bluuebunny/crossref_metadata_2025 huggingface dataset:
MEGAVOLTAGE PITUITARY IRRADIATION IN THE MANAGEMENT OF CUSHING'S DISEASE AND NELSON'S SYNDROME: LONG‐TERM FOLLOW‐UP
Authors: HOWLETT T. A. , PLOWMAN P. N. , WASS J. A. H. , REES L. H. , JONES A. E. , BESSER G. M.
Published: March 2008

We report the long‐term follow‐up of the clinical and biochemical effects of megavoltage pituitary irradiation (radiotherapy; RT), administered as primary or secondary therapy, for pituitary Cushing's disease and Nelson's syndrome in 52 patients. Irradiation was administered, from a 4–15 MeV linear accelerator, via a three‐field technique (two lateral, one frontal), to a total dose of 4500 cGy (rad) in 25 fractions over 35 days. Twenty‐one patients received RT as primary ablative therapy for Cushing's disease and were under follow‐up 5.8 to 15.5 years later (median 9.5 years). All were initially treated with metyrapone to induce normal mean plasma cortisol levels, and all achieved clinical remission on this therapy. At latest follow‐up, 12 (57%) are off all therapy, in clinical remission, with a normal mean cortisol through the day; however, only two show completely normal plasma cortisol responses to dynamic testing; four remain on medical therapy with metyrapone or op'DDD and all have required a steady dose reduction accompanied by falling plasma ACTH levels; five have required alternative therapy with bilateral adrenalectomy and/or transsphenoidal hypophysectomy. Fifteen patients received RT for Nelson's syndrome, developing after bilateral adrenalectomy, and have been followed up for 1.5 to 17.3 years (median 9–6 years). Fourteen patients showed progressive de‐pigmentation, shrinkage of the pituitary adenoma and fall in plasma ACTH levels to 1–72% (median 16%) of the pre‐RT basal value. In the remaining patient an initial fall in plasma ACTH was followed by tumour enlargement at 6 years, leading to death at 11 years after RT. Of the remaining patients, results are assessed in nine who received RT after unsuccessful transsphenoidal surgery, three after transfrontal surgery for aggressive macroadenomas, and four prophylactically after bilateral adrenalectomy. Radiotherapy remains a valuable second‐line therapy for Cushing's disease and its complications.
TAMOXIFEN PROLONGS LUTEAL PHASE IN PREMENOPAUSAL WOMEN BUT HAS NO EFFECT ON THE SIZE OF UTERINE FIBROIDS
Authors: LUMSDEN M. A. , WEST C. P. , BAIRD D. T.
Published: March 2008

Tamoxifen (20 mg per day) was administered for at least 3 months to six premenopausal women with uterine fibromyomata. In all the women there was an increased variability in the length of the menstrual and ovarian cycle associated with a significant lengthening of the luteal phase (16.9 ± 3.5 vs 12.5 ± 1.5 days, mean ± SD, P < 0.02). The concentration of oestradiol and progesterone in plasma and their metabolites in urine (oestrone glucuronide and pregnanediol) increased reflecting multiple follicular development and ovulation. There was a significant rise in the concentration of FSH during the luteal phase of the cycle (8.0 ± 2.9 vs 2.0 ± 1.7 U/I, P < 0.01). There was no change in the size of the uterine leiomyomata. These results demonstrate that the antioestrogen tamoxifen results in an increased secretion of gonadotrophins by antagonizing the effects of oestradiol at the hypothalamus and anterior pituitary. The lengthening of the luteal phase suggests oestradiol may play a role in the mechanism of luteal regression either locally or via feedback effect on gonadotrophins.
AN ATTEMPT TO ALTER THE PATHOPHYSIOLOGY OF POLYCYSTIC OVARY SYNDROME USING A GONADOTROPHIN HORMONE RELEASING HORMONE AGONIST—NAFARELIN
Authors: WILLIAMS IOLA A. , SHAW ROBERT W. , BURFORD GRAHAM
Published: March 2008

The aim of this study was to see whether the pathophysiology of polycystic ovary syndrome could be altered by suppressing the abnormal cycle of events associated with abnormal gonadotrophins and androgens. Fifteen women with polycystic ovary syndrome were treated with the GnRH agonist Nafarelin at a dosage of 200 μg twice daily intranasally for a period of 3 or 6 months. Eight of these women also had a dexamethasone suppression test 0.5 mg four times daily for 48 h before and after treatment with Nafarelin, in order to differentiate between an adrenal and ovarian source for the excess androgens. Gonadotrophins and androgens were well suppressed, LH to a mean of 1.5 IU/1, testosterone to 1.1 nmol/1 and androstenedione to 6.4 nmol/1. Three months after discontinuing Nafarelin, all these hormones had returned to pretreatment levels. The ultrasound appearance of the ovaries showed no consistent reduction in ovarian volume or the disappearance of ovarian follicles. Hirsutism showed slight improvement in four out of seven patients. After treatment one patient out of the eight complaining of infertility, conceived spontaneously and one patient ovulated on a reduced dosage of clomiphene. There was no change in the menstrual pattern of the others. Despite the achievement of good hormonal suppression, there was no change in the condition after therapy was discontinued suggesting that whatever the cause of the condition it remains a permanent situation.
PITUITARY FUNCTION IN ISOLATED GONADOTROPHIN DEFICIENCY
Authors: YEH JOHN , REBAR ROBERT W. , LIU JAMES H. , YEN SAMUEL S. C.
Published: March 2008

