Thara Vayali, ND

Tolle Totum

Heavy menstrual bleeding (HMB) is 1 of the most common presenting concerns in gynecology.¹ Some studies have reported that 30% of menstruating women experience HMB,^2,3 but multiple large scale reviews and cohort studies present figures that range from 4% to 51%, depending on age, types of assessments, and ethnicity.^4-7 Once diagnosed as menorrhagia or HMB, the treatment of choice is typically hormonal or surgical interventions to disrupt ovulatory cycles and stop menstrual bleeding entirely.^8,9 In 50% of hysterectomies performed for this reason, no organic pathology has been found.^2,3

This begs the question: What is the cause we are missing?

Definitions, Assessment, and Diagnosis

To truly understand how to diagnose HMB, 2 things are needed: a definition, and an appropriate method of assessment.

Menorrhagia – is defined as regular ovulatory cycles with menstrual blood loss of more than 80 mL per cycle, and/or menstrual bleeding for more than 7 days.¹⁰ It is synonymous with HMB; therefore, these terms will be used interchangeably in this review. Other menstrual problems that may be confused with menorrhagia include:¹⁰
Dysfunctional/abnormal uterine bleeding – a broad term that is sometimes used mistakenly to describe menorrhagia. It is a diagnosis of exclusion for heavy uterine bleeding that presents with anovulatory cycles in a majority (90%) of cases.
Metrorrhagia – bleeding at irregular intervals, with or without ovulation
Polymenorrhea – regular menstrual intervals, less than 21 days apart
Dysmenorrhea – painful menstrual cycles, which may or may not be accompanied by heavy bleeding

Population studies performed in 1966 and 1971 in Sweden & the Northern United Kingdom, respectively, are often cited as the basis for determining whether bleeding is normal or excessive, and few baseline studies have been done since. In those studies, 90% of women were found to lose an amount under 80 mL of blood per cycle. In addition, although iron depletion was observed to being at 60 mL of menstrual blood loss, hemoglobin (Hgb) and serum ferritin levels were adversely impacted at an average of 80 mL of blood loss.^11,12 Thus, menorrhagia came to be established as greater than 80 mL of menstrual blood loss, and this definition has been accepted clinically for half a century without question. The method to assess blood loss, established in 1964 and still used today, involves a clinically impractical test of chemical and spectrometric analysis of hematin in menstrual pads ^13,14 Furthermore, within the context of these studies, the severity of HMB was based on potential for anemia rather than blood loss or symptoms, and other impacts on health and quality of life have historically not been considered.

The Need for a New Perspective

What we may be missing with our focus on Hgb and 80 mL measurements is a malfunctioning endocrine network due to years of menstrual bleeding with chronic heavy monthly losses that do not reach the current threshold for a menorrhagia diagnosis, evaluation, and treatment. Women who experience missed menorrhagia, as I’ve come to call it, will present with menstrual blood losses of about 60 mL or more per cycle, low serum ferritin, and an array of symptoms such as fatigue, weight and hair changes, and extreme mood swings. The triad of conditions that I consistently see in women with missed menorrhagia includes iron deficiency, estrogen and progesterone imbalance, and thyroid dysfunction.

Despite the fact that a thorough history is the backbone of assessing female health, a subjective assessment of periods as “light,” “normal,” and “heavy” is often considered sufficient by clinicians; yet evidence shows the inaccuracy of these descriptors.⁸ Of women who report excess bleeding subjectively, only 34% had >80 mL of menstrual blood loss,¹⁵ suggesting that women may judge the quantity of blood loss based on its impact on their quality of life. Although they may not fit the clinical definition of HMB, their degree of blood loss may still have a significant impact on serum ferritin levels and may contribute to numerous symptoms.^15,16

Without accurate measurements, menorrhagia can go undiagnosed for years, until further endocrine or medical conditions begin to appear. We may discover that periods described as normal may, in fact, be characterized by large quantities of monthly blood loss that have been overlooked.

How Can We Best Assess Our Menstruating Patients?

