 116 ± 39 pmol/min. l × 103 in controls). No correlations were found between melatonin and LH, FSH or E2 levels.

CONCLUSIONS

These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion while in hypergonadotrophic hypogonadal males melatonin secretion is decreased. Testosterone treatment normalized melatonin concentrations in these patients. Taken together, the results suggest that GnRH, gonadotrophins and gonadal steroids modulate pineal melatonin in humans.
Adrenocorticotrophin‐independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide
Authors: Iida Keiji , Kaji Hidesuke , Matsumoto Hidenari , Okimura Yasuhiko , Abe Hiromi , Fujisawa Masato , Kamidono Sadao , Chihara Kazuo
Published: November 2003

The aetiology of ACTH‐independent macronodular adrenal hyperplasia (AIMAH) is uncertain. We examined a 55 year old man with Cushing's syndrome due to AIMAH, whose cortisol levels increased after stimulation with lysine‐8‐vasopressin (LVP) in vitro as well as in vivo. Abdominal MRI revealed nodular enlargement of both adrenal glands. No adenoma was evident on pituitary MRI. 131I‐adosterol scintigraphy exhibited marked uptake into both adrenal glands. Although baseline plasma cortisol levels were within normal limits, urinary free cortisol excretion was 3‐fold higher than the upper limit of the normal range. Plasma ACTH levels were undetectable. Oral dexamethasone failed to suppress plasma cortisol levels irrespective of dose, and administration of corticotrophin releasing hormone failed to increase plasma ACTH and cortisol levels. LVP injection failed to increase plasma ACTH levels, but elicited an increase in plasma cortisol levels. The direct stimulatory effect of LVP on cortisol secretion was confirmed in vitro in cultured adrenocortical cells from macronodules obtained at surgery. Food intake, gastric inhibitory polypeptide (GIP), or octreotide administration, which were reported to regulate cortisol release in patients with AIMAH, failed to affect plasma cortisol levels. In conclusion, plasma cortisol responsiveness to LVP, GIP, and octreotide is heterogeneous in patients with AIMAH.
Sertoli–Leydig cell tumour complicated by X chromosomal mosaicism
Authors: Hitosugi Masahito , Matsuoka Yasuo , Irimajiri Shoichiro , Fukuda Junya
Published: November 2003

We describe a case of well‐differentiated Sertoli–Leydig cell tumour (SLCT) of the ovary. A 48‐year‐old Japanese woman had had symptoms of virilization, i.e. alopecia and facial hair, for 8 years. Although the patient had given birth to three normal children, laboratory investigations revealed an elevated serum level of free testosterone and tripartite mosaicism (45X/46XX/47XXX). Computed tomography and magnetic resonance imaging revealed a tumour of the left ovary. After oophorectomy, the serum level of free testosterone returned to the normal range and symptoms of virilization resolved. To our knowledge, this is the first reported case of a patient with SLCT who had tripartite mosaicism and had given birth to normal children. Although the aetiology of SLCT is not known, we believe that SLCT is associated with sex chromosomal abnormalities at least in some cases.
Absence of mutations in exon 3 of the GnRH receptor in human gonadotroph adenomas
Authors: Kaye P. V. , Hapgood J. , Millar R. P.
Published: November 2003

BACKGROUND AND OBJECTIVE

The mechanisms of tumourogenesis for the majority of pituitary tumours are unknown. Mutations of G‐protein coupled receptors (GPCRs) have recently been described as important in diverse human diseases, including thyroid adenomas. To test this hypothesis in pituitary gonadotroph adenomas, we amplified and sequenced the GnRH receptor gene in 12 human tumours. We restricted our analysis to the third exon, since this represents the hotspot for activating mutations in other GPCRs.

PATIENTS

Pituitary adenoma tissue was identified from patients who had tumours resected and where a diagnosis of gonadotroph adenoma had been made on the basis of immunohistochemical demonstration of LH and/or FSH.

METHODS

Genomic DNA was extracted from paraffin‐embedded tissue of 18 gonadotroph adenomas. The third exon was successfully amplified by PCR in 12 cases and directly sequenced.

RESULTS

We found no missense point mutations or even silent polymorphisms in any tumour studied.

