Hyperandrogenic states in women: pitfalls in laboratory diagnosis

International audienceMeasuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women

Circadian rhythmicity of pain sensitivity in humans

Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is unknown. Using highly controlled laboratory constant routine conditions, we show that pain sensitivity is rhythmic over the 24-hours and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 hours of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ~80% of the full magnitude of pain sensitivity over the 24 hours, and that sleep-related processes account for only ~20%. Overall, our data reveal that the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans, with the oscillating timepiece located in the suprachiasmatic nuclei. Our findings highlight the need to consider the time of day in pain assessment, and suggest that personalized circadian medicine may be a promising approach to pain management

Bioavailability of Melatonin after Administration of an Oral Prolonged-Release Tablet and an Immediate-Release Sublingual Spray in Healthy Male Volunteers

Abstract Background The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism. Objective The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin. Methods In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters. Results The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C max: 2332 ± 950 pg/mL; T max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C max: 1151 ± 565 pg/mL; T max: 64.2 ± 44.2 min; p < 0.001 for comparison of C max and T max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC0–540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated. Conclusions The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form. Trial Registry Registration number: NCT04574141

Postoperative remission of non-invasive lactotroph pituitary tumor: A single-center experience

A subset of pituitary neuroendocrine tumors (PitNETs) have an aggressive behavior, showing resistance to treatment and/or multiple recurrences in spite of the optimal use of standard therapies (surgery, conventional medical treatments, and radiotherapy). To date, for aggressive PitNETs, temozolomide (TMZ) has been the most used therapeutic option, and has resulted in an improvement in the five-year survival rate in responders. However, given the fact that roughly only one third of patients showed a partial or complete radiological response on the first course of TMZ, and even fewer patients responded to a second course of TMZ, other treatment options are urgently needed. Emerging therapies consist predominantly of peptide receptor radionuclide therapy (20 cases), vascular endothelial growth factor receptor-targeted therapy (12 cases), tyrosine kinase inhibitors (10 cases), mammalian target of rapamycin (mTOR) inhibitors (six cases), and more recently, immune checkpoint inhibitors (one case). Here, we present the available clinical cases published in the literature for each of these treatments. The therapies that currently show the most promise (based on the achievement of partial radiological response in a certain number of cases) are immune checkpoint inhibitors, peptide receptor radionuclide therapy, and vascular endothelial growth factor receptor-targeted therapy. In the future, further improvement of these therapies and the development of other novel therapies, their use in personalized medicine, and a better understanding of combination therapies, will hopefully result in better outcomes for patients bearing aggressive PitNETs

Predicting early post-operative remission in pituitary adenomas: evaluation of the modified knosp classification

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Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients

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