bluuebunny/crossref_metadata_2025 huggingface dataset:
Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism*
Authors: Kirk J. M. W. , Savage M. O. , Grant D. B. , Bouloux P‐M. G. , Besser G. M.
Published: March 2008

OBJECTIVE This study was designed to determine the response to therapy using human chorionic gonadotrophin (hCG) and human menopausal gonadotrophin (hMG) in males with idiopathic isolated hypogonadotrophic hypogonadism (IHH), and to compare the responses in patients presenting with and without cryptorchidism.

DESIGN Analysis of male patients with IHH treated with hCG or combined hCG/hMG for a minimum of 6 months at St Bartholomew's Hospital. Clinical and endocrine assessment was performed in all patients prior to commencing therapy.

PATIENTS A total of 26 males with IHH have been treated with exogenous gonadotrophins. Thirteen patients (Group 1) had cryptorchidism (unilateral in 7, bilateral in 6) at presentation, and 13 (Group 2) did not.

MEASUREMENTS All patients had basal serum testosterone, LH and FSH determinations. An i.v. GnRH test was performed in 25 patients and an i.m. hCG stimulation test in 19. Testicular volume and serum testosterone were measured during both hCG and combined hCG/hMG therapy. Seminal analysis was performed at the start and monthly during hCG/hMG therapy.

RESULTS Eighty‐five per cent of the 13 patients in Group 1 had an olfactory defect (Kallmann's syndrome), compared with 23% of Group 2. Both groups of patients showed a subnormal response to initial i.v. GnRH and i.m. hCG testing. During hCG therapy only three patients in Group 1 and six In Group 2 achieved normal adult testosterone levels. The non‐cryptorchid group achieved a higher mean testicular volume on hCG therapy than the cryptorchid group (mean (SD); 4.7 (1.8) ml vs 3.0 (1.6) ml (P < 0.02)), and for all patients there was a correlation between initial and maximal testicular volume (R = 0.69, P = 0.001). Four patients in Group 1 and five patients in Group 2 were treated with combined hCG/hMG tor 6–15 months to induce fertility; only one patient in Group 1 achieved spermatogenesis, compared to all patients in Group 2 (leading to three pregnancies).

CONCLUSIONS These data indicate that patients with idiopathic hypogonadotrophic hypogonadism (IHH) have a poor response to hCG therapy in terms of testicular growth and normalization of serum testosterone. Final testicular volume is dependent on Initial testicular size. In addition, patients with IHH associated with cryptorchidism have a poor fertility potential to combined hCG/hMG therapy.
The ratio between serum levels of insulin‐like growth factor (IGF)‐I and the IGF binding proteins (IGFBP‐1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients
Authors: Juul Anders , Main Katharina , Blum Werner F. , Lindholm Jorgen , Ranke Michael B. , Skakkebaek Niels E.
Published: March 2008

OBJECTIVE Several in‐vitro studies have suggested that the biological actions of IGF‐I can be modified by the presence of specific IGF binding proteins. In man, the 24‐hour serum levels of IGF‐I and IGFBP‐3 remain constant, but short‐term changes in the IGF‐l/IGFBP‐3 ratio have been described following GH administration. Serum levels of IGF‐I and IGFBP‐3 decrease with age in normal adults and are elevated In active acromegaly due to excessive GH secretion. However, the Individual ratios between serum levels of IGF‐I and IGFBP‐3 in acromegalic and healthy adults have not been described previously.

METHODS AND MATERIALS We studied this ratio In 198 healthy adults and In 56 acromegalic patients, grouped according to their serum GH levels (group I GH < 2mLU/l II GH 2–10mLU/l; III GH > 10mLU/l). In all subjects a single blood sample was drawn for IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2, IGFBP‐3 and GH measurements by specific RIAs. In 38 of the patients a 24‐hour urinary collection was performed for GH determination.

RESULTS In healthy adults serum levels of IGF‐I and IGFBP‐3 decreased with Increasing age (r =−0.52 and r=−0.34, respectively, P< 0.0001). In addition, the molar IGF‐l/IGFBP‐3 ratio declined with increasing age (r =−0.44, P – 0.0001). In patients with acromegaly and high serum GH levels (group III), circulating IGF‐I was increased 7–97 standard deviations (SDS) and IGFBP‐3 was increased 4.20 SOS (P < 0.0001). Serum levels of IGF‐II were normal in all three groups (588 ± 240μ/l) whereas IGFBP‐1 and IGFBP‐2 levels were low and IGFBP‐2 levels decreased significantly with increasing serum GH levels (P < 0.0001). The molar IGF‐l/IGFBP‐3 ratio in the acromegalic patients was significantly higher than in the controls (P < 0.0001) and correlated significantly with urinary GH excretion (r = 0.67, P < 0.0001) as well as with serum GH levels (r = 0.73, P < 0.0001).

CONCLUSION We demonstrated a decreasing molar IGF‐l/IGFBP‐3 ratio with increasing age in healthy adults and an increased ratio between serum IGF‐I and IGFBP‐3 levels in acromegalic patients. As IGF‐II is normal and IGFBP‐1 and IGFBP‐2 are inversely correlated to the serum GH levels In the acromegalic patients, we speculate that the molar ratio between IGF‐I and IGFBP‐3 reflects free (biologically active) IGF‐I and Is dependent on GH levels.
Treatment with octreotide and bromocriptine in patients with acromegaly: an open pharmacodynamic interaction study
Authors: Fredstorp L. , Kutz K. , Werner S.
Published: March 2008

OBJECTIVE Several studies suggest that the combination of octreotide and bromocriptine is more effective than octreotide alone in reducing GH levels in patients with acromegaly. However, these studies have evaluated either the acute effects of single doses of octreotide and bromocriptine, or the effects of long‐term combination therapy, in which octreotide was given only twice a day. The aim of the study was to evaluate the effects of the combination of octreotide and bromocriptine compared to octreotide alone, using a treatment scheme of three daily injections of octreotide during a period long enough to ensure a pharmacokinetic and pharmacodynamic steady state.