CONCLUSION

We conclude that activating mutations of the GnRH receptor gene do not represent an important mechanism of pituitary gonadotroph tumourogenesis.
The effect of an intravenous infusion of IGF‐I and insulin on IGFBP‐1, IGFBP‐3, acid labile subunit, free and bound IGF‐I, catecholamines and potassium in normal volunteers during an amino acid and glucose clamp
Authors: Russell‐Jones D. L. , Umpleby A. M. , Shojaee‐Moradie F. , Boroujerdi M. A. , Jones R. H. , Baxter R. C. , Sönksen P. H.
Published: November 2003

OBJECTIVES

To investigate the effects of IGF‐I and insulin at doses equipotent with respect to hypoglycaemic effect on IGF‐I concentrations (free and bound), IGF binding proteins, catecholamines and potassium levels.

DESIGN

A glucose and amino acid clamp technique was used to investigate the effects of a 3 h intravenous infusion of either IGF‐I 43.7 pmol/kg/min (20 μg/kg/ h) or insulin 3.4 pmol/kg/min (0.5 mU/kg/min).

MEASUREMENTS

Circulating levels of total IGF‐I, free and bound IGF‐I, insulin, IGFBP‐1, IGFBP‐3, ALS, catecholamines and potassium were measured.

PATIENTS

6 normal human volunteers aged 21–49.

RESULTS

During the IGF‐I infusion, IGF‐I levels increased (P < 0.01) (26.6 ± 2.8–88.9 ± 14.2 nmol/l) and insulin levels fell (P < 0.05) (16.7 ± 2.9–7.2 ± 1.6 mu/l). During the insulin infusion, insulin levels increased (P < 0.01) (11.7 ± 1.6–56.7 ± 16 mu/l) and there was no change in IGF‐I. There was no significant change in IGFBP‐3 or ALS during the IGF‐I or insulin infusions. There was a significant (P < 0.05) fall in IGFBP‐1 levels from 27.1 ± 4.1–8.06 ± 1.6 μg/l during the insulin infusion and a significant (P < 0.05) rise during the first 120 min of IGF‐I infusion from 28.6 ± 6.3–67.9 ± 10.6 μg/l. There was a significant (P < 0.05) increase in free IGF‐I and IGF‐I bound to the 150 and 50 kD plasma fractions during the IGF‐I infusion. At basal and the end of the IGF‐I infusion adrenaline levels (pmol/l) were: 173 ± 22 and 174 ± 28; dopamine levels (pmol/l) were: 415 ± 87 and 470 ± 87; plasma potassium (mmol/l) was 4.2 ± 0.06 and 3.56 ± 0.13. At basal and the end of the insulin infusion adrenaline levels (pmol/l) were: 160 ± 38 and 163 ± 21; dopamine levels (pmol/l) were: 238 ± 26 and 316 ± 31; plasma potassium (mmol/l) was 4.2 ± 0.07 and 3.92 ± 0.17. There were no significant changes in plasma catecholamine concentrations with either infusion but potassium concentrations were significantly (P < 0.05) reduced during the IGF‐I infusion.

CONCLUSIONS

We conclude that an infusion of IGF‐I resulted in increased levels of both free and bound IGF‐I. IGF‐I and insulin under conditions of adequate substrate supply have acute effects on IGFBP‐1 and potassium physiology, but have little effect on IGFBP‐3, ALS or catecholamines.
Prospective study of bone loss in pre‐ and post‐menopausal women on L‐thyroxine therapy for non‐toxic goitre
Authors: De Rosa Giovina , Testa Americo , Giacomini Denise , Carrozza Cinzia , Astazi Pietro , Caradonna Paolo
Published: November 2003

OBJECTIVE

Hyperthyroidism is associated with increased bone turnover and bone resorption, but the effects of suppressive doses of thyroxine in treating non‐toxic goitre remain unclear. We carried out a longitudinal study to evaluate the effect on bone of L‐thyroxine (L‐T4) therapy in women with non‐toxic goitre.

SUBJECTS

Forty Caucasian women, 19 of whom were pre‐menopausal and 21 post‐menopausal, were studied before and after 12 months' L‐T4 therapy for non‐toxic goitre; 40 women matched for age, body mass index and menopausal status were used as controls.

