The interlink between thyroid autoimmunity and type 1 diabetes and the impact on male and female fertility.

The aim of this review is to discuss the several interconnections between thyroid autoimmunity and type 1 diabetes in terms of epidemiology, immunoserology, genetic predisposition, and pathogenic mechanisms. We will also analyze the impact of these conditions on both male and female fertility. A literature search was carried out using the MEDLINE/PubMed, Scopus, Google Scholar, ResearchGate, and Clinical Trials Registry databases with a combination of keywords. It was found that the prevalence of thyroid autoantibodies in individuals with type 1 diabetes (T1DM) varied in different countries and ethnic groups from 7 to 35% in both sexes. There are several types of autoantibodies responsible for the immunoserological presentation of autoimmune thyroid diseases (AITDs) which can be either stimulating or inhibiting, which results in AITD being in the plus phase (thyrotoxicosis) or the minus phase (hypothyroidism). Different types of immune cells such as T cells, B cells, natural killer (NK) cells, antigen presenting cells (APCs), and other innate immune cells participate in the damage of the beta cells of the islets of Langerhans, which inevitably leads to T1D. Multiple genetic and environmental factors found in variable combinations are involved in the pathogenesis of AITD and T1D. In conclusion, although it is now well-known that both diabetes and thyroid diseases can affect fertility, only a few data are available on possible effects of autoimmune conditions. Recent findings nevertheless point to the importance of screening patients with immunologic infertility for AITDs and T1D, and vice versa.

Prevalence and Clinical Management of Adrenal Tumour-Related Hyperandrogenism: A Narrative Review.

Hyperandrogenism is a condition in which the levels of androgen hormones in the blood are significantly increased and could be of an adrenal or ovarian origin. The adrenal androgens, normally secreted by the zona reticularis, are steroid hormones with weak androgen activity. The causes of hyperandrogenism are diverse and could be endogenous and exogenous. Androgen excess affecting different tissues and organs results in clinical features such as acne, hirsutism, virilization, and reproductive dysfunction such as oligomenorrhoea/amenorrhoea. Although androgen excess is rarely associated with adrenal tumours, it is important as it could be predictive of malignancy. A careful evaluation of the androgen pattern, also in patients with clear signs of hyperandrogenism, could be useful. Laboratory evaluation should focus on measuring total testosterone levels, followed by the estimation of other androgens such as dehydroepiandrosterone and androstenedione, and using visualisation procedures in the further management. The treatment of adrenal hyperandrogenism is eminently surgical, in consideration of the frequent malignant origin. The aim of this review is to elaborate and summarize the prevalence and clinical management of hyperandrogenism of an adrenal origin by describing the physiological mechanisms of adrenal androgen steroidogenesis, the clinical manifestations of hyperandrogenism with a special reference to hyperandrogenism in adrenal adenomas and carcinomas, and the diagnostic methods that will lead us to establishing the correct diagnosis and different treatment options to manage this condition according to the clinical presentation of the patient.

Secondary vs. primary pituitary xanthogranulomas: which yellow is more mellow?

Pituitary xanthogranulomatomas (XG) are a rare pathological entity caused by accumulation of lipid laden macrophages and reactive granuloma formation usually triggered by cystic fluid leakage or hemorrhage. Our aim was to compare clinical characteristics and presenting features of patients with secondary etiology of XG and those with no identifiable founding lesion (primary -"pure" XG) in order to gain new insights into this rare pituitary pathology. In a retrospective review of 714 patients operated for sellar masses, at tertiary center, we identified 16 (2.24%) with histologically confirmed diagnosis of pituitary XG over the period of 7 years (2015-2021). Patients were further analyzed according to XG etiology: "pure"- XG (n = 8) with no identifiable founding lesion were compared to those with histological elements of pituitary tumor or cyst - secondary XG (n = 8). We identified 16 patients (11 male), mean age 44.8 ± 22.3 years, diagnosed with pituitary XG. Secondary forms were associated with Ratke's cleft cyst (RCC, n = 2) and pituitary adenoma (PA, n = 6). The most common presenting features in both groups were hypopituitarism (75%), headache (68.5%) and visual disturbances (37.5%). Predominance of male sex was noted (males 68.75%, females 31.25%), especially in patients with primary forms. Patients with primary pituitary XG were all males (p = 0.0256) and more frequently affected by panhypopituitarism (87.5% vs. 25%, p = 0.0406) compared to patients with secondary causes. Hyperprolactinemia was noted in pituitary tumor group with secondary etiology only (p = 0.0769). Majority of lesions were solid on magnetic resonance imaging - MRI (81.25%). Distinct clinical phenotype was observed dependent on the etiology of XG.