Hypothalamic‐pituitary function was assessed in 24 individuals with isolated gonadotrophin deficiency (IGD). Thirteen had normal olfaction (Group I) while 11 (Group II) had anosmia (Kallmann's syndrome). In response to a 10 pg intravenous (i.v.) bolus of GnRH, the minimal dose required to evoke a consistent gonadotrophin response in normal subjects, the patients responded with significant LH and FSH increases over baseline (P < 0.01). In Group II patients, large doses (150 μg) of GnRH, which elicit maximal release of gonadotrophin in normal subjects did not increase gonadotrophin release beyond that produced by a 10 μg bolus. In response to two 10 μg GnRH doses, at times 0 and 120 min, the IGD patients responded with similar LH increases to both boluses (both P < 0.01 compared to baseline). The maximal PRL responses to arginine infusion and to TRH in the male patients were similar to those of normal males. However, in the IGD females, the PRL response to TRH was less than in normal females. The TSH responses to TRH in IGD males and females were similar to each other and similar to normal. The IGD male GH response to arginine infusion was comparable to that in normal males. We conclude that (1) IGD patients appear to retain minimal endogenous GnRH secretion so that the IGD pituitary responds to a minimal dose of GnRH without priming; (2) IGD is a heterogeneous syndrome in which affected individuals with and without normal olfaction represent parts of the spectrum of the same disease; and (3) except for the PRL response in females, the PRL, TSH and GH responses demonstrate that the IGD pituitaries are largely intact.
A CLOSE CORRELATION BETWEEN THE INHIBITORY EFFECTS OF INSULIN‐LIKE GROWTH FACTOR‐I AND SMS 201‐995 ON GROWTH HORMONE RELEASE BY ACROMEGALIC PITUITARY TUMOURS IN VITRO AND IN VIVO
Authors: LAMBERTS S. W. J. , VAN KOETSVELD P. , HOFLAND L.
Published: March 2008

In the present study we compared the in‐vitro effects of IGF‐I and SMS 201–995 on GH release by cultured tumour cells obtained from seven acromegalic patients with the preoperative in‐vivo GH dynamics, including the acute response to 50μg SMS 201–995 subcutaneously. IGF‐I and SMS 201–995 inhibited GH release during a 24 h incubation in four and five of the seven tumour cell preparations, respectively. The inhibitory effect of SMS 201–995 was greater than that exerted by IGF‐I (P < 0.01). There was a close correlation between the in‐vitro inhibitory effects of IGF‐I and SMS 201–995 (P < 0.01). In addition, the acute inhibitory effect of 50 μg SMS 201–995 on circulating GH levels in vivo correlated with the inhibitory effects in vitro of both SMS 201–995 (P < 0.01) and IGF‐I (P < 0.05). The inhibitory effects of IGF‐I and SMS 201–995 on GH release in vitro were shown to be additive in two of four tumours. There was no relation between the in‐vitro effects of IGF‐I and/or SMS 201–995 and several in‐vivo parameters, including fluctuations in GH levels, sleep‐induced GH release, a paradoxical increase of GH in response to TRH, and the circulating IGF‐I and PRL levels. In conclusion: (1) there is a close correlation between the sensitivity of GH release by cultured human adenoma cells to IGF‐I and SMS 201–995. (2) There is also a close correlation between the in‐vivo inhibitory effect on GH release of SMS 201–995 and the in‐vitro inhibitory effects of both SMS 201–995 and IGF‐I. (3) A subgroup of acromegalic patients harbour pituitary tumours in which the qualitative regulation of hormone secretion is similar to that of normal GH secretion.
PROLACTIN AND LUTEINIZING HORMONE PROFILES OF CURED ACROMEGALIC SUBJECTS
Authors: ROELFSEMA F. , FRÖLICH M. , DE BOER H.
Published: March 2008

The 24‐h PRL and LH hormone profiles were analysed of 16 cured male acromegalic patients who had undergone selective transsphenoidal surgery 4‐9 years previously. Eight of these patients also underwent pituitary irradiation. Blood samples were taken at 20‐min intervals; the PRL and LH data were analysed with the cluster program, ARIMA modelling, cross‐correlation techniques, Fourier analysis, and cosinor analysis. About 10‐11 PRL and LH peaks were demonstrated for both non‐irradiated and irradiated patients. The absolute heights of PRL pulses and the mean valley levels were significantly greater for irradiated patients than for non‐irradiated patients, but the increment in amplitude did not differ. A significant diurnal rhythm for PRL was found for all non‐irradiated patients but for only one irradiated patient. LH pulse area and amplitude were lower in the group of irradiated patients. The incremental responses of LH and PRL to GnRH and TRH, respectively, were lower in irradiated patients than in non‐irradiated patients. During the night (0200‐0800 h) the number of PRL pulses decreased in non‐irradiated patients but not in irradiated patients. Pulse nadirs and amplitudes increased during the evening and night in non‐irradiated patients but were constant in irradiated subjects. Bivariate modelling of the data for 14 patients revealed significant cross‐correlations between LH and PRL pulses in nine subjects. This study demonstrates that the pulsatile secretion of PRL and LH in treated acromegalics is basically normal. Additional radiation therapy, however, may lead to damage of the hypothalamus, as reflected by the absence of a circadian PRL rhythm. A direct influence on the pituitary by radiation is indicated by the decreased magnitude of LH pulses and the diminished response of LH and PRL after injection of GnRH and TRH, respectively.
THE EFFECT OF CALCITONIN ON GROWTH HORMONE SECRETION IN ACROMEGALY
Authors: LOOIJ B. J. , ROELFSEMA F. , FRÕLICH M.
Published: March 2008

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i. v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i. v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH‐releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.
INHERITANCE OF MINERALOCORTICOID EFFECTOR ABNORMALITIES OF HUMAN MONONUCLEAR LEUCOCYTES IN FAMILIES WITH PSEUDOHYPOALDOSTERONISM
Authors: WEHLING MARTIN , KUHNLE URSULA , DAUMER C. , ARMANINI DECIO
Published: March 2008