PATIENTS Eleven patients with acromegaly.

DESIGN AND MEASUREMENTS Different treatment regimes were performed during three periods. During the first period there was no administration of octreotide or bromocriptine, during the second period 100 μg octreotide was given subcutaneously three times a day, and during the third period 100 /ig octreotide was given subcutaneously three times a day in combination with bromocriptine, given orally 5 mg twice daily. When the patients were without any treatment a single oral dose of 5 mg bromocriptine was given at 0730 h. Individual GH levels were assessed as the mean value of 11 observations during the day, at hourly Intervals from 0730 to 1530 h, and at 1730 and 1930 h, and the GH levels for the whole group were calculated as the mean of the individual mean values. Serum IGF‐I and PRL were measured in fasting samples at 0730 h on the same days as GH. GH, IGF‐I, and PRL were evaluated at the end of each treatment regime.

RESULTS Basal mean GH value for all 11 patients was 54.2 ± 17.4 mU/l. During octreotide therapy mean GH value was significantly reduced compared to basal mean GH level; 19.86±6.82 mU/l (P<0 05). The reduction of mean GH during combination therapy was also significant compared to basal, 18.70 ±6.72 mU/l (P<0.05). Basal mean IGF‐I value for all 11 patients was 716 ±96 μg/l. During octreotide therapy mean IGF‐I value was significantly reduced compared to basal mean IGF‐I level; 458 ±100 μg/l (P<0.05). The reduction of mean IGF‐I during combination therapy was also significant compared to basal, 456 ±93 μg/l (P<0.05). There was no difference between the levels of mean IGF‐I during the two treatment periods. One patient, the only patient with hyperprolactinaemia, showed an additional reduction of GH levels of >50% during combination therapy. This was also the patient showing the most pronounced reduction of GH levels after the administration of a single dose of bromocriptine.

CONCLUSION When octreotide is administered three times a day, the additive effect of bromocriptine on GH and IGF‐I suppression seems to be negligible in most patients with acromegaly.
Relation between growth hormone and Cortisol spontaneous secretion in children
Authors: Martinelli Carlos E. , Moreira Ayrton C.
Published: March 2008

OBJECTIVE Dual effects of corticoids upon GH release in man have been described: a rapid, potentiating effect and a delayed suppressive one. Many investigators have used pharmacological doses of glucocorticoids in an attempt to detect this interaction of corticoids and GH. The aim of the present study was to determine the relationship between GH and Cortisol spontaneous secretion in children under physiological conditions.

DESIGN AND PATIENTS Nine children aged 7.5–13.5 years with different growth rates were evaluated over a 24‐hour period. Four were of normal stature (±2 SD) and five were below 2 SO (familial or constitutional short stature). Blood samples were obtained at 20‐minute intervals over a 24‐hour period.

MEASUREMENTS GH and Cortisol concentrations were measured by radioimmunoassay in each of the 73 samples collected.

RESULTS A significant correlation was obtained between mean 24‐hour Cortisol concentration and mean 24‐hour GH concentration (r= 0.83; P < 0.01), the sum of 24‐hour GH pulse amplitudes (r= 0.85; P < 0.01) and the highest 24‐hour GH concentration (r= 0.88; P < 0.01). A significant positive correlation was also detected between mean 24‐hour Cortisol concentration and the number of GH pulses over a 24‐hour period (r= 0.70; P < 0.05). However, there was no significant correlation between mean 24‐hour GH concentration and number of Cortisol pulses over a 24‐hour period. The correlation between number of Cortisol pulses and number of GH pulses was also non‐significant.

CONCLUSION These data suggest an interplay of spontaneous GH and Cortisol secretion in children. Physiological plasma Cortisol levels may play a role in brain‐pituitary regulatory mechanisms of GH secretion.
An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year
Authors: Jones S. L. , Trainer P. J. , Perry L. , Wass J. A. H. , Besser G. M. , Grossman A.
Published: March 2008

OBJECTIVE We audited our practice of insulin tolerance testing (ITT) in terms of safety and technical success. We reviewed the results of those tests performed over a 12‐month period. By relating peak Cortisol response to 0900 h screening Cortisol level, we determined whether we could reduce the number of tests performed.

DESIGN The results of all ITTs performed on our unit between 1 January and 31 December 1991 were reviewed.

PATIENTS AND MEASUREMENTS Patients were pre‐screened by measurement of serum Cortisol and thyroxine, and recording of an electrocardiogram. A subnormal serum thyroxine (<58 nmoi/l), 0900 h serum Cortisol (<100 nmol/l) or an abnormal ECG were taken as contraindications to the test. Minimum glucose and maximum Cortisol levels were recorded, along with peak GH responses when measured. The peak Cortisol response was compared to the screening and basal Cortisol levels.

