Cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement.

OBJECTIVE: The last decade has seen a proliferation in options for testosterone replacement. However, little is known as to the benefits of different treatment modalities. Our objective was to determine the testosterone prescription pattern and to examine the impact on various outcome measures. SUBJECTS AND METHODS: A total of 816 adult-onset hypopituitary males on stable pituitary replacement for at least 1 year were identified from the KIMS database. Patients were classified as either eugonadal (n = 106), or hypogonadal (n = 710) on intramuscular (IM, n = 558), oral (n = 74), transdermal (n = 61), and depot (n = 17) testosterone. RESULTS: After 1 year of stable pituitary replacement therapy, body composition, cardiovascular parameters, GH replacement and quality of life were not significantly different in androgen-replaced hypogonadal patients compared to eugonadal patients. There were no differences in outcome variables within the hypogonadal group according to the testosterone replacement regimen used and no difference in response to GH therapy. CONCLUSIONS: The majority of hypopituitary patients in the last decade have received IM testosterone. Body composition, cardiovascular parameters, GH replacement and quality of life were not different between eugonadal and hypogonadal patients and were not differentially affected by the mode of testosterone replacement. These findings are reassuring that there is no major difference in response to different testosterone replacement regimens.

Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.

BACKGROUND: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. AIM: To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)). SUBJECTS AND METHODS: Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls. RESULTS: Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. CONCLUSIONS: For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.

Membrane reinsertion of a myristoyl-peptidyl anchored extracellular domain growth hormone receptor.

The actions of GH are mediated through a cell surface cytokine receptor. We previously demonstrated that naturally occurring truncated membrane bound GH receptors (GHRs) can block GH receptor signaling. We have now investigated whether recombinant extracellular GHR can be conjugated to a myristoylated-peptide (mp) tail and inserted into cell membranes to modulate GHR signaling. Recombinant human extracellular domain (1-241) GHR was expressed in Escherichia coli, purified, and refolded from cell lysate. The free C-terminal cysteine was then reduced and conjugated to an activated preformed mp tail. The properties of the purified tailed GHR (GHR-mp) were then compared with those of the untailed purified GHR 1-241. Fluorescence-activated cell sorter analysis and cell surface binding assays demonstrated that GHR-mp inserted into the cell surface membranes of CHO cells, whereas untailed GHR 1-241 showed no insertion. In a cell-based bioassay GHR-mp partially inhibited wild-type GHR signaling, whereas GHR 1-241 had no effect. Truncated extracellular domain GHR can, when specifically modified with a membrane-localizing mp unit, insert into cell surface membranes and modulate GHR signaling.

Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study.

BACKGROUND: Testosterone replacement in hypogonadal males improves body composition, sexual function, and health-related quality of life. Male cancer survivors are at risk of androgen deficiency; however, when and in whom testosterone should be replaced remain unanswered questions. OBJECTIVE: The aim of our study was to define the prevalence of androgen deficiency in this patient group through assessment of testosterone levels and related measures. DESIGN: This was a cross-sectional, observational study of cases and controls. We recruited 176 cancer survivors and 213 controls, aged 25-45 yr. RESULTS: Of cancer survivors, 97% had received chemotherapy and 40% radiotherapy. Cancer survivors had lower total testosterone (tT) levels than controls (mean difference 2.67 nmol/liter; 95% confidence interval 1.58-3.76; P = 0.003), and 24 of 176 (13.6%; 95% confidence interval 9.3-19.5) had a tT less than 10 nmol/liter, which was less than 2.5% centile for controls. Cancer survivors had a greater fat mass, higher fasting insulin and glucose levels, increased fatigue, and reduced sexual function and health-related quality of life. In both cohorts, the tT correlated negatively with insulin levels and negatively with body fat mass; however, the difference in tT between them was independent of fat mass. We measured tT and SHBG and calculated bioavailable testosterone. The changes in calculated bioavailable testosterone were similar to tT. CONCLUSIONS: A significant proportion of young male cancer survivors had a frankly low tT associated with an increased fat mass and insulin level compared with controls. These factors would be predicted to improve in response to testosterone replacement therapy and provide a powerful argument for an interventional study of testosterone therapy in young male cancer survivors.

Doses and steroids to be used in primary and central hypoadrenalism.

