The pedicled myocutaneous flap as a choice reconstructive technique for immediate adjuvant brachytherapy in sarcoma treatment.

Successful treatment of soft-tissue sarcomas is highly dependent on total tumour resection coupled with adjuvant radiation therapy to achieve local control and decrease recurrence. Reconstruction of soft-tissue defects after resection aims to cover vital structures, while providing enough stable tissue to withstand adjuvant brachytherapy treatment. In the present study, pedicled myocutaneous flaps were used as a vital adjunct in the treatment of soft-tissue sarcoma, and our experience with 2 such patients is described. The flaps served to reconstruct large three-dimensional defects while providing stable coverage over brachytherapy hardware to allow for delivery of radiation in the immediate postoperative period. Pedicled locoregional myocutaneous flaps provide a safe, easy, and reliable reconstructive technique in the treatment of soft-tissue sarcoma.

Tracking With a Hierarchical Partitioned Particle Filter and Movement Modelling.

We present an approach to track human subjects using an articulated human framework. First, we describe the articulated hierarchical human model. Second, we develop a stochastic hierarchical, partitioned, particle filter based on the natural structure and limb dependency of the human body. We apply this to track human subjects in video sequences using likelihoods adapted to the hierarchical process. Finally, we evaluate the effectiveness of the described approach using publicly available datasets.

Modification of the cranial closing wedge ostectomy technique for the treatment of canine cruciate disease. Description and comparison with standard technique.

OBJECTIVE: To describe a modification of the cranial closing wedge ostectomy (CCWO) technique and to compare its efficacy to the standard technique on cadaveric specimens. METHODS: The standard and modified CCWO technique were applied to eight pairs of cadaveric tibiae. The following parameters were compared following the ostectomy: degrees of plateau levelling achieved (degrees), tibial long axis shift (degrees), reduction in tibial length (mm), area of bone wedge removed (cm²), and the area of proximal fragment (cm²). RESULTS: The size of the removed wedge of bone and the reduction in tibial length were significantly less with the modified CCWO technique. CLINICAL SIGNIFICANCE: The modified CCWO has two main advantages. Firstly a smaller wedge is removed, allowing a greater preservation of bone stock in the proximal tibia, which is advantageous for implant placement. Secondly, the tibia is shortened to a lesser degree, which might reduce the risk of recurvatum, fibular fracture and patella desmitis. These factors are particularly propitious for the application of this technique to Terrier breeds with excessive tibial plateau angle, where large angular corrections are required. The modified CCWO is equally effective for plateau levelling and results in an equivalent tibial long-axis shift. A disadvantage with the modified technique is that not all of the cross sectional area of the distal fragment contributes to load sharing at the osteotomy.

The concordance between serum anti-Mullerian hormone and testosterone concentrations depends on duration of hCG stimulation in boys undergoing investigation of gonadal function.

BACKGROUND: In boys undergoing investigation of gonadal function, the relationship between a single measurement of serum anti-Mullerian hormone (AMH) and hCG stimulated serum testosterone is unclear. AIM: The aim of the study was to assess concordance between serum AMH and testosterone concentrations following hCG stimulation of two different durations. METHODS: Samples from 284 children (M : F, 154 : 130) with a median age of 8 years (10th, 90th centiles, 0.25, 14) were used to establish an AMH reference range. Clinical data were reviewed in boys undergoing investigation of gonadal function and who had an AMH measurement and a hCG stimulated (3-day or 3-week) (n = 26) testosterone. Of these 26 boys, 11 had combined genital anomalies, whereas the rest had conditions such as isolated hypospadias, undescended testes or microphallus. Normal testosterone response to hCG stimulation was defined as a level greater than 3.5 nmol at day 4 and 9.5 nmol/l at day 22. RESULTS: In the reference group, the 5th centile AMH for boys below 1 year was 215 pmol/l and between 1 and 8 years 180 pmol/l. The 95th centile for girls for these respective age groups was 30 pmol/l and 25 pmol/l. In those cases where serum testosterone concentrations were available at day 1, day 4 and day 22 of the 3 week-hCG test, five cases had a normal serum testosterone at day 4 and three cases only showed such a response by day 22. In those where serum AMH was less than 180 pmol/l, a poor testosterone response of less than 3.5 nmol was observed in approximately seven of eight (88%) cases with a 3-day hCG stimulation test or the 3-week test. An AMH of greater than 180 pmol/l was associated with a normal testosterone response at day 4 in 10 out of 15 (67%) cases and at day 22 in eight of 11 (73%) cases. However, a low serum testosterone concentration of less than 3.5 nmol after the 3-day hCG test was only associated with a likelihood of a low AMH in three of eight (37%) cases. With the 3-week hCG test, a low day 22 testosterone of 9.5 mmol/l or less was associated with a low AMH of 180 pmol/l or less in four of seven (57%) cases. CONCLUSION: In boys undergoing investigation of gonadal function, the concordance between AMH and testosterone is better at day 22 than day 4. A normal AMH may provide useful information on overall testicular function but does not exclude the need for an hCG stimulation test.

Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry.

OBJECTIVE: To investigate the reported association between exaggerated adrenarche (EA) and reduced foetal growth and to identify possible risk factors for future morbidity in Scottish children with clinical features of EA. DESIGN: Three-year prospective study. MEASUREMENTS: Auxology, blood pressure (BP), biochemical analysis of blood and urine, pelvic ultrasound in girls. RESULTS: Fifty-two patients were recruited of whom one girl had nonclassical congenital adrenal hyperplasia (17-OHP 17 nmol/l) and one had insufficient blood for analysis. The final cohort comprised 42 girls of mean (SD) age 7.7 (0.99) and eight boys of 8.8 (0.67) years. Mean (SD) birth weight was 3.27 (0.49) and 3.10 (0.76) kg in girls and boys respectively. Height/weight SDS were 1.13/1.69 in girls and 1.69/1.88 in boys. Mean systolic/diastolic BP was 107.8/60.4 (50th-75th centile) in girls and 115.5/63.9 (75th-91st centile) in boys. Uterine and ovarian development was prepubertal. Median serum dehydroepiandrosterone sulphate (DHEAS) was 2.1 and 4.1 mumol/l, androstenedione 3.1 and 3.8 nmol/l in girls and boys respectively, with DHEAS within the reference range/undetectable in 18/2 and androstenedione in 12/6 patients. Fasting insulin was 9.0 and 15.0 mU/l in girls and boys respectively, with concomitant low normal SHBG. Anti-Mullerian hormone (AMH) was 15.7 pmol/l in 27 girls, compared with 5.0 pmol/l in normal girls aged 5-8 years. CONCLUSIONS: Our Scottish EA cohort showed female predominance, no evidence of reduced foetal growth, a tendency to overweight with commensurate mild hyperinsulinaemia and modest elevation of serum androgens in some patients. We have found raised AMH levels in the girls, indicating advanced ovarian follicular development.

Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative surgery for colon cancer.

AIM: To comprehensively compare the prognostic value of tumour- and patient-related factors in patients undergoing curative surgery for colon cancer. METHOD: From a database of 287 patients who underwent elective resection between 1997 and 2005, tumour factors including stage and host factors including systemic inflammatory response [modified Glasgow Prognostic Score (mGPS)] were identified. RESULTS: Median follow-up was 65 months. Over this period, 125 patients died, 80 from cancer. On multivariate analysis of all significant patient and tumour related factors, Dukes stage (P < 0.01), vascular invasion (P < 0.01) and the mGPS (P < 0.01) were independently associated with cancer-survival. Of the patient-related factors, age (P < 0.01), haemoglobin (P < 0.01), white-cell (P < 0.01), neutrophil (P < 0.01) and platelet (P < 0.01) counts, and alkaline phosphatase (P < 0.01) were most significantly associated with the mGPS. CONCLUSION: In addition to tumour-related factors such as Dukes stage and vascular invasion, the preoperative mGPS should be included to guide prognosis in patients undergoing curative resection for colon cancer.

