Autoimmune Disease in Turner Syndrome in Sweden: An up to 25 Years' Controlled Follow-up Study.

CONTEXT: Turner syndrome (TS) is the most common chromosomal aberration in women; it is the result of structural or numeric abnormalities in the X chromosome. Autoimmune hypothyroidism has been recognized as one of the more prominent disorders associated with TS. OBJECTIVE: This work aimed to study the prevalence of autoimmune diseases in TS. METHODS: A cross-sectional, longitudinal, 25-year follow-up study was conducted of patients from adult Turner centers at the University Hospitals, Sweden. During 1994 to 2020, a total of 503 women aged 16 to 71 years with TS were evaluated consecutively every fifth year according to national guidelines. A random population sample of women, n = 401, aged 25 to 44 years, from the World Health Organization Monitoring of Trends and Determinants for Cardiovascular Disease (MONICA) project served as controls. Serum thyrotropin, free thyroxine, vitamin B12, antithyroid peroxidase (anti-TPO), and antitransglutaminase antibodies were measured. RESULTS: Mean follow-up time (years) was 16 ± 7 for patients and 13 ± 1 for controls. From study start, the prevalence increased in TS for hypothyroidism 40% to 58%, vitamin B12 deficiency 5% to 12%, celiac disease 4% to 7%, positive anti-TPO 26% to 41%, and antitransglutaminase antibodies 6% to 8% (P < .0001 vs controls). Type 1 diabetes and Addison disease were rare. The only interrelationship was between hypothyroidism and vitamin B12 deficiency, both in TS and controls. No association between autoimmune disease and karyotype, antecedent growth hormone treatment, or ongoing estrogen hormone replacement, was seen in TS. CONCLUSION: In women with TS up to older than 80 years, more than half developed hypothyroidism, mainly autoimmune, during follow-up. Awareness of vitamin B12 deficiency and celiac disease throughout life is also recommended in women with TS.

Androgens impact on psychopathological variables according to CPRS, and EDI 2 scores: In women with bulimia nervosa, and eating disorder not otherwise specified.

Bulimia nervosa (BN) is characterized by binge eating, compensatory behavior, over-evaluation of weight and shape, which often co-occur with symptoms of anxiety and depression. Depression is the most common comorbid diagnosis in women with eating disorders. The role of androgens in the pathophysiology of depression has been recognized in recent years. However, the research on psychopathological comorbidity and androgen levels in bulimic disease is sparse. This study aimed to investigate, if there were any correlations between the androgens, testosterone (T), dehydroepiandrosterone sulphate (DHEAS), androstenedione (A4), 5α-dihydrotestosterone, (5α-DHT), and test scores of psychopathological variables, in women with bulimia nervosa (BN), eating disorder not otherwise specified of purging subtype (EDNOS-P) assessed by CPRS, and EDI 2. Women with DSM-IV diagnosis of BN (n = 36), EDNOS-P (n = 27), and healthy control subjects (n = 58) evaluated for fifteen psychopathological variables, i.a. depressive symptoms, impulsivity, personal traits, as well as serum androgen levels. All women were euthyroid, and polycystic ovarian syndrome (PCOS) diagnosis was excluded. Although androgen levels were almost equal for all three groups, significant correlations between core psychopathological symptoms (9/15) of bulimia nervosa and the most potent endogenous androgen, 5α-DHT, was found only in the EDNOS-P group. The role of 5α-DHT in women is not fully elucidated. Both animal and human studies have shown that the brain is able to locally synthesize steroids de novo and is a target of steroid hormones. Maybe these results can be interpreted in the light of differences in androgen receptor variability, metabolism and origin of T and 5α-DHT.

Aortic size predicts aortic dissection in Turner syndrome - A 25-year prospective cohort study.