Pregnancy outcomes and newborn characteristics in women with follicular fluid thyroid autoantibodies undergoing assisted reproduction.

Background: Higher levels of thyroid autoantibodies in follicular fluid (FF) of thyroid autoimmunity (TAI) positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development. Literature highlights that levothyroxine (LT4) treatment may attenuate the risk of adverse pregnancy outcomes. The aim of the study was to estimate the pregnancy and newborn outcomes in women with FF thyroid autoantibodies undergoing assisted reproductive technology (ART). Methods: The study population included 24 women with confirmed clinical pregnancy, 8 TAI positive and 16 TAI negative women. LT4 supplementation was applied in 20.8% patients, TAI positive. Results: Pregnancy outcomes were: twin pregnancy rate 41.7%, early miscarriage rate 8.3%, late miscarriage rate 4.2%, preterm birth rate 16.7%, term birth rate 70.8%, live birth rate 96.0%. There was significant difference in serum and in FF TgAbs (p< 0.001)between the groups according to TAI, while serum fT3 was lower in the group with TAI (p = 0.047). Serum P4 was higher in LT4 treated group (p = 0.005), with TAI, and newborns in this group had higher birth weight (p = 0.001) and height (p = 0.008). Maternal complications occurred in 23.8% of patients. No congenital malformations in newborns were noted. Conclusions: Thyroid autoantibodies present in FF may have an effect on the post-implantation embryo development, but have no effect on further course of pregnancy. The special benefit of LT4 treatment for successful ART outcome was demonstrated for newborn anthropometric parameters.

Climate Variables Related to the Incidence of Human Leishmaniosis in Montenegro in Southeastern Europe during Seven Decades (1945-2014).

Leishmaniosis (or leishmaniasis) is a neglected parasitosis most commonly transmitted by the sandfly bite. Changes in temperature, precipitation, and humidity can greatly affect the vectors and reservoir hosts. This study aimed to determine the association between temperature, air humidity, and weather conditions with the incidence of leishmaniasis in Montenegro during a seven-decade period (1945-2014) and to statistically compare and correlate the obtained data. In the studied period, there were 165 registered cases of leishmaniosis, 96.4%, in the coastal and central region of Montenegro, with an average incidence rate of 0.45/100.000. The visceral form of leishmaniosis predominated (99% of the cases), with only one case of cutaneous disease. Climate factors (average temperature, air humidity, and precipitation) had an impact on the occurrence of leishmaniosis in Montenegro. Air temperature elevated by 1 °C in all regions of Montenegro was significantly correlated with an increased incidence of leishmaniosis, by 0.150 (0.013 to 0.287; p < 0.05). In order to improve prevention and control of this disease, it is also necessary to investigate other factors with a possible impact on the number of cases of this neglected parasitosis.

Female infertility in the era of obesity: The clash of two pandemics or inevitable consequence?

