Citation for published version (APA): Verschueren, S. (2017). Systemic causes of heavy menstrual bleeding [Groningen]: Rijksuniversiteit Groningen

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1 University of Groningen Systemic causes of heavy menstrual bleeding Verschueren, Sophie IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Verschueren, S. (2017). Systemic causes of heavy menstrual bleeding [Groningen]: Rijksuniversiteit Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 6: Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding Sophie Wiewel-Verschueren H. Marieke Knol Ellen R. Klinkert Dorine W. Swinkels Tessel E. Galesloot André B. Mulder Karina Meijer Submitted

3 Chapter 6 Abstract Objective: The aim of this study was to evaluate thyroid function in women with objectively diagnosed heavy menstrual bleeding. Study design: Two hundred and five consecutive patients with regular heavy menstrual bleeding defined as Pictorial Blood loss Assessment Chart-score >100 were recruited at a tertiary hospital. Data were compared to female Nijmegen Biomedical Study population controls (n=1924). In patients in the first week after menstruation a gynecological examination was performed and blood was taken for investigation for systemic causes of increased blood loss. In 203 patients, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured. Descriptive statistics were computed for all study variables. Continuous variables, expressed as medians (Inter quartile range (IQR): quartile 1 (Q1)- quartile 3 (Q3)) were used for TSH and FT4. The chi-square test was performed to analyze differences in the prevalence of thyroid function. Results: Median Pictorial Blood loss Assessment Chart-score was 285 (IQR: ), 33% of patients had anemia (Hemoglobin <12 g/dl). Overt hypothyroidism (TSH>4.0 mu/l; FT4<11.0 pmol/l) was not seen in the patients, as opposed to 0.4% of the reference group (p=0.35). In the patients subclinical hypothyroidism (TSH>4.0 mu/l; FT pmol/l) was present in 5.4% versus 4.3% of controls (p=0.44). Overt (TSH<0.5 mu/l; FT4>19.5 pmol/l) and subclinical (TSH<0.5 mu/l; FT pmol/l ) hyperthyroidism was found in 1.5% and 2.0% of the patients, vs 0.6% (p=0.16) and 0.8% (p=0.08) in controls, respectively. No significant differences in thyroid function were seen between patients with and without gynecological abnormalities or those with and without coagulation disorders. Conclusion: Thyroid dysfunction occurs in women with heavy menstrual bleeding, but not more often than in the general population. Thyroid function should not be routinely measured in women with heavy menstrual bleeding. 94

4 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding Introduction Heavy menstrual bleeding (HMB) is a common problem among women in the reproductive age. An estimated 13-35% of women report HMB 1, 2 and every year, 5% of women between 30 and 49 years old consult a physician for HMB 3. Heavy menstrual bleeding is known to be associated with gynecological abnormalities like uterine fibroids, endometrial polyps and adenomyosis. However, HMB can also have a systemic cause, such as a bleeding disorder 4, 5, hormone dysbalance 6 or thyroid dysfunction. Thyroid disease is the second most common endocrine disease in women of reproductive age and has long been linked to menstrual disturbances 7. Thyroid stimulating hormone has both follicle-stimulating hormone and luteinizing hormonelike effects through their shared α subunit. As a result, negative feedback is downregulated, leading to a decreased secretion of luteinizing hormone and an ensuing decrease in progesterone. At the same time, decreased sex hormone binding globulin results in increased serum estriol and unbound estradiol, which in turn leads to elevated levels of circulating free estrogens. This prolonged, unopposed effect on the endometrium results in failure of anovulation and corpus luteum formation, ultimately leading to menometrorrhagia 7, 8. American guidelines advise to measure the thyroid function in women with HMB 9, 10. In contrast, routine testing of thyroid function is not included in the current guideline Heavy menstrual bleeding (2013) of the Dutch association of Obstetrics and Gynecologists 11. The NICE guideline does also not recommend routine testing of Chapter 6 thyroid function 12. An explanation for the discrepancy between the various guidelines could be the lack of good quality evidence of the role of thyroid function in HMB. Several studies have been performed on thyroid function and menstrual blood loss, but no objective measurements of menstrual blood loss were reported or the sample sizes were small 8, 13, 14. Therefore we studied thyroid function in a large cohort of women with heavy menstrual bleeding with validated measurements of blood loss, gynecological examination and analysis of other systemic causes of heavy menstrual bleeding. We 95