DESIGN

The minimal dosage of L‐T4 (mean ± standard error = 1.5 ± 0.1 μg/kg−1 day−1) was given to each patient to obtain subnormal but detectable serum TSH (≤ 0.2 mU/l). Patients and controls were assessed for minor determinants of bone loss rate, such as genetic and behavioural factors.

MEASUREMENTS

Bone mineral density (BMD) of the lumbar spine, femoral neck, trochanter and Ward's triangle was measured by dual‐energy X‐ray absorptiometry at baseline and 12 months; serum and urine markers of bone turnover was measured at baseline, 3, 6 and 12 months.

RESULTS

No significant difference was detected in BMD values between patients and controls either at presentation or at the 12‐month follow‐up. Pre‐menopausal patients showed a significant decrease in femoral neck BMD (−1.7 ± 0.6%, P < 0.05) while controls showed no change + 0.2 ± 0.9%, P = NS). Post‐menopausal patients showed a significant decrease in BMD of the lumbar spine (−1.3 ± 0.6%, P < 0.05; controls + 0.0 ± 0.4%, P = NS), femoral neck (−1.5 ± 0.6%, P < 0.05; controls −1.2 ± 0.8%, P = NS) and trochanter (−2.1 ± 0.8%, P < 0.05; controls −1.4 ± 0.9%, P = NS). In both pre‐ and post‐menopausal patients the serum markers of bone turnover, alkaline phosphatase and osteocalcin, showed an early and progressive increase. A linear relationship was found only between the 3‐month values of serum osteocalcin and the urine hydroxyproline/creatinine ratio in both pre‐menopausal (r = 0.87, P < 0.01) and post‐menopausal (r = 0.72, P < 0.05) patients. No correlation was found between bone loss or changes in bone turnover markers and L‐T4 dose or thyroid hormone levels.

CONCLUSION

This longitudinal study suggests that TSH‐suppressive therapy with L‐thyroxine for non‐toxic goitre significantly increases the bone mineral turnover and might contribute to a BMD reduction, more marked on cortical bone, in both pre‐ and post‐menopausal women.
Acute effects of intravenous amiodarone on sulphate metabolites of thyroid hormones in arrhythmic patients
Authors: Iervasi Giorgio , Clerico Aldo , Manfredi Cristina , Sabatino Laura , Biagini Andrea , Chopra Inder J.
Published: November 2003

OBJECTIVES

Factors that contribute to the remarkably rapid decrease in serum T3 and increase in reverse T3 (rT3) levels during illness, fasting, or treatment with some drugs (e.g. amiodarone) are not clear. In order to understand better the effect of acute amiodarone administration on T3 metabolism, especially the sulphation pathway, we performed a prospective study in 8 arrhythmic in‐patients treated with a loading dose of amiodarone.

DESIGN

Amiodarone was administered by i.v. infusion of 20 mg/kg/day on day 1 and 10 mg/kg/day on day 2, followed by 600 mg/day orally throughout the study. Two serum samples for amiodarone and hormone assays (thyroid hormones, TSH, and the sulphate metabolites of 3′‐T1, 3,3′‐T2, and T3) were collected before the start of therapy, every 12 h during the first 3 days of amiodarone administration, and then once a day for 2–10 days.

SUBJECTS

Eight patients (4 men and 4 women, aged 44–82 years), who were treated with amiodarone because of cardiac dysrhythmia, were enrolled in the study.

RESULTS

Serum concentrations of total T4 significantly increased in the last 3 days of the study (anova, P = 0.0002). However, serum total T3 progressively and significantly decreased throughout the study (anova, P < 0.0001). Serum free thyroid hormone concentrations (freeT3 and freeT4) did not significantly change during the study. Serum rT3 (anova, P < 0.0001) and TSH (anova, P = 0.0009) rapidly and progressively increased throughout the study. Starting from the first 24 h, serum concentrations of T3 sulphate (T3‐S) significantly and progressively increased from (mean ± SD) 0.057 ± 0.029 nmol/l under basal conditions to 0.089 ± 0.036 nmol/l after 5 days of amiodarone therapy (anova, P = 0.0011). Since total T3 levels progressively decreased throughout the study, the ratio of the T3‐S and total T3 values progressively increased from 4.8 ± 2.7% under basal conditions to 10.6 ± 7.3% after 5 days of amiodarone therapy (anova, repeated measures, P < 0.0001). Basal serum concentrations of sulphate metabolites of T2 (T2‐S, 2.22 ± 1.7 nmol/l) and T1 (T1‐S, 1.29 ± 0.74 nmol/l) did not significantly change throughout the study.

