Comprehensive meta-analysis of the effects of oral medroxyprogesterone acetate plus conjugated equine oestrogens on the lipid profile in women: Insights from randomized controlled trials.

BACKGROUND: Menopause is associated with elevated cardiovascular risk due to the loss of the cardioprotective effect of oestrogens. Postmenopausal women are often prescribed hormone replacement therapy (HRT) in order to control menopause symptoms and correct hormone imbalances; however, HRT can impact serum lipids' concentrations. At present, data on the effect of the administration of medroxyprogesterone acetate plus conjugated equine oestrogens (MPACEE) on the lipid profile in females are uncertain, as the investigations conducted so far have produced conflicting results. Thus, we aimed to clarify the impact of MPACEE prescription on the serum lipids' values in women by means of a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We employed a random-effects model based on the DerSimonian and Laird method to determine the combined estimates of the intervention's impact on the lipid profile. The computation of the weighted mean difference (WMD) and its corresponding 95% confidence interval (CI) relied on the mean and standard deviation values from both the MPACEE and control group, respectively. RESULTS: A total of 53 RCTs were included in the meta-analysis with 68 RCT arms on total cholesterol (TC), 70 RCT arms on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and 69 RCT arms on high-density lipoprotein cholesterol (HDL-C). Administration of MPACEE resulted in a significant reduction of TC (WMD = -11.93 mg/dL; 95% CI: -13.42, -10.44; p < .001) and LDL-C (WMD = -16.61 mg/dL; 95% CI: -17.97, -15.26; p < .001) levels, and a notable increase in HDL-C (WMD = 3.40 mg/dL; 95% CI: 2.93, 3.86; p < .001) and TG (WMD = 10.28 mg/dL; 95% CI: 7.92, 12.64; p < .001) concentrations. Subgroup analysis revealed that changes in the lipid profile were influenced by several factors: body mass index (for TC, HDL-C, TG), MPACEE dosages (for TC, LDL-C, HDL-C, TG), age (for TC, LDL-C, HDL-C, TG), durations of the intervention (for TC, LDL-C, HDL-C, TG), continuous/sequential administration of MPACEE (continuous for TC; sequential for LDL-C, TG) administration of MPACEE and serum lipids' concentrations before enrolment in the RCT (for TC, LDL-C, HDL-C, TG). CONCLUSIONS: MPACEE administration can influence serum lipids' concentrations in females by raising HDL-C and TG levels and reducing LDL-C and TC values. Therefore, postmenopausal women who suffer from hypercholesterolaemia might benefit from this type of HRT.

Validation of circulating microRNAs miR-142-3p and miR-598-3p in women with polycystic ovary syndrome as potential diagnostic markers.

