Treatment of Women with Heavy Menstrual Bleeding with a Combination Therapy of Agnus Castus and Tranexamic Acid - Experiences of a German Single Centre

Background: Heavy menstrual bleeding (HMB) is a common gynaecological problem and is the reason for 18-30% of gynaecological visits. In a European study in 4,502 women, 27.2% were diagnosed with HMB (Fraser et al., 2015). On the other hand, HMB is often associated with bleeding disorders (Shankar et al., 2004). The definition of HMB has different perspectives; from a subjective perspective HMB is defined as e excessive menstrual blood loss impacting on women's physical, social, emotional and/or mental quality of life, whereas from an objective perspective it is defined as excessive blood loss >80 ml per cycle (Munro et al., 2012). There are different approaches for treating HMB such as the administration of non-steroidal drugs, Desmopressin, herbal Vitex Agnus Castus (VAC), Tranexamic acid (TXA) or a hormonal therapy; moreover, HMB can also be treated surgically. The aim of this study was to test the efficacy of the specific HMB management used in our center: Women with HMB are treated usually with VAC, which optimizes the relation of estrogen to progesterone in the female body (Yavarikia et al., 2013). VAC can be used without using any hormones (Shahnazi et al, 2016), providing a treatment with a low impact on women's bodies. Additionally, TXA is given during the menstruation due to its antifibrinolytic effect. Furthermore, the "Pictural Blood-Loss-Assessment- Chart" (PBAC Score) is administered to analyze the menstrual blood loss. Methods: Two ad hoc patient-reported questionnaires were developed to test the efficacy of the HMB management in our center The baseline questionnaire includes the following aspects: menarche, duration, regularity, number of sanitary products, pain level, medical background and family history. During the first visit in our center women with HMB filled in the baseline questionnaire. In addition, laboratory tests are done including a comprehensive coagulation test and the examination of iron and hemoglobin levels. Moreover, we presented an application called "My Flow Score" to the patients, which calculates the PBAC score as a result of all entered sanitary products women use during their period. Women are prescribed VAC and/or TXA for the management of their HMB. After four months patients are scheduled for a follow up appointment. At that time they complete the follow-up questionnaire including the following aspects: compliance with the medication or the reason for the non-compliance, health complaints due to the medication, duration of the period, improvement, pain level, PBAC score if the patient did use the APP "My Flow Score" or if not the number of sanitary products. A blood test was taken and the HMB management was adapted to the patients' needs. Results: So far, 100 women with HMB with a median age of 14 years (range 9-50) were enrolled in our study. They had their menarche with a median age of 12 years (range 8-17). Diagnosis of women ranged from iron or folic acid deficiency to different forms of bleeding disorders; with the majority suffering from von Willebrand disease (43/100) followed by iron deficiency (14/100). One fifth of the patients had more than one diagnosis. 1/3 of patients received a treatment for the HMB previously, mainly contraceptives, TXA or VAC. 49% reported anomalies with regard to previous other bleeding; 25.8% had increased hematomas and 19.6% recurrent epistaxis. Most of them reported anomalies already in the family (60.2%). Before treatment women had a median PBAC Score of 169 (range 77-800) and reported a median pain level of 6.5 during menstruation on a scale ranging from 1 (low pain) to 10 (extreme pain). 87/100 women received VCA, of these 75.4% regularly and 85/100 women received TXA, of these 84.6% regularly. 81% of them received a combination of both medicines. Compared to before 28.8% of patients reported shorter duration of menstruation and reduced bleeding with treatment, 11.9% did not experience any improvement; the PBAC score decreased significantly (p<.0001). Conclusions: Although the type of diagnosis in women suffering from HMB had a great variation, these patients had a high disease burden with a relatively high level of pain and a high loss of blood assessed with the PBAC score. Thanks to a combination of VAC and TXA the disease burden in these women could be reduced, especially for the time of menstruation and amount of bleeding. VAC proved to be highly accepted by women due to its low treatment burden. Disclosures Von Mackensen: University Medical Centre Hamburg-Eppendorf: Current Employment; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy; Novo Nordisk: Consultancy; Biomarin: Speakers Bureau; CSL Behring: Speakers Bureau; Chugai/Roche: Membership on an entity's Board of Directors or advisory committees.

Key issues in the management of adolescents and young women with heavy menstrual bleeding

Despite high prevalence of heavy menstrual bleeding (HMB) in adolescents and young women, most recommendations are not specific for this population, which makes the diagnosis and management challenging. Gynecologists should be able to establish underlying causes of HMB, which most common are nonstructural in adolescents, and the severity of bleeding, to provide early diagnosis, using appropriate therapy for improving quality of life and iron deficiency prevention. First line management consists of hormonal therapy approved for HMB treatment, capable to normalize menstrual blood loss and iron metabolism parameters.

