Comparison of single- and double-dose methotrexate protocols for treatment of pregnancy of unknown location.

OBJECTIVE: The use of various methotrexate (MTX) protocols for the treatment of ectopic pregnancy is well established. This study aimed to evaluate the efficacy of single- and double-dose MTX protocols for the treatment of pregnancy of unknown location (PUL). STUDY DESIGN: This retrospective study was conducted in the Department of Gynaecological Endocrinology, University Hospital, Krakow, Poland. Haemodynamically stable women with PUL were enrolled between January 2014 and September 2023. Demographics, gestational age and treatment outcomes were compared between women in the single-dose MTX group and women in the double-dose MTX group. The primary outcome was the success rate, measured as the number of women treated without surgical intervention. The secondary outcome was the number of days of MTX needed to achieve an appropriate decrease in beta-human chorionic gonadotrophin (ß-hCG). RESULTS: Two hundred and eleven women (mean age 33 ± 1.8 years) with PUL were enrolled in the study, with an overall success rate of 89.1 %. Single- and double-dose MTX protocols were found to have comparable treatment success rates (93 % and 95 %, respectively). Women with lower initial serum ß-hCG (<2000 mIU/ml) had higher treatment efficacy compared with women with higher initial serum ß-hCG (96.5 % vs 71.4 %), regardless of protocol type. The length of hospital stay for the women treated with the single-dose MTX protocol was 1 day shorter compared with that for the women treated with the double-dose MTX protocol. CONCLUSION: Single- and double-dose MTX protocols have comparable efficacy and safety, and should be equally considered in women with PUL with initial ß-hCG < 2000 mIU/ml.

Nonclassical congenital adrenal hyperplasia: Metabolic and hormonal profile.

OBJECTIVE: To investigate both metabolic and hormonal profiles of untreated women with nonclassical congenital adrenal hyperplasia (NCCAH). The secondary objective was to compare above profiles with polycystic ovary syndrome (PCOS) women and healthy controls. DESIGN: Retrospective, case-control study. PATIENTS: Women assigned to one of the groups: (1) NCCAH (n = 216), (2) PCOS (n = 221), (3) regularly menstruating (n = 216). MEASUREMENTS: Lipid profile including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol along with both fasting glucose (Glu) and insulin (Ins) levels and hormonal parameters were determined among all participants. RESULTS: Both NCCAH and PCOS women had higher body mass index in comparison to the controls (+7% and 18.9%, respectively). NCCAH women exhibited higher TC (+34.1%) and fasting glucose levels (+18.9%) together with elevated testosterone (60.2%), dehydroepiandrosterone sulphate (28.1%), free androgen index (91.9%) and antimüllerian hormone (58%) in comparison to healthy controls. PCOS group showed unfavourably altered metabolic profile reflected by higher TC (+35.4%), TG (+25%), fasting Glu (+22%), fasting Ins (+34.4%) along with homoeostatic model assessment for insulin resistance (HOMA-IR; 36.2%) in comparison to the controls. NCCAH women showed both lower insulin (-28.5%) and HOMA-IR (-31.8%) levels when compared to the PCOS. CONCLUSIONS: NCCAH women showed less adversely altered metabolic profile than PCOS women, but not as favourable as in the healthy controls. Optimisation of screening for metabolic and reproductive health may help to initiate the treatment and improve treatment outcomes.

Increased Serum Levels of Phoenixin-14, Nesfatin-1 and Dopamine Are Associated with Positive Pregnancy Rate after Ovarian Stimulation.

