The relationship between temporal muscle thickness and disease activity in Cushing's disease.

OBJECTIVE: This study aimed to investigate the relationship between hypercortisolism and temporal muscle thickness (TMT) in Cushing's disease (CD). METHODS: A retrospective review of medical records was conducted for patients with CD who presented to our clinic between 2012 and 2022. Biochemical data and TMT measurements from sella imaging were evaluated during diagnosis and the first postoperative year. RESULTS: A total of 44 patients were included in the study, with an average age of 43.9 years, of which 38 were female. The mean TMT at the time of diagnosis was 19.07 ± 1.71 mm, with no significant difference between males and females (p = 0.097), and no correlation between the TMT and age at diagnosis (p = 0.497). There was an inverse relationship between TMT and serum cortisol levels, 24-h UFC, and midnight salivary cortisol at the time of diagnosis of CD (p < 0.05, for all). One year after surgery, TMT significantly increased in all patients compared to baseline (p < 0.001). Furthermore, patients who achieved postoperative remission had significantly higher TMT values compared to those who did not achieve remission (p = 0.043). Among the patients who achieved remission, those who achieved remission through surgery had significantly higher TMT compared to those who could not reach remission with surgery and patients who started medical treatment and achieved biochemical remission (p = 0.01). Patients with severe myopathy and sarcopenia had significantly lower TMT values than the others (p < 0.001). CONCLUSION: Temporal muscle thickness was found to be associated with disease activity and disease control in Cushing's disease.

Evaluation of sex hormone profile and semen parameters in acromegalic male patients.

OBJECTIVE: To investigate the changes in semen quality and bioavailable testosterone concentrations in acromegalic male patients according to their disease activity and compare them with patients with non-functional pituitary adenoma (NFA) and healthy controls (HC). METHODS: Twenty-four acromegalic patients with active disease, 22 acromegalic patients in remission, 10 HCs, and 10 patients with NFA were included. RESULTS: Total and calculated bioavailable testosterone concentrations were lower in patients with pituitary disease. Patients with acromegaly had more severely impaired total testosterone levels and semen parameters in comparison to HCs and patients with NFA. The degree of impairment was more prominent in acromegalic patients with active disease than acromegalic patients in remission. Acromegalic patients in remission had residual impairments in both semen quality and testosterone concentrations. Patients with NFA had the lowest concentrations of calculated bioavailable testosterone, followed by acromegalic patients with active disease and acromegalic patients in remission. Increasing growth hormone (GH) levels were found to be associated with both more severely impaired semen quality and androgen concentrations. CONCLUSION: Growth hormone hypersecretion can disturb reproductive biology and thereof semen quality. The reduction in semen quality and androgen levels may not fully recover upon disease control. Clinicians should be aware of the increased risk of impaired semen parameters and reduced total/bioavailable levels in acromegalic patients, especially in the setting of active disease.

How does pregnancy affect the patients with pituitary adenomas: a study on 113 pregnancies from Turkey.

OBJECTIVE: Data regarding pregnancies in relation to pituitary tumors are limited. The effects of pregnancy on pituitary adenomas and the effects of adenoma itself (hormonal activity, mass effects and pituitary insufficiency) and/or treatment on the ongoing gestation and developing fetus were evaluated. METHODS: The study was a retrospective study. A questionnaire involving questions regarding medical history before index gestation, history of related pregnancy, result of index gestation and postpartum follow-up of the patients was filled by the investigator in one of the eight Referral Endocrinology Centers from Turkey. RESULTS: One hundred and thirteen (83 prolactinoma, 21 acromegaly, 8 NFPA and 1 plurihormonal pituitary adenoma) pregnancies of 87 (60 prolactinoma, 19 acromegaly, 7 NFPA and 1 plurihormonal pituitary adenoma) patients were reviewed. The clinically important pregnancy-related tumor growth of pituitary adenomas was found to be low in previously treated adenomas. Prolactinomas were more likely to increase in size during pregnancy especially if effective prior treatment was lacking. The risk of hypopituitarism is also minimal due to pituitary adenomas during pregnancy. The results of pregnancies did not differ in patients who were on medical treatment or not for prolactinomas and acromegaly during gestation. Neural tube defect and microcephaly associated with maternal cabergoline use; Down syndrome and corpus callosum agenesis associated with maternal bromocriptine use; unilateral congenital cataract, craniosynostosis and microcephaly associated with maternal acromegaly were detected for the first time. CONCLUSION: Medical treatment can be safely done stopped in patients with prolactinoma and acromegaly when pregnancy is confirmed and reinstituted when necessary. Prospective studies may help to determine the effects of medical treatment during gestation on the mother and fetus.

