bluuebunny/crossref_metadata_2025 huggingface dataset:
Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome
Authors: Grulet H. , Hecart A.C. , Delemer B. , Gross A. , Sulmont V. , Leutenegger M. , Caron J.
Published: March 2008

OBJECTIVE The relationship between insulin resistance and hyperandrogenism led us to study insulin resistance in polycystic ovary syndrome (PCOS) in order to determine its prevalence and pathogenesis. DESIGN Blood samples were taken on the 8th day after menses commenced.

PATIENTS Sixty‐one women with PCOS, 30 with normal weight (BMK25 kg/m2) (group 1) and 31 with obesity (BMI<26 kg/m2) (group 2) were studied. They were divided also according to LH level: group A, low or normal LH (n==23) and group B, high LH (n= 38). Twenty lean control women and 16 obese control women were studied.

MEASUREMENTS Serum LH, testosterone, free testosterone, dehydroepiandrosterone, sex‐hormone binding globulin, androstenedione, and fasting insulin were measured. Insulin sensitivity was explored by the insulin tolerance test (ITT). ITT was performed by bolus i.v. insulin of 0 1 IU/kg. Blood glucose was measured before (– 5, 0) and after injection (3, 5, 7, 10, 15 minutes). Insulin sensitivity was given by the ratio of glycaemic variation to initial blood glucose (AG/G index).

RESULTS ΔG/G was correlated with other insulin resistance parameters, particularly fasting insulin r=–0.40, P<0.01. The PCOS groups had the following insulin resistances (mean ± SEM) compared to matched groups: ΔG/G lean PCOS vs lead controls: 0.45 ± 0.02 vs 0.61 ± 0.01, P< 0.001; ΔG/G obese PCOS vs obese controls: 0.32 ± 0.02 vs 0.40 ± 0.01, P<0.02. Insulin resistance was higher in group A than in group B: ΔG/G 0 29 ± 002 vs 0 45 ± 0 02, P < 0.001. The prevalence of insulin resistance was 63% in lean PCOS and 51% in obese PCOS. Positive correlations between AG/G index and LH were found in group 1 and 2, respectively r= 0.45, P<0.01 and r= 0.55, P<0.01.

CONCLUSION PCOS was associated with a significant decrease of insulin sensitivity, independent of obesity. The correlation between LH and insulin sensitivity suggests a complementary action in PCOS.
Effect of long‐term administration of progestogen on post‐menopausal bone loss: result of a two‐year, controlled randomized study
Authors: Trémollières F. , Pouilles J. M. , Ribot C.
Published: March 2008

OBJECTIVE We determined whether a progestogen given alone to post‐menopausal women may prevent bone loss.

STUDY DESIGN Thirty‐five early post‐menopausal women who had not received any form of treatment to prevent bone loss were randomly assigned to a 2‐year regimen of 500 μ g/day of a gestagen derived from 19‐norprogester‐one (Promegestone) or a placebo for 21 days out of a 28‐day treatment cycle. Bone mineral density of the spine was measured by dual photon absorptiometry.

RESULTS After 2 years of treatment bone mineral density decreased significantly in the placebo group by a mean of 4.5%. In the gestagen group, the rate of bone change was significantly lower as compared to the placebo group (‐1.3%± 1.2% vs −4.5%± 2% (mean ± SEM), P & lt; 0.05). There were no changes in the biochemical bone turnover parameters in the placebo group but in the gestagen group a significant decrease was observed in the urinary calcium excretion after 2 years.

CONCLUSION The results suggest that a gestagen with no androgenic action can partly counteract early post‐menopausal bone loss.
Effects of 17 months treatment using recombinant insulin‐like growth factor‐I in two children with growth hormone insensitivity (Laron) syndrome
Authors: Heinrichs C. , Vis H. L. , Bergmann P. , Wilton P. , Bourguignon J. P.
Published: March 2008

OBJECTIVE With the availability of recombinant insulin‐like growth factor‐I (recIGF‐I), it was possible to study whether this peptide could promote growth without noticeable side‐effects in patients with growth hormone insensitivity syndrome (Laron syndrome). We report data obtained before and during 17 months treatment using recIGF‐I, 40 μg/kg s.c. twice a day, in two Lebanese siblings.

PATIENTS The boy and the girl showed very short stature (‐6.8 and −6.1 SDS), high GH (79 and 147 IU/I), low plasma IGF‐I (0.12 and 0.18 U/ml) and undetectable GH‐binding protein. Height velocities were 4.3 and 3.8 cm/year before treatment which started at 8.4 and 6.8 years of age, respectively.

RESULTS After 1–8 weeks of therapy, biological evidence of IGF‐I effect was obtained from reduction in serum GH and increase in procollagen‐I. During the first 6 months of treatment, height velocity increased to 7.8 and 8.4 cm/year without any clinical evidence of side‐effects. Between 6 and 12 months, growth response decreased to 6.6 and 6.3 cm/year. Between 12 and 17 months, growth rate returned to pretreatment values. Changes in bone mineral density paralleled growth response and bone maturation increased by 1 5 and 2 0 years during the first 12 months of treatment. Daily assessment of blood sugar showed asymptomatic low values (< 2 8 mM/I) in 11/730 and 22/730 measurements in the boy and the girl, respectively.

