bluuebunny/crossref_metadata_2025 huggingface dataset:
ABNORMAL PUBERTAL DEVELOPMENT IN PRIMARY HYPOTHYROIDISM
Authors: PRINGLE P. J. , STANHOPE R. , HINDMARSH P. , BROOK C. G. D.
Published: March 2008

We have studied three patients (1M, 2F), age range 10.9 to 15.5 years, who had abnormal sexual maturation secondary to primary hypothyroidism. The boy had inappropriately large testes for his stage of puberty, the girls had isolated breast development and there was absence of pubertal growth acceleration. FSH, LH, TSH and GH secretion, pituitary imaging and ovarian ultrasound morphology were studied before and during thyroxine treatment. In the hypothyroid state, FSH levels were elevated with abnormal pulsatility and LH: FSH concentrations were reversed.
ENDOGENOUS OPIOIDS INHIBIT OXYTOCIN RELEASE DURING NICOTINE‐STIMULATED SECRETION OF VASOPRESSIN IN MAN
Authors: SECKL J. R. , JOHNSON M. , SHAKESPEAR C. , UGHTMAN S. L.
Published: March 2008

The effects of the opioid antagonist naloxone on the vasopressin (AVP) and oxytocin (OT) responses to nicotine were studied in male non‐smokers (21–30 years old). Either saline (n= 6) or naloxone (4 mg bolus 4.6 mg/h, n= 6) was infused i.v. during the study. After 60 min infusion the subjects smoked one high‐nicotine content cigarette. Naloxone infusion for 60 min did not alter basal plasma AVP or OT levels. Smoking led to a significant rise in plasma vasopressin in both saline and naloxone‐infused subjects (P < 0.05). There was no significant difference in the plasma AVP response to smoking between the two groups. Saline‐infused subjects did not show any change in plasma OT in response to smoking. Naloxone infusion was associated with a significant rise in OT from 1.3 ± 0.1 pmol/l to 4.3 ± 2.4 pmol/l 5 min after smoking (P < 0.05). We conclude that there is endogenous opioid‐mediated inhibition of OT which prevents its release when AVP is secreted in response to nicotine in man.
A STUDY ON THE FEASIBILITY OF SUPPRESSING OVARIAN ACTIVITY FOLLOWING THE END OF POSTPARTUM AMENORRHOEA BY INCREASING THE FREQUENCY OF SUCKLING
Authors: DIAZ S. , MIRANDA P. , BRANDEIS A. , CARDENAS H. , CROXATTO H. B.
Published: March 2008

The aim of the study was to test the effect of increasing the frequency of breastfeeding upon ovarian function following the end of postpartum amenorr‐hoea. Women exclusively breastfeeding (n= 14) who experienced their first postpartum menstruation between the third and fifth month after delivery were randomly allocated to an experimental (n= 7) and a control (n= 7) group and studied during the next two cycles. Women in the experimental group agreed to increase the number of breastfeeding episodes per day throughout the second cycle. Blood samples were drawn twice a week from the first to the third postpartum menstruation for prolactin, oestradiol and progesterone determinations. The number of breastfeeding episodes per day and night and the length of each episode were recorded daily. An average frequency of 11 nursing episodes per 24 h was reported during the first study cycle in both groups. The experimental group increased by 50% the breastfeeding frequency after the second menstruation while the control group kept its spontaneous feeding pattern. The increase of suckling frequency occurred mainly during day hours. The total breastfeeding time per 24 h was not increased. The length of the menstrual cycle was not altered by the increased suckling frequency. The endocrine pattern differed neither between the first and second cycle of the experimental group nor between the experimental and control group, with the exception of PRL levels which were higher in the experimental group throughout both cycles. Twenty cycles (71%) showed progesterone values compatible with ovulation (> 9.5 nmol/l). The highest progesterone values and the highest oestradiol values observed in the ovulatory cycles of lactating women were within the range found in non‐nursing fertile women. Plasma levels of PRL were significantly elevated in all cycles but one, in comparison with PRL levels in non‐nursing women. It is concluded that if cyclic ovarian function is reestablished early in fully nursing women, a mere increase in the number of breastfeeding episodes, without augmenting total suckling time and the frequency of nocturnal episodes, does not provide a sufficient stimulus to re‐suppress the pituitary‐ovarian axis.
LONG‐LASTING LOWERING OF SERUM GROWTH HORMONE AND PROLACTIN LEVELS BY SINGLE AND REPETITIVE CABERGOLINE ADMINISTRATION IN DOPAMINE‐RESPONSIVE ACROMEGALIC PATIENTS
Authors: FERRARI C. , PARACCHI A. , ROMANO C. , GEREVINI G. , BOGHEN M. , BARRECA A. , FORTINI P. , DUBINI A.
Published: March 2008

Cabergoline, the new long‐acting dopaminergic ergoline derivative, was given orally in single doses of 0.3 and 0.6 mg to eight dopamine‐responsive acromegalic patients. Serum GH and PRL levels were determined before treatment, 3,4, and 6 h and 1, 3, 5, 7 and 14 days after treatment. A control test with a single oral dose of 2.5 mg of bromocriptine was also performed. Cabergoline induced a marked fall in seurm PRL level, starting within 3 h and continuing for 7 days after administering 0.3 mg, and for 14 days after 0.6 mg. The mean maximal decrease was 49% after 0.3 mg and 63% after 0.6 mg and occurred after 24 h in both cases. The latter was of similar magnitude to that induced by bromocriptine (67% at 4 h). Serum GH levels did not change after 0.3 mg of cabergoline, but decreased significantly from 3 h to 3 days after 0.6 mg of the compound with a mean maximal decrease of 42% after 24 h, and from 3 to 6 h after giving bromocriptine (mean maximal decrease 63% at 4 h). Once a week repeated administration of 0.3–0.6 mg of cabergoline was carried out in six patients, five of whom had completed the acute study; a normalization of serum GH and insulin‐like growth factor I (IGF‐I) levels occurred iri three patients, one of whom had very high pretreatment values. In three poorly or non‐responsive patients, a better response, as assessed by both GH and IGF‐I levels, was induced by increasing the dose up to 0.6 mg twice or 0.4 mg three times a week; in one case this was associated with marked tumour shrinkage. Sustained normalization of PRL levels was achieved in all cases. These data indicate that a single dose of 0.6 mg of cabergoline inhibits GH as well as PRL secretion in dopamine‐responsive acromegalic patients and suggests that doses of 0.3–0.6
IMMUNOREACTIVE HUMAN CHORIONIC GONADOTROPHIN FROM THE CYST FLUID AND CSF OF PATIENTS WITH CRANIOPHARYNGIOMA
Authors: HARRIS P. E. , PERRY L. , CHARD T. , CHAUDRY L. , COOKE B. A. , TOUZEL R. , COATES P. , LOWE D. G. , AFSHAR F. , WASS J. A. H. , BESSER G. M.
Published: March 2008