Obesity is an epidemic that has led to a rise in the incidence of many comorbidities: among others, reduced fertility is often under-evaluated in clinical practice. The mechanisms underlying the link between reduced fertility and obesity are numerous, with insulin resistance, hyperglycaemia and the frequent coexistence of polycystic ovary syndrome being the most acknowledged. However, several other factors concur, such as gut microbiome alterations, low-grade chronic inflammation and oxidative stress. Not only do women with obesity take longer to conceive, but in vitro fertilization (IVF) is also less likely to succeed. We herein provide an updated state-of-the-art regarding the molecular bases of what we could define as dysmetabolic infertility, focusing on the clinical aspects, as well as possible treatment.

The Future Is Coming: Artificial Intelligence in the Treatment of Infertility Could Improve Assisted Reproduction Outcomes-The Value of Regulatory Frameworks.

Infertility is a global health issue affecting women and men of reproductive age with increasing incidence worldwide, in part due to greater awareness and better diagnosis. Assisted reproduction technologies (ART) are considered the ultimate step in the treatment of infertility. Recently, artificial intelligence (AI) has been progressively used in the many fields of medicine, integrating knowledge and computer science through machine learning algorithms. AI has the potential to improve infertility diagnosis and ART outcomes estimated as pregnancy and/or live birth rate, especially with recurrent ART failure. A broad-ranging review has been conducted, focusing on clinical AI applications up until September 2022, which could be estimated in terms of possible applications, such as ultrasound monitoring of folliculogenesis, endometrial receptivity, embryo selection based on quality and viability, and prediction of post implantation embryo development, in order to eliminate potential contributing risk factors. Oocyte morphology assessment is highly relevant in terms of successful fertilization rate, as well as during oocyte freezing for fertility preservation, and substantially valuable in oocyte donation cycles. AI has great implications in the assessment of male infertility, with computerised semen analysis systems already in use and a broad spectrum of possible AI-based applications in environmental and lifestyle evaluation to predict semen quality. In addition, considerable progress has been made in terms of harnessing AI in cases of idiopathic infertility, to improve the stratification of infertile/fertile couples based on their biological and clinical signatures. With AI as a very powerful tool of the future, our review is meant to summarise current AI applications and investigations in contemporary reproduction medicine, mainly focusing on the nonsurgical aspects of it; in addition, the authors have briefly explored the frames of reference and guiding principles for the definition and implementation of legal, regulatory, and ethical standards for AI in healthcare.

The Role of Cell and Gene Therapies in the Treatment of Infertility in Patients with Thyroid Autoimmunity.

There is a rising incidence of infertility worldwide, and many couples experience difficulties conceiving nowadays. Thyroid autoimmunity (TAI) is recognized as one of the major female infertility causes related to a diminished ovarian reserve and potentially impaired oocyte maturation and embryo development, causing adverse pregnancy outcomes. Growing evidence has highlighted its impact on spontaneously achieved pregnancy and pregnancy achieved by in vitro fertilization. Despite the influence of thyroid hormones on the male reproductive system, there is insufficient data on the association between TAI and male infertility. In past years, significant progress has been achieved in cell and gene therapies as emerging treatment options for infertility. Cell therapies utilize living cells to restore healthy tissue microenvironment and homeostasis and usually involve platelet-rich plasma and various stem cells. Using stem cells as therapeutic agents has many advantages, including simple sampling, abundant sources, poor immunogenicity, and elimination of ethical concerns. Mesenchymal Stem Cells (MSCs) represent a heterogeneous fraction of self-renewal, multipotent non-hematopoietic stem cells that display profound immunomodulatory and immunosuppressive features and promising therapeutic effects. Infertility has a genetic component in about half of all cases, although most of its genetic causes are still unknown. Hence, it is essential to identify genes involved in meiosis, DNA repair, ovarian development, steroidogenesis, and folliculogenesis, as well as those involved in spermatogenesis in order to develop potential gene therapies for infertility. Despite advances in therapy approaches such as biological agents, autoimmune disorders remain impossible to cure. Recent research demonstrates the remarkable therapeutic effectiveness of MSCs in a wide array of autoimmune diseases. TAI is one of many autoimmune disorders that can benefit from the use of MSCs, which can be derived from bone marrow and adipose tissue. Cell and gene therapies hold great potential for treating autoimmune conditions, although further research is still needed.