CONCLUSIONS Treatment of two patients with growth hormone insensitivity syndrome using 40 μ g/kg of IGF‐I twice a day resulted in increased linear bone growth and bone mineralization as well as increased bone maturation without remarkable adverse events. After 1 year of therapy, growth response could no longer be observed in these two patients.
Documentation of parathyroid carcinoma fifteen years after resection of a parathyroid ‘adenoma’
Authors: Ebner Susana , Emerson Charles H.
Published: March 2008

This report describes a 40‐year‐old man in whom the diagnosis of parathyroid carcinoma was made almost 15 years after resection of the primary lesion. The case emphasizes the importance of recognizing pre and intraoperative factors that differentiate between parathyroid adenoma and carcinoma and illustrates that surgical palliation is feasible in selected patients with parathyroid carcinoma.
The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle‐aged women: associations with serum lipids
Authors: Geul K. W. , van Sluisveld I. L. L. , Grobbee D. E. , Docter R. , de Bruyn A. M. , Hooykaas H. , van der Merwe J. P. , van Hemert A. M. , Krenning E. P. , Hennemann G. , Weber R. F. A.
Published: March 2008

OBJECTIVE We assessed the relative risk of both serum TSH and antithyroid antibody concentrations with regard to progression of thyroid failure and studied the lipid profiles of individuals with elevated TSH levels.

DESIGN, PATIENTS AND MEASUREMENTS In a randomly selected group of 427 women aged 40–60 (mean 55) years volunteering in an epidemiological survey in Zoetermeer, TSH and thyroid microsomal antibodies (TMA) were determined. Ten years after the initial survey only TSH was measured and the lipid profiles of the individuals with elevated serum TSH levels were studied and compared with a reference group.

RESULTS During follow‐up, four of 427 women were treated with thyroxine. Seventeen of 423 women initially had elevated serum concentrations of TSH (> 4 2 mU/l), 11 of whom were TMA positive. In the group of 406 women with initially a normal TSH, nine out of 37 (24%) TMA‐positive women developed elevated serum levels of TSH over 10 years. In contrast only 10 of 369 (3%) TMA‐negative women had elevated serum TSH levels 10 years after the initial survey (P < 0.001). Altogether, at the end of the observation period, 40% of TMA‐positive subjects had elevated serum TSH concentrations, compared to 3% in the TMA‐negative group (P < 0.01). TSH levels in the upper part of the normal range also appeared to have a predictive value: if those both with TSH levels between 2.0 and 4.2 and with a positive TMA status were contrasted with those without antibodies and low TSH, the crude relative risk was 71.5 (31.0–164.3), whereas the crude relative risk of presence versus absence of TMA was only 36.3 (18.8–70.3). Women with elevated TSH levels did not show changes in serum concentrations of total cholesterol (7 4 ± 1.1 mmol/l), apo‐A, (4.7 ± 1.0 mmol/l) and apo‐B (3.1 ± 0.7 mmol/l) lipoproteins, compared with control individuals (7.2 ± 1.3, 4.7 ± 0.8 and 3.0 ± 0.7 mmol/l, respectively).

CONCLUSIONS The determination of serum TMA in middle‐aged women can identify an important group of women at risk of developing an elevated serum TSH. TMA measurement is of potential use in the prevention of cardiovascular disease. An elevated serum TSH, however, in our study‐group does not seem to be accompanied by an abnormal lipid profile, as reported by others.
The regulation of insulin‐like growth factor binding protein (IGFBP)‐1 during prolonged fasting
Authors: Cotterill Andrew M. , Holly Jeffrey M. P. , Wass John A. H.
Published: March 2008

OBJECTIVE Insulin‐like growth factor binding protein (IGFBP)‐1 levels increase overnight, being inversely related to changes in insulin. With prolonged fasting IGFBP‐1 levels increase further. In animal studies high IGFBP‐1 levels increase plasma glucose levels possibly by regulating the insulin‐like actions of ‘bio‐available’ plasma IGF. Following prolonged fasting, there is an increase in insulin requirement. A proportion of this reversible insulin resistance may be due to inhibitory effects of high IGFBP‐1 levels on IGF action. This study examined the regulation of IGFBP‐1 in the presence of reversible insulin resistance.

SUBJECTS Nine normal adult volunteers, seven female and two male (mean age 27.6 ± SD 2.6 years, range 21.7–46.0 years) of normal body mass index were studied.

METHODS Subjects fasted from 2200 h day 0 to 0900 h day 3 (59 hours), the fast being completed with a 75‐g glucose meal. At least one week later, an 11‐hour overnight fast was performed, followed by a repeat glucose meal. Blood samples were taken at regular intervals from 0900 h day 1 and for 5 hours during both glucose meal studies via an indwelling cannula.

MEASUREMENTS Serum levels of IGFBP‐1, insulin, GH, glucose, IGF‐I and cortisol were measured at varying intervals during the fast and both glucose meal studies.

RESULTS Following the initial 11‐hour overnight fast IGFBP‐1 levels rose from (mean ± SEM) 32 ± 5 μg/l to reach a maximum of 144 ± 24μg/l after 32 hours of fasting. IGFBP‐1 levels then fluctuated, falling in the morning (93 ± 8μ/l) and then rising overnight (126 ± 9μ/l), but not regaining the initial peak levels. The increase of IGFBP‐1 from overnight fasting levels was associated with a fall in plasma insulin from 5.7 ± 0.7 to 2.2 ± 0.2 mU/l.

In comparison, 30 minutes after termination of the fast with the glucose meal, IGFBP‐1 levels fell from 120 ± 11 to 24 ± 2 μg/l within 4 hours. After an overnight fast IGFBP‐1 levels fell from 35 ± 5 to 13 ± 2 μg/l within 3 hours. There was glucose intolerance and increased insulin levels following the glucose meal preceded by the 59‐hour fast when compared with the overnight fast. The fall of IGFBP‐1 levels after the glucose meal was best expressed, taking into account subject variation, by the following regression equations: Glucose meal preceded by 11‐hour fast: log [IGFBP‐1] = 1 64–0 255 log [1 h previous insulin] (R2 0.51); Glucose meal preceded by 59‐hour fast: log [IGFBP‐1] 1.41–0.265 log [1 h previous insulin] ± 0.557 log [current glucose] (R2 0.82).

