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International Journal of Gynaecology... Aug 2023Abnormal uterine bleeding (AUB) is common, often debilitating, and may affect over 50% of reproductive-aged women and girls. Whereas AUB is a collection of symptoms that...
Abnormal uterine bleeding (AUB) is common, often debilitating, and may affect over 50% of reproductive-aged women and girls. Whereas AUB is a collection of symptoms that include intermenstrual bleeding and abnormalities in period duration, cycle length, and regularity, it is heavy menstrual bleeding (HMB) that is most contributory to iron deficiency and related anemia. It is apparent that AUB, in general, and HMB, in particular, remain underrecognized and underreported. FIGO created two systems for assessing and classifying AUB. FIGO System 1 defines the bleeding pattern using four primary descriptors: frequency, duration, regularity, and flow volume. FIGO System 2 provides a structured classification system of possible causes of AUB, using the acronym PALM-COEIN. "PALM" refers to structural causes of AUB (Polyp, Adenomyosis, Leiomyoma, Malignancy), and "COEI" refers to nonstructural causes (Coagulopathy, Ovulatory dysfunction, Endometrial, and Iatrogenic). The "N" is reserved for those entities that are currently not otherwise classified. Using FIGO System 1 as a gateway to FIGO System 2 streamlines the investigation of reproductive-aged women and girls with AUB. Understanding the pathogenesis of the FIGO System 2 "PALM-COEIN" causes helps interpret investigations and the onward management of AUB. Numerous evidence gaps exist concerning AUB; however, if researchers and trialists universally adopt FIGO Systems 1 and 2 for the assessment and diagnosis of AUB, clear translatable research findings can be applied globally.
Topics: Female; Humans; Adult; Uterine Hemorrhage; Uterine Diseases; Menorrhagia; Leiomyoma; Endometrium
PubMed: 37538019
DOI: 10.1002/ijgo.14946 -
The Cochrane Database of Systematic... May 2022Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences.
OBJECTIVES
To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB.
METHODS
We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA.
MAIN RESULTS
We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence).
AUTHORS' CONCLUSIONS
Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.
Topics: Amenorrhea; Antifibrinolytic Agents; Child, Preschool; Female; Humans; Menorrhagia; Network Meta-Analysis; Progestins; Quality of Life; Systematic Reviews as Topic
PubMed: 35638592
DOI: 10.1002/14651858.CD013180.pub2 -
Frontiers in Endocrinology 2023The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various...
PURPOSE
The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs.
METHODS
In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility.
RESULTS
PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea.
CONCLUSION
The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.
Topics: Humans; Female; Proprotein Convertase 9; Polycystic Ovary Syndrome; Genome-Wide Association Study; Mendelian Randomization Analysis; Menorrhagia; Oligomenorrhea; PCSK9 Inhibitors; Hypolipidemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Coronary Disease; Lipids; Infertility
PubMed: 38027179
DOI: 10.3389/fendo.2023.1295412 -
Lancet (London, England) Sep 2022Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids.
METHODS
PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed.
FINDINGS
Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups).
INTERPRETATION
Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy.
FUNDING
ObsEva.
Topics: Carboxylic Acids; Estradiol; Female; Humans; Leiomyoma; Menorrhagia; Norethindrone Acetate; Pyrimidines; Receptors, LHRH; Uterine Neoplasms
PubMed: 36116480
DOI: 10.1016/S0140-6736(22)01475-1 -
Best Practice & Research. Clinical... Jul 2023Obesity is a growing public health concern and is associated with a range of menstrual disorders, including heavy menstrual bleeding, oligomenorrhea, dysmenorrhea, and... (Review)
Review
Obesity is a growing public health concern and is associated with a range of menstrual disorders, including heavy menstrual bleeding, oligomenorrhea, dysmenorrhea, and endometrial pathology. Investigations may be more logistically challenging in those in the population with obesity, and because of the heightened risk of endometrial malignancy, there should be a low threshold for biopsy to exclude endometrial hyperplasia. Although treatment modalities for women with obesity are broadly similar to those with a normal BMI, additional consideration must be given to the risks associated with estrogen in obesity. Outpatient management of heavy menstrual bleeding is a developing field and outpatient treatment modalities are preferable in the population with obesity to avoid the morbidity associated with anesthetics.
Topics: Female; Humans; Menorrhagia; Endometrial Ablation Techniques; Hysterectomy; Menstruation Disturbances; Obesity
PubMed: 37279629
DOI: 10.1016/j.bpobgyn.2023.102343 -
Ugeskrift For Laeger May 2024This is a case report of a 44-year-old premenopausal woman who was admitted to hospital due to uncontrollable and life-threatening vaginal bleeding after starting...
This is a case report of a 44-year-old premenopausal woman who was admitted to hospital due to uncontrollable and life-threatening vaginal bleeding after starting rivaroxaban treatment for atrial fibrillation. She had a medical history with menorrhagia due to an intrauterine fibroma. She did not respond sufficiently to factor X supplement or other non-surgical medical interventions. The bleeding subsided after bilateral embolization of aa. uterinae.
