Risk of Fracture After Bilateral Oophorectomy.

Fragility fractures, resulting from low-energy trauma, occur in approximately 1 in 10 Danish women aged 50 years or older. Bilateral oophorectomy (surgical removal of both ovaries) may increase the risk of fragility fractures due to loss of ovarian sex steroids, particularly estrogen. We investigated the association between bilateral oophorectomy and risk of fragility fracture and whether this was conditional on age at time of bilateral oophorectomy, hormone therapy (HT) use, hysterectomy, physical activity level, body mass index (BMI), or smoking. We performed a cohort study of 25,853 female nurses (≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from age 50 years or entry into the cohort, whichever came last, until date of first fragility fracture, death, emigration, or end of follow-up on December 31, 2018, whichever came first. Cox regression models with age as the underlying time scale were used to estimate the association between time-varying bilateral oophorectomy (all ages, <51/≥51 years) and incident fragility fracture (any and site-specific [forearm, hip, spine, and other]). Exposure and outcome were ascertained from nationwide patient registries. During 491,626 person-years of follow-up, 6600 nurses (25.5%) with incident fragility fractures were identified, and 1938 (7.5%) nurses had a bilateral oophorectomy. The frequency of fragility fractures was 24.1% in nurses who were <51 years at time of bilateral oophorectomy and 18.1% in nurses who were ≥51 years. No statistically significant associations were observed between bilateral oophorectomy at any age and fragility fractures at any site. Neither HT use, hysterectomy, physical activity level, BMI, nor smoking altered the results. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pituitary-testis axis dysfunction following adjuvant androgen deprivation therapy.

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary-testis axis function in patients receiving adjuvant ADT.

Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass.

Menopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women.

CONTEXT: Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. OBJECTIVE: To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. METHODS: A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60 years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120 min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). RESULTS: Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p = 0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p = 0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p < 0.001) with comparable and modest s-PINP suppression over menopause (p = 0.13). Postprandial plasma GLP-1 (p = 0.006) and GLP-2 (p = 0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p = 0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. CONCLUSIONS: Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.

No evidence of a synergistic effect of HIV infection and diabetes mellitus type 2 on fat distribution, plasma adiponectin or inflammatory markers.

BACKGROUND: Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. METHODS: A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. RESULTS: HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2-(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. CONCLUSION: A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD.

Use of antidepressants in women after prophylactic bilateral oophorectomy: A Danish national cohort study.

OBJECTIVE: To investigate the association between prophylactic bilateral oophorectomy and use of antidepressants in women with a family history of cancer. METHODS: Nationwide population-based cohort study using Danish National Registries including women oophorectomized due to a family history of cancer (n = 2,002) and an age matched reference group (n = 18,018). Analyses were stratified by age at time of bilateral oophorectomy and use of hormone replacement therapy (HRT). RESULTS: Women oophorectomized at age ≤ 45 years were more likely to use antidepressants from the first year after bilateral oophorectomy (OR = 1.34; 95 % CI: 1.08-1.65) compared to the reference group. Women oophorectomized at age 46-55 years and at age >55 years had no significantly increased use of antidepressants (OR = 0.90; 95 % CI: 0.68-1.18 and OR = 1.14; 95 % CI: 0.81-1.61). The increased use of antidepressants in women oophorectomized at age ≤ 45 years was limited to women treated with HRT (OR = 1.51; 95 % CI: 1.18-1.94) whereas women oophorectomized at age ≤ 45 years not treated with HRT had no increased use of antidepressants (OR = 1.03; 95 % CI: 0.70-1.51). CONCLUSIONS: Women oophorectomized due to a family history of cancer at age ≤ 45 years were more likely to use antidepressants after bilateral oophorectomy. The increased use of antidepressants was limited to women treated with HRT. The study calls for further large-scale studies to understand how bilateral oophorectomy and concomitant HRT affects risk of depression in women with a family history of cancer.

Metabolic control and sex: A focus on inflammatory-linked mediators.

Men and women have many differing biological and physiological characteristics. Thus, it is no surprise that the control of metabolic processes and the mechanisms underlying metabolic-related diseases have sex-specific components. There is a clear metabolic sexual dimorphism in that up until midlife, men have a far greater likelihood of acquiring cardio-metabolic disease than women. Following menopause, however, this difference is reduced, suggestive of a protective role of the female sex hormones. Inflammatory processes have been implicated in the pathogenesis of cardio-metabolic disease with human studies correlating metabolic disease acquisition or risk with levels of various inflammatory markers. Rodent studies employing genetic modifications or novel pharmacological approaches have provided mechanistic insight into the role of these inflammatory mediators. Sex differences impact inflammatory processes and the subsequent biological response. As a consequence, this may affect how inflammation alters metabolic processes between the sexes. Recently, some of our work in the field of inflammatory genes and metabolic control identified a sexual dimorphism in a preclinical model and caused us to question the frequency and scale of such findings in the literature. This review concentrates on inflammatory-related signalling in relation to obesity, insulin resistance, and type 2 diabetes and highlights the differences observed between males and females. Differences in the activation and signalling of various inflammatory genes and proteins present another reason why studying both male and female patients or animals is important in the context of understanding and finding therapeutics for metabolic-related disease. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling.

