Uterine cancer

Uterine cancers are the most common female genital cancer in the developed world and the fourth most common malignancy in women. In South Africa and most developing countries it is the second most common genital tract malignancy after cervical carcinoma. While the incidence of uterine cancers is marginally higher in developed countries (5.9 vs 4 per 100,000), the disease-specific mortality rate is higher in developing countries. Uterine cancers include tumours that develop in the endometrium (carcinomas), the endometrial support cells (endometrial stromal sarcomas), and the myometrium (sarcomas). Endometrial carcinomas represent over 90% of uterine cancers, the incidence of which is increasing and is most likely driven by longer life expectancy, obesity, and a sedentary lifestyle. Most endometrial carcinomas present in postmenopausal women; however, in women with significant risk factors (such as unopposed endogenous oestrogen production as occurs in women with polycystic ovarian syndrome) or a genetic predisposition such as hereditary non-polyposis colorectal cancer (HNPCC)/Lynch 2 syndrome, tumours may present before the age of 40 years. Sarcomas constitute less than 10% of uterine cancers, the majority of which are leiomyosarcomas. Only 2% of uterine sarcomas originate in the endometrial stromal tissue. Most sarcomas present between the age of 40 and 60 years. For the purpose of this chapter, endometrial carcinomas and sarcomas will be discussed separately.

Association between subjective olfactory dysfunction and female hormone-related factors in South Korea

An association between olfactory dysfunction and female hormone level has been reported; however, no previous studies have investigated the correlation with life-long female hormone exposure. The aim of this study was to estimate the association between subjective olfactory dysfunction and various endogenous and exogenous female hormone-related factors including age at menarche and menopause, number of pregnancies and deliveries, age at first and last delivery, duration of breastfeeding, use of oral contraceptives, and use of hormone therapy. The study analysed a total of 3863 female participants using data from the Korean National Health and Nutrition Examination Survey V (2010–2012). The prevalence of olfactory dysfunction was 3.5% for premenopausal participants and 6.2% for postmenopausal women. Among premenopausal women (compared to women breastfed less than 12 months), the 12–24-month group (OR = 4.690, 95% CI = 1.431–15.369) and the 25–48-month group (OR = 6.548, 95% CI = 1.758–24.394) had higher rates of olfactory dysfunction. In postmenopausal women, starting menopause at a younger age was positively associated with olfactory dysfunction (OR = 0.939, 95% CI = 0.887–0.993). These data suggest that a longer duration of endogenous oestrogen deprivation is associated with subjective olfactory dysfunction.

Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice.We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).ob/ob mice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in male ob/ob mice. Intra-thoracic fat from ob/ob mice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS.Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.

Microparticles reveal cell activation during IVF – a possible early marker of a prothrombotic state during the first trimester

SummaryCell-derived microparticles (MPs) are known to be elevated in a number of diseases related to arterial and venous thromboembolism (VTE), such as acute myocardial infarction, VTE (deep-vein thrombosis and pulmonary embolism) and peripheral arterial disease. IVF-associated pregnancies have previously been shown to be associated with an increased incidence of VTE, mechanisms behind being unknown and sparsely studied. Our objective was to assess cell activation during IVF through analysis of MP levels and phenotype following ovarian stimulation. Thirty-one women undergoing IVF were included and blood samples were collected at down regulation of oestrogen and at high level stimulation with 10- to 100-fold increased endogenous oestrogen levels. MPs were analysed by flow cytometry and phenotyped according to size and protein expression. We found that overall phosphatidylserine positive platelet-, endothelial- and monocyte-derived MPs significantly increased following ovarian stimulation with increased levels of platelet activation markers CD40 ligand and P-selectin. Furthermore, there was an increase in endothelial-derived MPs exposing activation marker E-selectin and monocyte-derived MPs, while neutrophil-derived MPs decreased slightly. In conclusion we found a major increase in MPs and markers indicating cell activation in parallel with the profound oestrogen boost during IVF. To assess whether these changes in MPs are associated with thromboembolic events requires extended longitudinal studies.

GH responsiveness varies during the menstrual cycle

Objective: The GH–IGF-1 axis is affected by oestrogen. Both endogenous and exogenous oestrogen facilitates the central drive of pulsatile GH secretion. However, the effect on IGF-1 levels is more subtle, and a reduction in GH sensitivity has been proposed. The IGF generation test has confirmed reduced GH sensitivity with high doses of exogenous oestrogen. It is not known, however, whether fluctuant levels of endogenous oestrogen modify GH sensitivity. To investigate this further, women were challenged with the IGF-1 generation test at different stages of the menstrual cycle. Methods: Nine women (age 38(6) years (mean (s.d.)) with regular menstrual cycles were recruited. An IGF-1 generation test, s.c. injection of 7 mg GH, was performed in the early-follicular (EF), periovulatory (PO) and midluteal (ML) phases. IGF-1, insulin-like growth factor binding protein (IGFBP)-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h after GH administration. Results: Oestradiol levels were lower in the EF than PO or ML phases (32.6(7.8) vs 69.6(16.2) vs 66.6(23.6) pg/ml respectively (repeated measures ANOVA, P < 0.001)). Baseline IGF-1 was lower, but increment IGF-1 (peak minus baseline) was higher in the EF than PO or ML phases (baseline: 291.8(56.6) vs 335.0(55.2) vs 346.6(78.2) ng/ml (P = 0.008); increment IGF-1: 234.6(59.2) vs 194.7(37.8) vs 185.2(37.3) ng/ml (P = 0.008)). Conclusions: Increased endogenous oestrogen levels are associated with only a modestly elevated baseline IGF-1 from midcycle onward despite a previously reported twofold increase in GH secretion. In parallel with this apparent GH insensitivity, increased endogenous oestrogen levels are associated with reduction in GH sensitivity evidenced by reduction in increment IGF-1. This may have clinical implications for women with isolated GH deficiency with regular menstrual cycles on a fixed dose of GH. This possibility requires further study.