No significant long-term complications from inadvertent exposure to gonadotropin-releasing hormone agonist during early pregnancy in mothers and offspring: a retrospective analysis.

BACKGROUND: Administration of gonadotropin-releasing hormone agonist (GnRH-a) in the luteal phase is commonly used for pituitary suppression during in vitro fertilisation (IVF). There is an ineluctable risk of inadvertent exposure of spontaneous pregnancy to GnRH-a. However, little is known about the pregnancy complications and repregnancy outcomes of the affected women and the neurodevelopmental outcomes of the GnRH-a-exposed children. METHODS: Retrospective analysis was used to determine obstetric and repregnancy outcomes after natural conception in 114 women who naturally conceived while receiving GnRH-a during their early pregnancy over the past 17 years. The GnRH-a-exposed children were evaluated to determine their neonatal characteristics and long-term neurodevelopmental outcomes. The outcomes were compared to those of relevant age-matched control groups. RESULTS: Sixty-five women had 66 live births. The neonatal health outcomes and the incidence of maternal complications were similar in the GnRH-a-exposed and control groups. Thirty-one GnRH-a-exposed children, aged 2-8 years, were available for investigation of neurodevelopment. Except for one case of autism spectrum disorder, the full-scale intelligence quotient score was within the normal range and similar to that of the control group. Most mothers with successful pregnancies and about one-third of the women who had spontaneous abortions were subsequently able to conceive naturally again. IVF is recommended for repregnancy in women who have experienced ectopic pregnancies. CONCLUSIONS: Accidental exposure to GnRH-a in early pregnancy might be safe. Reproductive treatment suggestions for repregnancy should be made with consideration of the outcomes of the previously GnRH-a-exposed spontaneous pregnancy.

α-MSH ameliorates corneal surface dysfunction in scopolamine-induced dry eye rats and human corneal epithelial cells via enhancing EGFR expression.

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.

Effect of intraoperative secretin on operative outcomes in pancreatic resection: A randomized controlled trial.

BACKGROUND: Objectives: We performed a randomized, double-blind, placebo-controlled trial to determine if using Secretin intra-operatively to identify leaks and subsequently target operative intervention would decrease the frequency of clinically significant post-operative pancreatic fistula formation. METHODS: Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to receive intra-operative Secretin or placebo intra-operatively following the completed pancreaticojejunostomy or closure of the cut remnant stump. If a potential leak was identified, targeted therapy with directed suture placement was performed. RESULTS: 170 patients were randomized; 83 receiving placebo and 87 receiving Secretin. The rate of clinically significant fistula formation was 3% (3/87) in the Secretin group and 6% (5/83) in the placebo group (p = 0.489). The rate of biochemical leak was 29% (25/87) in the Secretin group and 19% (16/83) in the placebo group (p = 0.157). There were no Grade C post-operative fistula in either group. Of the 9% of patients in the Secretin group who had a targeted intra-operative intervention, none developed a clinically significant fistula. Adverse events were similar between groups. CONCLUSIONS: Compared to placebo, intra-operative Secretin administration was not associated with an overall reduction in clinically significant pancreatic fistula formation. However, patients with an intra-operative leak identified by Secretin may benefit from intervention (clinicaltrials.gov: NCT02160808).

Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence.

RESEARCH QUESTION: How effective is medical hormonal treatment in preventing endometriosis recurrence and in improving women's clinical symptoms and quality of life? DESIGN: This observational cross-sectional study evaluated the effects of hormonal medical treatment (progestins, gonadotrophin-releasing hormone analogues or continuous oral contraceptives) on endometriosis recurrence, current clinical symptoms and quality of life in three groups of patients: Group A (n = 34), no hormonal treatment either before or after the first endometriosis surgery; Group B (n = 76), on hormonal treatment after the first endometriosis surgery; and Group C (n = 75), on hormonal treatment both before and after the first endometriosis surgery. RESULTS: Group C patients were characterized by a lower rate of endometriosis reoperation (P = 0.011) and a lower rate of dysmenorrhoea (P = 0.006). Women who experienced repetitive endometriosis surgery showed worse physical (P = 0.004) and mental (P = 0.012) status than those who received a single surgery, independent of the treatment. CONCLUSION: Hormonal treatments represent a valid cornerstone of endometriosis management and may be useful as an alternative to surgery, but also before surgery, to plan better, and after surgery in order to reduce the risk of recurrence. Medical counselling is very helpful in choosing the correct and individualized endometriosis treatment. In fact, the gold standard for modern endometriosis management is the individualized approach and surgery should be considered, depending on the clinical situation and a patient's symptoms.

Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy.

