Sabine Naessén

Impaired cholecystokinin secretion and disturbed appetite regulation in women with polycystic ovary syndrome

Increased amount of abdominal fat and obesity are common in polycystic ovary syndrome (PCOS). A higher prevalence of bulimia nervosa and greater cravings for sweets have also been reported in these patients. The present study aimed to compare meal-related appetite and secretion of the ‘satiety peptide’ cholecystokinin (CCK) and glucose regulatory hormones in PCOS women and controls. Sixteen pairs of women with PCOS and controls matched for age and body mass index participated in the study. After an overnight fast, blood samples were collected during ingestion of a standardized meal. We determined basal and postprandial blood levels of CCK, insulin, C-peptide, glucagon, cortisol, growth hormone and glucose. Self-ratings of appetite were assessed by a visual analog scale. PCOS women had a significantly lower meal-related CCK response (p < 0.05) with no association with satiety, as in the controls (r = 0.64). There was a tendency to higher ratings of craving for sweets in PCOS women (p = 0.07) but no correlation with insulin, as in the controls (r = 0.50). Within the PCOS group, ratings of craving for sweets were inversely related to testosterone (r = −0.60) and the CCK response was positively correlated with levels of free testosterone (r = 0.50). We conclude that women with PCOS have reduced postprandial CCK secretion and deranged appetite regulation associated with increased levels of testosterone. Impaired CCK secretion may play a role in the greater frequency of binge eating and overweight in women with PCOS.

Association of estrogen receptor β gene polymorphisms with bulimic disease in women

In this study, we explored the potential association between estrogen receptor β (ERβ) and disease in a group of bulimic women. Eating disorders are much more common in females than in males, suggesting a possible role for female sex hormone signalling in the pathogenesis of these diseases. Furthermore, estrogen has been implicated in appetite regulation. The occurrence of menstrual disturbances is also increased in bulimic women. We studied 76 bulimic women and 60 controls, and found an association between two common polymorphisms in the ERβ gene with disease in this group of bulimic women. More detailed characterisation of the ERβ gene identified a novel variant changing the primary structure of ERβ protein in one bulimic patient. An initial functional characterization of this variant did not reveal any differences compared to the wild-type protein. Our findings point towards a possible role of ERβ and/or neighboring genes in the etiology of disease in bulimic patients.

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.

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.

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/cm2/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.

Estrone - a partial estradiol antagonist in the normal breast.

Abstract Oral hormone replacement therapy (HRT) based on estradiol-17β (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. Chinese abstract 口服激素替代治疗（HRT）基于17β-雌二醇（E2）大大增加了循环的雌酮（E1）的水平。E1是一种雌激素受体激动剂，但也可能是一个E2的部分拮抗剂。我们研究了46名健康绝经后女性每天口服E2 2mg和醋酸炔诺酮1mg后循环中E1在循环中E2与乳腺密度增加之间关系中的作用。治疗前和治疗6个月后分别测定乳腺密度及血清E1和E2。E1高水平时，乳腺密度与E1和E2的增加呈密切正相关。不断降低血清E1至上限，与E2的相关性加强而与E1的相关性消失。E1在高浓度时可能是体内正常乳腺组织内E2的部分拮抗剂，干扰了循环中E2和雌激素生物效应之间的联系。当研究循环中类固醇和它们作用的时候，结构相关的化合物具有较高浓度的时候必须要考虑，因为它们可能是部分拮抗剂。

Sex Hormones and Appetite in Women: A Focus on Bulimia Nervosa

Sex hormones play an important role in the regulation of appetite and energy metabolism. Estrogen is known to inhibit feeding, whereas progesterone and testosterone may stimulate appetite. There is increasing knowledge about the role of sex hormones in disturbed eating behavior. Bulimia nervosa is frequently associated with sex hormone disturbances, which may be secondary or primary to abnormal eating. Menstrual disorders and low estradiol levels are common although most bulimic women are of normal weight. Furthermore, polymorphisms in the estrogen receptor b gene have been associated with bulimic behavior. Increased androgens and clinical features of hyperandrogenism like acne, hirsutism, and polycystic ovary syndrome (PCO) are also frequent among bulimics. High testosterone levels in women have been associated with a greater craving for sweets, impaired impulse control, irritability, and depression. It has therefore been suggested that androgens may promote bulimic behavior. In support of this hypothesis, antiandrogenic treatment has been demonstrated to improve bulimic behavior. Oral contraceptives (OCs) with antiandrogenic properties reduce symptoms in bulimic patients in relation to decreased testosterone levels. The findings support that androgens could play a significant role in bulimic behavior. Antiandrogenic treatment may therefore develop into a new therapeutic approach in women with bulimia nervosa, especially in those bulimics with hyperandrogenic symptoms.

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

Abstract 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.

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

Abstract 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.