STUDY QUESTION: Circulating miRNAs previously associated with androgen excess in women might be used as diagnostic biomarkers for polycystic ovary syndrome (PCOS). SUMMARY ANSWER: Models based on circulating miR-142-3p and miR-598-3p expression show good discrimination among women with and without PCOS, particularly when coupled with easily available measurements such as waist-to-hip ratio (WHR) and circulating LH-to-FSH (LH/FSH) ratios. WHAT IS KNOWN ALREADY: The lack of standardization of the signs, methods, and threshold values used to establish the presence of the diagnostic criteria (hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology) complicates the diagnosis of PCOS. Certain biomarkers may help with such a diagnosis. We conducted a validation study to check the diagnostic accuracy for PCOS of several miRNAs that were associated with the syndrome in a small pilot study that had been previously carried out by our research group. STUDY DESIGN, SIZE, DURATION: This was a diagnostic test study involving 140 premenopausal women. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 71 women with PCOS and 69 healthy control women in the study. Both groups were selected as to be similar in terms of body mass index. We used miRCURY LNA™ Universal RT microRNA PCR to analyse the five miRNAs that had shown the strongest associations with PCOS in a much smaller pilot study previously conducted by our group. We studied diagnostic accuracy using receiver operating characteristics (ROC) curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Only the expression of two miRNAs, miR-142-3p and miR-598-3p, of the five studied, was different between the women with PCOS and the non-hyperandrogenic controls. The diagnostic accuracy of the combination of these circulating miRNAs was good (area under the ROC curve (AUC) 0.801; 95% CI: 0.72-0.88) and was further improved when adding WHR (AUC 0.834, 95% CI: 0.756-0.912), LH/FSH ratio (AUC = 0.869, 95% CI: 0.804-0.934) or both (AUC = 0.895, 95% CI: 0.835-0.954). We developed several models by selecting different threshold values for these variables favouring either sensitivity or specificity, with positive and negative predictive values as high as 88% or 85%, respectively. LIMITATIONS, REASONS FOR CAUTION: Patients included here had the classic PCOS phenotype, consisting of hyperandrogenism and ovulatory dysfunction; hence, the present results might not apply to milder phenotypes lacking androgen excess. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed in larger studies addressing different populations and PCOS phenotypes, these biomarkers may be useful to simplify the clinical diagnosis of this prevalent syndrome. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (grants PI15/01686, PIE16/00050, PI18/01122 & PI21/00116) and co-funded by European Regional Development Fund 'A way to make Europe'. Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) are also initiatives of the Instituto de Salud Carlos III. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Gonadal hormones in borderline personality disorder: implications for understanding symptoms and supporting treatment.

OBJECTIVE: To review the literature on the impact of gonadal hormones on features of borderline personality disorder. BACKGROUND: Oestrogen flux and absolute sex hormone levels are known to be associated with various mood states in women. We investigated whether this was particularly relevant for borderline symptoms in women with or without borderline personality disorder (BPD). METHODS: Systematic literature review. DISCUSSION: There is some evidence that borderline symptoms are more severe during certain phases on the menstrual cycle in non-clinical samples of women. There is also a small evidence base that suggests that women with BPD show symptom exacerbation during the late luteal phase of their menstrual cycle. CONCLUSION: More work is required to establish the nature and mechanisms of interactions between gonadal hormones and symptom expression in BPD patients, and therapeutic endeavours need stringent empirical testing.

Oral hormonal therapy as treatment option for abnormal uterine bleeding.

BACKGROUND: abnormal uterine bleeding is a very frequent reason for referral to gynaecologists and can deeply influence the quality of life. Once organic causes requiring surgical treatment are ruled out, clinicians should be able to manage these patients conservatively in the most effective way. MATERIALS AND METHODS: a search in PubMed/MEDLINE database was conducted in order to find relevant and recent meaningful sources for this narrative review. RESULTS: LNG-IUS 52 mg is the first-line treatment for non-organic causes. Nevertheless, it could be contraindicated or declined by the patient. Combined oral contraceptives (COC) and progestin-only pills inhibit the hypothalamic-pituitary-ovarian axis, preventing ovulation, and induce endometrial atrophy. Consequently, they are effective in treating AUB. Moreover, brand new pills containing a combination of oestrogens, progestins and GnRH antagonists are now available for the management of AUB related to uterine fibroids. CONCLUSIONS: In daily clinical practice, oral hormonal therapies are convenient and reversible tools to manage AUB when LNG-IUS 52 mg is contraindicated or turn down by the patient. Many oral hormonal therapies are prescribed to treat AUB, but only a few have been approved with this specific indication, therefore further large well-designed studies are necessary in order to compare the efficacy of different pills for treating AUB.

Even though LNG-IUS 52 mg is the first-line treatment for abnormal uterine bleeding, oral hormonal therapies should be effectively managed by gynaecologists in case of contraindications or patient's decline. Contraceptive pills are practical, but further studies are necessary to compare their efficacy and to approve them with the specific AUB indication.

Steroid hormone levels in postmenopausal hysterectomised women with and without ovarian conservation: the continuous endocrine function of the ovaries.