Obesity is associated with heavy menstruation that may be due to delayed endometrial repair

Heavy menstrual bleeding is common and debilitating but the causes remain ill defined. Rates of obesity in women are increasing and its impact on menstrual blood loss (MBL) is unknown. Therefore, we quantified BMI and MBL in women not taking hormones and with regular menstrual cycles and revealed a positive correlation. In a mouse model of simulated menstruation, diet-induced obesity also resulted in delayed endometrial repair, a surrogate marker for MBL. BrdU staining of mouse uterine tissue revealed decreased proliferation during menstruation in the luminal epithelium of mice on a high-fat diet. Menstruation is known to initiate local endometrial inflammation and endometrial hypoxia; hence, the impact of body weight on these processes was investigated. A panel of hypoxia-regulated genes (VEGF, ADM, LDHA, SLC2A1) showed consistently higher mean values in the endometrium of women with obesity and in uteri of mice with increased weight vs normal controls, although statistical significance was not reached. The inflammatory mediators, Tnf and Il6 were significantly increased in the uterus of mice on a high-fat diet, consistent with a pro-inflammatory local endometrial environment in these mice. In conclusion, obesity was associated with increased MBL in women. Mice given a high-fat diet had delayed endometrial repair at menstruation and provided a model in which to study the influence of obesity on menstrual physiology. Our results indicate that obesity results in a more pro-inflammatory local endometrial environment at menstruation, which may delay endometrial repair and increase menstrual blood loss.

Levonorgestrel intrauterine system in menorrhagia-an effective and acceptable alternative

Background: To study the efficacy, performance and acceptability of levonorgestrel intrauterine device (LNG-IUS) in treatment of women with menorrhagia.Methods: This was a descriptive, prospective and observational study conducted over a period of January 2015 to September 2020. Seventy-five (75) women presented with heavy menstrual bleeding having no contraindication for device underwent LNG-IUS insertion after consent. Menstrual pattern, pictorial blood loss assessment chart score (PBAC), rate of acceptability and satisfaction were recorded at 3 months, 6 months, 1, 2 and 3 years after insertion of LNG-IUS.Results: The most common bleeding pattern at 3 month post-insertion was inter-menstrual spotting followed by infrequent menses, oligomenorrhea and amenorrhea. LNG-IUS caused 45.19% reduction in menstrual blood loss (MBL) at 3 months, 81.48% at 1 year, 91.85% at 2 years and 97% at 3 years. Hemoglobin levels improved from mean baseline 8.9 mg/l to 12.8 mg/l at 3 years. Majority of women were satisfied with this minimally-invasive treatment with continuation rate of 94.66%. No major side-effects were noted.Conclusions: LNG-IUS is an excellent minimal invasive, highly effective in controlling blood loss and well-tolerated alternative for women with menorrhagia. Its fertility-sparing property makes it an emerging option for young women.

Study of menstrual pattern changes in patients accepting injection depo-medroxyprogesterone acetate versus levonorgestrel intrauterine system

Background: Changes in menstrual bleeding patterns are a major cause of hormonal contraceptive discontinuation. DMPA and LNG IUS both are hormonal contraceptives and are used by most of the women worldwide for various gynaecological conditions. The aim of the present study was to compare menstrual pattern changes in patients accepting injection DMPA and LNG-IUS for various gynaecological indications.Methods: This randomized controlled trial was conducted among 70 women aged 18 years or older with heavy menstrual bleeding in the department of Obstetrics and Gynaecology, Chhatrapati Shivaji Subharti Medical College, Meerut. The study comprised of two groups having 35 patients each i.e. Group 1 (patient who opted for LNG IUS) and Group 2 (patient who opted injection DMPA). The menstrual pattern changes were assessed at 1month, 3month and 6th month interval. Patient were asked to maintain a menstrual calendar wherein she would keep a record of the no. of days along with dates when she has spotting per vaginum/bleeding per vaginum and the amount of blood loss explained to her through the pictorial blood assessment chart.Results: Reduction in median menstrual blood loss was significantly greater in the LNG IUS group (-128.12mL, range -393.6 to 328.5 mL) than in the DMPA group arm -17.8 mL, range -271.5 to+78.6 mL, p<0.001).Conclusions: LNG IUS reduces menstrual blood loss more effectively than DMPA.