CONCLUSION In man, insulin appears to regulate circulating IGFBP‐1 levels in all circumstances, this regulation being unaffected by the resistance to insulin action induced by prolonged fasting. The high IGFBP‐1 levels were statistically related to the higher glucose levels and may have directly contributed to the increased insulin requirement observed after prolonged fasting.
ACTH‐independent Cushing's syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone
Authors: Close C. F. , Mann M. C. , Watts J. F. , Taylor K. G.
Published: March 2008

A 25‐year‐old primigravid woman presented with Cushing's syndrome at 23 weeks gestation; serum Cortisol was 1090 nmol/l at 0900 h, 1230 nmol/l at 2200 h; basal urinary free Cortisol excretion was 3680 nmol/24 h, and 8830 nmol/ 24 h after dexamethasone 8 mg daily for 48 hours; plasma ACTH was <1.1 pmol/l. CT scan of the adrenal glands showed bilateral adrenal hyperplasia. The hypercortisolism was controlled with metyrapone until elective delivery of the fetus by Caesarian section at 34 weeks gestation because of a decline in growth. No adverse fetal effects of metyrapone treatment were apparent, maternal outcome was uncomplicated and wound healing was unimpaired. Maternal adrenocortical function had returned to normal within 4 weeks of the cessation of pregnancy and biochemical remission has been maintained up to 9 months post‐partum. Metyrapone therapy is effective in controlling the hypercortisolism in certain cases of Cushing's syndrome complicating pregnancy.
Isolated congenital ACTH deficiency: a cleavage enzyme defect?
Authors: Nussey S. S. , Soo Shlu‐Ching , Gibsonf S. , Gout I. , White A. , Bain M. , Johnstone A. P.
Published: March 2008

The pro‐opiomelanocortin (POMC) gene encodes adreno‐corticotrophin (ACTH) which is derived from precursors by proteolytic cleavage. Congenital, isolated ACTH deficiency is rare but may be familial and fatal. The aetiology is unknown though defects at both hypothalamus and adenohypophysis have been postulated. We have studied a female presenting with hypoglycaemia in the neonatal period. When studied at 6 weeks of age, ACTH was unmeasurable even after injection of corticotrophin releasing hormone (CRH,_41). ACTH precursors, quantitated by two‐site immunuradiometric assay, were clearly measurable prior to treatment and were stimulated by CRH, 4, and suppressed by glucocorticoid administration. Concentrations of POMC, N‐terminal pro‐opiocortin (N‐POC) and β‐endorphin (β‐EP) were within the normal adult range during glucocorticoid replacement therapy; ACTH and βMipotrophin remained undetectable. The secretion of glucagon, measured by radioimmunoassay, in response to hypoglycaemia was normal. By sequencing polymerase chain reaction products from the patient's genomic DNA, the entire coding region of the POMC gene was established to be normal. The results are compatible with a cleavage enzyme defect.
Growth hormone dose regimens in adult GH deficiency: effects on biochemical growth markers and metabolic parameters
Authors: Møller Jens , Jørgensen Jens O. L. , Lauersen Torben , Frystyk Jan , Næraa Rune W. , Øsrskov Hans , Christiansen Jens S.
Published: March 2008

OBJECTIVE We examined the effects of different doses of GH on insulin‐like growth factor I (IGF‐I), IGF binding protein 3 (IGFBP‐3), body composition, energy expenditure, and various metabolites in GH deficient adults, in order to approach a metabolically appropriate GH dosage in young GH deficient adults.

DESIGN Ten GH deficient patients (age 21–43) were studied after 4 weeks without GH followed by three consecutive 4‐week periods, where the patients received in a fixed order GH 1,2 and 4 IU/m2 s.c. per day. At the end of each period the patients were hospitalized for a 24‐hour examination.

RESULTS Mean 24‐hour levels of GH (mIU/l) were 2.7±0.3 (0 GH), 7 2±0.9 (1), 10.8±1.5 (2) and 18.9±2.7 (4 IU/m2) (mean ±SEM) (P<0.01). Likewise, IGF‐I levels increased dose dependently from 61 ± 21 to 206 ± 65, 260 ± 70 and 468 ± 171 /μg/l (P < 0 05); serum IGF‐I in an age and sex matched control group was 248 ± 25 /μg/l. Corresponding serum IGFBP‐3 levels also increased from 1860 ±239 to 3261 ±379, 3762 ±434 and 4384 ±652 /μg/l (P = 001) respectively. Significant increases in diurnal serum insulin levels after 4 IU/m2 were recorded, whereas plasma glucose levels remained unchanged. Lipid intermediates increased dose independently during GH administration. GH caused a significant increase in resting energy expenditure, whereas the respiratory exchange ratio was unaltered. Fat mass was increased without GH therapy and decreased during the study. Four patients made complaints during 4 IU/m2 GH administration, probably related to GH induced fluid retention.

CONCLUSION Based primarily on IGF‐I and IGFBP‐3 levels our data suggest that a GH replacement dose in young GH deficient adults in the order of 1–2 IU/m2 per day is adequate. This is a relatively low dose as compared to dose regimens in children and adolescents.
Delta‐5‐androstenediol and its sulphate in serum and urine of normal adults and patients with endocrine diseases
Authors: Dikkeschei L. D. , Willemse P. H. B. , Wolthers B. G. , de Ruyter‐Buitenhuis A. W. , Nagel G. T.
Published: March 2008

OBJECTIVES We evaluated the role of delta‐5‐androste‐nediol (adiol) and its sulphates in health and endocrine diseases.

DESIGN Serum and urine samples from healthy adult men and pre and post‐menopausal women were analysed by gas chromatography‐mass spectrometry to establish reference values. In patients who were either evaluated or treated for endocrine diseases, sequential serum samples were collected and analysed.

PATIENTS Reference values were obtained from 24 healthy male, 23 premenopausal and 30 post‐menopausal female volunteers. Adiol and delta‐5‐androstenediol‐3‐sulphate (adiol‐3S) concentrations were determined in combination with other relevant steroids in patients with either pituitary (n= 5), adrenal (n= 2) or gonadal dysfunction (n= 1), or testicular carcinoma (n= 19).

