Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women's Endocrinology.

PURPOSE: To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. METHODS: A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. RESULTS: A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. CONCLUSION: This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.

Pseudohyperaldosteronism Due to Licorice: A Practice-Based Learning from a Case Series.

Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs.

Turner Syndrome: Pitfalls of Transition from Paediatric to Adult Health Care.

BACKGROUND: Turner Syndrome (TS) is a rare condition in females, characterized by complete or partial loss of one X chromosome, often in mosaic karyotypes. It is associated with a wide spectrum of health problems across the age span, which requires particular attention during the transition from childhood to adult age. OBJECTIVE: The aim of this study was to assess in a consecutive sample of TS patients the clinical, biochemical, and instrumental changes during the first period after the transition from paediatric to adult care. METHODS: Sixteen patients with TS were enrolled: 9 with the karyotype 45, X0 and 7 with a mosaic karyotype. Patients' clinical information was obtained from the management software of the Hospital of Padua. RESULTS: The median age for transition was 18 years. All patients received an appointment in adult clinics after the last visit with the paediatrician, however, 9 patients dropped out of followup by delaying the appointment by 1-2 years. After an average follow-up of 54±36.7 months, all patients presented a significant reduction in the values of insulinemia, HOMA index and HbA1c. Lumbar and proximal femur Z-score values improved, and the prevalence of overweight was reduced among patients on sex hormone replacement therapy for at least four years. CONCLUSIONS: This study confirms the necessity of a structured plan from paediatric to adult care for TS patients to avoid the risk of dropping out of the transition and future follow-up. A periodic monitoring protocol may guarantee an early detection and an effective correction of health complications associated with TS.

Transition from pediatrics to adult health care in girls with turner syndrome.

INTRODUCTION: Turner Syndrome is a rare condition secondary to a complete or partial loss of one X chromosome, leading to a wide spectrum of clinical manifestations. Short stature, gonadal dysgenesis, cardiovascular malformations, and dysmorphic features characterize its common clinical picture. AREAS COVERED: The main endocrine challenges in adolescent girls with Turner Syndrome are puberty induction (closely intertwined with growth) and fertility preservation. We discuss the most important clinical aspects that should be faced when planning an appropriate and seamless transition for girls with Turner Syndrome. EXPERT OPINION: Adolescence is a complex time for girls and boys: the passage to young adulthood is characterized by changes in the social, emotional, and educational environment. Adolescence is the ideal time to encourage the development of independent self-care behaviors and to make the growing girl aware of her health, thus promoting healthy lifestyle behaviors. During adulthood, diet and exercise are of utmost importance to manage some of the common complications that can emerge with aging. All clinicians involved in the multidisciplinary team must consider that transition is more than hormone replacement therapy: transition in a modern Healthcare Provider is a proactive process, shared between pediatric and adult endocrinologists.

First Evidence of Mineralocorticoid Receptor Gene and Protein Expression in Rat and Human Thyroid Tissues and Cell Cultures.

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue.

Heat inactivation of SARS-CoV 2 enabled the measurement of salivary cortisol during COVID-19 pandemic.

BACKGROUND AND AIM: Salivary cortisol has become an essential tool in the management of cortisol-related disease. In 2020 the sudden outbreak of COVID-19 pandemic caused several concerns about the use of saliva, due to the risk of contamination, and a European consensus further discourage using salivary cortisol. To decrease infectious risk, we handled specimens by applying a heat treatment to inactivate viral particles, further evaluating the impact of the COVID-19 pandemic on the use of salivary cortisol in clinical practice. MATERIAL AND METHODS: Saliva samples were exposed for 10 min at 70 °C, then cortisol was measured using LC-MS/MS. The number of salivary cortisol examinations from 2013 to 2022 was extracted from the local electronic database: those performed in 2019, 2020, and 2021 were analyzed and compared with the historical data. RESULTS: During 2020 we observed a decrease of 408 (-20%) examinations (p = 0.05) compared to 2019; especially in salivary cortisol daily rhythm and salivary cortisol/cortisone ratio (respectively reduction of 47% and 88%, p = 0.003 and p = 0.001). Analyzing year 2021 compared with 2020 we reported an increase of 420 examinations (+20%, p = 0.01), with a complete recovery of salivary cortisol measurement (considering 2019: p = 0.71). Major differences were observed between morning salivary cortisol (-20%, p = 0.017), LNSC (-21%, p = 0.012) and salivary cortisol rhythm (-22%, p = 0.056). No Sars-Cov2 infections related to working exposure were reported among laboratory's employers. CONCLUSIONS: We speculate that the adoption of an appropriate technique to inactivate viral particles in saliva specimens allowed the safety maintenance of salivary collections, also during the Sars-CoV-2 outbreak.