Preoperative Somatostatin Analogue Treatment Might Trigger Apoptosis and Autophagy in Tumor Tissues of Patients with Acromegaly: A Pilot Study.

OBJECTIVE: To evaluate the effect of preoperative somatostatin analog (SRL) treatment on proteins associated with apoptosis and autophagy in patients with acromegaly and to determine factors correlating with these parameters. METHODS: Ex-vivo tumor samples of 11 SRL-treated and 9 SRL-untreated patients were retrospectively included in the study. Apoptotic and autophagic proteins were determined via immunohistochemical staining and apoptosis was evaluated via in situ DNA end labeling (TUNEL). RESULTS: TUNEL, caspase-3, and ATG-5 immunopositivity was significantly increased (p<0.01, p=0.01, p=0.01, respectively), survivin and beclin-1 immunopositivity was significantly decreased (p=0.03, p=0.02, respectively) in SRL-treated patients as compared with SRL-untreated controls. Ki-67 index was decreased significantly in the SRL-treated group (p=0.01). Significant positive correlations were detected between TUNEL and caspase-3 immunopositivity (r=0.577, p<0.01), and between survivin and beclin-1 immunopositivity (r=0.503, p=0.03). Age at diagnosis, preoperative GH, IGF-1 levels, tumor size, and invasion status were not found to affect TUNEL positivity nor did they correlate with caspase-3, survivin, beclin-1, ATG-5 immunopositivity (p>0.05 for all). Preoperative SRL treatment was the only factor that had a significant effect on TUNEL positivity (adjusted R2=0.39, p=0.02). Preoperative treatment duration was positively correlated with TUNEL and caspase-3 immunopositivity (r=0.526, p=0.02; r=0.475, p=0.04, respectively) and negatively correlated with survivin immunopositivity (r=-0.533, p=0.01). CONCLUSIONS: Somatostatin analog treatment might induce apoptosis, increase autophagy, and decrease cell proliferation in GH-secreting adenomas. Also, proteins related to cross-talk between autophagy and apoptosis are upregulated after SRL treatment.

LONGER CECUM INSERTION TIME AND MORE INADEQUATE COLONIC PREPARATION IN PATIENTS WITH ACROMEGALY: IS A DIFFERENT COLONOSCOPY PREPARATION NEEDED?

PURPOSE: To investigate whether there is a difference between acromegalic and non-acromegalic cases in terms of bowel preparation and colonoscopic intervention. METHODS: Patients with controlled and uncontrolled acromegaly and as a control group (CG) patients without acromegaly between January 2010 and March 2014 were included. Groups were compared regarding adequacy of bowel preparation, cecal insertion time (CIT) and colonoscopy results. RESULTS: Fifty-nine patients with acromegaly (controlled n=30, uncontrolled n=29) and 73 age and gender matched volunteers without acromegaly were evaluated. CIT in cases with controlled, uncontrolled acromegaly cases and in CG was 5.33 [4.00-6.00], 7.00 [4.91-11.31], and 3.10 [2.35-4.65] minutes, respectively (p<0.001). Cases in CG had shorter CIT compared to controlled and uncontrolled acromegaly cases ( p=0.014 and p<0.001, respectively). There was no significant difference regarding CIT between controlled and uncontrolled acromegaly cases (p=0.247). Six (20%) of controlled acromegaly patients, 10 (35%) of uncontrolled acromegaly patients and three (4%) of CG had inadequate bowel cleansing (p<0.001). Although statistically insignificant, cases with inadequate bowel cleansing had tendency towards having prolonged CIT in comparison to cases with adequate bowel cleansing (6.00 [3.87-9.00] and 4.16 [2.95-5.70] minutes, respectively, p=0.07). CONCLUSION: Inadequate bowel cleansing is one of the main problems encountered during colonoscopic investigation/surveillance in acromegalic patients. Therefore, a different protocol for colonoscopy preparation may be needed for these cases.

Daily life reflections of acromegaly guidelines.