BACKGROUND: Women with Turner syndrome (TS) have an increased risk of aortic dissection. The current recommended cutoff to prevent aortic dissection in TS is an aortic size index (ASI) of ≥2.5 cm/m2. This study estimated which aortic size had the best predictive value for the risk of aortic dissection, and whether adjusting for body size improved risk prediction. METHODS: A prospective, observational study in Sweden, of women with TS, n = 400, all evaluated with echocardiography of the aorta and data on medical history for up to 25 years. Receiver operating characteristic (ROC) curves, sensitivity and specificity were calculated for the absolute ascending aortic diameter (AAD), ascending ASI and TS specific z-score. RESULTS: There were 12 patients (3%) with aortic dissection. ROC curves demonstrated that absolute AAD and TS specific z-score were superior to ascending ASI in predicting aortic dissection. The best cutoff for absolute AAD was 3.3 cm and 2.12 for the TS specific z-score, respectively, with a sensitivity of 92% for both. The ascending ASI cutoff of 2.5 cm/m2 had a sensitivity of 17% only. Subgroup analyses in women with an aortic diameter ≥ 3.3 cm could not demonstrate any association between karyotype, aortic coarctation, bicuspid aortic valve, BMI, antihypertensive medication, previous growth hormone therapy or ongoing estrogen replacement treatment and aortic dissection. All models failed to predict a dissection in a pregnant woman. CONCLUSIONS: In Turner syndrome, absolute AAD and TS-specific z-score were more reliable predictors for aortic dissection than ASI. Care should be taken before and during pregnancy.

Case report: acromegaly and breast cancer in a woman with turner syndrome.

PURPOSE: To present a case with a woman with Turner syndrome (TS) with acromegaly and breast cancer, in her medical history. METHOD: A descriptive case report of a single patient. RESULTS: The woman had short stature and lack of puberty and was not treated with hormones. When she was 36-year-old, acromegaly was diagnosed. She was treated with transsphenoidal surgery, followed by external radiation on the adenoma, without any affection on the pituitary gland. Annual controls revealed ordinary pituitary axes during 40 years' follow-up. She was treated for hypertension, had an aortic dilatation and started menopausal hormone therapy (MHT),1 mg estradiol and 0.5 mg norethisterone acetate daily, at the age of 50, due to osteoporosis. At the age of 60, she was diagnosed with breast cancer at the mammography screening. After, mastectomy, neoadjuvant radiation, and treatment with tamoxifen citrate were given due to the tubular breast cancer. CONCLUSIONS: Despite a possible growth hormone (GH) resistance and lack of endogenous estradiol in women with TS, this patient was diagnosed with acromegaly and breast cancer. This case demonstrates the potential for co-occurring two hormonally active tumors in a woman with TS with monosomy karyotype.

So similar and so different: Circulating androgens and androgen origin in bulimic women.

Hyper androgen state frequently can be diagnosed in bulimic women. Eating disorder not otherwise specified (EDNOS) recognized as a less severe form of bulimia nervosa (BN). The objective of the study was to determine whether androgen levels and androgen origin differs in bulimic women compared to control subjects. Forty-six women with bulimia nervosa (BN), 31 with eating disorder not otherwise specified, purging type (EDNOS P) and 56 matched healthy controls were studied with respect to serum testosterone (T), 5alpha-dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), deyhydroepiahndrosterone sulfate (DHEAS) and luteinizing hormone (LH) and to ovarian morphology. Despite all groups had almost identical androgen and SHBG levels; there were differences in the origin of circulating T and DHT. Correlation analysis suggest major differences in the formation of circulating testosterone (T) and 5α-dihydrotestosterone (DHT) with BN being more like the control subjects with peripheral formation from 4-androsterne-3,17-dione (A-4), dehydroepiandrosterone sulfate (DHEAS) and also from T. While in EDNOS group a possible direct ovarian T secretion and a DHEAS modulating action of androgens on pituitary gonadotropin secretion is present. The origin of circulating T and DHT differs between bulimics. Our findings do probably not reflect direct actions of circulating DHT on pituitary LH secretion in the women with EDNOS, but rather the effect of A-4, T via conversion to DHT in the central nervous system, indicating psych/endocrine differences between the two groups of bulimic women.

Dehydroepiandrosterone and/or its metabolites: possible androgen receptor antagonistic effects on digitized mammographic breast density in normal breast tissue of postmenopausal women.

Background Androgens, notably testosterone inhibit breast cell proliferation and negative correlations between free testosterone (fT) and breast cell proliferation as well as mammographic density have been described. Dehydroepiandrosterone (DHEA) is reported to be a partial androgen antagonist in breast tumor cells in vitro. Our aim was to investigate if circulating DHEA had any effects on the association between circulating fT and mammographic density in vivo in the normal postmenopausal breast. Methods We measured visual and digitized mammographic density and serum DHEA, testosterone, sex-hormone-binding globulin and calculated fT in 84 healthy untreated postmenopausal women. Results Significant negative correlations between fT and both visual and digitized mammographic density were strengthened when the median DHEA level decreased from 10.2 to 8.6 nmol/L. Thereafter, correlations became weaker again probably due to decreasing fT levels and/or sample size. There were no correlations between mammographic density and DHEA, at any of the DHEA concentration ranges studied. Serum levels of fT and DHEA were positively correlated. Conclusion Our findings demonstrate that circulating DHEA and/or its metabolites counteract the inhibitory action of fT on mammographic breast density.