A specific radioimmunoassay for the beta‐chain of human chorionic gonadotropin irHCGβ has demonstrated HCG‐like material to be present in craniopharyngioma cyst fluid in nine consecutive patients with craniopharyngioma. There was no detectable LH/HCG bioactivity as assessed using testosterone production from isolated Leydig cells from rat testis in seven samples tested. One patient was also found to have measureable irHCGβ in the cerebrospinal fluid (CSF), which fell to undetectable levels following surgery; in this patient, there was clinical evidence that the cyst fluid had leaked into the CSF pre‐operatively. Immunocytochemical staining for HCGβ and intact HCG was positive in five of the tumours. irHCGβ was not measurable in the serum of any of the patients.
WEIGHT GAIN AND REPRODUCTIVE FUNCTION: ULTRASONOGRAPHIC AND ENDOCRINE FEATURES IN ANOREXIA NERVOSA
Authors: TREASURE J. L. , WHEELER M. , KING E. A. , GORDON P. A. L. , RUSSELL G. F. M.
Published: March 2008

Pelvic ultrasonographic measurements and reproductive hormone levels in 36 patients with anorexia nervosa were followed as they gained weight during inpatient treatment. In 24 patients who were severely malnourished (69% of premorbid weight) the ovaries were small and amorphous and the levels of LH, FSH and oestfadiol were very low. Weight gain led to the appearance of multifollicular ovaries when levels of LH and oestradiol remained low but FSH levels had increased resulting in an LH: FSH ratio of less than 1. The emergence of a dominant follicle in 19 patients after weight gain (to 97% of premorbid weight) was accompanied by an increase in uterine area and associated with increased levels of LH and oestradiol and an LH: FSH ratio greater than 2. Among these patients with a dominant follicle at peak weight, 11 menstruated within a month of discharge.

The weight at which normal ovarian morphology returned was related to premorbid weight (P< 0.002) whereas body mass index (BMI) was poorly related. Our findings suggest that pelvic ultrasonography is probably the best indicator of the weight required for full endocrine recovery and offers advantages over sequential hormonal measurements, and is valuable in the management of patients with anorexia nervosa.
STRESSFUL LIFE EVENTS IN THE PATHOGENESIS OF CUSHING'S SYNDROME
Authors: SONINO N. , FAVA G. A. , GRANDI S. , MANTERO F. , BOSCARO M.
Published: March 2008

Some clinical observations suggested that stressful life events may play an aetiological role in Cushing's syndrome. However, there are no controlled investigations using standardized methods of life events assessment to substantiate this hypothesis. Events in the year before the first signs of disease onset were investigated in 30 consecutive patients with Cushing's syndrome (26 with a pituitary‐dependent form, three with an adrenal adenoma, and one with an adrenal carcinoma) and 30 control subjects matched for sociodemographic variables by means of Paykel's Interview for Recent Life Events. Patients with Cushing's syndrome reported significantly more stressful life events than a normal control group (P<0001) and had significantly more of the following: exits (P<005), undesirable (P<001) and uncontrolled (P<001) events. M ore events that had an objective negative impact (P<0.001) and more independent events (unlikely to be a consequence of the illness; (P<0001) were also reported. Such ratings were carried out by an independent rater unaware whether the event had occurred in patients or controls.

The results are suggestive of a causal relationship between stressful life events and Cushing's syndrome. Such relationship largely pertains to the hypothalamic‐pituitary forms of the illness. This is in agreement with a multifactorial model of pathogenesis in Cushing's disease and with current understanding of the complex interdependence of neurophysiological, biochemical and behavioural factors.
METABOLIC AND HORMONAL RESPONSES TO EXOGENOUS HYPERTHERMIA IN MAN
Authors: MØLLER N. , BECKWITH R. , BUTLER P. C. , CHRISTENSEN N. J. , ØRSKOV H. , ALBERTI K. G. M. M.
Published: March 2008

To study whether hyperthermia reproduces hormonal and metabolic responses seen in stress states such as mild infections, six normal male subjects underwent (i) a 3‐h hot bath and (ii) a 3‐h thermoneutral control period. During the hot bath body temperature rose by 1.2 ± 0.03°C (mean ± SEM) and significant peaks of circulating growth hormone (56 ± 9 vs 7 ± 4 mu/l), adrenaline (310 ± 34 vs 152 ± 39 pmol/l), glucagon (19.2 ± 4.3 vs 11.8 ± 2.3 pmol/l) and cortisol were recorded together with slight hyperinsulinaemia (6.5 ± 1.3 vs 5.3 ± 1.0 mU/l, P > 0.05). Hyperthermia was also accompanied by significant increases in circulating levels of free fatty acids (0.93 ± 0.1 vs 0.46 ± 0.1 mmol/l), 3‐hydroxybutyrate (196 ± 67 is 50 ± 18 μmol/l), glycerol (102 ± 10 vs 48 ± 5 μmol/l) and lactate. Blood alanine decreased and blood glucose remained constant. When an intravenous glucose tolerance test was performed during the last hour of hyperthermia signs of impaired first phase and enhanced second phase insulin responses were recorded. Calculated values for glucose disappearance also deteriorated (1.34 ± 0.19 vs 2.04 ± 0.50 %/min, P > 0.05). We conclude that hyperthermia mimics most major metabolic and hormonal changes observed during mild infection and could provide a model to study these conditions.
THE PITUITARY‐ADRENAL RESPONSE TO CRF‐41 IS UNALTERED BY INTRAVENOUS SOMATOSTATIN IN NORMAL SUBJECTS
Authors: STAFFORD P. J. , KOPELMAN P. G. , DAVIDSON KATHERINE , McLOUGHLIN LORRAINE , WHITE A. , REES L. H. , BESSER G. M. , COY D. H. , GROSSMAN A.
Published: March 2008