CONCLUSIONS

Our data indicate that a loading dose of intravenous amiodarone in patients with cardiac dysrhythmias is followed by a very rapid and progressive increase in circulating T3‐S levels, possibly due to an inhibition of type 1‐iodothyronine de‐iodinase. Since T2‐S and T1‐S, common final metabolites of the thyroid hormone sulphation pathways remained unchanged, our data suggest that the total amount of thyroid hormone degraded by sulphation pathways remains unaltered during amiodarone treatment. Finally our findings are compatible with the view that sulphation represents an important pathway for T3 metabolism in vivo in man.
Increase in haemoglobin concentrations in growth hormone deficient adults during human recombinant growth hormone replacement therapy
Authors: Ten Have S. M. T. H. , Van Der Lely A. J. , Lamberts S. W. J.
Published: November 2003

OBJECTIVE

Recombinant human growth hormone is being used increasingly in the treatment of GH deficiency in adults. In addition to erythropoietin, insulin‐like growth factor‐I (IGF‐I) has been demonstrated to stimulate hematopoiesis in animals, especially rodents. We have determined the effect of growth hormone (GH) administration on haematopoiesis.

PATIENTS AND DESIGN

Seventeen patients (10 males and 7 females; mean age 47 ± 2 years; range 30–59) with biochemically proven adult‐onset GH deficiency (GHD) were treated with human recombinant growth hormone (rhGH) as replacement therapy for more than 96 weeks in a dosage of 12.5 μg/kg/day (initial dosage during the first 4 weeks 6.25 μg/kg/day). The diagnosis of GHD had been confirmed using a standard arginine‐infusion test (0.5 g/kg body weight). Blood samples were collected for safety and efficacy parameters before and during the GH treatment period.

MEASUREMENTS

Routine methods were used for the haematological and biochemical measurements. IGF‐I concentrations were measured, using a commercial RIA kit.

RESULTS

From week 36 and onwards, we observed a significant increase in individual haemoglobin (Hb) concentrations, especially in the male patients. Mean Hb in the male patients before treatment amounted to 9.1 ± 0.2 mmol/l (range 8.1–10.5) and increased by 0.93 ± 0.2 mmol/l (P < 0.05) after 120 weeks of rhGH replacement therapy. The mean Hb concentration in female patients before treatment was 8.1 ± 0.1 mmol/l and an increase of 0.32 ± 0.1 mmol/l (P < 0.05) was observed after 120 weeks. For all 17 patients the mean increase in Hb after 120 weeks was 0.73 ± 0.2 mmol/l (P < 0.05). IGF‐I concentrations also increased during therapy from 86 ± 9 pg/l to 253 ± 26 pg/l within 24 weeks (P < 0.05). No significant changes in leucocyte or platelet counts were found.

CONCLUSIONS

Long‐term replacement therapy with rhGH in patients with adult‐onset GHD induces a significant increase in Hb concentrations, while serum leucocyte and platelet counts do not change.
Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel‐Lindau and RET genes
Authors: Bar Merav , Friedman Eitan , Jakobovitz Orit , Leibowitz Gil , Lerer Israela , Abeliovich Dvorah , Gross David J.
Published: November 2003

OBJECTIVE

von Hippel‐Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2) are autosomal dominant cancer syndromes. In both conditions, phaeochromocytoma is a prominent feature. It has recently been suggested that phaeochromocytoma can be the presenting and sole clinical manifestation of these multi–organ syndromes. The aim of this study was to ascertain the incidence of VHL and MEN2 among patients with sporadic phaeochromocytoma by mutational analysis.

PATIENTS

Twenty‐seven unrelated patients with biochemically and/or anatomically proven sporadic phaeochromocytoma were evaluated.

DESIGN AND MEASUREMENTS

Constitutional DNA obtained from the patients was analysed by single stranded conformational analysis (SSCP) for mutations within the VHL gene coding sequence and by denaturing gradient gel electrophoresis (DGGE) for predominant mutations in exons 10, 11 and 16 of the RET proto‐oncogene. The incidence of patients positive for either VHL or RET germline mutations was assessed.