Traditionally hydrocortisone has been the first choice for replacement therapy in patients with adrenal insufficiency. Paediatricians have used body surface area adjusted dosing and adult physicians have tended to use fixed doses twice or thrice daily. Cortisol secretion has a distinct circadian rhythm being low at the time sleep onset, rising from between 02.00 h and 04.00 h in the morning to peak just after the time of waking then falling during the day. The pharmacokinetics of immediate release hydrocortisone means that no treatment regimen is capable of simulating the normal circadian rhythm of cortisol. Recent data with hydrocortisone infusions suggests that circadian delivery of hydrocortisone can improve biochemical control of patients with adrenal insufficiency. It is anticipated in the future that modified release formulations of hydrocortisone will provide more optimal replacement therapy.

Pasireotide: successful treatment of a sparsely granulated tumour in a resistant case of acromegaly.

The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 µg/L (103-310 µg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 µg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103-310 µg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes. LEARNING POINTS: Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands.Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours.Patients with membranous expression of sst5 are likely to be more responsive to pasireotide.

A 36 residues insertion in the dimerization domain of the growth hormone receptor results in defective trafficking rather than impaired signaling.

Growth hormone insensitivity syndrome (GHIS) has been reported in a family homozygous for a point mutation in the GH receptor (GHR) that activates an intronic pseudoexon. The resultant GHR (GHR1-656) includes a 36 amino-acids insertion after residue 207, in the region known to be important for homodimerization of GHR. We have examined the functional consequences of such an insertion in mammalian cells transfected with the wild type (GHRwt) and mutated GHR (GHR1-656). Radio-ligand binding and flow cytometry analysis showed that GHR1-656 is poorly expressed at the cell surface compared with GHRwt. Total membrane binding and Western blot analysis showed no such difference in the level of total cellular GHR expressed for GHR1-656 vs GHRwt. Immunofluorescence showed GHR1-656 to have different cellular distribution to the wild type receptor (GHRwt), with the mutated GHR being mainly perinuclear and less vesicular than GHRwt. Western blot analysis showed GH-induced phosphorylation of Jak2 and Stat5 for both GHR1-656 and GHRwt, although reduced Stat5 activity was detected with GHR1-656, consistent with lower levels of expression of GHR1-656 than GHRwt at the cell surface. In conclusion, we report that GHIS, due to a 36 amino-acids insertion in the extracellular domain of GHR, is likely to be explained by a trafficking defect rather than by a signalling defect of GHR.

Estrogen replacement in women of fertile years with hypopituitarism.

BACKGROUND: What form of estrogen to prescribe a young hypopituitary woman with gonadal failure remains an open question despite evidence that oral estrogen therapy induces GH resistance and an increase in fat mass. METHODS: Using an international surveillance study of hypopituitary patients, we examined two questions: 1) What estrogen is prescribed to young women of fertile years with hypopituitarism? 2) Is there a difference in body composition or IGF-I levels dependent on the type of estrogen prescribed? RESULTS: Six hundred twenty-eight GH-deficient women, aged 18-50 yr, were identified. Three hundred thirteen had normal gonadal function, and 315 were receiving estrogen therapy; of these 14% were using transdermal estradiol, and 86% were taking an oral estrogen preparation (38% oral estradiol, 18% conjugated estrogens, and 30% ethinyl estradiol in the oral contraceptive). There was no difference in weight, waist/hip ratio, or body composition between the women taking different estrogen therapies. However, if the oral estrogen groups were combined, they showed less change in waist and hip measurement and had a greater waist/hip ratio after 1 yr of GH treatment compared with patients with normal gonadal function (0.85 vs. 0.83; P = 0.022). Patients taking ethinyl estradiol had lower age-adjusted IGF-I sd scores and required almost twice the GH dose to achieve an IGF-I sd score that remained lower than patients with normal gonadal function and patients receiving transdermal estradiol. CONCLUSIONS: 1) The majority of women of fertile years with hypo-pituitarism take oral estrogen replacement therapy. 2) Waist/hip ratio was greater in women taking oral estrogens, and there is indirect evidence that oral estrogens reduce the action of GH on fat mass. 3) Patients using the oral contraceptive had lower IGF-I levels and required twice the GH dose compared with patients receiving transdermal estradiol.

Patients with chronic pain and abnormal pituitary function require investigation.

Misuse of opioids is associated with abnormalities of pituitary function. Patients with chronic pain frequently complain of fatigue and undergo endocrine testing. To test whether oral opioid treatment causes abnormal pituitary function we prospectively assessed pituitary function in 37 patients with chronic pain who were receiving either oral opioid analgesia or non-opioid analgesia. Oral opioid treatment was not associated with abnormal pituitary function although a few patients had abnormal results mainly related to obesity. Our results suggest that patients with chronic pain who have abnormal endocrine results should have a complete assessment, since abnormal test results cannot be attributed to their analgesia.

Hypopituitary patients prefer a touch-screen to paper quality of life questionnaire.