We have previously reported that the hypothalamo‐pituitary‐adrenal response to insulin‐induced hypoglycaemia is normal while the cortisol release to pituitary stimulation by corticotrophin releasing factor (CRF‐41) is reduced in obesity. Impaired growth hormone (GH) secretion is also found in obesity which may result from altered central levels of somatostatin (SMS). We have investigated, by giving a simultaneous infusion of SMS to six volunteer normal weight men during a CRF test, whether it is possible for SMS to modify pituitary‐adrenal function. Each subject received intravenous CRF‐41 (0.5 μg/ kg) on two occasions during an infusion of isotonic saline or SMS (4 μg/min) in a randomized double‐blind study. Plasma GH, cortisol, ACTH and SMS were measured. Three subjects demonstrated GH peaks during saline infusion but no peaks were seen in any subject during SMS infusion. No significant difference was found between peak cortisol responses during saline or SMS infusion (SMS cortisol 443 ± 61 nmol/l, saline cortisol 485 ± 52 nmol/l); neither was there any difference in the ACTH responses. We conclude that SMS does not alter the pituitary response to CRF in normal weight men and is thus less likely to be responsible for the altered pituitary‐adrenal function seen in obesity. Further studies of alternative mechanisms are required to explain the cause of this abnormality.
PERIFUSION STUDIES OF BROMOCRIPTINE‐TREATED AND UNTREATED MACROPROLACTINOMAS: EFFECTS OF DOPAMINE, BROMOCRIPTINE AND TRH
Authors: BEVAN J. S. , BURKE C. W.
Published: March 2008

There have been no detailed in‐vitro studies of PRL secretion by human macroprolactinoma cells exposed to bromocriptine (BC) to within a few days of surgical removal. We have studied cells from four such tumours (serum PRL 7.05–247 U/l) and six untreated tumours (serum PRL 4–80.35 U/l) using a perifusion technique. The BC‐treated tumours had shown tumour shrinkage and were treated until 40–96 h before surgery, but in one patient serum PRL had not suppressed below 15 U/l despite chronic treatment. Pretreatment serum PRL responses to TRH were blunted in all 10 patients. During perifusion with dopamine (DA, 5 μmol/l) untreated prolactinomas had a higher PRL secretion rate (19.3 ± 2.7 μU/mg tissue/min, mean ± SEM) than BC‐treated (3.9 ± 0.7, P= 0.005). When DA was removed, PRL secretion from untreated tumours increased to 129.7 ± 18.7 μU/mg/min, but in three of the BC‐treated, little increase occurred. In the fourth (from the patient whose serum PRL had not fully suppressed) PRL secretion increased from 4.4 to 25.6 μU/mg/min after DA withdrawal, and DA and BC dose‐related inhibition of PRL was similar to that observed in untreated tumours. TRH (10 ng/ml), without DA, provoked increased PRL release from both untreated (266% basal secretion, n= 3) and BC‐treated (298%, n= 3) tumours; this effect was completely inhibited by DA (5 μmol/l). The absence of hormones other than PRL following potassium (55 mmol/l) excluded contaminating normal pituitary. We conclude: (1) The effects of BC on prolactinoma PRL secretion may persist for at least 4 days; (2) partial in‐vivo BC resistance can be due to factors other than DA receptor malfunction; (3) the apparent discrepancy between in‐vivo and in‐vitro TRH responses was consistent with the presence of increased hypothalamic DA tone in vivo; and (4) BC may have differential effects on TRH and DA‐controlled PRL pools in the tumourous lactotroph.
QUANTIFICATION OF URINARY GROWTH HORMONE (GH) EXCRETION BY CENTRIFUGAL ULTRAFILTRATION AND RADIOIMMUNOASSAY: APPRAISAL OF THE RELATIONSHIP BETWEEN 24 H URINARY GH AND MEAN 24 H SERUM GH LEVELS IN NORMAL AND ABNORMAL STATES OF GH SECRETION
Authors: WEISSBERGER A. J. , HO K. Y. , STUART M. C.
Published: March 2008

We have applied a simple method for the quantification of 24 h urinary GH excretion (24 h UGH), combining centrifugal ultrafiltration and radio‐immunoassay (RIA), to an appraisal of the relationship between 24 h UGH and mean 24 h serum GH levels in normal and abnormal states of GH secretion. Forty‐four subjects, comprising 13 normal adults, 12 short‐statured subjects and 19 subjects with active acromegaly, underwent blood sampling at 20‐min intervals and concurrent urine collection for 24 h. Mean 24 h serum GH and 24 h UGH were also determined in four post‐menopausal women before and during cyclical oestrogen replacement therapy, and 24 h UGH was measured in six normal men prior to and following the subcutaneous administration of biosynthetic GH (0.2 IU/kg).

Each subject's mean 24 h serum GH level was determined by assaying a ‘pooled’ sample, derived from equal aliquots of the 73 serum samples obtained during the 24 h study. The method for quantification of 24 h UGH employs centrifugal microconcentrators, and involves a 50‐fold concentration of urine, followed by dialysis and RIA. Surface adsorptive hormone loss during sample collection and ultrafiltration is minimized by the prior addition of bovine serum albumin to the urine collection container. Immunoreactive GH in ultrafiltered urine dilutes in parallel with the RIA standard curve. GH is stable in urine stored at −20°C for at least 12 months.

