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Marine Ollivier, Magalie Haissaguerre, Amandine Ferriere and Antoine Tabarin

Extract: We read with interest the paper of Young and al. in which the authors recommend avoiding Ketoconazole in the treatment of Cushing’s syndrome when patients display increased liver enzymes (> 2 fold the upper limit of normal (ULN)) (1). Severe hypercortisolism is a life-threatening condition and is considered as an endocrine emergency requiring a rapid and dramatic decrease in cortisol levels (2). Ketoconazole and metyrapone, in monotherapy or in association, have been recommended in this instance since they inhibit cortisol synthesis within hours and can normalize cortisol levels within days (2–4). Although poorly described in the literature, an increase in liver enzymes, that may be secondary to hepatic steatosis, is a common observation in severe Cushing’s syndrome (5). The presence of hepatic metastases may also alter liver function (1). Should we therefore avoid prescribing ketoconazole, a potent life-saving drug in severe Cushing’s syndrome, for a risk of idiosyncratic ketoconazole-induced hepatitis that is < 5% in large series (6)?

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Laurence Dumeige, Livie Chatelais, Claire Bouvattier, Marc De Kerdanet, Capucine Hyon, Blandine Esteva, Dinane Samara-Boustani, Delphine Zenaty, Marc Nicolino, Sabine Baron, Chantal Metz-Blond, Catherine Naud-Saudreau, Clémentine Dupuis, Juliane Léger, Jean-Pierre Siffroi, Bruno Donadille, Sophie Christin-Maitre, Jean-Claude Carel, Regis Coutant and Laetitia Martinerie

Objective

Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.

Methods

Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.

Results

Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).

Conclusion

This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

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Andrea Lamprecht, Jane Sorbello, Christina Jang, David J. Torpy and Warrick J Inder

Objective: To evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids.

Design and Methods: Cross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n=40) versus an age and sex-matched control group (n=25). Baseline pituitary function was assessed on blood samples collected prior to 0900h. Further testing with corticotropin (250μg IV) and metyrapone (30mg/kg) stimulation tests was undertaken on participants with serum cortisol <250nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function.

Results: Secondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users versus no controls (P=0.01). Opioid users with SAI had a higher median morphine equivalent daily dose (MEDD), P=0.037 – 50% with MEDD >200mg and 0% with MEDD <60mg had SAI. Among male participants, testosterone was inversely associated with body mass index (BMI) (P=0.001) but not opioid use. A non-significant trend to low testosterone <8nmol/L in male opioid users (11/24 opioid users vs 2/14 control, P=0.08) suggests a small sub-group with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scores P<0.001 compared to controls).

Conclusion: Long-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

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Domenico Albano, Francesco Bertagna, Mattia Bonacina, Rexhep Durmo, Elisabetta Cerudelli, Maria Gazzilli, Maria Beatrice Panarotto, Anna Maria Formenti, Gherardo Mazziotti, Andrea Giustina and Raffaele Giubbini

Objective

According to the 2015 American Thyroid Association (ATA) guidelines, thyroid ablation by iodine-131 (I-131) therapy is absolutely recommended only in patients with high-risk differentiated thyroid cancer (DTC). Often distant metastases are not recognized early and they can stay silent for long time. The aim of our study was to retrospectively analyze the prevalence of metastatic disease before and after I-131 and to evaluate the influence of the new ATA guidelines in the management of DTC.

Methods

We retrospectively analyzed 140 patients showing distant metastases. All metastases were detected by whole-body scan after I-131 and confirmed by histology and/or other imaging modalities.

Results

In 26/140 patients metastases were detected before I-131, while in 114/140 were discovered after I-131. Comparing patients with metastases detected before and after I-131, no differences were demonstrated considering age, sex, histotype, tumor size, multifocality of cancer and metastatic localization. Metastatic DTC discovered before radioiodine had higher thyroglobulin and received a higher radioiodine total activity and number of treatments. Considering patients with distant metastases, according to the 2015 ATA guidelines, 38 patients would have been categorized as high risk, 22 as low risk and 80 as intermediate risk. Among intermediate-risk patients, only in 25 cases (31%) I-131 treatment would have been appropriate according to 2015 ATA recommendations; in the remaining 56 cases (69%), I-131 would not have been recommended.

Conclusions

According to the 2015 ATA guidelines, most of metastatic patients would not have been treated after surgery, with the risk of late diagnosis and delayed treatment.