UNLABELLED: Health Related Quality of Life questionnaires are frequently used for research, however only recently has their use been recommended in the routine clinical management of pituitary patients. Questionnaires frequently have complex scoring systems, and may be cumbersome, limiting widespread application. Touch-screen technology can overcome these limitations. We have developed a touch-screen 'Questions on Life Satisfaction-Hypopituitarism' QLS-H (Flash 5 Action script, program design by IG) questionnaire and compared its use and accuracy with a paper version questionnaire in 50 pituitary patients who were attending routine clinics. The HRQoL Z-score for the patient group was lower than the average for the normal UK population, as might be predicted for this patient group. There was no statistically significant difference between scores obtained by the touch-screen and paper questionnaires; mean (SD) Z score was -1.33 (1.4) for touch-screen and -1.26 (1.5) for paper. The touch-screen was preferred by 80% of patients, and quicker to complete (<5min). Additionally, there were significant errors in 14 (28%) of manually scored paper questionnaires. IN CONCLUSION: Touch-screen QLS-H questionnaires have advantages over the paper version for the routine clinical assessment of patients with hypopituitarism.

Pegvisomant, a growth hormone-specific antagonist, undergoes cellular internalization.

GH binding to a receptor (GHR) dimer triggers signaling and internalization of the receptor/ligand complex. Pegvisomant is a specific GH antagonist developed for the treatment of acromegaly, and the basic molecule is GH with an amino acid substitution that blocks the conformational change necessary to generate functional GHR dimerization required for signal transduction. Pegvisomant has additional polyethylene glycol moieties to prolong its half-life in the circulation and improve clinical efficacy through reduced renal clearance. Pegvisomant has a long plasma half-life, and its mode of clearance has not been established. We have studied pegvisomant internalization and demonstrate that despite its size and prolonged plasma half-life, it is internalized by cells expressing the GHR. As pegvisomant does not activate intracellular signal transduction systems, our results support the concept that the conformational changes required for GHR signaling are not essential for the intracellular trafficking of the ligand and establish one potential contributing mechanism for pegvisomant clearance.

Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction.

Congenital GH insensitivity syndrome (GHIS) is usually the result of a mutation in the extracellular domain of the GH receptor (GHR). We report one of only a small number of mutations so far identified within the intracellular domain of the GHR. The probands are a 53-yr-old woman, height 114 cm (SD score, -8.7), peak GH 45 microg/liter during hypoglycemia, IGF-I 8.0 microg/liter [normal range (N) N 54-389], IGF binding protein-3 16 nmol/liter (N 61-254), GHBP 6.8% (N > 10); and her 57-yr-old brother, height 140 cm (SD score, -6), IGF-I 38.8 micro g/liter (N 54-290), IGF binding protein-3 30 nmol/liter (N 61-196). Both patients were homozygous for a 22-bp deletion in the DNA encoding the cytoplasmic domain of the GHR, resulting in a frameshift and premature stop codon. The resultant GHR is truncated at amino acid 449 (GHR1-449) after Box1, the Janus kinase 2 binding domain of the receptor. Functional studies in HEK293 and Chinese hamster ovary cells show GHR1-449 to have a cellular distribution similar to that of the wild-type GHR, judged by binding of iodinated GH, FACS analysis, and immunocytochemistry. Western blot analysis showed GH-induced phosphorylation of Janus kinase 2, signal transducer and activator of transcription (Stat)3, and Erk2 for both GHR1-449 and wild-type GHR. However, no Stat5 activity was detected in cells expressing GHR1-449, consistent with the fact that GHR1-449 contains no Stat5 binding site. In conclusion, we report two adult siblings with GHIS due to a mutation in the intracellular domain of GHR resulting in a selective loss of Stat5 signaling. Results are consistent with the hypothesis that the loss of signaling through the Stat5 pathway results in GHIS.

Pegvisomant: structure and function.

Pegvisomant is the pegylated form of mutant growth hormone (B2036). B2036 has increased affinity in one binding site and lowered affinity in its second binding site, it has been shown that this molecule still enables dimerisation of the growth hormone receptor at the cell surface but does not allow the necessary conformational changes for signalling. Pegylation decreases the antagonistic activity of B2036, however the rate of clearance of the pegylated B2036 is greatly reduced compared to the unpegylated form. Even though the antagonistic activity of pegvisomant is lower than B2036, the reduced rate of clearance makes it an effective clinical drug for the treatment of conditions such as acromegaly.

Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men.

