Non-alcoholic fatty liver disease through the female lifespan: the role of sex hormones.

The prevalence of non-alcoholic fatty liver disease (NAFLD) differs between various stages of the female lifespan. The aim of this review is to summarize current evidence on the association of NAFLD and circulating sex hormones and to explore the pathogenesis of NAFLD within the context of (1) sex hormone changes during the reproductive, post-reproductive female life and beyond and (2) the in vitro and in vivo evidence on pharmacological modulation in women on menopausal hormone treatment (MHT) or endocrine therapy after breast cancer. The fluctuation in estrogen concentrations, the relative androgen excess, and the age-related reduction in sex hormone-binding globulin are related to increased NAFLD risk. Moreover, the peri-menopausal changes in body composition and insulin resistance might contribute to the increased NAFLD risk. Whether MHT prevents or improves NAFLD in this population remains an open question. Studies in women with breast cancer treated with tamoxifen or non-steroidal aromatase inhibitors point to their adverse effects on NAFLD development, although a more pronounced effect of tamoxifen is reported. Future studies focusing on the underlying pathogenesis should identify subgroups with the highest risk of NAFLD development and progression into more aggressive forms, as well as elucidate the role of hormone therapies, such as MHT.

Risk of developing metabolic syndrome after gestational diabetes mellitus - a systematic review and meta-analysis.

PURPOSE: A systematic review and meta-analysis were conducted to quantitatively synthesize the current evidence regarding the risk of developing metabolic syndrome (MetS) in women with a personal history of gestational diabetes mellitus (GDM), without pre-existing diabetes, compared with those without a history of GDM. METHODS: Four electronic databases [MEDLINE (via PubMed), Scopus, Cochrane Library, PROSPERO] were searched for relevant literature until July 29th 2020. Cochran's Q test was applied for the assessment of heterogeneity. The random-effects model was applied by calculating the odds ratio (OR) and 95% confidence interval (CI) for each study. Publication bias was estimated with Egger's linear regression test. RESULTS: The results from 23 studies (10,230 pregnant women; 5169 cases, 5061 controls), indicated that women with a history of GDM had a higher risk of developing MetS compared with those without such a history (OR 3.45; 95% CI 2.80-4.25, p < 0.0001). This risk remained higher, independently of maternal age and ethnicity (although the risk was not as high in Asians; OR 2.11; 95% CI 1.27-3.52). The risk of developing MetS was even higher in studies where women with GDM had increased body mass index (BMI) compared with the controls (OR 4.14; 95% CI 3.18-5.38). CONCLUSIONS: The risk for developing MetS following delivery is higher in women with a history of GDM compared with women without such a history. Timely recognition and appropriate intervention are critical to halt progression to MetS and its associated morbidity.

Efficacy of parathyroidectomy compared with active surveillance in patients with mild asymptomatic primary hyperparathyroidism: a systematic review and meta-analysis of randomized-controlled studies.

OBJECTIVE: Parathyroidectomy (PTx) has an established benefit in patients with symptomatic primary hyperparathyroidism (PHPT). However, its efficacy in mild asymptomatic PHPT has not been proven. This study aimed to systematically review and meta-analyze the best available evidence from randomized-controlled trials comparing the efficacy of PTx over conservative management (non-PTx) on skeletal outcomes [fractures and bone mineral density (BMD)], nephrolithiasis risk and quality of life (QoL) in patients with mild asymptomatic PHPT. METHODS: A comprehensive literature search was conducted in PubMed, Scopus and Cochrane databases, from conception to February 23, 2020. Data were extracted from the studies that fulfilled the eligibility criteria and were synthesized quantitatively (fixed or random effects model) as relative risks and percentage mean differences (MD) with 95% confidence intervals (CI). I2 index was employed for heterogeneity. RESULTS: Four studies were included in the meta-analysis. There was no difference in fracture risk between PTx and active surveillance. The PTx group demonstrated higher BMD [MD 3.55% (95% CI 1.81, 5.29) in lumbar spine and 3.44% (95% CI 1.39, 5.49) in total hip, without difference in femoral neck and forearm] and lower calcium concentrations (MD - 13.26%, 95% CI - 7.10, - 19.43) compared with the non-PTx group. No difference was observed between groups regarding nephrolithiasis or QoL indices, except for general health (higher in PTx group). CONCLUSIONS: In patients with mild asymptomatic PHPT, PTx increases BMD and reduces serum calcium concentrations. However, its superiority over active surveillance in terms of fracture risk, nephrolithiasis and QoL cannot be supported by current data.

