Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

OBJECTIVE: To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. DESIGN: A population-based cohort study using the Korean National Health Insurance Services database. SETTING: Nationwide health insurance database. POPULATION: Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. METHODS: The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). MAIN OUTCOME MEASURES: Incidence of CVD (a composite of myocardial infarction and stroke). RESULTS: The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. CONCLUSIONS: This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

The potent contraceptive gestodene exerts insulinotropic effects through its a-ring reduced metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.

PURPOSE: The contraceptive gestodene is a potent synthetic progestin used in several low-dose contraceptive formulations. Clinical studies reported a relationship between long-term use of combined oral contraceptives containing gestodene (GDN) and profound alterations in glucose metabolism in women. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether GDN may induce estrogen-like effects, even though GDN does not interact with estrogen receptors. The aim of this study was to investigate whether GDN affect pancreatic ß-cell activity, directly or through its conversion to other bioactive metabolites. METHODS: The effects of GDN and its two derivatives 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN on insulin 2 (Ins II) and glucokinase (Gk) expression and glucose-stimulated insulin secretion were determined in pancreatic islets from female rats. RESULTS: Gestodene did exert significant effects on islet ß-cells activity. The most striking finding was that 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN had greater stimulatory effects on Ins II and Gk expression than that observed with GDN, consistent with their effects on glucose-stimulated insulin secretion. The effects on gene expression induced by GDN-derivatives were abolished by ICI 182,780 and MPP. In addition, the presence of inhibitors of androgen and progestin-metabolizing enzymes eliminated gene expression induced by GDN. These results indicated that GDN is metabolized to A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect ß-cell activity. CONCLUSIONS: Altogether, the data suggest that 19-nortestosterone-derived contraceptives such as GDN, possess insulinotropic effects through their conversion into metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.

Impact of Continuous Estroprogestin Treatment on Circulating Microparticle Levels in Deep Endometriosis Patients.

There has been increasing interest in the study of new pathogenic mechanisms in endometriosis (END), including the coagulation/fibrinolysis system and its link with inflammation and tissue remodeling. It has been suggested that END patients, especially with deep-infiltrating (DE) forms, could present a hypercoagulable state revealing higher levels of proinflammatory and procoagulant markers, such as total circulating microparticles (cMPs) and cMP-TF (tissue factor), released by cells in response to damage, activation, or apoptosis. However, no previous study has assessed the effect of END hormonal treatments on cMP and cMP-TF levels. Therefore, the aim of this study was to evaluate the impact of these treatments on cMP and cMP-TF levels in DE patients. Three groups were compared: DE patients receiving a continuous combined oral contraceptive regimen (CCOCR) (n = 41), DE patients without CCOCR (n = 45), and a control group (n = 43). cMP and cMP-TF levels were evaluated in platelet-free plasma. A significant decrease in the total cMP levels was found in the DE group with CCOCR versus the group without CCOCR, reflecting a higher chronic inflammatory status in DE patients that decreased with the treatment. cMP-TF levels were higher in DE patients receiving CCOCR versus those not receiving CCOCR, suggesting that treatments containing estrogens play a predominant role in suppressing the inhibitory pathway of TF.

Comparative evaluation of low-level light therapy and ethinyl estradiol and desogestrel combined oral contraceptive for clinical efficacy and regulation of serum biochemical parameters in primary dysmenorrhoea: a prospective randomised multicentre trial.