RESULTS

Twenty‐six of 27 patients had normal SSCP patterns in all three VHL gene exon segments and only one patient, with an atypical clinical presentation, had an aberrant pattern in exon 3 which upon DNA sequencing was shown to harbor a G to A transversion mutation at nucleotide 695. All patients had normal RET exon 10, 11 and 16 DGGE migration patterns.

CONCLUSION

Most, if not all, patients with typical unilateral sporadic phaeochromocytoma do not have von Hippel‐Lindau disease or MEN2. Thus, clinical and/or molecular investigation for von Hippel‐Lindau disease and MEN2 in this patient population does not appear to be indicated.
Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults
Authors: Johannsson Gudmundur , Rosén Thord , Bengtsson Bengt‐Åke
Published: November 2003

OBJECTIVE

Until now, GH treatment in GH‐deficient adults has employed dose schedules of GH based on body weight or body surface area and has ignored individual responsiveness to GH. This trial has studied the effects of an individualized GH dose adjusted to match a combination of clinical response, normalization of serum IGF‐I concentration and body composition.

DESIGN AND PATIENTS

Two closely‐matched groups, each comprising 30 GH‐deficient adults, 38 men and 22 women aged 48 years, were treated with GH for 12 months. The high dose (HD) group received a target dose of 12 μg/kg per day and the individualized dose (ID) group received an initial daily GH dose of 0.17 or 0.33 mg per day (0.5 and 1 IU, respectively), independent of body weight, with dose adjustments thereafter.

MEASUREMENTS

Serum concentrations of IGF‐I, lipoprotein(a), insulin, calcium, intact PTH, osteocalcin and blood glucose were measured. Body composition was determined according to a 4‐compartment model using total body potassium and tritiated water as input variables. Total body nitrogen was measured by in vivo neutron activation and total body bone mineral content by dual energy X‐ray absorptiometry.

RESULTS

At 12 months, the daily dose of GH was 0.55 ± 0.03 mg and 0.45 ± 0.03 mg in the HD and ID groups, respectively (P < 0.05). In the HD group, the mean serum IGF‐I increased to levels well above the predicted level, while in the ID group the mean serum IGF‐I normalized. Side‐effects were experienced by 70% of the subjects in the HD group and by 30% in the ID group (P < 0.001). A similar response to GH in terms of body composition, glucose homeostasis, lipoprotein(a) and blood pressure was obtained in both treatment groups. However, the treatment response in terms of serum calcium, intact PTH and osteocalcin was more marked in the HD group.

CONCLUSIONS

Similar efficacy, with a lower dose of GH and fewer side‐effects, was obtained by considering individual responsiveness to GH as compared to higher doses of GH adjusted to match body weight.
The role of radioactive iodine in the treatment of advanced differentiated thyroid carcinoma
Authors: Pelikan D. M. V. , Lion H. L. , Hermans J. , Goslings B. M.
Published: November 2003

OBJECTIVE

131I therapy may be beneficial for patients with advanced differentiated thyroid cancer (DTC) but there have been relatively few studies of the prognostic factors which influence the outcome. We have evaluated differences in outcome in relation to histology, localization of tumour, differentiation grade, age and sex after 131I as the only secondary treatment for advanced stages of DTC.

DESIGN

Retrospective study of a selected patient group treated according to a fixed protocol.

PATIENTS

We studied the outcome in 86 patients with stage pN3, pT4 or pM1 out of total of 432 patients treated for DTC from 1970 until 1991.

RESULTS

The overall cure rate of 131I therapy after a mean follow‐up of 12.1 years was 50% (papillary 65% vs follicular 23%). The overall 5‐year progression free survival (PFSR) was 66%. Three out of 11 patients with bone metastases from follicular cancer were cured after a mean dose of 13.2 GBq, significantly less than the average dose of 28.4 GBq given to all patients with bone metastases. In the univariate analysis of 5‐year PFSR histology (papillary 79% vs follicular 43%), differentiation grade (well differentiated 81% and moderately differentiated 31%), tumour stage (pN3100%, pT4 77% and M1 48%), and age (≤ 60 years 85% vs > 60 years 46%) were significant prognostic factors. A multivariate analysis showed differentiation grade, histology and age to be significant prognostic variables for outcome (moderately vs well differentiated: RR = 3.16, follicular vs.papillary: RR = 2.56 and age > 60 vs age ≤ 60: RR = 2.43).