This study aims to clarify the effect of postmenopausal bilateral oophorectomy on plasma steroid hormone levels. Women who were submitted in the postmenopausal period to hysterectomy for uterine benign conditions were divided into two groups: 18 women had isolated hysterectomy and 11 had hysterectomy with bilateral salpingo-oophorectomy. In both groups serum hormone levels were quantified by solid phase extraction and gas chromatography and tandem mass spectrometry. Differences in dehydroepiandrosterone (DHEA), testosterone, androstenedione and oestradiol were determined in both groups. The analysis revealed lower steroid levels in the bilateral salpingo-oophorectomy group when compared to the isolated hysterectomy group with statistically significant differences found for DHEA (5.8 ± 3.2 vs. 9.4 ± 4.4 ng/mL; p = 0.019) and oestradiol (0.69 ± 0.4 vs. 1.48 ± 4.3 ng/mL; p = 0.007). The results are consistent with a significant endocrine activity of the postmenopausal ovary. The clinical consequences of these findings need to be clarified and postmenopausal prophylactic bilateral salpingo-oophorectomy re-evaluated.IMPACT STATEMENTWhat is already known on this subject? Although it is consensual that premenopausal prophylactic bilateral oophorectomy should not be performed because it has harmful effects on women's health, the evidence regarding the effects of postmenopausal prophylactic bilateral oophorectomy is scarce and this procedure continues to be a regular practice. Few studies have demonstrated that postmenopausal ovaries still have endocrine activity that may impact older women's health.What do the results of this study add? This is the first study to compare hormone levels of postmenopausal women based on their hysterectomy and oophorectomy status using GC-MS/MS, a highly sensitive bioanalytical assay for the measurement of steroid hormones. Previous studies relied on immunoassays and did not compare DHEA levels, which according to the intracrinology theory is a precursor for androgens and oestrogens. In this study, statistically significant lower levels of DHEA and oestradiol were found after postmenopausal bilateral salpingo-oophorectomy.What are the implications of these findings for clinical practice and/or further research? This is a pilot study that may lead to further investigation in this area to clarify the impact of the prophylactic removal of postmenopausal ovaries on older women's health and lead to changes in surgical procedures.

Recurrence after stopping anticoagulants in women with combined oral contraceptive-associated venous thromboembolism: A systematic review and meta-analysis.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Circulating oestradiol determines liver lipid deposition in rats fed standard diets partially unbalanced with higher lipid or protein proportions.

The ingestion of excess lipids often produces the accumulation of liver fat. The modulation of diet energy partition affects this process and other metabolic responses, and oestrogens and androgens are implied in this process. Ten-week-old male and female rats were fed with either standard rat chow (SD), SD enriched with coconut oil (high-fat diet, HF), SD enriched with protein (high-protein diet, HP) or a 'cafeteria' diet (CAF) for 1 month. HF and CAF diets provided the same lipid-derived percentage of energy (40 %), HP diet protein energy derived was twice (40 %) that of the SD. Animals were killed under anaesthesia and samples of blood and liver were obtained. Hepatic lipid content showed sex-related differences: TAG accumulation tended to increase in HF and CAF fed males. Cholesterol content was higher only in the CAF males. Plasma oestradiol in HF and HP males was higher than in CAF. Circulating cholesterol was inversely correlated with plasma oestradiol. These changes agreed with the differences in the expression of some enzymes related to lipid and energy metabolism, such as fatty acid synthetase or phosphoglycolate phosphatase. Oestrogen protective effects extend to males with 'normal' diets, that is, not unbalanced by either lipid or protein, but this protection was not enough against the CAF diet. Oestradiol seems to actively modulate the liver core of 2C-3C partition of energy substrates, regulating cholesterol deposition and lactate production.

Association between menopausal hormone therapy use and mortality risk: a Swedish population-based matched cohort study.