We aimed to compare low-level light therapy with oral contraceptive pills for pain relief and serum levels of nitric oxide and prostaglandin E2 in patients with primary dysmenorrhoea. This was a randomised, active comparator-controlled, multicentre study. In total, 156 patients were randomised to receive either low-level light therapy with light-emitting diodes (LED) applying on two acupoints, namely, conception vessel 4 (CV4) and CV6 or conventional treatment with oral Marvelon, 30 µg of ethinyl estradiol and 150 µg of desogestrel (DSG/EE), for three consecutive menstrual cycles. The main outcome was the proportion of patients who achieved 33% or more decrease in pain scores measured using the visual analogue scale, which was deemed as efficient rate. Absolute changes in visual analogue scale scores, serum levels of nitric oxide (assessed by nitrites and nitrates reflecting nitric oxide metabolism) and prostaglandin E2 (measured by enzyme-linked immunosorbent assay) were the secondary outcomes. A total of 135 patients completed the study (73 in the light therapy group and 62 in the DSG/EE group). The efficient rate at the end of treatment was comparable between the groups (73.6% vs. 85.7%, χ2 = 2.994, p = 0.084). A more significant reduction in pain scores was observed in the DSG/EE group (39.25% vs. 59.52%, p < 0.001). Serum levels of prostaglandin E2 significantly decreased from baseline but did not differ between groups (- 109.57 ± 3.99 pg/mL vs. - 118.11 ± 12.93 pg/mL, p = 0.51). Nitric oxide concentration remained stable in both groups. Low-level light therapy with LED-based device applied on acupuncture points CV4 and CV6 demonstrated a similar level of dysmenorrhoea pain reduction to DSG/EE combined contraceptive. Both treatment modalities achieved clinically meaningful levels of pain reduction. Registration on ClinicalTrials.gov: TRN: NCT03953716, Date: April 04, 2019.

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis.

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

COVID-19, gender and estroprogestins, what do we know?

The new coronavirus disease-19 (COVID-19) pandemic has rapidly spread all around the world, eliciting many questions and doubts about the pathogenesis of the disease and treatment. Mortality has been related to a prothrombotic state. Risk factors for the infection and for severe forms of COVID-19 have still to be defined. According to data collected, women appear to be less prone to severe forms of the disease and their mortality was lower than for men. The role of female hormones in the modulation of inflammation may be the reason behind this gender gap.Considering the prothrombotic state activated by the virus, hormone therapies have been placed under investigation as possible increasing risk factors for severe forms. Moreover, new vaccines and their rare thrombotic side effects have increased the concern about this issue.The goal of this review is to go over the mechanisms that lead up to thrombosis during COVID-19, trying to explain the possible reasons why women seem to be naturally protected. The expert opinions about whether to continue/discontinue hormonal therapies are reviewed. Moreover, available data about the so-called 'vaccine induced immune thrombotic thrombocytopaenia' caused by vaccines against COVID-19 are discussed.

The effect of tibolone treatment on lipid profile in women: A systematic review and dose-response meta-analysis of randomized controlled trials.

Inconsistencies exist with regard to influence of tibolone treatment on the lipid profile. The reasons for these inconsistencies might derive from several factors, i.e., differences in baseline variables, intervention duration, participants' health status or baseline body mass index (BMI). To address these inconsistencies, based on a systematic search in Scopus, PubMed/Medline, Web of Science, and Embase for papers published until 21 December 2020, we conducted the current dose-response meta-analysis of randomized controlled trials (RCTs) to determine the impact of tibolone treatment on the lipid profile. The overall findings were derived from 26 RCTs. Tibolone administration decreased total cholesterol (TC) (weighted mean difference, WMD: -18.55 mg/dL, CI: -25.95 to -11.16, P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (WMD: -9.42 mg/dL, CI: -11.83 to -7.01, P < 0.001) and triglyceride (TG) (WMD: -21.43 mg/dL, CI: -27.15 to -15.70, P < 0.001) levels. A significant reduction in LDL-C occurred when tibolone was prescribed for ≤ 26 weeks (WMD: -7.64 mg/dL, 95% CI: -14.58 to -0.70, P = 0.031) versus > 26 weeks (WMD: -8.84 mg/dL, 95% CI: -29.98, 12.29, P = 0.412). The decrease in TG (WMD: -22.64 mg/dL) and TC (-18.55 mg/dL) concentrations was more pronounced in patients with BMI ≥ 25 kg/m2versus BMI < 25 kg/m2. This systematic review and meta-analysis discovered that tibolone decreases TC, HDL-C and TG levels. LDL-C concentrations are significantly reduced when tibolone administration lasts for ≤ 26 weeks.