A 5-year-old boy with cryptorchidism and pubic hair: investigation and management of apparent male disorders of sex development in mid-childhood.

BACKGROUND: Late presentation of congenital adrenal hyperplasia as a 46,XX disorder of sex development due to 11-beta hydroxylase deficiency is uncommon. Such a case raises issues regarding appropriate investigation and management. CASE HISTORY: A 5-year-old boy who had recently moved to the United Kingdom presented at the endocrinology clinic with recurrent abdominal pain. He was normotensive and had a history of ambiguous genitalia since birth, a relatively small penis, bilateral cryptorchidism and pubic hair. A systematic workup revealed low anti-Mullerian hormone levels for age and sex and elevated serum testosterone, androstenedione and deoxycortisol levels. A urinary steroid profile confirmed a diagnosis of 11-beta hydroxylase deficiency. The child's karyotype was 46,XX. Further genetic analysis revealed a compound heterozygote mutation in the CYP11B1 gene. Ultrasound scan showed evidence of Mullerian structures and accumulation of menstrual blood in the vagina (haematocolpos). Following discussion at a multidisciplinary clinic, the patient did not undergo sex reassignment and subsequently proceeded to surgery for removal of the Mullerian structures. CONCLUSIONS: This case emphasizes the importance of a systematic approach to investigation of older children presenting with apparent male undermasculinisation. It also raises important issues about gender reassignment in mid-childhood and the indications for removal of Mullerian organs in a 46,XX boy.

Feline combined diaphyseal radial and ulnar fractures. A retrospective study of 28 cases.

Feline combined diaphyseal radial and ulnar fractures were reviewed in a retrospective study of cases that were admitted to two university teaching hospitals. A high incidence of complications was noted, with 6/26 (23.1%) of cases requiring revision surgery. Open fractures were significantly more likely to require revision surgery. The two main repair methods were external skeletal fixation (ESF) or radial plating. The success rate was greater for radial plating, with only 1/10 (10%) cases requiring revision versus 4/14 (28.6%) for ESF. However, ESF tended to be applied to the more complicated fractures. Stabilisation of both bones proved to be an effective repair strategy with only 1/8 cases (12.5%) requiring revision versus 5/18 cases (27.8%) where only one bone was stabilised. Synostoses and radiohumeral luxation were noted as complications associated with the fractures stabilised by ESF. Final limb function following recovery was assessed as 'good' or 'excellent' in 93.3% of cases.

Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects.

BACKGROUND: Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (-344T) in the 5' regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11beta-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5' UTR of CYP11B1 (-1859 G/T, -1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary-adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess. METHODS: To test this, we examined hypothalamic-pituitary-adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (-344T/C) and CYP11B1 (-1859 G/T, -1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied. RESULTS: Subjects with SNPs associated with reduced 11-hydroxylation efficiency (-344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0.05) and an altered cortisol-ACTH relationship (decreased cortisol-ACTH ratio, P < 0.02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (-344T CYP11B2 r = 0.508, P < 0.004; TTGG CYP11B1 r = 0.563, P < 0.003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects. CONCLUSIONS: Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.

A biomechanical comparison of six different double loop configurations for use in the lateral fabella suture technique.

Six different double loop configurations which could be applied to the lateral fabella suture (LFS) technique were subjected to in vitro mechanical testing. Three double loop, single strand and three double loop, double strand configurations were tested. The strongest configuration, with a significantly higher mean ultimate load and load at yield, was the interlocking loop configuration. This is a novel configuration which has not previously been reported. The three double loop, single strand configurations all had higher mean ultimate loads than the double loop, double strand configurations. The double strand group with uneven loop length performed very poorly, with significantly lower mean stiffness and ultimate load than all of the single strand groups. This group also developed unacceptably high levels of elongation during high level cyclic loading.

Prolonged human chorionic gonadotrophin stimulation as a tool for investigating and managing undescended testes.