BACKGROUND: The net effect of menopausal hormone therapy on the risk of death is understudied, and current evidence is conflicting. Our aim was to investigate the association between menopausal hormones and risk of all-cause, cardiovascular, and cancer-specific mortality, based on the Swedish Prescribed Drug Registry and National Patient Registry. METHODS: This Swedish population-based matched cohort study included all women, 40 years or older, who had received at least one prescription of systemic menopausal hormone therapy between 2005-2014 (n = 290,186), group level matched 1:3 to non-users (n = 870,165). Multivariable conditional logistic regression models estimated the relative risk of all-cause and cause-specific mortality, adjusting for several clinical factors and comorbidities. RESULTS: Ever-use of menopausal hormones was associated with a slightly lower overall odds of all-cause (OR = 0.97, 95%CI 0.95-0.98) and cardiovascular (OR = 0.97, 95%CI 0.95-0.99) mortality, whilst 30% lower overall odds of cancer-related mortality (OR = 0.70, 95%CI 0.68-0.72) was shown. The odds of all-cause and cancer-related mortality were consistently reduced among women who began menopausal hormone therapy ≤60 years, whereas the association with cardiovascular mortality was inconsistent. In contrast, oestrogen-only therapy was associated with elevated odds of all-cause (OR = 1.14, 95%CI 1.11-1.16) and cardiovascular mortality (OR = 1.04, 95%CI 1.01-1.06) among women who began treatment at ≥70 years. Among current users, oestrogen-only therapy was associated with higher odds of all-cause (OR = 1.48, 95%CI 1.44-1.52) and cardiovascular mortality (OR = 1.24, 95%CI 1.20-1.28), whereas past use of oestrogen-only therapy suggested lower odds of mortality. CONCLUSIONS: Our generalisable data suggest that early menopausal hormone treatment initiation does not increase the odds of mortality. However, the role of oestrogens in particularly cardiovascular mortality remains to be investigated.

Transition from gynaecomastia to lipomastia in pubertal boys.

OBJECTIVE: Gynaecomastia is frequent in pubertal boys and is regarded as a self-limiting abnormality. However, longitudinal studies proving this hypothesis are scarce. DESIGN: Longitudinal follow-up study (median 2.4, range 1.0-4.8 years). METHODS: The regression of breast diameter was analysed in 31 pubertal boys aged 11.7-16.1 (median 13.2) years with gynaecomastia. Furthermore, weight changes (as BMI-SDS) and pubertal stage, oestradiol [E2], oestriol, oestrone, androstenedione, testosterone [T], dihydrotestosterone, gonadotropins, IGF-1, and IGFBP-3 serum concentrations determined at first clinical presentation were related to breast diameter regression determined by palpation and disappearance of breast glandular tissue in ultrasound in follow-up to identify possible predictors of breast regression. RESULTS: During the observation period, the breast diameter decreased (in median -1 (interquartile range [IQR] -5 to +1) cm). At follow-up, 6% of boys had no breast enlargement any more, and 65% developed lipomastia. Gynaecomastia was still present in 29%. None of the analysed hormones was related significantly to breast diameter regression or disappearance of breast glandular tissue. In multiple linear regression analyses adjusted for observational period, as well as age and BMI-SDS at first presentation, changes in BMI-SDS (ß-coefficient 6.0 ± 2.3, p = .015) but not the E2/T ratio or any other hormone determined at baseline was related to changes in breast diameter. CONCLUSIONS: Breast diameter regression seems not to be predictable by a hormone profile in pubertal boys with gynaecomastia. In pubertal boys presenting with gynaecomastia, conversion to lipomastia of smaller volume is common. The reduction of weight status was the best predictor of breast diameter regression.

Skeletal disproportion in girls with Turner syndrome and longitudinal change with growth-promoting therapy.