CCDC114, DNAI2 and TOP2A involves in the effects of tibolone treatment on postmenopausal endometrium.

BACKGROUND: This study aimed to explore the molecular mechanisms of tibolone treatment in postmenopausal women. METHODS: The gene set enrichment profile, GSE12446, which includes 9 human endometrial samples from postmenopausal women treated with tibolone (tibolone group) and 9 control samples (control group), was downloaded from GEO database for analysis. Differentially expressed genes (DEGs) in tibolone vs. control groups were identified and then used for function and pathway enrichment analysis. Protein-protein interaction (PPI) network and module analyses were also performed. Finally, drug-target interaction was predicted for genes in modules, and then were validated in Pubmed. RESULTS: A total of 238 up-regulated DEGs and 72 down-regulated DEGs were identified. These DEGs were mainly enriched in various biological processed and pathways, such as cilium movement (e.g., CCDC114 and DNAI2), calcium ion homeostasis, regulation of hormone levels and complement/coagulation cascades. PPI network contained 368 interactions and 166 genes, of which IGF1, DNALI1, CCDC114, TOP2A, DNAH5 and DNAI2 were the hue genes. A total of 96 drug-gene interactions were obtained, including 94 drugs and eight genes. TOP2A and HTR2B were found to be targets of 28 drugs and 38 drugs, respectively. Among the 94 obtained drugs, only 12 drugs were reported in studies, of which 7 drugs (e.g., epirubicin) were found to target TOP2A. CONCLUSIONS: CCDC114 and DNAI2 might play important roles in tibolone-treated postmenopausal women via cilium movement function. TOP2A might be a crucial target of tibolone in endometrium of postmenopausal women.

Association of tibolone and dementia risk: a cohort study using Korean claims data.

OBJECTIVE: Few studies have examined whether tibolone (TIB), a type of hormone replacement therapy widely used in Asia and Europe, affects dementia risk in postmenopausal women. Our study aims to investigate the association of TIB and dementia risk in Korean women aged 50-80 years. METHODS: A population-based longitudinal study was conducted using the Korean National Health Insurance Service claims database merged with national health examination data from 2002 to 2015. Among 13,110 participants, exposure to TIB was determined using the standardized defined daily dose (DDD) system from 2003 to 2007. Starting from 2007, participants were followed up for overall dementia, Alzheimer's disease (AD) and vascular dementia (VD) until 2015. Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of dementia according to TIB use. RESULTS: TIB use was not significantly associated with the risk of total dementia (aHR = 1.040; 95% CI = 0.734-1.472; p = .827), AD (aHR = 0.949; 95% CI = 0.652-1.381; p = .785) and VD (aHR = 1.245; 95% CI = 0.631-2.457; p = .528). CONCLUSIONS: Our results suggest that TIB use does not have a significant association with dementia risk. Further randomized controlled trials are necessary to elucidate the role of exogenous hormones in the development of dementia.

Long-Term Medical Therapy after Laparoscopic Excision of Ovarian Endometriomas: Can We Reduce and Predict the Risk of Recurrence?