BACKGROUND: We study the relationship between phoenixin (PNX-14), nesfatin-1 (NES-1), dopamine (DA) and oxytocin (OT) levels together with pregnancy rates in women after ovarian stimulation (OS). METHODS: In a prospective case-control study, 56 infertile women were enrolled from the Department of Gynecological Endocrinology University Hospital. Infertile women age < 40 years old, with polycystic ovary syndrome (PCOS), confirmed tubal patency and suitable sperm quality were included. Blood samples were drawn twice-before the initiation of OS and before the human chorionic gonadotropin (hCG) administration. Assessments of PNX-14, NES-1, DA and OT serum levels were performed. Pregnancy rates after OS were observed. RESULTS: Pregnant women showed higher baseline NES-1 and OT levels (+29.2% and +44%) but not PNX-14 and DA levels when compared to non-pregnant ones. In pregnant women, positive correlations between OT and prolactin, PRL (r = 0.47, p = 0.04), as well as between OT and NES-1 (r = 0.55, p = 0.02), were observed at baseline. At baseline, an OT level increase was associated with a positive pregnancy rate (per 100 pg/mL, OR = 1.39, 95% CI 1.04-1.74), while after OS, higher PNX-14 was a predictor of pregnancy (by 10 pg/mL, OR = 1.23, 95%CI 1.07-1.39). Post-stimulation PNX-14, NES-1 and DA concentrations were higher in pregnant women compared to non-pregnant ones (+17.4%, +26.1%, and +45.5%, respectively; all p < 0.05). In the pregnant group, OT levels were 2.7-times lower than in the remainder (p = 0.03). Moreover, in pregnant participants, a negative association between NES-1 and PNX (r = -0.53, p = 0.024) was observed. CONCLUSION: Elevated PNX-14, NES-1 and DA along with decreased OT levels were observed in women who achieved pregnancy.

GnRH Antagonist Protocol Enhances Coagulation During Controlled Ovarian Stimulation for IVF.

Changes in coagulation and fibrinolysis have been reported in women undergoing controlled ovarian hyperstimulation (COH) supporting a potential hypercoagulable condition related to this treatment. This study aimed at evaluating the changes in fibrin clot properties and thrombin generation induced by two different COH protocols: long with gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant). Primary outcomes included determination of plasma fibrin clot properties, including clot permeability (Ks) and efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1 + 2) and endogenous thrombin potential (ETP) and fibrinolysis inhibitor levels. One hundred twenty-nine infertile women were included in the final analysis. The GnRH-ant protocol resulted in increased ETP (+ 9.8%) and reduced Ks (- 2.4%). Conversely, COH with the GnRH-a protocol reduced thrombin generation by decreasing both ETP (- 6.6%) and F1 + 2 (- 30.8%) together with favorably altered fibrin clot properties represented by increased Ks (+ 21.7%) and reduced CLT (- 13.8%) as well as decreased PAI-1 levels (by 2.5 times). The GnRH-ant compared to the GnRH-a protocol increased PAI-1 levels (+ 77.3%), thrombin generation (9.3% higher ETP), and Ks (+ 13.7%). In the GnRH-a group, post-COH Ks was 14.3% higher (Ks ≥ 7.92 × 10-9 cm2) in women with positive vs. negative pregnancy outcomes. Our results show that the GnRH-ant protocol enhanced thrombin generation and slightly decreased fibrin clot density. COH with the GnRH-a reduced thrombin generation and improved fibrin clot features. This trial was registered (NCT04166825). Clinical Trial Registration Number: NCT04166825.

Human Papillomavirus Infection: Knowledge, Risk Perceptions and Behaviors among SMW and AFAB.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) in the United States, and persistent HPV infection has been established as playing a major role in the development of cervical cancer. Providing HPV vaccination and regular screening tests have reduced the risk of developing cervical cancer or helped to detect the cancer at an early stage. Despite the above measures, cervical cancer still remains a major public health problem worldwide. Infection with HPV, and consequently cervical cancer, affects all people with an intact cervix, so not only heterosexual women, but also women from sexual minorities (SMW) together with people assigned female at birth (AFAB). These populations may be even more likely to develop cervical cancer, mainly because they are less likely to be aware of HPV transmission and prevention of cervical cancer. In our review, we summarized the current state of HPV knowledge, collected data assessing the orientation of this issue among SMW and AFAB, and indicated the causes of possible negligence in the prevention of cervical cancer.