OBJECTIVE: Short stature in Turner syndrome (TS) may be accompanied by skeletal disproportion. This retrospective study investigates growth and disproportion from early childhood to adult height. STUDY DESIGN: Data were collected from 59 girls prior to growth hormone (rhGH) treatment and in 30 girls followed up longitudinally. Standard deviation scores (SDS) for height (Ht), sitting height (SH) and sub-ischial leg length (LL) were compared and a disproportion score (SH SDS - LL SDS) calculated. RESULTS: In 59 girls, mean (SD) age 6.6 (2.1) years prior to rhGH treatment, LL SDS of -3.4 (1.1) was significantly lower than SH SDS of -1.2 (0.8) [p < .001]. In girls with Ht SDS < -2.0, disproportion score was > +2.0 in 27 (63%), cf eight (50%) with Ht SDS ≥ -2.0. For the longitudinal analysis, skeletal disproportion prior to rhGH was +2.4 (1.1) and +1.7 (1.0) on rhGH but prior to introduction of oestrogen [p < .001]. Disproportion at adult height was +1.1 (0.8), which was less marked than at the earlier time points [p < .001 for both comparisons]. Change in disproportion SDS over the first two years of rhGH predicted overall change in disproportion from baseline to adult height [R2 51.7%, p < .001]. CONCLUSION: TS is associated with skeletal disproportion, which is more severe in the shortest girls and present in only half of those with milder degrees of short stature. Growth-promoting therapy may improve disproportion during both the childhood and pubertal phases of growth. Change in disproportion status two years after starting rhGH helps predict disproportion at adult height.

Characterisation of testicular function and spermatogenesis in transgender women.

STUDY QUESTION: Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? SUMMARY ANSWER: Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. WHAT IS KNOWN ALREADY: Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. PARTICIPANTS/MATERIALS, SETTING METHODS: The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. MAIN RESULTS AND THE ROLE OF CHANCE: Suppressed testosterone levels (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. LIMITATIONS, REASONS FOR CAUTION: Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. WIDER IMPLICATIONS OF THE FINDINGS: HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. STUDY FUNDING/COMPETING INTEREST(S): D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Polyphenol intake and cognitive decline in the Seguimiento Universidad de Navarra (SUN) Project.

The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between polyphenol intake and 6-year change in cognitive function in the 'Seguimiento Universidad de Navarra' (SUN) Project, a Spanish prospective cohort study. Changes (final - initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 (sd 5) years, 69·7 % male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified score. Polyphenol intake was derived from a validated semi-quantitative FFQ and matching food composition data from the Phenol-Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (ßQuintile (Q) 5 v. Q1 0·81; 95 % CI 0·12, 1·51; Ptrend = 0·020) and stilbenes (ßQ5 v. Q1 0·82; 95 % CI 0·15, 1·49; Ptrend = 0·028) was associated with more favourable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake, and wine in stilbene intake. The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.

Sex differences in metabolic regulation and diabetes susceptibility.

Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.

Menopausal hormone therapy treatment options and ovarian cancer risk: A Swedish prospective population-based matched-cohort study.

Although menopausal hormone therapy (MHT) seemingly increases the risk of ovarian cancer, evidence is insufficient whether the risk varies between various MHT formulations, regimens and administration modes. With the aim of filling these knowledge gaps, we investigated the effect of different MHT treatment options on the risk of ovarian cancer. This prospective Swedish population-based matched-cohort study included all women ≥40 years having used systemic MHT between 2005 and 2012 (288,950 ever-users), group-level matched (1:3) to 866,546 nonusers. MHT use was ascertained from the Swedish Prescribed Drug Registry and data was linked to several national health data registries. Multivariable conditional logistic regression provided odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for parity, and comorbidities. Current EP-MHT use was associated with a modestly increased risk of ovarian cancer (OR = 1.38, 95% CI 1.18-1.62), while no consistent risk was found among past users (OR = 1.00, 95% CI 0.84-1.18). Current continuous testosterone derived (OR = 1.50, 95% CI 1.15-1.96) regimens increased the risk whereas progesterone derived (OR = 1.48, 95% CI 1.00-2.21) regimens increased the risk marginally. Nonsignificant positive associations were observed for sequential regimens (OR = 1.87, 95% CI 0.70-5.08; OR = 1.54, 95% CI 0.96-2.47, respectively). An inverse relationship was observed for all E-MHT use (OR = 0.25, 95% CI 0.22-0.29), but this association might partly be explained by underreporting of oophorectomies or tubal ligations. Current cutaneous EP-MHT (OR = 1.28, 95% CI 0.81-2.02) suggested a possibly lower risk than oral MHT (OR = 1.48, 95% CI 1.25-1.75). In conclusion EP-MHT, notably continuous regimens, were associated with a modestly increased risk of ovarian cancer. The role of E-MHT requires further clarification.