This cross-sectional study examined the neurodevelopment of a large, prenatally diagnosed population of boys with 47,XXY; investigated the potentially positive effects of early hormonal therapy (EHT) on language, cognition, and motor in this population; and identified novel at risk biomarkers associated with 47,XXY. Two-hundred and seventy two evaluations were collected from 148 prenatally diagnosed boys with 47,XXY between 0 and 36 months and separated into one of three groups, depending on visit age: Y1 (0-12 months; n = 100), Y2 (13-24 months; n = 90), and Y3 (25-36 months; n = 82). Those who received EHT (administered by 12 months) were further separated (Y1, n = 37; Y2, n = 34; Y3, n = 30). Neurodevelopmental evaluations consisted of Preschool Language Scales, Early Language Milestone Scale, and Bayley Scales of Infant and Toddler Development and evaluated the effect of EHT on auditory comprehension, expressive communication, receptive language, cognition, and motor. EHT was found to be associated with a positive effect within the first year of life in these domains, as well as in the second and third year of life. Additionally, three novel at-risk biomarkers were identified in this cohort: feeding difficulties in infancy, positional torticollis, and the need for orthotics. The positive effects of EHT observed in language, cognition, and motor at variable stages within the first 3 years of life provide additional evidence into the possible efficacy of early biological treatment for boys with 47,XXY to address the neurodevelopmental dysfunction.

Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data.

INTRODUCTION: As far as we know, no studies to date have investigated the psychobiological correlates of sexual distress (SD) nor the impact of hormonal treatment (HT) on SD in transgender persons. AIM: To evaluate the psychobiological correlates of SD and assess the effects of HT on SD in transgender persons without gender-affirming surgery. METHODS: A consecutive series of 301 transgender persons (160 transwomen and 141 transmen) was considered for the cross-sectional study, and a subset of 72 subjects was studied in a 2-year follow-up. A physical examination was performed. Blood samples were drawn for determination of cortisol levels. Subjects completed psychometric measures. During 2 years of HT, the evaluation of SD was prospectively repeated. MAIN OUTCOME MEASURE: Psychobiological correlates of SD in transgender population. Changes in SD during gender affirming hormonal treatment. CLINICAL IMPLICATIONS: Knowing how hormonal treatment influence SD will help care providers when counseling transgender people. STRENGTHS & LIMITATIONS: To the authors' knowledge, this is the first study prospectively evaluating the impact of gender affirming hormonal treatment on sexual distress in transgender individuals. The main limitations are represented by the small size of the sample and the use of questionnaires validated only in the cisgender population. RESULTS: SD showed a positive correlation with body uneasiness (P < .0001) and with dissatisfaction toward gender-related body parts or shapes (all P < .05). In addition, SD correlated positively with general psychopathology (P < .0001), alexithymia, social anxiety, and humiliation scales (all P < .05). In transmen, SD was positively associated with autism levels (P < .005), as well as with cortisol levels (P < .02). A significant correlation between SD and perceived discrimination was observed in transwomen (P < .05). In transwomen, SD was positively associated with hair density and negatively with breast growth (both P < .05). Finally, in transmen, a negative correlation was found between SD and hair density (P < .05). When the impact of HT on SD was evaluated, a significant reduction of SD was observed across time in both transwomen and transmen (P = .001 and P = .01, respectively). CONCLUSIONS: The present results support the efficacy of HT in reducing SD in transgender persons. Ristori J, Cocchetti C, Castellini G, et al. Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med 2020;17:142-151.

Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence.

