Turner syndrome (TS) is a well-known sex chromosome disorder/difference in sex development characterized by premature ovarian failure with hypoestrogenism, short stature, specific physical features, and increased prevalence of comorbidities [1, 2, 3]. Total or partial loss and structural abnormalities of the second X chromosome in phenotypic females may be associated with variable severity of clinical manifestations; therefore, TS might be diagnosed at different stages of the lifespan [4]. Typically, patients with TS are diagnosed in childhood and receive complex medical care in pediatric settings per evidence-based recommendations [3, 4, 5]. However, the transition to adult healthcare services is often associated with different hurdles, such as a lack of a multidisciplinary approach, insufficient evidence for the optimal treatment regimens, as well as significantly reduced financial reimbursement of medical consultations and investigations by local health insurance funds for older women in comparison to children [6]. Additionally, some patients are diagnosed with TS as adults, leading to delayed hormonal treatment and possible long-term complications [7, 8].

The main objectives of medical care in TS children and adolescents are growth improvement by growth hormone treatment (GHT) and puberty induction [4, 5]. In adulthood, major priorities include maintenance of hormone-replacement therapy (HRT), counseling about fertility and available assisted reproductive technologies, and early identification and treatment of concomitant diseases [4, 5]. TS is associated with an increased prevalence of cardiovascular, renal, gastrointestinal, metabolic, and autoimmune disorders leading to increased mortality [4, 5]. One of the significant threats in TS women is fatal aortic dissection or rupture, which could affect relatively young patients, especially in the presence of underlying risk factors such as aortic abnormalities or hypertension [3]. The proper estimation of disease burden in TS is possible only by targeted standardized multidisciplinary evaluation; otherwise, many disorders would be omitted [9].

In recent years, comprehensive guidelines for holistic adult care have been developed [4, 10]. However, most pieces of evidence emerge from a few European countries with national registers, such as Denmark, Sweden, and the UK [10]. Conversely, data about adult TS care in other countries are insufficient.

Accordingly, the present study aims to describe a cohort of adult East-European TS patients and to highlight pitfalls in long-term medical care.

The presented results summarize the clinical characteristics of an adult TS patient group in a single tertiary East European endocrine center. More than one-third of patients were diagnosed as adults despite their short stature, pubertal delay, and additional symptoms. Most newly diagnosed adult women were referred for evaluation because of menstrual disturbances. At the same time, growth and additional symptoms were not considered as factors imposing the search for endocrinological help by some patients, especially in families where most members were of relatively short stature. Our results are in line with data from adult Indian patients diagnosed with TS because of amenorrhea in more than three-quarters of cases [12]. The evaluation of growth based on personal anthropometric data and parental height measurements may be a valuable tool for identifying abnormalities not only in children, but adults as well [13]. Thus, the auxological assessment should not be overlooked in routine adult endocrinological practice, as sometimes happens.

The median age of diagnosis of our TS cohort was 15 years, akin to those established in extensive population-based Danish studies [7, 14] and, unsurprisingly, higher than those reported by pediatric investigations from the same and other countries [8, 15]. Additionally, Bulgarian patients with 45, X monosomy had been diagnosed approximately five years earlier than patients with other karyotypes as in Denmark, despite the significant differences in socioeconomic status and health care organization of both countries [7, 14].

Fifty-five percent of our patients demonstrated monosomic TS, a percentage slightly higher than expected based on the published prevalence. For instance, the prevalence of 45, X karyotype was 32.1% in a recent study of pediatric TS patients of the same ethnic group [16]. Implementing prenatal screening programs in different countries, including ours, may account for decreased monosomic TS incidence because of a high rate of prenatal detection and induced abortions [14]. On the other hand, it might be assumed that a predominance of patients with prominent clinical features were referred to our tertiary center. Perhaps, the follow-up of mosaic TS individuals with milder symptoms was conducted by general practitioners, local endocrinologists, and gynecologists. The same suggestion could also explain the zero-fertility rate in our group, along with other factors, such as the financial and emotional burden of in vitro procedures.

According to our results, GHT has been associated with approximately 5 cm gain in final height. It should be emphasized that some of the treated TS individuals had started GHT with a substantial delay due to late diagnosis leading to suboptimal results. Therefore, the growth hormone effects in our cohort were slightly lower than those in other countries. The largest recent retrospective Brazilian study reported a mean height difference of 6.2 cm between non-treated TS patients and those treated with GHT for approximately five years on a standard dose [17]. A meta-analysis of nine randomized controlled trials using recombinant GHT concluded that treated TS girls were, on average, 7.2 cm taller than non-treated patients [18]. However, in international clinical practice, the final height gain varies widely between 2.10 cm and 10.69 cm, a gap attributable to different ages at initiation and duration of GHT, individual genetic features and adherence to therapy, as well as concomitant use of estrogens and oxandrolone [18, 19, 20].