CONCLUSIONS

131I can be an effective treatment in patients with advanced differentiated thyroid cancer at all sites and can cure, on average, 50% of all patients with advanced differentiated thyroid cancer.
Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types
Authors: Corbetta Sabrina , Pizzocaro Alessandro , Peracchi Maddalena , Beck‐Peccoz Paolo , Faglia Giovanni , Spada Anna
Published: November 2003

OBJECTIVE

We have investigated the prevalence of MEN 1 in patients with recognized pituitary adenomas. Since hyperparathyroidism is present in nearly 95–100% of patients with MEN 1 and frequently is the first condition to be identified, the study was limited to the identification of patients with hyperparathyroidism while the screening for gastroenteropancreatic (GEP) lesions was carried out in patients with both pituitary and parathyroid lesions.

PATIENTS AND MEASUREMENTS

Serum total and ionized calcium, phosphate and intact PTH 1‐84 (EASIA) were measured in 166 patients (68 with non‐functioning pituitary adenoma, 42 with prolactinoma, 35 with GH‐secreting adenoma, 17‐with ACTH‐screening adenoma, 1 with TSH‐secreting adenoma, 1 with FSH‐secreting adenoma and 2 with an only α‐subunit secreting adenoma) referred to our clinic from 1990 to 1996. Plasma gastrin, somatostatin, pancreatic polypeptide and vasoactive intestinal peptide were measured by RIA in patients with hyperparathyroidism.

RESULTS

Eight of 166 patients (4.8%) were found to have primary hyperparathyroidism and among these 2 also had a gastrinoma while there was no evidence of other GEP tumours. Considering the tumour type, 6 had prolactinoma (14.3%), 1 GH‐secreting adenoma (2.8%) and 1 non‐functioning adenoma (1.5%). In most patients the diagnosis of pituitary tumour was made several years before that of hyperparathyroidism (from 1 to 15 years) although 6 patients had previously suffered from urolithiasis and one had undergone gastric resections for recurrent peptic ulcers. One patient was identified as a MEN 1 gene carrier and 2 had relatives with signs and symptoms referable to parathyroid or GEP lesions.

CONCLUSIONS

The study shows a prevalence of 4.8% of primary hyperparathyroidism in unselected patients with known pituitary tumours similar to that reported in a previous study. By contrast, the prevalence of MEN 1 in patients with prolactinoma was definitely high (14.3%). In most patients the diagnosis of pituitary tumours was made several years before that of hyperparathyroidism. Although the patients were believed to harbour a sporadic pituitary tumour, most of them had had signs and/or symptoms referable to one or both of the other organs involved in MEN 1, often concomitantly with those of pituitary tumours. These data indicate that the diagnosis of MEN 1 syndrome is missed in a substantial proportion of patients with prolactinomas and therefore the screening of these patients for the syndrome is strongly recommended.
Lower cortisol levels after oral glucose in subjects with insulin resistance and abdominal obesity
Authors: Fernández‐Real José‐Manuel , Ricart Wifredo , Casamitjana Roser
Published: November 2003

BACKGROUND

It has been shown previously that morning cortisol levels decline after oral glucose, but no report has been published regarding the changes in serum cortisol in relation to insulin sensitivity or degree of obesity.

SUBJECTS AND DESIGN

We studied the effects of oral glucose during a standard oral glucose tolerance test on cortisol levels in 7 obese subjects (body mass index (BMI) 29.7 ± 3.3 kg/m2) and in 8 control subjects (BMI 24.9 ± 3.2 kg/m2). Cortisol concentrations were normalized to time 0 because of wide between subject variation. On another day, a frequently sampled intravenous glucose tolerance test with minimal model analysis was performed, obtaining the insulin sensitivity index (SI). Anthropometric measurements included different skinfolds and bioelectric impedance.