OBJECTIVE: To observe the outcome in a group of children with undescended testes (UDT) given prolonged human chorionic gonadotrophin (hCG) stimulation as part of their management. STUDY DESIGN: Retrospective review of 16 prepubertal boys given intramuscular hCG, 1500 U, on Days 1, 2 and 3 and then twice a week for 2 weeks with assessment of serum testosterone (T), SHBG, dihydrotestosterone (DHT) and androstenedione (A) on Days 1, 4 and 22. RESULTS: In seven boys (44%), peak rise in T was by Day 4; in 5 boys (31%), the rise was by Day 22 and in the remainder, serum T stayed low. The median Day1 testosterone : androstenedione (T : A) ratio rose from 0.4 (range 0.2-1.5) to 1.7 (range 0.2-5.3) at Day 4 (P < 0.05) with no further rise by Day 22. The median dihydrotestosterone : testosterone ratio (DHT : T) at Day 1 and Day 4 remained unchanged. SHBG levels were more likely to be lower at Day 22 than at Day 4. The mean testosterone : SHBG (T : SHBG) ratio as a marker of androgen sensitivity was 0.2 (1SD 0.1). Bilateral testicular descent deemed immediate surgery unnecessary in 3 out of 15 (20%) boys where outcome data were available. CONCLUSION: Whilst a 3-day hCG stimulation regimen may exclude 17beta-hydroxysteroid dehydrogenase-3 and 5alpha-reductase deficiencies, some boys with cryptorchidism may require more prolonged stimulation to assess androgen production and sensitivity. The possibility that this regimen leads to a reduced need for orchidopexy requires further exploration.

Salivary Testosterone Levels and Health Status in Men and Women in the British General Population: Findings from the Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

CONTEXT: Salivary T (Sal-T) measurement by liquid chromatography-tandem mass spectroscopy resents the opportunity to examine health correlates of Sal-T in a large-scale population survey. OBJECTIVE: This study sought to examine associations between Sal-T and health-related factors in men and women age 18-74 years. DESIGN AND SETTING: Morning saliva samples were obtained from participants in a cross-sectional probability-sample survey of the general British population (Natsal-3). Self-reported health and lifestyle questions were administered as part of a wider sexual health interview. PARTICIPANTS: Study participants included 1599 men and 2123 women. METHODS: Sal-T was measured using liquid chromatography-tandem mass spectroscopy. Linear regression was used to examine associations between health factors and mean Sal-T. RESULTS: In men, mean Sal-T was associated with a range of health factors after age adjustment, and showed a strong independent negative association with body mass index (BMI) in multivariable analysis. Men reporting cardiovascular disease or currently taking medication for depression had lower age-adjusted Sal-T, although there was no association with cardiovascular disease after adjustment for BMI. The decline in Sal-T with increasing age remained after adjustment for health-related factors. In women, Sal-T declined with increasing age; however, there were no age-independent associations with health-related factors or specific heath conditions with the exception of higher Sal-T in smokers. CONCLUSIONS: Sal-T levels were associated, independently of age, with a range of self-reported health markers, particularly BMI, in men but not women. The findings support the view that there is an age-related decline in Sal-T in men and women, which cannot be explained by an increase in ill health. Our results demonstrate the potential of Sal-T as a convenient measure of tissue androgen exposure for population research.

Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).

BACKGROUND: Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/mL versus 5.04+/-2.09 ng/mL, P<0.001). In univariate analysis, for each 1 SD increase in leptin, the relative risk (RR) of an event increased by 1.25 (95% confidence interval [CI], 1.10 to 1.43; P<0.001). There was minimal change in this RR with correction for body mass index (RR, 1.24; 95% CI, 1.06 to 1.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, 1.20; 95% CI, 1.02 to 1.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.001) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, 1.18; 95% CI, 1.00 to 1.39; P=0.05) at the expense of C-reactive protein. CONCLUSIONS: We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.

The utility of three different methods for measuring urinary 18-hydroxycortisol in the differential diagnosis of suspected primary hyperaldosteronism.

