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Semin Reprod Med 2011; 29(5): 400-409
DOI: 10.1055/s-0031-1287664
© Thieme Medical Publishers

Molecular and Cellular Causes of Abnormal Uterine Bleeding of Endometrial Origin

Hilary O.D Critchley1 , Jacqueline A. Maybin1
  • 1MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, Midlothian, United Kingdom
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Publication History

Publication Date:
07 November 2011 (online)

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ABSTRACT

Women today may reasonably anticipate in the order of some 400 menstrual cycles over their reproductive lifespan. The endometrium is thus subject to repeat cycles of shedding and repair and notably healing of the endometrium post menses is “scarless”. The local molecular and cellular mechanisms involved in post menstrual resolution of the inflammatory events associated with menstruation and endometrial repair remain to be fully determined. Menstrual complaints are common. It is highly likely that unrestrained local inflammatory events and/ or deficient repair processes within the endometrium contribute to the women's experience of heavy menstrual bleeding (HMB). The management of women with HMB may need to utilize therapeutic approaches that optimize endometrial repair processes, post menses. These approaches may be necessary in addition to current therapies that hitherto have focused on limiting the local inflammation associated with menstruation. Research endeavors thus need to focus upon the molecular and cellular causes of problematic uterine bleeding. Herein the events associated with pre-menstrual progesterone withdrawal, limitation of blood loss, the expression of vasoactive mediators and factors that may modulate vascular morphology are described. Such lines of enquiry and knowledge will be essential if novel targets for treatment of menstrual bleeding complaints, such as HMB, are to be identified.