There was a highly significant correlation between 24 h UGH and mean 24 h serum GH values obtained from the combined population of normal adults (including the post‐menopausal women during oestrogen therapy) and short‐statured subjects (r=0.69,P> 0.0001). A significant correlation was also found in short‐statured subjects alone (r= 0.63,P> 0.05). In contrast, there was no significant correlation between 24 h UGH and mean 24 h serum GH in subjects with active acromegaly, and their 24 h UGH values were not distinguishable from those of the ‘non‐acromegalic’ subjects. A significant increase in 24 h UGH occurred in the post‐menopausal women given cyclical oestrogen replacement therapy (9.7 ± 2.6 (mean ± SE) to 24.6 ± 1.0 μIU/mmol creatinine,P> 0.02), reflecting the increase in their mean 24 h serum GH levels (0.8 ± 0.3 to 5.3 ± 0.7 mIU/l,P> 0.01). Twenty‐four hour UGH increased from 4.6 ± 0.6 to 17.1 ± 2.1 μIU/mmol creatinine (P> 0.002) in the men given biosynthetic GH. Twenty‐four hour UGH measurements reflect mean 24 h serum GH levels in normal adults and short‐statured subjects. While the measurement of 24 h UGH shows promise as an investigative tool, our results cast doubt on its use in the diagnosis of acromegaly.
EFFECTS OF INTRANASAL CALCITONIN ADMINISTRATION ON PITUITARY GH RESPONSE TO hGHRH (1–29)NH2 IN NORMAL ADULT SUBJECTS
Authors: GIUSTINA ANDREA , ROMANELLI GIUSEPPE , DOGA MAURO , PIZZOCOLO GIUSEPPE , GIUSTINA GIANNI
Published: March 2008

Studies in man demonstrated that intramuscular salmon (s) calcitonin (CT) administration blunted pituitary GH response to hypothalamic stimuli such as arginine infusion and insulin‐induced hypoglycaemia. However, the mechanisms underlying this inhibiting action of CT are still unclear. The aim of our study was to investigate the effects of intranasal (i.n.) and i.m. sCT administration on GH secretion elicited by direct pituitary stimulation in man with human GH‐releasing hormone (GHRH) (1–29)NH2. Seven healthy non‐obese volunteers (five men, two women; mean age ± SDM 25 ± 2) underwent a bolus intravenous injection of GHRH, 100 pg, alone or associated with sCT, administered either i.n., 300 IU, or i.m., 100 IU. Our data demonstrate a significant decrease in GH secretion after GHRH when either i.n. or i.m. sCT is administered. GH peak (mean ± SDM); GHRH alone 22.9 ± 2.5 is GHRH plus i.n. sCT, 8.9 ± 1.5 μg/l, P > 0.001; or vs GHRH plus i.m. sCT 12.3 ± 2.5 μg/l, P > 0.001. Area under the curve of GH secretion: GHRH alone 1211 ± 196 vs GHRH plus i.n. sCT 551 ± 116 μg 120 min/l, P > 0.001; or vs GHRH plus i.m. sCT 700 ± 167 μg 120 min/l, P > 0.001. We conclude that sCT is able to inhibit GHRH‐stimulated GH secretion in man.
INSULIN‐LIKE GROWTH FACTOR 1 AND BONE TURNOVER IN GLUCOCORTICOID‐TREATED AND CONTROL SUBJECTS
Authors: REID I. R. , GLUCKMAN P. D. , IBBERTSON H. K.
Published: March 2008

The role of the growth hormone‐somatomedin axis in the genesis of steroid osteoporosis has been studied by measuring circulating insulin‐like growth factor I (IGF‐1) levels in asthmatic subjects either receiving or not receiving therapy with oral glucocorticoids. There was no difference in IGF‐1 levels between the two groups (60.6 μg/l (95% confidence interval 47.3–77.8) in the control subjects vs 69.1 μg/l (49.3–96.9) in the steroid‐treated group). IGF‐1 declined with age in the control subjects but not in those taking steroids. When IGF‐1 levels were correlated with biochemical indices of bone turnover, a significant relationship was found with urine hydroxyproline in the control subjects (r=0.55, P<0.02) but not in those taking steroids. It is concluded that glucocorticoid therapy does not alter mean circulating levels of IGF‐1 but that the growth hormone‐somatomedin axis may influence bone turnover in normal subjects. Interference by glucocorticoids with the normal regulation of IGF‐1 and its influence on bone turnover is suggested.
THE EFFECT OF THYROID DISEASE ON PROINSULIN AND C‐PEPTIDE LEVELS
Authors: BEER S. F. , PARR J. H. , TEMPLE R. C. , HALES C. N.
Published: March 2008

C‐peptide and proinsulin levels were studied in hyper and hypothyroidism both pre and post‐treatment and in comparison to matched normals. Fasting C‐peptide was reduced in untreated hyperthyroidism (0.4 ± 0.2 (mean ± SEM) vs 0.7 ± 0.2 nmol/l, P<0.05) but returned to normal levels following treatment. Fasting proinsulin was elevated in untreated hyperthyroidism (3.6 ± 0.7 vs 2.4 ± 0.5 pmol/l, P<0.05) also returning to normal after treatment. A similar pattern was seen after oral glucose. The increased proinsulin and reduced C‐peptide suggest there may be a defect of proinsulin processing in hyperthyroidism.

Fasting C‐peptide was reduced in untreated hypothyroidism (0.4 ± 0.1 vs 0.7 ± 0.1 nmol/l, P<0.05) and also returned to normal after treatment. Fasting proinsulin did not differ significantly from controls. However, proinsulin was reduced after oral glucose (4.7 ± 0.7 vs. 7.9 ± 2.0 pmol/l, P<0.05) as was C‐peptide (0.9 ± 0.2 vs 2.6 ± 0.3 nmol/l, P<0.05). Both returned to normal after treatment. These findings suggest there are abnormalities of proinsulin and C‐peptide levels in both hyper and hypothyroidism.
RESISTANCE OF METASTATIC PANCREATIC ENDOCRINE TUMOURS AFTER LONG‐TERM TREATMENT WITH THE SOMATOSTATIN ANALOGUE OCTREOTIDE (SMS 201–995)
Authors: WYNICK D. , ANDERSON J. V. , WILLIAMS S. J. , BLOOM S. R.
Published: March 2008

Ten patients with metastatic pancreatic endocrine tumours were treated with the long‐acting somatostatin analogue octreotide (SMS 201–995). Three patients showed no response, clinically or biochemically, and treatment was therefore withdrawn. The seven remaining patients continued treatment for a median period of 28 months (range 13–54 months). Treatment was initially effective, symptoms improved and the concentrations of tumour‐related hormones were reduced.