PURPOSE: To determine the differences in acromegaly diagnosis, treatment, and follow-up among Turkish endocrinologists, and to investigate how the published guidelines are applied in clinical practice. METHODS: The questionnaire was formatted as an electronic survey, conducted between November and December 2015, and sent weekly for 6 weeks via e-mail to 528 endocrinologists in Turkey. RESULTS: The questionnaire was answered by 37.4 % of endocrinologists. Insulin-like growth factor-1 and nadir growth hormone level after 75 g oral glucose tolerance test (nadir GH-OGTT) were the most commonly preferred methods for the initial diagnosis. A total of 49.5 % of the participants reported using preoperative medical therapy (MT) either routinely or on a case-to-case basis. Somatostatin analogs were the most commonly used drugs, both in pre- and postoperative MT. Disease activity following surgery was assessed in the 3rd postoperative month using IGF-1 levels. Similarly, IGF-1 monitoring was preferred in the follow-up period. Monitoring nadir GH-OGTT levels was the most commonly used method in the assessment of discordant test results. The dose titration was done at month 3 after the start of MT. Resistance to SRLs was considered after using the maximal dose for at least 6 months. Pegvisomant was generally used in second- and third-line therapy. Similarly, cabergoline was not preferred in monotherapy by the majority of participants. Radiotherapy was considered in patients with incomplete response to surgery and medical treatments. CONCLUSIONS: Although there were subtle differences, clinical practice guidelines were usually followed among Turkish endocrinologists.

The problem of unrecognized acromegaly: surgeries patients undergo prior to diagnosis of acromegaly.

PURPOSE: To reveal the variety of symptoms experienced by patients before acromegaly diagnosis and to emphasize unneeded surgeries that patients undergo related to acromegaly prior to diagnosis of the disease. METHODS: In total, 490 consecutive adult patients with acromegaly who were treated at our institution between 1998 and 2014 were included in this cross-sectional study, of which 313 could be contacted. Participants were questioned about their complaints at initial consultation and at the time of diagnosis, the first medical professional who they consulted, interval between onset and diagnosis, and surgeries they had undergone. RESULTS: This study included 313 participants, of whom 181 were women. The mean age was 48.8 ± 12.0 years. Patients most frequently presented with acral growth of hands and feet (32.6%) and headache (26.2%). Internists were the medical specialists who were most frequently first consulted (29.4%) then neurosurgeons (11.8%). Acromegaly was generally diagnosed by endocrinologists (55%), followed by neurosurgeons (23%). The median elapsed period prior to diagnosis was 24 months, interquartile range 6.0-48.0 months. Some 45.7% had undergone surgery; 35.2% were related to acromegaly symptoms: head and throat surgery (12.8%), nose surgery (9.3%), thyroidectomy (6.4%), carpal tunnel surgery (4.8%). The delay period for patients who had an operation prior to acromegaly diagnosis was significantly longer than for those who had no operations (p < 0.001). CONCLUSIONS: Acromegaly patients mostly present to internal medicine professionals. Surgeries related to acromegaly complications and symptoms before diagnosis cause a long delay period before diagnosis. Medical staff must be more aware of the clinical aspects of acromegaly.

Xanthomatous hypophysitis.

Xanthomatous hypophysitis (XH) is the rarely seen primary form of hypophysitis. The histological differential diagnosis includes other causes of hypophysitis, Erdheim-Chester disease (ECD), Langerhans cell histiocytosis, Rosai-Dorfman disease and plasma cell granulomas. We present a 39-year-old woman admitted to our department with headache, menstrual irregularity and galactorrhea. The MRI revealed a lesion with a central cystic/necrotic region and a diameter of almost 1cm. Histologic examination showed an inflammatory infiltrate of numerous foamy histiocytes, surrounding the necrotic tissue. On immunohistochemical sections, infiltrating foamy cells stained strongly positive for CD68, and negative for CD1a and S100. After establishing the diagnosis of XH, the patient underwent glucocorticoid treatment. XH should be considered in the differential diagnosis of pituitary lesions. Since XH is rare, it is difficult to assess the efficacy of medical/surgical treatment of this entity accurately.

Medical therapy of acromegaly in Turkey.

Acromegaly is associated with multiple co-morbidities and risk of premature mortality. Mortality rate of acromegalic patients is similar to that of the general population when normal GH levels are achieved. Surgery is the mainstay of acromegaly but when surgery fails to achieve disease control, or when surgery is impossible or contraindicated, patients are offered medical therapy and/or radiotherapy. Current medical therapy modalities were revised in this short review.

Ret proto-oncogene mutations in apparently sporadic Turkish medullary thyroid carcinoma patients: Turkmen study.