MEASUREMENTS After addition of deuterated adiol as internal standard, serum and urine samples were extracted. Steroid sulphates were hydrolysed. The extracts and hydrolysates were purified on HPLC, adiol was derivatized and finally quantified by gas chromatography‐mass spectrometry.

RESULTS The calculated reference ranges for adiol and adiol‐3S concentrations in serum are respectively: in men 1.78–7.24 and 123–579 nmol/l, in premenopausal women 0 65–6 93 and 21 2–298 nmol/l and in post‐menopausal women 0 29–2 90 and 61–184 nmol/l. Urinary values varied considerably. In the population with endocrine abnormalities serum adiol and adiol‐3S concentrations were compared with other relevant steroids.

CONCLUSIONS The wide concentration range of adiol and adiol‐3S in urine makes analysis of these steroids in urine of little clinical value. Serum concentrations of adiol and adiol‐3S are higher in men than in women. Premenopausal values are higher than post‐menopausal. Adiol and adiol‐3S in serum are significantly correlated in pre and post‐menopausal women, r= 0 51 and r= 0–69 respectively, but not in men. In endocrine patients the serum concentrations of adiol show an ACTH or LH dependency in women; adiol correlates with Cortisol, dehydroepian‐drosterone or androstenedione and, in males, additionally with testosterone. However, in several situations adiol correlates with none of these steroids. Although adiol secretion can be stimulated by ACTH and LH, the level of serum adiol is also determined by other factors. Finally, in adrenal carcinoma serum adiol and adiol‐3S may be used as tumour markers.
Combined 17α‐hydroxylase/17,20‐lyase deficiency caused by heterozygous stop codons in the cytochrome P450 17α‐hydroxylase gene
Authors: Rumsby G. , Skinner C. , Lee H. A. , Honour J. W.
Published: March 2008

OBJECTIVE To determine the genetic defect underlying congenital adrenal hyperplasia due to 17α‐hydroxylase deficiency in a genetic female.

DESIGN Blood samples were used as a source of genomic DNA. A library of size selected genomic DNA sequences was prepared. In addition, portions of the 17α‐hydroxylase gene were amplified by the polymerase chain reaction and the gene products sequenced.

PATIENTS Samples were obtained from a patient with sexual infantilism, lack of secondary sexual characteristics and hypertension. Streak gonads were found on laparoscopy.

RESULTS Two point mutations were found, one in exon 3 and one in exon 4 which generate premature stop codons at codons 194 and 239 in place of glutamate and arginine respectively. The mutation in exon 3 has not previously been reported in patients with 17α‐hydroxylase deficiency.

CONCLUSION The protein product of these defective genes could be expected to be severely truncated with no catalytic activity. This is in keeping with the complete lack of Cortisol and sex steroid output in this patient. The polymerase chain reaction provides faster access to gene sequence information than previous procedures based on library screening prior to sequencing.
Pregnancy associated osteoporosis
Authors: Dunne Fidelma , Walters Boni , Marshall Tim , Heath David A.
Published: March 2008

OBJECTIVE Previous literature reports have suggested that osteoporosis associated with pregnancy is a rare event. We have examined the prevalence of this condition and compiled data on the largest group of such patients in the literature.

PATIENTS AND DESIGN With the help of the National Osteoporosis Society 35 women with pregnancy associated osteoporosis were identified. These women were matched with a control group from our already established computer data bank for age, weight, height and calcium status. Detailed questionnaires were sent to the osteoporotic sufferers enquiring about their present condition, past medical and drug history, and their menstrual, lactational and obstetric histories. They were also asked to complete a detailed dietary history to establish their calcium status. A questionnaire was also completed by the parents of these women and the parents of the control group, asking specifically about fracture history.

RESULTS Twenty‐nine women had idiopathic osteoporosis associated with pregnancy, while in six, the condition may have resulted from drug therapy or associated diseases. Pain occurring late in the first full term pregnancy was the most common presentation. The natural history was for the condition to improve with time. There was a significantly higher prevalence of adult related fractures (P < 02) occurring at an earlier age in the mothers of these women compared to a control population.

CONCLUSION We have identified 35 women who have developed osteoporosis during or shortly after pregnancy and in only six of them could a recognized underlying cause be suggested. These findings would suggest that idiopathic osteoporosis associated with pregnancy may be more common than the current literature suggests. The higher prevalence of fractures in the mothers of our population compared to controls raises the question of a possible associated genetic factor in the aetiology of this condition.
Two different pathogenetic mechanisms may play a role in acne and in hirsutism
Authors: Toscano Vincenzo , Balducci Rina , Bianchi Patrizia , Guglielmi Rinaldo , Mangiantini Adele , Rossi Fabia G. , Colonna Loredana M. , Sciarra Francesco
Published: March 2008

OBJECTIVE Acne is one of the most common skin disorders. Androgens are known to play an important and possibly central role. Androgens secreted from ovaries and adrenal glands (androstenedione, dehydroepiandro‐sterone and its sulphate, testosterone) and target tissue‐produced androgens (testosterone and its 5α‐reduced metabolite, dihydrotestosterone) have been implicated. Although the sebaceous gland and the hair follicle form a single morphological entity, the pilosebaceous unit, acne and hirsutism do not always appear concomitantly, thus leading to the supposition that these two structures may have different degrees of sensitivity to similar androgenic stimulation.

DESIGN AND PATIENTS To determine whether acne and hirsutism are the clinical expression of a different androgen metabolism at target tissue levels we studied 90 randomly selected patients who came to our Out‐patient Department for diagnosis and treatment during the last 2 years with isolated acne of mild to severe degree and 52 patients with idiopathic hirsutism without acne or history of acne.

Twenty‐four women without acne or hirsutism and without a history of endocrine disease were studied as controls.