OBJECTIVE: Urine 18-hydroxycortisol (18-OHF) measurements are claimed to discriminate between primary hyperaldosteronism due to Conn's syndrome/adrenal adenoma or idiopathic bilateral adrenal hyperplasia (BAH), and also to identify cases of glucocorticoid-suppressible hyperaldosteronism (GSH). We have evaluated three urine 18-OHF methods using a panel of urine samples from patients with hypertension. DESIGN: Clinical methods comparative study. METHODS: Urine samples from patients with primary hyperaldosteronism due to either adenoma (n = 6), BAH (n = 6), GSH (n = 9), or essential hypertension (n = 38) were analysed without knowledge of the diagnosis using three different methods in different laboratories. These included 'in-house' radioimmunoassay (RIA), 'in-house' time-resolved fluorometric assay (DELFIA), and gas chromatography mass spectrometry (GC-MS). RESULTS: The three assays showed good correlation, but there were large bias differences: RIA bias was greater than DELFIA which was greater than GC-MS. Discrimination between adenoma and BAH patients was best for the DELFIA method, with no overlap between results for these two groups. All three methods gave significantly elevated results for the GSH group compared with the BAH and essential hypertension groups. No assay distinguished BAH from essential hypertension. CONCLUSION: Measurement of urine 18-OHF may be a useful additional test in the differential diagnosis of primary hyperaldosteronism. The clinical diagnostic value of urinary 18-OHF measurements is method-dependent with the DELFIA assay having the best discriminatory value.

Effect of weight loss and the inflammatory response on leptin concentrations in gastrointestinal cancer patients.

Animal research suggests that leptin may have an important role in the regulation of energy balance. The role of leptin in the progressive involuntary weight loss associated with cancer in humans is of considerable interest. However, such studies are limited. In this study, we compared circulating leptin concentrations in gastrointestinal cancer patients and weight loss (n = 27) with those of healthy subjects (n = 27). The effect of the presence of an inflammatory response on leptin concentrations was also examined. There were significantly lower leptin concentrations in male (median, 2.4 microg/liter; range, <0.5-6.0 microg/liter) and female (median, 3.4 microg/liter; range, <0.5-9.8 microg/liter) cancer patients than there were in male (median, 6.5 microg/liter; range, 3.1-10.9 microg/liter) and female (median, 18.7 microg/liter; range, 8.0-31.5 mcirog/liter) healthy subjects (P < 0.001). However, the leptin concentrations in both patients and normal subjects were related to the predicted percentage of body fat (r = 0.731; P < 0.001). Circulating leptin concentrations in the cancer patients were not altered by the presence of an inflammatory response. These results suggest that cancer anorexia/cachexia is not due to a simple dysregulation of leptin production.

Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone.

The administration of exogenous testosterone (T) to eugonadal men causes suppression of gonadotropin secretion and thus of spermatogenesis. This is currently being investigated as a possible method of hormonal male contraceptive, but complete suppression of spermatogenesis to azoospermia is induced in only 50-70% of Caucasian men; the remainder maintain a low rate of spermatogenesis. The basis for this polymorphism in response is unclear. The enzyme 5 alpha-reductase (5 alpha R) converts T to dihydrotestosterone (DHT) and is important in determining the magnitude of the androgen stimulus in some tissues. We investigated whether the maintenance of spermatogenesis in men remaining oligozoospermic while receiving suppressive doses of T is associated with evidence of increased 5 alpha R activity. Thirty-three normal men were given 200 mg T enanthate (TE), im, weekly in a clinical trial of hormonal male contraception. The MCR of T (MCRT) and the conversion ratio of T to DHT (CRT-DHT) were measured by infusion of [3H]T, plasma levels of DHT and androstanediol glucuronide (AdiolG) were measured by RIA, and 24-h urinary steroid metabolites were measured by capillary column gas chromatography. Sperm density decreased in all men; 18 achieved azoospermia by 20 weeks of treatment, and the remainder had a mean sperm density of 2.0 +/- 0.8 x 10(5)/mL at that time. This treatment caused increases in plasma T levels and MCRT, but with no differences between azoospermic and oligozoospermic responders. There were no differences in CRT-DHT plasma DHT, or AdiolG before treatment, but after 16 weeks, CRT-DHT had increased in the oligozoospermic responders, but not in the azoospermic responders. TE treatment increased plasma DHT and AdiolG levels in both groups, but the increases in both 5 alpha R metabolites were significantly greater in the oligozoospermic responders. Urinary excretion of etiocholanolone and androsterone was increased after 16 weeks of TE treatment, but did not differ between the two groups, andetiocholanolone/androsterone ratios did not differ greatly from unity. There was no change in urinary excretion of tetrahydrocortisol, allo-tetrahydrocortisol, or cortisone after 16 weeks of TE treatment in either group. These results suggest that after TE administration there is a selective increase in 5 alpha R activity in those men who remain oligozoospermic, but not in those becoming azoospermic. This difference in the androgenic milieu may underlie the incomplete suppression in the oligozoospermic responders, in whom a low rate of spermatogenesis is maintained despite the apparent absence of gonadotropins.