Worsening of symptoms and rising levels of tumour‐related hormone concentrations occurred a median of 5 months (range 1–6 months) after the start of therapy and were initially reversed by increasing the dose of octreotide over a median of 10 months (range 6–16 months). However, after a median of 13 months (range 5–34 months) at the maximum dosage, symptoms recurred and were no longer responsive to a further increase in dosage of octreotide or other therapeutic measures. All patients died within a period of 5 months once this resistant phase of their illness had been reached.
SPONTANEOUS GROWTH HORMONE (GH) PULSATILITY IS THE MAJOR DETERMINANT OF GH RELEASE AFTER THYROTROPHIN‐RELEASING HORMONE IN ADOLESCENT DIABETICS
Authors: EDGE J. A. , HUMAN D. H. , MATTHEWS D. R. , DUNGER D. B.
Published: March 2008

GH release is abnormally regulated in insulin‐dependent diabetes (IDDM), and paradoxical stimulation of GH release after TRH has been reported. However, overnight GH pulsatility is increased in IDDM, and it may be difficult to distinguish TRH‐stimulated release from spontaneous secretory episodes. To resolve this question, we carried out two overnight GH profiles followed by either TRH or saline control tests in six adolescents with IDDM; ages 11.4–14.7 years, duration IDDM 2.4–6.7 years.

A rise in GH was seen in four of six following TRH, but with no consistent pattern. A rise was also seen in four of six following saline. Peak GH levels were similar after TRH and saline (19.3 ± 4.4 vs 25.8 ± 5.5 mU/l; mean ± SEM). Mean blood glucose was no different during TRH and saline tests (9.5 ± 1.6 vs 7.5 ± 0.6 mmol/l).

The two subjects who had an early GH peak after TRH were those in whom GH levels had already begun to rise, suggesting the coincident occurrence of a spontaneous GH pulse. The timing of the next GH pulse could be predicted equally well after TRH and saline from the overnight secretory profile using autocorrelation.

Paradoxical GH stimulation after TRH is not seen in adolescents with IDDM, but apparent responses may be due to timing coincident with the increased spontaneous pulsatility.
EFFECT OF MORPHINE ON CORTISOL AND PROLACTIN SECRETION IN ANOREXIA NERVOSA AND DEPRESSION
Authors: ZIS ATHANASIOS P. , REMICK RONALD A. , CLARK CAMPBELL M. , GOLDNER ELLIOT , KELLY GRANT B. E. , BROWN GREGORY M.
Published: March 2008

Endogenous opioid peptides are involved in feeding regulation, and alterations in opioidergic regulation have been implicated in the pathophysiology of eating disorders. To investigate further this hypothesis, we conducted a placebo‐controlled study of the effect of the opiate alkaloid morphine on cortisol and prolactin secretion in six patients with anorexia nervosa and six age‐matched healthy volunteers, and compared the results with those obtained in nine depressed patients. Basal cortisol but not basal prolactin levels were elevated in patients with anorexia nervosa and patients with depression. Following the administration of morphine plasma concentrations of cortisol levels declined progressively and at a similar rate in all three groups. The prolactin response to morphine was attenuated significantly in patients with depression. Neither the cortisol and prolactin response to morphine in the anorectic patients nor the cortisol response in the depressed patients we observed in this study suggests altered opiate receptor sensitivity. However, the decreased prolactin response to morphine in depressed patients remains compatible with this hypothesis.
NASAL CALCITONIN FOR TREATMENT OF ESTABLISHED OSTEOPOROSIS
Authors: OVERGAARD K. , RIIS B. J. , CHRISTIANSEN C. , PØADENPHANT J. , JOHANSEN J. S.
Published: March 2008

Thirty‐seven women with established osteoporosis completed a one‐year double‐blind, placebo‐controlled study with the primary aim of examining the effect of nasal salmon calcitonin (200 IU daily) on bone and calcium metabolism. All the women received a daily calcium supplement of 500 mg. For comparison we also report data from an age‐matched group of healthy women who did not receive calcium supplementation. The bone mineral measured in the forearm (single photon absorptiometry) and spine (dual photon absorptiometry) showed a similar pattern during treatment. The calcitonin group (n = 17) did not lose bone mineral in comparison with the placebo (n= 20) and the control groups (n= 19) (P< 0.01). The biochemical estimates of both bone resorption and bone formation decreased highly significantly in the calcitonin group (P< 0.001) and were unchanged in the control group, whereas the placebo (calcium) group showed intermediate values. Neither subjective nor objective side‐effects occurred in any of the groups. We conclude that nasal calcitonin is a realistic treatment of established osteoporosis.
HETEROGENEITY OF THE POLYCYSTIC OVARY SYNDROME: CLINICAL, ENDOCRINE AND ULTRASOUND FEATURES IN 556 PATIENTS
Authors: CONWAY G. S. , HONOUR J. W. , JACOBS H. S.
Published: March 2008

This paper reports an analysis of the clinical, endocrine and ultrasound data within a population of 556 patients with ultrasound‐diagnosed polycystic ovaries. Compared with those not so affected, hirsutism was associated with a higher mean serum testosterone concentration, infertility was associated with higher mean gonadotrophin concentrations, obesity was associated with a higher mean serum testosterone concentration, hyperprolactinaemia was associated with a lower mean serum testosterone concentration and smaller ovaries, alopecia was associated with lower mean serum LH and testosterone concentrations, and acanthosis nigricans was associated with obesity and a raised mean serum testosterone concentration. The heterogeneity illustrates the limitations in the use of specific clinical or endocrine criteria as requirements for the diagnosis of the polycystic ovary syndrome.
VARIABLE EFFECTS OF RU 486 ON ENDOMETRIAL MAINTENANCE IN THE LUTEAL PHASE EXTENDED BY EXOGENOUS hCG
Authors: CROXATTO HORACIO B. , SALVATIERRA ANA MARIA , CROXATTO HECTOR D. , SPITZ IRVING M.
Published: March 2008