5 Chapter 6 compared the prevalence of thyroid dysfunction in women with heavy menstrual bleeding with that in the general population. Methods Patients & controls Between March 2007 and March 2015, we included 205 consecutive patients who were referred to the University Medical Center of Groningen (UMCG) in a study on systemic causes of HMB (see figure 1). Inclusion criterium was a history of heavy, regular (every days) menstrual periods. Exclusion criteria were: Pictorial Blood loss Chart-score <100 (see below), known bleeding disorder, use of any intrauterine device within 2 months prior to inclusion, and treatment with antifibrinolytics, anticoagulants, non-steroidal anti-inflammatory agents, progestagens or combined oral contraceptives. Referred patients who were potentially eligible received a structured questionnaire by mail to obtain information about baseline characteristics: medical, obstetrical and gynecological history and previous treatment for heavy menstrual bleeding. Eligible women were invited to our clinic and underwent a gynecological examination and pelvic ultrasonography in the first week after their menstruation. This study was approved by the Institutional Review Board of the University Medical Center of Groningen. Informed consent was obtained from all patients. This study is part of a project on systemic causes of heavy menstrual bleeding. We previously published on prevalence of coagulation disorders in a part of this cohort 15. Data were compared to data from the general population. These data were obtained from the Nijmegen Biomedical Study (NBS), a population-based survey conducted by the Department for Health Evidence and the Department of Laboratory Medicine of the Radboud university medical center. In 2002, age and sex stratified randomly selected inhabitants of the municipality of Nijmegen received an invitation to fill out a postal questionnaire on, e.g., lifestyle and medical history, and to donate an 8.5 ml blood sample in a serum separator tube and a 10 ml EDTA blood sample. The response to the questionnaire was 43% (N=9350). Sixty nine percent (N=6468) of the responders donated blood samples. Hoogendoorn et al. 16 described 96

6 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding the thyroid function in this group. We extracted the subgroup of women aged years for comparison to our patient group (n=205). Pictorial Blood loss Assessment Chart-score Patients received a letter with information and instructions on the Pictorial Blood loss Assessment Chart (PBAC) 17, 18, prior to their first clinic visit. The accompanying PBAC was filled out in the menses before their hospital appointment. A PBAC-score of 100 based on the scoring system of Higham et al. 18 was defined as heavy menstrual bleeding. Laboratory measurements Venous blood was collected from the antecubital vein with a vacuum system in the first week after menstruation. The blood samples were taken before the gynecological examination. Serum thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) were measured with the Modular Analyzer with a two-sided electrochemiluminescence immunoassay (Roche, Mannheim, Germany). The reference interval used in our laboratory for TSH is mu/l and for FT pmol/l. Blood samples were also obtained for complete blood cell counts, ferritin, prothrombin time, activated partial thromboplastin time, fibrinogen, platelet aggregations, von Willebrand factor, factor VIII, factor IX, factor XI, factor XII and factor XIII, as described previously 15. Chapter 6 Details of laboratory measurements of TSH and FT 4 in the Nijmegen Biomedical Study were described previously 16. Data analysis Hypothyroidism was classified as overt if TSH was >4.0 mu/l and FT 4 was <11.0 pmol/l and as subclinical if TSH was >4.0 mu/l and FT 4 was 11.0 pmol/l. Hyperthyroidism was classified as overt if TSH was <0.5 mu/l and FT 4 was >19.5 pmol/l and as subclinical if TSH was <0.5 mu/l and FT 4 was 19.5 pmol/l. Thyroid pathology was defined as reporting thyroid disease, history of thyroid 97