KEYWORDS

Abnormal uterine bleeding - heavy menstrual bleeding - endometrium - mechanisms

REFERENCES

  • 1 Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life.  Int J Fertil. 1967;  12 (1 Pt 2) 77-126
    Google Scholar
  • 2 Maybin J, Critchley H. Repair and regeneration of the human endometrium.  Expert Rev Obstet Gynecol. 2009;  4 283-298
    Google Scholar
  • 3 Finn CA, Pope M. Control of leucocyte infiltration into the decidualized mouse uterus.  J Endocrinol. 1986;  110 (1) 93-96
    Google Scholar
  • 4 Salamonsen LA. Tissue injury and repair in the female human reproductive tract.  Reproduction. 2003;  125 (3) 301-311
    Google Scholar
  • 5 King AE, Critchley HO. Oestrogen and progesterone regulation of inflammatory processes in the human endometrium.  J Steroid Biochem Mol Biol. 2010;  120 (2–3) 116-126
    Google Scholar
  • 6 Maybin J. Secrets of the womb. The Max Perutz Prize 2009. Available at: http://wwwguardiancouk/education/2009/aug/31/max-perutz-science-writing-prize
    Google Scholar
  • 7 National Institute for Health and Clinical Excellence .Clinical Guideline 44; Heavy menstrual bleeding. Available at: http://www.nice.org.uk/nicemedia/pdf/CG44FullGuideline.pdf Accessed May 20, 2011
    Google Scholar
  • 8 Lethaby A, Hickey M, Garry R, Penninx J. Endometrial resection/ablation techniques for heavy menstrual bleeding.  Cochrane Database Syst Rev. 2009;  (4) CD001501
    Google Scholar
  • 9 Coulter A, Peto V, Doll H. Patients' preferences and general practitioners' decisions in the treatment of menstrual disorders.  Fam Pract. 1994;  11 (1) 67-74
    Google Scholar
  • 10 Cromwell DA, Mahmood TA, Templeton A, van der Meulen JH. Surgery for menorrhagia within English regions: variation in rates of endometrial ablation and hysterectomy.  BJOG. 2009;  116 (10) 1373-1379
    Google Scholar
  • 11 Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel.  Contraception. 2007;  75 (6, Suppl) S93-S98
    Google Scholar
  • 12 McLennan CE, Rydell AH. Extent of endometrial shedding during normal menstruation.  Obstet Gynecol. 1965;  26 (5) 605-621
    Google Scholar
  • 13 Gaide Chevronnay HP, Galant C, Lemoine P, Courtoy PJ, Marbaix E, Henriet P. Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium.  Endocrinology. 2009;  150 (11) 5094-5105
    Google Scholar
  • 14 Critchley HO, Kelly RW, Brenner RM, Baird DT. The endocrinology of menstruation—a role for the immune system.  Clin Endocrinol (Oxf). 2001;  55 (6) 701-710
    Google Scholar
  • 15 Critchley HO, Kelly RW, Baird DT, Brenner RM. Regulation of human endometrial function: mechanisms relevant to uterine bleeding.  Reprod Biol Endocrinol. 2006;  4 (Suppl 1) S5
    Google Scholar
  • 16 Ponnampalam AP, Weston GC, Trajstman AC, Susil B, Rogers PA. Molecular classification of human endometrial cycle stages by transcriptional profiling.  Mol Hum Reprod. 2004;  10 (12) 879-893
    Google Scholar
  • 17 Critchley HO, Robertson KA, Forster T, Henderson TA, Williams AR, Ghazal P. Gene expression profiling of mid to late secretory phase endometrial biopsies from women with menstrual complaint.  Am J Obstet Gynecol. 2006;  195 (2) 406 e1-e16
    Google Scholar
  • 18 Talbi S, Hamilton AE, Vo KC et al.. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.  Endocrinology. 2006;  147 (3) 1097-1121
    Google Scholar
  • 19 Fan X, Krieg S, Kuo CJ et al.. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium.  FASEB J. 2008;  22 (10) 3571-3580
    Google Scholar
  • 20 Galant C, Berlière M, Dubois D et al.. Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding.  Am J Pathol. 2004;  165 (1) 83-94
    Google Scholar