RESULTS A total of 161 tests were performed, 135 of which fulfilled our inclusion criteria. The test was technically successful in all but 5 of these; a significant adverse event occurred in one patient with full recovery after reversal of hypoglycaemia. Thirty‐two patients had a suboptimal serum Cortisol response to hypoglycaemia: screening Cortisol level ranged from 128 to 493 nmol/l and 0900 h serum Cortisol measured prior to the ITT from 97 to 431 nmol/l. The lowest level of screening Cortisol above which all patients would be expected to achieve the normal peak Cortisol of 580 nmol/l or over is therefore 494 nmol/l. If this cut‐off level had been adopted, 10 (8%) ITTs need not have been performed if their only purpose had been to assess Cortisol reserve. Altering the criterion for the necessary peak Cortisol to 500 nmol/l did not affect the number of ITTs required. Our lower limit for testing could not be revised upwards from 100 nmol/l. Adequacy of Cortisol reserve did not predict a normal GH response to insulin‐induced hypoglycaemia.

CONCLUSIONS When performed in an experienced endocrine unit with adequate supervision, the insulin tolerance test is a safe procedure. According to the current sample, fewer tests would be performed without detriment to patient care if those with a screening Cortisol of greater than 500 nmol/l did not proceed to testing, unless the purpose of the test was also to exclude GH deficiency. A lower limit of 100 nmol/l appears reasonable and need not be revised upwards.
Osteopenia as a feature of the androgen insensitivity syndrome
Authors: Soule Steven G. , Conway Gerard , Prelevic Gordana M. , Prentice Malcolm , Ginsburg Jean , Jacobs Howard S.
Published: March 2008

OBJECTIVE The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density In SIX patients with androgen Insensitivity.

DESIGN A cross‐sectional retrospective study.

MEASUREMENTS Bone mineral density was measured by means of a Dexa (Hologic QDR 1000 scanner). The diagnosis of androgen Insensitivity was confirmed in each patient by karyotype and assay of sex hormones.

RESULTS The five adult patients with androgen insensitivity had been exposed to both defective androgen action and variable periods of oestrogen deficiency. The latter resulted from the low circulating oestrogen concentrations (for premenopausal females) before gonadectomy and inadequate oestrogen replacement afler gonadectomy. All five adults with androgen insensitivity had osteopenia in both the lumbar spine (T‐score −1.52 to −3.85) and femoral neck (T‐ score −1.34 to −4.91).

CONCLUSIONS Osteopenia in patients with androgen insensitivity may relate to defective androgen action, oestrogen deficiency or a combination of the two. These observations have implications for the management of patients with androgen insensitivity and may provide insight into the effects of androgens on the female as well as the male skeleton.
Cardiac flow velocity in women with the polycystic ovary syndrome
Authors: Prelevic Gordana M. , Beijic Teodora , Balint‐Peric Ljiljana , Ginsburg Jean
Published: March 2008

OBJECTIVE Women with the polycystic ovary syndrome (PCOS) often have several of the known risk factors for cardiovascular disease, including hyperinsulinaemia. We have therefore investigated variables of cardiac flow in young women with PCOS and related them to blood levels of reproductive hormones (LH, FSH, oestradiol and testosterone) and also of insulin.

DESIGN A prospective study.

PATIENTS Twenty‐six young women with PCOS (mean age 22.8 ± 0.9 years; mean BMI 23.0 ± 0.8) and 11 healthy age matched women with regular ovulatory cycles (mean age 26.3 ± 1.7 years; mean BMI 22.9 ± 0.9).

MEASUREMENTS Cardiac flow was measured by pulsed wave Doppler echocardiography in the follicular phase of the cycle in controls and oligomenorrhoeic women; there was no special timing for amenorrhoeic women. The indicators assessed were: ejection fraction (EF), pre‐ejection time (PEP), ejection time (ET), peak systolic flow velocity (PFV), acceleration time (AT), flow velocity integral (FVI), mean acceleration (MA), diastolic time (DT), early diastolic filling time (EI), atrial filling time interval (AI), peak velocity of the early diastolic filling (PE) and peak velocity of the atrial filling (PA). Serum LH, FSH, oestradiol, testosterone, SHBG and insulin concentrations were analysed by standard RIA.

RESULTS Significantly lower PFV (1.055 ± 0.025 vs 1.242 ± 0.054, P= 0.0006) and MA (17.06 ± 0.57 vs 23.00 ± 1.49, P= 0.0001) and longer AT (0.063 ± 0.001 vs 0.056 ± 0.004, P= 0.026) were found in women with PCOS as compared to age matched controls. Significant negative correlation between serum fasting insulin concentration and EF (r=‐0.725, P= 0.002), PFV (r=−0.719, P= 0.0025), FVI (r=−0.654, P= 0.003) and MA (r=−0.757, P= 0.001) was observed In the 15 women with PCOS in whom insulin was measured.

CONCLUSION An inverse relation between serum fasting insulin level and left ventricular systolic outflow parameters suggests that insulin is associated with the decreased systolic flow velocity observed in women with PCOS.
High incidence of juvenile Graves’disease in Hong Kong
Authors: Wong Gary W. K. , Kwok M. Y. , Ou Yvonne
Published: March 2008

OBJECTIVE Childhood Graves’disease has been reported to be rare and epidemiological data on its incidence are limited. In our Paediatric Endocrine Clinic, Graves’disease was the most common thyroid disorder seen. There is no previous epidemiological study on Graves’disease in Chinese children. This study was performed to determine the incidence of childhood Graves’disease in Hong Kong Chinese.

