Impact of hormonal contraception on endometrial histology in patients with Lynch syndrome, a retrospective pilot study.

Hormonal contraception (HC) is a well-recognized protection against endometrial cancer (EC) in the general population. It has not been established if this is also applicable to women with Lynch syndrome (LS), a condition associated with a up to 50% lifetime risk of developing EC. The objective of this study was to evaluate if the use of HC influences the incidence of endometrial hyperplasia and EC in women with LS by comparing the histology of annual endometrial biopsies obtained in patients with LS who are using HC versus non-users. This is a retrospective cohort study conducted with endometrial biopsies obtained in women 30 to 50 years of age with LS. The Pearson Chi-square test was performed to compare the prevalence of cancer and hyperplasia in the HC users and in the non-HC users groups. A total of 164 endometrial biopsies obtained among 75 women were suitable for analysis. Among the 86 biopsies obtained in the non-HC group, 81.4% (70/86) were normal. Two cases of endometrial carcinoma (2.3%) and 6 endometrial hyperplasia without atypia were found (7.0%). Among the 78 biopsies performed in patients using HC, 78.2% (61/78) were normal. Three endometrial hyperplasia without atypia (3.8%) and three cases of EC were diagnosed (3.8%). This study suggests that, in women of 30 to 50 years of age with LS, the use of hormonal contraception does not seem to decrease the occurrence of endometrial hyperplasia/carcinoma on annual endometrial histology.

Second-trimester medical abortion after exposure to lorlatinib during early pregnancy, a case report.

Use of Lorlatinib, a third-generation tyrosine kinase inhibitor currently indicated in the treatment of non-small-cell lung cancer (NSCLC) with ALK or ROS1 gene fusion, is formally contra-indicated during pregnancy due to teratogenic effects observed during pre-clinical studies. We report the case of a 38-year-old woman with a ROS1-positive NSCLC, successfully treated with lorlatinib as second line therapy, who became pregnant while on treatment. Due to significant disease progression 12 weeks after lorlatinib stop and the great uncertainty on the pregnancy outcome, she finally decided to interrupt the pregnancy at 22 weeks of gestation. Echography and gross infant examination did not reveal any malformation. Pregnancies occurring under this kind of new oncologic treatment is expected to happen more frequently in the future. It seems therefore important to us to report any information on the topic to increase our level of knowledge and improve decision-making.

Human Chorionic Gonadotropin and Early Embryogenesis: Review.

Human chorionic gonadotropin (hCG) has four major isoforms: classical hCG, hyperglycosylated hCG, free ß subunit, and sulphated hCG. Classical hCG is the first molecule synthesized by the embryo. Its RNA is transcribed as early as the eight-cell stage and the blastocyst produces the protein before its implantation. This review synthetizes everything currently known on this multi-effect hormone: hCG levels, angiogenetic activity, immunological actions, and effects on miscarriages and thyroid function.

Restoration of Fertility in Patients with Spontaneous Premature Ovarian Insufficiency: New Techniques under the Microscope.

Premature ovarian insufficiency (POI), a condition affecting up to 1% of women by the age of 40 years, is characterized by an extremely low chance of spontaneous pregnancy. Currently, fertility restoration options are virtually nonexistent for this population. To become pregnant, the only solution is egg donation. Interestingly, animal studies have provided encouraging results in terms of fertility restoration, and consequently, research has begun into the most promising approaches for women suffering from POI. The PubMed database was searched for studies in which techniques aiming at restoring fertility in women with spontaneous POI were tested. Although robust studies are lacking, the literature suggests a positive effect of certain techniques on fertility restoration in women with POI. The most promising approaches seem to be intraovarian injection of autologous platelet-rich plasma or of mesenchymal stem cells. In addition to these, in vitro and mechanical activation of dormant follicles and etiology-driven therapies have also been studied with mixed results. No safety concerns were raised in these studies. The absence of robust studies does not allow us to draw meaningful conclusions on the efficacy or superiority of any single technique at this stage, and so research in this area should continue using robust study designs, i.e., multicenter randomized controlled trials including sufficient subjects to achieve statistical power.

Polycystic ovarian syndrome and infertility: overview and insights of the putative treatments.

Infertility concerns 15% of the couples. Management of female infertility requires a complete history of the patient followed by a physical, gynecological and endocrine examination. Infertility etiology will be investigated thanks to different tests including ovarian function and reserve assessment, search for uterine abnormalities and evaluation of tubal permeability. Polycystic ovarian syndrome (PCOS) is a predominant cause of infertility and a common gyne-endocrine disorder affecting 7 to 15% of women in reproductive age. Behavioral, medical and surgical treatments have been evaluated in order to improve the fertility of women with PCOS. Lifestyle modifications (stop smoking, physical exercise and weight loss when necessary) are of the utmost importance. Clomiphene citrate remains the first line of medical treatment of infertility in women with PCOS in absence of other male or female causes of infertility. Use of metformin solely for infertility is not recommended in absence of metabolic anomaly and new treatment as myoinositol is emerging. Surgical techniques aiming to enhance ovulation and pregnancy rate are an option when medical treatment failed. Ovarian drilling by laparoscopy or by transvaginal hydrolaparoscopy is taking a larger place in the treatment of infertility. In vitro maturation and fertilization remain the third-line of treatment in PCOS.

Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone.

OBJECTIVES: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). STUDY DESIGN: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. RESULTS: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. CONCLUSIONS: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. IMPLICATIONS STATEMENT: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.

Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters.

OBJECTIVE: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC). STUDY DESIGN: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28-day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG). RESULTS: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value <0.05 vs E4/DRSP), and +219% for EE/DRSP (p-value <0.05 vs E4/DRSP). Changes to prothrombin fragment 1 + 2 and SHBG for E4/DRSP, EE/LNG, and EE/DRSP were +23%, +71%, and +64% (p-value <0.05 vs E4/DRSP); and +55%, +74% and +251% (p-value <0.05 vs E4/DRSP), respectively. At cycle 6, changes to other hemostasis parameters for E4/DRSP were similar or smaller than for EE/LNG or EE/DRSP. CONCLUSIONS: In this study, changes in hemostasis parameters after treatment with 6 cycles of E4/DRSP were smaller or similar to those observed for EE/LNG. Similar, but more pronounced changes were also observed versus EE/DRSP, which supports the hypothesis that the effect of COCs on hemostasis parameters is mainly mediated by the estrogenic component. Further studies are needed to provide more insight into the venous thromboembolic risk of E4/DRSP. IMPLICATIONS STATEMENT: This study reports that the effects on hemostasis parameters of a COC containing 15 mg E4/3 mg DRSP are less or similar to those for EE/LNG or EE/DRSP. It also demonstrates that the choice of estrogen modulates the effects of COCs on hemostasis parameters.

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety.

OBJECTIVE: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (-66% vs -49%, P = 0.032) and W12 (-82% vs -65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (-0.59 vs -0.33, P = 0.049) and W12 (-1.04 vs -0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS: Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.

Video Summary:http://links.lww.com/MENO/A591.

Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control.

OBJECTIVES: This study evaluated acceptability, user satisfaction, body weight control and general well-being of estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). METHODS: In this open-label, multi-centre, dose-finding, 6-cycle study, 396 healthy women of reproductive age were randomised into five treatment groups in a 24/4-day regimen: 15 mg or 20 mg E4 combined with either 3 mg DRSP or 150 µg LNG, and as reference estradiol valerate (E2V) combined with dienogest (DNG). Data on acceptability, user well-being, satisfaction and body weight were collected. RESULTS: The number of completers was the highest in the 15 mg E4/DRSP group (91.1%), and the lowest for 20 mg E4/LNG (70.1%). The largest proportion of treatment satisfaction was reported for 15 mg E4/DRSP (73.1%), and the lowest for 15 mg E4/LNG (50.6%). The number of women willing to continue with the assigned study treatment was the highest in the 15 mg E4/DRSP group (82.1%) and the lowest for 20 mg E4/LNG (58.3%). Well-being with E4/DRSP combinations was statistically significantly better than with E4/LNG combinations: OR (95% CI) 2.00 (1.13; 3.53) and 1.93 (1.06; 3.56) for 15 and 20 mg E4, respectively, and comparable to E2V/DNG. Proportion of women with a 2 kg or more weight loss after 3 and 6 cycles was the highest in the 15 mg E4/DRSP group (30.7 and 36.7%, respectively). CONCLUSIONS: The present study shows that 15 mg estetrol combined with 3 mg DRSP is associated with a high-user acceptability and satisfaction, and with a favourable body weight control.

Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol.

OBJECTIVE: The effects of estetrol (E4), a natural fetal estrogen, combined with drospirenone (DRSP) were evaluated on plasma levels of sex hormone-binding globulin (SHBG), angiotensinogen and 12 hemostasis markers. STUDY DESIGN: Combinations of 3 mg DRSP with 5 or 10 mg E4 were compared with YAZ® (20 mcg ethinyl estradiol and 3 mg DRSP; EE/DRSP) in parallel groups of 15-18 healthy young women. Main outcome was the relative change from pretreatment to the end (day 24±1) of the third treatment cycle. RESULTS: All E4 combinations showed low estrogen impact compared to EE/DRSP. Effects on SHBG and angiotensinogen of 10 mg E4 combined with DRSP were 15%-20% that of EE/DRSP. Both E4/DRSP combinations reduced D-dimer level and the 5 mg E4/DRSP combination also decreased fragment 1+2. CONCLUSIONS: The reduction in coagulation markers suggests an anticoagulant effect from DRSP. The indications of a low thrombosis risk for E4 preparations should be validated in larger studies. IMPLICATION STATEMENT.

Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA).