Fibrin clot properties among women with endometriosis and the impact of ovarian stimulation.

RESEARCH QUESTION: Is there a difference in fibrin clot phenotype in women with endometriosis before and after ovarian stimulation? DESIGN: Prospective study including 73 infertile women in two age-matched groups: (i) with confirmed endometriosis (n = 29); (ii) without endometriosis (n = 44). Assessments of plasma fibrin clot permeability (Ks), efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1+2 [F1+2] and endogenous thrombin potential [ETP]) and fibrinolysis inhibitors were performed together with clinical pregnancy rate. RESULTS: Endometriosis was associated with increased thrombin generation, reflected by both higher F1+2 (+96.1%, P = 0.005) and ETP (+14.2%, P = 0.014) along with unfavourably altered fibrin clot properties represented by lower Ks (-31%, P < 0.001) and prolonged CLT (+13.5%, P = 0.02), compared with the non-endometriosis group. Moreover, women with endometriosis had higher plasminogen activator inhibitor-1 (PAI-1; +272%, P = 0.004) concentrations and alpha-2-antiplasmin activity (+39.9%, P < 0.001) in contrast to the other group. Ovarian stimulation led to reduction in F1+2 (-48.1%, P < 0.001), improvement of fibrin clot phenotype reflected by higher Ks (+25.9%, P < 0.001) and shortened CLT (-11.9%, P < 0.001), along with lower PAI-1 (-54%, P = 0.016) compared with the baseline in women with endometriosis. CONCLUSIONS: Endometriosis is associated with the prothrombotic fibrin clot phenotype and increased thrombin generation. Ovarian stimulation favourably alters fibrin clot properties and leads to comparable pregnancy outcomes to those in women without endometriosis.

Plasma Fibrin Clot Properties Are Unfavorably Altered in Women following Venous Thromboembolism Associated with Combined Hormonal Contraception.

The use of hormonal contraception is associated with an increased risk of venous thromboembolism (VTE). Unfavorably altered fibrin clot phenotype has been reported in patients following unprovoked VTE who are at risk of recurrences. It remains unknown whether fibrin clot characteristics in women with contraception-related VTE differ from those in unprovoked VTE. We studied three age-matched groups of women: (1) after contraception-related VTE, (n = 48) (2) after unprovoked VTE (n = 48), and (3) controls (n = 48). Plasma fibrin clot permeability (K s), turbidity of clot formation, efficiency of fibrinolysis using clot lysis time (CLT), and rate of increase in D-dimer during lytic clot degradation (D-Drate), along with thrombin generation and fibrinolysis proteins were determined. Compared with the controls, patients following contraception-related and unprovoked VTE formed faster (lag phase, -8.8% and -20.4%, respectively) fibrin clots of increased density (K s , -8.6% and -13.4%, respectively) displaying impaired fibrinolysis as evidenced by prolonged CLT (+11.5% and +14.5%, respectively) and lower D-Drate (-7.1% and -5.6%, respectively), accompanied with higher plasminogen activator inhibitor-1 (PAI-1, +14.9% and +17.8%, respectively) and elevated peak thrombin generation (+63.8% and +36.7%, respectively). The only differences between women with unprovoked and contraception-related VTE were lower fibrin mass in plasma clots (D-Dmax, -8.6%), along with higher peak thrombin generation (+19.8%) and shorter lag phase (-6.8%) in the latter group. This study suggests that women after contraception-related VTE, similar to those following unprovoked VTE, have denser fibrin clot formation and impaired clot lysis. These findings might imply higher risk of VTE recurrence in women with the prothrombotic clot phenotype.

Challenging iatrogenic menopause. Oncofertility programme in Poland - a single-centre experience.