MEASUREMENTS In both groups of patients, plasma levels of sex hormone binding globulin, of dihydrotestosterone, and of 3α‐androstanediol and of its glucuronide were evaluated. In all patients the percentage of free testosterone and the testosterone/sex hormone binding globulin ratio were also calculated.

RESULTS Patients with acne and those with isolated hirsutism showed significantly decreased sex hormone binding globulin plasma levels. The values of the percentage free testosterone and those of the testosterone/sex hormone binding globulin ratio were, on the contrary, higher with respect to the controls, although there were no statistically significant differences between the two groups. Significantly increased plasma levels of dihydrotestosterone with respect to the controls were observed in patients with acne or in those with hirsutism. However, while all patients with hirsutism showed increased plasma values of 3α‐androstanediol and its glucuronide, all patients with acne showed plasma levels within the normal range, independently of the precursor plasma levels.

CONCLUSIONS Our results demonstrate that dihydrotestosterone is further reduced to 3α‐androstanediol and its glucuronide only in hirsute patients but not in acne patients. These results suggest that dihydrotestosterone may undergo different metabolic pathways at skin levels and support the hypothesis that the two clinical manifestations may be the expression of the different metabolic fate of dihydrotesterone itself. Moreover, our results demonstrate that 3α‐androstanediol and its glucuronide cannot be used as plasma markers of target‐tissue produced androgens in all hyperandrogenic conditions.
Plasma 19‐hydroxyandrostenedione is elevated in patients with high renin essential hypertension
Authors: Sekihara Hisahiko , Yonemitsu Keiko , Yazaki Yoshio
Published: March 2008

OBJECTIVES We have reported that 19‐hydroxyandrostenedione (19‐OH‐A‐dione) functions as an amplifier of the sodium‐retaining and hypertensive action of aldosterone. We therefore measured 19‐hydroxyandrostenedione in hypertensive patients.

PATIENTS AND MEASUREMENTS We studied 53 normal male control subjects and 63 male patients with essential hypertension (48 patients with normal renin essential hypertension and 15 patients with high renin essential hypertension). Plasma 19‐OH‐A‐dione levels were measured by RIA.

RESULTS Plasma 19‐OH‐A‐dione concentrations in control subjects and patients with normal and high renin essential hypertension were 115 ± 46 (meaniSD), 112 ± 49 and 201 ± 79 pmoI/I, respectively. Patients with high renin essential hypertension showed significantly higher 19‐OH‐A‐dione concentrations than did control subjects. The evaluation of the correlation between plasma 19‐OH‐A‐dione concentrations and plasma renin activity revealed that plasma 19‐OH‐A‐dione concentrations in hypertensive subjects rose gradually with an increase in plasma renin activity. Therefore, a significant correlation was found between plasma renin activity and plasma 19‐OH‐A‐dione (r= 0 586, P < 0001). In contrast, in control subjects, no significant correlation was found between plasma renin activity and plasma 19‐OH‐A‐dione (r=0 059, P<0 05).

conclusions The secretion of 19‐OH‐A‐dione from the adrenal cortex is under the control of the renin‐angiotensin system in hypertensives but not in normotensives.
Impact of 2 weeks high dose growth hormone treatment on basal and insulin stimulated substrate metabolism in humans
Authors: Meller N. , Møller J. , Jørgensen J. O. L. , Ovesen P. , Schmitz O. , Albert K. G. M. M. , Christiansen J. S.
Published: March 2008

OBJECTIVE Short‐term, high dose growth hormone (GH) treatment has been advocated in many catabolic disease states. It is likely that some of the anabolic effects of GH are mediated through activation of lipolysis, but the metabolic impact of therapeutically relevant GH exposure is not known in detail. The present study was accordingly designed to assess the effects of such GH exposure on basal and insulin stimulated intermediary metabolism.

DESIGN, PATIENTS AND MEASUREMENTS Six healthy young females were examined following daily injections of GH (12 IU/day) or saline for 2 weeks in a placebo controlled design. Each study consisted of a 3 hour basal period and a 2 hour hyperinsulinaemic euglycaemic clamp.

RESULTS GH treatment caused (1) increased levels of IGF‐I (382 ± 46 vs 294 ± 22 /μg/l, P < 0 05) and (2) increased basal values of free fatty acids (714 ±40 (GH) vs 634 ±64 (placebo) μmol/l, P<0 05), 3‐hydroxybutyrate (118 3 ± 42 8 (GH) vs 57 7 ± 21 6 (placebo) μmol/l, P < 0 05), glycerol (54–3 ±8–2 (GH) vs 41–4 ±8–4 (placebo) μmol/l, P<0 05) and forearm uptake of 3‐hydroxybutyrate, together with increments of plasma glucose (5 28 ±0–11 (GH) vs 4 87±0 16 (placebo) mmol/l, P<0 05). Basal forearm uptake of glucose, isotopically determined glucose turnover and serum levels of GH, insulin and C‐peptide were unaltered.

During the clamp GH treatment was associated with (1) a 40% decrease in the administered amount of glucose (M‐value) (P<0 05) and (2) a 70% decrease in forearm glucose uptake (P<0 05).

Indirect calorimetry revealed a 15% increase in resting energy expenditure (P<0 05) and a decreased basal respiratory exchange ratio (0 75 (GH) vs 0 80 (placebo), P<0 05), presumably reflecting increased lipid oxidation. CONCLUSIONS Administration of GH in a therapeutic dose for 2 weeks, despite apparently normal daytime levels of major metabolic hormones, induces significant increases in circulating lipid fuel substrates, increased energy expenditure and lipid oxidation, together with insulin resistance. Such effects should be considered when applying GH treatment schedules clinically.
Abnormal twenty‐four hour pattern of pulsatile luteinizing hormone secretion and the response to naloxone in women with hyperprolactinaemic amenorrhoea
Authors: Tay Clement C. K. , Glasier Anna F. , Illingworth Peter J. , Baird David T.
Published: March 2008

OBJECTIVE Hyperprolactinaemic amenorrhoea is associated with disturbances of pulsatile gonadotrophin secretion. The underlying mechanism remains unclear and the aim of this study was to investigate the 24‐hour secretory pattern of gonadotrophins in women with hyperprolactinaemic amenorrhoea. The effect of opioid blockade using naloxone infusion on LH secretory pattern was also studied.

