**4. Telomeres in endocrine diseases**

#### **4.1. Polycystic ovary syndrome (PCOS)**

To the best of our knowledge, the first endocrine disease, in which telomere length was investigated, was polycystic ovary syndrome (PCOS) [43]. PCOS is characterized by polycystic ovaries, irregular menstrual cycles, androgen excess, and insulin resistance [44]. PCOS is a complex and multigenetic disorder, in which single nucleotide polymorphisms (SNPs) in several genes have been found to be associated. Phenotypes of the disease vary according to the ethnic origin, race, genetic factors, and other environmental factors [45,46]. In addition, no single etiologic factor was able to fully account for the pathogenesis of this disorder. Interest‐ ingly, patients with PCOS exhibited a significantly shorter telomere length than the controls after adjusting for age [43]. In addition, significant negative correlation between telomere length and dehydroepiandrosterone sulfate (DHEA-S) was observed. There are several lines of evidences, which suggest that oxidative stress plays a role in the pathogenesis of PCOS [47, 48]. Telomere shortening can cause dysregulation of the insulin sensitivity, mitochondrial function, and Ca2+ metabolism [49,50], suggesting a causal role of shortened telomere length in the development of PCOS. Conversely, an elevated oxidative stress associated with the androgen excess, abdominal adiposity, insulin resistance, and obesity might play a role in telomere shortening.

#### **4.2. Cushing's syndrome**

Cushing's syndrome is characterized by excessive secretion of cortisol, which leads to increased mortality and severe morbidity, including cardiovascular risk, obesity, fatigability, osteopenia, and impaired quality of life [51]. These comorbidities are not completely reversible after the biochemical control [52]. Hyperstimulation of hypothalamus-pituitary-adrenal (HPA) axis and subsequent hypercortisolemia may also occur in several kinds of psychiatric disorders or life stressors [53]. Interestingly, these situations are reportedly associated with shortened telomeres, in which chronic stress and enhanced HPA axis are observed. For example, patients with depression exhibited shorter telomere length than healthy controls [54]. Telomere length of newborn baby was shorter in proportion to the stress levels experienced by the mother during her pregnancy [55]. The exposure to violence or neglect in childhood was associated with shorter telomere length either in children or retrospectively in adults [56]. *In vitro* analysis has revealed that high levels of glucocorticoid reduce a 50% of telomerase activity in lymphocytes [57]. In this aspect, to elucidate the reason why comorbidities of Cushing's syndrome are not completely recover after a biochemical control, Aulinas et al. [58] hypothesized that shortening of telomere might occur in Cushing's syndrome and evaluated the telomere length in patients with Cushing's syndrome. They evaluated 77 patients with Cushing's syndrome (59 pituitary adenoma, 17 adrenal adenoma, and 1 ectopic; 21 with active disease). Although mean telomere length in patients with Cushing's syndrome and age-, sex-, and smoking-matched controls were comparable, in the longitudinal evaluation, telomere length was shorter in active disease than controlled disease after adjustment for age. They also showed that dyslipidemic patients with Cushing's syndrome had shorter telomere length than non-dyslipidemic patients with Cushing's syndrome and total cholesterol and triglycerides negatively correlated with telomere length. In addition, inflammatory markers and serum levels of CRP and IL-6 were also negatively correlated with telomere length in patients with Cushing's syndrome [59]. These observations suggested that hypercortisolism might nega‐ tively regulate telomere maintenance through the production of inflammatory cytokines or lipids.

#### **4.3. Acromegaly**

might impair the regenerative capacity in response to liver injury, which might result in liver

To the best of our knowledge, the first endocrine disease, in which telomere length was investigated, was polycystic ovary syndrome (PCOS) [43]. PCOS is characterized by polycystic ovaries, irregular menstrual cycles, androgen excess, and insulin resistance [44]. PCOS is a complex and multigenetic disorder, in which single nucleotide polymorphisms (SNPs) in several genes have been found to be associated. Phenotypes of the disease vary according to the ethnic origin, race, genetic factors, and other environmental factors [45,46]. In addition, no single etiologic factor was able to fully account for the pathogenesis of this disorder. Interest‐ ingly, patients with PCOS exhibited a significantly shorter telomere length than the controls after adjusting for age [43]. In addition, significant negative correlation between telomere length and dehydroepiandrosterone sulfate (DHEA-S) was observed. There are several lines of evidences, which suggest that oxidative stress plays a role in the pathogenesis of PCOS [47, 48]. Telomere shortening can cause dysregulation of the insulin sensitivity, mitochondrial function, and Ca2+ metabolism [49,50], suggesting a causal role of shortened telomere length in the development of PCOS. Conversely, an elevated oxidative stress associated with the androgen excess, abdominal adiposity, insulin resistance, and obesity might play a role in