INTRODUCTION: Menopause is defined as a 12-month period of time when menstruation permanently ceases. In some cases, menopause may be caused by external factors - for example gonadotoxic treatment that irreversibly damages ovarian tissue leading to loss of its hormonal and reproductive function. Oncofertility is a discipline that merges oncology and reproductive medicine, giving patients a chance to experience parenthood after gonadotoxic treatment is finished. AIM OF THE STUDY: The purpose of the study is to present the implementation and first outcomes of the Oncofertility Programme in the University Clinic of Endocrinological Gynaecology and Gynaecology, University Hospital in Krakow, Poland. MATERIAL AND METHODS: Patients interested in fertility preservation have been consulted in the University Clinic of Endocrinological Gynaecology and Gynaecology in Krakow since April 2016. Preliminary qualification to one of the available methods (embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation) was conducted. Patients declaring a wish to join the programme were then referred to one of the three infertility treatment centres cooperating with the University Clinic, in order to undergo the chosen procedure. RESULTS: During a period of 24 months, 18 patients were consulted. The youngest consulted patient was 20 years old, the oldest 39. Two years after the first consultation, a telephone survey among consulted patients was carried out to verify whether the patients finally underwent oncofertility procedures, and to ask about their reproductive status. CONCLUSIONS: The problem of fertility issues being inadequately addressed results in low referral rates to oncofertility programmes. Attempts to raise awareness of oncofertility possibilities among oncologists should be undertaken because critically few patients are being referred to oncofertility centres.

The thin red line - postmenopausal abnormal uterine bleeding with endometrial thickness less than 4 mm.

AIM OF THE STUDY: To evaluate the risk of endometrial malignancy in postmenopausal women with abnormal uterine bleeding (AUB) with endometrial thickness ≤ 4 mm. MATERIAL AND METHODS: Histological assessment of endometrial samples obtained via hysteroscopy or curettage was performed in 57 women. RESULTS: Women with premalignancy or malignancy (24.6%) had higher endometrial thickness (by 9.7%, p = 0.01) compared to women with benign condition. Out of 12 women with atypical hyperplasia (21.1%), 5 women (8.8%) were diagnosed with simple and 7 women (12.3%) had complex hyperplasia, whereas 2 (3.5%) were diagnosed with malignancy. CONCLUSIONS: Postmenopausal women with AUB and endometrial echo ≤ 4 mm are less likely to have a malignant condition. However, the role of histological evaluation cannot be undermined, especially in women at high risk of endometrial cancer, and routine endometrial biopsy should be considered. We recommend a change in the cut-off to 2 mm in routine practice.

Current management of cervical cancer in Poland-Analysis of the questionnaire trial for the years 2002-2014 in relation to ASCO 2016 recommendations.

OBJECTIVES: To assess the survival of patients with cervical cancer (CC). Since the recommendations concerning cervical cancer management adopted by Polish medical societies do not differ significantly from the ESGO or non-European guidelines, and the fact that evaluation of the system for CC treatment in Poland, as well as the mortality rate of Polish women with CC, which is 70% higher than the average for European Union (EU) countries, justifies the hypothesis that treatment of CC in Poland deviates from the Polish and international recommendations. This article puts forward the current management of cervical cancer in Poland and discusses it in the context of ASCO guidelines. MATERIAL AND METHODS: A survey retrospective multicenter analysis of the medical records of 1247 patients with cervical cancer who underwent treatment for disease and who had completed at least two years of follow-up. RESULTS: Although concurrent radiotherapy and chemotherapy is a standard treatment of FIGO IB to IVA cervical cancer patients in enhanced- and maximum-resources settings, in our analysis, we found that the percentage of women subjected to chemotherapy was lower than in countries where total survival rates were lower. CONCLUSION: Within the IA to II A cervical cancer patients studied group, the methods of treatment remained in line with ASCO guidelines for countries with the highest standard of care. Although concurrent radiotherapy and chemotherapy is a standard treatment of FIGO IB to IVA cervical cancer patients in enhanced- and maximum-resources settings, in our analysis, we found that the percentage of women subjected to chemotherapy was lower than in countries where total survival rates were lower. Our findings, together with the inconsistencies within the cervical cancer screening program, may be one of the explanations of poorer survival rate of women with cervical cancer in Poland.