This study was designed to assess the features and conditions for endometrial bleeding induction with the synthetic antiprogestin and antiglucocorticoid RU 486 during hCG‐induced prolongation of the luteal phase. Eighteen healthy, surgically sterilized women and another five women with an intrauterine contraceptive device (IUD) participated. All subjects received hCG which was injected daily in increasing doses (500 to 15 000 IU) from day 9 to day 15 of the luteal phase. Ten subjects received hCG alone, and groups of three to 16 subjects received hCG combined with RU 486 (25, 50, 100,200 or 400 mg/day). RU 486 administration was commenced on day 12 following the LH surge and given either for 1, 4 or 7 consecutive days. In certain cycles, tamoxifen (20 mg/day) was given for 4 consecutive days with hCG, or with hCG and RU 486. All treatment cycles were separated by one or two resting cycles. Frequent blood samples were taken to monitor the endocrine response.

Treatment with hCG alone or with the various combinations of RU 486 produced similar serum levels of oestradiol and progesterone which were equivalent to those observed during early pregnancy. With hCG alone, the onset of bleeding was on day 21–24 after the LH surge, coinciding with the drop in oestradiol and progesterone. With RU 486 doses of 50 mg/day or more, an early bleeding episode almost invariably occurred on day 14–17 after the LH surge in the presence of high circulating steroid levels. In contrast, 25 mg/day RU 486 for 4 days failed to induce this early onset of bleeding in three out of six cases. Tamoxifen did not cause early bleeding and failed to potentiate the effect of RU 486. In 43% of the cycles treated with RU 486, a second bleeding episode occurred on days 22–24 after the LH surge coincident with the drop of steroids. This late bleeding was less frequent (17%) in the subgroup receiving a total dose of 700 or 800 mg RU 486. In those cycles that exhibited a second bleeding episode coincident with the fall in progesterone, endometrial biopsies, taken shortly after the initial early bleeding had stopped, showed a mixed proliferative and secretory endometrium, suggestive of incomplete shedding. In contrast, only proliferative endometrium, compatible with complete shedding, was evident in cycles characterized by the absence of a second bleeding episode. It is concluded that during maintenance of corpus luteum function with exogenous hCG, RU 486 can induce endometrial bleeding despite high circulating progesterone and oestradiol levels. With the lower doses of RU 486 this bleeding is often accompanied by incomplete sloughing of the endometrium leading to a second bleeding episode at the time of corpus luteum demise.
IS OLEIC ACID THE THYROXINE BINDING INHIBITOR IN THE SERUM OF ILL PATIENTS?
Authors: HAYNES I. G. , LOCKETT S. J. , FARMER M. J. , FITCH N. J. , BRADWELL A. R. , SHEPPARD M. C. , RAMSDEN D. B.
Published: March 2008

The possibility that oleic acid is the thyroxine binding inhibitor in the serum of seriously ill patients was investigated. 3H‐Oleic acid was shown to bind directly to human thyroxine‐binding globulin (TBG) by the techniques of one and two‐dimensional immunoelectrophoresis in combination with autoradiography. However, no correlation was seen between serum thyroxine concentration and oleic acid concentration in two groups of patients, one of which underwent routine cholecystectomy, whilst the other group was admitted to an intensive therapy unit (mortality 75%). No correlation was seen between serum total thyroxine concentration and either stearic, palmitic, linoleic or arachidonic acid concentrations in these groups. Therefore, it was concluded that oleic acid was unlikely to be the circulating inhibitor of thyroxine binding.
HEPATIC MICROSOMAL ENZYME INDUCTION AND ADRENAL CRISIS DUE TO o,p’DDD THERAPY FOR METASTATIC ADRENOCORTICAL CARCINOMA
Authors: HAGUE R. V. , MAY W. , CULLEN D. R.
Published: March 2008

Two cases are described in which metastatic adrenocortical carcinoma associated with Cushing's syndrome was treated with mitotane (o,p'DDD). The first patient had initially been treated by bilateral adrenalectomy and, whilst responding to mitotane biochemically and by remission of metastases, experienced repeated episodes of adrenal crisis requiring a substantial increase in steroid therapy. The second patient failed to respond to the drug, but evidence of hepatic enzyme induction was noted during its administration. It is suggested that hepatic microsomal enzyme induction can occur in association with treatment with mitotane and that this can lead to an increased destruction of exogenous steroid with clinical consequences.
PERSISTENT HYPERINSULINAEMIC HYPOGLYCAEMIA OF INFANCY: LONG‐TERM TREATMENT WITH THE SOMATOSTATIN ANALOGUE SANDOSTATIN†
Authors: GLASER BENJAMIN , LANDAU HEDDY , And ADINA SMILOVICI , NESHER RAFAEL
Published: March 2008

Six infants with severe, persistent hyperinsulinaemic hypoglycaemia were treated with the long‐acting somatostatin analogue SMS 201–995 (Sandostatin, Sandoz, Basle, Switzerland). Effective control of hypoglycaemia without the need for parenteral glucose was achieved in five of the six cases with doses ranging from 10 to 40 μg/kg day given either by four S.C. injections per day, or by continuous subcutaneous infusion (CSI). One has been well controlled on SMS 10 μg/kg day for 17 months as an out‐patient without requiring surgery, while the five others underwent sub‐total pancreatectomy after receiving short courses of the drug. In two patients where hypoglycaemia persisted after sub‐total pancreatectomy SMS was effective in inhibiting insulin secretion and preventing hypoglycaemia. Plasma somatomedin concentrations and linear growth were not suppressed in any patient. It is concluded that Sandostatin is useful in the pre and post‐operative management of most infants with this syndrome. In selected cases this analogue of somatostatin may also be a long‐term treatment option in place of pancreatectomy.
THE INFLUENCE OF ANTITHYROID DRUGS AND IODINE ON THYROID CELL MHC CLASS II ANTIGEN EXPRESSION
Authors: DAVIES TERRY F. , YANG CLEMENT , PLATZER MICHAEL
Published: March 2008

