AUB-L – When is the leiomyoma the culprit?

Blog Post by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

I frequently am approached by surgically ambitious residents (registrars) with a pitch that goes something like this:

“I have a 47 year old patient with menometrorrhagia from a 13 week size symptomatic fibroid uterus who wants a hysterectomy. When can we do it?”

Typically the patient hasn’t been adequately investigated as the assumption is that the leiomyomas (fibroids), detected with some combination of manual examination and ultrasound are indeed the cause of the abnormal bleeding – this, coupled with an irrational exuberance for surgery, results in a patient who “wants” a hysterectomy. So what is wrong with this story?

In the United States, at least, by the age of 50, leiomyomas are present in almost 70 per cent of Caucasians and more than 80 per cent of women of African ancestry. (1) Since most of these women don’t have any symptoms, an astute observer should conclude that most “fibroids” are asymptomatic. So when the symptom of abnormal uterine bleeding (AUB) occurs in a woman who can be demonstrated to have leiomyomas, the clinician should be challenged to distinguish AUB that is caused by the myomas from that which occurs for other reasons. Those familiar with the varied causes of AUB in the reproductive years, detailed in FIGOs new classification system, will recognize that there are a large number of potential entities, both structural, and those unrelated to visible pathology, that could coexist with asymptomatic leiomyomas and be the actual cause of the abnormal bleeding.(2) So, you might ask, if that is the case, which leiomyomas contribute to AUB and which do not?

To answer this, we should look to the FIGO system, which has a subclassification for leiomyomas. When a woman presents with AUB and is found to have one or more submucous leiomyomas (Types 0, 1, & 2), she is categorized as having AUB-Lsm; if the endometrial cavity is normal, meaning that none of the leiomyomas distort the cavity by deviating the endometrium (Types 3-8), she is categorized as having AUB-Lo (“o” standing for other leiomyomas or those outside the endometrial cavity). While we need more well-designed studies, the present hypothesis is that the leiomyoma likely must directly contact the endometrium for the lesion to contribute to the AUB; in other words, the leiomyoma must be submucous in location, a circumstance that can be noted in the FIGO system as “AUB-Lsm”.

What is the evidence for such a relationship? Until recently, most of the evidence was indirect, with studies showing that removal of submucous leiomyomas resulted in the predictable improvement in the symptom of heavy menstrual bleeding. However, more recently, we are beginning to assemble the molecular puzzle, as it is apparent that leiomyomas manufacture factors such as TGF-Beta3 that can impact the endometrium, if it is nearby, by interfering with the action of the unlikely substance bone morphogenetic protein (BMP), that adversely impacts some of the mechanisms involved in local control of menstrual bleeding.(3) It takes little imagination to see that if the leiomyoma is remote from the endometrium, such an impact would be reduced or eliminated altogether.

So when we interview the resident’s patient with a structured history, we frequently find that indeed the patient has the irregular bleeding typically associated with an ovulatory disorder (AUB-O) and, despite the presence of Type 4 and 5 leiomyomas, evaluation with office hysteroscopy, contrast sonography or MRI, demonstrates a normal endometrial cavity. In such instances, the endocrine etiology of the problem is amenable to a host of medical interventions including combination oral contraceptives and cyclical or continuous progestins – and, such patients may even have a discernable and treatable cause of the anovulation, ranging from hypothyroidism, obesity or personal stress. Alternatively, the hysteroscopy or contrast sonography might identify a polyp or smaller Type 0 or 1 lesion that can be removed easily, often in the office. So the patient’s options are frequently are far more numerous than hysterectomy, and often safer and relatively painless. So just because you find leiomyomas in a woman with AUB, doesn’t mean that the two are related – taking the time to critically evaluate all the potential contributors to the symptom of AUB may relieve your patient from the unlikely notion of “wanting” a hysterectomy.

More about AUB-L can be found in the book Abnormal Uterine Bleeding, from Cambridge Medical Press.(4)

1. Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188:100-7.
2. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113:3-13.
3. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. The Journal of clinical endocrinology and metabolism. 2011;96:412-21.
4. Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

How Common is AUB-C?