Fertility preservation in pregnant cancer patients after first-trimester abortion: a new challenge with possible solutions.

Fertility preservation in pregnant women recently diagnosed with cancer can be a challenge. Raised levels of human chorionic gonadotropin (Beta-hCG) and progesterone in this population of patients may pose a problem for the prompt initiation of controlled ovarian stimulation (COS) due to a potential negative feedback of these hormones on folliculogenesis; however, it is not feasible to wait for negativization of serum beta-hCG levels before starting controlled ovarian stimulation. In literature, very few cases have been reported regarding the preservation of fertility in pregnant women recently diagnosed with cancer. We performed an extended revision of the literature to evaluate the current knowledge of the management of fertility preservation in women with cancer and we examined two cases closely. The first case study involved a cancer patient who underwent surgical abortion at 6.5 weeks of gestation followed by administration of mifepristone to detach any minimal residual trophoblast and consequently to decrease serum beta-hCG and progesterone levels before starting COS. In the second case study, the cancer patient underwent surgical abortion at 7.1 weeks of gestation and simultaneous unilateral oophorectomy for ovarian tissue cryopreservation due to a limited time for COS. By analyzing the results of these studies, it could be hypothesized that mifepristone administration may favor the decrease of serum beta-hCG and progesterone levels in order to permit rapid initiation of COS. In cases where COS is not feasible, ovarian tissue cryopreservation should be considered as an alternative fertility preservation technique.

Ketosis-prone Diabetes and Hypogonadism: A New Clinical Association to be Aware of ?

BACKGROUND: Ketosis-prone diabetes (KPD) is an emerging entity, sharing features of both type 1 diabetes mellitus and type 2 diabetes mellitus. Patients with KPD usually present with diabetic ketoacidosis without the classic phenotype of autoimmune type 1 diabetes. In most cases, they are Afro-American adults, who require insulin therapy for the management of acute decompensation, then usually encountering insulin-free remission for prolonged periods of time with diet or with non-insulin agents. Meanwhile, hypogonadism is a known condition that could be associated with higher risk of developing both type 1 and type 2 diabetes and could be a risk factor for decompensated diabetes. The association of KPD and hypogonadism is reported for the first time in literature. CASE PRESENTATION: Here we report two peculiar cases of young African patients, affected by KPD and hypergonadotropic hypogonadism, respectively Klinefelter's syndrome and primary ovarian failure. Both patients were treated promptly for the ketoacidosis with intravenous fluids combined with continuous insulin infusion, and then switched to subcutaneous regimen. After the correct clinical evaluation, oral antidiabetic drugs were added. CONCLUSION: KPD remains an under-recognized and under-diagnosed type of diabetes. As hypogonadism is strongly linked to dysmetabolic disorders, the evaluation of sex hormones should be performed at the onset of diabetes. Further studies should investigate the hypothalamic-pituitary-gonadal axis and its role in the development of KDP and its manifestations and complications.

Therapeutic Plasma Exchange for the Treatment of Hyperthyroidism: Approach to the Patient with Thyrotoxicosis or Antithyroid-Drugs Induced Agranulocytosis.