Effects of treatment for psoriasis on circulating levels of leptin, adiponectin and resistin: a systematic review and meta-analysis.

BACKGROUND: Metabolic syndrome, a risk factor of cardiovascular disease, is more common in patients with psoriasis than in the general population. Circulating adipokine concentrations are altered in patients with psoriasis and are suggested to represent the pathophysiological link between psoriatic lesions and metabolic alterations. OBJECTIVES: To perform a systematic review of the literature for studies that investigated possible differences in circulating levels of leptin, adiponectin or resistin in patients with psoriasis before and after any treatment intervention, and to meta-analyse the best evidence available. METHODS: A search was conducted in three databases (PubMed, Central and Embase). Eligible for the review were studies that assessed leptin, adiponectin or resistin concentrations in patients with psoriasis before and after any topical or systemic treatment. RESULTS: After treatment, blood concentrations of leptin were similar to those before treatment [standardized mean difference (SMD) 0·06, 95% confidence interval (CI) -0·09 to 0·20], with no heterogeneity among studies (I2 = 0%, P = 0·88). After treatment, blood concentrations of adiponectin were similar to those before treatment (SMD -0·14, 95% CI -0·34 to 0·05), with significant heterogeneity among studies (I2 = 36·8%, P = 0·032). After treatment, blood concentrations of resistin were significantly lower than those before treatment (SMD 0·50, 95% CI 0·20-0·79), with significant heterogeneity among studies (I2 = 61·4%, P < 0·001). CONCLUSIONS: There is no evidence that treatment for psoriasis modifies leptin and adiponectin concentrations. However, treatment intervention reduces resistin concentrations, a finding that is expected to be of clinical importance.

Association of follicle-stimulating hormone receptor single nucleotide polymorphisms with fertility in Greek men.

BACKGROUND AND OBJECTIVE: Although several epidemiological studies have been conducted, the impact of follicle-stimulating hormone receptor (FSHR) polymorphisms on male infertility remains unclear. The aim of this study was to investigate the prevalence of specific FSHR single nucleotide polymorphisms (SNPs) in the Greek population and associate the latter with the clinical phenotype. PATIENTS AND METHODS: We enrolled 96 subjects: men with idiopathic non-obstructive azoospermia (n = 78) were compared with a control group of fertile men (n = 18) for SNPs in FSHR positions c.-29, c.566, c.919, and c.2039. The SNP in position 566 (c.566C > T) was assessed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and the other three SNPs (c.-29G > A, c.919A > G, c.2039A > G) with single-strand conformation polymorphism (SSCP); all of them were validated with DNA sequence. RESULTS: No polymorphisms were detected in positions c.-29 and c.919 (c.-29G > A, c.919A > G). The heterozygous SNP (AG) at position 2039 was associated with different size of the right testis (p = 0.008). There was no association between the c.566C > T SNPs polymorphism and hormonal or semen parameters. The combination SNP 2039 AA with 566 CT revealed significant association with FSH and LH concentrations. CONCLUSIONS: FSHR SNPs at positions c.-29, c.566, c.919, and c.2039 (c.-29G > A, c.566C > T, c.919A > G, c.2039A > G) do not appear to play specific roles in male infertility. Larger studies are needed to confirm these results.

Consequences of hyperthyroidism in male and female fertility: pathophysiology and current management.

Thyroid hormone acts on the oocytes, sperm and embryo during fertilization, implantation and placentation. Both hypothyroidism and hyperthyroidism may influence fertility. However, evidence of the association of hyperthyroidism with infertility is scarce and sometimes conflicting. Thyroid hormone influences human reproduction via a variety of mechanisms at both the central and the peripheral level. Infertility may occur in hyperthyroid men and women, but it is usually reversible upon restoration of euthyroidism. This review aims to summarize the available data on the association of hyperthyroidism and infertility in both men and women and to provide practical suggestions for the management of these patients.