In‐vitro effects of aldosterone on intracellular sodium and potassium concentrations have been described for normal human mononuclear leucocytes (HML). After incubation for 1 h at 37|MoC, intracellular sodium and potassium in HML are significantly higher in the presence of 1.4 nM aldosterone than after incubation without aldosterone. As published earlier, these effects were absent in patients with pseudohypoaldosteronism. In the present paper, the families of seven patients with pseudohypoaldosteronism (index cases) were studied. In the first family, two siblings were affected by the disease and had a reduced number of mineralocorticoid (MC) receptors on HML. Intracellular sodium and potassium in HML from these patients did not show a response to 1.4 nM aldosterone. The parents, who were first cousins, had no history of disease and normal receptor data, but in the mother, the response of HML electrolytes to aldosterone was abnormal. In the second family, the mother of a child with pseudohypoaldosteronism, the mother's sister, and her son, had low numbers of MC receptors. Only the aunt of the index case had an uncertain history of the disease. The MC effector mechanism was abnormal in both children and both mothers studied. In a third family, the effector defect was present only in HML of the father. In three further families the abnormality of the effector mechanism was detected in HML of the patient's mother. These data suggest an autosomal dominant inheritance of pseudohypoaldosteronism with variable expression of the gene. The abnormality of the MC effector mechanism seems to be a more sensitive means than the determination of aldosterone plasma levels and MC receptor studies to identify gene carriers without clinical symptoms.
THE EFFECTS OF ACUTE EXERCISE ON PULSATILE LH RELEASE IN HIGH‐MILEAGE MALE RUNNERS
Authors: McCOLL E. M. , WHEELER G. D. , GOMES P. , BHAMBHANI Y. , CUMMING D. C.
Published: March 2008

Evidence suggests that acute exercise and endurance training has a suppressive effect on the hypothalamic—pituitary—gonadal (HPG) axis in men and women. To determine if training and acute exercise influence the neuroendocrine regulation of the HPG axis in men we examined pulsatile LH release in six male endurance runners with a training volume of at least 80 km per week, and compared this with values in six age‐matched sedentary controls. Blood samples were obtained through an indwelling i.v. cannula from the subjects at 15‐min intervals for 6 h following 24 h without significant physical activity and again, in the runners, following 60 min of running at a speed equivalent to 5% below the anaerobic threshold. Mean LH pulse frequency and amplitude, as well as areas under the LH pulses and total LH curve, were calculated but only the mean post‐exercise area under the total LH curve area was significantly lower than basal values (P<0.05) following exercise compared with the resting values in runners. Other measures of LH release did not change with acute exercise. Basal and pre‐exercise testosterone levels were also measured and found to be at the lower end of normal men. The mean pre‐exercise serum testosterone levels were significantly higher than basal levels. Mean testosterone levels, mean pulse amplitude, and mean area under the LH curve were significantly lower in resting runners than in the controls. The data suggest that exercise induces a general lowering of LH levels but does not inhibit LH pulsatile release. An anticipatory increase in serum testosterone occurred before exercise.
EFFECTS OF INHIBITION OF CHOLESTEROL SYNTHESIS BY SIMVASTATIN ON THE PRODUCTION OF ADRENOCORTICAL STEROID HORMONES AND ACTH
Authors: MOL M. J. T. M. , STALENHOEF A. F. H. , STUYT P. M. J. , HERMUS A. R. M. M. , DEMACKER P. N. M. , VAN 'TLAAR A.
Published: March 2008

Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single‐blind, placebo‐controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol ± SD = 10.74 ± 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17‐hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short‐term infusion of ACTH; the ACTH and cortisol response during insulin‐induced hypoglycaemia. Total serum cholesterol decreased by 35.0 ± 8.1% (P < 0.001) and low‐density lipoprotein (LDL) cholesterol by 39.8 ± 9.8% (P < 0.001); high‐density lipoprotein (HDL) increased by 9.2 ± 11.1% (P < 0.001). Basal levels of ACTH were higher after simvastatin (2.9 ± 1.9 pmol/1 vs 4.1 ± 2.9 pmol/l; P < 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 ± 0.23 μmol/l vs 0.78 ± 0.10 μmol/l; P < 0.05), but was unaltered during insulin‐induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic‐pituitary‐adrenal axis.
EVALUATION OF TSH RECEPTOR ANTIBODY BY ‘NATURAL IN VIVO HUMAN ASSAY’ IN NEONATES BORN TO MOTHERS WITH GRAVES’ DISEASE
Authors: TAMAKI H. , AMINO N. , IWATANI Y. , TACHI J. , KIMURA M. , MITSUDA N. , ICHIHARA K. , TANIZAWA O. , MIYAI K.
Published: March 2008