Primary hyperthyroidism is an endocrine disorder characterized by excessive thyroid hormone synthesis and secretion by the thyroid gland. Clinical manifestations of hyperthyroidism can vary from subclinical to overt forms. In rare cases, hyperthyroidism may represent a clinical emergency, requiring admission to an intensive care unit due to an acute and severe exacerbation of thyrotoxicosis, known as a thyroid storm. First-line treatment of hyperthyroidism is almost always based on medical therapy (with thioamides, beta-adrenergic blocking agents, glucocorticoids), radioactive iodine or total thyroidectomy, tailored to the patient's diagnosis. In cases of failure/intolerance/adverse events or contraindication to these therapies, as well as in life-threatening situations, including a thyroid storm, it is necessary to consider an alternative treatment with extracorporeal systems, such as therapeutic plasma exchange (TPE). This approach can promptly resolve severe conditions by removing circulating thyroid hormones. Here we described two different applications of TPE in clinical practice: the first case is an example of thyrotoxicosis due to amiodarone treatment, while the second one is an example of a severe adverse event to antithyroid drugs (agranulocytosis induced by methimazole).

Long-Lasting Effects of Spironolactone after its Withdrawal in Patients with Hyperandrogenic Skin Disorders.

OBJECTIVE: Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. METHODS: Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. RESULTS: After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. CONCLUSION: Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

Imaging or Adrenal Vein Sampling Approach in Primary Aldosteronism? A Patient-Based Approach.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, associated with an increased risk of cardiovascular and cerebral disease, compared to essential hypertension. Therefore, it is mandatory to promptly recognize the disease and offer to the patient the correct diagnostic-therapeutic process in order to reduce new-onset cardiovascular events. It is fundamental to define subtype classification (unilateral or bilateral disease), in order to provide the best treatment (surgery for unilateral and medical treatment for bilateral disease). Here, we report five clinical cases of different subtypes of PA (patients with monolateral or bilateral PA, nondiagnostic AVS, allergy to iodinated contrast, and patients not suitable for surgery), with particular attention to the diagnostic-therapeutic process and the different approaches tailored to a single case. Since PA is a spectrum of various diseases, it needs a personalized diagnostic-therapeutic process, customized for the individual patient, depending on previous medical history, suitability for the surgery and patient's preferences.

Serological Evidence and Self-reported Outcomes in Patients with Adrenal Insufficiency during the first waves of COVID-19 in the North-East Italy.

OBJECTIVE: COVID-19 is a potentially serious new infection firstly broken out in the North East Italy during Spring 2020. Patients with adrenal insufficiency (AI) have a known increased risk of infections, that could precipitate to adrenal crisis. Even COVID-19-related psycho-social impact could affect their health, requiring a dynamic adaptation of daily glucocorticoid (GC) therapy. The aim of this study was to evaluate the incidence of COVID-19 infection and self-reported outcomes in AI patients after the first pandemic waves. METHODS: Open-label, cross-sectional monocentric study on 84 (65 primary, 19 secondary) AI patients, resident in Veneto and followed-up in our out clinical of Endocrine Unit. All patients underwent serological investigation of anti-SARS-CoV2 IgG and purpose-built "ADDI-COVID" questionnaire by August 2020 and were recontacted to reevaluate COVID-19 infection occurrence in March-April 2021. RESULTS: All patients resulted negative to the serological test for anti-SARS-CoV2 IgG at the end of the first pandemic wave. After the third wave, COVID-19 infection occurred in 8 patients without need of hospitalization. Half patients felt an increased risk of COVID-19 infection, significantly associated with increased stress and GC stress-dose. Only one patient reported adrenal crisis stress-correlated. The majority of AI workers changed working habits, significantly reducing COVID-19-related stress. CONCLUSION: AI patients did not show an increased incidence of COVID-19, but the perception of increased COVID-19 infection risk significantly impacts their psychological well-being, working habits and GC daily doses. Therapeutic patient education is crucial especially for AI workers to prevent and treat situations that could lead to an adrenal crisis.

TSH-receptor autoantibodies in patients with chronic thyroiditis and hypothyroidism.

OBJECTIVES: The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases. METHODS: The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR. RESULTS: TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16-45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients. CONCLUSIONS: TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease.

Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism.

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens.