bluuebunny/crossref_metadata_2025 huggingface dataset:
GH substitution does not alter the pulsatile pattern of LH in amenorrhoeic growth hormone deficient women
Authors: De Boer  , Van Der Veen  , Schoemaker
Published: March 2003

OBJECTIVE

GH substitution in GH‐deficient (GHD) children promotes pubertal development. In some GHD women, secondary amenorrhoea occurs after discontinuation of GH treatment. This study was designed to investigate whether GH substitution directly influences the GnRH pulse generator. For this reason, the pulsatile release of LH was studied in amenorrhoeic GHD women before and during GH substitution.

DESIGN

GH deficiency was confirmed by an insulin tolerance test. During a 24‐h period, blood samples were drawn every 10 min for determination of LH, FSH and GH levels. Oestradiol and IGF‐1 were determined at 1000 h and 2200 h. After the first test day, patients started with GH substitution, 0.25 IU/kg/week. During month 6 of GH treatment, the 24 h blood sampling was repeated.

SUBJECTS

Ten amenorrhoeic GH‐deficient women participated in the trial. All were diagnosed as GH deficient during childhood or adolescence. Eight of them had been treated with GH during childhood. Seven women suffered from primary amenorrhoea and three from secondary amenorrhoea. Six women were started with GH substitution after the first test day (according to randomization in a larger study).

MEASUREMENTS

LH and GH were determined every 10 min and FSH every 60 min. LH pulse detection was conducted using a validated statistical method.

RESULTS

Prior to GH treatment, the LH pulse interval did not show a diurnal pattern as found during normal pubertal development. During GH treatment, IGF‐1 levels rose significantly. No differences were found in mean LH, LH pulse amplitude and LH pulse interval before and during GH treatment. Oestradiol levels did not change either.

CONCLUSIONS

GH substitution in amenorrhoeic GH‐deficient women does not alter the pulsatile pattern of LH. This may suggest that GH treatment does not influence central nervous system control of gonadotropin secretion in GHD patients.
Osteoporosis and fractures in Turner syndrome–importance of growth promoting and oestrogen therapy
Authors: Landin‐Wilhelmsen Kerstin , Bryman Inger , Windh Marianne , Wilhelmsen Lars
Published: March 2003

OBJECTIVE

Turner syndrome (TS) is a chromosomal aberration (45,X) characterized by endogenous oestrogen deficiency and short stature. The aim was to study body composition, bone mineral density, fracture frequency, social and life style factors and biochemical bone markers, as well as hormones, in adults with TS in comparison with a female random population sample.

PATIENTS

Seventy women with TS responded to questionnaires. They underwent physical examination, bone mineral density measurement with Dual Energy X‐ray Absorptiometry (DEXA) and blood sampling. Mean age was 31 ± 12 (range 16–71) years. A random population sample of women from the WHO MONICA Project, Göteborg (25–64 years) served as controls (n = 740).

RESULTS

Women with TS were shorter than the controls and had lower body weight and lean body mass (P < 0.0001). Body mass index and waist/hip circumference ratio were higher in TS (P < 0.0001). Osteoporosis was present in seven TS women, six above 45 years of age. None of these had received oestrogen substitution continuously. Fractures (all types) were reported by 11 (16%) TS women (six (50%) above 45 years) compared with 5% in the population sample (P < 0.001). Four TS women with fractures had osteoporosis, all above 45 years of age. Osteoporosis and fractures did not differ between women with the 45,X karyotype and those with mosaicism. Impaired hearing was reported by 40%, and 73% wore glasses. Six percent among TS were smokers compared with 25% in the population (P < 0.001). TS women reported a lower degree of leisure time physical activity than controls (P < 0.001). Parathyroid hormone and osteocalcin were higher among TS (P < 0.02 and 0.001). Insulin‐like growth factor‐I was similar. Ninety‐one percent of all TS had oestrogen substitution and 96% of TS below 25 years of age had received growth hormone treatment.

CONCLUSION

Osteoporosis and fractures were common above, but not below, 45 years of age in Turner syndrome. It is probable that modern therapy, including growth promoting and continuous oestrogen therapy, will prevent osteoporotic fractures in the future.
Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency
Authors: Carani Cesare , Rochira Vincenzo , Faustini‐Fustini Marco , Balestrieri Antonio , Granata
Published: March 2003

OBJECTIVE

In order to evaluate the role of oestrogens on human male sexual behaviour, the gender‐identity, psychosexual orientation and sexual activity of a man with a congenital lack of oestradiol resulting from an inactivating mutation of the aromatase P450 gene was investigated. The psychosexual and sexual behavioural evaluations were performed before and during testosterone treatment and before oestradiol treatment, during three phases of different dosages of oestradiol treatment.

DESIGN

The study was performed before (phase A) and during (phase B) testosterone enanthate treatment (250 mg i.m. every 10 days, for 6 months), during testosterone withdrawal (phase C), and during each of the following transdermal oestradiol treatments: 50 μg twice a week for 6 months (phase D); 25 μg twice a week for 9 months (phase E), and 12.5 μg twice a week for 9 months (phase F).