While there are chemical analyses and pictorial blood loss charts,^17-19 the most clinically useful measure of quantity of blood loss comes from patient reports of how many tampons, pads, or cups are used fully on the heaviest days of flow.^8,15,16 Low ferritin can correctly identify 60% of women with menorrhagia,^7,8 and adding reports of clot size and rate of collection device changes at capacity during full flow increases identification of menorrhagia to 76%.^15,16 Clinicians who want to use these patient reports need to know the capacity of each of these collection devices. For example, 1 average fully soaked super pad holds 10 mL of blood, a super tampon holds 12 mL of blood, and a collection cup holds 30 mL of blood.¹⁹ With this knowledge, device changes x capacity can be quickly calculated in clinic to a gather a general idea of how much menstrual blood is actually being lost.

The Impact of Blood Loss

The mechanism of menorrhagia is still unclear, but we do know that blood flow is controlled by hemostasis, vasoconstriction, and endometrial repair.^10,20,21 Importantly, these factors are affected by iron stores, estrogen and progesterone levels, and thyroid function, which each can then exacerbate and compound HMB.

Clinically, we may see a patient with refractory iron deficiency, thyroid hormone levels that respond to treatment slowly, and/or premenstrual syndrome unresponsive to hormone balancing therapies. When a patient presents with 1 or more of these conditions, consider that the woman may be experiencing a multi-faceted, but unreported, chronic menorrhagia. While we may not be able to identify the initiating cause, when a presenting concern seems to be unresponsive to proven treatments, approaching the concern from another angle may improve outcomes.

Let’s look at each of these concerns and their relationship with menorrhagia:

Iron Deficiency
Iron is depleted through HMB, and its depletion can compound menstrual blood losses. Anemia is a coexisting concern with menorrhagia, as established above. Extreme iron deficiency and iron overload are dangerous for multiple organ systems, but moderate changes in iron levels also can impact the delicate balance of hemostatic and fibrinolytic mechanisms in the endometrial tissue.^10,20-23 Although the exact mechanism by which iron deficiency exacerbates HMB is unknown, iron is known to be involved in properly functioning coagulation cascades. Iron losses can result in improper fibrin and platelet formation.^22-26 Healthy menstrual flow rests on the ability to generate proper fibrin plugs to control bleeding while promoting adequate fibrinolysis to inhibit clot organization and adhesions.^{10, 20-23}

Estrogen/Progesterone Imbalance
Estrogen is a key stimulator of endometrial growth during the proliferative menstrual phase.^20,27 Unopposed estradiol can cause anovulatory bleeding, in which the endometrial lining grows beyond its vascular capacity and degenerates.^20,27 If ovulation occurs, a rise in progesterone limits the growth of the endometrial lining.

During the luteal phase, progesterone influences vasoconstricting prostaglandins and the production of clotting factors in the endometrial cells. The build-up of these factors assists the initial controlled hemorrhage of menstruation.^10,20 Progesterone inhibits the fibrinolytic, proteolytic and anticoagulant actions of matrix metalloproteinases (MMP) present in the endometrial lining. Progesterone withdrawal at the end of the luteal phase initiates shedding of the lining which is then continued by MMP that break down endometrial tissue. ^10,20,21,28 The repair process is primarily associated with vascular endothelial growth factor (VEGF), which seems to be found in the endometrial cells through the cycle when estrogen and progesterone are within appropriate ranges.²⁰

Lowered luteal progesterone can impact HMB by decreasing the build-up of required factors for early coagulation, increasing MMP activity, and decreasing VEGF. This can lead to uncontrolled and prolonged endometrial tissue breakdown and damage.^20,28 The combination of elevated follicular estrogen and low luteal progesterone levels establishes excess endometrial growth, uncontrolled shedding, and damaged repair cycle, which increases the likelihood of HMB.

Hypothyroid
Women have a higher incidence of hypothyroidism than men.²⁹ Thyroid disease is most often associated with anovulatory bleeding, due to an elevation in prolactin and reduction in gonadotropin releasing hormone.³⁰ In addition, serum estradiol and progesterone levels have a measurable impact on thyroid function, whether or not cycles are ovulatory: Estradiol raises thyroxine binding globulin (TBG), increasing the bound fraction of thyroxine and decreasing the free fraction of thyroxine, and progesterone increases free thyroxine levels.^31-35 Beyond this, estrogen has been shown to suppress the effects of T3.^32,36 Therefore, when estrogen is elevated and progesterone is low during the luteal phase of a menstrual cycle, not only does it impact hemostasis and vasoconstriction, it has the potential to hinder thyroid function.

Iron and thyroid have a 2-way relationship: Because thyroxine is involved in iron absorption and incorporation into erythrocytes and iron is involved in the conversion of T4 to T3, low thyroid function can be caused by and can cause iron deficiency.^37,38 When iron deficiency occurs with hypothyroidism, treatment with a combination of nutrient therapy and thyroxine therapy has been found to be more effective than either alone^37,43

Treatment of subclinical hypothyroidism has been found to improve menorrhagia;^41,42 nevertheless, the exact relationship between menorrhagia and hypothyroidism has not been firmly established.^7,39,40

The Interconnected Web

It seems that iron deficiency, low thyroid function, and estrogen and progesterone imbalances prime the uterus for a bloody mess, no matter what we call it. Before heading toward medical or surgical treatments, HMB is usually treated with anti-inflammatory approaches without addressing the trio of possible conspirators. Understanding the nature of HMB and its web-like interconnections with hormones and nutrients can help us to better serve our female patients through accurate assessment and thorough exploration of its possible causes and sequelae.

References:

1. Nicholson WK, Ellison SA, Grason H, Powe NR. Patterns of ambulatory care use for gynecologic conditions: A national study. Am J Obstet Gynecol.2001;184(4):523-530.
2. El-Hemaidi I, Gharaibeh A, Shebatat H. Menorrhagia and bleeding disorders. Curr Opin Obstet Gynecol. 2007;19(6):513-520.
3. Oehler M, Rees MC. Menorrhagia: An update. Acta Obstet Gynecol Scand.2003;82(5):405-422.
4. Harlow SD, Campbell OM. Menstrual dysfunction: a missed opportunity for improving reproductive health in developing countries. Reprod Health Matters. 2000;8(15):142-147.
5. Harlow SD, Campbell OM. Epidemiology of menstrual disorders in developing countries: A systematic review. Br J Obstet Gynaecol. 2004;111(1):6-16.
6. Karlsson TS, Marions LB, Edlund MG. Heavy menstrual bleeding significantly affects quality of life. Acta Obstet Gynecol Scand. 2014;93(1):52-57.
7. National Institute for Health and Clinical Excellence. Heavy Menstrual Bleeding. Clinical Guidelines. London, England: RCOG Press; 2007.
8. Apgar BS, Kaufman AH, George-Nwogu U, Kittendorf A. Treatment of menorrhagia. Am Fam Phys. 2007;75(12):1813-1819.
9. Gupta J, Kai J, Middleton L, et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med. 2013;368(2):128-137.
10. Livingstone M, Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Repr Update. 2002; 8(1):60-67.
11. Cole S, Billewicz W, Thomson A. Sources of variation in menstrual blood loss.J Obstet Gynecol. 1971;78(10):933-939.
12. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study: Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand.1966;45(3):320-351
13. Hallberg L, Nilsson L. Determination of Menstrual Blood Loss. Scand J Clin Lab Invest.1964;16:244-248.
14. Schumacher U, Schumacher J, Mellinger U, et al. Estimation of menstrual blood loss volume based on menstrual diary and laboratory data. BMC Women’s Health.2012;12:24.
15. Warner PE, Critchley HO, Lumsden MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcomes in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol. 2004;190(5):1216-1223.
16. Toxqui L, Perez-Granados AM, Blanco-Rojo R, et al. A simple and feasible questionnaire to estimate menstrual blood loss: relationship with hematological parameters in young women. BMC Women’s Health.2014;14:71.
17. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990;97(8):734-739.
18. Reid PC, Coker A, Coltart R. Assessment of menstrual blood loss using a pictorial chart: a validation study. 2000;107(3):320-322
19. The Menorrhagia Research Group. Quantification of menstrual blood loss.Obstetrician Gynaecologist. 2004;6:88-92.
20. Maybin J, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21(6):748-761
21. Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding Menopause. 2011;18(4):408-411.
22. Livesey JA, Manning RA, Meek JH, Jackson JE, Kulinskaya E, Laffan MA, Shovlin CL. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax. 2012;67(4):328-33.
23. Jankun J, Landeta P, Pretorius, E Lipinski, B. Unusually clotting dynamics of plasma supplemented with iron (III). Int J Mol Med.2014;33(2):367-372.
24. Davies J, Kadir RA. Endometrial hemostasis and menstruation.Rev Endocrin Metab Disord. 2012;13(4):289-299.
25. Franchini M, Targher G, Montagnana M, Lippi G. Iron and thrombosis. Ann Hemat.2008;87:167-173.
26. Roeloffzen WW, Kluin-Nelemans HC, Bosman L, de Wolf JT. Effect of red blood cells on hemostasis. Transfusion. 2010;50(7):1536-1544.
27. Bulun SE. Endometriosis. N Engl J Med.2009;360(3):268-279.
28. Gaide Chevronnay HP, Selvais C, Emonard H, et al. Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta.2011;1824(1):146 -156.
29. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol.1995;43(1): 55-68.
30. Verma I, Sood R, Juneja S, Kaur S. Prevalence of hypothyroidism in infertile women and evaluation of response of treatment for hypothyroidism on infertility. Int J App Basic Med.2012;2(1):17-19.
31. Ben-Rafael Z, Strauss JF,  Arendash-Durand B, et al. Changes in thyroid function tests and sex hormone binding globulin associated with treatment by gonadotropin. Fertil Steril.1987;48(2):318-320.
32. Santin AP, Furlanetto TW. Role of Estrogen in Thyroid function and growth regulation. J Thyroid Res.2011;Article ID 875125.
33. Sathi P, Kalyan C. Hitchcock L, Pudek M, Prior JC. Progesterone therapy increases free thyroxine levels. Clin Endocrinol. 2013;79(2):282-287.
34. Arafah BM. Increased need for thyroxin in women with hypothyroidism during estrogen therapy. N Engl J Med.2001;344(23);1743-1749.
35. Mazer NA. Interaction of Estrogen Therapy and thyroid hormone replacement in post-menopausal women. Thyroid2004;14 (supp 1): S27-34.
36. Vasudevan N, Ogawa S, Pfaff D. Estrogen and thyroid hormone receptor interactions: Physiological flexibility by molecular specificity. Physiol Rev. 2002;82(4):923-944.
37. Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: A randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2009;94(1):151-156.
38. Eftekhari MH, Keshavarz SA, Jalali M, et al. The relationship between iron status and thyroid hormone concentration in iron-deficient Iranian girls. Asia Pac J Clin Nutr.2006;15(1):50-55.
39. Prentice A. Medical management of menorrhagia. 1999;319(7221):1343-5.
40. Weeks A. Menorrhagia and hypothyroidism. 2000;230(7235):649.
41. Higham JM, Shaw RW. The effect of thyroxine replacement on menstrual blood loss in a hypothyroid patient. Br J Obstet Gynaecol. 1992;99(8):695-696.
42. Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. Am J Obstet Gynecol.1989;160(3):673-677.
43. Ravanbod M, Asadipooya K, Kalantarhormozi M, et al. Treatment of iron deficiency anemia in patients with subclinical hypothyroidism. Am J Med. 2013;126(5):420-4.

Thara Vayali, ND, graduated from the Boucher Institute of Naturopathic Medicine in 2011. She earned degrees in Nutritional Sciences from UBC in 2003 and Environmental Communications from Royal Roads University in 2007. In addition to her clinical and research focus on hormones, she teaches therapeutic yoga and writes regularly on mindfulness techniques for the University of British Columbia. She is the founder of Change Natural Medicine and Pop Up Medicine, both of which offer care in accessible, innovative formats. Her private practice in Vancouver, BC is focused on endocrinology, gastrointestinal health, and biomechanics.