The levonorgestrel intrauterine system in contraception

The levonorgestrel intrauterine system (LNG IUS) releases 20 microg/24 h of levonorgestrel from a polymer cylinder mounted on a T-shaped frame and covered with a release rate-controlling membrane. It is approved for 5-year use. The most outstanding features of LNG IUS are its high contraceptive efficacy and reduction of menstrual blood flow. No single mode of action can account for its contraceptive efficacy. The endometrium becomes thin and inactive, and the cervical mucus turns scanty and viscous. Although ovulation may be disturbed to some degree, estradiol production continues normally. The Pearl index for LNG IUS from large clinical trials is 0.1. Extrauterine pregnancies occur in 1 in 5000 users per year. Both the volume of menstrual blood loss and the number of bleeding days are reduced. During the first year of use, 20% of women become amenorrheic. There is an initial increase in the mean number of bleeding and spotting days, but in 3 to 6 months the number of bleeding and spotting days is the same as observed in copper IUD-users. The variation between individuals is wide and unpredictable. There are also additional health benefits secondary to the inactivation of the endometrium: increased hemoglobin, decreased dysmenorrhea, a possible decrease in pelvic inflammatory disease. LNG IUS may also decrease the growth of fibroids. LNG IUS is well accepted by users, with typical annual continuation rates above 80% in clinical studies.     

Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model

Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlying pathogenesis of menstrual disorders remain poorly investigated up to date. Among others, this is based on a lack of appropriate pre-clinical animal models. We here employ a mouse menstruation model induced by priming mice with gonadal hormones and application of a physical stimulus into the uterus followed by progesterone removal. As in women, these events are accompanied by menstrual-like bleeding and tissue remodeling processes, i.e. disintegration of decidualized endometrium, as well as subsequent repair. We demonstrate that the onset of bleeding coincides with strong upregulation of inflammatory mediators and massive granulocyte influx into the uterus. Uterine granulocytes play a central role in regulating local tissue remodeling since depletion of these cells results in dysregulated expression of matrix modifying enzymes. As described here for the first time, uterine blood loss can be quantified by help of tampon-like cotton pads. Using this novel technique, we reveal that blood loss is strongly reduced upon inhibition of endometrial vascularization and thus, is a key regulator of menstrual bleeding. Taken together, we here identify angiogenesis and infiltrating granulocytes as critical determinants of uterine bleeding and tissue remodeling in a mouse menstruation model. Importantly, our study provides a technical and scientific basis allowing quantification of uterine blood loss in mice and thus, assessment of therapeutic intervention, proving great potential for future use in basic research and drug discovery.     

Progesterone receptor modulators and progesterone antagonists in women's health

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.     

Transcervical resection of endometrium in women with menorrhagia.

As an alternative to hysterectomy 16 women with menorrhagia were treated with hysteroscopic transcervical resection of the endometrium with an unmodified urological resectoscope. Twelve patients requested total resection of the endometrial lining with the intention of producing amenorrhoea, and four chose partial resection and hypomenorrhoea. Surgery was completed successfully in 15; the remaining woman, who had an acutely retroflexed uterus, sustained a uterine perforation during insertion of the rigid hysteroscope. There were no important postoperative complications, and 13 patients were discharged from hospital the day after operation. Follow up for up to six months showed beneficial effects on the duration of menses and the subjective assessment of menstrual blood loss and pain in the treated women, six of them becoming amenorrhoeic after total resection. Hysteroscopy at three months in 13 patients showed fibrosis confined to the upper half of the uterine cavity. Endouterine biopsy specimens showed the presence of microscopic deposits of normal endometrium in 10 women. Although these results are preliminary, transcervical resection of the endometrium may have an important role in managing this common complaint.     