Bone disease in patients with haemophilia A and B--where are we now?

It is evident that haemophilia A and B are associated with decreased bone mass in both adults and children. Decreased physical activity and vitamin D deficiency are some of the major factors leading to bone loss. Hepatitis C virus (HCV) infection may also contribute to low bone mineral density (BMD). However, definite conclusions regarding the exact prevalence and pathogenesis of osteoporosis cannot be conducted yet, due to the small sample size and significant heterogeneity among studies. Discordant findings with regard to the skeletal site of low BMD have also been reported. Furthermore, data on fracture risk are sparse. The use of the Fracture Risk Assessment Tool (FRAX) for assessing fracture risk, regular BMD assessment at the age of 25 and thereafter, careful evaluation of risk factors associated with bone loss and optimal calcium and vitamin D intake are recommended. Long-term prophylactic factor replacement therapy, resistance exercise and bisphosphonates, in severe cases of increased fracture risk, can prevent bone loss.

Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review.

A considerable number of studies have examined vitamin D status during pregnancy. Although data from observational studies denote vitamin D hypovitaminosis (deficiency or insufficiency) during pregnancy is associated with a plethora of adverse maternal and neonatal outcomes, data from interventional (supplementation) trials fail to reveal a significant impact on maternal and offspring health. The aim of this narrative review was to critically appraise the methodology of the most representative published randomized controlled trials in an attempt to explain the difference between observational and supplementation results. We found that this difference could be attributed to a variety of factors, namely: (i) study design (lack of a specific outcome in conjunction with timing of supplementation, enrolment of participants with heterogeneous vitamin D status); (ii) pitfalls in the interpretation of vitamin D equilibrium (lack of determination of plasma half-life); (iii) supplementation regimen (administration of a wide range of regimens, in terms of dose, bolus and form); (iv) geographical characteristics (vitamin D needs could vary significantly within a country, particularly in areas with a wide range of latitude gradient); (v) adaptations of vitamin D metabolism during pregnancy (vitamin D and calcium equilibrium are changed during pregnancy compared with the non-pregnant state) and (vi) supplementation of populations with low baseline 25(OH)D values would likely manifest beneficial effects. All these parameters should be taken into consideration in the design of future vitamin D supplementation trials.

Maternal vitamin D status in pregnancy and offspring bone development: the unmet needs of vitamin D era.

Data from animal and human studies implicate maternal vitamin D deficiency during pregnancy as a significant risk factor for several adverse outcomes affecting maternal, fetal, and child health. The possible associations of maternal vitamin D status and offspring bone development comprise a significant public health issue. Evidence from randomized trials regarding maternal vitamin D supplementation for optimization of offspring bone mass is lacking. In the same field, data from observational studies suggest that vitamin D supplementation is not indicated. Conversely, supplementation studies provided evidence that vitamin D has beneficial effects on neonatal calcium homeostasis. Nevertheless, a series of issues, such as technical difficulties of current vitamin D assays and functional interplay among vitamin D analytes, prohibit arrival at safe conclusions. Future studies would benefit from adoption of a gold standard assay, which would unravel the functions of vitamin D analytes. This narrative review summarizes and discusses data from both observational and supplementation studies regarding maternal vitamin D status during pregnancy and offspring bone development.

Bone mineral density in men and children with haemophilia A and B: a systematic review and meta-analysis.