Neonatal thyrotoxicosis induced by transferred TSH receptor antibody (TRAb) is the ideal human in‐vivo experimental system for the evaluation of TRAb. The clinical significance of circulating TRAb in Graves’ disease was evaluated by this ‘natural in‐vivo human assay’. TRAb activity in vitro was measured by radioreceptor assay (thyrotrophin‐binding inhibitor immunoglobulin, TBII) and sensitive cAMP accumulation assay using FRTL‐5 cells (thyroid‐stimulating antibody, TSAb). Further, the binding‐stimulation index (B‐S index) was newly introduced, which was the most useful indicator for prediction of neonatal thyrotoxicosis, calculated as the product of TBII and TSAb (Tamaki et al., 1988a). Maternal serum TRAb indices showed highly significant correlations with the serum free T4 index (FT4I) and free T3 index (FT3I) in neonates (5–10 days after birth) born to 20 mothers with Graves’ disease who had positive TBII and/or TSAb (FT4I: r= 0.825 for TBII, r= 0.908 for TSAb, r= 0.944 for the B‐S index, P > 0.001; FT3I: r = 0.622 for TBII, P > 0.01, r= 0.812 for TSAb, r= 0.791 for the B‐S index, P > 0.001; n= 20). In contrast, in 57 untreated adult patients with hyperthyroid Graves’ disease, the FT4I and FT3I levels were not correlated with any of the TRAb indices. The linear regression relationship between the B‐S index and FT4I found in neonates was applied to values in adult patients with Graves’ disease, and the patients were divided into three groups on the basis of the 95% confidence limit: high, normal, and low responders of thyroid hormone (FT4I) secretion to the B‐S index. FT4I and the ratio of FT4I to the B‐S index were highest and the TRAb indices were lowest in the high responders, while FT4I and the FT4I/B‐S index ratio were lowest and the TRAb indices were highest in the low responders. The FT4I/B‐S index ratio was inversely correlated with the titres of antithyroid microsomal antibody in all the adult patients with untreated Graves’ disease (r=−0.288, P >0.05). The results suggest that in‐vitro assays using animal thyroid cells and cAMP as an index of response are suitable for detecting circulating thyroid stimulating activity in vivo. Secretion of thyroid hormones in Graves’ disease may be regulated not only by circulating thyroid‐stimulating antibodies but also by intrathyroidal stimulatory factors or by inhibitory or destructive factors.
OSMOREGULATION OF THIRST AND VASOPRESSIN SECRETION IN KALLMANN'S SYNDROME
Authors: THOMPSON C. J. , WHITE M. C. , BAYLIS P. H.
Published: March 2008

It has been suggested that abnormalities of thirst and vasopressin secretion commonly coexist with Kallmann's syndrome. Out‐patient plasma osmolality, plasma sodium and 24‐hour urine volume were similar in 10 patients with Kallmann's syndrome and 10 matched controls. Six patients underwent dynamic testing of osmoregulation with hypertonic sodium chloride infusion. There were similar rises in plasma AVP concentration in patients (0.4 ± 0.1–6.2 ± 1.2 pmol/l, P > 0.001) and controls (0.4 ± 0.1– 5.7 ± 1.0 pmol/l P > 0.001). Thirst ratings rose in similar fashion in patients (0.7 ± 0.3–6.2 ± 1.0 cm, P > 0.001) and controls (1.0 ± 0.3–7.2 ± 0.5 cm, P > 0.001). Drinking rapidly abolished thirst and lowered AVP concentrations in both groups before major changes in plasma osmolality occurred. Linear regression analysis defined similar osmotic thresholds for thirst onset and vasopressin release in the two groups, and there was no difference in the calculated sensitivity of the osmoreceptor/vasopressin secretory unit as defined by the slopes of the regression lines. We conclude that osmoregulation is normal in Kallmann's syndrome.
PLASMA GROWTH HORMONE PROFILES AND SLEEP: A STUDY OF 13 TREATED ACROMEGALICS
Authors: DE BOER H. , ROELFSEMA F. , FRÖLICH M. , KAMPHUISEN H. A. C. , VAN SETERS A. P.
Published: March 2008

The plasma growth hormone profiles and sleep patterns of 13 treated male acromegalic patients, aged 29–67 years, were studied. All patients had undergone selective pituitary transsphenoidal surgery 4–9 years previously; five patients had also undergone supplemental pituitary irradiation. Blood samples were taken at 20‐min intervals; the sleep patterns were obtained by EEG. GH reserve was assessed after insulin‐induced hypoglycaemia and GHRH (1–44) with and without pyridostigmine. The profiles were analysed with the aid of the Pulsar program. Seven out of eight non‐irradiated patients had 1–3 nocturnal GH peaks; in the irradiated group only one patient had a normal profile. The GH reserve after insulin‐induced hypoglycaemia was normal in seven out of eight non‐irradiated patients, and subnormal in all five irradiated patients. In the latter group the GH reserve was diminished when tested with GHRH. One patient from each group had a severe apnoea syndrome; in both cases there was no nocturnal GH increase. The percentage sleep stage 1 was lower for irradiated patients when compared with non‐irradiated patients, but the 14 other sleep parameters did not differ. From this study we conclude that the physiological regulation of GH secretion is restored in surgically treated patients. Radiation therapy may lead to pituitary and hypothalamic damage, which could affect spontaneous GH secretion.
SELECTIVE DEFECT IN GONADOTROPHIN SECRETION IN PATIENTS WITH AUTONOMIC FAILURE
Authors: WILLIAMS T. D. M. , LIGHTMAN S. L. , JOHNSON M. R. , CARMICHAEL D. J. S. , BANNISTER R.
Published: March 2008

We studied the neuroendocrine effects of a condition associated with abnormal hypothalamic amines. Hypothalamo‐anterior pituitary function was assessed in five male subjects with autonomic failure (AF) and in five age and sex‐matched controls. All subjects showed normal gonadotrophin and TSH responses to GnRH and TRH, respectively. In control subjects, intravenous infusion of naloxone caused a significant rise in overall LH concentrations as well as increased frequency and amplitude of LH pulses. In contrast, in AF subjects naloxone did not alter LH concentrations or increase LH pulse frequency. Naloxone also caused an increase in neurosecretory GH pulses not only in AF subjects but also in the controls. These results suggest that in man, ascending catecholamine pathways are important in the control of gonadotrophin secretion. The markedly different response of GH to an opioid antagonist in elderly subjects should be further investigated.
PROLACTINOMAS PRESENTING AS PRIMARY AMENORRHOEA AND DELAYED OR ARRESTED PUBERTY: RESPONSE TO MEDICAL THERAPY
Authors: HOWLETT T. A. , WASS J. A. H. , GROSSMAN A. , PLOWMAN P. N. , CHARLESWORTH M. , TOUZEL R. , REES L. H. , SAVAGE M. O. , BESSER G. M.
Published: March 2008