DESIGN AND PATIENTS We established a registry of childhood Graves’disease in 1990 at our centre, which has a catchment population of 1 010 000 with 240 000 under 15 years of age. Graves’disease was diagnosed on clinical features, diffuse thyroid gland enlargement, elevated free thyroxine or trilodothyronine levels with suppressed TSH level. All confirmed cases were recorded prospectively. Population data were obtained from the Statistics Department of the Hong Kong Government. RESULTS Forty‐six Chinese children under 15 years of age had a confirmed diagnosis of Graves’disease during the study period from January 1990 to December 1994. The overall incidence was 3.8/100 000/year with a 95% confidence interval of 1.8–7.3/100 000/year. Incidence was low in children under 4 years. The highest incidence was in girls between 10 and 14 years of age at 15.5/100 000/year. The cumulative incidence for boys and girls of developing Graves’disease during the first 15 years was 11 and 104 per 100 000 respectively.

CONCLUSIONS Our data demonstrate a very high incidence of Graves’disease in Hong Kong Chinese children, with an overall incidence about 5 times that reported in Danish children. A female predominance was found in all three age groups (0–4, 5–9 and 10–14 years) and was particularly striking in the adolescent girls.
Neuroendocrine evidence for an association between hypothyroidism, reduced central 5‐HT activity and depression
Authors: Cleare A. J. , McGregor A. , O'Keane V.
Published: March 2008

OBJECTIVE The incidence of depression in those with hypothyroidism is increased compared to healthy populations, though the mechanism for this Is unclear. We tested the hypothesis that central 5‐HT activity is reduced in hypothyroidism, and that this subsequently lowers the threshold for developing depression.

PATIENTS Twenty subjects entered the study: 10 drug free hypothyroid patients and 10 age, sex, weight and menstrual cycle matched controls.

MEASUREMENTS Patients were diagnosed as being depressed using DSM‐IIIR criteria and rated using the Hamilton Rating Scale for Depression (HAM‐D) and Beck Depression Inventory (BDI). Cortisol and prolactin responses to dexfenfluramine, a centrally acting 5‐HT releasing agent, were used as an Index of central 5‐HT responsivity.

RESULTS Both cortisol and PRL responses were reduced in the hypothyroid group relative to the controls. Peak cortisol responses were inversely correlated to TSH levels. Four of the 10 patients were clinically depressed. Depressed patients had higher TSH levels than their non‐depressed counterparts, and TSH levels were positively correlated with HAM‐D and BDI scores.

CONCLUSIONS These findings support animal work suggesting that hypothyroidism reduces central 5‐HT activity. They also suggest a threshold effect in that higher TSH levels predicted both lower 5‐HT mediated endocrine responses and the presence of clinical depression.
Serum testosterone and its relation to bone mineral density and body composition in normal males
Authors: Ongphiphadhanakul B. , Rajatanavin R. , Challurkit L. , Piaseu N. , Teerarungsikul K. , Sirisriro R. , Komindr S. , Puavilai G.
Published: March 2008

OBJECTIVE Bone mineral density (BMD) declines with age in both men and women, predisposing the elderly to osteoporosis and fractures. Although there are extensive data about post‐menopausal osteoporosis, there is relatively little information concerning the decrease in BMD with age in normal men, particularly the contribution of declining gonadal function with age to BMD. In the present study, we investigated the effect of age on the pituitary‐gonadal axis in normal males and its relation to BMD and body composition.

SUBJECTS Ninety healthy Thai males in the Bangkok Metropolitan area without a history of smoking or significant alcohol consumption were studied.

MEASUREMENTS Serum testosterone (T), free testosterone (FT), LH and FSH were measured by radioimmunoassay in fasting blood samples obtained In the morning between 0600 and 1000h. BMD at anteroposterior L2‐L4, lateral L2‐L4, femoral neck, femoral trochanter and Ward's triangle were determined by dual‐energy X‐ray absorptiometry.

RESULTS There were significant declines with age in BMD at lateral L2‐L4 (r= 0.37, P < 0.001), femoral neck (r=−0.49, P<0.0001), Ward's triangle (r=−0.54, P < 0.0001) but not at anteroposterior L2‐L4 or femoral trochanter. Serum FT (r=−0.56, P < 0.0001) but not T (r=−0.19, P= 0.07) decreased with age. Serum LH (r= 0.27, P <0.001) and FSH (r= 0.4, P <0.0001) increased with age suggesting a defect in gonadal androgen synthesis or possibly a secretion of bioinactive LH. Serum FT concentrations were significantly correlated to lateral L2‐L4 (r= 0.27, P<0.05), femoral neck (r= 0.48, P < 0.0001) and Ward's triangle (r= 0.50, P < 0.0001) BMD. After controlling for age, declining FT with age was still associated with a decrease In BMD in femoral neck (P < 0.05) and Ward's triangle (P < 0.05) but not in lateral L2‐L4. The proportion of body fat increased with age (r= 0.3, P < 0.01). Decreased serum T, but not FT, was associated with increased body fat after age was taken into account (P < 0.0001).

CONCLUSIONS There is a decline in serum free testosterone together with increases In LH and FSH with age In healthy males. The decrease in serum free testosterone Is partially associated with the age‐related decline in bone mineral density added to the effect of age at the femoral neck and Ward's triangle. Testosterone but not free testosterone Is associated with age‐related increase in body fat.
Autonomous nodular hyperplasia of the adrenal cortex: tertiary hypercortisolism?
Authors: Sturrock Nigel D. C. , Morgan Linda , Jeffcoate William J.
Published: March 2008

Two cases of Cushing's syndrome are reported in which apparently autonomous adrenal adenomata were associated with the presence of pituitary tumours. In one case the patient was apparently cured by unilateral adrenalectomy, although she was noted to have radiological evidence of an intrasellar tumour; serum cortisol was not suppressed by dexamethasone and ACTH was undetectable. Serum ACTH in the second case was initially 31 ng/l but became undetectable during the course of investigation. Transsphenoidal removal of a corticotroph adenoma did not affect serum cortisol and she proceeded to unilateral adrenalectomy. The pathogenesis of autonomous macronodular hyperplasia is discussed, as well as the options for management.
No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B
Authors: Toogood Andrew A. , Eng Charis , Smith Darrin P. , Ponder Bruce A. J. , Shalet Stephen M.
Published: March 2008

Multiple endocrine neoplasia type 28 (MEN 28) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto‐oncogene.