We have investigated the influence of antithyroid drugs (methimazole and propylthiouracil) and sodium iodide on the expression of major histocompatibility (MHC) class II antigen expression in human and rat thyroid cells. While methimazole and propylthiouracil significantly inhibited lectin‐induced MHC class II (HLA‐DR) antigen in crude human thyroid monolayer preparations these drugs had no influence on γ‐interferon induction of class II antigens in similar cell preparations. Hence, antithyroid drugs probably had a direct effect on thyroid monolayer T cells which are known to effect the lectin induction of MHC class II antigen via T‐cell secretion of the cytokine, γ‐interferon (IF). Sodium iodide, similarly, had no direct influence on human thyroid cell MHC class II antigen expression induced by γ‐IF. However, iodide significantly inhibited the γ‐IF‐induced expression of MHC class II antigens in a proliferating rat thyroid cell clone derived from FRTL‐5 cells (clone 1B‐6). In the rat thyroid cell clone this antagonistic action appeared to be exerted via inhibition of TSH‐induced proliferation.

These data add further support to the multifactorial nature of the profound immunosuppressive influence of antithyroid drugs in autoimmune thyroid disease and experimental thyroiditis. In contrast, iodides may have a major, and often overlooked, influence on thyroid cell proliferation and antigen expression.
ANTITHYROID DRUGS IN THE TREATMENT OF HYPERTHYROIDISM OF Graves' DISEASE: LONG‐TERM FOLLOW‐UP OF 434 PATIENTS
Authors: HEDLEY A. J. , YOUNG R. E. , JONES S. J. , ALEXANDER W. D. , BEWSHER P. D. ,   SCOTTISH AUTOMATED FOLLOW‐UP REGISTER GROUP
Published: March 2008

A study of antithyroid drug (ATD) therapy with a mean follow‐up period of 10 years (range 2–25) in 434 patients with Graves' disease has been made by linking hospital records with those of a central follow‐up register. The majority (89%) were treated with carbimazole and 87% received combined therapy with triiodothyronine (T3) (73%) or thyroxine (T4) (14%). Sixty‐one per cent were assessed for T3 suppression tests on completion of treatment, of whom 61% (95% CL, 55‐67%) suppressed. The overall 5‐year cumulative proportion developing recurrent hyperthyroidism was 54‐62% with rates of 26‐44% in suppressed patients and 65‐79% in those not suppressed. In unsuppressed patients, most (72%) of the recurrences occurred within 1 year with only an additional 10% predicted up to 10 years. In suppressed patients 30% of recurrences occurred in the first year, 60% between 1 and 5 years and a further 10% between 5 and 10 years. Suppression with T3 is probably the best and cheapest predictor of outcome but has an accuracy of only 70% for both positive and negative tests which limits its usefulness in planning long‐term follow‐up and surveillance. A standard format should be adopted for the analysis and reporting of follow‐up studies, based on actuarial methods of estimating the cumulative proportion with recurrences or other events, to facilitate comparisons between different centres.
RELATIONSHIP BETWEEN THE PUBERTAL FALL INSEX HORMONE BINDING GLOBULIN AND INSULIN‐LIKE GROWTH FACTOR BINDING PROTEIN‐I. A SYNCHRONIZED APPROACH TO PUBERTAL DEVELOPMENT?
Authors: HOLLY J. M. P. , SMITH C. P. , DUNGER D. B. , HOWELL R. J. S. , CHARD T. , PERRY L. A. , SAVAGE M. O. , CIANFARANI S. , REES L. H. , WASS J. A. H.
Published: March 2008

In a cross‐sectional study of 69 normal adolescents we have found sex hormone‐binding globulin (SHBG) levels to fall in both males and females throughout the pubertal period. Multiple regression analysis revealed a close negative correlation with insulin in both sexes. Weaker correlations were also found between SHBG and circulating androgen concentrations, in both males and females. Similar results were also obtained for a second circulating binding protein of primarily hepatic origin. This low molecular weight insulin‐like growth factor (IGF) binding protein I (IBP‐I) is one of two distinct classes of IGF binding proteins which bind IGF‐I and IGF‐II. IGF‐I in turn mediates, at least in part, the actions of growth hormone. IBP‐I also fell throughout puberty, correlating with the increasing insulin levels. In addition IBP‐I correlated with androgen levels in both sexes. These similarities between SHBG and IBP‐I, together with a strong correlation across puberty between the levels of the two binding proteins themselves (r= 0.737, P < 0.001), suggest common mechanisms of control over the circulating levels of these two binding proteins. The association with insulin raises the possibility of a synchronized modulation of the actions of sex steroids and IGFs by nutritional intake. Thus pubertal growth and sexual development may occur over the same time with both modulated according to nutritional intake, linked through pancreatic insulin release, to hepatic production of SHBG and IBP‐I.
PERIFUSION OF HUMAN GRANULOSA‐LUTEAL CELLS: RESPONSE TO LH STIMULATION
Authors: WEISS T. J. , STEELE P. A. , UMAPATHYSIVAM K.
Published: March 2008

LH pulse frequency and amplitude vary significantly during the menstrual cycle; however, it is not clear what significance the secretory pattern has for the ovary. We have developed an in‐vitro perifusion system in which luteinized human granulosa cells (GC) can be exposed to various patterns of gonadotrophin stimulation. GC were recovered following follicle aspiration for in‐vitro fertilization, grown on Cytodex‐3 for 6 days, and then perifused with medium containing LH (or hCG), delivered with differing pulse frequencies and amplitudes. When pulses of LH were applied to the cells, progesterone secretion rose initially and then fell to the baseline as the LH concentration declined. Pulsatile administration of LH, over a period of 10 h, stimulated progesterone secretion more efficiently than did continuous LH. Finally, delivery to the cells of pulses of hCG, a ligand known to bind to the LH receptor but with binding characteristics distinct from those of LH, failed to elicit pulses of progesterone.
RETURN OF FERTILITY AFTER TWELVE YEARS OF AUTOIMMUNE OVARIAN FAILURE
Authors: TAYLOR R. , SMITH N. M. , ANGUS B. , HORNE C. H. W. , DUNLOP W.
Published: March 2008

Autoimmune ovarian failure is widely regarded as irreversible, although ovarian biopsy characteristically shows follicles surrounded by lymphocytes. Two previous reports of pregnancy in this condition both followed institution of steroid replacement therapy (Finer et al., 1985; Cowchock et al., 1988). We report a case in which fertility spontaneously returned to normal twelve years after the diagnosis of autoimmune ovarian failure.
THE KIDNEY IS THE MAJOR SITE OF CORTISONE PRODUCTION IN MAN
Authors: WHITWORTH J. A. , STEWART P. M. , BURT D. , ATHERDEN S. M. , EDWARDS C. R. W.
Published: March 2008

The major site of cortisol metabolism in man has been thought to be the liver. Studies in patients with either congenital or acquired deficiency of 11β‐hydroxysteroid dehydrogenase (an enzyme responsible for the interconversion of cortisol to cortisone) suggested that the kidney was an important site of cortisone production.