Primary hyperparathyroidism associated with acquired long QT interval and ventricular tachycardia.

SUMMARY: We present a 54-year-old patient admitted to the emergency department due to loss of consciousness. The initial ECG registered monomorphic ventricular extrasystoles and prolonged QT interval (QT corrected (QTc) >500 ms). Sustained ventricular tachycardia (VT) was registered on 24-h Holter ECG monitoring, which clinically was presented as a crisis of consciousness. Coronary angiography and other visualization methods were normal. Implantable cardioverter-defibrillator (ICD) implantation was planned for the purpose of secondary prevention of sudden cardiac death (SCD). Laboratory and hormonal analyzes revealed primary hyperparathyroidism (PHPT), chronic kidney disease, and hypokalemia. Neck ultrasound showed a 25 mm, sharply outlined homogenous tumor mass which was separated from thyroid gland (TG) and exerted a mild impression on lower parts of the left lobe. Dual wash technetium-99m sestamibi parathyroid scintigraphy with single-photon emission CT (SPECT)/CT also showed the uptake of tracer behind the lower half of the left lobe of the TG. Surgical treatment, lower left parathyroidectomy, was performed, and pathohistological analysis verified parathyroid adenoma. The patient was rhythmically and hemodynamically stable for 7 days after surgery, without additional complaints, and was discharged from the hospital. Timely diagnosis of PHPT, correct assessment and surgical treatment, did not lead our patient to unnecessary ICD implantation. Our case suggests an additional intertwining of electrolyte disorders and ventricular arrhythmias in PHPT and more importantly emphasizes the need for caution when indicating ICD, even in patients with the most serious life-threatening arrhythmias. LEARNING POINTS: Electrolyte abnormalities in PHPT can have highly malignant consequences, and the occurrence of hypokalemia in the presence of hypercalcemia is underestimated in PHPT, and the consequences can be life-threatening. Although hypercalcemia causes shortened QT interval, concomitant severe hypokalemia may overcome hypercalcemia and prolong QT interval, even in the absence of structural heart disease or LQTS. Timely diagnosis of PHPT, correct assessment and surgical treatment, do not lead to unnecessary ICD implantation.

Weight-centric pharmacological management of type 2 diabetes mellitus - An essential component of cardiovascular disease prevention.

Obesity and overweight are contributing factors for diseases such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and ultimately, cardiovascular (CV) disease. Obesity is imposing an increasing health burden in rich and poor nations, with almost 30% of people globally now either obese or overweight - a staggering 2.1 billion. The link between obesity and T2DM is widely held to involve two adverse effects: obesity-induced insulin resistance and ß-cell failure. This "unified field theory" raises questions about whether defects favoring progressive weight gain and metabolic impairment also contribute to ß-cell decompensation. The concept of weight-centric management of T2DM is considered justified because of the strong negative impact of obesity on the effects of treatment of diabetes. Two pharmacotherapy options are considered: drugs developed primarily for blood glucose control that also exert a favorable effect on body weight and drugs developed primarily to induce weight loss that also have a favorable effect on glycemia. Treating hunger counter-regulatory mechanisms will have an additional effect on glucose control in T2DM. This narrative review addresses advances in pharmacotherapy for the management of obesity and obesity-related co-morbidities, with a focus on T2DM. It is also important to identify the correct balance between weight-centric and glucose-centric management of T2DM.

Gaucher disease in Montenegro - genotype/phenotype correlations: Five cases report.

BACKGROUND: The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD. CASES SUMMARY: Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient). CONCLUSION: The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.

Influenza surveillance: determining the epidemic threshold for influenza by using the Moving Epidemic Method (MEM), Montenegro, 2010/11 to 2017/18 influenza seasons.