The mutation in codon 918 has been described in 69 out of 72 families with MEN 28. We have studied a brother and sister who undoubtedly have the features of MEN 28 as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto‐oncogene, and although exons 2–20 have also been sequenced, no abnormality has been found

DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 28, but in an individual with some of the features of MEN 28 would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto‐oncogene does not always exclude the diagnosis of MEN 28. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.
Effects of cholinergic modulation on serum insulin‐like growth factor4 and its binding proteins in normal and diabetic subjects*
Authors: Ismall I. S. , Mlell J. P. , Scanlon M. F. , Peters J. R.
Published: March 2008

OBJECTIVE We wished to study alterations In serum Insulin‐like growth factor‐I (IGF‐I) and its binding proteins in subjects with insulin dependent diabetes mellitus (IDDM) and possible relations with metabolic and GH secretory status, before and after cholinergic modulation. In addition, we have Investigated whether cholinergic modulation exerts any effects on IGF‐I secretion, Independently of any actions on GH secretory status.

DESIGN All subjects received OH releasing hormone (GHRH) 1‐44; 80 μg i.v.) alone and 60 minutes following 120mg of pyridostigmine orally or 200 mg of plrenzepine orally. The three tests were carried out In random order at least one week apart. Blood was sampled at 15‐mInute Intervals over 120 minutes.

PATIENTS Twelve male subjects with IDDM and no clinical evidence of complications were selected on the basis of HbA1 levels to provide a wide range of metabolic control. SIX normal male subjects were also studied.

MEASUREMENTS Serum IGF‐I, IGF‐binding protein 1 (IGFBP‐1) and IGFBP‐3 were measured at regular intervals throughout the study. Fasting plasma glucose and HbA1 were measured before each study to provide measures of metabolic control.

RESULTS Serum IGF‐I and IGFBP‐3 levels were significantly lower while serum IGFBP‐I levels were significantly higher In the diabetic subjects. Plrenzepine had no effect on serum IGF‐I, IGFBP‐1 or IGFBP‐3 In diabetic subjects but caused a significant Increase In serum IGF‐I and IGFBP‐3 levels in normal subjects.

Pyridostigmine had no effect on IGF‐I, IGFBP‐1 or IGFBP‐3 In either diabetic or normal subjects. IGFBP‐1 levels were significantly correlated with fasting plasma glucose but no correlation was demonstrated between measures of diabetic control and serum IGF‐I or IGFBP‐3 levels In diabetic subjects, nor was there any correlation between OH responses to GHRH alone or after plrenzepine or pyridostigmine pretreatment and serum levels of IGF‐I, IGFBP‐1 or IGFBP‐3.

CONCLUSION These data confirm that subjects with IDDM have reduced serum IGF‐I and IGFBP‐3 and Increased IGFBP‐1 levels, the latter being directly related to the fasting plasma glucose concentrations. The absence of any relation between changes In the IGF‐I system and altered GH neuroregulation after cholinergic modulation suggests that changes In IGF‐I are not the sole contributors to the altered GH neuroregulation which occurs In IDDM. We have also shown an acute stimulatory effect of pirenzepine on serum IGF‐I and IGFBP‐3 In normal subjects which Is not present in IDDM although the underlying mechanism Is unknown.
Autonomous hyperparathyroidism in X‐linked hypophosphataemia
Authors: Knudtzon Jergen , Halse Johan , Monn Elrik , Nesland Aasve , Nordal Knut P. , Paus Povel , Selp Martin , Sund Ståle , Sedall Gunnar
Published: March 2008

Four patients with familial hypophosphataemic rickets developed significant hypercalcaemia which persisted after discontinuation of vitamin D therapy. They had increased PTH levels and were operated for hyperparathyroldism at the ages of 18, 20, 24 and 45 years, respectively. Three of the patients had previously received phosphate treatment and one patient developed hyperparathyroldism 7 years after treatment with calcitriol. Histological evaluation revealed different degrees of parathyroid hyperplasia in all patients, with persistently Increased PTH and/or calcium levels after surgery. The possibility of autonomous hyperparathyroldism should be evaluated in the follow‐up of patients with X‐linked hypophosphataemic rickets.
Pseudo‐tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases
Authors: Tabarin Antolne , Catargi Bogdan , Chanson Phillppe , Hieronimus Sylvie , Corcuff Jean‐Benoit , Laurent Françols , Harter Michel , Drouillard Jacques , Roger Patrick
Published: March 2008

We report the cases of four patients with occult, and one patient with overt, ectopic ACTH syndrome. Cushing's syndrome was cured by removal of the ACTH secreting tumour, op'DDD, ketoconazole or bilateral adrenalectomy. SIX to 14 months after remission of hypercortisolism, follow‐up computed tomography or magnetic resonance imaging of the thorax revealed in all five patients an anterior mediastinal mass 3‐5 cm in length that suggested a thymic carcinoma. Exploratory thoracotomy was performed in four cases and allowed the removal of an enlarged, but normal, thymus. Histological examination revealed no tumour but showed benign thymic hyperplasia with negative immunostaining for ACTH. Thymic enlargement spontaneously disappeared 11 months after its demonstration in the patient who did not undergo thoracotomy. The mechanism of this abnormality is thought to be thymic depletion resulting from high plasma cortisol concentrations followed by‘rebound’thymic hyperplasia when cortisol levels fall. Physicians involved in the management of patients with Cushing's syndrome must be aware of this entity In order to avert a diagnostic thoracotomy.
Human TRH receptor messenger ribonucleic acid levels in normal and adenomatous pituitary: analysis by the competitive reverse transcription polymerase chain reaction method
Authors: Kaji Hidesuke , Xu Yue , Takahashi Yutaka , Abe Hiromi , Tamaki Norihiko , Chihara Kazuo
Published: March 2008

