AUB-E – What have we learned?
July 6, 2011 Leave a comment
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)
One way to look at AUB-E is to categorize it into two types of entities: first, those that result in premature release of blood from the tissue of the endometrium, and second, disorders of local endometrial hemostasis. Acyclical bleeding originating in the endometrium probably results from some combination of inflammatory disorders or disruptions of angiogenesis that are currently under investigation.(4) However, at the present time, it would be reasonable to state that we know far more about factors that impact endometrial hemostasis at the time of menstruation.
Understanding the factors involved in endometrial hemostasis starts with the realization that the human endometrium is a unique biological entity, as no other tissue is designed to bleed physiologically. In the absence of pregnancy, local forces are marshaled to set in motion processes that result in shedding the unused functionalis and (once again) preparation of the endometrium to receive and nourish a 6-day embryo. This process of endometrial shedding is associated with bleeding and the endometrium, charged with achieving hemostasis, realizes that goal by orchestrating a number of relatively unique mechanisms. It always surprises me that despite about 30 years of research on local endometrial hemostasis and the relationship of related disorders to HMB, few textbooks have integrated these concepts into the education of medical students, family practitioners, obstetricians and gynecologists and other practitioners in the realm of women’s reproductive health.
In a unique way, platelets have a secondary, and even marginal role in the establishment of endometrial hemostasis during menstruation, while integrity of the systemic coagulation pathways is elevated to an even more important role. What is also unique to the endometrium is the gonadal steroid-related local production of vasoconstrictors such as endothelin-1 and prostaglandin F-2µ that appear to collectively result in spasm of the local arterioles thereby allowing the systemic system to create a vascular “plug”. It is apparent that in women with HMB secondary to AUB-E that there is an attenuated impact of these local factors, either because they are produced in subnormal amounts, or because of the existence of excesses of substances that compete at the level of the blood vessel such as nitric oxide, PG E2 and PG I2 each of which cause vasodilation. Excess levels of plasminogen activator, or decreased levels of plasminogen activator inhibitor also appear to be commonly present, a circumstance that results in excess local plasmin and resulting premature breakdown of the fibrin monomers that are critical to maintenance of the intravascular clot or plug.
Unfortunately, there are no currently-available clinical tests that exploit this knowledge in a way that would allow the clinician to customize therapeutic interventions. Nevertheless, there exist a number of agents that can impact the disorders of local endometrial hemostasis in a clinically significant fashion. Cyclooxygenase inhibitors can reduce the levels of PG E2 and PG I2 while tranexamic acid can lower the levels of plasmin by inhibiting plasminogen activation, an approach that seems to result in a reduction in the volume of menstrual blood loss in AUB-E by 40-60%. It is also apparent that systemic or locally administered progestin-based therapy such as combination oral contraceptives or intrauterine progesterone-releasing systems can also have a beneficial impact. More about AUB-E can be found in the book Abnormal Uterine Bleeding, from Cambridge Medical Press.(8)
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. Hale GE, Hughes CL, Burger HG, Robertson DM, Fraser IS. Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition. Menopause. 2009;16:50-9.
3. 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.
4. Maybin JA, Critchley HO, Jabbour HN. Inflammatory pathways in endometrial disorders. Molecular and cellular endocrinology. 2011;335:42-51.
5. Malcolm CE, Cumming DC. Does anovulation exist in eumenorrheic women? Obstet Gynecol. 2003;102:317-8.
6. Van Voorhis BJ, Santoro N, Harlow S, Crawford SL, Randolph J. The relationship of bleeding patterns to daily reproductive hormones in women approaching menopause. Obstetrics and gynecology. 2008;112:101-8.
7. De Souza MJ, Miller BE, Loucks AB, Luciano AA, Pescatello LS, Campbell CG, et al. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. The Journal of clinical endocrinology and metabolism. 1998;83:4220-32.