Vascular dysfunction as a cause of endometrial bleeding

Introduction.?Heavy menstrual bleeding (HMB) and the spotting and bleeding (S/B) associated with the use of hormonal contraceptives are distinct entities affecting endometrial vasculature and hemostasis. Materials and methods.?An overview of the major etiologies and potential treatments for each condition is provided. Results.?HMB is potentially caused by several different hemostatic dysfunctions. Combination oral contraceptives, levonorgestrel-releasing intrauterine system, non-steroidal anti-inflammatory drugs, and anti-fibrinolytics all have been shown to have some degree of efficacy in treating HMB. The basic cause of HMB is unknown in the majority of cases. Endometrial S/B related to hormonal contraceptives is a common occurrence and may well have a common etiology in altered angiogenesis resulting in abnormal blood vessels with fragile vessel walls. There is no effective treatment for this problem. Conclusions.?Medical therapy for HMB is limited and effective for reducing blood loss during menstruation. There is no effective treatment for the S/B associated with hormonal contraceptives.     

Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate,mefenamic acid,and tranexamic acid.

OBJECTIVE: To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia. DESIGN: Randomised controlled trial. SETTING: A university department of obstetrics and gynaecology. SUBJECTS: 76 women with dysfunctional uterine bleeding. INTERVENTIONS: Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly. MAIN OUTCOMES MEASURES: Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient''s estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events. RESULTS: Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid. CONCLUSIONS: Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery.     

Regulation of human endometrial function: mechanisms relevant to uterine bleeding

This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function--including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding.     

冷刀系统与宫腔镜下能量系统分别联合芬吗通治疗中重度宫腔粘连疗效对比

摘要 目的：对比分析冷刀系统与宫腔镜下能量系统分别联合芬吗通治疗中重度宫腔粘连疗效。方法：选取2020年1月-2022年1月我院收治的中重度宫腔粘连患者80例为研究对象,分为对照组（n=40）和观察组（n=40）。对照组采用宫腔镜下能量系统联合芬吗通治疗,观察组采用冷刀系统联合芬吗通治疗。对比两组临床指标、临床疗效、月经恢复情况、并发症发生情况。结果：观察组手术时间、术中出血量、手术次数、术后出血量均短/少于对照组（P<0.05）。术后12个月观察组临床疗效（90.00%）显著高于对照组（65.00%）（P<0.05）。术后8~14个月两组的月经恢复情况均改善,观察组月经恢复情况较对照组更优（P<0.05）。观察组术后感染、子宫腺肌病、子宫穿孔、水中毒等并发症的总发生率（7.50%）低于对照组（47.50%）（P<0.05）。结论：冷刀系统联合芬吗通治疗宫腔粘连具有显著疗效,不仅对患者的危害更小,还有利于月经恢复,减少并发症,改善预后。     

宫内节育器与宫腔支撑球囊联合应用治疗中重度宫腔粘连中的临床效果

摘要 目的：探讨宫内节育器与宫腔支撑球囊联合应用治疗中重度宫腔粘连的临床效果。方法：选择2016年12月至2019年8月于西安交通大学第一附属医院宫腔镜诊疗中心接受宫腔镜下中重度宫腔粘连分解术的患者共96例,采用随机对照表法将其分为两组。对照组48例,术后宫腔内放置宫内节育器(intrauterine contraceptive device,IUD);研究组48例,术后放置宫腔支撑球囊(intrauterine support balloon,ISB),3~5 d后更换为宫内节育器。两组术后均给予为期3月的人工周期治疗。术后1月,复查宫腔镜了解宫腔有无再粘连并取出宫内节育器,以此评估手术效果是否有效,术后3月时随访其月经来潮情况。统计比较两组术后5 d内阴道出血量、C反应蛋白水平、发热、下腹痛以及节育器或支持球囊有无脱落等情况,术后1月手术效果及术后3月月经恢复情况。结果：研究组的手术有效率及月经改善比例均显著高于对照组(P<0.05),术后5 d内阴道出血量显著少于对照组(P<0.05);下腹痛及球囊脱落事件发生率显著低于对照组(P<0.05)。两组在C反应蛋白水平、发热发生率对比无统计学差异(P>0.05)。结论：与单独使用宫内节育器相比,联合使用宫腔支撑球囊能提高中重度宫腔粘连分解手术有效率,改善月经,减少术后出血,不增加感染风险,但球囊易于脱落且会增加患者下腹疼痛。     

Effects of an intrauterine copper device on serum copper, endometrial histology, and ovarian, hepatic, and renal functions in the Japanese monkey (Macaca fuscata fuscata).