MEASUREMENTS

Sexual behaviour was investigated by a sexological interview and by a 2‐month self‐reported daily diary performed during each phase of the protocol study. Furthermore, during each oestradiol treatment (phase C, D, E and F), a study of depression, anxiety trait and sexual behaviour was performed by the Beck Depression Inventory (BDI), the Spielberger Trait Anxiety Inventory (STAI) and the Golombok‐Rust Inventory of Sexual Satisfaction (GRISS), respectively. Sexual orientation and gender‐identity were evaluated by the BEM Sex Role Inventory (BSRI). Serum testosterone and oestradiol were measured during each phase of the study.

RESULTS

Before oestradiol treatment (phase C), serum oestradiol was undetectable, while it rose to 356.1, 88.1 and 55.1 pmol/l during phases D, E and F, respectively. Before any oestradiol treatment, during phase D, phase E and phase F serum testosterone was 18.13, 0.72, 14.3 and 18.51 nmol/l, respectively. The patient's gender‐identity as assessed by BSRI and by the sexological interview was clearly male. The psychosexual orientation evaluated by BSRI, by the sexological interview and by the analysis of the self‐filled diary was heterosexual. Relevant modification of the patient's sexual behaviour occurred only during oestrogen treatment. This was more evident during both phase E and phase F, and concerned the behavioural parameters with an increase of libido, frequency of sexual intercourse, masturbation and erotic fantasies. A reduction of BDI and STAI scores was detected during the oestrogen phases.

CONCLUSIONS

The study of the sexual behaviour in this man with aromatase deficiency suggests that oestrogens in humans do not affect gender‐identity and sexual orientation but could have a role in male sexual activity.
FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance
Authors: McIver Bryan , Grebe Stefan K. G. , Wang Liang , Hay Ian D. , Yokomizo  , Liu Wanguo , Goellner John R. , Grant Clive S. , Smith David I. , Eberhardt Norman L.
Published: March 2003

OBJECTIVE

The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis.

DESIGN

Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo‐preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control.

PATIENTS

We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients.

MEASUREMENTS

Single stage and nested reverse transcription polymerase chain reaction (RT‐PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis.

RESULTS

Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT‐PCR, most often in FTC, while single stage RT‐PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT‐PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities.

CONCLUSIONS

Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell‐derived thyroid neoplasms.
Management of the nontoxic multinodular goitre: A European questionnaire study
Authors: Bonnema Steen J. , Bennedbæk Finn N. , Wiersinga Wilmar M. , Hegedüs Laszlo
Published: March 2003

BACKGROUND AND OBJECTIVE

The optimum management strategy for the patient with a multinodular nontoxic goitre is still a matter of debate. Our aim was to assess the attitudes towards management of such patients throughout Europe by means of a questionnaire.

DESIGN

The questionnaire was circulated to all clinician members of the European Thyroid Association (ETA). A case report was followed by diagnostic investigations and choice of therapy in the index case (a 42‐year‐old woman with an irregular nontender bilaterally enlarged thyroid of 50–80 g and no clinical suspicion of malignancy). Eleven variations of the basic case report were proposed in order to evaluate the impact on management of each alteration.

SUBJECTS AND METHODS

One hundred and sixty‐seven members replied to the letter, and 120 individuals from 22 countries completed the questionnaire (corresponding to approximately two‐thirds of the clinical members of the ETA).

RESULTS

Based on the index case, serum TSH was the routine choice of 100%, and serum free T4/T4‐index was included by 74%. Serum TPO autoantibodies, Tg autoantibodies and calcitonin were measured by 65%, 49% and 32%, respectively. The median number of blood tests used was four (range 1–11). Considerable intercountry variations were seen in the preferred imaging methods. Ninety‐one percent of the clinicians would use at least one imaging modality. Ultrasound (US) was used by 84%, thyroid scintigraphy by 76%, and both methods by 69%. US had first priority (53% vs. 19% for scintigraphy). If scintigraphy was performed, fine‐needle aspiration cytology was routinely used by 17% (inhomogeneous uptake) and 95% (dominant ‘cold’ area), and 63% used US‐guidance. L‐T4 treatment was supported by 52% of the clinicians, iodine supplementation by 4%, radioiodine by 6% and surgery by 10%. In the case of a suppressed serum TSH, radioiodine treatment was preferred by 44%, while surgery was the favoured recommendation in four clinical variations with a large goitre or suspicion of malignancy. Marked differences between the countries were suggested by L‐T4 therapy being the dominant treatment in Italy, France and Germany in contrast to the prevailing use of radioiodine in Denmark and a wait and see policy in the UK.

CONCLUSIONS

Fundamental differences between European countries exist as regards diagnosis and treatment of the multinodular nontoxic goitre suggesting difficulties in reaching a consensus.
Serum inhibin B levels in community‐dwelling elderly men1
Authors: Mahmoud  , Goemaere  , De Bacquer  , Comhaire  , Kaufman
Published: March 2003

BACKGROUND AND OBJECTIVE

Ageing in men is accompanied by a decline of Leydig cell function, with a 50% decrease of the population means for serum free testosterone between age 25 and 75 years. Information on Sertoli cell function and spermatogenesis in the elderly is scarce. Studies on seminal parameters in ageing men have suggested that spermatogenesis may be fairly well maintained in the elderly, but they included mostly selected subjects and only few men over 60 years. More systematic studies are lacking. The aim of the present study was to assess serum inhibin B levels in elderly men as an index of global Sertoli cell function and spermatogenic activity.

SUBJECTS AND MEASUREMENTS

Specific immunoassays were used to determine serum levels of inhibin B, gonadotrophins, testosterone and oestradiol in blood obtained between 0800 and 1000 h. from 189 ambulatory, community‐dwelling elderly men (age: 70–85 years) and, for comparison, from 51 middle–aged (35–54 years) and 50 young (< 35 years) controls.