7 Chapter 6 surgery, and/or use of l-thyroxine and/or thyrostatic drugs. Subgroup analyses were performed, in patients with and without coagulation disorders, and in patients with and without gynecological abnormalities. Coagulation disorders were platelet function defects, decreased von Willebrand factor, and/or coagulation factor deficiencies. Platelet function defects were defined as defects in one or more platelet aggregation tests (5 different agonists used). Low von Willebrand factor was defined as von Willebrand factor antigen (VWF:Ag) and/or von Willebrand ristocetin cofactor (VWF: RCo) < 50%. Coagulation factor deficiencies were defined as FVII <65%, FVIII < 50%, FIX <65% and FXI <65%, based on local normal reference values. Submucous uterine fibroids more than 2 cm in diameter or uterine polyps were considered as gynecological abnormalities. For the patient population we merged two cohorts (Registration number at the Institutional Review Board of the University Medical Center of Groningen: NL and NL ), powered for other outcomes. For this study the number of patients was therefore not powered for a significant difference in thyroid dysfunction at the start of the study. Descriptive statistics were computed for all study variables. Continuous variables, expressed as medians (Inter quartile range (IQR): quartile 1 (Q1)- quartile 3 (Q3)) were used for TSH and FT4 of the patients. The chi-square test was performed to analyze differences in the prevalence of thyroid function both in the whole study population and in subgroup analyses. A p-value of 0.05 was considered statistically significant. Data were analyzed using SPSS statistics 22 (SPSS Inc., Chicago, IL). Results We measured TSH and FT 4 in 203 of the 205 women with HMB. The included patients with heavy menstrual bleeding had a median pictorial bleeding assessment chart-score of 285 (Q1-Q3: ) and 33% had anemia (Hb<12 g/dl). The baseline characteristics of the patients and reference group are described in table 1. Overt hypothyroidism was not seen in the patient group, as opposed to 0.4% in the reference group (p=0.35). In the patients subclinical hypothyroidism was present in 5.4% compared to 4.3% in the reference group (p=0.44). Overt and subclinical 98

8 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding hyperthyroidism was found in 1.5% and 2.0% of patients, vs 0.6% (p=0.16) and 0.8% (p=0.08) in the reference group, respectively. There are also no significant differences in thyroid dysfunction when limiting the analysis to patients without either gynecological abnormalities or coagulation disorders (N = 103) compared to the reference group. Subgroup analyses No differences in thyroid function were seen between patients with and without gynecological abnormalities or those with and without coagulation disorders (Table 2 and 3). Discussion Main Findings We observed that the prevalence of thyroid dysfunction in women with HMB did not differ from the prevalence in the general population. The prevalence of subclinical hypothyroidism was relatively high in both women with HMB and the general population. Overt thyroid dysfunction is rare, both in patients with HMB and the general population. We hypothesized that if thyroid dysfunction were relevant, this would be most clear in those patients with no other explanations for HMB. However, our subgroup (with and without gynecological abnormalities and with and without coagulation Chapter 6 disorders) analyses did not identify conditions under which additional measurements of thyroid function are warranted. These observations reinforce the notion that in patients with HMB measurements for thyroid function have no added value. Strengths and Limitations Strengths of our study are the application of a validated method (PBAC-score) for heavy menstrual bleeding; it therefore provides a objective way into the severity of the amount of blood loss, contrary to existing studies 13, 14. These studies used subjective bleeding definitions. However, women s own subjective assessment of 99

9 Chapter 6 bleeding heaviness is often differs from measured blood loss 19. We choose not to correct for (thyroid) medication, as this was also not done in the reference group. If the patient uses thyroid medication and is well controlled, the patient is comparable to the general population 16. Therefore, correction is not necessary. In our study we did not have a direct control group, which can be seen as a weakness of our study. However, our reference group consists of a large Dutch cohort, which is drawn from the same population as our study. As these groups are similar, this negates the necessity of direct controls. Also, the prevalence of thyroid dysfunction in the reference group is comparable to the prevalence in other population wide thyroid function studies Interpretation From our study, we can confidently say that the prevalence of (subclinical) hypothyroidism is not higher in our patients than in the general population. For hyperthyroidism, however, our study is less well powered. Similar to the general population, (subclinical) hyperthyroidism has a lower prevalence among patients with HMB than (subclinical) hypothyroidism 20, 21, 23. To enable definitive conclusions on the relative prevalence of hyperthyroidism in patients with HMB and the general population, a much larger sample size would be required. However, hypothyroidism has been reported to be more strongly implicated in HMB than hyperthyroidism, which makes such a study less relevant from a clinical perspective 8, 13. Previous studies have described (subclinical) hypothyroidism related to HMB 8, 13. Unfortunately, these studies did not use the same tests that are used in clinical practice and in our study. In the study of Wilansky 8 22% of women with HMB were classified as having mild primary hypothyroidism, classified by a positive thyrotropinreleasing hormone test. These women had a small but significant elevation of basal levels of TSH and lowering of FT 4 levels compared to the women with a negative thyrotropin-releasing hormone test, but their results were still within the reference range and patients were not classified on their own ratio of TSH/FT 4. Blum 13 showed significant higher levels of TSH in women with menorrhagia compared to the controls, 100