OBJECTIVES: This study aims to assess vaginal bleeding patterns and cycle control of oral contraceptives containing estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). STUDY DESIGN: An open-label, multicentre, randomised, dose-finding study lasting six cycles in healthy women aged 18-35 years was used. Four treatments (15 mg or 20 mg E4, combined with either 3 mg DRSP or 150 mcg LNG) were administered in a 24/4-day regimen. A marketed dosing regimen of estradiol valerate with dienogest (E2V/DNG) served as reference since it contains (like E4) a natural oestrogen. RESULTS: A total of 396 women were randomised, of whom 389 received study medication, and 316 completed the study. By cycle 6, the frequencies of unscheduled bleeding and/or spotting and absence of withdrawal bleeding were the lowest in the 15 mg E4/DRSP group (33.8% and 3.5%, respectively). In the E2V/DNG reference group, these frequencies were 47.8% and 27.1%, respectively. By cycle 6, the frequency of women with absence of withdrawal bleeding was <20% for all E4 treatment groups: 3.5-3.8% combined with DRSP and 14.0-18.5% combined with LNG. By cycle 6, unscheduled intracyclic bleeding was reported by <20% of women in the 20 mg E4/LNG group (18.9%) and in the 15 mg E4/DRSP group (16.9%). CONCLUSION: This study showed that, of the four treatment modalities investigated, the 15 mg E4/DRSP combination has the most favourable bleeding pattern and cycle control. IMPLICATIONS: Due to its favourable bleeding pattern and cycle control, the 15 mg E4/DRSP combination is the preferred combination for further phase III clinical development.

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study.

OBJECTIVES: The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women. METHODS: This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 µg levonorgestrel; or 20 µg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. RESULTS: A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. CONCLUSIONS: Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.

Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives.

OBJECTIVES: Estetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4 blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. METHODS: This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 µg LNG; or 20 µg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated. RESULTS: A total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4 groups, and the effects on triglycerides elicited by the E4 groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4 groups. CONCLUSIONS: E4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters.

Development and validation of the French version of a tool assessing patient's expectations in lower limb osteoarthritis.

OBJECTIVE: The Hospital for Special Surgery (HSS) Hip Replacement Expectations Survey and Knee Replacement Expectations Survey are validated tools developed to measure patients' preoperative expectations for hip and knee arthroplasty. These instruments have possible uses in both daily practice and research. Our objective was to assess the test-retest reliability and the construct validity of the French version of the surveys. METHODS: Patients scheduled for total hip (n = 82) or knee replacement (n = 61) aged 38-90 years were included. All completed the HSS Hip or Knee Replacement Expectations Survey and the Expectation WOMAC to determine concurrent validity. The test-retest reliability was assessed using the intraclass coefficient correlation (ICC), the Bland and Altman Method and the coefficient of variation; the internal consistency was assessed by the Cronbach α coefficient. The construct validity was investigated using the Pearson correlation coefficient and floor and ceiling effects by percentage frequency of lowest or highest possible score achieved by respondents. RESULTS: 143 patients scheduled for hip or knee arthroplasty were included. The reliability was excellent between the test and the rested total score, with an ICC of 0.902 (0.853-0.936) and CV of 4.06% for the French Hip Replacement Expectations Survey and 0.865 (0.786-0.917) and CV of 7.7% for the French Knee Replacement Expectations Survey, without bias. The Cronbach α coefficient was 0.72 for hip Survey and 0.82 for knee Survey showing a good internal consistency. Pearson correlation coefficients of 0.45 and 0.48 between Expectations WOMAC and HSS, respectively for hip Survey and knee Survey, were observed but with systematic bias. The lowest possible score was not reported by any patient and only three patients (3.66%) scheduled for hip arthroplasty reported the highest possible score. CONCLUSIONS: The French version of the HSS Hip or Knee Replacement Expectations Survey is a reliable and valid questionnaire and compares favourably with the original English version. Therefore, this new version may help French-speaking clinicians to evaluate expectations before lower limb arthroplasty.

Impact of a new levonorgestrel intrauterine system, Levosert(®), on heavy menstrual bleeding: results of a one-year randomised controlled trial.

OBJECTIVE: To evaluate a new levonorgestrel-releasing intrauterine system (LNG-IUS) called Levosert(®) for the treatment of heavy menstrual bleeding (HMB) in comparison to the reference product Mirena(®). METHODS: A multicentre, randomised, controlled trial, in non-menopausal women diagnosed with functional HMB (defined as menstrual blood loss [MBL] ≥ 80 mL) randomised to either Levosert(®) or Mirena(®) and followed for up to one year. MBL was evaluated using a validated modified version of the Wyatt pictogram. RESULTS: A total of 280 women were randomised (141 to Levosert(®) and 139 to Mirena(®)). During the one-year treatment period, both Levosert(®) and Mirena(®) dramatically decreased MBL and increased haemoglobin and ferritin levels. There were no statistically significant differences between Levosert(®) and Mirena(®) regarding any of the parameters evaluated during the study. Similar bleeding patterns were observed in both groups. Levosert(®) was inserted with the same ease as Mirena(®). Both treatments were associated with identical expulsion rates and no perforations occurred in either treatment group. CONCLUSION: Levosert(®), a new LNG-IUS designed to release the same daily amount of LNG as Mirena(®), is highly effective in the treatment of HMB. No differences were observed between Levosert(®) and Mirena(®) regarding all evaluated outcomes, including safety profile.