BACKGROUND: In 2009, an improved influenza surveillance system was implemented and weekly reporting to the World Health Organization on influenza-like illness (ILI) began. The goals of the surveillance system are to monitor and analyse the intensity of influenza activity, to provide timely information about circulating strains and to help in establishing preventive and control measures. In addition, the system is useful for comparative analysis of influenza data from Montenegro with other countries. AIM: We aimed to evaluate the performance and usefulness of the Moving Epidemic Method (MEM), for use in the influenza surveillance system in Montenegro. METHODS: Historical ILI data from 2010/11 to 2017/18 influenza seasons were modelled with MEM. Epidemic threshold for Montenegro 2017/18 season was calculated using incidence rates from 2010/11-2016/17 influenza seasons. RESULTS: Pre-epidemic ILI threshold per 100,000 population was 19.23, while the post-epidemic threshold was 17.55. Using MEM, we identified an epidemic of 10 weeks' duration. The sensitivity of the MEM epidemic threshold in Montenegro was 89% and the warning signal specificity was 99%. CONCLUSIONS: Our study marks the first attempt to determine the pre/post-epidemic threshold values for the epidemic period in Montenegro. The findings will allow a more detailed examination of the influenza-related epidemiological situation, timely detection of epidemic and contribute to the development of more efficient measures for disease prevention and control aimed at reducing the influenza-associated morbidity and mortality.

Etanercept in the treatment of Graves' ophthalmopathy with primary hypothyroidism and rheumatoid arthritis.

Graves' ophthalmopathy (GO) is an autoimmune disease affecting ocular and orbital tissues. Overproduction of tumor necrosis factor α (TNF-α) in rheumatoid arthritis (RA) and GO has destructive consequences. The subject of this paper is a case of a female patient initially diagnosed with primary hypothyroidism substitution with levothyroxine, and subsequent diagnosis of RA with insufficient therapeutic efficacy of a standard medication. Three years later, the patient presented symptoms and signs of GO. Etanercept was administrated for RA, and after four months, an improvement of the eye symptoms and reduced exophthalmos were observed and confirmed using visual methods. Graves' ophthalmopathy association with primary hypothyroidism is uncommon. The treatment of RA using etanercept led to clinical improvement of GO symptoms, which indicates that RA and GO may share similar pathogenic features. The paper suggests that etanercept may suppress the symptoms and clinical signs of GO. However, controlled trials are needed to further evaluate the effect of TNF-α inhibitors, particularly etanercept, and to compare its side effects with the current options for medical treatment.

Follicular fluid thyroid autoantibodies, thyrotropin, free thyroxine levels and assisted reproductive technology outcome.

OBJECTIVE: Although there are substantial data linking thyroid autoimmunity (TAI) and infertility, data regarding assisted reproductive technology (ART) outcomes and TAI markers in follicular fluid (FF) of women undergoing ART are scarce. Objective of the study was to assess the association of the levels of thyroid autoantibodies in FF and ART outcome expressed as the achieved pregnancies. METHODS: This study enrolled 52 women undergoing ART (26 TAI positive subjects and 26 age and body mass index matched TAI negative controls). Blood samples were drawn before the initiation of protocol for controlled ovarian stimulation, and thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) levels were measured. TSH, fT4, TPOAbs, TgAbs and progesterone levels were also measured in FF. RESULTS: There were no significant differences between the groups regarding mean levels of FF TSH and FF fT4. Statistically significant correlation was discovered regarding the levels of serum and FF TPOAbs (0,961, p<0.001 in TAI positive, 0,438, p = 0.025 in TAI negative group) and TgAbs (0,945, p<0.001 in TAI positive, 0,554, p = 0.003 in TAI negative group). Pregnancies rates per initiated cycle and per embryotransfer cycle were significantly different between TAI positive and TAI negative group, (30.8% vs 61.5%), p = 0.026 and (34.8% vs 66.7%), p = 0.029, respectively. Multivariate analysis showed that TAI positive women had less chance to achieve pregnancy (p = 0.004, OR = 0.036, 95% CI 0.004-0.347). CONCLUSIONS: Higher levels of thyroid autoantibodies in FF of TAI positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development.