10 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding although the levels were within the reference range. In ten patients who were in the highest quartile of TSH a thyrotropin-releasing hormone test was performed. All of these women were classified as having occult hypothyroidism by a positive test, but the thyrotropin-releasing hormone test was not performed in their control group. Because thyrotropin-releasing hormone tests are no longer a regular diagnostic tool we did not perform these in our study. We did also not compare the average TSH and FT 4 values in the general population with the TSH and FT 4 of the patients, as these average values do not reflect the classification of individual patient values, which are of clinical importance. Conclusion Our data do not support the routine use of thyroid function tests in women with heavy menstrual bleeding. Testing for thyroid function is indicated only when there are clear symptoms of thyroid disease. Acknowledgements We thank professor Ate J.G. van der Zee and professor Hanneke C. Kluin-Nelemans for their contribution to this manuscript. The Nijmegen Biomedical Study is a population based survey conducted at the Department for Health Evidence, and the Department of Laboratory Medicine of the Radboud university medical center. Principal investigators of the Nijmegen Biomedical Study are Lambertus Kiemeney, André Verbeek, Dorine Swinkels and Barbara Franke. Chapter 6 101

11 Chapter 6 Figure 1: Study flowchart. Legend: HMB: heavy menstrual bleeding; PBAC: Pictorial Blood loss Assessment Chart; * postmenopausal, postcoital or intermenstrual blood loss, anticoagulations, chronic non steroidal anti-inflammatory agents use; PBAC<100; bleeding disorder; IUD or progestagens ** postcoital or intermenstrual blood loss, anticoagulations. Table 1: Baseline characteristics. Patients (n=203) Reference group (n=1924) Median age in years (range) 43 (18-55) 39 (18-55) Thyroid pathology in % (n) 7.4 (15) 4.8 (93) Legend: In patients reference values for TSH were mu/l and for FT 4 were pmol/l; In the reference group reference values for TSH were miu/l and for FT 4 were pmol/l. Thyroid pathology was defined as reporting thyroid disease, thyroid surgery, and/or use of l-thyroxine and/or thyrostatic drugs. 102

12 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding Table 2: Thyroid function in patients with and without gynecological abnormalities. No gynecological abnormalities Gynecological abnormalities (n=63) p-value (n=140) Median TSH in mu/l, (IQR) 1.82 ( ) 1.71 ( ) 0.86 Median FT 4 in pmol/l, (IQR) 15.7 ( ) 15.4 ( ) 0.56 Hypothyroidism, % (n) 0 (0) 0 (0) - Subclinical hypothyroidism, 4.3 (6) 7.9 (5) 0.37 % (n) Hyperthyroidism, % (n) 2.1 (3) 0 (0) 0.24 Subclinical hyperthyroidism, 2.1 (3) 1.6 (1) 0.77 % (n) Legend: Hypothyroidism is defined as TSH>4.0 mu/l and FT 4 <11.0 pmol/l; subclinical hypothyroidism is defined as TSH>4.0 mu/l and FT pmol/l; hyperthyroidism is defined as TSH<0.5 mu/l and FT 4 >19.5 pmol/l; subclinical hyperthyroidism is defined as TSH<0.5 mu/l and FT pmol/l. Table 3: Thyroid function in patients with and without coagulation disorder. No coagulation Coagulation p-val- disorder (n=154) disorder (n=49) ue Medianv TSH in mu/l, (IQR) 1.75 ( ) 1.97 ( ) 0.54 Median FT 4 in pmol/l, (IQR) 15.7 ( ) 15.3 ( ) 0.33 Hypothyroidism, % (n) 0 (0) 0 (0) - Chapter 6 Subclinical hypothyroidism, % (n) 5.8 (9) 4.1 (2) 0.64 Hyperthyroidism, % (n) 1.3 (2) 2.0 (1) 0.71 Subclinical hyperthyroidism, % (n) 1.3 (2) 4.1 (2) 0.22 Subclinical hyperthyroidism, % (n) 2.1 (3) 1.6 (1) 0.77 Legend: Hypothyroidism is defined as TSH>4.0 mu/l and FT 4 <11.0 pmol/l; subclinical hypothyroidism is defined as TSH>4.0 mu/l and FT pmol/l; hyperthyroidism is defined as TSH<0.5 mu/l and FT 4 >19.5 pmol/l; subclinical hyperthyroidism is defined as TSH<0.5 mu/l and FT pmol/l. 103