Markers of human endometrial hypoxia can be detected in vivo and ex vivo during physiological menstruation

STUDY QUESTION Can markers of human endometrial hypoxia be detected at menstruation in vivo? SUMMARY ANSWER Our in vivo data support the presence of hypoxia in menstrual endometrium of women during physiological menstruation. WHAT IS KNOWN ALREADY Current evidence from animal models and human in vitro studies suggests endometrial hypoxia is present at menstruation and drives endometrial repair post menses. However, detection of human endometrial hypoxia in vivo remains elusive. STUDY DESIGN, SIZE, DURATION We performed a prospective case study of 16 women with normal menstrual bleeding. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductively aged female participants with a regular menstrual cycle underwent objective measurement of their menstrual blood loss using the alkaline haematin method to confirm a loss of &lt;80 ml per cycle. Exclusion criteria were exogenous hormone use, an intrauterine device, endometriosis or fibroids &gt;3 cm. Participants attended for two MRI scans; during days 1–3 of menstruation and the early/mid-secretory phase of their cycle. The MRI protocol included dynamic contrast-enhanced MRI and T2* quantification. At each visit, an endometrial sample was also collected and hypoxia-regulated repair factor mRNA levels (ADM, VEGFA, CXCR4) were quantified by RT-qPCR. MAIN RESULTS AND THE ROLE OF CHANCE Women had reduced T2* during menstrual scans versus non-menstrual scans (P = 0.005), consistent with menstrual hypoxia. Plasma flow (Fp) was increased at menstruation compared to the non-menstrual phase (P = 0.0005). Laboratory findings revealed increased ADM, VEGF-A and CXCR4 at menstruation on examination of paired endometrial biopsies from the menstrual and non-menstrual phase (P = 0.008; P = 0.03; P = 0.009). There was a significant correlation between T2* and these ex vivo hypoxic markers (P &lt; 0.05). LIMITATIONS, REASONS FOR CAUTION This study examined the in vivo detection of endometrial hypoxic markers at specific timepoints in the menstrual cycle in women with a menstrual blood loss &lt;80 ml/cycle and without significant uterine structural abnormalities. Further research is required to determine the presence of endometrial hypoxia in those experiencing abnormal uterine bleeding with and without fibroids/adenomyosis. WIDER IMPLICATIONS OF THE FINDINGS Heavy menstrual bleeding (HMB) is a common, debilitating condition. Understanding menstrual physiology may improve therapeutics. To our knowledge, this is the first in vivo data supporting the presence of menstrual hypoxia in the endometrium of women with normal menstrual bleeding. If aberrant in those with HMB, these non-invasive tests may aid diagnosis and facilitate personalized treatments for HMB. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Wellbeing of Women grant RG1820, Wellcome Trust Fellowship 209589/Z/17/Z and undertaken in the MRC Centre for Reproductive Health, funded by grants G1002033 and MR/N022556/1. H.O.D.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc; Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for articles on abnormal uterine bleeding. TRIAL REGISTRATION NUMBER N/A.

A CASE REPORT ON EFFECTIVE MANAGEMENT OF ASRIGDARA

Any uterine bleeding outside the normal volume, duration, regularity or frequency is considered as abnormal uterine bleeding (AUB). Nearly thirty percent of all gynaecological outpatient attendants are for AUB. Abnormal menstrual bleeding pattern have been traditionally expressed by terms like menorrhagia, metrorrhagia, polymenorrhagia & oligomenorrhoea. Normal menstrual cycle interval is 28 days (21-35 days), menstrual flow duration 4-5 days and normal menstrual blood loss should be 35ml (20-80 ml). Any deviation in the above criteria comes under abnormal uterine bleeding, means excessive amount of bleeding or increased duration of bleeding during menstruation or both termed as AUB. In Ayurveda same is described as Pradara. A female patient aged 22 years visited OPD of Prasuti Tantra and Stri Roga department of NIA, with complaints of heavy menstrual bleeding and prolonged menstrual bleeding more than seven days since six months. Pictorial blood loss assessment chart was used to assess the amount of blood loss before and after treatment. SF-36 questionnaire was assessed to know the improvement in quality of life. Patient was given Kutajashtakaleha 10 gm BD with cows milk.

Is body mass index associated with irregular menstruation: a questionnaire study?

Background Irregular menstrual cycles including the length of cycles and menses, and heavy menstrual blood loss are linked to many gynaecological diseases. Obesity has been reported to be associated with irregular menstrual cycles. However, to date, most studies investigating this association are focused on adolescence or university students. Whether this association is also seen in adult women, especially women who had a history of birth has not been fully investigated. Methods Questionnaire data were collected from 1012 women aged 17 to 53 years. Data on age, weight and height, gravida, the length of menstrual cycles and menses, and the number of pads used during menses were collected. Factors associated with menstrual cycle according to BMI categories were analysed. Results There were no differences in the length of menstrual cycles and menses in women of different body mass index (BMI) groups. However, there was a significant difference in menstrual blood loss in women of different BMI categories. The odds ratio of having heavy menstrual blood loss in obese women was 2.28 (95% CL: 1.244, 4.193), compared to women with normal weight, while there was no difference in the odds ratio of having heavy menstrual blood loss in overweight, compared to normal weight, women. In contrast, the odds ratio of having heavy menstrual blood loss in underweight women was 0.4034 (95% CL: 0.224, 0.725), compared to women with normal weight. Conclusion Although BMI was not correlated with the length of menstrual cycle and menses, BMI is positively associated with menstrual blood loss. Our data suggest that BMI influences menstrual blood loss in women of reproductive age and weight control is important in women’s reproductive years.