Topics: Humans; Rivaroxaban; Female; Adult; Factor Xa Inhibitors; Uterine Hemorrhage; Atrial Fibrillation; Leiomyoma; Menorrhagia; Uterine Neoplasms
PubMed: 38847299
DOI: 10.61409/V01240012 -
Current Opinion in Obstetrics &... Oct 2023Fibroids are benign pelvic masses and constitute the most common gynaecological condition. They create a significant health and social burden to many women because of... (Review)
Review
PURPOSE OF REVIEW
Fibroids are benign pelvic masses and constitute the most common gynaecological condition. They create a significant health and social burden to many women because of heavy menstrual bleeding and fibroid pressure symptoms. Many women will be faced with the dilemma of surgical management to improve their symptoms at some point of their reproductive age. The aim of this article is to identify current surgical management of fibroids describing the technical steps, advantages, disadvantages and risks of each method.
RECENT FINDINGS
The surgical management of fibroids remains challenging, as the overall prevalence, the clinical experience and the patient awareness is increasing because of an upgrade in our sonographic and magnetic resonance diagnostic tools. Unfortunately not every patient is able to benefit from tailor-made surgery that holistically evaluates individual needs including fertility aspirations.
SUMMARY
This article provides the most current synopsis of every available surgical modality for fibroid management. Large prospective multicentre cohort studies are needed to definitely determine the most suitable operation for any individual suffering with fibroids; and perhaps artificial intelligence may offer a valuable tool in the future data analysis.
Topics: Female; Humans; Uterine Neoplasms; Prospective Studies; Artificial Intelligence; Leiomyoma; Menorrhagia
PubMed: 37548229
DOI: 10.1097/GCO.0000000000000903 -
Fertility and Sterility Oct 2022Abnormal uterine bleeding (AUB) is a clinical entity which can lead to iron deficiency anemia. Classification according to the acronym PALM-COEIN (polyp, adenomyosis,... (Review)
Review
Abnormal uterine bleeding (AUB) is a clinical entity which can lead to iron deficiency anemia. Classification according to the acronym PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy, and hyperplasia; coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified) provides a structured approach to establish the cause of AUB. The goal of this review is to discuss the different mechanisms and the relationship between uterine disorders and AUB. Heavy menstrual bleeding, a subgroup of AUB, is more closely related to the presence of uterine fibroids. The relationship between heavy menstrual bleeding and uterine fibroids remains poorly characterized, particularly the understanding of endometrial function in women with structural myometrial features such as leiomyomas. A number of theories have been proposed in the literature and are discussed in this review. Uterine adenomyosis is also a frequent cause of AUB, and its pathogenesis is still far from being fully elucidated. The mechanisms contributing to its development are multifactorial. Many theories lean toward invasion of the myometrium by endometrial cells. Both clinical and basic studies favor the theory of direct invasion, although de novo development of adenomyosis from Müllerian rests or stem cells has not been ruled out. Development of adenomyotic lesions involves repeated tissue injury and repair. In addition, this review describes the other causes of AUB such as endometrial polyps, cesarean scar defects, and uterine vascular abnormalities. Endometrial polyps are often asymptomatic, but approximately 68% of women have concomitant AUB. Histologic alterations in the lower uterine segment in patients who had undergone cesarean sections were identified and may explain the cause of AUB.
Topics: Adenomyosis; Anemia; Female; Humans; Iron Deficiencies; Leiomyoma; Menorrhagia; Polyps; Pregnancy; Uterine Diseases; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 36182260
DOI: 10.1016/j.fertnstert.2022.08.011 -
Biology of Reproduction Dec 2019Abnormal uterine bleeding (AUB) is an extremely common problem and represents a clinical area of unmet need. It has clinical implications and a high cost for the... (Review)
Review
Abnormal uterine bleeding (AUB) is an extremely common problem and represents a clinical area of unmet need. It has clinical implications and a high cost for the healthcare system. The PALM-COEIN acronym proposed by FIGO may be used as a foundation of care; it improves the understanding of the causes of AUB, and in doing so facilitates effective history taking, examination, investigations, and management. Heavy menstrual bleeding, a subset of AUB, is a subjective diagnosis and should be managed in the context of improving the woman's quality of life. Available evidence suggests that there is poor satisfaction with standard treatment options often resulting in women opting for major surgery such as hysterectomy. Such women would benefit from a tailored approach, both for diagnosis and treatment, highlighting the deficiency of biomarkers in this area. This article focuses on the causes of AUB as per the PALM-COEIN acronym, the researched biomarkers in this area, and the potential pathogenetic mechanisms. In the future, these approaches may improve our understanding of AUB, thereby enabling us to direct women to most suitable current treatments and tailor investigative and treatment strategies to ensure best outcomes, in keeping with the principles of personalized or precision medicine.
Topics: Adenomyosis; Anovulation; Biomarkers; Blood Coagulation Disorders; Female; Humans; Leiomyoma; Menorrhagia; Metrorrhagia; Polyps; Precision Medicine; Uterine Diseases; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 30388215
DOI: 10.1093/biolre/ioy231