13 Chapter 6 Table 4: Thyroid function in patients without gynecological abnormalities and without coagulation disorder compared to the reference group. Patients with no gynecological abnormalities and no coagulation Reference group (N=1924) p-value disorder (N=103) Hypothyroidism, % (n) 0 (0) 0.4 (8).51 Subclinical hypothyroidism, % (n) 3.9 (4) 4.4 (82).85 Hyperthyroidism, % (n) 1.9 (2) 0.6 (12).12 Subclinical hyperthyroidism, % (n) 1.9 (2) 0.8 (15).21 Legend: Hypothyroidism is defined as TSH>4.0 mu/l and FT 4 <11.0 pmol/l; subclinical hypothyroidism is defined as TSH>4.0 mu/l and FT pmol/l; hyperthyroidism is defined as TSH<0.5 mu/l and FT 4 >19.5 pmol/l; subclinical hyperthyroidism is defined as TSH<0.5 mu/l and FT pmol/l. 104

14 Prevalence of thyroid dysfunction is not increased in women with heavy menstrual bleeding References Santer M, Warner P, Wyke S. A Scottish postal survey suggested that the prevailing clinical preoccupation with heavy periods does not reflect the epidemiology of reported symptoms and problems. J Clin Epidemiol 2005 Nov;58(11): Cote I, Jacobs P, Cumming DC. Use of health services associated with increased menstrual loss in the United States. Am J Obstet Gynecol 2003 Feb;188(2): Warner P, Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray G. Referral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management. BMJ 2001 Jul 7;323(7303): Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev 2000;(2):CD Clarke A, Black N, Rowe P, Mott S, Howle K. Indications for and outcome of total abdominal hysterectomy for benign disease: a prospective cohort study. Br J Obstet Gynaecol 1995 Aug;102(8): Ray S, Ray A. Non-surgical interventions for treating heavy menstrual bleeding (menorrhagia) in women with bleeding disorders. Cochrane Database Syst Rev 2014 Nov 26;11:CD Kronenberg HM, Melmed S, Polonsky KS, Larsen PR editors. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders Elsevier. Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. Am J Obstet Gynecol 1989 Mar;160(3): Colletti L, Schanbacher A, Scholz E, Scrimpsher L, Wilder O. Evaluation and management of ovulatory heavy menstrual bleeding (HMB) in primary care. 2012; Available at: Accessed 07/29, Committee on Practice Bulletins-Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol 2012 Jul;120(1): Hehenkamp WJK, Reekers JA, Ankum WM, Coppus SFPJ, Janssen CAH, Lohle PNM, et al. Dutch guideline: Hevig menstrueel bloedverlies (HMB). 2013; Available at: ws% pdf. Accessed 08/04, National Institute for Health and Care Excellence (NICE). Heavy menstrual bleeding (Clinical Guideline 44). January 2007; Available at: guidance.nice.org.uk/cg44. Accessed 07/20, Blum M, Blum G. The possible relationship between menorrhagia and occult hypothyroidism in IUD-wearing women. Adv Contracept 1992 Dec;8(4): Attia AH, Youssef D, Hassan N, El-Meligui M, Kamal M, Al-Inany H. Subclinical hyperthyroidism as a potential factor for dysfunctional uterine bleeding. Gynecol Endocrinol 2007 Feb;23(2): Knol HM, Mulder AB, Bogchelman DH, Kluin-Nelemans HC, van der Zee AG, Meijer K. The prevalence of underlying bleeding disorders in patients with heavy menstrual bleeding with and without gynecologic abnormalities. Am J Obstet Gynecol 2013 Sep;209(3):202.e1-202.e7. Hoogendoorn EH, Hermus AR, de Vegt F, Ross HA, Verbeek AL, Kiemeney LA, et al. Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex. Clin Chem 2006 Jan;52(1): Janssen CA, Scholten PC, Heintz AP. Reconsidering menorrhagia in gynecological practice. Is a 30-year-old definition still valid? Eur J Obstet Gynecol Reprod Biol 1998 May;78(1): Higham JM, O Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990 Aug;97(8): Chimbira TH, Anderson AB, Turnbull A. Relation between measured menstrual blood loss and patient s subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br J Obstet Gynaecol 1980 Jul;87(7): Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977 Dec;7(6): Chapter 6 105

15 Chapter Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med 1985 Aug;145(8): Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000 Feb 28;160(4): Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002 Feb;87(2):

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