Atanaska Elenkova

Background: Polycystic ovarian syndrome (PCOS) and the non-classic form of congenital adrenal hyperplasia (NC-CAH) are hyperandrogenic conditions with overlapping clinical symptoms but different genetic backgrounds. The possible interrelationships between the two conditions remain unclear; thus, the present study aims to investigate the prevalence of CYP21A2 exon 7 genetic variants in patients with PCOS and to explore the possible associations of the polymorphisms with adrenocortical hormonal production. Methods: The CYP21A2 exon 7 region was genotyped in 80 unrelated female patients with PCOS and 12 women with NC-CAH. The associations between genetic variants, clinical characteristics, and adrenocortical hormones were investigated. Results: The pathogenic CYP21A2 NC-CAH variant c.844G>T; p.(Val282Leu) was found in 66.7% (8/12) of patients with NC-CAH but in none of the individuals with PCOS. The benign rs1554305325, rs6465, rs6472, and rs6477 genetic polymorphisms were not related to clinical hyperandrogenism. The rs6472 polymorphic alleles were associated with increased adrenocorticotropic hormone (ACTH) (5.5 vs. 3.4 pmol/L, p = 0.022) and cortisol (460.5 vs. 366.5 nmol/L, p = 0.016) levels. The rs6465 variant alleles were significantly associated with lower pregnenolone (1.43 vs. 3.1 ng/mL, p = 0.031) and ACTH (2.5 vs. 4.5 pmol/L, p = 0.030) levels in the unadjusted model but not after adjustment for potential confounders (p > 0.05). Conclusions: The p.(Val282Leu) variant is very common among Bulgarian patients with NC-CAH but it has not been found in our cohort of women with PCOS. The CYP21A2 exon 7 polymorphisms might be associated with cortisol levels in the patients with PCOS. Further larger studies are needed to confirm or reject the current findings in different ethnic groups.

Background and Clinical Significance: Anti-Müllerian hormone (AMH) is a dimeric glycoprotein secreted from the granulosa cells of the preantral and small antral follicles, which has entered routine clinical practice as a valuable tool for the diagnosis of different ovarian disorders. Increased AMH levels have been recommended as a criterion for polycystic ovary syndrome (PCOS). However, its widespread use remains limited due to analytical diversity and contradictory age-specific thresholds, among other factors that modulate AMH levels. Case Presentation: Herein, we present a rare case series of women with increased AMH levels. The difficulties in the differential diagnosis of patients with elevated AMH levels, because of PCOS combined with pituitary dysfunction, increased ovarian volume, or granulosa cell tumors (GCTs), are discussed. Conclusions: The presented rare cases of increased AMH emphasize the important role of AMH as a diagnostic marker in women with hypogonadotropic hypogonadism and granulosa cell tumors. On the other hand, it is still unknown if increased AMH produced by unusually enlarged or supernumerary ovaries should be considered as actual PCOS cases or as a specific subgroup. Additionally, the unusual case of GCTs with pronounced AMH and LH increase but normal steroids supports the pathophysiological role of AMH for the development of neuroendocrine dysfunction. Moreover, it suggests that GCTs should be considered in the differential diagnosis of chronic anovulation even in women with normal ovarian steroid production in case of unusually high AMH levels for the age. Further studies are needed to explain PCOS heterogeneity and to ensure proper differential diagnosis for every affected woman.

Background: Polycystic ovarian syndrome (PCOS) is a common female endocrinopathy, but its interrelations with arterial hypertension (AH) are still debatable. Therefore, the present study aims to explore the risk factors for hypertension in a large group of well-phenotyped women with PCOS. Methods: The data of 1047 Bulgarian PCOS patients diagnosed according to Rotterdam criteria in the period 2005–2022 were studied retrospectively. The risk factors for hypertension were estimated in the PCOS women with different phenotypes. Results: The prevalence of AH was 17.6% among the PCOS women, with 4.2% of them being on antihypertensive treatment. The AH prevalence was increased in women with the “classic” phenotype compared to others (18.9% vs. 12.9%, p = 0.037). The most important risk factors associated with hypertension were the presence of diabetes mellitus type 2 (DMT2), obesity, family history of AH, and age ≥ 30 years (p < 0.001). The prevalence of impaired glucose tolerance (IGT) but not impaired fasting glucose was also related to the development of AH. Conclusions: The leading independent factors associated with hypertension in PCOS patients are the presence of DMT2, IGT, obesity, family history of hypertension, and age, but not the degree of hyperandrogenism. Population-based studies, including distinct ethnic groups, are needed to reveal the pathophysiology and the optimal clinical management of AH in PCOS.