INTRODUCTION: Several steps in the transitioning process may affect sexual desire in transgender people. This is often underexposed by those providing gender-affirming care. AIM: To prospectively assess sexual desire during the first 3 years of hormonal therapy (HT) in transgender people. METHODS: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence. At baseline, different psychological questionnaires were administered. Sex steroids were measured at each follow-up visit. Data were analyzed cross-sectionally and prospectively. MAIN OUTCOME MEASURE: Prospective analysis of total, dyadic (with another person), and solitary (with oneself) sexual desire in 766 participants (401 transgender women [TW], 364 transgender men [TM]) was carried out using the Sexual Desire Inventory (SDI) questionnaire during a 3-year follow-up period, starting at the initiation of HT. Other factors associated with prospective changes were assessed. RESULTS: In TW, total, dyadic, and solitary SDI scores decreased during the first 3 months of HT. However, after 36 months, total and dyadic SDI scores were higher than baseline scores. Solitary scores after 36 months were comparable with baseline scores. In TM, total, dyadic, and solitary SDI scores increased over the first 3 months, remaining stable thereafter. However, total and dyadic SDI scores after 36 months were comparable with baseline scores, whereas solitary scores remained higher than baseline. Factors associated with a prospective increase in SDI scores included having undergone gonadectomy, no longer experiencing menstrual bleeding or higher gender dysphoria levels at baseline (in TM only). CLINICAL IMPLICATIONS: This study offers clear data on the time course of sexual desire after starting HT and thereby helps to inform people who want to start HT. Transgender people can be informed that changes in sexual desire after initiating HT are temporary. Over a longer period of time, the current research does not suggest induction of hypoactive sexual disorder in TW or long-term increased sexual desire in TM. STRENGTH & LIMITATIONS: Strengths include the prospective design of this large multicentric study, the well-defined cohort, controlling for HT, sex steroids, and other factors. Limitations include performing a data lock, the absence of an objective measure of sexual desire, and the timing of laboratory measurements. CONCLUSION: Gender-affirming HT only induces short-term changes in sexual desire in transgender people. Over a longer period of time, a net increase in dyadic sexual desire in TW receiving feminizing HT and sexual desire scores comparable with baseline in TM receiving virilizing HT, were observed. Defreyne J, Elaut E, Kreukels B, et al. Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence Study. J Sex Med 2020;17:812-825.

Hormone therapy decision-making processes: Transgender youth and parents.

INTRODUCTION: This study explored how transgender (trans) youth and parents of trans youth made decisions around hormone therapy initiation as well as trans youth experiences of barriers to care. METHODS: Participants included 21 trans youth (ages 14-18) and 15 parents of trans youth who resided in British Columbia, Canada. Data for this grounded theory research consisted of transcripts and lifeline drawings collected through semi-structured interviews conducted August 2016 through February 2017. RESULTS: The decision-making processes of youth and of parents are illustrated in three-phase temporal models, starting with discovery, leading to (inter)action while seeking care, and reflection after hormone therapy initiation. Youth who sought hormone therapy were clear about their decision to access this care. Throughout these processes, youth experienced numerous parent- and system-related barriers to care. Youth with the lowest levels of parent support experienced more system barriers, with non-binary/genderfluid youth experiencing greater barriers and less support for hormone therapy than youth with binary genders. A new barrier identified in this study was health care provider imposed requirements for parental involvement and/or approval, which rendered some youth unable access to hormone therapy. CONCLUSIONS: Health care providers should be aware of the deliberation and information-seeking in which youth engage prior to seeking care as well as the temporally misaligned decision-making processes of youth and parents. Understanding the challenges trans youth experience due to insufficient parental support and system barriers can provide important context for health care providers striving to provide accessible, gender-affirming care and decision-making support for trans youth.

Intrauterine CRH-treated PBMC in repeated implantation failure.

BACKGROUND: The intrauterine administration of activated autologous peripheral blood monocytes (PBMC) prior to embryo transfer seems to improve reproductive outcomes in women with repeated implantation failure (RIF). We have previously shown that the intrauterine administration of PBMC treated with corticotropin-releasing hormone (CRH) prior to blastocyst transfer (day 5) improves significantly the clinical pregnancy rate of women with RIF. In the present crossover pilot study, we have investigated whether CRH-PBMC treatment could be of benefit in case of fresh early cleavage stage embryo transfer (day 3) in women with RIF. METHODS: Twenty-six (n = 26) women with at least three previous failed IVF attempts and no history of clinical pregnancy in the past were recruited in this study. Ovarian stimulation was performed following either the long or the short protocol. PBMC were collected during the oocyte retrieval, were treated with CRH, and transferred in the uterine cavity 2 days later. Good quality cleavage stage embryos were transferred at day 3, following oocyte retrieval. RESULTS: Following the intrauterine administration of CRH-treated autologous PBMC, 15/26 clinical pregnancies occurred (57.69%). Compared to the null result of the same women prior to recruitment, this observation was considered significant (P < 10-2 ). CONCLUSION: Our findings further support the role of the intrauterine administration of CRH-treated PBMC as an effective approach when transferring cleavage stage embryos in women with RIF. Prospective randomized studies are needed to clarify whether such intervention could be of benefit in clinical practice.

Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia.

PURPOSE OF REVIEW: New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide. RECENT FINDINGS: Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described. As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.

Glucagon regulation of carbohydrate metabolism in rainbow trout: in vivo glucose fluxes and gene expression.