Fourteen patients presented with arrested pubertal development associated with prolactin‐secreting pituitary tumours; serum prolactin ranged from 4000–104300 mU/1 in the ten females and 920–68000 in four males. Skull X‐ray showed a markedly expanded pituitary fossa in eight patients. CT scan and/or air encephalography showed macroadenomas in nine, of whom seven had large suprasellar extensions to their tumours, yet only five had complained of headache and only two had visual field defects. All were treated with bromocriptine (7.5–60 mg/day) which lowered prolactin substantially in all and into the normal range in 11 (range < 60–3090, median 105 mU/1). Puberty thereafter progressed spontaneously in 13, but in one patient, whose prolactin did not suppress completely, menarche could be induced only with clomiphene. Anterior pituitary function improved on bromocriptine. In seven patients with macroadenomas, tumour shrinkage into the pituitary fossa was complete and in two others incomplete shrinkage was followed by transsphenoidal hypophysec‐tomy. Seven patients received pituitary irradiation, six after bromocriptine‐induced shrinkage and one after transsphenoidal surgery. At follow‐up 6 months to 10 years (median 5 years) after presentation,' ten remain on bromocriptine with a suppressed serum prolactin, one has a normal prolactin after surgery, and three are off bromocriptine with residual hyperprolactinae‐mia (418–4680 mU/1). To date, four females have become pregnant and one male has fathered two children.

Prolactinomas are an important, albeit rare, cause of arrested puberty and should therefore be sought. Most patients respond well to bromocriptine, with or without pituitary irradiation.
THE EFFECT OF OVINE CORTICOTROPHIN‐RELEASING FACTOR ON THE HORMONAL RESPONSE TO INSULIN‐INDUCED HYPOGLYCAEMIA
Authors: HOWLETT T. A. , GROSSMAN A. , McLOUGHLIN L. , PERRY L. , WHITE A. , COY D. H. , REES L. H. , BESSER G. M.
Published: March 2008

In order to investigate the role of hypothalamic corticotrophin‐releasing factor (CRF41) in the mediation of the pituitary ACTH response to hypoglycaemia, eight normal adult males were studied on four occasions. Commencing at 0830 h after an overnight fast, each received, in double‐blind, random order, intravenous boluses of: A, normal saline control; B, soluble insulin 0.15U/kg; C, ovine CRF41 (oCRF41) 100 μg; D, soluble insulin 015U/kg followed immediately by oCRF41 100 μg. Adequate hypoglycaemia (blood glucose < 2–2 mmol/1) was achieved in each subject when insulin was given alone or with oCRF41, and there was no difference in the glucose nadir between the 2 days. Peak plasma ACTH was significantly higher after insulin plus oCRF41 than after insulin alone (P<0.05) or oCRF41 alone (P<0.01) and this enhancement of ACTH release was most marked in the first phase of the response at 30 min (P<0.001, b vs d). There was no difference in the peak serum Cortisol response whether oCRF41 and insulin were given alone or together and although the area under the Cortisol curve was greater after insulin plus oCRF41, this difference was explicable simply on the basis of the earlier onset of the Cortisol response to oCRF41.

There were no differences in the serum GH responses to hypoglycaemia on the 2 days. We conclude that during the initial, rising phase of the ACTH response to hypoglycaemia, secretion of hypothalamic CRF41 is not maximally stimulated and that changes in ACTH release are mediated by changes in another hypothalamic factor, the action of which is enhanced by simultaneous administration of a maximal stimulating dose of oCRF41.
INSULIN‐LIKE GROWTH FACTOR BINDING PROTEINS IN FOLLICULAR FLUID FROM NORMAL DOMINANT AND COHORT FOLLICLES, POLYCYSTIC AND MULTICYSTIC OVARIES
Authors: HOLLY J. M. P. , EDEN J. A. , ALAGHBAND‐ZADEH J. , CARTER G. D. , JEMMOTT R. C. , CIANFARANI S. , CHARD T. , WASS J. A. H.
Published: March 2008

There is now considerable evidence that the insulin‐like growth factors (IGFs) IGFs in ovarian physiology, the presence and functions of these IGFBPs will need to be characterized play an important role in the human ovary. It has also recently become apparent that the physiological activity of the IGFs is modulated by a number of specific binding proteins (IGFBPs). In order to understand the role of the. As an initial step towards this we have investigated the presence of the various binding proteins by Western ligand blotting and have measured the levels of one of them, IGFBP‐1, in follicular fluid (FF) obtained from unstimulated dominant and cohort follicles in 19 normal women and in eight patients with polycystic and one with multicystic ovaries. In normal women, IGFBP‐1 levels in dominant follicles were similar to matched serum levels but were significantly lower in cohort follicles. IGFBP‐1 levels correlated with FF‐volume (r= 0.58, P < 0.001) and with paired serum levels (r= 0.63, P < 0.001). In post‐LH surge dominant follicles this relationship with serum levels no longer held and in three out of nine subjects FF levels were higher than in serum. Thus IGFBP‐1 in normal human FF appears to be partly derived from the circulation but with additional local production in the larger developing dominant follicles. Western ligand blotting revealed five IGF‐binding proteins in FF running parallel with those identified in serum, suggesting that the IGFBP species previously identified in serum may also be present in FF. The two bands in positions corresponding to the components of the large (150kDa) binding complex were, as in serum, the predominant forms and in most FF samples these were even more prominent than in the accompanying serum sample. This contrasts with previous studies in lymph which suggested that the 150kDa complex was largely retained in the circulation. All three small IGFBPs varied considerably between FF samples even within an individual; each IGFBP varied independently of the other IGFBPs. Our results demonstrate that at least four discrete IGFBPs are present in FF and suggest that each may be produced independently within the ovary.
INOSITOL PHOSPHOLIPID TURNOVER AND INTRACELLULAR Ca2+ RESPONSES TO THYROTROPHIN‐RELEASING HORMONE, GONADOTROPHIN‐RELEASING HORMONE AND ARGININE VASOPRESSIN IN PITUITARY CORTICOTROPH AND SOMATOTROPH ADENOMAS
Authors: LEVY A. , LIGHTMAN S. L. , HOYLAND J. , MASON W. T.
Published: March 2008