Blog Post by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

Among the varied causes of the symptom of heavy menstrual bleeding (HMB) in reproductive aged women are congenital disorders of hemostasis, commonly called coagulopathies. In the new FIGO PALM-COEIN classification system for causes of AUB in the reproductive years, such women are categorized as having AUB-C.(1) While there exist a number of such entities, by far, the most common is von Willebrand disease (vWD), a disorder that has a mean prevalence of about 13% in women of all ages with HMB.(2) There exist three recognized variants of vWD; the majority has the mild Type 1 form that can only be diagnosed with certainty using specific testing for von Willebrand factor (vWF). Type 2 vWD is a quantitative deficiency where vWF levels are typically 10-45% of normal while Type 3 is a serious deficiency that adversely impacts hemostasis even in the face mild injury or menses. Other less common factor-based coagulopathies are caused by deficiencies in Factors II, V, VII, VIII, IX, X, XI and XII. Of course, AUB-C can be also caused by iatrogenic means secondary to the use of anticoagulants. Because it is not clear to what degree the mild variants of inherited coagulopathies contribute to symptom of HMB in a given woman it is important to always perform a complete evaluation considering all of the elements in FIGO’s PALM-COEIN classification system.

AUB-C may present initially at menarche, when the adolescent, perhaps for the first time, has to attain satisfactory hemostasis over a large bleeding surface – the endometrium. The problem can be compounded because at menarche, many, if not most, such bleeds are anovulatory, where the endometrium is already deficient in endometrial vasoconstrictors such as PG F2-α and endothelin-1 that are largely dependent on the production of progesterone. When added to the delay in presentation fostered by the embarrassment and immaturity of the typical adolescent, menarcheal girls with von Willebrand disease and other disorders of systemic hemostasis are at great risk for a serious episode of HMB. Indeed, one study has reported that almost 20% of young girls who presented in the emergency department with acute HMB have AUB-C. (3)

So how does one diagnose AUB-C? The first step is to have a high index of suspicion. So when an adolescent presents around menarche with acute HMB, steps should be taken to evaluate for a systemic disorder of hemostasis. For other women, there is evidence that a structured history can identify about 90% of the women with laboratory evidence of von Willebrand disease. Any woman with lifelong heavy menstrual bleeding is at risk, as are those with a family history, or with a personal history of frequent bruising, bleeding with brushing teeth or unexplained bleeding associated with childbirth or surgical procedures.(4, 5) For women who fail the screen, the process should start with non-specific assays including prothrombin time (PT), partial thromboplastin time (PTT), ABO blood type and Ivy bleeding time as well as more specific assays measuring vWF, Ristocetin co-factor and Factor VIII . Other assays such as those for platelet aggregation or more rare factor deficiencies can be obtained as appropriate, depending on the clinical situation, and the advice of a consulting hematologist. Of course, the evaluation of any individual with AUB, including HMB, should be performed considering focal lesions of the lower genital tract as well as the other potential contributors to the bleeding categorized in FIGO’s PALM-COEIN system, two of which (AUB-E and AUB-O) have been discussed in previous editions of this blog.

Treatment of women with AUB-C will vary according to the severity of the disorder, the desires regarding current and future fertility, and the response to simple interventions such as tranexamic acid and local or systemic progestin-containing regimens. More about AUB-C can be found in the book Abnormal Uterine Bleeding, from Cambridge Medical Press.(6)

1. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113:3-13.
2. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734-40.
3. Claessens EA, Cowell CA. Acute adolescent menorrhagia. American journal of obstetrics and gynecology. 1981;139:277-80.
4. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet. 1998;351:485-9.
5. Kouides PA, Conard J, Peyvandi F, Lukes A, Kadir R. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005;84:1345-51.
6. Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

AUB-E – What have we learned?

Blog Post  by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

When abnormal uterine bleeding (AUB) occurs unrelated to structural abnormalities (polyps, adenomyosis, leiomyomas, and hyperplasia or malignancy) clinicians often feel challenged to find a diagnosis.

So in this circumstance, what are the mechanisms involved in the genesis of AUB? Certainly, there are iatrogenic causes like oral, transdermal or intrauterine contraception, that, in the new FIGO Classification of Causes of AUB in the Reproductive Years are termed AUB-I.(1) But absent iatrogenic contributors, there are a number of potential causes of AUB that may be present in the context of a structurally normal uterus (or one with structural abnormalities that do not contribute to the AUB). In a previous edition of this blog, I discussed ovulatory dysfunction (AUB-O), which we now know may reflect erratic or absent ovulation, and may even occur in women who ovulate but who have premature development of estradiol-producing follicles in the luteal phase, the so-called luteal out of phase (LOOP) follicular event. (2) In a future edition, we will discuss the prevalence and clinical impact of disorders of systemic hemostasis, or coagulopathies (AUB-C), one of which, von Willebrand disease, can be identified in about 13% of women with heavy menstrual bleeding (HMB).(3) But AUB can occur in women with normal ovulatory function, and without coagulopathies because of abnormalities that reside in the endometrium, a set of entities that are collectively called AUB-E.(1)

So what causes AUB-O?

Blog Post  by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

In the reproductive years, many women with abnormal uterine bleeding (AUB) have a disorder of ovulation – a group of entities designated “AUB-O” in the new FIGO classification system for causes of AUB in the reproductive years.(1) But what are these ovulatory disorders, and how are they diagnosed and treated?