SUMMARY: Although haemophilia is not considered among the classic causes of secondary osteoporosis, the present meta-analysis provides strong evidence that men with haemophilia have a significant reduction in both lumbar spine and femoral bone mineral density, which appears to begin in childhood. INTRODUCTION: Haemophilia is not considered among the classic causes of secondary osteoporosis. The aim of this study was to systematically review the literature for case-control trials that have studied bone mass in males with haemophilia and to meta-analyze the best evidence available. METHODS: Electronic databases MEDLINE, EMBASE and CENTRAL were systematically searched for case-control trials that have studied bone mass in men or boys with haemophilia. Standardized mean difference (SMD) for bone mineral density (BMD) in the lumbar spine was the main study outcome and SMD in femoral neck and total hip BMD the secondary ones. Patient and control characteristics, such as age, body mass index (BMI), level of physical activity and blood-borne infections were recorded as possible predictors of the main outcome. RESULTS: Thirteen studies were included in the systematic review and ten in the main outcome meta-analysis. Men with haemophilia demonstrated reduced lumbar spine [random effects SMD [95 % confidence interval (CI)] = -0.56 (-0.84, -0.28), between-study heterogeneity (I (2)) = 51 %] and femoral neck BMD [random effects SMD (95 % CI) = -0.82 (-1.21, -0.44), I (2) = 63 %] compared with controls, which indicated a large and clinically significant association. Similar results were obtained for children [random effects SMD (95 % CI) = -0.92 (-1.77, -0.07), I (2) = 92 %]. No evidence of publication bias was detected. There was no evidence that age, BMI, level of physical activity or presence of blood-borne infections predicted lumbar spine BMD. CONCLUSIONS: This meta-analysis shows that men with haemophilia present a significant reduction in both lumbar spine and hip BMD, which appears to begin in childhood.

The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B.

Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, the utility of bone turnover markers (BTM) remains unknown. The aim of this study was to evaluate bone metabolism in men with haemophilia and to investigate associations between BTM and bone disease. Serum N- (NTX-I), C-terminal telopeptide of type I collagen (CTX-I) and tartrate-resistant acid phosphatase band-5b (TRAP-5b), as bone resorption markers, and osteocalcin (OC) and bone-specific alkaline phosphatase (b-ALP), as bone formation markers, were assessed. Seventy men with haemophilia A (n = 59) or B (n = 11) were studied. Patients with low BMD had significantly higher b-ALP concentrations compared with those with normal BMD (12.8 ± 1.60 vs. 9.72 ± 0.58 µg/L, P = 0.009), without any differences in the other BTM. NTX-I and CTX-I concentrations were negatively associated with oestradiol levels and hip BMD and positively with human immunodeficiency virus infection, number of affected joints and arthropathy scores. B-ALP and OC concentrations were negatively associated with hip BMD, severity of haemophilia and fracture history, and positively with the number of affected joints and testosterone concentrations. After multivariate analysis, NTX-I levels remained negatively associated with oestradiol levels, whereas b-ALP concentrations negatively correlated with the level of physical activity and positively with the number of affected joints. Increased bone metabolism exists in men with haemophilia and low BMD. Increased b-ALP levels may identify patients at high risk for fracture. Increased number of target joints, low physical activity and low oestradiol concentrations are independently associated with increased bone metabolism.

Selenomethionine treatment in patients with autoimmune thyroiditis: a prospective, quasi-randomised trial.

AIMS: To test whether selenium administration affects autoantibodies to thyroid peroxidase (anti-TPO) and thyroglobulin (anti-TG) titres in chronic autoimmune (Hashimoto's - HT) thyroiditis. METHODS: A prospective, open-label, quasi-randomised study in 86 HT patients (n = 86) assigned to either selenomethionine (Seme) 200µg daily for 3 months (Se3, n = 15) or 6 months (Se6, n = 46) or placebo (Control, n = 25). Serum Se, anti-TPO, anti-TG and thyroid hormones were measured in all patients at baseline, 3 and 6 months. A subgroup of 18 patients (twelve on Se6 and six controls) were subjected in thyroid fine-needle biopsy at baseline and 6 months to detect changes in lymphocyte infiltration. RESULTS: No significant difference in anti-TPO levels was recorded after 3 (p = 0.88) or 6 months (p = 0.62) on Seme. Anti-TG levels decreased both at 3 months (p = 0.001) and 6 months (p = 0.001). No significant changes in thyroid stimulating hormone, free thyroxine and free triiodothyronine levels or in the lymphocytes' number in thyroid cytology specimens were detected. Age, gender, duration of disease, baseline anti-TPO levels and per cent change in Se levels could not predict the response of anti-TPO levels to Seme administration. CONCLUSION: Our data suggest that Seme administration in pharmacological doses for a period of 6 months seems to have no significant effect on serum thyroid auto-antibodies' levels or lymphocyte infiltration of the thyroid gland.