OBJECTIVE Little is known about the mechanism of diversity in in‐vivo hormonal responsiveness to TRH in patients with functional pituitary adenomas. In order to clarify the relation between the responsiveness to TRH and TRH receptor messenger ribonucleic acid (mRNA) expression, we attempted to measure TRH receptor mRNA levels in human pituitary adenoma tissues by competitive reverse transcription polymerase chain reaction (RT‐PCR) method.

PATIENTS Pituitary tissue samples were obtained at autopsy from 5 patients without pituitary disease. Pituitary adenoma tissue samples were obtained at surgery from 18 patients with pituitary adenoma (4 non‐functioning, 8 pro‐lactinoma, 4 acromegaly, 1 Cushing's disease and 1 FSH producing adenoma).

METHODS Partial TRH receptor cDNA from a human GH producing adenoma cDNA library was ampilfied by PCR under low stringency conditions using primers encoding the transmembrane domains III and VI of pituitary TRH receptor cDNA. The partial sequence of the amplified cDNA determined by a dideoxy‐chain termination method was identical to the corresponding sequence of human TRH receptor cDNA. A competitor was generated by deleting the inner 111 bp from the amplified TRH receptor cDNA and subcloning. RNA extracted from human pituitary was reverse transcribed and co‐amplified with competitor by PCR under higher stringency conditions. The TRH receptor mRNA levels, expressed as the relative intensity against the amplified levels of competitor, were compared among various pituitary tissues.

RESULTS The relative TRH receptor mRNA levels of pituitary tissues in patients without pituitary disease were detectable and variable (M±SD) (0·370 ± 0·231, n= 5), and slightly but not significantly lower than those in patients with pituitary tumours (0·598 ± 0·265, n= 18). In patients with prolactinoma, the relative levels of TRH receptor mRNA were quite variable (0·02–1·170, 0·604 ± 0·358, n= 8) and not correlated with PRL responsiveness to TRH (responder 0·457; non‐responder 0·340–0·950). In patients with acromegaly, TRH receptor mRNA was detectable not only in the paradoxical GH responder to TRH (0·718) but also In the non‐responder (0·758 and 0·765). In one patient with Cushing's disease, a relatively low level of TRH receptor mRNA could be detected (0·415). In the patient with a FSH producing tumour whose plasma FSH did not respond to TRH, a small amount of TRH receptor mRNA was detectable (0·447).

CONCLUSIONS in patients with functioning pituitary adenomas, hormonal responsiveness to TRH in vivo might not be assessable by TRH receptor mRNA levels in the adenoma cells.
Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature
Authors: Powrie J. K. , Powell Y. , Ayers A. B. , Lowy C. , Sönksen P. H.
Published: March 2008

Lymphocytic adenohypophysitis can cause pituitary expansion and hypopituitarism closely mimicking the features of a pituitary adenoma. Discrimination between these two conditions is of importance since, despite the similarity of their presentation, there are significant differences in pathophysiology. In contrast to pituitary adenoma, lymphocytic adenohypophysitis occurs almost exclusively in young women in relation to pregnancy, there is a preference for destruction of ACTH and TSH secreting cells and computed tomographic scanning shows uniform contrast enhancement in a proportion of cases. There is, as yet, no proven specific non‐surgical treatment. There are anecdotal reports of a beneficial effect of steroids but there is also evidence that spontaneous resolution may occur. We have reviewed the literature and report two new cases of lymphocytic adenohypophysitis both of whom exhibited early striking diffuse homogeneous contrast enhancement on magnetic resonance imaging scanning which we suggest may be a diagnostic feature of this condition.
Is IGF binding protein‐3 assessment helpful for the diagnosis of GH deficiency?
Authors: Cianfarani S. , Boemi S. , Spagnoli A. , Cappa M. , Argirò G. , Vaccaro F. , Bitti M. L. Manca , Boscherlni B.
Published: March 2008

OBJECTIVE The measurement of serum immunoreactive IGFBP‐3 levels has been proposed as a screening test to Identify children with growth hormone deficiency (GHO). We tested the sensitivity and specificity of the IGFBP‐3 assessment In comparison with the measurement of IGF‐I.

DESIGN We assessed the IGFBP‐3 and IGF‐I circulating levels in normal subjects and patients with GHD or idiopathic short stature (ISS).

PATIENTS Eighty‐two normal subjects, 16 GHD, and 10 children with ISS were studied. Controls were divided into three age groups: group A, 1‐4 years (n= 16); group B, 5‐9 years (n= 35), and group C, 10‐14 years (n= 31)

MEASUREMENTS All subjects underwent standard anthropometry. In short patients, GH secretory status was assessed by clonidine and arginine stimulation tests. IGFBP‐3 and IGF‐I circulating levels were measured by radioimmunoassay.