Estrone - a partial estradiol antagonist in the normal breast.

Oral hormone replacement therapy (HRT) based on estradiol-17ß (E2) greatly increases circulating estrone (E1) levels. E1 is an estrogen receptor agonist but may also be a partial E2 antagonist. We investigated the effects of circulating E1 on the association between circulating E2 and the increase in mammographic density (∂MD) in 46 healthy post-menopausal women treated with E2 2 mg and norethisterone acetate 1 mg daily. MD and serum E1 and E2 were measured before and after 6 months of treatment. At high E1 levels, ∂MD showed significant positive correlations leading to increase (∂-values) in both E1 and E2. Lowering the upper serum E1 limit strengthened the correlations to ∂E2 while the significant correlations to ∂E1 disappeared. E1 at high concentrations may act as a partial E2 antagonist also in the normal breast in vivo and disturb relationships between circulating E2 and biological estrogen effects. When investigating the relations between circulating steroids and their effects, structurally related compounds, which may act as partial antagonists, have to be considered, at least when they are present in higher concentrations.

Long-term follow-up of bone density, general and reproductive health in female survivors after treatment for haematological malignancies.

The purpose of this study was to assess the ovarian function, fertility and bone mineral density in women who previously had treatment for different haematological malignancies (HMs). The overall survival and cure rates of patients with HMs have improved dramatically. The treatment affects fertility and bone density. Fifty-two premenopausal women, from Stockholm region, were included in the study between 1998 and 2002, followed until 2011. The diagnoses were acute lymphoblastic leukaemia (n = 6), acute myeloid leukaemia (n = 10), chronic lymphocytic leukaemia (n = 1), chronic myeloid leukaemia (n = 12), Hodgkin lymphoma (n = 12) and non-Hodgkin lymphoma (n = 11). Before treatment, women without children (43/52), when possible, were offered fertility preservation options. The mean age at diagnosis was 27, at final evaluation 39 yr. Thirty-seven patients received HSCT; 26 allogeneic, 11 autologous. Before allogeneic HSCT, nineteen patients had myeloablative conditioning; seven had reduced-intensity conditioning. Eleven patients got total body irradiation. Eight patients were transplanted with grafts from an HLA-identical sibling donor, while 18 had unrelated donors. All women were in a menopausal state post-therapy. Hormone replacement therapy (HRT) was given, and bone mineral density (BMD) was measured every other year. The serum levels of parathyroid hormone (PTH), free and bound calcium was within normal range. BMD measurements showed a slight increase over time in the spine with a mean of 0.015 g/cm(2) /yr. Four spontaneous pregnancies resulted in two babies and two discontinued pregnancies; two pregnancies were achieved with oocyte donation and surrogacy and one woman adopted a child. HRT sustains BMD in long-term survivors from HMs. This study highlights the importance of HRT and fertility issues in this patient group.

Megestrol acetate may stimulate the production of insulin-like growth factor 1 in breast tissues of women with breast cancer.

BACKGROUND: In women with breast cancer who were treated with either continuous tamoxifen alone or sequential tamoxifen followed by megestrol acetate (MA), we demonstrated significant positive associations between the breast tumor estrogen receptor (ER) and an increase in serum sex hormone-binding globulin (SHBG) during tamoxifen treatment. We interpreted this as "ER uniformity" in different tissues, e.g., breast, liver. No other associations with ER were found. In the same study, the breast tumor progesterone receptor (PR) was determined. Our aim was to see if there were any associations between PR and endocrine changes during MA treatment. METHODS: The breast tumor PR before treatment and serum insulin-like growth factor I (∂IGF-1), steroids, steroid-binding proteins, and insulin before and during treatment were measured in 17 postmenopausal women with breast cancer who were treated sequentially with tamoxifen 40 mg/day followed by MA 160 mg/day in alternating 3-month periods. RESULTS: During MA treatment periods, the levels of IGF-1 and insulin increased significantly, whereas the levels of androgens, SHBG, corticosteroid-binding globulin, and cortisol decreased significantly. Significant positive correlations were found between the PR content and increments in ∂IGF-1 but not between PR and any other endocrine change. CONCLUSIONS: PR expression in human liver is very weak, but malignant and normal breast tissues secrete considerable amounts of growth hormone and IGF-1 in vitro and in vivo. This activity is stimulated by progestogens. The association between PR and ∂IGF-1 may therefore reflect a direct PR-mediated action of MA on malignant and normal human breast tissues in vivo.

Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal.

BACKGROUND: The eating disorder bulimia nervosa (BN) is characterized by frequent episodes of binge eating, followed regularly by inappropriate compensatory behavior, such as self-induced vomiting. OBJECTIVE: The current investigation was designed to examine possible alterations in the secretion of the gastrointestinal satiety peptides glucagon-like peptide 1 (GLP-1) and pancreatic polypeptide (PP) in women with BN. DESIGN: Twenty-one women with BN and 17 healthy control subjects of comparable age and BMI were recruited. After fasting overnight, the subjects provided blood samples during ingestion of a standardized meal and self-rated their appetite on a visual analog scale. Fasting and meal-related secretion of the incretin GLP-1 and the meal-related feedback signal PP and insulin and glucose as indicators of the metabolic homeostasis were analyzed. RESULTS: Women with BN had significantly lower fasting and postprandial serum concentrations of GLP-1 (P < 0.01) and PP (P < 0.05) than did the control subjects. Furthermore, both the basal (P < 0.001) and peak (P < 0.05) concentrations of insulin were significantly attenuated in the bulimic subjects, whereas glucose concentrations were normal. As a consequence, the bulimic homeostasis model assessment of insulin index values were also lower (P < 0.001). CONCLUSIONS: Women with BN secrete abnormally low amounts of GLP-1 and PP, possibly because of the adaption to large meals in the form of enlarged gastric capacity and reduced muscle tone in the gastric wall. Attenuated secretion of these gastrointestinal satiety peptides may play a role in the maintenance of bulimic behavior.

Bone mineral density in bulimic women--influence of endocrine factors and previous anorexia.

OBJECTIVE: Data concerning bone mineral density (BMD) in bulimia nervosa are contradictory and include both low and normal values. The aim of the present study was to elucidate possible endocrine-and nutrition-related factors predicting BMD in bulimic women. DESIGN: Cross-sectional study. METHODS: Seventy-seven bulimic patients and 56 age- and body mass index (BMI)-matched healthy controls were examined with respect to BMD (dual energy X-ray absorptiometry) and to serum levels of hormones and metabolic factors. RESULTS: Bulimics had significantly lower spinal BMD and higher frequency of osteopenia in the total body than controls. Furthermore, bulimic women had significantly lower levels of estradiol-17beta and free thyroxine and significantly higher cortisol levels compared with controls. Among the bulimics, 31.2% had present menstrual disturbance, 51.9% had a history of amenorrhea and 23.4% had previous anorexia nervosa. Subgroups of bulimics with a history of amenorrhea and previous anorexia nervosa had significantly lower total and spinal BMD than controls, whereas those without such history did not differ from the controls. In univariate analysis, a history of amenorrhea, cortisol, testosterone, previous anorexia nervosa, and BMI showed significant associations with spinal BMD. Multiple regression analysis including all significant variables revealed previous anorexia nervosa to be the strongest determinant of spinal BMD, accounting for 34% of the variance, while associations between endocrine factors and BMI disappeared. CONCLUSIONS: Low bone mass in bulimics may be explained by previous anorexia nervosa, whereas endocrine variables related to BMD seem to be secondary determinants that are dependent on previous anorexia nervosa and BMI.

Polycystic ovary syndrome in bulimic women--an evaluation based on the new diagnostic criteria.

An association between bulimia nervosa and polycystic ovary syndrome (PCOS) has been suggested but also questioned. Since there is still a controversy about this issue, we investigated clinical and biochemical symptoms of PCOS according to the new diagnostic criteria in a large group of bulimic women compared with controls. Seventy-seven women with bulimia and 59 matched healthy women were investigated with respect to menstrual status, polycystic ovaries, hirsutism, acne and sex hormone levels. We found increased occurrence of menstrual disturbances, hirsutism and PCOS in bulimic women, whereas ovarian variables and acne did not differ from controls. Hirsutism score and indices of biologically active testosterone were positively correlated in bulimics but not in controls, while there were no major differences in serum androgens. In conclusion, this study supports an increased frequency of PCOS in bulimic women and may also indicate increased androgen sensitivity in these women. PCOS may promote bulimic behavior since androgens have appetite-stimulating effects and could impair impulse control. Menstrual disturbances and clinical signs of hyperandrogenism should be evaluated in bulimics in order to provide adequate medical care and treatment.