  • 21 Marbaix E, Kokorine I, Moulin P, Donnez J, Eeckhout Y, Courtoy PJ. Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases.  Proc Natl Acad Sci U S A. 1996;  93 (17) 9120-9125
    Google Scholar
  • 22 Critchley HO, Jones RL, Lea RG et al.. Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy.  J Clin Endocrinol Metab. 1999;  84 (1) 240-248
    Google Scholar
  • 23 Hannan NJ, Jones RL, Critchley HO et al.. Coexpression of fractalkine and its receptor in normal human endometrium and in endometrium from users of progestin-only contraception supports a role for fractalkine in leukocyte recruitment and endometrial remodeling.  J Clin Endocrinol Metab. 2004;  89 (12) 6119-6129
    Google Scholar
  • 24 Hapangama DK, Critchley HO, Henderson TA, Baird DT. Mifepristone-induced vaginal bleeding is associated with increased immunostaining for cyclooxygenase-2 and decrease in prostaglandin dehydrogenase in luteal phase endometrium.  J Clin Endocrinol Metab. 2002;  87 (11) 5229-5234
    Google Scholar
  • 25 Milne SA, Jabbour HN. Prostaglandin (PG) F(2alpha) receptor expression and signaling in human endometrium: role of PGF(2alpha) in epithelial cell proliferation.  J Clin Endocrinol Metab. 2003;  88 (4) 1825-1832
    Google Scholar
  • 26 Milne SA, Perchick GB, Boddy SC, Jabbour HN. Expression, localization, and signaling of PGE(2) and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle.  J Clin Endocrinol Metab. 2001;  86 (9) 4453-4459
    Google Scholar
  • 27 Sales KJ, List T, Boddy SC et al.. A novel angiogenic role for prostaglandin F2alpha-FP receptor interaction in human endometrial adenocarcinomas.  Cancer Res. 2005;  65 (17) 7707-7716
    Google Scholar
  • 28 Sales KJ, Maldonado-Pérez D, Grant V et al.. Prostaglandin F(2alpha)-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium-calcineurin-NFAT pathway.  Biochim Biophys Acta. 2009;  1793 (12) 1917-1928
    Google Scholar
  • 29 Keightley MC, Brown P, Jabbour HN, Sales KJ. F-Prostaglandin receptor regulates endothelial cell function via fibroblast growth factor-2.  BMC Cell Biol. 2010;  11 8
    Google Scholar
  • 30 Bonatz G, Hansmann ML, Buchholz F, Mettler L, Radzun HJ, Semm K. Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle.  Int J Gynaecol Obstet. 1992;  37 (1) 29-36
    Google Scholar
  • 31 Jones RL, Hannan NJ, Kaitu'u TJ, Zhang J, Salamonsen LA. Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation.  J Clin Endocrinol Metab. 2004;  89 (12) 6155-6167
    Google Scholar
  • 32 Critchley HO, Kelly RW, Brenner RM, Baird DT. Antiprogestins as a model for progesterone withdrawal.  Steroids. 2003;  68 (10–13) 1061-1068
    Google Scholar
  • 33 Salamonsen LA, Woolley DE. Menstruation: induction by matrix metalloproteinases and inflammatory cells.  J Reprod Immunol. 1999;  44 (1–2) 1-27
    Google Scholar
  • 34 Salamonsen LA, Lathbury LJ. Endometrial leukocytes and menstruation.  Hum Reprod Update. 2000;  6 (1) 16-27
    Google Scholar
  • 35 Le Y, Zhou Y, Iribarren P, Wang J. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease.  Cell Mol Immunol. 2004;  1 (2) 95-104
    Google Scholar
  • 36 Kaitu'u-Lino TJ, Morison NB, Salamonsen LA. Neutrophil depletion retards endometrial repair in a mouse model.  Cell Tissue Res. 2007;  328 (1) 197-206
    Google Scholar
  • 37 Wynn TA. Cellular and molecular mechanisms of fibrosis.  J Pathol. 2008;  214 (2) 199-210
    Google Scholar
  • 38 Eidukaite A, Tamosiunas V. Endometrial and peritoneal macrophages: expression of activation and adhesion molecules.  Am J Reprod Immunol. 2004;  52 (2) 113-117
    Google Scholar
  • 39 Markee JE. Menstruation in intraocular transplants in the rhesus monkey.  Contrib Embryol Carnegie Inst. 1940;  28 219-308
    Google Scholar
