bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term efficacy and safety of a permeation‐enhanced testosterone transdermal system in hypogonadal men
Authors: Arver Stefan , Dobs Adrian S. , Meikle A. Wayne , Caramelli Kim E. , Rajaram Lakshminaryan , Sanders Steven W. , Mazer Norman A. 
Published: November 2003

OBJECTIVEAn important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation‐enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12‐month period.DESIGNOpen‐label, multicentre study with four consecutive periods: Period I (3 weeks)—evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)—androgen washout; Period III (3–4 weeks)—single‐dose pharmacokinetic studies of TTD systems; Period IV (12 months)—efficacy, safety, and steady‐state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared.PATIENTSThirty‐seven hypogonadal men 21–65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three).MEASUREMENTSMorning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24‐hour time‐average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters.RESULTSTwelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24‐hour time‐average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2–4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate‐specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 μg/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens.CONCLUSIONSThe permeation‐enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.
Prepubertal and pubertal growth, timing and duration of puberty and attained adult height in patients with congenital hypothyroidism (CH) detected by the neonatal screening programme for CH — a longitudinal study
Authors: Dickerman Zvi , De Vries Liat 
Published: November 2003

OBJECTIVEWe have evaluated parameters of growth, the pubertal process and attained adult height in patients with congenital hypothyroidism (CH) of various aetiologies, diagnosed by the neonatal screening programme, and followed up longitudinally. To the best of our knowledge, no such data are available in the published literature. Our aim was to define the most important factors affecting these parameters.PATIENTS AND MEASUREMENTSThirty patients with CH (20 females and 10 males) diagnosed by neonatal screening (dysgenetic (n = 15), ectopic thyroid (n = 11), and enzymatic defect (n = 4)), treated with levo‐thyroxine (L − T4) since the age of ≤ 4 months, and followed up at intervals of 1–6 months for a mean period of 11.4 (range 5–19.6) years were evaluated.Detailed anthropometric measurements were performed by the same trained nurse, and pubertal stages were evaluated according to Tanner's criteria for breast or genitalia and pubic hair. Serum T4 and TSH levels were measured at each clinic visit using commercial kits. Bone age (BA) was determined at 6–12 month intervals using the Greulich & Pyle method. Seventeen patients attained adult height at the time of the report.RESULTSMean L − T4 dose of 7.9 (range 5.2–14.0) to 2.4 (range 1.3–3.4) μg/kg/day at various ages corrected the serum free T4 (f‐T4) levels to normal (> 10 pmol/l) in 95% of determinations, and the TSH level was reduced to < 10 mIU/l in 54% of the determinations during the follow‐up period. Length at initiation of therapy (mean −0.15, (range −2.5–2.1) SDS), height at onset of puberty (mean −0.4, (range −1.8–1.8) SDS) and adult height (mean 0.2 (range −1.4–2.0) SDS, n = 17) were within the normal range (0.00 ± 2 SDS). Onset and duration of puberty were normal in both sexes, and total pubertal growth contributed 19.1% (M) and 16.4% (F) to adult height. Peak height velocity (mean 10.6 (range 7.3–15.1) (M) and mean 8.0 (range 6.2–15.5) (F) cm/year) was within the normal range and occurred at the expected BA (14y;M and 12y; F). The attained average adult height was in close proximity to the average target height in both males and females. A significant positive correlation was found between the average L − T4 daily dose administered during the first 6 months of treatment and the attained adult height.CONCLUSIONSEarly detection by neonatal screening and treatment of congenital hypothyroidism enables normal prepubertal and pubertal growth and achievement of normal adult height, following normal puberty. Adult height in congenital hypothyroidism is significantly correlated with parental height and the mean L − T4 daily dose administered over the first 6 months of treatment. A dose of at least 8.5μg/kg/day is recommended during this period. Periodical adjustments of L − T4 daily dose should be guided by clinical observation and serum free T4 levels.
Demonstration of fragments with thyroid stimulating activity from Thyroid stimulation blocking antibodies‐IgG molecules by papain digestion
Authors: Kouki Tsuyoshi , Inui Takehiro , Yamashiro Kei , Hachiya Takashi , Ochi Yukio , Kajita Yoshihiro , Takasu Nobuyuki , Sato Yasushi , Nagata Atsuo 
Published: November 2003