Sex hormone replacement therapy in periodontology-A systematic review.

OBJECTIVE: To analyse whether sex hormone replacement therapy (HRT) improves periodontal parameters and dental implants osseointegration in humans. MATERIALS AND METHODS: Electronic databases and hand searches were performed from June to August 2018 in SciELO, LILACS and PubMed/MEDLINE. Human observational and interventional studies that evaluated the following parameters were included: clinical attachment loss (CAL), probing pocket depth (PPD), bleeding on probing (BOP), radiographic bone loss (RBL) or osseointegration. RESULTS: Initial search retrieved 1,282 non-duplicated articles. Fifteen studies were selected after inclusion criteria were applied. All studies were performed in postmenopausal women. Mean differences for PPD reduction ranged from 0.02 to 0.2 mm in HRT-positive patients; mean CAL gain -0.18 to 0.54 mm; mean RBL reduction -0.87 to 0.15 mm; and mean BOP reduction 9%-30.3%. Failure rate of dental implants increased -5.5% to 11.21% when HRT was used. CONCLUSIONS: Very low but consistent evidence suggests a reduction in BOP and no impact on RBL in postmenopausal women receiving HRT. There are inconsistent reports that suggest that HRT in postmenopausal women: (a) improves or does not impact PPD reduction and CAL gain; and (b) does not impact or increase implant loss. In summary, there is no evidence to support HRT prescription for either men or women for periodontal/implant placement purposes.

Effect of ovariectomy on maxilla and mandible dimensions of female rats.

OBJECTIVE: The role of oestrogen in craniofacial growth still remains unclear. Therefore, the present study aimed to assess the effect of oestrogen deficiency on maxilla and mandible dimensions. SETTING AND SAMPLE POPULATION: The study was conducted at the Department of Pediatric Dentistry at the School of Dentistry of Ribeirão Preto, University of São Paulo, and used forty female Wistar rats. MATERIAL AND METHODS: Ovariectomy (OVX) and placebo surgery (Sham) were performed when animals were twenty-one days old (prepubertal stage). Dimensions of the maxilla and mandible were assessed by craniometric analysis using radiographs, during and after puberty of the animals (45 and 63 days old, respectively). Quantitative real-time PCR and immunohistochemical analyses were performed to determine the expression and localization, respectively, of oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERß) in different growth sites of the evaluated structures at puberty. The differences between the groups for each outcome were evaluated using the t test with an established alpha error of 5%. RESULTS: There were significant differences between the OVX and Sham groups for horizontal and vertical linear measurements in the maxilla and the mandible at both pubertal and post-pubertal stages (P < .05). The ovariectomized rats showed significantly greater measures for all dimensions assessed. No differences in gene expression of ERα and ERß were identified at the different growth sites between the OVX and Sham groups (P > .05). Immunohistochemical analyses revealed the presence of both oestrogen receptors in osteoblasts and chondrocytes in the midpalatal suture and mandibular condyle, respectively, in the OVX and Sham groups. CONCLUSION: Our results suggest that oestrogen deficiency from the prepubertal stage might increase the growth of the maxilla and mandible in female rats.