  • 40 Smith SK. Regulation of angiogenesis in the endometrium.  Trends Endocrinol Metab. 2001;  12 (4) 147-151
    Google Scholar
  • 41 Abel MH, Zhu C, Baird DT. An animal model to study menstrual bleeding.  Res Clin Forums. 1982;  4 25-34
    Google Scholar
  • 42 Pickles VR. A plain-muscle stimulant in the menstruum.  Nature. 1957;  180 (4596) 1198-1199
    Google Scholar
  • 43 O'Reilly G, Charnock-Jones DS, Davenport AP, Cameron IT, Smith SK. Presence of messenger ribonucleic acid for endothelin-1, endothelin-2, and endothelin-3 in human endometrium and a change in the ratio of ETA and ETB receptor subtype across the menstrual cycle.  J Clin Endocrinol Metab. 1992;  75 (6) 1545-1549
    Google Scholar
  • 44 Ahmed A, Li XF, Shams M et al.. Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site.  J Clin Invest. 1995;  96 (2) 848-857
    Google Scholar
  • 45 Hellebrekers BW, Trimbos-Kemper TC, Trimbos JB, Emeis JJ, Kooistra T. Use of fibrinolytic agents in the prevention of postoperative adhesion formation.  Fertil Steril. 2000;  74 (2) 203-212
    Google Scholar
  • 46 Gleeson N, Devitt M, Sheppard BL, Bonnar J. Endometrial fibrinolytic enzymes in women with normal menstruation and dysfunctional uterine bleeding.  Br J Obstet Gynaecol. 1993;  100 (8) 768-771
    Google Scholar
  • 47 Nordengren J, Pilka R, Noskova V et al.. Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1) mRNA and protein in endometrial tissue during the menstrual cycle.  Mol Hum Reprod. 2004;  10 (9) 655-663
    Google Scholar
  • 48 Christiaens GC, Sixma JJ, Haspels AA. Morphology of haemostasis in menstrual endometrium.  Br J Obstet Gynaecol. 1980;  87 (5) 425-439
    Google Scholar
  • 49 Gleeson NC, Buggy F, Sheppard BL, Bonnar J. The effect of tranexamic acid on measured menstrual loss and endometrial fibrinolytic enzymes in dysfunctional uterine bleeding.  Acta Obstet Gynecol Scand. 1994;  73 (3) 274-277
    Google Scholar
  • 50 Preston JT, Cameron IT, Adams EJ, Smith SK. Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia.  Br J Obstet Gynaecol. 1995;  102 (5) 401-406
    Google Scholar
  • 51 Ludwig H, Spornitz UM. Microarchitecture of the human endometrium by scanning electron microscopy: menstrual desquamation and remodeling.  Ann N Y Acad Sci. 1991;  622 28-46
    Google Scholar
  • 52 Cao W, Mah K, Carroll RS, Slayden OD, Brenner RM. Progesterone withdrawal up-regulates fibronectin and integrins during menstruation and repair in the rhesus macaque endometrium.  Hum Reprod. 2007;  22 (12) 3223-3231
    Google Scholar
  • 53 Tresserra F, Grases P, Ubeda A, Pascual MA, Grases PJ, Labastida R. Morphological changes in hysterectomies after endometrial ablation.  Hum Reprod. 1999;  14 (6) 1473-1477
    Google Scholar
  • 54 Wood C, Rogers P. A pregnancy after planned partial endometrial resection.  Aust N Z J Obstet Gynaecol. 1993;  33 (3) 316-318
    Google Scholar
  • 55 Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle.  Am J Obstet Gynecol. 1979;  133 (8) 859-867
    Google Scholar
  • 56 Padykula HA, Coles LG, Okulicz WC et al.. The basalis of the primate endometrium: a bifunctional germinal compartment.  Biol Reprod. 1989;  40 (3) 681-690
    Google Scholar
  • 57 Gargett CE, Masuda H. Adult stem cells in the endometrium.  Mol Hum Reprod. 2010;  16 (11) 818-834
    Google Scholar
  • 58 Lumsden MA, Kelly RW, Baird DT. Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2 alpha.  Br J Obstet Gynaecol. 1983;  90 (12) 1135-1140
    Google Scholar
  • 59 Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding.  Br J Obstet Gynaecol. 1981;  88 (4) 434-442
    Google Scholar