OBJECTIVE: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R-/- animals. METHODS: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R-/-) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. RESULTS: Female IL-18R-/- mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R-/- mice was lost with aging. By 72 weeks of age, IL-18R-/- mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R-/- mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. CONCLUSIONS: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R-/- mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R-/- mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment.

Mortality and Risk of Cancer After Prophylactic Bilateral Oophorectomy in Women With a Family History of Cancer.

BACKGROUND: Current international guidelines recommend systemic hormone therapy (HT) to oophorectomized women until the age of natural menopause. Despite an inherited predisposition to estrogen-dependent malignancies, the guidelines also apply to women oophorectomized because of a family history of cancer. The objective of this study was to investigate the impact of HT on mortality and risk of cancer in women oophorectomized because of a family history of cancer. METHODS: A nationwide, population-based cohort was used to study women oophorectomized because of a family history of cancer (n = 2002). Comparison cohorts included women from the background population individually matched on age (n = 18 018). Oophorectomized women were subdivided into three groups: oophorectomized at 1) age 45 years or younger not using HT, 2) age 45 years or younger using HT, 3) older than age 45 years, and their respective population comparison cohorts. RESULTS: Women oophorectomized at age 45 years or younger using HT had increased overall mortality (mortality rate ratio [MRR] = 3.45, 95% confidence interval [CI] = 1.53 to 7.79), mortality because of cancer (MRR = 5.67, 95% CI = 1.86 to 17.34), and risk of overall cancer (incidence rate ratio [IRR] = 3.68, 95% CI = 1.93 - 6.98), primarily reflected in an increased risk of breast cancer (IRR = 4.88, 95% CI = 2.19 - 10.68). Women oophorectomized at age 45 years or younger not using HT and women oophorectomized at older than age 45 years did not have increased mortality, mortality because of cancer, or risk of overall cancer, but they had increased risk of breast cancer (IRR = 2.64, 95% CI = 1.14 to 6.13, and IRR = 1.72, 95% CI = 1.14 to 2.59, respectively). CONCLUSIONS: Use of HT in women oophorectomized at age 45 years or younger with a family history of cancer is associated with increased mortality and risk of overall cancer and breast cancer. Our study warrants further investigation to establish the impact of HT on mortality and cancer risk in oophorectomized women with a family history of cancer.

[Treatment of adrenocortical carcinomas is challenging]. / Diagnose og behandling af binyrebarkkarcinom.

Adrenocortical carcinomas (ACC) are rare tumours responsible for only 0.02% of the total number of malignant diseases. However the ACC are aggressive with a mean fiveyears survival of 20-50% and are often associated with increased production of adrenocortical hormones. The effect of the treatment is controversial and often based on small retrospective series or expert opinions. Centralization, international attention and collaboration in the treatment of ACC are mandatory. Randomized clinical trials are needed to determine the best treatment strategy in order to increase survival in patients with ACC.

[Lack of uniformity in the treatment of thymomas]. / Usikkerhed om behandlingsstrategien ved tymomer.

Thymomas are the most frequently occurring tumours of the anterior mediastinum. However, they only constitue less than 1% of the total number of malignant diseases. The incidence in the USA is 0.15 per 100.000 persons per year, and the disease is most frequent in persons between 40 and 60 years of age. Because of the rarity of thymomas, lack of uniformity in treatment has been a major problem over the years. Therefore, international collaborations have been established, and national oncological centralisation of management has been arranged in order to improve the treatment and prognosis.

Capecitabine and oxaliplatin as second-line treatment in patients with carcinoma of unknown primary site.

BACKGROUND: Treatment of patients with carcinoma of unknown primary site (CUP) remains a challenge, and no effective second-line treatment has been identified. In CUP patients who are non-responsive or relapse early after first-line platinum/taxane-based regimens, it is likely that gastrointestinal (GI) tract tumours may be overrepresented. These patients could be candidates for GI tract-directed therapy. We here report the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine. PATIENTS AND METHODS: Patients received capecitabine orally (1000 mg/m(2)) twice daily, days 1-14, and oxaliplatin (130 mg/m(2)) intravenously on day 1 in a three-week schedule. RESULTS: Twenty-five CUP patients received a median of three cycles of capecitabine and oxaliplatin as second-line treatment. Histopathological assessments suggested the primary site to be of GI tract origin in the majority of the patients (76%). We found an objective response rate of 13%, a median progression-free survival and overall survival rate of 2.3 and 3.9 months, respectively, and 32% of patients alive at one year after initiation of second-line therapy. The regimen was well tolerated by most patients. CONCLUSIONS: This study, demonstrates that there is still a significant need for improved second-line therapy in CUP patients.