Severe acute respiratory infection surveillance in Montenegro, 2014-2017.

AIM: The study aim was to analyze the epidemiology and clinical characteristics of severe acute respiratory infection (SARI) cases and to compare demographic and clinical characteristics as well as outcomes of influenza-positive SARI cases to those of influenza-negative SARI cases in Montenegro. METHODS: SARI surveillance was established in 2014 in nine healthcare institutions. Retrospective analysis of case-based surveillance data pertaining to all reported SARI cases during three seasons was conducted. RESULTS: Among the 90 identified SARI cases, 64 (71%) were influenza positive. Death outcome was reported in 25 (28%) of all registered SARI cases. Cardiovascular disease was more prevalent among the patients in the influenza-positive SARI group (36% vs. 12%, p = .021), as was concurrence of two or more chronic medical conditions (57% vs. 30%, p = .042). These patients were also more likely to be immunocompromised (16% vs. 0%, p = .057) and have viral pneumonia (14.4% vs. 20.3%, p = .017), compared to those in the influenza-negative SARI group. Younger age, presence of cardiovascular disease and being immunocompromised were patient characteristics independently associated with SARI related to influenza. CONCLUSION: Continued and extended monitoring of SARI is necessary in order to fully assess the burden of flu disease, define risk groups and establish better control measures.

Haemorrhagic fever with renal syndrome in Montenegro, 2004-14.

From 2004 to 2014, 106 cases of Human haemorrhagic fever with renal syndrome were notified in Montenegro, with a peak in 2014. Most of the cases occurred in summer, in the North-east and Central Montenegro, a hilly/mountainous area, that provides suitable habitats for the main rodent carriers. Cases were mainly males (71) and exposures were often working outdoor or spending time visiting mountains and lakes. Incidence correlated with average annual temperature increase and average annual rainfalls decrease, but not with land cover. Environment and climate effects on HFRS in Montenegro need further investigation to get insight into future trends.

Epidemiological Surveillance of Leishmaniasis in Montenegro, 1992-2013.

INTRODUCTION: The diseases caused by Leishmania are spread worldwide and represent a significant public health problem. OBJECTIVE: The aim of this study was to present the results of epidemiological surveillance of leishmaniasis in humans in Montenegro in the period from 1992 to 2013. METHODS: The study was planned and realized as a descriptive epidemiological study.The sample included patients of leishmaniasis in Montenegro in the period from 1992 to 2013. The health and demographic data were collected from medical records.The disease was microbiologically proven in the patients. For statistical analysis the χ2-test was used, which examined the significance of the incidence rate. RESULTS: During this period, 66 cases of leishmaniasis were identified (40 men and 26 women) aged 0 to 62 (mean 15.61 ± 16.76 years). A visceral form of the disease was diagnosed in 65 (98%) patients, and one patient was diagnosed with cutaneous leishmaniasis. The average incidence rate for the abovementioned period is 0.48 per 100,000 inhabitants. The highest average incidence rate was identified in patients up to seven years of age (3.50 per 100,000 inhabitants). The highest average incidence rates of leishmaniasis were identified in the coastal region of Montenegro, while seasonal distribution indicates that the disease occurs throughout the year with predominance in late spring and summer. CONCLUSION: The research has shown that Montenegro is among the countries with low incidence of leishmaniasis. Nevertheless, because of leishmaniasis re-emergence in the entire Mediterranean Basin, a comprehensive research of ecological and epidemiological characteristics of leishmaniasis, including better monitoring and notification system, is required.