RESULTS

All age groups combined, serum inhibin B was only weakly negatively correlated to age (Spearman correlation coefficient: − 0.17; P < 0.01) and more strongly to serum FSH (− 0.52; P < 0.001). In a multiple regression analysis serum FSH, but not age or serum free testosterone, emerged as an independent determinant of serum inhibin B levels. An age‐related decline of median inhibin B levels in the study population was essentially limited to the younger age groups, with stable levels between age 35 and 79 years, and only a modest further decrease thereafter. There was a progressive age‐related increase of serum FSH across age groups with, consequently, a marked decrease of the serum inhibin B : FSH ratio. The prevalence of men presenting with low serum inhibin B (below 10th percentile for inhibin B levels in men < 35 years), indicative of deficient Sertoli cell function and spermatogenesis, increased most strikingly between men < 35 years and those 35–54 years, which contrasts with the more progressive increase at an older age of the prevalence of low serum (free) testosterone.

CONCLUSION

Global testicular Sertoli cell function and spermatogenic activity, as assessed indirectly through serum inhibin B levels, appear to be well maintained in ambulatory elderly men, albeit there are age‐related alterations at the level of the Sertoli cells as indicated by a progressive increase of testicular drive by pituitary FSH.
Cardiovascular risk markers in hypothalamic amenorrhoea
Authors: Miller Karen K. , Grinspoon Steven , Klibanski Anne
Published: March 2003

OBJECTIVE

To determine whether women with oestrogendeficiency due to hypothalamic amenorrhoea (HA) would demonstrate a lipid and lipoprotein pattern similar to that seen in menopause with higher total cholesterol (TC), LDL, triglyceride and Lp(a) and lower HDL levels than women with regular menstrual cycles.

DESIGN

Cross‐sectional.

PATIENTS

Fifty subjects: 21 women with HA and 30 eumenorrhoeic controls (NL) matched for age, BMI and fat‐free mass.

MEASUREMENTS

Lipid and lipoprotein levels.

RESULTS

There was a significant difference in Lp(a) levels in the HA group between women with >19% fat intake and those <19% fat intake (352 ± 231 vs. 116 ± 62 mg/l, P = 0.006). Percent fat intake was the most significant determinant of Lp(a) levels in HA, accounting for 51% of the variation in Lp(a) levels. Mean HDL levels were higher in the women with HA compared with the controls (1.3 ± 0.3 vs. 1.1 ± 0.2 mmol/l, P = 0.002). There was no significant difference between the groups in TC [4.4 ± 0.9 (HA) vs. 4.1 ± 0.8 mmol/l (NL), P > 0.05], LDL [2.8 ± 0.6 (HA) vs. 2.7 ± 0.7 mmol/l (NL), P > 0.05], triglycerides [1.8 ± 0.5 (HA) vs. 1.7 ± 0.5 mmol/l (NL), P > 0.05] or Lp(a) [234 ± 199 (HA) vs. 247 ± 222 (NL) mg/l, P > 0.05] levels.

CONCLUSION

Reduced Lp(a) levels were associated with low dietary fat in women with HA. Moreover, in contrast to menopausal oestrogen deficiency, young women with HA and oestrogen deficiency have increased levels of HDL and no increases in TC, LDL and triglycerides. These data suggest that the negative effects of oestrogen deficiency on cardiovascular risk factors may be modified in women with hypothalamic amenorrhoea.
The prevalence of polycystic ovaries in women with a history of gestational diabetes
Authors: Kousta Eleni , Cela Ester , Lawrence Natasha , Penny Anna , Millauer Barbara , White Davinia , Wilson Helen , Robinson Stephen , Johnston Desmond , McCarthy Mark , Franks Stephen
Published: March 2003

OBJECTIVE

Women with a history of gestational diabetes mellitus (GDM) and women with polycystic ovary syndrome (PCOS) both demonstrate abnormalities in insulin action and secretion, and both are at increased risk of developing type 2 diabetes. To determine whether these similarities reflect a common pathophysiological basis, we examined the prevalence of ultrasound‐based polycystic ovarian morphology in a large multiethnic group of women with a history of GDM and a group of women who had normal glucose tolerance during pregnancy.

PATIENTS AND DESIGN

We studied 91 women with previous GDM (48 European, 20 South Asian, 10 Afro‐Caribbean and 13 of other or mixed ethnicity) and 73 normoglycaemic control women (56 European, one South Asian, 14 Afro‐Caribbean and two of other or mixed ethnicity), a median (interquartile range) of 20 (11–36) and 29 (17–49) months postpartum, respectively. A detailed history was taken, and the prevalence of PCO morphology on ultrasound scan was assessed. Fasting lipids, insulin, glucose status, gonadotrophins and testosterone were measured. Estimates of β‐cell function (%B) and insulin sensitivity (%S) were derived using the HOMA algorithm.

RESULTS

Women with previous GDM had higher fasting glucose (5.4 (4.8–6.0) vs. 4.7 (4.4–5.0) mmol/l, P < 0.0001) and features reminiscent of syndrome X: higher BMI (26.4 (22.8–31.4) vs. 23.8 (21.0–27.5) kg/m2, P = 0.002), waist/hip ratio (0.82 (0.79–0.88) vs. 0.77 (0.73–0.81), P < 0.0001), fasting insulin (165 (68–299) vs. 54 (24–156) pmol/l, P < 0.0001), triglycerides (1.1 (0.8–1.6) vs. 0.8 (0.6–1.1) mmol/l, P < 0.0001) and lower insulin sensitivity (%S) (27 (16–62) vs. 86 (34–139)%, P < 0.0001) compared to control women. The prevalence of PCO was higher in the previous GDM group than in the control subjects (47/91 (52%) vs. 20/73 (27%), χ2 = 9.86, P = 0.002 overall, odds ratio 2.7, P = 0.007 by logistic regression allowing for ethnicity). There was no difference in any metabolic parameter between the post‐GDM PCO group and the post‐GDM normal ovaries group, but irregular cycles were more prevalent in the PCO group (22/47 (47%) vs. 9/44 (21%), χ2 = 7.03, P = 0.008).

CONCLUSIONS

We found a higher prevalence of polycystic ovarian morphology in women with a history of gestational diabetes. Among the women with previous gestational diabetes, irregular cycles were more prevalent in the PCO group than in the women with normal ovarian morphology, but no other differences in endocrine or metabolic parameters were detected. These findings confirm an association between PCO and gestational diabetes and suggest that women with gestational diabetes display metabolic abnormalities irrespective of ovarian morphology.
Beta cell function declines with age in glucose tolerant Caucasians
Authors: Chiu Ken C. , Lee Nancy P. , Cohan Pejman , Chuang Lee‐Ming
Published: March 2003

OBJECTIVE

As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function.

SUBJECTS AND DESIGN

We enrolled 149 healthy, glucose tolerant and normotensive Caucasians (age 35 ± 1 years, body mass index 26.07 ± 0.44 kg/m2, waist‐hip ratio 0.842 ± 0.009 cm/cm, mean ± standard error). A cross‐sectional study was designed to examine the impact of age on insulin sensitivity and beta cell function. Their beta cell function (percentage B [%B]) and insulin sensitivity (percentage S [%S]) were estimated using the homeostasis model assessment.

RESULTS

Simple regression analysis revealed that %B declined with age (P = 0.008) while no relation was found between %S and age (P = 0.769). A stepwise regression analysis revealed that body mass index and diastolic blood pressure explained 14.7% of variation in %S, while age, waist‐hip ratio, gender, and systolic blood pressure had no influence on %S. Age, body mass index and diastolic blood pressure together accounted for 21.7% of variation in %B, with age being an independent variable.

CONCLUSIONS

In the present study, we showed that beta cell function declined with age at a rate of about 1% per year. In contrast, insulin sensitivity was not affected by ageing. Our observations suggest that the age‐related decline in glucose tolerance is primarily related to the loss of beta‐cell function.
Recovery of growth hormone secretion following cabergoline treatment of macroprolactinomas
Authors: George L. D. , Nicolau N. , Scanlon M. F. , Davies J. S.
Published: March 2003

OBJECTIVE

Cabergoline therapy normalizes prolactin levels and reduces the size of macroprolactinomas. However there are no data indicating whether cabergoline can normalize growth hormone secretion in patients who were growth hormone deficient at the time of diagnosis of a macroprolactinoma.

SUBJECTS AND METHODS

We studied nine patients with biochemical and radiological evidence of a macroprolactinoma who were also growth hormone deficient (peak growth hormone response to insulin‐induced hypoglycaemia < 10 mU/l). Patients were assessed before and after cabergoline therapy to assess their growth hormone secretory status, IGF‐I levels, cortisol response and change in tumour size.

RESULTS

Treatment with cabergoline was associated with a significant reduction in prolactin concentration (74341 ± 31939 mU/l vs. 265.9 ± 86.3, P = 0.009). The mean change in peak growth hormone response to insulin‐induced hypoglycaemia was significantly greater following cabergoline therapy compared with pretreatment levels (33.5 ± 11.8 mU/l vs. 4.34 ± 1.21 mU/l, P = 0.022). However IGF‐I levels were not different after treatment when compared with baseline although a nonsignificant trend towards improvement was noted (24.2 ± 3.97 nmol/l vs. 18.4 ± 4.94 nmol/l, P = 0.058). The mean peak cortisol concentration was 407.7 ± 64.1 nmol/l before treatment with a nonsignificant rise to 477.4 ± 84.8 nmol/l, P = 0.813 after treatment. These changes were associated with a significant reduction in mean maximal tumour diameter (21.2 ± 2.9 mm vs. 29.1 ± 2.8 mm, P = 0.009). There was no significant difference in either prolactin concentration or tumour size pre‐ or post‐treatment between those who recovered growth hormone secretion and those that did not. Six of the nine (67%) patients recovered a normal growth hormone response (> 10 mU/l) after cabergoline therapy. Those that remained growth hormone deficient after treatment were all panhypopituitary at baseline while those that recovered showed only partial anterior hypopituitarism.

CONCLUSION

These data indicate that growth hormone secretion may recover following successful reduction of prolactin levels after cabergoline therapy for a mean of 22 months (range 6–28 months) in most but not all subjects with a macroprolactinoma. It is therefore advisable that individuals with a macroprolactinoma in whom growth hormone replacement therapy is being considered undergo repeat assessment of growth hormone secretion following medical treatment.
Age‐related changes of serum sex hormones, insulin‐like growth factor‐1 and sex‐hormone binding globulin levels in men: cross‐sectional data from a healthy male cohort
Authors: Leifke Eckhard , Gorenoi Vitali , Wichers Christian , Von Zur Mühlen Alexander , Von Büren Erico , Brabant Georg
Published: March 2003

The age‐dependent decline of the gonadal and somatotopic axis has been causally linked to frailty in the elderly by their effects on muscle mass and bone mineral density. However, for healthy men data on serum oestrogens and androgens, as well as IGF‐1, as a common outcome measure covering the whole adult age range are scarce. We therefore studied healthy, nonobese male subjects between 20 and 80 years of age to asses their morning concentrations of total (T), free (FT), bioavailable testosterone (bT), oestradiol (E2), bioavailable oestradiol (bE2), oestrone (E1), sex‐hormone binding globulin (SHBG), and insulin‐like growth factor 1 (IGF‐1).

Five hundred and seventy‐two male healthy volunteers with a BMI < 30 kg/m2 recruited from regular blood donors and senior sports clubs participated in the study. Serum samples were obtained during morning hours and T, FT, E2, E1, SHBG, albumin and IGF‐1 were measured by radio‐immunoassay systems. In addition, bT and bE2 were calculated. A potential relationship between sex hormones and IGF‐1 was tested by multiple regression analysis including age and BMI.

Ageing was negatively related to serum levels of sex steroids and IGF‐1 (both P < 0·0001) with a mean decrease (youngest vs. oldest) of 51% for T, 64% for FT, 78% for bT, 32% for E2, 62% for bE2, 29% for E1 and 51% for IGF‐1 starting in early adulthood whereas SHBG increased after the 5th decade of life (anovaP < 0·001). The decline of sex hormones and IGF‐1 remained relatively unchanged after adjustment for BMI. Multiple regression analysis revealed an age‐and BMI– independent association between oestradiol and IGF‐1.

In contrast to the female situation sex hormones in healthy, nonobese men decline continuously with age. This process has already started in the third decade, and is paralleled by a decline of IGF‐1 serum levels leading to a substantial proportion of elderly men with markedly lowered serum levels of bioavailable sex hormones and IGF‐1 compared to the young adult male range. With the recent demonstration of beneficial effects of androgen replacement therapy in healthy males on general well being, muscle mass and bone mineral density the present data may underline the importance of more detailed studies on the biological significance of hormonal changes in men with age.
The testosterone:androstenedione ratio in male undermasculinization
Authors: Faisal Ahmed S. , Iqbal Asma , Hughes Ieuan A.
Published: March 2003

Recent reports suggest that low testosterone:androstenedione (T:A) ratio following hCG stimulation may be a useful method of diagnosing 17β‐hydroxysteroid dehydrogenase‐3 (17 βHSD3) deficiency. The aim of this study was to establish the range of T:A ratios in cases of undermasculinization with proven aetiologies other than 17 βHSD3.

Register‐based study of cases of male undermasculinization reported to a central database by clinicians.

Amongst the 421 cases of under‐masculinization, 114 cases had testosterone and androstenedione levels before and after hCG stimulation. Of the 114, there were 18 cases of abnormal testes, 17 cases of complete androgen insensitivity syndrome (CAIS), 68 cases of partial AIS (PAIS). Of the 17 cases of CAIS, 13 had evidence of androgen receptor (AR) dysfunction; in the PAIS cohort, 26 cases had evidence of AR dysfunction.

Analysis of T:A ratios in the above cohorts and comparison of these ratios to those in a group of previously described cases of 17 βHSD3 deficiency with a mean ratio of 0·4 (SD: 0·2)

The median age (range) for the CAIS, PAIS and abnormal testes cohort was 1·25 years (0·06–16·5), 0·7 years (0·02–40·3) and 0·5 years (0·04–6·5), respectively. In CAIS, the median T:A rose from 0·4 (0·1 to 8·0) to 4·5 (0·5–16·7); in PAIS, median T:A rose from 0·7 (0·1 to 15) to 3·9 (0·3–20·5); in cases with abnormal testes, median T:A rose from 0·4 (0·1 to 5·6) to 0·6 (0·1–3·6). The median post‐hCG T:A ratio was significantly lower in the abnormal testes cohort (P < 0·01). None of the cases of AIS with AR mutation had a low T:A ratio. Only four out of 84 cases diagnosed as AIS had a T:A ratio less than 0·8 (mean + 2SD in 17βHSD3 deficiency). In one of the four cases, the T:A ratio rose to 3·5 following a prolonged hCG stimulation test.

Deficiency of 17βHSD3 should be considered in 46XY undermasculinization if the post‐hCG stimulation T:A ratio is less than 0·8. However, low T:A ratios may be encountered in conditions such as abnormal testes. Before embarking on mutational analysis, we would also recommend careful evaluation for testicular dysgenesis including a prolonged hCG stimulation test in cases with a low T:A ratio.
Determinants of sex hormone‐binding globulin in normal postmenopausal women
Authors: Wu Fiona , Ames Ruth , Evans Margaret C. , France John T. , Reid Ian R.
Published: March 2003

OBJECTIVE To examine the factors influencing the levels of sex hormone‐binding globulin (SHBG) in normal postmenopausal women by assessing the relationship between SHBG and measured anthropometric, metabolic and hormonal variables.

DESIGN Cross‐sectional, observational study.

