BACKGROUND Polycystic ovary syndrome (PCOS) is associated with insulin resistance and features in common with the metabolic syndrome (MetS)—factors shown to predict cardiovascular risk and type 2 ...diabetes. We investigated the prevalence and characteristics of the MetS in PCOS by three definitions—World Health Organization (WHO), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and International Diabetes Federation (IDF)—and compared that with the background population. METHODS Cross-sectional study of 168 women with PCOS and 883 age-matched controls from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. RESULTS Prevalence of the MetS in PCOS subjects was 33% by WHO, 37% by NCEP-ATP-III and 40% by IDF criteria, compared with 10% by NCEP-ATP-III and 13% by IDF in controls (P < 0.001). MetS by WHO criteria was not calculated in the AusDiab population. Age was an independent predictor of MetS in PCOS and controls. The prevalence of MetS was significantly higher among those with PCOS (P = 0.027) in obese women (BMI > 30 kg/m2), and higher but not significantly so in overweight (BMI 25–30 kg/m2) women (P = 0.052). Dehydroepiandrosterone sulphate was associated with a lower risk of the MetS—Odds ratio 0.86 (95% confidence interval, 0.77–0.97, P = 0.011). CONCLUSIONS An approximate 4-fold increase in the prevalence of the MetS in women with PCOS compared with the general population, consistent with the proposed major role of insulin and obesity in the syndrome, implies greater risk of cardiometabolic disease in women with PCOS. However, this estimate is likely to vary according to PCOS definition, ethnicity and different aetiological pathways to PCOS.
Introduction: This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for ...testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.)
Main recommendations: Key points and recommendations are:
Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.
Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle‐stimulating hormone (FSH) concentrations. Measurement of sex hormone‐binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.
Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.
Currently, there are limited data from high‐quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.
Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non‐specific consequences of non‐reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.
Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.
Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.
Aims/hypothesis
In the double-blind placebo-controlled Fenofibrate Intervention and Event Lowering in Diabetes trial (
n
= 9,795), fenofibrate reduced major cardiovascular events in type 2 diabetes. ...Sex-related differences in fenofibrate response could be clinically relevant and were pre-specified analyses.
Methods
Women (
n
= 3,657) and men (
n
= 6,138) with type 2 diabetes not using statins were assigned fenofibrate (200 mg/day) or placebo for 5 years. Effects on lipoproteins and total cardiovascular events were evaluated by sex.
Results
Baseline total, LDL-, HDL- and non-HDL cholesterol and apolipoproteins A-I and B differed between sexes, and these and triacylglycerol levels improved with fenofibrate in both sexes (all
p
< 0.001). Fenofibrate reduced total, LDL- and non-HDL cholesterol and apolipoprotein B more in women (all
p
< 0.001), independent of menopausal status and statin uptake. Adjusted for covariates, fenofibrate reduced total cardiovascular outcomes (cardiovascular death, fatal and non-fatal stroke and carotid and coronary revascularisation) by 30% in women (95% CI 8%, 46%;
p
= 0.008) and 13% in men (95% CI −1%, 24%;
p
= 0.07) with no treatment-by-sex interaction (
p >
0.1). In patients with high triacylglycerol levels and low HDL-cholesterol, fenofibrate reduced total cardiovascular outcomes by 30% (95% CI −7%, 54%) in women and 24% (95% CI 2%, 42%) in men, with no treatment-by-sex interaction (
p >
0.1).
Conclusions/interpretation
Fenofibrate improved the lipoprotein profile more in women than men. Cardiovascular event reductions with fenofibrate were consistently similar in women and men, both overall and among those with low HDL-cholesterol and high triacylglycerol levels. These data provide reassurance about fenofibrate efficacy in women and men. Both sexes with type 2 diabetes should be considered for fenofibrate therapy for cardioprotection.
Context: There is an association between nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS). Marine-derived omega-3 fatty acids have favorable effects on cardiovascular ...risk and could reduce liver fat in NAFLD.
Objective: The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors.
Design and Setting: We conducted a randomized, crossover study at a tertiary cardiovascular research center.
Subjects: Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m2) participated in the study.
Intervention: We compared 4g/d of omega-3 fatty acids with placebo over 8 wk.
Main Outcome Measures: The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure.
Results: Omega-3 fatty acids significantly decreased liver fat content compared with placebo 10.2 (1.1) vs. 8.4 (0.9)%; P = 0.022. There was also a reduction in triglycerides 1.19 (1.03–1.47) vs. 1.02 (0.93–1.18) mmol/liter; P = 0.002, systolic blood pressure 124.1 (12.1) vs. 122.3 (14.5) mm Hg; P = 0.018, and diastolic blood pressure 73.2 (8.4) vs. 69.7 (8.3) mm Hg; P = 0.005 with omega-3 fatty acids compared with placebo. Omega-3 fatty acids particularly decreased hepatic fat in women with hepatic steatosis, defined as liver fat percentage greater than 5% 18.2 (11.1) vs. 14.8 (9.3)%; P = 0.03.