Cushing's syndrome is characterized by excessive secretion of cortisol, which leads to increased mortality and severe morbidity, including cardiovascular risk, obesity, fatigability, osteopenia, and impaired quality of life [51]. These comorbidities are not completely reversible after the biochemical control [52]. Hyperstimulation of hypothalamus-pituitary-adrenal (HPA) axis and subsequent hypercortisolemia may also occur in several kinds of psychiatric disorders or life stressors [53]. Interestingly, these situations are reportedly associated with shortened telomeres, in which chronic stress and enhanced HPA axis are observed. For example, patients with depression exhibited shorter telomere length than healthy controls [54]. Telomere length of newborn baby was shorter in proportion to the stress levels experienced by the mother during her pregnancy [55]. The exposure to violence or neglect in childhood was associated with shorter telomere length either in children or retrospectively in adults [56]. *In vitro* analysis has revealed that high levels of glucocorticoid reduce a 50% of telomerase activity in lymphocytes [57]. In this aspect, to elucidate the reason why comorbidities of Cushing's syndrome are not completely recover after a biochemical control, Aulinas et al. [58] hypothesized that shortening of telomere might occur in Cushing's syndrome and evaluated the telomere length in patients with Cushing's syndrome. They evaluated 77 patients with Cushing's syndrome (59 pituitary adenoma, 17 adrenal adenoma, and 1 ectopic; 21 with active

fibrosis.

**4. Telomeres in endocrine diseases**

**4.1. Polycystic ovary syndrome (PCOS)**

148 Telomere - A Complex End of a Chromosome

telomere shortening.

**4.2. Cushing's syndrome**

Patients with acromegaly exhibit reduced life expectancy and increased comorbidities, such as DM, hypertension, cardiovascular and cerebrovascular diseases, and malignant diseases, which are also known as age-related diseases. Underlying mechanisms of these increased agerelated diseases are mainly explained by over secretion of GH and IGF-I; however, precise mechanisms have not been fully elucidated. Therefore, we investigated the telomere length of peripheral leukocytes in patients with acromegaly [60]. Intriguingly, patients with acromegaly exhibited shorter telomere length compared with patients with nonfunctioning pituitary adenoma or healthy control subjects. In addition, telomere length in acromegaly was nega‐ tively correlated with the disease duration, suggesting that exposure to increased serum GH or IGF-I levels may reduce telomere length. *In vitro* analysis revealed that not GH but IGF-I increased the telomere shortening rate per one cell division in human skin fibroblasts. Furthermore, IGF-I–treated cells showed cellular senescence and increased expression of SASP-related cytokines (e.g., IL-6). It has been reported that the development of age-related diseases, such as DM and vascular diseases, is associated with cellular senescence and SASP [8]. Together with our data, it is suggested that cellular senescence induced by telomere shortening may be involved in the increased morbidity and mortality in acromegalic patients.

The underlying mechanisms of how excess IGF-I induces telomere shortening and subsequent cellular senescence remain unclarified. It has been reported that various factors, including ROS, defects in the telomere repair system, inflammatory reactions, and increased cellular turn over, cause telomere shortening [61]. Intriguingly, oxidative stress was enhanced both in GHtransgenic rats and patients with acromegaly [62]. In addition, it has been reported that IGF-I enhances ROS-p53 pathway and subsequent cellular senescence in cultured cells with a confluent status [63]. Bayram et al. [64] also reported that patients with acromegaly exhibited increased oxidative stress and DNA damage. Furthermore, the causal role of increased oxidative stress in telomere shortening has been reported. Human fibroblasts cultured under 40% oxygen, in which oxidative stress is increased, exhibited an accelerated rate of telomere shortening [33] and inhibition of the glutathione-dependent antioxidant system results in telomere shortening and senescence in human endothelial cells [65]. Taken together, although further investigations are needed, we speculate that the increased oxidative stress associated with the increased serum levels of IGF-I may lead to the telomere shortening in patients with acromegaly.