DESIGN The secretory patterns of LH, FSH, PRL and their responses to naloxone infusion were studied by serial blood samples collected at 10‐minute intervals for 24 hours. On the following day, naloxone was infused at a dose of 1 6 mg per hour for 4 hours.

PATIENTS Eight women with hyperprolactinaemic amenorrhoea, two women hyperprolactinaemic but with normal ovarian cycles, and nine control subjects in the early follicular phase of menstrual cycle.

MEASUREMENTS Concentrations of LH, FSH and PRL were measured in plasma samples obtained at 10‐minute intervals for 24 hours. In one woman, concentrations of urinary oestrone glucuronide were measured daily during treatment with pulsatile GnRH.

RESULTS The number of LH pulses per 24 hours was significantly fewer in women with hyperprolactinaemic amenorrhoea than in those with hyperprolactinaemia with normal cycles or control subjects (mean ± SEM 4.5 ± 2.4 vs 13.5 ± 2.5 vs 17 3±0 8, P<0 001). The magnitude of each episode of secretion was significantly higher in the hyperprolactinaemic amenorrhoeic women (P<005) so the overall mean concentrations of LH throughout the 24‐hour period was similar in the three groups (5 2±1 1, 4.8±0 8 and 5.2 ±0.4 U/I respectively). In women with hyperprolactinaemic amenorrhoea there was no significant change in the pattern of LH secretion during sleep in contrast to the control women in whom there was a slowing in the LH pulse frequency during the night. There was no significant change in the mean concentrations of LH, FSH and PRL during the naloxone infusion. There were also no significant changes in the LH pulse frequency in response to naloxone infusion when compared with an equivalent period of time in the previous 24 hours. In one hyperprolactinaemic amenorrhoeic woman, follicular development, ovulation and pregnancy were induced when gonadotrophin releasing hormone (GnRH) was infused in a pulsatile manner at a dose of 5 μg every 90 minutes.

CONCLUSIONS The suppression of normal ovarian cycles in women with hyperprolactinaemic amenorrhoea is due to a significant reduction in frequency of LH (GnRH) secretion which is not due to an increase in hypothalamic opioid activity. As normal ovarian cycles can occur or be induced by exogenous GnRH in hyperprolactinaemia, it is unlikely that a high level of prolactin by itself inhibits follicular development and ovulation.
Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhoea
Authors: Genazzani Alessandro D , Petraglia Felice , Volpogni Cristina , Pianazzi Francesco , Montanini Vanna , D'Ambrogio Gerardo , Genazzani Andrea R.
Published: March 2008

OBJECTIVE Since growth hormone (GH) is administered as a co‐gonadotrophic factor in ovulation induction, this study aimed to assess the action of GH on the episodic pulsatile release of LH and FSH in amenorrhoeic patients. PATIENTS AND DESIGN Nineteen patients affected by hypothalamic amenorrhoea were enrolled for this study: group A, 9 patients with normal gonadotrophins; group B, 10 patients with low gonadotrophins. Both groups were studied during GH infusion (0015 IU/min for 4 hours) and after 7 days of GH administration (0 1 IU/kg/day). Patients underwent a 4‐hour pulsatility study, with blood sampling every 10 minutes. A standard GnRH test (10 μ g i.v. bolus) was performed immediately after the pulsatility evaluation.

MEASUREMENTS LH and FSH were assayed with an IFMA method; oestradiol and IGF‐I were assayed by RIA and IRMA, respectively.

PULSE DETECTION Time series were analysed with Detect program.

RESULTS All patients showed similar LH and FSH pulsatile characteristics both under baseline conditions and during GH infusion. After 7 days of GH administration, episodic FSH release showed no change in either group. On the contrary, LH pulse frequency (mean ± SE) significantly increased in group A (4 0±0 2 peaks/4h, P&kt;0 05), while putse amplitude (baseline, 3.9± 0 6 IU/I; after 7 days, 2.9±0.3 IU/I, P<0 05), and integrated LH plasma concentrations (baseline, 7.6 ±1–1 IU/I; after 7 days, 5±0 8 IU/I, P<0 05) were significantly decreased. No significant changes were observed for LH pulse frequency, amplitude or integrated LH plasma concentrations in hypogonado‐trophinaemic patients (group B). Plasma oestradiol levels were significantly increased only in group A (baseline, 154 18±23 8 pmoI/I; after 7 days, 380 3±110 1 pmoI/I, P < 005), while IGF‐I levels were significantly increased in both groups after 7 days of GH administration (P<0 05). No significant differences were observed in the gonadotropin responses to GnRH test before and after GH administration.

CONCLUSIONS The present study showed that the administration of GH in amenorrhoeic patients determines the significant changes in episodic LH release in those subjects with normal LH plasma levels and suggests that the action of GH may be dependent upon the ovarian‐pituitary feedback action.
Recombinant human growth hormone therapy does not increase microalbuminuria in children with short stature
Authors: Levine Daniel , Kreitzer Paula , Freedman Samuel , Trachtman Howard
Published: March 2008

OBJECTIVE Concerns have been raised about possible adverse effects of growth hormone on renal function. We measured microalbuminuria as a sensitive index of early glomerular damage in children being treated with recombinant human growth hormone.

DESIGN AND PATIENTS Microalbuminuria was measured in a group of 17 children with short stature being treated with recombinant human growth hormone and in a group of 13 patients with idiopathic short stature not receiving therapy.

MEASUREMENTS Microalbuminuria was measured by a commercially available ELISA and urinary creatinines were determined using a Beckman creatinine analyser.