PIP: The administration of exogenous testosterone (T) to eugonadal men causes suppression of gonadotropin secretion and thus of spermatogenesis. This is currently being investigated as a possible method of hormonal male contraceptive, but complete suppression of spermatogenesis to azoospermia is induced in only 50-70% of Caucasian men; the remainder maintain a low rate of spermatogenesis. The basis for this polymorphism in response is unclear. The enzyme 5 alpha-reductase (5 alpha R) converts T to dibydrotestosterone (DHT) and is important in determining the magnitude of the androgen stimulus in some tissues. We investigated whether the maintenance of spermatogenesis in men remaining oligozoospermic while receiving suppressive doses of T is associated with evidence of increased (TE), im, weekly in a clinical trial of hormonal male contraception. The MCR of T (MCRT) and the conversion ratio of T to DHT (CRT-DHT) were measured by infusion of [3H]T, plasma levels of DHT and androstanediol glucuronide (AdiolG) were measured by RIA, and 24-h urinary steroid metabolites were measured by capillary column gas chromatography. Sperm density decreased in all men; 18 achieved azoospermia by 20 weeks of treatment, and the remainder had a mean sperm density of 2.0 +/- 0.8 x and MCRT, but with no differences between azoospermic and oligozoospermic responders. There were no differences in CRT-DHT plasma DHT, or AdiolG before treatment, but after 16 weeks, CRT-DHT had increased in the oligozoospermic responders, but not in the azoospermic responders. TE treatment increased plasma DHT and AdiolG levels in both groups, but the increases in both 5 alpha R metabolites were significantly greater in the oligozoospermic responders. Urinary excretion of etiocholanolone and androsterone was increased after 16 weeks of TE treatment, but did not differ between the two groups, andetiocholanolone/androsterone ratios did not differ greatly from unity. There was no change in urinary excretion of tetrahydrocortisol, allo-tetrahydrocortisol, or cortisone after 16 weeks of TE treatment in either group. These results suggest that after TE administration there is a selective increase in 5 alpha R activity in those men who remain oligozoospermic, but not in those becoming azoospermic. This difference in the androgenic milieu may underlie the incomplete suppression in the oligozoospermic responders, in whom a low rate of spermatogenesis is maintained despite the apparent absence of gonadotropins. In the UK, physicians recruited 33 healthy men aged 21-41 to a clinical trial of weekly intramuscular injections of 200 mg testosterone enanthate (TE) (Testoviron) for up to 18 months. 18 (55%) of the men achieved azoospermia after 20 weeks of treatment. The sperm density in the remaining 15 men (45%) stabilized at a mean density of 2(+or- 0.8) million/ml and stayed oligozoospermic for the remainder of the clinical trial. Plasma samples taken immediately before and 1, 2, 4, and 7 days after the 1st and 16th TE injections and after 2, 4, 8, and 12 weeks of treatment allowed the researchers to compare the activity of 5alpha-reductase (5alphaR). 5alphaR converts T to the more potent androgen dihydrotestosterone (DHT) and plays a key role in determining the magnitude of the androgen stimulus in some tissues. Exogenous testosterone (T) increased plasma T levels and the mean conversion rate of T (MCRT), but there were no differences between azoospermic and oligozoospermic men. Before treatment there were no differences in plasma DHT and androstanediol glucuronide (AdiolG) levels between the two groups. After 16 weeks, the conversion ratio of T to DHT (CRT-DHT) increased in oligozoospermic men (3.1% vs. 4%; p 0.05) but not in azoospermic men, whereas before treatment it was essentially the same in both groups. Exogenous T significantly increased both plasma DHT and AdiolG levels in both groups, but the increases in both these 5alphaR metabolites were significantly higher in oligozoospermic men than azoospermic men (p 0.02 and 0.01, respectively). (Abstract Truncated)