Patients diagnosed with TS earlier than others tended to be on GH and estrogen treatment. The differences in mean age and estrogen use corresponded to a better lipid profile in GH-treated women compared to non-treated. Accordingly, Irzyniec et al. [21] found better lipid parameters in adult TS patients treated with GH during childhood compared to other TS women. In contrast to Polish data, the blood count characteristics, including thrombocytes and follicle-stimulating hormone levels, did not differ between the two investigated groups in our study. The early age of TS diagnosis leading to early GHT initiation has been considered a fundamental prerequisite for optimal GH effects [22]. However, other factors may also influence access and adherence to GH therapy and its efficiency, e.g., lower socioeconomic status, emotional issues, and poor understanding of drug therapy benefits and risks [23]. Thus, the positive influence of GHT in adulthood may reflect not only the biological effects of GH but also the healthier habits and nutrition and easier access to healthcare services of TS women with higher socioeconomic status.

Unfortunately, our results showed that 44% of hypogonadal TS patients at 18 years or above either had not started HRT or had discontinued it. The late TS diagnosis in amenorrheic women suggests that access to specialized endocrinological and/or gynecological consultations should be facilitated. On the other hand, the main factor associated with HRT self-discontinuation was not the development of absolute contraindications or lack of endocrinological evaluation but the poor understanding of therapy’s importance. The percentage of estrogen-treated patients in our country was twice as low as in Denmark and Italy, where 83% to 92.5% of adult TS patients received HRT or oral contraceptives [24, 25]. However, our data were similar to those reported by an Australian study showing a lack of hormonal treatment in 37% of adult TS patients [26]. The proper education of TS women about HRT benefits is the only way to ensure continuous adherence to therapy and to achieve the long-lasting positive effects of estrogens on bone, metabolism, and cognition [27]. As in other studies [1, 24, 25], bone density in half of the investigated women from our TS group was strongly decreased, corresponding to the low estrogen exposure. Current European guidelines recommend sufficient calcium intake, avoidance of vitamin D deficiency, and monitoring of bone density every five years in patients with TS or more frequently in case of estimated abnormalities [4, 28]. HRT is needed until the physiological age of menopause not only for the prevention of bone loss but also for improving the cardiovascular and sexual health of TS women [4, 28].

As expected, the evaluation of TS patients for concomitant diseases revealed a high prevalence of metabolic disturbances. Dyslipidemia was established in 50% of investigated patients, while overt DM type 2 was found in 6.6% of patients. The prevalence of DM type 2 was close to that reported by most studies (5%–10%) [4, 26, 29] but lower than that observed in the USA (25%) [30]. The prevalence of thyroid diseases and hypothyroidism in our cohort was similar to that of other European countries [1, 31]. Cardiological and renal comorbidity distribution was close to expected [1, 32]. Cardiological abnormalities were more prevalent in monosomic compared to mosaic patients, as in other studies [32, 33].

In contrast, the established prevalence of hypertension (11%) was much lower than expected based on international reports, varying between 16% and 50% [1, 25, 29, 34]. The high percentage of hypertension in TS patients has been associated with hypoestrogenism leading to increased sympathetic activity and with concomitant metabolic, cardiological, and/or renal abnormalities [35]. Ethnic and lifestyle peculiarities may explain the different prevalence of hypertension in distinct study cohorts, but increased blood pressure could also be underdiagnosed [35, 36, 37]. Our results strongly support current international recommendations suggesting ambulatory 24-h blood pressure monitoring in all adult TS patients at transition and at least once every five years after that to diagnose nocturnal hypertension [37, 38].

In conclusion, our study confirmed that late diagnosis of TS in many patients leads to poor hormonal treatment. Moreover, the data showed the imperative for better education about evidence-based benefits and risks of HRT in young hypogonadal women. Diagnosis of concomitant endocrinological diseases in our TS patients, has been significantly more accurate compared to non-endocrine conditions. The main cause for the observed discrepancy is that TS patients’ care has been provided primarily by local endocrinologists. These results support the worldwide need for dedicated multidisciplinary teams focused on TS diagnosis and follow-up in adulthood [5, 6, 39]. Additionally, the recommended laboratory investigations and imaging studies should be financially supported by local health insurance funds as a condition sine qua non to achieve a similar level of TS care in high-income and low-income countries.

Datasets are available from the corresponding author on reasonable request after permission from the local authorities.

RR—extraction, statistical analysis, and drafting of the manuscript; RR, AE, SZ—design, analysis of data, manuscript revision. All authors read and approved the final manuscript.

All subjects gave written informed consent permitting the research use of their pseudonymized data. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by USHATE “Acad. Iv Penchev” (approval number: 4/18.02.2019).

Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest. Ralitsa Robeva is serving as one of the Guest editors of this journal. We declare that Ralitsa Robeva had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Panagiotis Anagnostis.