RESULTS

The waist‐to‐hip ratio (WHR) was similar between the 2 groups, but abdominal skinfold was significantly higher in the obese group (OG) (158.8 ± 42.9 vs. 113.6 ± 27.7,P = 0.03). Fat mass, percentage of fat mass, triceps and subscapular skinfolds, systolic and diastolic blood pressure, VLDL‐cholesterol, total triglycerides and VLDL‐triglycerides were slightly higher in the obese group (OG). Area under the curve for glucose (AUCg) after OGTT was also significantly higher in OG (9.9 ± 2.4 vs. 7.1 ± 0.5 mmol/l, P = 0.02) in contrast to area under the curve for insulin (102 ± 60 vs. 73.8 ± 26.7 mU/l, P = NS), or glucose effectiveness (0.015 ± 0.004 vs. 0.015 ± 0.009 min−1, P = NS). Subjects with the highest WHR of both groups exhibited a greater cortisol suppression (56 ± 0.09 vs. 41 ± 0.17, P = 0.05). Normalized serum cortisol after OGTT was significantly lower from minute 60 to 120 in the OG (P = 0.001, 0.003 and 0.01 at 60, 90 and 120 minutes, respectively). The maximal cortisol suppression was 59.2% in the OG in comparison with 43% in the control group (P = 0.027). This maximal cortisol suppression correlated weakly with the maximal insulin response after oral glucose (r = 0.49, P = 0.07). In a multiple linear regression analysis, with maximal cortisol suppression as dependent variable, both BMI (P = 0.03) and SI (0.02) contributed to the variance of maximal cortisol suppression (R2 = 0.40).

CONCLUSION

We show that differences in cortisol decline are at least partially attributed to differences in insulin sensitivity and to differences in abdominal fat. This abdominal‐related decrease of cortisol might support the concept that the increased visceral adipose tissue mass with a high density of glucocorticoid receptors enhances the metabolism of cortisol. Perhaps the subjects with higher abdominal fat or insulin resistance are prone to lower cortisol levels after carbohydrate‐rich intakes in the morning. These lower cortisol levels, behaving as a positive feed‐back signal, might generate higher ACTH and cortisol responses after protein‐rich meals at mid‐day.
Metastatic parathyroid carcinoma in the MEN2A syndrome
Authors: Jenkins P. J. , Satta M. A. , Simmgen M. , Drake W. M. , Williamson C. , Lowe D. G. , Britton K. , Chew S. L. , Thakker R. V. , Besser G. M.
Published: November 2003

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.
Regionalization of occult pancreatic insulinomas with the arterial stimulation venous sampling (ASVS) technique
Authors: Tsagarakis S. , Kaskarelis J. , Malagari C. , Platis O. , Trivizas P. , Vrachliotis G. , Thalassinos N.
Published: November 2003

Non‐invasive modalities (ultrasound, computerized tomography, MRI and somatostatin receptor scintigraphy) often fail to localize insulinomas smaller than 1.5 cm in diameter. Recently, regionalization of such occult insulinomas was facilitated by the arterial stimulation and venous sampling (ASVS) technique, using calcium as the insulin secretagogue. However, so far experience with this technique has been limited to a few tertiary referrals centres worldwide. In these case studies we report our experience in three consecutive patients with occult insulinomas.

Three consecutive patients (all men 34, 51 and 56 years of age) with insulin‐mediated hypoglycaemia were studied. Diagnosis of insulin hypersection was established by the finding of a high amended insulin : blood sugar ratio during fasting. Localization of a pancreatic mass lesion was unsuccessful by ultrasound, CT and/or MRI in all patients. Two patients had negative octreotide scans. In all patients after the infusion of calcium sequentially into the gastroduodenal, splenic and the superior mesenteric arteries, insulin levels rose significantly in right hepatic vein samples giving rise to diagnostic gradients from the splenic artery (in 2 patients) and gastroduodenal artery (in 1 patient), regionalizing insulinomas in the tail and head or neck of the pancreas respectively. The simultaneously obtained angiogram was positive in only 1 patient, in whom it corresponded to the insulin gradient. Regionalization of these occult tumours was subsequently confirmed at laparoscopy in the 2 patients operated.

It is concluded, that the arterial stimulation venous sampling technique is an effective method in regionalizing occult insulinomas and should complement invasive angiography whenever the latter procedure is performed.