  • 60 Willman EA, Collins WP, Clayton SG. Studies in the involvement of prostaglandins in uterine symptomatology and pathology.  Br J Obstet Gynaecol. 1976;  83 (5) 337-341
    Google Scholar
  • 61 Baird DT, Cameron ST, Critchley HO et al.. Prostaglandins and menstruation.  Eur J Obstet Gynecol Reprod Biol. 1996;  70 (1) 15-17
    Google Scholar
  • 62 Smith OP, Jabbour HN, Critchley HO. Cyclooxygenase enzyme expression and E series prostaglandin receptor signalling are enhanced in heavy menstruation.  Hum Reprod. 2007;  22 (5) 1450-1456
    Google Scholar
  • 63 Smith SK, Abel MH, Kelly RW, Baird DT. A role for prostacyclin (PGi2) in excessive menstrual bleeding.  Lancet. 1981;  1 (8219) 522-524
    Google Scholar
  • 64 Battersby S, Critchley HO, de Brum-Fernandes AJ, Jabbour HN. Temporal expression and signalling of prostacyclin receptor in the human endometrium across the menstrual cycle.  Reproduction. 2004;  127 (1) 79-86
    Google Scholar
  • 65 Murata T, Ushikubi F, Matsuoka T et al.. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor.  Nature. 1997;  388 (6643) 678-682
    Google Scholar
  • 66 Ueno A, Naraba H, Ikeda Y et al.. Intrinsic prostacyclin contributes to exudation induced by bradykinin or carrageenin: a study on the paw edema induced in IP-receptor-deficient mice.  Life Sci. 2000;  66 (12) PL155-PL160
    Google Scholar
  • 67 Smith OP, Battersby S, Sales KJ, Critchley HO, Jabbour HN. Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor receptor and the extracellular signaling receptor kinase 1/2 pathway.  Endocrinology. 2006;  147 (4) 1697-1705
    Google Scholar
  • 68 Marsh MM, Malakooti N, Taylor NH, Findlay JK, Salamonsen LA. Endothelin and neutral endopeptidase in the endometrium of women with menorrhagia.  Hum Reprod. 1997;  12 (9) 2036-2040
    Google Scholar
  • 69 Hurskainen R, Teperi J, Paavonen J, Cacciatore B. Menorrhagia and uterine artery blood flow.  Hum Reprod. 1999;  14 (1) 186-189
    Google Scholar
  • 70 Mints M, Hultenby K, Zetterberg E et al.. Wall discontinuities and increased expression of vascular endothelial growth factor-A and vascular endothelial growth factor receptors 1 and 2 in endometrial blood vessels of women with menorrhagia.  Fertil Steril. 2007;  88 (3) 691-697
    Google Scholar
  • 71 Girling JE, Rogers PA. Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin-TIE signalling system.  Reproduction. 2009;  138 (6) 883-893
    Google Scholar
  • 72 Abberton KM, Healy DL, Rogers PA. Smooth muscle alpha actin and myosin heavy chain expression in the vascular smooth muscle cells surrounding human endometrial arterioles.  Hum Reprod. 1999;  14 (12) 3095-3100
    Google Scholar
  • 73 Kooy J, Taylor NH, Healy DL, Rogers PA. Endothelial cell proliferation in the endometrium of women with menorrhagia and in women following endometrial ablation.  Hum Reprod. 1996;  11 (5) 1067-1072
    Google Scholar
  • 74 Hewett P, Nijjar S, Shams M, Morgan S, Gupta J, Ahmed A. Down-regulation of angiopoietin-1 expression in menorrhagia.  Am J Pathol. 2002;  160 (3) 773-780
    Google Scholar
  • 75 Malik S, Day K, Perrault I, Charnock-Jones DS, Smith SK. Reduced levels of VEGF-A and MMP-2 and MMP-9 activity and increased TNF-alpha in menstrual endometrium and effluent in women with menorrhagia.  Hum Reprod. 2006;  21 (8) 2158-2166
    Google Scholar
  • 76 Arkonac BM, Foster LC, Sibinga NE et al.. Vascular endothelial growth factor induces heparin-binding epidermal growth factor-like growth factor in vascular endothelial cells.  J Biol Chem. 1998;  273 (8) 4400-4405
    Google Scholar
  • 77 Blum S, Issbrüker K, Willuweit A et al.. An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression.  J Biol Chem. 2001;  276 (36) 33428-33434
    Google Scholar