OBJECTIVES: Up to 32% of women experience anatomic recurrence after conservative surgery for endometriomas, while pain recurs in 10-40% of cases. Long-term postoperative hormonal therapy is recommended to prevent disease recurrence. We evaluated the efficacy of long-term therapy with estroprogestins (EPs) or progestins (Ps) in preventing endometrioma recurrence, as identifiable cysts and subjective symptoms, after laparoscopic excision. DESIGN: This retrospective cohort study included 375 women submitted to laparoscopic endometrioma excision. Women were followed up at 6 and 12 months and then yearly after surgery. Based on postoperative medical therapy, women were divided into 4 groups: nonusers, cyclic EP users, continuous EP users, and progestogen users. Materials, Setting, Methods: Anamnestic and anthropometric characteristics were collected as well as clinical and surgical data. Gynecological examination, and transvaginal and transabdominal ultrasound scans were performed. Pain (numerical rating score >5) and endometrioma recurrence at ultrasound (ovarian cyst with typical sonographic features ≥10 mm in mean diameter) were recorded at each examination. The reoperation rate in women with recurrence was investigated. RESULTS: The median follow-up was 3.7 years with a maximum of 16.7 years. Most patients used EPs (119 cyclic and 61 continuous users), 95 used P, and 100 were nonusers. In 135 women (36%), endometriotic cyst recurrence was diagnosed, with a mean diameter of 18.7 ± 10.8 mm (range 10-55 mm). The median recurrent cyst-free time was 7.9 years (95% CI 5.8-10.8). Dysmenorrhea was the first symptom to reappear, affecting 162 patients (43.2%). Upon multivariable regression analysis, continuous users had a lower risk of relapse (OR 0.56, 95% CI 0.32-0.99), in terms of both cysts and symptom recurrence, than patients who received no medications. The reoperation rate was 16.2%. LIMITATIONS: The main limitation of this study is its retrospective design. Also, women switching therapies throughout the follow-up period were sorted into one of the study groups based on the longest treatment taken, without considering the discontinuation rates. CONCLUSIONS: Long-term EPs, administered in a continuous regimen and starting immediately after conservative surgery for endometriomas, seem to reduce the disease recurrence risk.

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.

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge.

BACKGROUND: Tibolone is a synthetic steroid used in clinical practice for the treatment of climacteric symptoms and osteoporosis. Active metabolites of tibolone, generated in target tissues, have an affinity for estrogen and androgen receptors. Astrocytes are direct targets for estrogenic compounds and previous studies have shown that tibolone protects brain cortical neurons in association with a reduction in reactive astrogliosis in a mouse model of traumatic brain injury. Since phagocytosis is a crucial component of the neuroprotective function exerted by astrocytes, in the present study, we have assessed whether tibolone regulates phagocytosis in primary astrocytes incubated with brain-derived cellular debris. METHODS: Male and female astrocyte cell cultures were obtained from newborn (P0-P2) female and male Wistar rats. Astrocytic phagocytosis was first characterized using carboxylate beads, Escherichia coli particles, or brain-derived cellular debris. Then, the effect of tibolone on the phagocytosis of Cy3-conjugated cellular debris was quantified by measuring the intensity of Cy3 dye-emitted fluorescence in a given GFAP immunoreactive area. Before the phagocytosis assays, astrocytes were incubated with tibolone in the presence or absence of estrogen or androgen receptor antagonists or an inhibitor of the enzyme that synthesizes estradiol. The effect of tibolone on phagocytosis was analyzed under basal conditions and after inflammatory stimulation with lipopolysaccharide. RESULTS: Tibolone stimulated phagocytosis of brain-derived cellular debris by male and female astrocytes, with the effect being more pronounced in females. The effect of tibolone in female astrocytes was blocked by a selective estrogen receptor ß antagonist and by an androgen receptor antagonist. None of these antagonists affected tibolone-induced phagocytosis in male astrocytes. In addition, the inhibition of estradiol synthesis in the cultures enhanced the stimulatory effect of tibolone on phagocytosis in male astrocytes but blocked the effect of the steroid in female cells under basal conditions. However, after inflammatory stimulation, the inhibition of estradiol synthesis highly potentiated the stimulation of phagocytosis by tibolone, particularly in female astrocytes. CONCLUSIONS: Tibolone exerts sex-specific regulation of phagocytosis in astrocytes of both sexes, both under basal conditions and after inflammatory stimulation.