OBJECTIVE: A phase I single centre, open label study of the pharmacokinetics and tolerability of a buccal testosterone tablet (COL 1621) was carried out. DESIGN: Twelve testosterone-deficient males were treated with the buccal tablet twice daily for 7 consecutive days. Multiple blood samples were drawn for testosterone, dihydrotestosterone (DHT), bioavailable testosterone and sex hormone-binding globulin (SHBG). RESULTS: After COL 1621, means+/-S.D. serum testosterone level increased to a peak concentration of 26.6+/-5.8 nmol/l (7.7+/-1.7 ng/ml) at 4.8+/-5.8 h and stayed in the eugonadal range. Steady state was achieved within the first 24 h and was maintained in the normal range. The bioavailable testosterone, DHT and free testosterone index followed a pattern very similar to that of testosterone. The mean serum testosterone to DHT ratio was within the normal male range throughout treatment. There was only one treatment-related adverse event (headache). Two-thirds of patients indicated that treatment with COL 1621 was acceptable and that the tablet was convenient to use. Six patients (50.0%) preferred COL 1621 to their previous testosterone replacement therapy, two patients gave preference to their previous treatment and three patients found both treatments to be equally acceptable. Data for one patient was not available. CONCLUSION: We conclude that COL 1621 can efficiently elevate serum testosterone and DHT levels in hypogonadal men within the first day of application, achieve a steady state within 24 h and maintain serum testosterone in the normal range with a twice-daily treatment regimen. COL 1621 provides an effective alternative oral testosterone replacement therapy that gives physiological levels of testosterone and is well tolerated by the patients.

Serum leptin and leptin binding activity in children and adolescents with hypothalamic dysfunction.

Marked disturbance in eating behaviour and obesity are common sequelae of hypothalamic damage. To investigate whether these were associated with dysfunctional leptin central feedback, we evaluated serum leptin and leptin binding activity in 37 patients (age 3.5-21 yr) with tumour or trauma involving the hypothalamic-pituitary axis compared with 138 healthy children (age 5.0-18.2 yr). Patients were subdivided by BMI <2 SDS or > or = 2 SDS and healthy children and children with simple obesity of comparable age and pubertal status served as controls. Patients had higher BMI (mean 1.9 vs 0.2 SDS; p <0.001), a greater proportion had BMI > or = 2 SDS (54% vs 8%; p <0.001) and higher serum leptin (mean 2.1 vs 0.04 SDS; p <0.001) than healthy children. Serum leptin (mean 1.1 vs -0.1 SDS; p = 0.004) and values adjusted for BMI (median 0.42 vs 0.23 microg/l:kg/m2; p = 0.02) were higher in patients with BMI <2 SDS. However, serum leptin adjusted for BMI was similar in patients with BMI > or = 2 SDS compared to corresponding controls (1.08 vs 0.95; p = 0.6). Log serum leptin correlated with BMI SDS in all subject groups but the relationship in patients with BMI <2 SDS was of higher magnitude (r = 0.65, slope = 0.29, p =0.05 for difference between slopes) than in healthy controls (r = 0.42, slope = 0.19). Serum leptin binding activity (median 7.5 vs 9.3%; p = 0.02) and values adjusted for BMI (median 0.28 vs 0.48 % x m2/kg; p <0.001) were lower in patients than in healthy children. The markedly elevated leptin levels with increasing BMI in non-obese patients with hypothalamic-pituitary damage are suggestive of an unrestrained pattern of leptin secretion. This along with low leptin binding activity and hence higher free leptin levels would be consistent with central leptin insensitivity.

Endocrine, metabolic, nutritional and body composition abnormalities are common in advanced intensively-treated (transplanted) multiple myeloma.

Modern treatment strategies have increased life expectancy in multiple myeloma, but little is known about the endocrine, metabolic and nutritional status of long-term survivors. We performed endocrine, metabolic, bone, body composition and nutritional evaluations in 32 patients with intensively-treated, advanced but stable, myeloma a median duration of 6 years from diagnosis and three lines of intensive treatment, including at least one haematopoietic SCT procedure. All patients were off active treatment. There was a high prevalence of endocrine dysfunction: hypothyroidism (9%), hypogonadism (65% males) and elevated prolactin (19%). Adrenocortical function was preserved despite large cumulative corticosteroid pretreatment. Biochemical markers were consistent with postmenopausal status in all females and infertility in males. Nutritionally, 59% were vitamin D insufficient/deficient, reduced serum folate in 25% and vitamin B12 in 6%. Total body DEXA scanning confirmed 'sarcopenic-obesity' in 65%, but reduced bone density was seen in a minority. We conclude that potentially correctable endocrine, metabolic and nutritional abnormalities are prevalent in heavily-treated patients with stable multiple myeloma. Preservation of bone supports the efficacy of bisphosphonate treatment from diagnosis, but sarcopenic-obesity may contribute to frailty. Ultimately, multi-system screening and appropriate interventions may optimise quality of long-term survival and further studies are warranted.