Differential effect of the ultra-low dose and standard estrogen plus dydrogesterone therapy on thrombin generation and fibrinolysis in postmenopausal women.

INTRODUCTION: The objective of this study was to estimate the effects of different doses of oral hormone therapy (HT) on thrombin generation and fibrinolytic activity in postmenopausal women after 12 months of treatment. MATERIAL AND METHODS: Thrombin generation, fibrinolysis activators and inhibitors were determined before and after 12 months of treatment. Participants (180) were assigned (1:1:1) as follows: (1) standard HT group, 17ß-estradiol (1 mg/day) with dydrogesterone (5 mg/day); (2) ultra-low dose HT group, 17ß-estradiol (0.5 mg/day) with dydrogesterone (2.5 mg/day); (3) control group, no treatment. RESULTS: The standard HT led to a higher concentration of prothrombin 1 + 2 fragment (by 5.8%) with lower antithrombin activity (by 6.1%). Compared with baseline, we observed a reduction in mean antithrombin activity in the standard HT group and increases in mean levels of prothrombin 1 + 2 fragment in two HT groups. We found decreases after treatment in both standard and ultra-low dose HT groups in plasminogen activator inhibitor-1 (PAI-1) activity (-32.4% and -19.6%, respectively) and PAI-1 antigen (-9.9% and -7.8%, respectively). Intergroup analysis revealed reduction in both mean PAI-1 activities and PAI-1 antigen levels in the two treatment groups when compared with the control. CONCLUSION: Contrary to the standard estrogen plus dydrogesterone treatment, ultra-low dose HT revealed positive effects on hemostasis by intensifying fibrinolysis through a decrease in both PAI-1 activity and antigen levels, and with no impact on thrombin generation.

Effects of ultra-low-dose versus standard hormone therapy on fibrinolysis and thrombin generation in postmenopausal women.

OBJECTIVE: To assess the effects of different doses of oral hormone therapy (HT) on thrombin generation and fibrinolysis. STUDY DESIGN: One hundred fifty postmenopausal women were assigned in a randomized controlled study in which the effect of standard dose (1mg 17ß-estradiol/5mg dydrogesterone), ultra-low-dose HT (0.5mg 17ß-estradiol/2.5mg dydrogesterone) on fibrinolysis and coagulation was compared to controls. Factors measured included plasma clot lysis time (CLT), fibrinolysis activators and inhibitors, thrombin generation (prothrombin fragments 1+2 [F1+2], endogenous thrombin potential [ETP]), normalized activated protein C sensitivity ratio (nAPCsr), and factor (F)VIII activity and were determined before and after 24 weeks of HT. RESULTS: In ultra-low-dose group posttreatment CLT tended to be shorter when compared to standard HT (-7%) and control group (-4%) with reduced plasminogen activator inhibitor-1 (PAI-1) antigen (by -16% vs both groups). Higher mean changes from baseline between ultra-low-HT group and standard group in CLT (-7.4 vs 3.05) and PAI-1 antigen concentration (-5.1 vs 0.9) were observed. Standard HT, compared with the ultra-low-dose HT, led to higher F1+2 (+9%) and FVIII activity (+37%). CONCLUSIONS: In contrast to the standard HT, ultra-low-dose HT may enhance fibrinolysis through reduced PAI-1 levels.

Thromboprophylaxis in women undergoing gynecological surgery or assisted reproductive techniques: new advances and challenges.