Effects of tibolone or continuous combined oestradiol and norethisterone acetate on lipids, high-density lipoprotein subfractions and apolipoproteins in postmenopausal women in a two-year, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effects of (a) tibolone, (b) continuous combined oestrogen plus progestogen and (c) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy postmenopausal women. STUDY DESIGN: Randomized, single-centre, placebo-controlled, double-blind study. PATIENTS: One hundred and one postmenopausal women were randomized (1:1:1) into one of three groups taking daily 2.5 mg tibolone, continuous oral oestradiol-17ß 2 mg plus norethisterone acetate 1 mg daily (E2 /NETA) or placebo. MAIN OUTCOME MEASURES: Fasting serum lipid, lipoprotein and apolipoprotein concentrations measured at baseline and after 6, 12 and 24 months of treatment. RESULTS: Both tibolone and E2 /NETA lowered plasma total cholesterol concentrations relative to placebo. With tibolone, high-density lipoprotein cholesterol (HDL-C) was reduced (-27% at 24 months, P < .001), the greatest effect being in the cholesterol-enriched HDL2 subfraction (-40%, P < .001). Tibolone's effect on HDL concentrations was also apparent in the principal HDL protein component, apolipoprotein AI (-29% at 24 months, P < .001). However, there was no significant effect of tibolone on low-density or very low-density lipoprotein cholesterol (LDL-C and VLDL-C, respectively). By contrast, the greatest reduction in cholesterol with E2 /NETA was in LDL-C (-22% at 24 months, P = .008). E2 /NETA reduced HDL-C to a lesser extent than tibolone (-12% at 24 months, P < .001). Effects on HDL apolipoproteins were similarly diminished relative to tibolone. E2 /NETA had no effect on VLDL-C or on the protein component of LDL, apolipoprotein B. CONCLUSION: Tibolone reduces serum HDL. E2 /NETA reduces LDL cholesterol but not apolipoprotein B, suggesting decreased cholesterol loading of LDL. Any impact these changes may have on CVD risk needs further investigation.

A prospective, single-centre, single-arm, open label study of the long term use of a gonadotropin releasing hormone agonist (Triptorelin SR, 11.25 mg) in combination with Tibolone add-back therapy in the management of chronic cyclical pelvic pain.

BACKGROUND: Chronic cyclic pelvic pain (CCPP) affects women's quality of life and pituitary downregulation is often used for symptomatic relief. However, prolonged suppression of ovarian function is associated with menopausal side effects and can lead to osteoporosis. Currently, the use of gonadotropin releasing hormone agonists (GnRHa) for treatment of CCPP is usually restricted to 6-9 months, limiting their efficacy. There is limited information regarding safety and efficacy with longer-term use. The aim of this study is to examine the safety and efficacy of long-term (24 months) pituitary down-regulation with the GnRHa (Triptorelin SR) with add-back therapy (ABT) using Tibolone for symptom relief in women with CCPP. METHODS: A single-arm, prospective clinical trial at a Tertiary University Teaching Hospital of 27 patients receiving Triptorelin SR (11.25 mg) and Tibolone (2.5 mg). Outcomes measures were the safety of treatment assessed by clinical examination, haematological markers, liver and renal function tests and bone mineral density (BMD) at 12, 18 and 24 months as well as at 6 months post-treatment. Pain and health-related quality of life (HR-QoL) assessed using the endometriosis health profile (EHP-30) and chronic pain grade (CPG) questionnaires. RESULTS: There was no evidence for any significant harmful effects on any of the measured haematological, renal or liver function tests. Although results regarding the effect on BMD are not conclusive there is an increased risk of development of osteopaenia after 12 months of treatment. Pain and HRQoL assessments showed significant improvement during medication, but with deterioration after treatment cessation. CONCLUSION: Long- term Triptorelin plus Tibolone add-back therapy in women suffering from CCPP does not appear to be associated with significant serious adverse events apart from the possibility of deterioration in the BMD that needs to be monitored. This mode of therapy appears to be effective in pain relief and in improving quality of life over a 24-month period. TRIAL REGISTRATION: Clinical trials database NCT00735852.