Transdermal testosterone application: pharmacokinetics and effects on pubertal status, short-term growth, and bone turnover.

The aim of the study was to assess the effect of transdermal testosterone on free testosterone concentrations in saliva and on short-term growth and bone turnover in boys with growth or pubertal delay. A prospective, randomized, crossover study was conducted over 26 wk with 4 wk of run-in, 8 wk of treatment I (8 or 12 h), 4 wk of washout, 8 wk of treatment II (8 or 12 h), and 4 wk of final washout. The main outcome measures were salivary testosterone profiles during the different study periods; weekly change in lower leg length (LLL) as measured by knemometry, i.e. LLL velocity; absolute and percentage change in bone alkaline phosphatase (bALP) levels; and deoxypyridinoline cross-links measured in urine. Eight boys who took part in the study had a median age of 13.5 yr (range, 12.4-14.9 yr), testicular volume of 3 ml (range, 2-6 ml), height SD score of -2.4 (range, -1.44 to -3.35), and bone age delay of 2 yr (range, 1-3.2 yr). Median salivary testosterone during 8- and 12-h treatments [179 pg/ml (range, 7-3579 pg/ml) and 150 pg/ml (range, 12-3472 pg/ml) (not significant)] was significantly higher than during the run-in and washout blocks (P < 0.0001) [9 pg/ml (range, <7 to 122 pg/ml) and 13 pg/ml (range, <7 to 285 pg/ml) (not significant)]. LLL velocity in the treatment blocks (median, 0.64 mm/wk; range, 0.1-1.08 mm/wk) was significantly higher than during the run-in and washout periods (median, 0.48 mm/wk; range, -0.06 to 0.92 mm/wk) (P < 0.001). The main rise in bALP occurred during the first treatment block with a median percentage change in bALP of 44.2% (range, -4 to 87%) and a smaller percentage change in bALP at the end of the second treatment block of 9.8% (range, -4 to 55%). The increases in bALP were not significantly different between the 8- and 12-h treatment periods, and there was no significant decline during the washout periods. Overnight transdermal testosterone application, as Virormone (5 mg), may be a potentially acceptable method of induction of puberty and stimulates short-term growth and bone turnover.

Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement.