The impact of oral hormonal contraception on metformin action on hypothalamic-pituitary-thyroid axis activity in women with diabetes and prediabetes: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: The impact of metformin on thyrotropin levels is sex-dependent. No previous study has assessed whether sex steroids determine metformin action on thyrotrope and thyroid cell functioning. The aim of the present study was to compare the effect of this agent on hypothalamic-pituitary-thyroid axis activity and thyroid function tests between women receiving oral contraceptive pills and women not using any contraception. METHODS: The study population included 52 women with subclinical hypothyroidism and prediabetes or diabetes, 20 of whom had been using oral contraceptive pills for at least 12 months before the beginning of the study. Over the entire study period (4 months), all participants received oral metformin (1.7-3 g daily). Circulating levels of glucose, insulin, thyrotropin, free thyroid hormones, oestradiol, gonadotropins and prolactin were measured, while the structure parameters of thyroid homeostasis and the degree of insulin sensitivity were calculated at the beginning and at the end of the study. RESULTS AND DISCUSSION: The study groups differed in oestradiol, gonadotropins and prolactin levels and in structure parameter inference approach (SPINA)-GT. In both groups, metformin reduced glucose levels, homeostasis model assessment 1 of insulin resistance index (HOMA1-IR), thyrotropin levels and Jostel's thyrotropin index, as well as increased SPINA-GT. In women receiving oral contraceptive pills, the drug slightly decreased serum prolactin levels. The impact on metformin on HOMA1-IR, thyrotropin, prolactin, Jostel's thyrotropin index and SPINA-GT was more pronounced if women received oral contraception, as well as more pronounced in patients treated with higher doses of this agent. Treatment-induced changes in thyrotropin and Jostel's thyrotropin index correlated with their baseline values, baseline levels of oestradiol and gonadotropins, as well as with the degree of a reduction in HOMA1-IR. WHAT IS NEW AND CONCLUSION: This study is the first one to have shown that oral oestrogens potentiate the effect of metformin on hypothalamic-pituitary-thyroid axis activity.

Simultaneous quantification of oestrogens and androgens in the serum of patients with benign prostatic hyperplasia by liquid chromatography-Tandem mass spectrometry.

Benign prostate hyperplasia (BPH) is a common disease in elderly men. It has been found that the occurrence of BPH was closely related to dysregulated steroid hormones. Here, a rapid, sensitive, accurate and specific method for the quantitative profiling of five androgens in man serum was developed and validated by the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using this method, dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), androsterone (A), dihydrotestosterone (DHT), oestrone (E1) and oestradiol (E2) were quantified in serum from man with and without BPH. BPH patients were characterised by the decreases in DHEA, A4 and T as well as increases in DHT, E2 and E1 in serum. Meanwhile, DHEA and DHT in serum were screened as sensitive biomarkers of BPH patients. This study will provide a new perspective of dysregulated steroid hormones for the diagnosis and prevention of BPH.

Prenatal exposure to oestrogens estimated by digit ratio (2d/4d) and breast size in young nulliparous women.

Digit ratio (2d/4d) in humans is commonly used as a proxy for the exposure to oestrogens and androgens in prenatal life. Masculinisation/feminisation in adults may be also related to digit ratio and therefore to the oestrogen/androgen ratio in prenatal life. It has been shown, for instance, that Waist-to-Hip ratio (WHR) and the amount and distribution of body fat are related to digit ratio in women. A species-specific, sexually dimorphic morphological trait in humans is also a pair of permanent breasts that develop during puberty, under the influence of oestrogens. Here we test if prenatal exposure to oestrogens (in relation to androgens), measured by digit ratio, may also be related to breast size in young, nulliparous women. 133 Turkish students (mean age 22.2) were measured. Breast size was calculated as the difference between breast and under-breast circumferences. We found that when controlling for body mass index (BMI), both right and left digit ratios correlate positively with breast size. This relationship is stronger for the digit ratio of the right hand, which confirms that this side is a better measure of sex differences. Thus, higher exposure to oestrogens in prenatal life is related with stronger expression of a sexually dimorphic trait, such as breast size, in adult women.

Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome.

OBJECTIVE: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17ß oestradiol (E2 ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome. METHODS: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. RESULTS: After treatment, least square mean (SE) total E2 concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1 ) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E2 (300 vs 76 [±52]), 4-hydroxy-E1 (450 vs 105 [±113]), 2-hydroxy-E1 (3094 vs 740 [±684]) and 16α-hydroxy-E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group. CONCLUSIONS: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens' first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.