  • 78 Cullen W. Of the menorrhagia, or the immoderate flow of the menses. In: First Lines of the Practice of Physic. Vol 3, Part 1, Book IV. Edinburgh, Scotland: Bell & Bradfute; 1796
    Google Scholar
  • 79 Huang KC. The Pharmacology of Chinese Herbs. London, UK; Tokyo, Japan: CRC Press; 1993: 275-278
    Google Scholar
  • 80 Small GR, Hadoke PW, Sharif I et al.. Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis.  Proc Natl Acad Sci U S A. 2005;  102 (34) 12165-12170
    Google Scholar
  • 81 McDonald SE, Henderson TA, Gomez-Sanchez CE, Critchley HO, Mason JI. 11Beta-hydroxysteroid dehydrogenases in human endometrium.  Mol Cell Endocrinol. 2006;  248 (1-2) 72-78
    Google Scholar
  • 82 Rae M, Mohamad A, Price D et al.. Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation.  J Clin Endocrinol Metab. 2009;  94 (4) 1443-1450
    Google Scholar
  • 83 Lee T, Nesselroth SM, Olson ET et al.. Thrombospondin-1-induced vascular smooth muscle cell chemotaxis: the role of the type 3 repeat and carboxyl terminal domains.  J Cell Biochem. 2003;  89 (3) 500-506
    Google Scholar
  • 84 Girling JE, Rogers PA. Recent advances in endometrial angiogenesis research.  Angiogenesis. 2005;  8 (2) 89-99
    Google Scholar
  • 85 Munro MG. Abnormal Uterine Bleeding. Cambridge, UK: Cambridge University Press; 2010
    Google Scholar
  • 86 Lacey Jr JV, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma.  Maturitas. 2009;  63 (1) 39-44
    Google Scholar
  • 87 Hamou JE. Hysteroscopy and Microcolpohysteroscopy. Norwalk, CT: Appleton and Lange; 1992
    Google Scholar
  • 88 Livingstone M, Fraser IS. Mechanisms of abnormal uterine bleeding.  Hum Reprod Update. 2002;  8 (1) 60-67
    Google Scholar
  • 89 Fraser IS, Baird DT. Endometrial cystic glandular hyperplasia in adolescent girls.  J Obstet Gynaecol Br Commonw. 1972;  79 (11) 1009-1015
    Google Scholar
  • 90 Fraser IS, Michie EA, Wide L, Baird DT. Pituitary gonadotropins and ovarian function in adolescent dysfunctional uterine bleeding.  J Clin Endocrinol Metab. 1973;  37 (3) 407-414
    Google Scholar
  • 91 Van Look PF, Hunter WM, Fraser IS, Baird DT. Impaired estrogen-induced luteinizing hormone release in young women with anovulatory dysfunctional uterine bleeding.  J Clin Endocrinol Metab. 1978;  46 (5) 816-823
    Google Scholar
  • 92 Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome.  Best Pract Res Clin Obstet Gynaecol. 2004;  18 (5) 671-683
    Google Scholar
  • 93 Claessens EA, Cowell CA. Acute adolescent menorrhagia.  Am J Obstet Gynecol. 1981;  139 (3) 277-280
    Google Scholar
  • 94 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 (1) 50-59
    Google Scholar
  • 95 Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle.  Fertil Steril. 2003;  80 (1) 116-122
    Google Scholar
  • 96 Hale GE, Manconi F, Luscombe G, Fraser IS. Quantitative measurements of menstrual blood loss in ovulatory and anovulatory cycles in middle- and late-reproductive age and the menopausal transition.  Obstet Gynecol. 2010;  115 (2 Pt 1) 249-256
    Google Scholar
  • 97 Brown JB, Kellar R, Matthew GD. Preliminary observations on urinary oestrogen excretion in certain gynaecological disorders.  J Obstet Gynaecol Br Emp. 1959;  66 (2) 177-211
    Google Scholar
  • 98 Fraser IS, Baird DT. Blood production and ovarian secretion rates of estradiol-17 beta and estrone in women with dysfunctional uterine bleeding.  J Clin Endocrinol Metab. 1974;  39 (3) 564-570
    Google Scholar

Hilary O.D. CritchleyM.D. 

MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute

47 Little France Crescent, Edinburgh, Midlothian EH16 4TJ, UK

Email: hilary.critchley@ed.ac.uk

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