The only thing “typical” about women with ovulatory disorders is that they do not have the characteristics of normal ovulation – ie predictable menstrual bleeding, with a reliable cycle length of 22 to 35 days and duration and flow that is consistent from period to period.(2) Instead, these women are often plagued with uncertainty – uncertainty about the time of onset, and, frequently, the volume and duration of bleeding. 

Abnormal uterine bleeding

Blog Post  by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

Many medical students, registrars/residents, primary care physicians and even gynecologic specialists struggle when confronted with a patient with abnormal uterine bleeding (AUB) in the reproductive years. This is no surprise as both the investigation and management of abnormal AUB in such women has been hampered by confusing and inconsistently applied nomenclature and the lack of standardized methods for investigation and categorization of the various potential causes of the problem.(1, 2) Terms such as “menorrhagia” and “dysfunctional uterine bleeding” frequently have different meanings in different environments, often resulting in misinterpretation of patients, colleagues, and textbooks or the medical literature. In addition, while many potential causes of AUB are invisible such as endometrial defects or coagulopathies, many uterine entities that are discernable, such as adenomyoais, leiomyomas, and endometrial polyps, are frequently asymptomatic.

Subfertility treatment in the 21st Century

Blog Post by Gab Kovacs, International Medical Director, Monash IVF, and Professor of Obstetrics and Gynaecology, Monash University, Toorak, Victoria, Australia

The approach to subfertility has certainly changed in the last few decades. Couples’ expectations have changed, and the community now accepts that there is no longer “infertility”. With all the various methods of parenting, every couple can have a family, thus “Subfertility” is a more accurate term.

 The principles of investigating a couple have not changed, it is still considering the “eggs”, “sperm” and “tubes” as the primary fertility parameters. If these are normal we then consider the couple as “idiopathic subfertility” and we contemplate whether there is a problem in gamete/embryo transport,  fertilization or implantation.  Whilst in-vitro fertilization techniques can help with the first two, implantation failure is still an ongoing challenge.  In fact it merges with the problem of recurrent early pregnancy loss, another problem area of reproductive medicine.

Haematological malignancies – a complex and expensive diagnosis

Blog Post by Wendy Erber , Consultant Haematologist and Clinical Director, Haemo-Oncology Diagnostic Service, Haematology Department, Addenbrooke’s Hospital, Cambridge

The diagnosis of haematological malignancies is complex, expensive and evolving rapidly. There is a myriad of diagnostic tests that can be applied to the analysis of malignant hematological disease. Which of these many tests should be performed and on which sample and at what time-point in the progress of the disease? As director of a large haemato-oncology diagnostic service and supervisor of haematologists in-training, I have seen the difficulties trainees have experienced, and the time, effort and resources wasted on poorly focused testing due to lack of knowledge in these areas.

Cambridge reproductive biologist Robert Edwards awarded the Nobel Prize for Medicine

 ESHRE warmly and proudly welcomes today’s announcement that the Cambridge reproductive biologist Robert Edwards has been awarded the Nobel Prize for Medicine.

Bob was a founder member of ESHRE and became the Society’s first chairman in 1985. The following year, under his drive and direction, ESHRE published the first issue of its journal, Human Reproduction, with Bob as editor, a role he was to continue for the next 15 years. Working with the gynaecologist Patrick Steptoe, Bob had pioneered the birth of the world’s first IVF baby, Louise Brown, who was born in Oldham, UK, on 25th July 1978. Her birth – as well as Bob’s own enthusiasm and personal guidance – proved an inspiration to many other groups around the world to establish their own IVF programmes.

Making of the brain and the birth of consciousness

Blog Post by Hugo Lagercrantz, Karolinska Institutet, Stockholm

The birth of consciousness is one of the three most fundamental stages of creation like the origin of the universe and life according to Thomas Mann and cited by Christof Koch. When does the human infant become conscious? Is the fetus conscious? Even the preterm infant seems to be aware of him/her –self and reacts to pain at a cortical level where consciousness is processed. The newborn responds more to human voices than noise and looks longer  on human faces. Consciousness can be defined as the hump from what is happening at the neuronal level  to subjective feeling. Although the newborn is probably conscious only at a minimal level, all the ”atoms” of  consciousness – the neurons in the cortex are formed before birth. Synaptogenesis has also started long before birth, but it peaks after about one year. The newborn brain is more like a jungle than a computer and it is necessary to prune the brain and organize the neuronal network before full consciousness is achieved. Putative neurotransmitters involved in consciousness like acetylcholine and norepinephrine and their receptors appear also at an early stage.