ACTA ENDOCRINOLOGICA (BUC)

The topic of fertility preservation has been gaining increasing importance since the beginning of this century. The reasons for this development are the advances in oncological therapy over the past few decades, with cure rates of approximately over 90%, and the fact that starting families is increasingly postponed in later periods of life in industrialized countries. Since March 2020 the whole medical and non-medical world experiences a pandemic due to Covid-19 (coronavirus disease 2019) which has never been seen before. This created a plenty of challenges for both, the patients and healthcare providers. This review article presents the fertility-protective methods currently available for women and men suffering from cancer with their clinical approach, value, advantages and disadvantages. Besides, it focuses on the changes and special considerations which have to be taken into account during pandemic times including preventive measures as well as the patient`s access to the fertility preserving options. In conclusion every premenopausal woman and every man with incomplete family planning suffering from cancer should be counselled about the existing fertility preserving techniques before commencing cancer therapy.

Melanoma has a significant mortality and its growing incidence is associated with important social and health care costs. Thus, investigation of the complex mechanisms contributing to emergence and development of melanoma are of real interest both in scientific research and clinical practice. Estrogens play an important role in the emergence and development of certain types of cancer, such as breast cancer, endometrial cancer and ovarian cancer, but their role in development of cutaneous melanoma is still a matter of debate. Various data suggest that increased levels of endogenous estrogens during pregnancy or exposure to exogenous estrogens by use of oral contraceptives (OCs) and hormone replacement therapy (HRT) may have a potential role in melanoma development and progression. Moreover, there were revealed several intracellular pathways which can support the connection between estrogens, estrogen receptors (ER) and melanoma. While ER-β plays an antiproliferative role, ER-α promotes cell growth and cellular atypia. Thus, inhibition of ER-β activity in the skin can increase the risk for development of cutaneous melanoma and spread of metastatic cells. However, despite recent advances in this area, the exact role and clinical implications of estrogens and estrogen receptors in melanoma are still not entirely understood and require further investigations

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Anaplastic thyroid cancer (ATC) is a highly uncommon (less than 2% of thyroid malignancies) and aggressive type of cancer, with aggressive behavior and, therefore, exhibiting poor prognosis. ATC tumors are automatically labeled as stage IV disease regardless of standard criteria such as tumor burden or metastasis. ATC tumors require a diversified treatment approach that includes surgical resection, followed by a complete an aggressive combination of radiation and chemotherapy and/or palliative care. Despite best efforts, 1-year overall survival of patients is 20% to 40% with nearly universal mortality rate. Consequently, novel approaches (targeted therapy, immunotherapy) have been studied, alone or in combination, to improve the dire prognosis of these patients. BRAF V600E mutation is the most common genetic mutation found in ATC. We report the case of a 57-year-old man diagnosed with stage IVc (undifferentiated) ATC with hepatic and osseous metastases. The molecular analysis of the tumor revealed a V600E BRAF-mutation. The patient was treated with Dabrafenib and Trametinib, and achieved remission 5 weeks after starting the treatment. Subsequently, he had a thyroidectomy, and pembrolizumab was added to the two tyrosine kinase inhibitors. 9 months later he is still in remission. This case illustrates the importance of obtaining molecular information in anaplastic thyroid cancer and the urgent need of studies investigating the combination of tyrosine kinase inhibitors and check-point inhibitors in patients with V600E BRAF- mutations.

Surgery plays a major role as a first-line treatment of the different etiologies of Cushing’s syndrome (CS) and bilateral adrenalectomy (BA) is extremely effective as a second line, so that there seems to be little room for medical treatment (MT). However, during the past years several drugs acting either on ACTH secretion or cortisol synthesis have been developed, so that MT of CS might be reassessed. After briefly analyzing the efficiency and tolerance of surgical and medical treatments of CS we try to distinguish consensual and controversial indications for MT. We believe the former include “pre-operative treatment” in rare patients in whom the severity of CS is likely to increase the risks of surgery; “inoperability” for rare patients who cannot be operated even when CS is controlled and “surgical failure or recurrence”, mainly in patients Cushing’s disease (CD) not in remission after TSS. Controversial indications include “unavailability of an expert surgeon”, which we believe does not make sense when the cost of MT is taken into consideration. Finally in patients with the “surgical failure or recurrence” indication the balance between efficacy and side effects of MT should be balanced with the efficacy and side effects of BA.

Aim. The purpose of this study was to examine various hormonal, biochemical and environmental factors (i.e., smoking and alcohol intake) and to investigate their possible correlation to the development of polycystic ovary syndrome (PCOS). The main objective was to evaluate the associations between hormonal profile and the antimüllerian hormone (AMH) levels in PCOS patients and their relation to environmental factors. Patients and Methods. In two gynecological clinics, 38 women with PCOS (defined according to the Rotterdam criteria) were enrolled and observed in relation to AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), Δ4-androstendione (Δ4- A), dehydroepiandrosterone sulfate (DHEA-S) and glucose plasma concentrations. Obesity, smoking and alcohol exposure were also studied. Results. AMH, T, Δ4-Α, DHEA-S, LH and FSH were increased in 76.3%, 50%, 31.8%, 23.7%, 21% and 18.4% of the patients, respectively. The LH/FSH ratio and glucose concentrations increased abnormally in 18.4% and 15.8% of the patients, respectively. AMH and T levels were both increased in 47.4% of the patients whereas both AMH and LH levels increased in 21% of the patients. Smoking, alcohol intake, obesity and glucose concentrations were not associated with AMH concentrations. On the contrary, high levels of T and LH were linked to higher levels of AMH. FSH concentrations were not increased in these patients. Conclusion. AMH is an important hormonal parameter for the diagnosis of PCOS. Larger clinical controlled studies are necessary in an effort to further investigate the inclusion of AMH measurement in the diagnostic criteria of PCOS.

Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus nongenetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activate BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Background. Coronary artery disease (CAD), often asymptomatic, is the most common cause of morbidity, mortality and costs in diabetes. Early detection of CAD in patients with diabetes may be of paramount importance and substantially improve the outcome in diabetic patients. Objective. The aims of the current study were to determine if there are significant differences concerning the prevalence of occult CAD in asymptomatic type 2 diabetic patients compared to asymptomatic nondiabetic patients. Design, subjects and methods. The authors retrospectively reviewed a group of 120 non-diabetic (77 men, 43 women, mean age 61±10.2 years) and 120 diabetic (81 men, 39 women, mean age 58±11.4 years) asymptomatic patients that underwent coronary computed tomography angiography (CCTA) for various reasons between January 2013 and January 2014. Results. Coronary plaques were identified in 105 diabetic patients (87.5%) and in 75 non-diabetic patients (62.5%) the prevalence being significantly different (p=0.023). Regarding plaque composition and degree of stenosis, we found a higher prevalence of calcified (p=0.016) and significantly stenotic (≥50% luminal narrowing) plaques (p=0.008) in the diabetic group. Agatston calcium score, relevant for atherosclerotic plaque load, was higher (p=0.005) in type 2 diabetic patients (350.3) compared to non-diabetic patients (158.7). Conclusion. CCTA could represent a screening method able to detect silent atherosclerotic plaques thus contributing to the prevention of acute coronary syndrome (ACS) by an early and adequate treatment of CAD. Obstructive atherosclerotic plaques can be accurately identified using CCTA, limiting the use of invasive imaging methods and selecting patients that could benefit of coronary revascularization.

Context. Osteonecrosis (ON) is bone death caused by inadequate blood supply and its optimal management remains uncertain. Objective. We describe the outcomes of BP (pamidronate) treatment in our patients. Design. Data regarding clinical, laboratory, magnetic resonance imaging (MRI) studies, and bone mineral density measurements (BMD) were recorded before and one year after treatment (reevaluation). The severity of the clinical picture was assessed using the criteria of the common terminology criteria for adverse events (CTCAE). Subjects and Methods. There were four female patients (patient 1, acute lymphoblastic leukemia; patient 2, immune thrombocytopenic purpura; patients 3 and 4, systemic lupus erythematosus) .All of them had been treated with high-dose prednisolone. Clinical picture of all patients were consistent with grade 3 according to CTCAE(: severe symptoms, limiting self-care ). Results. ON lesions were multifocal in the lower limbs in all of them and none of them had any fractures. All of them had been treated with high-dose glucocorticoid. Patients were treated with pamidronate (1 mg/kg/day, with maximum dose of 60 mg/day, for two days, quarterly). At the time of re-evaluation(one year after treatment), the lesions were stable on MRI, and their clinical condition was consistent with grade 1 according to CTCAE(asymptomatic). No side effects related to the use of bisphosphonates were observed except for increased BMD (SD score of 2.9) in one of the patients. Conclusions. Pamidronate may be an effective treatment for the improvement of functional impairment and pain among patients with severe osteonecrosis (ON) lesions.

Objective. To examine the prevalence of laryngopharyngeal reflux disease (LPRD) in patients with hypothyroidism.\r\nMaterials and Methods. A total of 85 patients with hypothyroidism vs 31 matched controls were recruited. Demographic data was collected and an RSI questionnaire\r\nfilled. A score > 10 was considered diagnostic of LPRD. The average score of every question was computed for all patients and compared to the corresponding average score in controls.\r\nResults. Mean age of hypothyroidism patients was 44.92 ? 13.77 years (83% females). One third of subjects were smokers and 10% had allergy. In 78.8% of the cases Hashimoto?s disease was the etiological factor and 22.4% patients had history of thyroidectomy. At the time of examination, only 30% had a TSH > 4.2 mU/L. There was\r\na borderline significance where more patients than controls had a RSI > 10 (24.7% patients vs. 9.1% controls), but with non-significant difference (p = 0.077). Similarly, closer\r\nexamination of those with TSH > 4.2mU/L compared to those with controls revealed a higher prevalence in the former group, but statistically non-significant (p = 0.275). A\r\ncomparison between those with TSH > 4.2 mU/L and cases diagnosed with hypothyroidism and normal TSH revealed no\r\nsignificant difference in the prevalence of LPRD. All laryngopharyngeal questions had a score higher in the hypothyroid group than controls.\r\nConclusion. LPRD is more prevalent in hypothyroidism patients compared to normal individuals, but with nonstatistically significant difference. The prevalence of symptoms should alert physicians to the possibility of LPRD and prompt further diagnostic tests and therapeutic intervention.