Glucagon increases fish glycaemia, but how it affects glucose fluxes in vivo has never been characterized. The goal of this study was to test the hypothesis that glucagon stimulates hepatic glucose production (rate of appearance, Ra) and inhibits disposal (rate of disposal, Rd) in rainbow trout. Changes in the mRNA abundance of key proteins involved in glycolysis, gluconeogenesis and glycogen breakdown were also monitored. The results show that glucagon increases glycaemia (+38%) by causing a temporary mismatch between Ra and Rd before the two fluxes converge below baseline (-17%). A novel aspect of the regulation of trout gluconeogenesis is also demonstrated: the completely different effects of glucagon on the expression of three Pepck isoforms (stimulation of pck1, inhibition of pck2a and no response of pck2b). Glycogen phosphorylase was modulated differently among tissues, and muscle upregulated pygb and downregulated pygm Glucagon failed to activate the cAMP-dependent protein kinase or FoxO1 signalling cascades. We conclude that trout hyperglycaemia results from the combination of two responses: (i) an increase in Ra glucose induced by the stimulation of gluconeogenesis through transcriptional activation of pck1 (and possibly glycogen phosphorylase), and (ii) a decrease in Rd glucose via inhibition of glycogen synthase and glycolysis. The observed decrease in glucose fluxes after 4 h of glucagon administration may be caused by a counter-regulatory response of insulin, potentially linked to the decrease in pygm transcript abundance. Overall, however, these integrated effects of glucagon only lead to modest changes in glucose fluxes that partly explain why trout seem to be unable to control glycaemia very tightly.

Gender-Affirming Hormone Treatment Induces Facial Feminization in Transwomen and Masculinization in Transmen: Quantification by 3D Scanning and Patient-Reported Outcome Measures.

INTRODUCTION: Hormone treatment induces feminization of the body in transwomen and masculinization in transmen. However, the effect of hormone treatment on facial characteristics is still unknown. AIM: We aimed to study whether hormone treatment induces facial feminization and masculinization and how this potential change affects satisfaction and self-esteem. METHODS: In this single-center cohort study, we included 27 transwomen and 15 transmen who received standardized hormone treatment in the Center of Expertise on Gender Dysphoria, VU University Medical Center Amsterdam. Facial 3-dimensional images were obtained at baseline and at 3 and 12 months. At each image, 22 facial landmarks were placed. Furthermore, the FACE-Q Satisfaction with Facial Appearance Overall and the Rosenberg self-esteem scale were obtained at the same measurement points. MAIN OUTCOME MEASURES: The main outcome measures included the relative local shift of skin in millimeters in the 22 landmarks in the transverse (x-axis), coronal (y-axis), and sagittal (z-axis) anatomic axes, the color maps, and the outcomes of the questionnaires. RESULTS: After 12 months, cheek tissue in transwomen increased, with 0.50 mm (95% CI 0.04-0.96) in the x-axis and 1.08 mm (95% CI 0.31-1.85) in the z-axis. Tissue in the jaws decreased with -0.60 mm (95% CI -1.28-0.08) in the x-axis and -0.18 mm (95% CI -0.03-0.33) in the y-axis. Cheek tissue in transmen decreased with -0.45 mm (95% CI -1.00-0.11) in the x-axis and -0.84 mm (95% CI -1.92-0.25) in the z-axis. These changes already started after 3 months. An increase in satisfaction with the facial appearance was found in both transwomen and transmen. There were no changes in reported self-esteem. CLINICAL IMPLICATION: These results could lead to more realistic expectations of facial changes. Furthermore, our results suggest that the face continues to change for at least a year, which could suggest that performing facial feminization surgery after 1 year of hormone treatment might be too early. STRENGTH & LIMITATIONS: This study is the first that provides insight into the facial changes in transgender individuals receiving hormone treatment, and it introduces an objective method to examine (small) facial changes. Our study is limited by the poor reliability of the landmarks, the difficulty of facial fixation, and the lack of gender-specific questions in the questionnaires. CONCLUSIONS: Hormone treatment in transwomen induces an increase in cheek tissue and a decrease in jaw tissue. In transmen a tendency of decrease in cheek tissue and an increase in jaw tissue was found. These changes are in the direction of the desired gender. Tebbens M, Nota NM, Liberton NPTJ, et al. Gender-Affirming Hormone Treatment Induces Facial Feminization in Transwomen and Masculinization in Transmen: Quantification by 3D Scanning and Patient-Reported Outcome Measures. J Sex Med 2019;16:746-754.

Increment of plasma glucose by exogenous glucagon is associated with present and future renal function in type 2 diabetes:a retrospective study from glucagon stimulation test.

BACKGROUND: Glucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs. METHODS: A total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE). RESULTS: In correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease. CONCLUSION: Our results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.

Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning.