We have studied the inositol phospholipid turnover response to thyrotrophin‐releasing hormone (TRH) gonadotrophin‐releasing hormone (GnRH) and arginine vasopressin (AVP) in five corticotroph and six somatotroph pituitary adenomas. GnRH (100 nM) increased inositol phospholipid turnover in five of five somatotroph adenomas tested by an average of 36.4 |Mp 9.4% (mean |Mp SE). In a fifth, which was too small to allow inositol phospholipid turnover to be assessed, GnRH produced a rapid increase in mean intracellular calcium ion concentration. Only one of five corticotroph adenomas responded to GnRH with an increase in inositol phospholipid turnover of 19%. In contrast, all the somatotroph and corticotroph adenomas tested (four of four and five of five respectively) increased inositol phospholipid turnover in response to AVP (100 nM), by an average of 61 |Mp 11.8% and 415 |Mp 186% respectively. The finding of an inositol phospholipid or intracellular Ca2+ response to thyrotrophin‐releasing hormone (TRH) (100 nM) in three of five somatotroph adenomas (Ca2+ increasing from 50 to 175 nM in one and inositol phospholipid turnover increasing by 172 |Mp 1.9% and 49 |Mp 5.2% in two) and to GnRH in all five somatotroph adenomas concurs with the common clinical finding of paradoxi‐cal growth hormone responses to these releasing factors in patients with acromegaly. The lack of such a response in three of the four corticotroph adenomas suggests that the appearance of GnRH and TRH receptors on adenomatous pituitary cells is not common to all cells.
THE CORTICOTROPHIN RELEASING HORMONE TEST IN LATE PREGNANCY: LACK OF ADRENOCORTICOTROPHIN AND CORTISOL RESPONSE*
Authors: SCHULTE HEINRICH M. , WEISNER DIETRICH , ALLOLIO BRUNO
Published: March 2008

Biologically active corticotrophin‐releasing‐hormone (CRH) is produced by the placenta in large amounts and can be measured in the maternal circulation during third trimester of pregnancy. Its physiological significance is unknown. To further investigate the action of CRH in pregnancy, we performed a standard CRH‐test (1 μg/kg synthetic human CRH) in seven pregnant women 1 week prior to their calculated delivery data and 4‐5 weeks post‐partum. No response of plasma ACTH to CRH administration could be measured in any of the third trimester pregnant women. Post‐partum, basal ACTH levels were significantly lower (1.6 |Mp 0.3 vs 5.3 |Mp 0.2 pmo1/1) and reacted promptly to CRH administration (1.6 |Mp 0.3–4.2 |Mp 0.5 pmol/1; P < 0.05). Concentrations of cortisol in plasma and salivary cortisol paralleled the ACTH response to administration of CRH. However, one pregnant woman experienced physical and emotional stress during the CRH‐test and reacted with a sharp rise in cortisol secretion. The lack of the ACTH and cortisol response in this study to exogenously administered CRH in third trimester pregnancy may be due to high circulating glucocorticoid concentrations, desensitization of the pituitary corticotroph and/or in part due to circulating specific CRH‐carrier protein.
THE INDEPENDENT EFFECTS OF HYPERANDROGENAEMIA, HYPERINSULINAEMIA, AND OBESITY ON LIPID AND LIPOPROTEIN PROFILES IN WOMEN*
Authors: GRAF MARGARET J. , RICHARDS CHARLOTTE J. , BROWN VIRGIL , MEISSNER LES , DUNAIF ANDREA
Published: March 2008

We performed this study to clarify the independent effects of hyperandrogenaemia, hyperinsulinaemia, and obesity on lipid and lipoprotein levels in women with hyperandrogenaemia (HA) and anovulation which we designated as the polycystic ovary syndrome (PCO). We examined fasting lipid, lipoprotein, sex hormone and insulin levels in 38 women (21 obese (ob), 17 non‐obese (nob) with HA and anovulation (PCO) and 38 normal ovulatory women (21 obese, 17 non‐obese), matched for age and weight. The women with PCO had significantly increased androgen levels compared to the normal women. However, total oestradiol levels were similar in the PCO and normal women. Mean fasting insulin levels and 2‐h glucose levels (both P < 0.001) were significantly higher in ob PCO women. There were significant decreases (P|Ml0.01) in high‐density lipoprotein (HDL) levels in both the obese groups (ob PCO and ob normal) compared to the non‐obese (nob PCO and nob normal) groups. Otherwise, mean lipid and lipoprotein levels did not differ in the ob or the nob PCO women compared to the control groups. The correlations between sex hormone, lipid and lipoprotein levels differed in the four groups of women. After statistical adjustment for potential hormonal interactions, nob PCO women had significant positive correlations between testosterone and LDL levels (R=0.51, P < 0.05) and insulin and TTG levels (R. 0.61, P < 0.01). Ob normal women had a significant positive correlation between oestrone and TTG levels (R=0.44, P|Ml0.05). We conclude that (1) PCO women are in a low to intermediate risk group for cardiovascular disease based on their lipid and lipoprotein profiles; (2) obesity, but neither hyperandrogenaemia nor hyperinsulinaemia, was associated with significant decreases in HDL levels and was therefore the major factor affecting lipid profiles in PCO; (3) a significant relationship existed between androgen and lipoprotein levels only in nob PCO women, suggesting that the mechanisms underlying these associations are complex.
DECREASING INCIDENCE OF THYROTOXICOSIS IN AN ENDEMIC GOITRE INLAND AREA OF SWEDEN
Authors: LUNDGREN EWA , CHRISTENSEN SVEND BORUP
Published: March 2008