Background: Addison’s disease (AD) is a rare disorder that often develops in the context of autoimmune polyglandular syndromes. However, the prevalence of rheumatological autoimmune diseases and corresponding autoimmune markers in AD is poorly investigated. Therefore, the present study aims to explore systemic and organ-specific immune markers in a cohort of AD patients from a single tertiary endocrine center. Material and methods: In total, 43 adult AD patients and 31 controls were included in the study. 21-hydroxylase autoantibodies (21OHAb), glutamic acid decarboxylase autoantibodies (GADAbs), zinc transporter-8 autoantibodies (ZnT8Abs), antibodies against nuclear antigens (ANAs), autoantibodies against cyclic citrullinated peptides (CCPAbs), rheumatoid factors (RFs), IgG autoantibodies against cardiolipin (ACLAbs), and autoantibodies against beta-2-Glycoprotein I (β2-GPIAbs) were measured in all participants. Results: An increased prevalence of antibodies against RFs (27.91% vs. 0%, p < 0.001) and ANAs (13.95% vs. 0%, p = 0.037) was found in AD patients compared to controls. Moreover, the titers of 21-hydroxylase and RF antibodies correlated positively (r = +0.269, p = 0.020). The AD patients tended to show an increased prevalence of subthreshold ACL antibody reactivity compared to controls. All patients diagnosed with type 1 diabetes mellitus were GADAb- but not ZnT8Ab-positive. Conclusions: The results show an increased prevalence of ANA and RF positivity in AD patients compared to controls and a significant association between 21-OHAb and RF positivity. ZnT8Ab positivity was not typical for adult AD patients from our ethnic group, while GADAbs were an essential marker for autoimmune diabetes mellitus. Extensive studies in different ethnic groups are needed to establish the clinical significance of various immunological markers for AD comorbidity and the appropriate follow-up protocols for patients with different antibody positivity.

The purpose was to assess the level of medication adherence (MA) and related factors among individuals with acromegaly. The secondary goal was to assess the quality of life of patients and whether and how it correlates with the level of adherence. A prospective one-year study was conducted among patients with acromegaly diagnosed, treated, and monitored in the reference center for rare endocrine diseases in Bulgaria in 2021. Clinical data, patients reported outcomes, and health economics data were collected to define the predictors of non-adherence to medicines. Medication adherence level was assessed through a free Morisky–Green 4-item questionnaire. A total of 179 patients with acromegaly were observed. Approximately 62% were female, 50% were between 41 and 60 years, and the mean age at diagnosis was 40.4 years. The response rate to the questionnaires was 53% (n = 95; mean age 53.5 years, 73% female and 26% male). Patients with high levels of MA reported higher median values for the 36-Item Short Form Health Survey (SF-36) in comparison with those with low levels: 65.5 vs. 48.5 (p = 0.017). Similar results for EQ-5D-3L (3-level EuroQol 5D version) values and the level of MA were found: 0.656 vs. 0.796 (p = 0.0123). A low level of adherence was revealed in 34.7% of the patients, with no difference among different age groups. A significant positive determinant for adherence was years lived with acromegaly (OR = 5.625, 95% CI 1.7401–18.1832, p = 0.0039), as shorter duration was related to higher odds for high level of adherence. The current study demonstrates the importance of MA assessment for patients with acromegaly in Bulgaria. The medication adherence to the prescribed therapy among the observed group of patients with acromegaly varied as the percentage of adherent patients was around 65%. Still, there are low-adherent patients, and the responsible factors should be further investigated.