Tibolone, alendronate, and simvastatin enhance implant osseointegration in a preclinical in vivo model.

OBJECTIVES: The objective of the study was to evaluate and compare the effect of different drugs such as simvastatin, alendronate, and tibolone for titanium implant osseointegration enhancement. MATERIALS AND METHODS: Eighty female albino Wistar rats were equally divided into five groups: Group I (ovariectomy), Group II (sham ovariectomy), Group III (alendronate + ovariectomy), Group IV (simvastatin + ovariectomy), and Group V (tibolone + ovariectomy). Three months after ovariectomy, we performed bilateral titanium intramedullary nailing in all groups, followed by oral administration of alendronate, simvastatin, or tibolone for 12 weeks. Examinations included micro-CT, mechanical pull-out test, histology, and bone serum markers. RESULTS: Peri-implant micro-CT analysis showed a significantly higher overall bone tissue in tibolone compared to the ovariectomy group, while no significant difference was found between the treatment groups. Sham ovariectomy, alendronate, and tibolone groups had a higher body mass density compared to ovariectomy and simvastatin groups. All treatment groups had a greater thickness of the peri-implant compact bone layer compared to ovariectomy group, but the results were not statistically significant. Tibolone presented the highest values in pull-out test, but alendronate showed more consistently positive results compared to other groups. Osteocalcin had in the tibolone group almost three times the value in the ovariectomy group, but the results were not statistically significant. CONCLUSION: The hypothesis that alendronate, simvastatin, and tibolone enhance the osseointegration process of intramedullary titanium implants in ovariectomized rats has been accepted, while tibolone could offer the best results.

Osteoporosis management in Australian general practice: an analysis of current osteoporosis treatment patterns and gaps in practice.

BACKGROUND: Among Australians aged 50 and over, an estimated 1 in 4 men and 2 in 5 women will experience a minimal trauma fracture during their remaining lifetime. Effective fracture prevention is hindered by substantial undertreatment, even of patients who clearly warrant pharmacological therapy. Poor adherence to osteoporosis treatment is also a leading cause of repeat fractures and hospitalisation. The aim of this study was to identify current osteoporosis treatment patterns and gaps in practice in Australia, using general practice data, and to explore general practitioners' (GPs') attitudes to osteoporosis treatment and their views on patient factors affecting osteoporosis management. METHODS: The study was conducted in two phases. Phase 1 was a longitudinal retrospective cohort study which utilised data from MedicineInsight - a national general practice data program that extracts longitudinal, de-identified patient data from clinical information systems (CISs) of participating general practices. Phase 2 included semi-structured, in-depth telephone interviews with a sample of MedicineInsight practice GPs. Data were analysed using an inductive thematic analysis method informed by the theory of planned behaviour. RESULTS: A diagnosis of osteoporosis was recorded in 12.4% of patients over the age of 50 years seen in general practice. Of those diagnosed with osteoporosis, almost a quarter were not prescribed osteoporosis medicines. From 2012 to 17, there was a progressive increase in the number of denosumab prescriptions, while prescriptions for bisphosphonates and other osteoporosis medicines decreased. More than 80% of patients who ceased denosumab treatment had no subsequent bisphosphonate prescription recorded. Interviews with GPs revealed beliefs and attitudes that may have influenced their intentions towards prescribing and osteoporosis management. CONCLUSIONS: This study suggests that within the Australian general practice setting, osteoporosis is underdiagnosed and undertreated. In addition, it appears that most patients who ceased denosumab treatment had no record of subsequent antiresorptive therapy, which would place them at risk of further fractures. The study supports the need for the development of clinical education programs addressing GP knowledge gaps and attitudes, and the implementation of specific interventions such as good reminder/recall systems to avoid delays in reviewing and treating patients with osteoporosis.