OBJECTIVESThyroid stimulation blocking antibodies (TSBAb) inhibit TSH action and may have a role in the pathogenesis of hypothyroidism. In order to study the relationship between blocking and stimulating activities we have examined the biologically active fragments in TSBAb‐IgG molecules after papain digestion.DESIGNBoth thyroid stimulating (TS) activity (cAMP production in thyroid cells) and TSH binding inhibitory (TBI) activity (determined by TSH receptor assay) in sera from patients with primary hypothyroidism were examined after digestion with papain‐Sepharose in the presence of cysteine. The digested IgG was separated into unbound (UF) and bound (BF) fractions on a Protein A‐Sepharose column. Each fraction was then gel‐filtrated on a Sephadex G‐100 column.RESULTSTS activity was found within one hour after hydrolysis in 5 out of 7 antibodies, then gradually decreased after more prolonged incubation. Both TS and TBI activities in the UF and the BF from Protein A were found in Fab (Mr 50 kD) and the second protein peak (Fc with trace amounts of Fab), respectively. The biological activity in the second protein peak was suggested as being derived from Fab fraction, because the activity bound to the anti‐F(ab′)2 column. However, the first peak (undigested IgG) in the BF had neither TS nor TSB activity. The TS activity in the retarded fraction (less than Mr 20 kD) in the UF gradually increased with prolonged digestion.CONCLUSIONSThe conversion of Thyroid stimulation blocking antibodies activity to thyroid stimulating activity by papain digestion suggests that the inherent thyroid stimulating activity located in the Fab portion of the IgG molecule is unmasked by papain cleavage. We also suggest that the thyroid stimulating activity in the retarded fraction in the unbound fraction may be released from hydrolysis of the Fab portion of the IgG molecule.
Somatostatin receptor imaging in somatotroph and non‐functioning pituitary adenomas: correlation with hormonal and visual responses to octreotide
Authors: Borson‐Chazot Françoise , Houzard Claire , Ajzenberg Christiane , Nocaudie Marie , Duet Michèle , Mundler Olivier , Marchandise Xavier , Epelbaum Jacques , Gomez De Alzaga Maria , Schäfer Judith , Meyerhof Wolfgang , Sassolas Geneviève , Warnet André 
Published: November 2003

OBJECTIVEA multicentre study was undertaken to determine the value of somatostatin receptor (sst) scintigraphy in predicting hormonal and visual responses to octreotide treatment in GH‐secreting and non‐functioning pituitary adenomas.SUBJECTS AND METHODSSomatostatin receptor scintigraphy was performed in 48 patients (19 acromegaly, 29 non‐functioning pituitary adenomas with ophthalmological defects). Results were expressed as an uptake index of the pituitary area. A threshold for positivity was determined in 23 subjects considered as controls. Thirty‐five patients were treated for 1 month with octreotide (300 μg daily). The therapeutic response was assessed on GH and IGF‐I suppression or evolution of the ophthalmological defects. The relationships between the somatostatin receptor scintigraphy result, the therapeutic effect of octreotide and in vitro studies performed in 12 tumours were studied.RESULTSFrom the results of control subjects the uptake index threshold for positivity was 2. In patients, somatostatin receptor scintigraphy was positive in 64% and there was no relationship between uptake index and tumour size. In GH tumours, somatostatin receptor scintigraphy was positive in 68%; uptake index was related to octreotide‐induced GH and IGF I suppression. The positive predictive value was 100% and the negative predictive value was 50%. In vitro studies showed detectable binding sites for somatostatin with sst2 and sst5 expression in the 4 GH tumours studied although somatostatin receptor scintigraphy was negative in 2 cases. In non‐functioning pituitary adenomas somatostatin receptor scintigraphy was positive in 62%. Based on visual effects, the positive predictive value was 61% and the negative predictive value was 100%. A wide distribution of somatostatin binding sites was found in 8 non‐functioning pituitary adenomas with expression of sst2 only.CONCLUSIONIn the conditions of the study, in patients with acromegaly, positive somatostatin receptor scintigraphy predicts a hormonal response but the value of somatostatin receptor scintigraphy is limited by its low negative predictive value. In patients with non–functioning pituitary adenomas, negative somatostatin receptor scintigraphy predicts that there will be no visual improvement during octreotide treatment.
Changes in gonadotrophin response to gonadotrophin releasing hormone in normal women following bilateral ovariectomy
Authors: Alexandris E. , Milingos S. , Kollios G. , Seferiadis K. , Lolis D. , Messinis I. E. 
Published: November 2003