Four hundred and sixty‐seven new cases of thyrotoxicosis were diagnosed during the period 1975‐1 984 in a demographically well defined Swedish inland county, with about 134000 inhabitants, where goitre has been considered endemic. This corresponds to a mean annual incidence of all thyrotoxicosis of 34–7/100 000. The mean incidence of toxic diffuse goitre was 16.6/100 000 and of toxic nodular goitre 18–4/100 000. The mean incidence of all thyrotoxicosis fell from 39.2 to 30.2/100000/year between the first and the second 5‐year period of the study (P <0.01); this was entirely due to a decrease in the incidence of toxic nodular goitre (22.6 to 14.1/100000/year) whereas the incidence of toxic diffuse goitre did not change significantly. The decrease in the incidence of toxic nodular goitre was evenly distributed over all age groups and over rural and urban areas of the county.
BONE MINERAL DENSITY AND THYROID HORMONE THERAPY
Authors: RIBOT C. , TREMOLLIERES F. , POUILLES J. M. , LOUVET J. P.
Published: March 2008

The purpose of this study was to evaluate prospectively the evolution of femoral and vertebral bone mineral density (BMD) in hypothyroid subjects treated with replacement doses (mean |Mp SD dose of L‐thyroxine = 135 |Mp 32 μg/day) as compared to an untreated group. Vertebral bone density was also measured in other patients who had been treated for at least 2 years with either suppressive (mean dose =154 |Mp 36 μg/day, n= 28) or replacement doses (mean dose = 104 |Mp 52 μg/day, n= 21) according to the thyrotrophin response (TSH) to the thyrotrophin releasing hormone (TRH) administration. In primary hypothyroid patients, a mean decrease of 5.4% (P < 0.01) for vertebral BMD, 7.3% (P <0.01) for trochanter and 7% (P < 0.001) for femoral neck was observed after 1 year of treatment. This loss was unrelated either to age or to menopausal status (ANOVA). A clinical and hormonal state of euthyroidism was reached since the 3rd month of treatment. Fasting urinary calcium/creatinine excretion was increased significantly (P < 0.05) at the 3rd month, and plasma osteocalcin (OC) increased significantly from the 3rd month onwards (P < 0.05) up to the 12th month (P < 0.025). In the cross‐sectional study, vertebral BMD was not significantly different from age‐matched normal values in patients receiving either substitutive or suppressive doses of LT4. These results suggest that in the case of primary hypothyroidism even appropriate thyroid replacement therapy could lead during the first year of treatment to a significant reduction in vertebral and femoral BMD. However, the fact that an increased fracture rate has not been documented in long‐term treated patients, and the results of our cross‐sectional study, suggest that this bone mass reduction could be transient and reversible due to new bone formation at the end of the resorptive sequence.
THYROXINE‐BINDING PREALBUMIN GENE POLYMORPHISM: A POPULATION STUDY
Authors: AKBARI M. T. , FITCH N. J. , FARMER M. , DOCHERTY K. , SHEPPARD M. C. , RAMSDEN D. B.
Published: March 2008

The human thyroxine‐binding prealbumin (TBPA) gene was examined for restriction fragment length polymorphism (RFLP) in normal subjects and a subject with euthyroid hyperthyroxinaemia, due to increased thyroxine binding by TBPA, using 16 restriction enzymes. Only Taq I and Msp I were shown to detect RFLPs. In a male of the normal population and one of his daughters, an additional Taq I site was found in the 3|M′‐flanking region of the TBPA gene. The RFLP in a subject with euthyroid hyperthyroxinaemia was due to the deletion of a MspI site. All three subjects with RFLPs were heterozygous.
RAPID AND LONG‐LASTING SUPPRESSION OF PROLACTIN SECRETION AND SHRINKAGE OF PROLACTINOMAS AFTER INJECTION OF LONG‐ACTING REPEATABLE FORM OF BROMOCRIPTINE (PARLODEL LAR)*
Authors: SCHETTINI GENNARO , LOMBARDI GAETANO , MEROLA BARTOLOMEO , COLAO ANNAMARIA , MILETTO PAOLO , CARUSO ENZO , LANCRANJAN IOANA
Published: March 2008

Five patients with PRL‐secreting macroadenoma and nine patients with PRL‐secreting microadenoma or idiopathic hyperprolactinaemia were treated with monthly administrations of long‐acting bromocriptine suitable for repeatable injections (Parlodel LAR) for 1–12 cycles of treatment. A significant shrinkage of tumour mass and the recovery of visual field defects were observed in patients with macroprolactinoma. Plasma PRL levels decreased to 16.8 and 18.1% of pretreatment values, in macroprolactinoma and idiopathic or microadenoma‐tous hyperprolactinaemic subjects, respectively, during the first cycle of treatment, reaching the normal range in three patients of each group. During the following cycles of treatment, two patients with macroprolactinoma and one patient with idiopathic or microadenomatous hyperprolactinaemia became normoprolactinaemic. Adverse reactions generally did not last beyond the first days of administration and decreased with the progression of the treatment. In conclusion, its effectiveness and the fact that it is well tolerated, may suggest that this form of bromocriptine may be used as a first therapeutic approach for patients with PRL‐secreting adenomas, particularly when shrinkage of a macroadenoma is urgently required.
THE EFFECT OF AMIODARONE ON THE CONTROL OF HYPERTHYROIDISM BY PROPYLTHIOURACIL
Authors: RAJATANAVIN RAJATA , CHAILURKIT LA‐OR , KONGSUKSAI ATANA , TEERAVANINTHORN UTHAI , HIMATHONGKAM THEP
Published: March 2008