Chronic simultaneous exposure of common carp (Cyprinus carpio) from embryonic to juvenile stage to drospirenone and gestodene at low ng/L level caused intersex.

Synthetic progestins are emerging contaminants of the aquatic environment with endocrine disrupting potential. The main aim of the present study was to investigate the effects of the synthetic progestins gestodene, and drospirenone on sex differentiation in common carp (Cyprinus carpio) by histological analysis. To gain insights into the mechanisms behind the observations from the in vivo experiment on sex differentiation, we analyzed expression of genes involved in hypothalamus-pituitary-gonad (HPG) and hypothalamus-pituitary-thyroid (HPT) axes, histology of hepatopancreas, and in vitro bioassays. Carp were continuously exposed to concentrations of 2 ng/L of single progestins (gestodene or drospirenone) or to their mixture at concentration 2 ng/L of each. The exposure started 24 h after fertilization of eggs and concluded 160 days post-hatching. Our results showed that exposure of common carp to a binary mixture of drospirenone and gestodene caused increased incidence of intersex (32%) when compared to clean water and solvent control groups (both 3%). Intersex most probably was induced by a combination of multiple modes of action of the studied substances, namely anti-gonadotropic activity, interference with androgen receptor, and potentially also with HPT axis or estrogen receptor.

On the dimorphism and the pressure-temperature state diagram of gestodene, a steroidal progestogen contraceptive.

The pressure-temperature phase diagram of the dimorphism of the contraceptive drug gestodene is constructed using the temperature and enthalpy of fusion of form I (469.5K, 107Jg-1), and those of the endothermic transition from form II to form I (311K, 8.52Jg-1). At ordinary pressure, the sign of the enthalpy of this transition indicates that these polymorphs are enantiotropically related and that form II, whose melting temperature is calculated to be about 452K, is the stable form at room temperature. Considering the inequality in the specific volumes of the two polymorphs, it is shown that the two forms remain enantiotropically related on increasing pressure, because the I-II equilibrium and the melting equilibria I-L and II-L diverge as a consequence of the negative slope dP/dT of the solid-solid equilibrium. In addition, it is demonstrated that the heats of dissolution, inferred from solubility measurements, lead to virtually the same value of the heat of transition from II to I as for the differential scanning calorimetry measurements.

Increased risk for stress urinary incontinence in women with postmenopausal hormone therapy.

INTRODUCTION AND HYPOTHESIS: The impact of estradiol-based hormone therapy (HT) on the incidence of stress urinary incontinence (SUI) is unknown. Therefore, we compared the use of such HT regimens and tibolone in women with and without SUI. METHODS: The women with a history of SUI operation (N = 15,002) were identified from the Finnish National Hospital Discharge Register, and the control women without such an operation (N = 44,389) from the Finnish Central Population Register. The use of HT was traced from the National Drug Reimbursement Register, and the odd ratios (ORs) with 95% confidence intervals (95% CIs) for SUI were calculated by using the conditional logistic regression analysis. RESULTS: The cases had used any HT more often than the controls. The use of systemic estradiol-only or estradiol-progestin therapy was accompanied by an increased SUI risk (OR 3.8, 95% CI: 3.6-4.0 and OR 2.7, 95% CI: 2.6-2.9 respectively). The use of estradiol with noretisterone acetate showed a higher risk of increase than that with medroxyprogesterone acetate. Age over 55 years at the initiation of systemic HT was accompanied by a higher SUI risk increase than that under 55 years of age. The use of tibolone, an estradiol + levonorgestrel-releasing intrauterine device, or vaginal estradiol also increased the risk. CONCLUSIONS: The use of HT regimens may predispose to the de novo development or worsening of pre-existing SUI. Thus, caution is needed when these regimens are prescribed to women with mild stress-related urine leakage or with established SUI risk factors.