A copper intrauterine device (Cu-IUD) was inserted transabdominally into the uterine cavity of eight Japanese monkeys (Macaca fuscata fuscata) for 4 to 6 months, and effects on various organ functions were examined. Results showed no significant effects on the menstrual cycle length, serum levels of LH, estradiol-17 beta, progesterone or clinical biochemical data such as serum copper, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactic dehydrogenase, and blood urea nitrogen. Histology revealed edema and infiltration of eosinophilic leukocytes in the endometrium treated with a Cu-IUD.     

Uterine peristalsis-induced stresses within the uterine wall may sprout adenomyosis

Adenomyosis is a disease in which ectopic endometrial glands and stromal cells appear in the uterine myometrium. This pathology is common among women of reproductive age, and in addition to chronic pelvic pain and heavy periods it may also cause infertility. The ‘tissue injury and repair’ mechanism in response to increased intrauterine pressures was proposed as the etiology for migration of fragments of basal endometrium into the myometrial wall. In order to investigate this mechanism, a conceptual two-dimensional model of the uterine wall subjected to intrauterine pressures was implemented using ADINA commercial software. The stress field within the uterine wall was examined for a variety of intrauterine sinusoidal pressure waves with varying frequencies. The results revealed that: (1) as the wavelength of the subjected pressure wave decreased, high concentration of stresses developed near the inner uterine cavity; (2) as the pressure wave frequency increased, high gradients of the stresses were obtained; (3) at menstrual phase, the highest stresses obtained at the endometrial–myometrial interface. Therefore, increased uterine activity results in high stresses which may lead to tissue lesions and detachment of endometrial cells.     

Menstrual cycle-associated alteration of sulfogalactosylceramide in human uterine endometrium: possible induction of glycolipid sulfation by sex steroid hormones

The human uterine endometrium is a tissue in which cell proliferation and differentiation are strictly controlled by sex steroid hormones, and these hormone-controlled cellular events occurring in association with the menstrual cycle of the uterine endometrium should be accompanied by characteristic molecular and metabolic changes. To characterize the menstrual cycle at the molecular level, we analyzed the glycolipids of human uterine endometrium in the proliferative and secretory phases of the menstrual cycle. Neutral glycosphingolipids from uterine endometrium comprised globo-series glycosphingolipids, such as GlcCer, LacCer, Gb3Cer, and Gb4Cer, and the relative concentrations remained constant in the two phases. However, in the case of acidic glycosphingolipids, although the concentrations of sialoglycosphingolipids remained at constant levels in the two phases, sulfatide, I3-SulfoGalCer, dramatically increased from the proliferative to the secretory phase, amounting to 7-17 nmol/g dry weight in the proliferative phase and 115-245 nmol/g dry weight in the secretory phase. Since sulfatide was the only glycolipid that changed in association with the menstrual cycle, it is likely that the sulfotransferase responsible for the synthesis of sulfatide might be induced by sex steroid hormones, estrogen and progesterone, and that sulfatide might play an essential biological role in the secretory phase of the menstrual cycle in the uterine endometrium.     

宫颈多重缝扎术联合子宫动脉上行支结扎治疗难治性出血的效果

目的:探究宫颈多重缝扎术联合子宫动脉上行支结扎治疗难治性出血的效果及安全性。方法:选取2014年9月～2018年10月我院收治的剖宫产术后难治性出血患者70例进行回顾性分析,根据术中止血方式不同分为两组,对照组(35例)患者行宫腔纱布填塞联合双侧子宫动脉上行支结扎术,观察组(35例)患者行宫颈多重缝扎术联合双侧子宫动脉上行支结扎术。比较两组患者的止血效果、术中和术后出血量、术后恢复情况及并发症的发生情况。结果:治疗后,观察组患者的止血有效率显著高于对照组(P0.05);观察组患者术中和术后2 h、12 h和24 h的出血量显著低于对照组(P0.05);两组患者月经量和子宫复旧情况相比无统计学差异(P0.05),观察组患者住院时间、恶露持续时间、月经恢复时间均显著短于对照组(P0.05);两组患者不良反应发生率相比无统计学差异(P0.05)。结论:宫颈多重缝扎术联合子宫动脉上行支结扎可显著降低术中和术后出血量,止血效果较好,可促进患者术后恢复,且不增加并发症的发生率。     