Thyroid diseases and female reproduction.

Thyroid diseases are very common in women of reproductive age. The aim of this study was to review the current evidence on physiology, pathophysiology, diagnosis and management of women with thyroid disorders that are currently seeking fertility, undergoing assisted reproduction technologies (ART) or being pregnant. Normal thyroid function is essential for normal function of the gonadal axis, thus important in maintaining normal reproductive capacity. On the contrary, any type of thyroid dysfunction may reduce the likelihood of pregnancy; the latter can be restored to normal after appropriate treatment. Over eight million children have been born as a result of assisted reproduction techniques (ART) since 1978. As these procedures are becoming more common in clinical practice, the exact impact of thyroid status on reproductive outcomes as well as that of drugs used in ART on thyroid function has to be fully elucidated. Maternal thyroid function is crucial, especially during the first weeks of gestation, for offspring's wellness and brain development. On the other hand, normal physiological mechanisms during gestation can have a major impact on maternal thyroid function. As human chorionic gonadotropin (hCG) has a thyroid stimulating hormone (TSH)-like effect, high hCG concentrations are associated with thyroid stimulation, both functionally (lower serum TSH concentrations) and anatomically (increased thyroid volume). Although the association between maternal hypothyroidism and increased perinatal morbidity has been described for over a century, more recently, even the presence of anti-thyroid antibodies has been associated with adverse pregnancy outcomes, such as recurrent abortions and placental abruption. This is of major clinical significance, as anti-thyroid antibodies are surprisingly prevalent in pregnancy, especially during the first two trimesters.

Hormone therapy for postmenopausal endometrial cancer survivors: a survey among Greek obstetricians-gynaecologists.

PURPOSE OF INVESTIGATION: In this study we evaluated the prescription attitude of Greek obstetricians-gynaecologists towards hormone replacement therapy (HRT) for endometrial cancer survivors. METHODS: An anonymous questionnaire was sent to 900 members of the Hellenic Society of Obstetrics and Gynaecology, presenting a hypothetical case of an endometrial cancer survivor with indications for HRT, followed by a series of relevant questions. RESULTS: Three hundred and three valid responses were received and analysed according to age, gender and practice setting. HRT would be prescribed by 30.4% of gynaecologists; as far as type of regimen is concerned, 67.4% would prescribe tibolone, 22.8% estrogen-only and 9.8% estrogen plus progestagen. In contrast, 69.6% would not prescribe HRT due to the fear of endometrial cancer recurrence (88.2%), development of breast cancer (2.8%) or both (4.7%); among them, 28.4% would prescribe central nervous system (CNS) medications, selective estrogen receptor modulators (SERMs), phyto-oestrogens or biphosphonates, as alternates. CONCLUSIONS: One out of three Greek gynaecologists would prescribe HRT to endometrial cancer survivors. Alternative therapies, mainly CNS medications, would be suggested by the opposers.

Comparison of single versus multiple courses of antenatal betamethasone in patients with threatened preterm labor.

PURPOSE OF INVESTIGATION: To compare single versus multiple courses of antenatal betamethasone administration with regards to the morbidity and mortality of preterm neonates. METHODS: One-hundred and twenty-two women with threatened preterm labor were allocated to three different betamethasone schedules: 1) two doses of betamethasone 12 mg, intramuscularly, 24 hours apart (standard treatment) (n = 41); 2) standard treatment plus a third dose of 12 mg after seven days (n = 41); and, 3) standard treatment plus one dose of 12 mg every seven days until delivery (n = 40). Neonatal morbidity and mortality as well as maternal morbidity were evaluated. RESULTS: Neonatal parameters, such as frequency of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis and neonatal mortality were not significantly different among the three groups for both singleton and multiple pregnancies. Similarly, maternal parameters were not significantly different among the three groups. CONCLUSION: The administration of multiple betamethasone courses in threatened preterm labor is not superior to single courses with regards to neonatal morbidity and mortality, as well as to maternal morbidity.

Gabapentin and pregabalin in the treatment of fibromyalgia: a systematic review and a meta-analysis.