Conclusions: Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. Whether this translates into a reduction in cardiometabolic events warrants further study.
Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS.
Breast cancer survivorship is increasing, due to earlier diagnosis of the disease and more effective therapies. Long-term endocrine sequelae, including early menopause, bone health, fertility ...implications and menopausal symptoms, are important survivorship issues. Ovarian failure is common with chemotherapy and options for preserving fertility in young women include ovarian suppression during chemotherapy and oocyte or embryo cryopreservation before chemotherapy. Tamoxifen as adjunct therapy in premenopausal women leads to ovarian stimulation, sometimes ovulation and occasionally pregnancy with important teratogenic implications. Aromatase inhibitor therapy with or without gonadotrophin releasing hormone (GnRH) agonist leads to profound bone loss and anti-resorptive therapy is advised to prevent fracture. Tamoxifen acts to preserve bone in postmenopausal women but not premenopausal women. Pregnancy is not discouraged in young women with early breast cancer, even to the point of pausing adjunct therapy in order to conceive. However, menopausal hormone therapy is discouraged even years later. Non-hormonal therapy for menopausal symptoms in breast cancer survivors is available but, in some cases, estrogen-containing therapy may be worthy of consideration for quality of life in the informed patient.Breast cancer survivorship is increasing, due to earlier diagnosis of the disease and more effective therapies. Long-term endocrine sequelae, including early menopause, bone health, fertility implications and menopausal symptoms, are important survivorship issues. Ovarian failure is common with chemotherapy and options for preserving fertility in young women include ovarian suppression during chemotherapy and oocyte or embryo cryopreservation before chemotherapy. Tamoxifen as adjunct therapy in premenopausal women leads to ovarian stimulation, sometimes ovulation and occasionally pregnancy with important teratogenic implications. Aromatase inhibitor therapy with or without gonadotrophin releasing hormone (GnRH) agonist leads to profound bone loss and anti-resorptive therapy is advised to prevent fracture. Tamoxifen acts to preserve bone in postmenopausal women but not premenopausal women. Pregnancy is not discouraged in young women with early breast cancer, even to the point of pausing adjunct therapy in order to conceive. However, menopausal hormone therapy is discouraged even years later. Non-hormonal therapy for menopausal symptoms in breast cancer survivors is available but, in some cases, estrogen-containing therapy may be worthy of consideration for quality of life in the informed patient.
Context:
Serum total calcium (tCa) is routinely measured for diagnosing calcium disorders but may not reflect levels of biologically active ionized calcium (iCa) in disease or detect all cases of ...primary hyperparathyroidism.
Objective:
We investigated the utility of measuring iCa and tCa for diagnosing primary hyperparathyroidism.
Design:
This was an observational, retrospective, cross-sectional study.
Patients:
We studied a biochemistry cohort of consecutive ambulatory outpatients with suspected bone or calcium metabolism disorders referred for calcium metabolism biochemistry panels and a surgical cohort of consecutive tertiary hospital patients whose parathyroid specimens were submitted to a single center, and consecutive parathyroidectomy patients of a single surgeon with specimens submitted to a different center.
Results:
In 5490 biochemistry cohort patients, discordance between iCa and tCa in classifying calcium status occurred in 12.6% of cases overall but was worse in hypercalcemic (whether defined by tCa and/or iCa) cases (49%) and hypocalcemic cases (92%). Reliance on tCa alone would miss 45% with ionized hypercalcemia. In 315 biochemistry cohort cases with PTH-dependent hypercalcemia, 130 (41%) had isolated ionized hypercalcemia at diagnosis. In 143 patients with histologically proven parathyroid disease, 24% had isolated ionized hypercalcemia at diagnosis. These patients were younger (P = 0.022) with milder ionized hypercalcemia and better renal function (both P ≤ 0.001) than patients presenting with concurrently elevated iCa and tCa.
Conclusion:
In abnormal calcium states, tCa frequently disagrees with iCa in classifying calcium status. Histologically proven parathyroid disease can present with isolated ionized hypercalcemia. Measurement of iCa is required to accurately assess calcium status and improve diagnostic accuracy.
Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are ...lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms.
We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18–70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138.
Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 –39% 95% CI –46 to –31 vs placebo –26% –33 to –18; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 17% of 65 patients in the Q-122 group vs nine 14% of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events.
Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy.
QUE Oncology.
Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of ...loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.
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