OBJECTIVEPituitary responsiveness to GnRH varies throughout the normal menstrual cycle. We have investigated whether there are differences in the ovarian mechanisms which regulate gonadotrophin secretion between the follicular and the luteal phase of the cycle.DESIGNNormally ovulating women were studied during the first week following hysterectomy plus bilateral ovariectomy performed either in the mid‐ to late follicular phase (follicle size 16 mm) or in the early to midluteal phase (5 days post LH peak). The response of LH to a single dose of 10 μg GnRH was investigated 2 hours before the operation and every 12 hours after the operation until postoperative day 4 and every 24 hours until day 8.PATIENTSFourteen normally cycling premenopausal women with normal FSH (<10 IU/l). Seven women were ovariectomized in the follicular and 7 in the luteal phase.MEASUREMENTSPituitary response to GnRH was calculated as the net increase in FSH (▵FSH) and LH (▵LH) at 30 minutes above the basal value.RESULTSBasal levels of FSH and LH before the operation were significantly lower in the luteal than the follicular phase (P  <  0.05), while those of oestradiol (E2) were similar. Also, similar were ▵LH and ▵FSH values. Serum progesterone and immunoreactive inhibin (Ir‐inhibin) concentrations before the operation were higher in the luteal than the follicular phase (P  <  0.05). Following the operation, serum E2, progesterone and Ir‐inhibin values declined dramatically, while basal FSH and LH as well as ▵FSH values showed a gradual and significant increase. The percentage increase in FSH and LH values (mean  ±  SEM) on day 8 after the operation was similar in the follicular (453  ±  99% and 118  ±  35% respectively) and the luteal phase (480  ±  71% and 192  ±  45% respectively). In contrast to ▵FSH, ▵LH values after a temporal increase 12 hours from the operation, remained stable in the follicular phase and declined significantly in the luteal phase up to day 4.CONCLUSIONSBasal gonadotrophin secretion during the normal menstrual cycle is predominantly under a negative ovarian effect. It is suggested that in contrast to FSH, the secretion of LH in response to GnRH is controlled by different ovarian mechanisms during the two phases of the menstrual cycle.
Glucocorticoid replacement therapy: are patients over treated and does it matter?
Authors: Peacey Steven R. , Guo Chun‐Yuan , Robinson Anthony M. , Price Alun , Giles Martin A. , Eastell Richard , Weetman Anthony P. 
Published: November 2003

BACKGROUND AND OBJECTIVES Adequate assessment of patients on glucocorticoid replacement therapy is of great importance to avoid the consequences of under or over treatment, but no simple test is available for this. The aims of this study were (1) to assess adequacy of glucocorticoid replacement in hypoadrenal patients, (2) to correlate serum cortisol levels (cortisol day curve) with 24‐hour urine free cortisol excretion and (3) to assess the impact of glucocorticoid dose optimization on markers of bone formation and bone resorption.DESIGN Cross‐sectional study of current replacement therapy and a prospective study of the effect of dose alteration on bone turnover markers.PATIENTS Thirty‐two consecutive patients on replacement glucocorticoid therapy (12 Addison’s disease, 20 hypopituitarism) from a University teaching hospital out‐patient department.MEASUREMENTS Serum and urinary cortisol, osteocalcin, N‐telopeptide of type I collagen (NTX) and bone mineral density.RESULTS 28/32 (88%) patients required a change of therapy; 24/32 (75%) a total reduction in dose, 18/32 (56%) a change in replacement therapy regimen or drug and 14/32 (44%) both changes. The mean daily dose of hydrocortisone was reduced from 29.5 ± 1.2 to 20.8 ± 1.0 mg. A significant correlation was found between peak cortisol and 24‐hour urine free cortisol/creatinine (Spearman correlation r = 0.60, P < 0.0001; n = 51). Following hydrocortisone dose reduction, median osteocalcin increased from 16.7 μg/l (range 8.2–65.7) to 19.9 μg/l (8.2–56.3); P < 0.01, with no change in the NTX/creatinine ratio.CONCLUSIONS A high proportion of patients on conventional corticosteroid replacement therapy are over treated or on inappropriate replacement regimens. To reduce the long term risk of osteoporosis, corticosteroid replacement therapy should be individually assessed and over replacement avoided.
Mutations of the 5α‐reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α‐reductase‐2 deficiency
Authors: Canto Patricia , Vilchis Felipe , Chávez Bertha , Mutchinick Osvaldo , Imperato‐McGinley Julianne , Pérez‐Palacios Gregorio , Ulloa‐Aguirre Alfredo , Pablo Méndez Juan 
Published: November 2003