SUBJECTS and METHODS Seventy normal postmenopausal women aged 47–71 years (mean 58 years), participated in the study. Information was collected on medical, reproductive and smoking history, alcohol use, dietary intake and physical activity. Body composition measurements using dual‐energy absorptiometry, and analyses of biochemical and hormonal indices were performed.

RESULTS Bivariate correlation coefficients indicated that SHBG was inversely related to body weight (r = − 0·44), fat mass (r = − 0·35), and abdominal obesity (r = − 0·42). It was also inversely related to the glucose and insulin levels during an oral glucose tolerance test (− 0·24 < r < − 0·40), serum oestradiol (r = − 0·26), and physical activity (r = − 0·24). Multiple regression analysis indicated that significant independent correlates of SHBG concentration were fat mass, physical activity, alcohol intake, serum oestradiol, and insulin‐like growth factor‐1, all having a negative impact on SHBG.

CONCLUSIONS From these observed associations, it is concluded that maintenance of body weight, moderate alcohol consumption, and physical activity will tend to reduce SHBG concentrations in postmenopausal women, thereby increasing the levels of free oestradiol. This mechanism could mediate the beneficial effects of these factors in preventing the development of osteoporosis and cardiovascular disease.
Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures
Authors: Takahashi Masaaki , Naitou Kenichi , Ohishi Tsuyoshi , Kushida Kazuhiro , Miura Masakazu
Published: March 2003

OBJECTIVE

To examine serum undercarboxylated osteocalcin (OC) with application of an ELISA in normal women and in osteoporotic patients with vertebral fractures or hip fractures, and to investigate the effects of vitamin K and/or D treatment on undercarboxylated OC and intact OC in vertebral fractures.

PATIENTS

They were 43 premenopausal (PRE) and 48 postmenopausal healthy females (POST), 89 osteoporotic patients with vertebral fractures (VX) and, 24 patients with hip fracture (HX).

MEASUREMENTS

Intact OC was measured by an IRMA and undercarboxylated OC was measured by an ELISA.

RESULTS

Intact osteocalcin was significantly higher in POST and VX than in PRE, and was significantly lower in HX than in POST and VX. Undercarboxylated OC tended to be higher in POST, VX and HX than in PRE, but not significantly. The ratio of undercarboxylated OC to intact OC was significantly higher in HX than in POST and in VX. After 4 weeks treatment with K, D, and K + D to 56 VX, undercarboxylated OC decreased significantly in the groups with K and K + D. Intact OC tended to increase slightly in the groups given K, D, K + D, but not significantly so. Vitamin K and vitamin K + D markedly decreased the ratio of undercarboxylated/intact OC to approximately 80%. On the other hand, vitamin D did not decrease that ratio.

CONCLUSIONS

There was a disproportion of undercarboxylated osteocalcin to intact osteocalcin between postmenopausal women and osteoporotic patients with vertebral fractures or hip fractures. Vitamin K did decrease undercarboxylated osteocalcin, vitamin D did not change undercarboxylated osteocalcin, and vitamin D did not enhance the effect of vitamin K on undercarboxylated osteocalcin.
Growth hormone and the heart
Authors: Colao Annamaria , Marzullo Paolo , Di Somma Carolina , Lombardi Gaetano
Published: March 2003

Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in GH deficiency and excess. Experimental and clinical studies have supported the evidence that GH and IGF‐I are implicated in cardiac development. In most patients with acromegaly a specific cardiomyopathy, characterized by myocardial hypertrophy with interstitial fibrosis, lympho‐mononuclear infiltration and areas of monocyte necrosis, results in biventricular concentric hypertrophy. In contrast, patients with childhood or adulthood‐onset GH deficiency (GHD) may suffer both from structural cardiac abnormalities, such as narrowing of cardiac walls, and functional impairment, that combine to reduce diastolic filling and impair left ventricular response to peak exercise. In addition, GHD patients may have an increase in vascular intima‐media thickness and a higher occurrence of atheromatous plaques, that can further aggravate the haemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. However, several lines of evidence have suggested that the cardiovascular abnormalities can be partially reversed by suppressing GH and IGF‐I levels in acromegaly or after GH replacement therapy in GHD patients.

Recently, much attention has been focussed on the ability of GH to increase cardiac mass suggesting its possible use in the treatment of chronic nonendocrine heart failure. In fact, GH administration can induce an improvement in haemodynamic and clinical status in some patients. Although these data need to be confirmed in more extensive studies, such promising results seem to open new perspectives for GH treatment in humans.
An influence of variation in the aldosterone synthase gene (CYP11B2) on corticosteroid responses to ACTH in normal human subjects
Authors: Davies Eleanor , Holloway Christine D. , Ingram Mary C. , Friel Elaine C. , Inglis Gordon C. , Swan Lorna , Hillis W. Stewart , Fraser Robert , Connell John M. C.
Published: March 2003

OBJECTIVE Previous evidence suggests that the efficiency of 11β‐hydroxylase is at least partly heritable and also that it may be mildly impaired in essential hypertension. In both cases, assessment of activity was based on the response of 11‐deoxycorticosterone (DOC) and 11‐deoxycortisol to ACTH. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldosterone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of −344C to T in a putative steroidogenic factor‐1 (SF‐1) binding site and the other, the intron conversion, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11β‐hydroxylation were studied.