BACKGROUND: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study. METHODS: In this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18-50 years old, males, with BMI 20-30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT. RESULTS: Responses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 µg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1-38.1) vs 4.80 (0.33-27.36) µg/L; p = 0.015], and prolactin [24.3 (10.5-67.45) vs 10.50 (6.21-43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL. CONCLUSIONS: We found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of "hormonal conditioning" in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.

Glucose and insulin response after intravenous and subcutaneous somatostatin administration in healthy horses.

Equine metabolic syndrome (EMS) is prevalent in the equine population, and somatostatin analogs might be useful for diagnosis and/or treatment of EMS in horses. The purpose of this study was to evaluate the glucose and insulin responses to subcutaneous and intravenous administration of somatostatin. Six healthy research horses were included in this prospective study. An initial pilot study was performed to assess several different doses (10-22 µg/kg [4.5-10 µg/lb]) in two horses, then a final dosage of 22 µg/kg (10 µg/lb) was administered to six horses IV and SQ in a two-period randomized cross-over study performed over a 3-month study period. Blood samples were collected for measurement of plasma insulin and glucose concentrations during a 24-hr study period. Both IV and SQ somatostatin resulted in decreased insulin and increased glucose concentrations. SQ somatostatin resulted in a longer clinical effect, with return to baseline insulin occurring at 1.5 hr postadministration, versus 45 min for IV. Both IV and SQ administration of somatostatin to normal horses resulted in decreased insulin and increased glucose concentrations, likely due to suppression of insulin secretion by somatostatin. A more prolonged effect was seen following SQ administration as compared to IV administration, and no adverse effects were noted at varying doses. This study provides additional information regarding the effect of somatostatin administration on insulin and glucose concentrations in clinically healthy horses.

Animal Models for Human Polycystic Ovary Syndrome (PCOS) Focused on the Use of Indirect Hormonal Perturbations: A Review of the Literature.

Hormonal disturbances, such as hyperandrogenism, are considered important for developing polycystic ovary syndrome (PCOS) in humans. Accordingly, directly hormone-regulated animal models are widely used for studying PCOS, as they replicate several key PCOS features. However, the pathogenesis and treatment of PCOS are still unclear. In this review, we aimed to investigate animal PCOS models and PCOS-like phenotypes in animal experiments without direct hormonal interventions and determine the underlying mechanisms for a better understanding of PCOS. We summarized animal PCOS models that used indirect hormonal interventions and suggested or discussed pathogenesis of PCOS-like features in animals and PCOS-like phenotypes generated in other animals. We presented integrated physiological insights and shared cellular pathways underlying the pathogenesis of PCOS in reviewed animal models. Our review indicates that the hormonal and metabolic changes could be due to molecular dysregulations, such as upregulated PI3K-Akt and extracellular signal-regulated kinase (ERK) signalling, that potentially cause PCOS-like phenotypes in the animal models. This review will be helpful for considering alternative animal PCOS models to determine the cellular/molecular mechanisms underlying PCOS symptoms. The efforts to determine the specific cellular mechanisms of PCOS will contribute to novel treatments and control methods for this complex syndrome.

Intranasal Glucagon.

Glucagon is an essential drug, used for the management of hypoglycaemia. Currently available injectable preparations are cumbersome, difficult to use and not easily acceptable by many patients. Injection glucagon is also not available in all parts of the world. Intranasal glucagon offers a novel, effective and convenient mode of delivery of this emergency drug. This review covers the basic and clinical pharmacology of nasal glucagon, and describes its potential use in practice.

The Medico-Legal 'Making' of 'The Transgender Child'.

Thirty years ago, the transgender child would have made no sense to the general public, nor to young people. Today, children and adolescents declare themselves transgender, the National Health Service diagnoses 'gender dysphoria', and laws and policy are developed which uphold young people's 'choice' to transition and to authorize stages at which medical intervention is permissible and desirable. The figure of the 'transgender child' presumed by medicine and law is not a naturally occurring category of person external to medical diagnosis and legal protection. Medicine and law construct the 'transgender child' rather than that the 'transgender child' exists independently of medico-legal discourse. The ethical issue of whether the child and young person can 'consent' to social and medical transition goes beyond legal assessment of whether a person under16 years has the mental capacity to consent, understand to what s/he is consenting, and can express independent wishes. It shifts to examination of the recent making of 'the transgender child' through the complex of power/knowledge/ethics of medicine and the law of which the child can have no knowledge but within which its own desires are both constrained and incited.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis.

AIM: To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM). METHODS: Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or ≥1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and >2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of ≥3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR) RESULTS: Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P<0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by >10% and the physician global by >40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features. CONCLUSION: Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. TRIAL REGISTRATION NUMBER: NCT01906372; Results.