RESULTS IGFBP‐3 and IGF‐I levels were closely related (r= 0.51, P < 0.0001) and IGFBP‐3 was less age dependent than IGF‐I (r= 0.57, P < 0.02 vsr= 0.64, P= 0.0001). Sensitivity (true positive ratio) and specificity (true negative ratio) of IGFBP‐3 measurement were 50 and 92% respectively, whereas sensitivity and specificity of IGF‐I assessment were 75 and 90% respectively. Below the age of 5 years, sensitivity was 20% for IGFBP‐3 and 40% for IGF‐I; specificity was 94% for IGFBP‐3 and 88% for IGF‐I.

CONCLUSIONS IGFBP‐3 measurement had poor sensitivity in detecting growth hormone deficient patients, offering no diagnostic advantage over IGF‐I, even in the first years of life, although, due to the high specificity, the finding of subnormal levels of IGFBP‐3 was strongly suggestive of growth hormone deficiency. The presence of low IGFBP‐3 and IGF‐I levels in a short child with normal GH response to provocative tests should prompt further Investigations, such as the determination of spontaneous GH secretion or assessment of the GH binding proteins together with an IGF‐I and/or IGFBP‐3 generation test, In order to Identify neurosecretory dysfunction or GH receptor deficiency. Finally, we believe that there is no definitive test for diagnosing or excluding growth hormone deficiency and detailed analysis of the results of endocrine tests, clinical findings and other laboratory and radiological Information is necessary to maximize diagnostic accuracy
Genetic counselling in complete androgen insensitivity syndrome: trinucleotide repeat polymorphisms, single‐strand conformation polymorphism and direct detection of two novel mutations in the androgen receptor gene
Authors: Davles Helen R. , Hughes Leuan A. , Patterson Mark N.
Published: March 2008

OBJECTIVE Androgen Insensitivity syndrome Is a disorder of male sexual development which results In varying degrees of undervlrlllzatlon In 46XY Individuals with functional testes. In the most severe form, complete androgen insensitivity syndrome (CAIS), patients have a normal female appearance. Although CAIS Is not life‐threatening, affected individuals are Infertile and require counselling, gonadectomy, hormone therapy, and sometimes vaginoplasty. Many families therefore request genetic counselling. Defects in the androgen receptor gene account for most if not all cases of CAIS. The purpose of this study was to evaluate the use of the polyglutamlne and polyglycine trinucleotide repeat polymorphisms in the first exon of the androgen receptor gene for carrier status determination In three CAIS families. In two of these families novel mutations In the androgen receptor gene were subsequently identified which allowed confirmation of carrier status and also a prenatal diagnosis to be made in one family.

PATIENTS Three CAIS families were studied. The Index cases all presented with a clinical phenotype typical of CAIS.

measurements Family members were typed Initially for the polyglutamlne repeat. In one family this was not Informative and the polyglycine repeat was therefore studied. In this and one further family, the androgen receptor gene was sequenced to Identify the mutation causing the CAIS.

RESULTS On the basis of Information from trinucleotide repeat analysis carrier status could be assessed In each family. In one family, evidence for somatic instability of the polyglutamlne repeat was found. In the same family, a novel mutation In the androgen receptor gene, which substituted valine for leucine 881, was identified. Other family members were subsequently typed for the mutation and a prenatal diagnosis was performed. A novel mutation was also identified in a second family substituting the glycine codon at position 371 with a stop codon. Other family members were typed for this mutation.

CONCLUSIONS Both the polyglutamlne and polyglycine repeat polymorphisms are useful for the genetic counselling of complete androgen Insensitivity syndrome families. In some cases, however, where the family history is limited, more precise information can be provided only once the androgen receptor mutation causing the complete androgen Insensitivity syndrome has been Identified.
DNA synthesis by pituitary tumours, with reference to plasma hormone levels and to effects of bromocriptine
Authors: Lloyd H. M. , Jacobi J. M. , Willgoss D. A.
Published: March 2008

BACKGROUND AND OBJECTIVE In parathyroid adenomas and experimentally in the normal rat pituitary gland, cell replication and secretory activity were previously shown to be correlated. A similar relationship has now been investigated In human pituitary tumours, since this could have relevance to their growth and aetiology. The effect of bromocriptine on the two variables was examined.

PATIENTS Data were derived from 50 patients undergoing operation for pituitary tumour, including 15 with acromegaly and 11 with prolactinoma.

MEASUREMENTS Preoperative plasma levels of GH, PRL and gonadotrophins were measured by radioimmunoassay. DNA synthesis, an Index of cell replication, was measured in vitro in freshly removed tumour tissue. Nuclear diameter of tumour cells was measured in histological sections and immunostainlng for relevant hormones was carried out on tumour tissue.

RESULTS DNA synthesis was correlated (P<005) with plasma hormone levels in cases of prolactinoma, both treated and not treated with bromocriptine, and In a group of putative FSH secreting tumours from male patients. The correlation was not significant in cases of acromegaly. Comparisons of mean values between groups treated and not treated with bromocriptine showed significantly lower DNA synthesis and mean nuclear diameter In prolactinomas under treatment but not In GH secreting tumours.

CONCLUSIONS The findings In prolactinomas suggest a close relationship between secretion and tumour cell replication dependent on still undefined agents, but including dopamine, affecting both variables, and isoforms of PRL, which may stimulate or inhibit replication of PRL secreting cells. The basis of the relationship In FSH secreting tumours Is unknown. The relationship was absent In the non‐homogeneous group of GH secreting tumours. When secretion and growth are correlated, the secretory process may be the site of the primary abnormality in the tumour cell. Evidence that bromocriptine inhibits tumour cell replication was obtained for prolactinomas but not for GH secreting tumours.
The evolution of radiation‐induced growth hormone deficiency in adults is determined by the baseline growth hormone status
Authors: Toogood Andrew A. , David W. , Ryder J. , Beardwell Colin G. , Shalet Stephen M.
Published: March 2008

OBJECTIVE Recent studies of GH replacement have suggested several beneficial effects for GH deficient adults. It would therefore be helpful to predict the time of onset of GH deficiency after external pituitary irradiation. We have studied the evolution of GH deficiency with time In patients irradiated for pituitary adenomas and other hypothalamic pituitary tumours.