RESULTS The level of microalbuminuria was 0 484 ± 0 275 g albumin/mol creatinine (mean ± SD) in the patients receiving growth hormone and 0 681 ±0 574 g albumin/mol creatinine in the untreated controls. There was no statistically significant difference between these values.

CONCLUSIONS Treatment with recombinant human growth hormone does not cause an increase in microalbuminuria in children with normal renal function. This supports the safety of this medication in growth hormone deficient children with normal renal function.
Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing's syndrome: Is combined CRF and TRH stimulation of value?
Authors: McNally Paul G. , Bolia Amman , Absalom Steve R. , Falconer‐Smith James , Howlett Trevor A.
Published: March 2008

OBJECTIVE We determined whether the measurement of hormones in pituitary blood permits correction for dilution by non‐pituitary blood during bilateral simultaneous inferior petrosal sinus blood sampling in Cushing's syndrome. DESIGN Bilateral simultaneous inferior petrosal sinus blood sampling was performed after combined hCRF and TRH stimulation. Peak ACTH concentrations were corrected for the TSH and PRL inter‐sinus ratio, assuming uniform secretion of both hormones into each inferior petrosal sinus.

PATIENTS Eight patients with clinical and biochemical features of Cushing's syndrome.

MEASUREMENTS Basal and stimulated ACTH, TSH and PRL concentrations were measured after bilateral simultaneous inferior petrosal sinus blood sampling and simultaneously from a peripheral forearm vein.

RESULTS Basal central peripheral ACTH ratio misdiagnosed four of eight patients as having non‐pituitary disease. Peak uncorrected ACTH central:peripheral ratio erroneously suggested two of eight patients had non‐pituitary disease. ACTH central: peripheral ratio corrected by TSH and PRL correctly predicted pituitary‐dependent disease in all eight cases and provided correct lateralization data in four of five patients with a unilateral pituitary microadenoma.

CONCLUSION This study suggests that measuring other hormones in pituitary blood after TRH stimulation can offer a simple and reliable method for correcting for dilution by non‐pituitary blood during bilateral simultaneous inferior petrosal sinus blood sampling in Cushing's syndrome.
Modulation of IGF‐I receptors by exogenous hGH treatment in constitutionally short children
Authors: Eshet R. , Klinger B. , Silbergeld A. , Laron Z.
Published: March 2008

OBJECTIVE To study the in‐vivo regulation of IGF‐I binding sites on erythrocytes (RBC) following administration of growth hormone (hGH) to constitutionally short children. Recently, owing to biosynthetic techniques, treatment with hGH has been administered not only to children with GH deficiency but also to children with constitutional growth delay and with familiaf short stature.

PATIENTS AND DESIGN Growth hormone (rhGH‐Norditropin, Novo/Nordisk) was administered at a dose of 0 1 U/kg/ day s.c. to 11 children with constitutional short stature. Before and at 1–2 months after initiation of treatment IGF‐I binding sites and serum IGF‐I were determined. Erythrocytes were separated from whole blood by centrifugation over Ficoll Hypaque and used to assess IGF‐I binding sites.

RESULTS Serum IGF‐I levels increased from 14 93 ±1 50 nmoI/I (mean±SEM) to 30 29 ±2 32 nmoI/I, with a mean difference of 15 38 + 2 21 (P= 0 00001). Concomitantly, the number of binding sites per cell decreased from 5 77 ±0.81 sites per celt (m±SEM) to 2 10 ±0 36, with a mean difference of ‐ 3 67 ± 0 76 (P= 0.0003). The dissociation constant (Kd) also decreased from 0 47±016 MM (m±SEM) to 0.10±0 02 with a mean difference of 0 37±0.16 (P=0.02), indicating an increase in the affinity of the receptors.

CONCLUSION Treatment of children with constitutional short stature with hGH raises the circulating IGF‐I levels and down‐regulates the IGF‐I receptors: This study shows that IGF‐I is capable of regulating its homologous receptor concentrations in vivo and it is suggested that the measurement of IGF‐I binding sites on RBC may be used for the diagnosis of subtle states of resistance to IGF‐I.
Luteinizing hormone secretion and hypoandrogenaemia in critically ill men: effect of dopamine
Authors: Van den Berghe Greet , de Zegher Francis , Lauwers Peter , Veldhuls Johannes D.
Published: March 2008

OBJECTIVE Critical Illness has been associated with decreased LH secretion and lowering of testosterone. Dopamine is often used for vasoactive support in these patients. We therefore aimed to Investigate LH secretion during severe illness and particularly the effect exerted by dopamine on LH in such patients.

PATIENTS AND DESIGN In a randomized, controlled study of critically 111 adult male polytrauma patients (n= 8), we evaluated the effect of prolonged (83‐298 hours) dopamine infusion (5μg/kg/mln I.v.) on the dynamics of LH secretion and on serum testosterone Concentrations. The effect of brief (15‐21 hours) dopamine administration was documented in an additional randomized, controlled, crossover study involving 6 patients.

MEASUREMENTS Serum LH concentrations were measured by IRMA. The LH profiles, obtained by blood sampling every 20 minutes for 9 hours during two consecutive nights, were examined by deconvolution analysis. Serum testosterone concentrations were measured by RIA once per study night. RESULTS We found that before dopamine initiation and within 24 hours of dopamine withdrawal, the mean serum LH concentrations, the LH secretory amplitude, the amount of LH secreted per burst, the mean LH secretion rate and the number of LH pulses were higher than during dopamine infusion, being increased by a median of 161 % (P= 0·006), 98% (P= 0·03), 106% (P= 0·03). 164% (P= 0·01) and 25% (P= 0·008) respectively. However, without dopamine administration the amplitude and mass of the LH secretory bursts still appeared to be low, whereas the pulse frequency remained elevated. After dopamine withdrawal, LH secretion increased significantly within 3 hours. Serum testosterone levels were very low and dopamine infusion appeared not to affect them within 24 hours.