BACKGROUND AND OBJECTIVE Male pseudohermaphroditism due to 5α‐reductase deficiency was originally described in 1974. Recently, 5α‐reductase Type 2 gene defects have been found generally to be due to point mutations within the 5 exons of the 5α‐reductase‐2 gene. In this report, we describe the molecular study of patients with 5α‐reductase deficiency.DESIGN Previously diagnosed patients with 5α‐reductase deficiency were sampled in order to perform molecular studies.PATIENTS Eight 5α‐reductase deficient individuals from 6 unrelated families.MEASUREMENTS Single‐strand conformational polymorphism and DNA sequencing were performed after polymerase chain reaction amplification of each of the 5 exons of the gene.RESULTS Five different missense mutations were found. In 4 patients a cytosine to guanine substitution was observed at codon 212 in exon 4. Two siblings presented a cytosine to adenine substitution at codon 207 in exon 4. Another patient exhibited a guanine to adenine substitution at codon 34 in exon 1, whilst one individual presented 2 mutations: a guanine to adenine substitution at codon 115 in exon 2 and a guanine to adenine substitution at codon 203 in exon 4 (previously undescribed mutation).CONCLUSIONS The presence of the same mutation in 4 patients from 3 families indicates the increased prevalence of this mutation in a particular ethnic group, suggesting a common ancestry for the gene defect in these patients. The existence of hot spots is supported by the mutations in codons 34 and 207 which have also been found in other ethnic groups. Interestingly, the patient who presented 2 different mutations, one of them previously undescribed, was reared as a male and exhibited a more masculine phenotype. Further studies in patients with this and other mutations will be needed to verify genotype–phenotype correlation.
Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia
Authors: Habib Fouad K. , Ross Margaret , Tate Rothwell , Chisholm Geoffrey D. 
Published: November 2003

OBJECTIVE The 5α‐reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5α‐reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5α‐reductase activity of the gland in men with BPH treated with the drug for 3 months.DESIGN AND PATIENTS Twenty‐eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double‐blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months.MEASUREMENTS Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5α‐reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels.RESULTS There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT(P= 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5α‐reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5α‐reductase activity of the gland and tissue DHT concentrations.CONCLUSIONS Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5α‐reductase responsible for the accumulation of DHT in the gland.
Effect of insulin on serum levels of dehydroepiandrosterone metabolites in men
Authors: Lavallée Bernard , Provost Pierre R. , Kahwash Ziad , Nestler John E. , Bélanger Alain 
Published: November 2003

OBJECTIVE Insulin was found to decrease the concentration of serum dehydroepiandrosterone (DHEA) and DHEA‐sulphate (DHEAS) and recent data suggest that an increase in the metabolic clearance rate of DHEA (MCRDHEA) may be involved. In this study, we have investigated the effects of insulin on DHEA metabolism in men. PATIENTS A total of 10 men were enrolled into the study, and all subjects completed the study. Subjects were healthy, non‐obese, and 20–30 years old. DESIGN DHEA was administered intravenously to subjects, alone or in combination with insulin. A hyperinsulinaemic‐euglycaemic clamp was initiated for subjects with the insulin infusion and euglycaemia was maintained by checking blood glucose and adjusting the rate of a 25% dextrose infusion as needed. Serum was collected before DHEA infusion, during DHEA infusion after attaining steady state (3.5–4h), and during DHEA plus insulin infusion (6–6.5h) (steady state) and then assayed for DHEA, DHEA metabolites, and DHEA acylation by LCAT. RESULTS Results showed rapid transformation of DHEA into androst‐5‐ene‐3β,17β‐diol, DHEA fatty‐acid esters (DHEA‐FA), androstenedione and 5α‐androstan‐3α‐ol‐17‐one glucuronide (androsterone glucuronide) whereas DHEAS, testosterone, androstane‐3α,17β‐diol glucuronide and oestradiol serum levels were not affected. When insulin was simultaneously infused once steady‐state DHEA levels had been attained, we observed a decline only in DHEA, DHEA‐FA and DHEAS levels, with no effect on other steroids examined. Although serum DHEA esterification was not affected by DHEA, a stimulation by insulin was observed. CONCLUSIONS These results suggest that insulin increases the DHEA metabolic clearance rate by stimulating its conversion to DHEA‐FA and by enhancing uptake of DHEA‐FA by peripheral tissues.