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Brandon P Galm, E Leonardo Martinez-Salazar, Brooke Swearingen, Martin Torriani, Anne Klibanski, Miriam A Bredella and Nicholas A Tritos

Background

There are limited predictors of prognosis in patients with clinically non-functioning pituitary adenomas (NFPAs). We hypothesized that MRI texture analysis may predict tumor recurrence or progression in patients with NFPAs undergoing transsphenoidal pituitary surgery (TSS).

Objective

To characterize texture parameters on preoperative MRI examinations in patients with NFPAs in relation to prognosis.

Methods

Retrospective study of patients with NFPAs who underwent TSS at our institution between 2009 and 2010. Clinical, radiological and histopathological data were extracted from electronic medical records. MRI texture analysis was performed on coronal T1-weighted non-enhanced MR images using ImageJ (NIH). MRI texture parameters were used to predict tumor recurrence or progression. Both logistic regression and Cox proportional hazard analyses were conducted to adjust for potential confounders.

Results

Data on 78 patients were analyzed. On both crude and multivariable-adjusted analyses, mean, median, mode, minimum and maximum pixel intensity were associated with the risk of pituitary tumor recurrence or progression after TSS. Patients whose tumor mean pixel intensity was above the median for the population had a hazard ratio of 0.44 (95% CI: 0.21–0.94, P = 0.034) for recurrence or progression in comparison with tumors below the median.

Conclusions

Our data suggest that MRI texture analysis can predict the risk of tumor recurrence or progression in patients with NFPAs.

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Walter L Miller

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term ‘CAH’ is generally used to mean ‘steroid 21-hydroxylase deficiency’ (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, ‘non-classic’ defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.

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Mamta N Joshi, Benjamin C Whitelaw and Paul V Carroll

Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.

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Ilpo Huhtaniemi

The two pituitary gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and in particular LH-stimulated high intratesticular testosterone (ITT) concentration, are considered crucial for spermatogenesis. We have revisited these concepts in genetically modified mice, one being the LH receptor (R)-knockout mouse (LuRKO), the other a transgenic mouse expressing in Sertoli cells a highly constitutively active mutated Fshr (Fshr-CAM). It was found that full spermatogenesis was induced by exogenous testosterone treatment in LuRKO mice at doses that restored ITT concentration to a level corresponding to the normal circulating testosterone level in WT mice, ≈5 nmol/L, which is 1.4% of the normal high ITT concentration. When hypogonadal LuRKO and Fshr-CAM mice were crossed, the double-mutant mice with strong FSH signaling, but minimal testosterone production, showed near-normal spermatogenesis, even when their residual androgen action was blocked with the strong antiandrogen flutamide. In conclusion, our findings challenge two dogmas of the hormonal regulation of male fertility: (1) high ITT concentration is not necessary for spermatogenesis and (2) strong FSH stimulation can maintain spermatogenesis without testosterone. These findings have clinical relevance for the development of hormonal male contraception and for the treatment of idiopathic oligozoospermia.

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Cheol Ryong Ku, Thierry Brue, Katharina Schilbach, Stanislav Ignatenko, Sandor Magony, Yoon-Sok Chung, Byung-Joon Kim, Kyu Yeon Hur, Ho-Cheol Kang, Jung Hee Kim, Min Seon Kim, Aldona Kowalska, Marek Bolanowski, Marek Ruchala, Svetozar Damjanovic, Juraj Payer, Yun Jung Choi, Su Jin Heo, Tae Kyoung Kim, MinKyu Heo, Joan Lee and Eun Jig Lee

Objective

Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients.

Design

This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea.

Methods

Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity.

Results

Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin.

Conclusions

GX-H9 has the potential for up to twice-monthly administration.

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Luca Persani, Tiziana de Filippis, Carla Colombo and Davide Gentilini

The technological advancements in genetics produced a profound impact on the research and diagnostics of non-communicable diseases. The availability of next-generation sequencing (NGS) allowed the identification of novel candidate genes but also an in-depth modification of the understanding of the architecture of several endocrine diseases. Several different NGS approaches are available allowing the sequencing of several regions of interest or the whole exome or genome (WGS, WES or targeted NGS), with highly variable costs, potentials and limitations that should be clearly known before designing the experiment. Here, we illustrate the NGS scenario, describe the advantages and limitations of the different protocols and review some of the NGS results obtained in different endocrine conditions. We finally give insights on the terminology and requirements for the implementation of NGS in research and diagnostic labs.