Wild fulvous fruit bats (Rousettus leschenaulti) exhibit human-like menstrual cycle

We investigated the menstrual cycle of wild fulvous fruit bats (Rousettus leschenaulti), focusing on changes in the endometrial and ovarian structure and pituitary and steroid hormones. The menstrual cycle lasts for 33 days in bats studied in their natural habitat and in captivity. Vaginal bleeding was restricted to a single day (Day 1). A preovulatory follicle was found in the ovary on Day 18 when the levels of LH and FSH reached their maxima, accompanied by a thickened endometrium. On Day 24, serum levels of progesterone and estradiol-17 were also maximal, and uterine glands increased in size. After that, the levels of progesterone dropped precipitously, leading to menstrual bleeding. Both the morphologic and hormonal changes observed in fulvous fruit bats during the menstrual cycle resemble similar changes in humans. Fulvous fruit bats may be useful nonprimate laboratory models to study menstruation and menstrual dysfunction.     

宫血宁治疗宫内节育器后异常出血的疗效观察

目的：探讨宫血宁胶囊用于治疗宫内放置节育器后异常子宫出血的临床疗效。方法：350例宫内置器后异常出血患者随机分为观察组（175例）与对照组（175例）,其中观察组给予宫血宁胶囊治疗,对照组给予抗菌止血常规西药治疗,比较两组患者治疗前后月经异常变化情况及治疗效果。结果：①观察组治愈率、总有效率分别为56.00%和92.57%,对照组治愈率、总有效率为25.71%和75.43%,组间差异有统计学意义（P〈0.01）。②经过治疗,观察组与对照组患者月经异常症状均得到明显缓解,与治疗前比较差异有显著性（P〈0.01）,其中观察组患者经量增多、经期延长和经间点滴出血等症状例数分别减少至9例、7例和1例,对照组减少至34例、30例和15例,组间差异有统计学意义（P〈0.05）。③经过治疗,观察组患者平均月经持续时间从11.74±4.69d减少至6.92±2.34d,对照组从12.11±5.25d减少至9.28±3.14d,两组间差异有统计学意义（P〈0.05）。结论：宫血宁胶囊可有效治疗因宫内放置节育器所引起的子宫异常出血,且疗效优于抗菌止血西药治疗,值得进一步推广。     

Heparin-like activity in uterine fluid.

Uterine fluid was collected from a group of normal patients and a group of patients with menorrhagia. Heparin-like activity was detected in 34 out of 38 samples using an anti-Xa heparin assay. The heparin-like activity in uterine fluid was inhibited by adding the heparin antagonist hexadimethrine bromide to the assay. Concentrations of fibrinogen-fibrin degradation products (FDPs) were measured in five samples of uterine fluid. FDPs in the concentration detected had no effect on the anti-Xa assay. Heparin-like activity was higher in the group with menorrhagia, although the differences were not significant. Heparin-like activity increased throughout the menstrual cycle and decreased during menstruation, suggesting a possible cyclical variation in activity. There was no correlation between mast cell numbers in the endometrium and myometrium and heparin-like activity in uterine fluid and no correlation between the numbers and the stage in the menstrual cycle. In a few patients with intrauterine contraceptive devices (IUCDs) heparin-like activity was increased.     