WHAT IS KNOWN AND OBJECTIVES: Fibromyalgia (FBM) is a common chronic pain disorder affecting up to 2% of the general population. Current treatment options are mostly symptom-based and limited both in efficacy and number. Two promising alternatives are gabapentin (GP) and pregabalin (PB). We aimed to estimate the efficacy and safety/tolerability of the two compounds in FBM through a systematic review and a meta-analysis of relevant randomized double-blind placebo-controlled (RCT) were performed. DATA SOURCES, EXTRACTION AND ANALYSIS: A literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL and the reference lists of relevant studies. Responders to treatment (>30% reduction in mean pain score) and dropouts due to lack of efficacy were used as primary outcome measures. Dropout rates and incidence of common adverse outcomes were also investigated. Four RCTs, reporting data on 2040 patients, were reviewed and three of them using PG were included in the meta-analysis. RESULTS: Pregabalin at a dose of 600, 450 and 300 mg per day is effective in FBM compared to placebo (NNT: 7, upper 95% CI: 12, 450 mg). A number of adverse events (AE), such as dizziness, somnolence, dry mouth, weight gain, peripheral oedema, is consistently associated with treatment at any dose and could lead one out of four patients to quit treatment (NNH: 6, lower 95% CI: 4, 600 mg). Indirect comparison meta-analysis suggests that PB at a dose of 450 mg per day could result in more responders than at 300 mg, but this result needs to be interpreted with caution as there were no significant differences between 600 and 300 mg or between 600 and 450 mg. Data on GP is limited. WHAT IS NEW AND CONCLUSIONS: The analysis indicates that PB at a dose of 450 mg per day is most likely effective in treating FBM, although AE are not negligible. Further evidence is necessary for more conclusive inferences.

Ovarian tissue cryopreservation and transplantation to delay menopause: facts and fiction.

Ovarian tissue cryopreservation and transplantation (OTCT) is increasingly being used in young cancer patients for fertility restoration and prevention of premature ovarian insufficiency (POI) and has recently been advocated as a method to delay menopause. This is accomplished by cryopreserving ovarian tissue that is excised laparoscopically in thin pieces at a young age. Cryopreserved tissue will be transplanted at menopause, when ovarian function is no longer present. Transplantation may need to be repeated several times to achieve long-term restoration of ovarian function. However, it is unknown whether ovarian grafts result in a normal steroid pulsatile secretion, similar to that present during reproductive years. In addition, it is not known whether the need to restore ovarian activity appears earlier in women who undergo OTCT to delay menopause, although indirect data suggest that this is likely to be true. Until today, no cohort or comparative studies evaluating OTCT as a potential alternative to hormone replacement therapy (HRT) have been published and, thus, there is no evidence to suggest that OTCT is superior to HRT in terms of both efficacy and safety. Given the availability of alternative, established treatments for managing menopausal symptoms, as well as the multiple unanswered questions regarding the method, it is imperative that, before OTCT is regarded as a mainstream technique for management of menopausal symptoms, further evaluation and clinical investigation are undertaken.

Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis.

Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine essential for osteoclast differentiation, activation, and survival. Denosumab, a human monoclonal antibody against RANKL, constitutes a promising antiresorptive agent for osteoporosis. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2009. We selected randomized controlled trials (RCTs) of denosumab in women with low bone mass that described the changes on bone markers and bone mineral density (BMD) as well as the adverse events including fracture risk. We analyzed data from nine RCTs involving 10 329 participants. Although denosumab universally decreased bone markers and increased lumbar and hip BMD, the efficacy evaluation based on percentage (%) mean change from the baseline was not possible due to missing data. Denosumab was not associated with a significant reduction in fracture risk [OR (95% CI) 0.74 (0.33 to 1.64), p=0.45]. Increased risk of serious adverse events [OR (95% CI) 1.83 (1.10 to 3.04), p=0.02] and serious infections [OR (95% CI) 4.45 (1.15 to 17.14), p=0.03] were evident. In conclusion, although effective as an antiresorptive agent, denosumab has not yet proved its efficacy on fracture risk reduction while increased infection risk questions its safety.