METHODS AND RESULTS Normal subjects (n = 135) were genotyped and those homozygous for either or both the polymorphisms were given ACTH (250 µg, i.v.). Plasma was sampled before and 30 minutes after administration. Basal concentrations of DOC, corticosterone, 11‐deoxycortisol and cortisol and responses of corticosterone and cortisol to ACTH were not affected by genotype. However, the responses of DOC (P = 0·002 and P = 0·001, respectively) and 11‐deoxycortisol (P = 0·025 and P = 0·002, respectively) were significantly greater in subjects homozygous for SF‐1 T and/or intron conversion than in those homozygous for SF‐1 C and/or normal intron.

CONCLUSIONS These results indicate different 11β‐hydroxylase efficiencies. Thus, variation in CYP11B2 appears to affect the product of CYP11B1. The mechanism is unclear. The close proximity of the two genes may lead to competition for transcription factors or specific differences in intron 2 may affect transcription. Alternatively, the polymorphisms may be acting as markers for adjacent functional genetic variations.
Genetic analysis of the cytochrome P‐450c17α (CYP17) and aldosterone synthase (CYP11B2) in Japanese patients with 17α‐hydroxylase deficiency
Authors: Takeda Yoshiyu , Yoneda Takashi , Demura Masashi , Furukawa Kenji , Koshida Hideo , Miyamori Isamu , Mabuchi Hiroshi
Published: March 2003

OBJECTIVE To determine the clinical and molecular genetic characterization of two Japanese patients with 17α‐hydroxylase deficiency, we analysed the 17α‐hydroxylase/17,20‐lyase gene (CYP17). Next, to clarify the mechanism of hypoaldosteronism in 17α‐hydroxylase deficiency, we analysed the expression of aldosterone synthase (CYP11B2) messenger RNA and sequenced CYP11B2 in these patients.

PATIENTS Patient 1 (46 XY), phenotypically female, sought medical attention for hypertension, amenorrhea and infantile genitalia. Patient 2 (46 XX), phenotypically female, presented for hypertension and amenorrhea. Hormonal data in both patients showed decreased levels of sex steroids, cortisol, aldosterone and plasma renin activity and extreme elevation of deoxycortisol.

DESIGN Direct sequencing of CYP17 and CYP11B2 was performed using genomic DNA from the patients. An expression studies of mutated forms of CYP17 was performed using COS‐1 cells. The expression of CYP11B2 messenger RNA in mononuclear leucocytes (MNLs) of these patients and normal subjects was measured using the competitive polymerase chain reaction method. The effect of renin secretion stimulation on the levels of CYP11B2 messenger RNA in MNLs of normal subjects was also studied.

RESULTS We detected two novel genetic defects in 17α‐hydroxylase. Sequence analysis revealed one base pair deletion (T) at codon 243 in exon 4 in patient 1. CYP17 in patient 2 contained a point mutation (C to T) at position 415 in exon 8. Transfected cells of mutant from patient 1 had no 17α‐hydroxylase or 17,20‐lyase activity. The R415C mutant protein showed very weak activity of 17α‐hydroxylase or 17,20‐lyase activity. In the renin secretion stimulating test, the increase in CYP11B2 messenger RNA levels in MNLs was parallel with that of plasma aldosterone concentration. The expression of CYP11B2 mRNA in NMLs of these patients was lower compared to controls. No mutations in CYP11B2, including the 5′ flanking region, were found.

CONCLUSIONS These results indicate that the novel mutations of the CYP17 gene found in these patients inactivate cytochrome P450c17 function, and that hypoaldosteronism in these patients may be partly explained by a decreased activity of aldosterone synthase, which is regulated at the transcriptional level.
The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection
Authors: Midorikawa Sanae , Sanada Hironobu , Hashimoto Shigeatsu , Suzuki Takayuki , Watanabe Tsuyoshi
Published: March 2003

OBJECTIVE Several recent studies have indicated that patients with adrenal incidentaloma often have disturbed glucose tolerance or/and hypertension. It is unclear whether these metabolic conditions could be caused by adrenal incidentaloma. We investigated the prevalence of disturbed glucose tolerance, hypertension and insulin resistance in the patients with non‐functioning adrenal incidentaloma and evaluated the changes of the parameters such as glucose tolerance, blood pressure and insulin sensitivity after adrenalectomy.

PATIENTS AND METHODS Among 15 patients with incidentally discovered adrenal tumours in our department from 1996 to 1999, 4 patients were diagnosed as having pre‐clinical Cushing's syndrome and the other 11 as having non‐functioning tumours based on detailed endocrinological examinations including dexamethasone suppression testing. Four tumours with pre‐clinical Cushing's syndrome and 8 tumours out of 11 patients with non‐functioning tumours were diagnosed histopathologically as adrenocortical adenomas and the other 3 as of non‐adrenal origin including a myelolipoma, an adrenal vascular cyst and an endothelioma. The prevalence of disturbed glucose tolerance was determined with an oral glucose tolerance test, and insulin sensitivity was evaluated by the method of steady state of plasma glucose (SSPG).