Adipose-Derived Stromal Vascular Fraction Cell Effects on a Rodent Model of Thin Endometrium

Endometrial dysfunction affects approximately 1% of infertile women, and there is currently no standard therapy for improving fertility treatment outcomes in these patients. In our study, we utilized a rodent model of thin endometrium to test whether intrauterine application of adipose-derived stromal vascular fraction cells (SVF) could improve morphological and physiological markers of endometrial receptivity. Using anhydrous ethanol, endometrial area and gland density were significantly reduced in our model of thin endometrium. Application of SVF was associated with a 29% reduction in endometrial vascular endothelial growth factor (VEGF) expression and significant increases in uterine artery systolic/diastolic velocity ratios and resistance index values, suggesting reduced diastolic microvascular tone. However, no significant improvements in endometrial area or gland density were observed following SVF treatment. 3D confocal imaging demonstrated poor engraftment of SVF cells into recipient tissue, which likely contributed to the negative results of this study. We suspect modified treatment protocols utilizing adjuvant estrogen and/or tail vein cell delivery may improve SVF retention and therapeutic response in subsequent studies. SVF is an easily-obtainable cell product with regenerative capability that may have a future role in the treatment of infertile women with endometrial dysfunction.     

The effect of semen extender,seminal plasma and raw semen on uterine and ovarian blood flow in mares

Transrectal color Doppler sonography was used to evaluate the effect of intrauterine infusion of skim milk semen extender, seminal plasma and raw semen on the endometrium and blood flow in the uterine and ovarian arteries in mares. Six Trotter mares (mean age: 12 years) were examined during estrus in three cycles. Each mare received an intrauterine infusion of 20 ml of skim milk semen extender, seminal plasma or raw semen during estrus in one of three cycles. Blood flow measurements in both uterine and ovarian arteries and the determination of intrauterine fluid via sonography were performed before each infusion and 1, 3, 6, 12, and 24 h after infusion. Forty-eight hours later, the intrauterine infusion and measurements were repeated using the same time intervals. Changes in blood flow were detected using transrectal color Doppler sonography and were evaluated using the mean time-averaged maximum velocity (TAMV) of the blood flow. Cytological and bacteriological examination of uterine swabs performed 48 h after the second infusion revealed less inflammation and bacterial growth in mares infused with skim milk semen extender than in those infused with seminal plasma or raw semen. There was an increase in intrauterine fluid as early as 1 h after infusion of any of the substances. The infusion of skim milk semen extender had no effect on uterine blood flow. Within 1 h after infusion of seminal plasma or raw semen, there was an increase in the TAMV values of both uterine arteries (P<0.05). In contrast, ovarian blood flow increased only in the artery ipsilateral to the preovulatory follicle and only after the infusion of raw semen (P<0.05). In conclusion, the changes in uterine perfusion observed after intrauterine infusion may be associated with endometrial inflammation and vasodilatory components in the seminal plasma, whereas the changes seen in ovarian blood flow are possibly attributable to the interaction between sperm and oviduct.     

Biological characteristics of human menstrual blood‐derived endometrial stem cells

Successful isolation of human endometrial stem cells from menstrual blood, namely menstrual blood‐derived endometrial stem cells (MenSCs), has provided enticing alternative seed cells for stem cell‐based therapy. MenSCs are enriched in the self‐regenerative tissue, endometrium, which shed along the periodic menstrual blood and thus their acquisition involves no physical invasiveness. However, the impact of the storage duration of menstrual blood prior to stem cell isolation, the age of the donor, the number of passages on the self‐renewing of MenSCs, the paracrine production of biological factors in MenSCs and expression of adhesion molecules on MenSCs remain elusive. In this study, we confirmed that MenSCs reside in shedding endometrium, and documented that up to 3 days of storage at 4°C has little impact on MenSCs, while the age of the donor and the number of passages are negatively associated with proliferation capacity of MenSCs. Moreover, we found that MenSCs were actually immune‐privileged and projected no risk of tumour formation. Also, we documented a lung‐ and liver‐dominated, spleen‐ and kidney‐involved organic distribution profile of MenSC 3 days after intravenous transfer into mice. At last, we suggested that MenSCs may have potentially therapeutic effects on diseases through paracrine effect and immunomodulation.