Leptin contributes to the regulation of body weight in healthy individuals and is secreted by adipocytes in a diurnal pattern, with superimposed pulsatility. The circulating leptin concentration is increased in both normally obese and untreated adult GH deficiency, a syndrome characterized by increased adiposity. Leptin circadian rhythm is preserved in adult GH deficiency patients; however, an ultradian rhythm and pulsatility has previously not been reported. Alterations in plasma leptin concentration in obese individuals and adult GH deficiency patients after GH replacement have been attributed to changes in body fat mass. In our present study leptin circadian and ultradian rhythm, leptin pulsatility and its relationship with body fat mass were examined in 12 adult GH deficiency patients (6 men) before and 1 month after GH replacement. All subjects with adult GH deficiency had hypopituitarism subsequent to pituitary surgery and were stabilized on conventional pituitary hormone replacement. Plasma leptin was measured over 24 h at 30-min intervals, and changes in body composition were recorded using bioelectrical impedance. The 24-h mean leptin concentration decreased from 2.04 +/- 0.04 nmol/liter in untreated adult GH deficiency patients to 1.64 +/- 0.03 nmol/liter after 1 month of GH replacement (P < 0.0001). Before GH replacement, patients demonstrated a significant mean leptin circadian rhythm (P < 0.001), with a mesor of 2.05 +/- 0.03 nmol/liter and a superimposed ultradian frequency of 2.0 +/- 0.1 cycles/d. After GH replacement, the circadian rhythm was preserved (P < 0.001), but mesor decreased to 1.65 +/- 0.01 nmol/liter (P < 0.0001), and leptin ultradian frequency increased to 16.0 +/-0.2 cycles/d (P < 0.0001). Pulse analysis (ULTRA) revealed 3.1 +/- 0.9 pulses/24 h in untreated adult GH deficiency patients, which significantly increased to 9.9 +/- 2.2 pulses/24 h after 1 month of GH replacement (P < 0.001). There was no significant change in body mass index or body fat mass after 1 month of GH replacement. The body fat percentage significantly reduced from 36.5 +/- 2.8% to 35.5 +/- 2.7% after 1 month of GH replacement (P < 0.05). This change in body fat percentage was explained by a significant increase in lean body mass, from 56.2 +/- 2.8 kg at baseline to 57.4 +/- 2.7 kg after 1 month (P < 0.05). A significant correlation was observed between plasma leptin and body fat percentage at baseline and 1 month after GH replacement (both, r = 0.7; P < 0.01) in the absence of a significant correlation between leptin and body fat mass before and after GH replacement (P = 0.13 and P = 0.11, respectively). Thus, untreated adult GH deficiency is associated with elevated 24-h leptin concentration, preserved circadian rhythm, and decreased pulsatility. The secretory pattern is restored after GH replacement, with a significant reduction in the 24-h mean leptin concentration, maintenance of circadian rhythm, and increased pulsatility. This GH-induced change in the leptin secretory pattern precedes significant changes in body fat mass and may therefore be independent of changes in adipose tissue. Restoration of leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future.

Women with steroid 5 alpha-reductase 2 deficiency have normal concentrations of plasma 5 alpha-dihydroprogesterone during the luteal phase.

Steroid 5 alpha-reductase 2 deficiency has been identified in two adult women from unrelated families, one a homozygote and the other a compound heterozygote. The homozygote carries the G183S mutation and is the sister of an affected male; the compound heterozygote (R246W/splice junction abnormality) is married to a heterozygote (splice junction abnormality) and is the mother of two compound heterozygotes and two homozygotes. The fact that these two women are the mothers of seven children and appear to be endocrinologically normal confirms the previous deduction that this disorder is not manifest in women. Concentrations of plasma 5 alpha-dihydroprogesterone were normal in these two women during the luteal phase; this finding implies that circulating 5 alpha-dihydroprogesterone in women is derived principally from the steroid 5 alpha-reductase 1 isoenzyme and leaves unresolved the question of whether 5 alpha-dihydroprogesterone plays a physiological role in women.

Nocturnal secretory dynamics of inhibin B and testosterone in pre- and peripubertal boys.

To investigate the secretory dynamics of testosterone and inhibin B, we collected samples every 20 min from 2000 h to 0800 h in 20 boys. Boys in group 1 (n = 5) were aged less than 8 yr, group 2 (n = 5) were aged more than 8 yr but 1.5 yr or more before pubertal onset, group 3 (n = 5) were studied 1.0 yr or less before pubertal onset, and group 4 (n = 5) were in early puberty. Testosterone increased after midnight in peripubertal boys, coinciding with the onset of LH pulsatility, and showed a pulsatile pattern in 6 of 10 of these boys. Cross-correlation analysis indicated significant temporal coupling between LH and testosterone. Inhibin B was higher in groups 3 and 4, compared with groups 1 and 2 (P < 0.01) and showed a downward trend overnight with no evidence of pulsatility and no evidence of short-term interactions with LH, FSH, or testosterone. Inhibin B and LH nocturnal means were both inversely correlated with time before pubertal onset (r(s) > or = -0.85, P < 0.01). Only LH nocturnal mean and amplitude, respectively, contributed independently to prediction of testosterone and inhibin B nocturnal means, explaining 71 and 65% of their variability. We conclude that both testosterone and inhibin B are related to nocturnal LH release in peripubertal boys but over different time scales.