CONCLUSION We documented decreased LH secretory pulse amplitude and mass with Increased pulse frequency, as well as very low serum testosterone concentrations in critically ill men. Dopamine Infusion further suppressed LH release by decreasing secretory burst amplitude, mass and frequency, possibly through an inhibitory action at both the pituitary and the hypothalamic level.
Inhibition of growth hormone release after the combined administration of CHRH and GHRP‐6 in patients with Cushing's syndrome
Authors: Leal‐Cerro Alfonso , Pumar Alfonso , Garcia‐Garcia Emlllo , Dieguez Carlos , Casanueva Felipe F.
Published: March 2008

OBJECTIVE In patients with Cushing's syndrome there is a blunted OH response to all types of stimuli. Although Inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the bask mechanism is unknown. His‐d‐TRP‐ALA‐TRP‐d‐Phe‐Lys‐NH2 (GHRP‐6) is a synthetic hexapeptlde which releases GH by a direct pituitary effect through receptors other than GHRH receptors. Furthermore, the combined administration of GHRH and GHRP‐6 is able to induce a large OH discharge even in some pathological states such as obesity, associated with GH blockade.

To gain further insight into the disrupted mechanisms of GH secretion, Cushing's syndrome patients were challenged with either GHRH, GHRP‐6 or GHRH together with GHRP‐6. A group of normal subjects was included for control purposes.

DESIGN Three different tests were undertaken: (a) GHRH 100 μg I.v.; (b) GHRP‐6 100 μg I.v. and (c) GHRH plus GHRP‐6 100 μg I.v. of each; administered to each subject on different days, at least 4 days apart.

PATIENTS Ten patients (8 women, 2 men) with untreated Cushing's syndrome, 9 Cushing's disease and 1 adrenal adenoma. Five healthy volunteers (3 women, 2 men) of similar ages served as a control group.

MEASUREMENTS Plasma OH levels were measured by immunoradiometric assay.

RESULTS The areas under the curve (AUC) of OH secretion (mean ± SEM In μ/1/120 mi) in the control subjects after each test were: GHRH, 1420 ± 330; GHRP‐6, 2278 ± 290 and GHRH plus GHRP‐6,7332 ± 592 (P < 0·05 vs each compound alone). The AUCs for Cushing's syndrome patients were: GHRH, 248 ± 165; GHRP‐6 530 ±170 and for GHRH plus GHRP‐6, 870 ± 258 (P < 0·05 vs GHRH alone). After the combined stimulus only one out of the ten patients with hypercortisolism showed a GH peak over 20 μ/l, while ail the controls had a peak over 04mU/l.

CONCLUSIONS GHRP‐6 induced OH secretion as well as the OH discharge elicited by GHRH and GHRP‐6 are considerably reduced in Cushing's syndrome patients. This suggests that the main impairment of GH secretion in that pathological state resides at pituitary level.
Abnormal response of luteinizing hormone beta subunit to thyrotrophin‐releasing hormone in patients with non‐functioning pituitary adenoma
Authors: Gil‐dei‐Alamo Paloma , Pettersson Kim S. I. , Saccomanno Katia , Spada Anna , Faglia Giovanni , Beck‐Peccoz Paoio
Published: March 2008

OBJECTIVE it has been suggested that the response of free β‐subunit of LH (LHβ) to TRH Is the most useful in‐vivo marker of gonadotroph adenomas in patients with non‐functioning pituitary adenomas (NFPA). The aim of the present study was to investigate LHβ secretion in patients with NFPA in whom other markers of gonadotroph adenomas, such as supranormal basal concentrations or responses of intact gonadotrophins to TRH, were absent.

DESIGN AND PATIENTS Serum basal levels Of LHβ, LH and FSH were evaluated in 80 patients with NFPA showing normal levels of intact gonadotrophin, 20 with PRL‐secreting adenomas, 25 with OH‐secreting adenomas and 58 healthy subjects. Moreover, LHβ, LH, FSH and alpha‐subunit (α‐SU) were evaluated in 27 patients with NFPA In whom intact gonadotrophin responses to TRH were absent, 8 with PRL‐oma, 7 with GH‐oma and 17 healthy subjects before and 20,30 and 60 minutes after the intravenous administration of either 200 μg TRH or placebo. A response was considered present when serum LHβ increased by at least 50% above basal levels.

MEASUREMENTS LHβ was evaluated using a new assay based on the sequestration of the combined and free α‐SU by an anti α‐SU blotinylated monoclonal antibody (MAb) and the subsequent measurement of the LHβ by an IFMA method employing two MAbs directed towards two different epitopes on LHβ. intact LH and FSH were assayed with an IFMA method and α‐SU with an IRMA method.

RESULTS in basal conditions, no significant difference in the mean values of LHβ was observed among patients with different types of tumour and normal controls. In 9 of 27 (33%) patients with NFPA, TRH caused an abnormal elevation of serum LHβ (net increase 410 ± 403%, range 71‐1300) which was completely dissociated from changes in intact gonadotrophins. Of the 5 patients who had a TRH test repeated after transsphenoidal surgery, abnormal LHβ responses disappeared in 2 and were maintained in 3. Disappearance of LHβ response occurred only in patients in whom improvement of visual field and radiological imaging after adenomectomy was observed. in contrast, in ail patients with pituitary tumours other than NFPA and healthy subjects a response to TRH was absent (net increase ranging from 0 to 23%). immunofluorescence, performed on 14 NFPA removed from patients either responsive or unresponsive to TRH, showed a variable proportion of cells positive for LHβ, without a significant difference between the two groups.

CONCLUSIONS These results indicate that measurement of basal LHβ is of poor value in the diagnosis of non‐functioning pituitary adenomas and the identification of gonadotroph adenomas among non‐functioning pituitary adenomas. Conversely, an abnormal response of free LHβ to TRH occurs in about a third of patients with low/normal basal gonadotrophins unresponsive to TRH stimulation.