In 88 patients with proven renal disease but normal liver function, arbitrarily divided into four groups on the basis of plasma creatinine, 0900 h plasma cortisone was significantly reduced in all groups when compared with 47 controls (e.g. 21 ± 3 nmol/1 (mean ± SEM) in patients with plasma creatinine >0.45 mmol/1 vs 62 ± 3 nmol/1 in controls, P < 0.001). 0900 h plasma cortisol was not significantly different. There was an inverse correlation between plasma creatinine and plasma cortisone (r=−0.55, p < 0.01). Four anephric patients had a 0900 h plasma cortisone level of 6 ± 1 nmol/1.

We conclude that the kidney is a major site for the conversion of cortisol to cortisone and hence cortisone production in man. The relevance of this to the pathophysiology of salt and water metabolism in renal disease remains to be elucidated.
EFFECT OF CV 205‐502 IN HYPERPROLACTINAEMIC PATIENTS INTOLERANT OF BROMOCRIPTINE
Authors: NEWMAN CONNIE B. , HURLEY ARLENE M. , KLEINBERG DAVID L.
Published: March 2008

CV 205‐502 (Sandoz), an octahydrobenzol [g]quinoline, is a long‐acting dopamine agonist which inhibits prolactin secretion. We conducted a phase 2 clinical study in 10 hyperprolactinaemic women (nine of whom were previously intolerant of bromocriptine) in order to determine (1) the dose at which CV 205–502 exerted its prolactin‐lowering effect; (2) the nature of adverse reactions associated with long‐term therapy; and (3) whether patients who were intolerant of bromocriptine could tolerate CV 205–502. At first patients were randomized to take initial doses of either 0.02 or 0.05 mg daily at bedtime. Thereafter these doses of medication were gradually increased either to the point of normalizing serum prolactin (to 0.70 IU/1 or 20 ng/ml) or to a maximum dose of 0.14 mg daily. The lower initial dose was ineffective and had to be increased in all patients. The higher initial dose (0.05 mg) normalized prolactin in three of five women within 24 h. During chronic administration of the final dose of CV 205–502 (mean 0.09 mg a day), serum prolactin decreased from a mean level of 9.19 |Mp 4.9 (SEM) IU/1 to a mean level of 1.55 ± 0.49 IU/1 (n= 10 patients). Prolactin was normalized in five patients. Two patients, one of whom had been previously unresponsive to bromocriptine, and another unresponsive to pergolide with regard to prolactin inhibition, were also unresponsive to CV 205–502. Nausea, the side‐effect responsible for these patients' previous intolerance of bromocriptine, occurred in six of 10 patients taking CV 205‐502 but was much less disabling and did not cause any of the patients to stop this medication. Only one patient taking CV 205‐502 discontinued treatment because of adverse effects (light‐headedness).
TESTICULAR ENLARGEMENT AND ELEVATED SERUM INHIBIN CONCENTRATIONS OCCUR IN PATIENTS WITH PITUITARY MACROADENOMAS SECRETING FOLLICLE STIMULATING HORMONE
Authors: HESELTINE D. , WHITE M. C. , KENDALL‐TAYLOR P. , DE KRETSER D. M. , KELLY W.
Published: March 2008

We studied four male patients with pituitary macroadenomas. Before treatment all had high serum FSH concentrations, but LH and testosterone were normal or subnormal; all patients were found to have large testes. All had had normal sexual function, and three patients had fathered children. After pituitary surgery there were decreases in serum gonadotrophins and testosterone, which were accompanied by decreases in testicular volumes. hCG stimulation tests in two patients showed normal responses of testosterone and oestradiol, confirming normal Leydig cell function. Inhibin levels were increased in two patients studied when FSH levels were high, suggesting a defect in gonadal‐pituitary feedback control. Later, as FSH concentrations decreased to normal, so did inhibin levels. Histology showed that increased testicular size was due to increased lengths of seminiferous tubules. The association of pituitary macroadenomas, large testes and increased serum inhibin has not been reported previously. Assessment of testicular size in patients with raised serum FSH is important, since enlarged testes suggest the likely pathogenesis is that of a pituitary gonadotrophinoma, rather than primary gonadal failure. Increased inhibin levels may then confirm this, and be a biochemical marker for these tumours.
VIRILIZING ADRENAL ADENOMA IN AN ADULT WITH THE BECKWITH‐WIEDEMANN SYNDROME: PARADOXICAL RESPONSE TO DEXAMETHASONE
Authors: CLOUSTON W. M. , CANNELL G. C. , FRYAR B. G. , SEARLE J. W. , MARTIN N. I. , MORTIMER R. H.
Published: March 2008

An adult woman with Beckwith‐Wiedemann syndrome, hemihypertrophy and an androgen‐secreting adrenal adenoma is described. She presented with a 7‐year history of progressive virilization and was found to have high plasma levels of testosterone and dehydroepiandrosterone (DHEA) sulphate and elevated levels of urinary metabolites of testosterone and its precursors. Administration of dexamethasone was associated with progressive rises in plasma 17 αOH progesterone, 11β‐desoxycortisol, DHEA sulphate, androstenedione and testosterone, together with increased urinary excretion of androsterone, 11βOH androsterone, etiocholanolone, DHEA, and 16αOH DHEA. Hormone levels fell to normal following removal of the tumour.