OBJECTIVE: Medullary thyroid carcinoma (MTC) frequently occurs in a sporadic form, but a substantial number of cases are hereditary and appear as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Germline mutations in ret proto-oncogene have been shown to be the underlying cause of MEN2 syndromes. DESIGN: We carried out a multi-center study that aimed to perform mutational analysis of so called sporadic MTC patients. METHODS: Fifty-six MTC patients verified by histopathologic examination were subjected to genetic analysis. Exon 10, 11, 13, 14, 15 and 16 of the ret gene were analyzed by DNA sequencing and restriction enzyme digestion method. RESULTS: Among 56 apparently sporadic MTC patients, we identified 6 (10.7%) ret germline mutation carriers. Three individuals carried mutations at codon 634 in exon 11, one at codon 618 in exon 10, and two at codon 804 in exon 14. Identification of the predisposition gene mutation has allowed DNA-based strategy for direct mutation detection in patients with apparently sporadic MTCs. A substantial number of patients with apparently sporadic MTC carried germline mutations and 50% of their first degree relatives are expected to have or to develop MTC and/or other endocrine tumors. CONCLUSIONS: These results indicate the importance of careful genetic surveillance of any patient with apparently sporadic MTCs.

Effect of sex hormones on lipid peroxidation in women with polycystic ovary syndrome, healthy women, and men.

Recently, the influence of free radicals and lipid peroxides on many diseases, the effect of sex hormones on lipid peroxidation and antioxidant effects of estrogens have received considerable interest. In the present study we aimed to investigate the relationship between sex hormones and both lipid peroxidation and glutathione content in women with polycystic ovary syndrome (POS), in healthy women and in healthy men. We measured levels of lipid peroxides and sex hormones in plasma and levels of glutathione in erythrocytes of all cases. We evaluated the level of thiobarbituric acid reactive substances (TBARS) as an index of lipid peroxides and erythrocyte glutathione level as an index of antioxidant. We found that plasma levels of free testosterone, dehydroepiandrosterone sulfate (DHEAS) and estradiol significantly higher in the women with POS group than in the healthy women group. There was no significant difference in the levels of both plasma TBARS and erythrocyte glutathione, between women with POS group and healthy women group. Plasma DHEAS levels of healthy men and women with POS were similar. Plasma TBARS level was higher and erythrocyte glutathione level was lower in the healthy men group than in both the healthy women group and in the women with POS group. These data imply that testosterone has an oxidant effect. DHEAS which is an antioxidant, has a protective role in females with POS. Estrogens have an antioxidant effect but this action changes according to its dominant degradation pathway.

The effect of prolactin and bromocriptine on human peripheral immune status.

The aim of this study was to determine the influence of elevated serum prolactin (PRL) levels on the peripheral lymphocyte subsets in patients with hyperprolactinemia. For this purpose we studied 20 hyperprolactinemic patient lymphocyte subsets by flow cytometry on their hyperprolactinemic state and after their serum prolactin concentration was normalized with bromocriptine (BC) alone or BC and surgery. We observed decreased absolute numbers and percentage of Natural Killer (p=0.0009 and 0.0001, respectively) and CD3/CD25 lymphocytes (p = 0.009 and 0.002) in hyperprolactinemic patients, compared to 8 sex- and age-matched normal controls. There was no correlation between PRL levels and CD16/56 and CD3/CD25 numbers (p=0.72 and 0.33, respectively). We did not find any significant difference in absolute numbers (p = 0.95) and percentage (p = 0.84) of B-lymphocytes of hyperprolactinemic patients, as compared with normal controls. We did not detect any increase in absolute cell numbers of CD16/CD56 (p = 0.21) and CD3/CD25 (p = 0.61) of BC-treated patients when compared to their hyperprolactinemic state. We demonstrated an increase in CD8-cells (p = 0.0173) and a decrease in CD4/CD8 ratio (p = 0.036) in hyperprolactinemic patients treated with BC. There was also an increase in the number of activated T-cells (CD3/HLA DR) in this group, compared to normal controls and the hyperprolactinemic state of the same patients (p = 0.04). In conclusion, elevated PRL levels do not lead to an "overstimulation" of the B-cells, but deteriorate the cytotoxic function.

An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for hPTTG family.

A novel proto-oncogene, PTTG (Pituitary Tumor Transforming Gene), was isolated in our laboratory by virtue of its increased expression in rat pituitary tumor cell lines. Cells which overexpress human or rat PTTG form tumors in athymic mice. hPTTG is highly expressed in cancer cell lines, pituitary adenomas and in normal testis, suggesting that hPTTG protein has different tissue-specific interactions in normal cells and in cancer. Alternatively, different hPTTG gene family members may be functional in normal development and in tumorigenesis. While mapping the chromosomal location of hPTTG to 5q33, we discovered a second gene, hPTTG2, which is intronless and maps to chromosome 4p12. Using gene-specific oligonucleotide hybridization in a PCR-ELISA assay, we determined that hPTTG2 is expressed in both normal and tumorous pituitary. However, high levels of hPTTG mRNA in cancer cell lines are due to increased expression of hPTTG1. Thus, this family of proto-oncogenes appears to differentially participate in tumor-specific pathogenesis.