DESIGN Analysis of serial peak GH responses to Insulin hypoglycemia following external irradiation to the hypothalamlc‐pitultary axis using statistical models which allowed for age, sex, previous surgery and the pre‐radiotherapy GH peak response.

PATIENTS Eighty‐five non‐acromegalic adults (48 male), 75 of whom had either a pituitary adenoma or a craniopharyngioma and 10 who had other tumours in the hypothalamic‐pituitary region. All the patients had received a radiation dose between 37.5 and 45 Gy divided into 15 fractions given over 21 days.

MEASUREMENTS The GH responses to an insulin tolerance test (ITT) performed as part of the regular endocrine follow‐up In patients who received Irradiation to the hypothalamic‐pituitary region.

RESULTS Three hundred and forty‐five ITTs were performed over a period of 10 years following radiotherapy. There was a decline In the modelled mean peak GH response to an ITT over the first 5 years which then appeared to plateau. Using an extended model, women had higher GH peak responses than men and this difference was maintained throughout the ten‐year period. The magnitude of the post‐radiotherapy peak GH response at any given time was dependent on the baseline peak GH response, but the rate of the decrease was not affected (P= 0.66). To develop severe GH deficiency (peak GH response less than 5mU/l) after radiotherapy it took patients with baseline GH peaks of 30, 20 and 10mU/l approximately 4 years, 3 years and 1 year respectively. Those patients with a baseline GH peak of greater than 50mU/l are unlikely to develop severe GH deficiency within the first 5 years following radiotherapy.

CONCLUSION These results provide an insight into the pattern of the decline In GH secretion following radiotherapy in patients with pituitary disease and the factors affecting It. This Information will help the clinician predict the frequency and timing of GH deficiency in patients irradiated for pituitary disease and the potential need for GH replacement therapy.
Bioactive GH‐like immunoglobulins G in active acromegaly: response to long‐term treatment with bromocriptine*
Authors: Campino Carmen , Szecowka Jaroslaw , Lopez Jose M. , Seron‐Ferre Maria
Published: March 2008

In acromegaly, certain forms of circulating immuno reactlve hGH are not true 6H but IgGs which possess G H biological activity (bioactive G H‐like IgGs). In this study, we tested the effect of bromocriptine on circulating bioactive G H‐like IgGs In an acromegalic woman. Increasing doses of oral bromocriptine (2.5, 5.0 and 7.5mg/day) were administered (for 2, 8 and 6 months respectively). TRH tests were performed before treatment and at the end of treatment with each dose. The patient was without detectable pituitary or extra‐pituitary tumour by magnetic resonance imaging. Her serum contained bioactive G H‐like IgGs equivalent to 240mU/l of hGH and elevated insulin‐like growth factor I (IGF‐I; 9500 U/l). Basal hGH was 12.8 μ/l and Increased to 220mU/l 15 min after TRH (200 μg, l.v.). In addition, in the basal samples of each test we measured total IgGs (radial immunodiffusion), bioactive GH‐like IgGs (isolated by Sephadex and protein A affinity chromatography and assayed using the Nb2 cell assay) and IGF‐I(RIA). Bromocriptine treatment gradually reduced serum levels of bioactive GH‐like IgGs and IGF‐I, with significant falls observed first at 10 months of treatment. Bioactive GH‐like IgGs were 240, 240, 36‐0 and <0.124mU/l and IGF‐I levels were 9500,8700,4000 and 3100 U/l at 0,2,10 and 16 months of treatment, respectively. In contrast, IR‐hGH response to TRH decreased after 2 months of treatment to 89 mU/l and to 49.2 mU/l at the end of the study while basal IR‐hGH remained between 13 and 8‐4 mU/l. Basal PRL fell to almost undetectable levels. Bromocriptine treatment decreased the G H response to TRH and the serum concentration of bioactive G H‐like IgGs and IGF‐I. The striking similarity between the pattern of decrease of serum bioactive GH‐like IgGs and IGF‐I supports the presence of an immuno component in our patient's acromegaly
Octreotide exacerbated fasting hypoglycaemia in a patient with a proinsulinoma; the glucostatic importance of pancreatic glucagon
Authors: Gama R. , Marks V. , Wrlght J. , Teale J. D.
Published: March 2008

Octreotide, a long‐acting somatostatin analogue, has been used to alleviate hypoglycaemia In patients with Insulinomas. Transient worsening of fasting hypoglycaemia following octreotide has also been described (Stehouwer et al., 1989).

We describe a patient with a‘proinsullnoma’in whom octreotide caused rapid and prolonged symptomatic worsening of fasting hypoglycaemia. Catecholamine and Cortisol counterregulatory hormonal responses were normal but those of glucagon and GH were Impaired.

Acute neuroglycopaenlc symptoms were present during octreotide induced hypoglycaemia, which was accompanied by and attributed to an acute reduction in pancreatic glucagon secretion in the presence of persistent and unsuppressed hyperproinsullnaemla. This suggests that glucagon may be Important in maintaining glucose homeostasis in chronic hypoglycaemia due to endogenous hyperinsulinlsm even though its concentration in the peripheral blood Is not raised.