RESULTS All 12 patients with adrenocortical adenoma exhibited insulin resistance based on the SSPG (6·9–13·2 mmol/l). Before surgical removal of the tumours, the SSPG titre was relatively higher in the patients with pre‐clinical Cushing's syndrome than in those with non‐functioning with adrenocortical adenoma (mean value 11·65 vs. 8·99 mmol/l), whereas 2 of the 3 patients with non‐adrenocortical tumours did not have insulin resistance. Among the 12 patients with adrenocortical adenoma, 7 (58%) and 9 (75%) patients exhibited hypertension and disturbed glucose tolerance, respectively. After removal of the tumours, SSPG of the patients with adrenocortical adenoma, but not that of the other 3 patients with non‐cortical tumours, was significantly decreased compared to pre‐adrenalectomy values. There are no significant differences in the changes of SSPG titres between in pre‐clinical Cushing's syndrome and in non‐functioning adrenocortical adenoma. Systolic blood pressure, but not diastolic blood pressure, was also significantly decreased in the patients with adrenocortical adenoma.

CONCLUSION High prevalences of disturbed glucose tolerance, insulin resistance and hypertension were found among the patients with non‐functioning adrenocortical tumours. Adrenocortical adenoma may be one of the risk factors for insulin resistance that is believed to induce disturbed glucose tolerance and/or hypertension. Therefore, it is useful to evaluate insulin resistance for the patients with adrenal incidentalomas since results are likely to be helpful in deciding whether to remove the tumour by surgery.
Ras mutations are rare in solitary cold and toxic thyroid nodules
Authors: Krohn Knut , Reske Alexander , Ackermann Frank , Müller Anke , Paschke Ralf
Published: March 2003

OBJECTIVE Activation of ras proto‐oncogenes as a result of point mutations is detectable in a significant percentage of most types of tumour. Similar to neoplasms of other organs, mutations of all three ras genes can be found in thyroid tumours. H‐, K‐ and N‐ras mutations have been detected in up to 20% of follicular adenomas and adenomatous nodules which were not functionally characterized. This raises the question as to whether ras mutations are specific for hypofunctional nodules and TSH receptor mutations for hyperfunctioning nodules.

DESIGN To investigate ras and TSH receptor mutations with respect to functional differentiation we studied 41 scintigraphically cold nodules and 47 toxic thyroid nodules. To address the likelihood of a somatic mutation we also studied the clonal origin of these tumours.

MEASUREMENTS Genomic DNA was extracted from nodular and surrounding tissue. Mutational hot spots in exons 1 and 2 of the H‐ and K‐ras gene were PCR amplified and sequenced using big dye terminator chemistry. Denaturing gradient gel electrophoresis (DGGE) was used to verify sequencing results for the H‐ras gene and to analyse the N‐ras gene because its greater sensitivity in detecting somatic mutations. Clonality of nodular thyroid tissue was evaluated using X‐Chromosome inactivation based on PCR amplification of the human androgen receptor locus.

RESULTS Monoclonal origin was detectable in 14 of 23 informative samples from cold thyroid nodules. In toxic thyroid nodules the frequency of clonal tissue was 20 in 30 informative cases. Only one point mutation could be found in the N‐ras gene codon 61 (Gly to Arg) in a cold adenomatous nodule which was monoclonal. In toxic thyroid nodules no ras mutation was detectable.

CONCLUSION Our study suggests that ras mutations are rare in solitary cold and toxic thyroid nodules and that the frequent monoclonal origin of these tumours implies somatic mutations in genes other than H‐, K‐ and N‐ras.
Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas
Authors: Kim Kyongsong , Arai Keiko , Sanno Naoko , Osamura R. Yoshiyuki , Teramoto Akira , Shibasaki Tamotsu
Published: March 2003

OBJECTIVE The level of growth hormone (GH), growth hormone secretogogue (GHS) and GHS receptor (GHSR) messenger ribonucleic acid (mRNA) expression has been reported as being higher in GH‐producing pituitary adenomas than in other types of pituitary adenomas. Recently, ghrelin, an endogenous ligand specific for GHSR, was isolated. Therefore, we attempted to clarify whether ghrelin mRNA is expressed in various types of human pituitary adenoma by competitive reverse transcription‐polymerase chain reaction (RT‐PCR). We also examined the relationship between the levels of ghrelin or GHSR mRNA and hormonal and tumour characteristics in patients with pituitary adenomas.

PATIENTS Pituitary adenoma tissue was obtained at surgery from 13 patients with acromegaly, 4 with prolactinomas, 5 with gonadotrophin (Gn)‐producing adenomas, 4 with non‐functioning adenomas, 2 with ACTH‐producing adenomas and 2 with TSH‐producing adenomas.

METHODS The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT‐PCR method.

RESULTS Ghrelin mRNA was detected in all pituitary adenoma tissues examined, with the highest mean level detected in non‐functioning adenomas, a moderate level in GH‐producing adenomas and Gn‐producing adenomas, and the lowest level in prolactinomas. The level of ghrelin mRNA expression in GH‐producing adenomas correlated negatively with the size of the adenoma (n = 13) (r = − 0·756, P = 0·0028). Furthermore, the mean level of ghrelin mRNA expression in high‐grade (III and IV of Hardy classification) GH‐producing adenomas was significantly lower than that in low‐grade (I and II) GH‐producing adenomas (P = 0·0016). GHSR mRNA was also detected in all pituitary adenomas with the highest mean level in GH‐producing adenomas, a moderate level in nonfunctioning adenoma, and the lowest level in prolactinoma and Gn‐producing adenomas.

CONCLUSIONS Ghrelin mRNA, in addition to GHSR mRNA, is expressed in various types of pituitary adenoma with different levels of expression in each type. Our findings suggest that ghrelin produced in pituitary adenoma may play some role in the mechanism underlying the development of adenoma cells through autocrine and/or paracrine pathways.