We studied the efficacy of amiodarone (800, 600, 400 and 200 mg orally daily during weeks 1, 2, 3 and 4, respectively) plus propylthiouracil (PTU, 100 mg orally every 8 h) in comparison to PTU alone in the early treatment (28 days) of Graves'disease patients. Circulating T3 and T4 decreased earlier and more markedly in the amiodarone plus PTU‐treated group. An initial rise of circulating rT3 above the base‐line value followed by a gradual decline was observed in the former group while only a decline below the base‐line values was observed in the latter group. The resting pulse rate decreased and body weight increased significantly in the amiodarone plus PTU‐treated group. In the PTU‐treated group, significant weight gain was observed later in the course of treatment while no significant reduction in pulse rate was observed. No major side‐effects of amiodarone were observed during the course of treatment. This study suggested that the combination of amiodarone and PTU was more efficacious than PTU alone in reducing circulating T3, T4 and clinical hyperthyroidism early in the course of treatment of patients with Graves'disease. This regimen has an additional potential advantage because of the antiarrhythmic property of amiodarone, especially in situations when a beta‐blocker is contraindicated.
OVERNIGHT URINARY GROWTH HORMONE MEASUREMENT IN THE DIAGNOSIS OF ACROMEGALY
Authors: LUNT H. , TUCKER J. , BULLEN H. , GIBBS C. , WILKIN T. J.
Published: March 2008

Several studies report higher urinary GH excretion in acromegalic patients compared to control subjects. We investigated the diagnostic potential of overnight urinary GH excretion in acromegaly, using a recently developed enzyme‐linked immunosorbent assay. Overnight urine samples were obtained from 117 control subjects and nine patients with untreated acromegaly. GH excretion was higher in acromegalic patients compared to control subjects, with geometric mean total overnight values of 46.35 and and 5.73 μU respectively. The range for total overnight urinary GH in control subjects was 0.75–21.75μU and two of the nine patients with untreated acromegaly had GH measurements within this range. Urinary GH measurements were corrected using predictive clinical variables but this resulted in minimal improvement in discrimination between control subjects and acromegalic patients. Lack of complete discrimination between control subjects and acromegalic patients limits the usefulness of a single overnight urinary GH measurement as a screening test for acromegaly.
IN‐VIVO BIOACTIVITY OF GONADOTROPHIN SURGE ATTENUATING FACTOR (GnSAF)
Authors: MESSINIS IOANNIS E. , TEMPLETON ALLAN
Published: March 2008

Gonadotrophin surge attenuating factor (GnSAF) is a nonsteroidal ovarian factor responsible for the attenuation of the endogenous LH surge in superovulated cycles. To study the bioactivity of GnSAF in vivo, the pituitary response to exogenous GnRH was investigated in 13 normally ovulating women during spontaneous and FSH‐treated cycles. GnRH experiments were per‐formed at three stages of both spontaneous and FSH cycles, i.e. early (n = 8), mid‐ (n = 8) and late follicular phase (n = 8). LH response to GnRH increased significantly from the early to late follicular phase in the spontaneous cycles, while in the FSH cycles it decreased significantly in mid‐ and increased in late follicular phase. A marked attenuation of the LH response to GnRH during both the mid‐ and late follicular phase was seen in the FSH as compared to the corresponding spontaneous cycles. We conclude that in superovulated cycles small, growing follicles produce GnSAF.
EFFECT OF ENHANCEMENT OF ENDOGENOUS CHOLINERGIC TONE WITH PYRIDOSTIGMINE ON GROWTH HORMONE (GH) RESPONSES TO GH‐RELEASING HORMONE IN PATIENTS WITH CUSHING'S SYNDROME
Authors: LEAL‐CERRO A. , PEREIRA J. L. , GARCIA‐LUNA P. P. , ASTORGA R. , CORDIDO F. , CASANUEVA F. F. , DIEGUEZ C.
Published: March 2008

Growth hormone (GH) secretion in patients with Cushing's syndrome is diminished to all the stimuli tested so far but the precise mechanisms through which this occurs are unknown. In order to investigate whether increased somatostatinergic tone might be responsible for this alteration, we studied the effect of pyridostigmine (120 mg p. o. at ‐60 min), which activates cholinergic synapses and thus suppresses hypothalamic somatostatin release on GH responses to GHRH (100 μg, i. v. at 0 min), in six patients with Cushing's syndrome. We found that while pyridostigmine markedly potentiated GH responses to GHRH, in all the normal subjects tested (n=12), neither GHRH alone nor GHRH plus pyridostigmine elicited any increase in GH secretion in any of the patients with Cushing's syndrome. This suggests that chronic glucocorticoid excess induces marked alterations in the hypothalamic control of GH secretion.
THE INFLUENCE OF OCTREOTIDE TREATMENT ON PULSATILE GROWTH HORMONE RELEASE IN ACROMEGALY
Authors: ROELFSEMA F. , de BOER H. , FRÖLICH M.
Published: March 2008

The pulsatile release of GH was investigated in eight active acromegalic patients before and during a subcutaneous infusion of 300 μg octreotide/24 h for 4 weeks. The number of GH pulses increased from a basal value of 14.4/24h to 16‐3/24h during octreotide therapy. At the same time the mean GH concentration, valley concentration, peak height and amplitude decreased significantly. The inhibitory effect of octreotide on pulse characteristics did not depend on the time of day. IGF‐I levels also decreased significantly; in five patients normal levels were reached. IGF‐I levels correlated significantly with the mean GH level (r = 0.714, P > 0‐001), mean valley concentration (r=0.697, P > 0.00) and, to a lesser extent, area under the curve (r = 0‐436, P=0.033), but not the number of pulses. Plasma octreotide levels did not correlate with pulse parameters. In all but one patient a circadian rhythm was present during both the basal study and octreotide therapy. Compared with surgically treated acromegalics, the number of GH pulses was higher in untreated and octreotide‐treated patients. This study demonstrates the pulsatile release of GH in active acromegaly both before and during octreotide therapy. This result suggests that endogenous GHRH is important for the generation of GH pulses in this disease.