Venous thromboembolism (VTE) affects 0.1-0.3% people each year. The risk of VTE following gynecological surgery and invasive procedures is well established and presents one of the major challenges in gynecological practice. Moreover, commonly use assisted reproductive techniques (ART) are reported to increase the risk of VTE. Despite continued efforts to reduce its incidence, postoperative VTE remains the second most common perioperative complication and the third most common cause of mortality. Several practice guidelines have been developed regarding prophylaxis and treatment of VTE. However, there is a large inconsistency between the recommendations and the medical practice in various centers. Moreover, prophylaxis in gynecological patients and women undergoing ART should be chosen individually for the patient, taking into account the possible risk factors for VTE and perioperative bleeding complications. Until recently, the percentage of women, who have not received anticoagulant prophylaxis or administrated it inadequately may reach 50%. This paper presents the current recommendations regarding thromboprophylaxis in women undergoing gynecological surgery or assisted reproductive techniques and addresses challenging practical issues in this field.

Heavy menstrual bleeding in women treated with rivaroxaban and vitamin K antagonists and the risk of recurrent venous thromboembolism.

Anticoagulants increase the risk of heavy menstrual bleeding (HMB). We sought to investigate the incidence, predictors and management of HMB in women on rivaroxaban compared to those on vitamin K antagonists (VKA). We addressed the issue as to whether HMB is associated with VTE recurrences. We performed a single-center prospective study in menstruating women aged 18-55years treated with rivaroxaban or VKA≥3months since the index VTE episode. Seventy six women on rivaroxaban and 45 patients on VKA were included. Patients on rivaroxaban more commonly reported HMB compared with those on VKA (31 [41%] vs. 8 [18%], p=0.009). Women treated with rivaroxaban more frequently needed interventions to reduce menstruation compared with those on VKA (29 [38%] vs. 6 [13%], p=0.004). During the median follow-up time of 13months, there were 8 (11%) recurrent VTE on rivaroxaban and 3 (7%) on VKA (p=0.5). Rivaroxaban treatment predisposed to HMB (odds ratio [OR] 3.2, 95% [confidence interval] CI 1.4-8.2, p=0.007) and the interruption of anticoagulant treatment for 2-3days (OR 3.2, 95% CI 1.1-11.6, p=0.033). HMB during the rivaroxaban treatment predisposed to recurrent VTE (OR 5.3, 95% CI 1.1-33.3, p=0.038). In menstruating women following VTE, rivaroxaban is associated with a two-fold higher risk of HMB compared with VKA. HMB predisposes to recurrent VTE episode, most likely due to the short interruptions of anticoagulation.

Plasma fibrin clot properties in postmenopausal women: effects of hormone therapy.

OBJECTIVE: Postmenopausal women are at risk of thromboembolic events. It is unclear whether menopause alters fibrin clot properties. The aim of our study was to assess the effects of menopause and hormone therapy on clot characteristics. METHODS: Ex vivo plasma clot permeability, turbidity, and susceptibility to lysis were determined in 70 premenopausal and 70 postmenopausal women (a case-control study). From the postmenopausal group, 30 women were randomly assigned (1:1) to a 24-week oral or transdermal treatment with 17ß-estradiol, combined with norethisterone acetate (2 mg + 1 mg/d or 0.05 mg + 5 mg/d, respectively). RESULTS: Compared with premenopausal women (aged 29.2 ±â€Š2.60 y), postmenopausal women (aged 49.7 ±â€Š3.4 y; P = 0.009) were characterized by higher fibrinogen levels (by 36.8%), lower C-reactive protein levels (by 36.9%), and lower clot permeability (by 10.5%); also after adjustment for fibrinogen (all P < 0.05), with no difference in turbidimetric or fibrinolytic variables. Estrogen plus progestogen therapy led to higher maximal absorbency of fibrin gels by 6.0% (P < 0.05), whereas all other fibrin variables remained unchanged. Compared with transdermal hormone therapy, 24-week oral therapy was associated with higher absorbency of plasma clots by 16% (P < 0.05), without any other changes in fibrin characteristics. CONCLUSIONS: Menopause age is associated with the formation of denser fibrin clots. Estrogen plus progestogen therapy has a minor effect on plasma fibrin properties, but leads to the formation of thicker and more branched fibrin fibers, particularly during oral administration.