Women gain weight and fat mass despite lipectomy at abdominoplasty and breast reduction.

OBJECTIVES: In animal models, fat removal results in compensatory weight gain. No study has reported measurement of weight following lipectomy in humans. We have examined changes in weight in patients who underwent lipectomy. METHODS: In a retrospective analysis, 16 patients who had abdominoplasty and 17 patients who underwent bilateral breast reduction were compared with 16 patients who had carpal tunnel syndrome release. Following this, a prospective study was carried out on 7 subjects awaiting abdominoplasty and 12 subjects awaiting bilateral breast reduction surgery. RESULTS: In the retrospective study, all three patient groups gained weight following surgery. The abdominoplasty group was heavier before surgery and showed greatest weight gain but there was no statistically significant difference in weight gain between the groups. In the prospective study, the abdominoplasty group had a mean fat removal of 1.77 kg and breast reduction group had a mean of 3.22 kg. Eighteen months following surgery the abdominoplasty group showed a significant mean increase in body weight (mean increase: 4.82 kg) and body mass index (BMI) (mean increase: 1.66 kg/m(2)). In the bilateral breast reduction group, there was a non-significant mean gain in weight (mean increase: 0.67 kg) and BMI (mean increase: 0.21 kg/m(2)). CONCLUSIONS: Patients undergoing lipectomy during abdominoplasty and bilateral breast reduction will gain weight in the long term. This weight gain probably reflects the expected gain in weight without surgery as a similar finding is observed in patients who have undergone surgery without lipectomy. These results highlight the limitation of lipectomy as a weight control measure.

Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism.

Clinical studies suggest there may be a threshold concentration of serum testosterone below which replacement will result in skeletal and psychological benefit. We evaluated the response to testosterone in men with borderline hypogonadism. A randomized double-blind placebo-controlled trial in 39 men over age 40 years presenting with sexual dysfunction and a borderline low testosterone level (total testosterone <10 nmol/L or free androgen index <30%). Patients were randomized to Testoderm TTS body patch (5 mg/day, n = 20) or a placebo patch (n = 19) for 6 months, followed by open-label testosterone replacement for a further 6 months in all patients. During the placebo-controlled phase of the study serum testosterone increased significantly on testosterone vs. placebo treatment (p = 0.004); this was associated with a decrease in total body fat mass (p = 0.019) and increase in haemoglobin level (p = 0.036). There were no significant changes in lean body mass, markers of bone turnover, and measures of bone mineral density (BMD). There was evidence of difference in quality of life according to the Male Erectile Dysfunction Quality of Life questionnaire (MEDQoL score, p = 0.017), mainly accounted for by deterioration in the placebo arm. When the active treatment period was combined for placebo and testosterone groups, the within-patient analysis showed a significant effect of testosterone to decrease markers of bone resorption (uNTX/Cr, p = 0.007; iFDPD/Cr, p = 0.0006) and to increase lean body mass (p = 0.001). There was little convincing evidence from this study that testosterone replacement is likely to have major benefit in men over age 40 years with borderline hypogonadism and sexual dysfunction. However, there was evidence of suppression in bone resorption and hence longer and larger studies are needed to examine its effect on BMD.

Timing and type of glucocorticoid replacement in adult congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is one of the commonest inherited diseases. Treatment during childhood is directed towards obtaining normal growth. There is an extensive literature on management of CAH during childhood but little published on how patients should be treated as adults. CAH results in increased adrenocorticotropic hormone levels driving the adrenal to produce cortisol and thereby excessive cortisol precursors which are predominantly androgenic. In normal individuals there is a marked circadian rhythm in cortisol release with the lowest levels occurring shortly after midnight and rising between 02.00 and 03.00 h to peak at around 06.00-08.00 h after waking. The treatment of choice for children with CAH is hydrocortisone three times daily. There is no consensus on treating adults. A recent survey by the UK Society for Endocrinology showed that hydrocortisone was the most popular steroid, followed by dexamethasone and then prednisolone. Sixty percent of respondents used a reverse circadian pattern of glucocorticoid treatment and only 16% used a dose based on weight or surface area. In a recent study we demonstrated that the most important variable determining hydrocortisone bioavailability is weight and we advocated a weight-related dosing regimen monitored using a nomogram for serum cortisol. .

Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.