ABSTRACT
Uterine fibroids are common but their role in infertility and effect on embryo implantation
is unclear. There is evidence that submucosal fibroids are associated with poor reproductive
outcome and that treatment with myomectomy is associated with an improvement in pregnancy
rates. Various theories have been proposed to explain this relationship. Fibroids
cause a mechanical distortion of the endometrial cavity-their presence may alter gamete
and embryo transport (due to blockage of the tubal ostia or by altering uterine contractility
and peristalsis) and subsequent embryo implantation (due to compression of the endometrium).
They may lead to disruption of the junctional zone within the myometrial layer, affecting
general uterine function in the initial stages of embryo invasion and later placentation.
Altered vasculature due to the abnormal expression of angiogenic factors by uterine
fibroids (such as basic fibroblast growth factor and platelet-derived growth factor)
could play a role in a reduced implantation rate in patients with fibroids. Similarly,
changes in the endometrium mediated by inflammation and factors involved in the process
of fibrosis (such as transforming growth factor) could also have a detrimental effect.
In addition, fibroids may affect gene expression pattern in the endometrium (such
as HOXA10 ), disrupting the window of implantation. The supporting evidence for these theories
is discussed in this review.
KEYWORDS
Uterine fibroids - implantation - pregnancy - angiogenesis - fibrosis
REFERENCES
1
Cramer S F, Horiszny J A, Leppert P.
Epidemiology of uterine leiomyomas. With an etiologic hypothesis.
J Reprod Med.
1995;
40(8)
595-600
2
Payson M, Leppert P, Segars J.
Epidemiology of myomas.
Obstet Gynecol Clin North Am.
2006;
33(1)
1-11
3
Stewart E A.
Uterine fibroids.
Lancet.
2001;
357(9252)
293-298
4
Townsend D E, Sparkes R S, Baluda M C, McClelland G.
Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis by
glucose-6-phosphate dehydrogenase.
Am J Obstet Gynecol.
1970;
107
1168-1173
5
Rein M S, Friedman A J, Barbieri R L, Pavelka K, Fletcher J A, Morton C C.
Cytogenic abnormalities in uterine leiomyomata.
Obstet Gynecol.
1991;
77
923-926
6
Linder D, Gartler S M.
Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study
of leiomyomas.
Science.
1965;
150
67-69
7
Mashal R D, Fejzo M L, Friedman A J et al..
Analysis of androgen receptor DNA reveals the independent clonal origins of uterine
leiomyomata and the secondary nature of cytogenetic aberrations in the development
of leiomyomata.
Genes Chromosomes Cancer.
1994;
11
1-6
8
Pollow K, Sinnecker G, Boquoi E, Pollow B.
In vitro conversion of estradiol-17beta into estrone in normal human myometrium and
leiomyoma.
J Clin Chem Clin Biochem.
1978;
16
493-502
9
Fayed Y M, Tsibris J C, Langenberg P W, Robertson Jr A L.
Human uterine leiomyoma cells: binding and growth responses to epidermal growth factor,
platelet-derived growth factor, and insulin.
Lab Invest.
1989;
60
30-37
10
Lumsden M A, West C P, Hawkins R A, Bramley T A, Rumgay L, Baird D T.
The binding of steroids to myometrium and leiomyomata (fibroids) in women treated
with the gonadotrophin-releasing hormone agonist Zoladex (ICI 118630).
J Endocrinol.
1989;
121
389-396
11
Tommola P, Pekonen F, Rutanen E M.
Binding of epidermal growth factor and insulin-like growth factor I in human myometrium
and leiomyomata.
Obstet Gynecol.
1989;
74
658-662
12
Maruo T, Ohara N, Wang J, Matsuo H.
Sex steroidal regulation of uterine leiomyoma growth and apoptosis.
Hum Reprod Update.
2004;
10(3)
207-220
13
Shimomura Y, Matsuo H, Samoto T, Maruo T.
Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal
growth factor expression in human uterine leiomyoma.
J Clin Endocrinol Metab.
1998;
83(6)
2192-2198
14
Gao Z, Matsuo H, Nakago S, Kurachi O, Maruo T.
p53 Tumor suppressor protein content in human uterine leiomyomas and its down-regulation
by 17 beta-estradiol.
J Clin Endocrinol Metab.
2002;
87
3915-3920
15
Sasaki H, Ohara N, Xu Q et al..
A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured
human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
J Clin Endocrinol Metab.
2007;
92(2)
616-623
16
Catherino W, Salama A, Potlog-Nahari C, Leppert P, Tsibris J, Segars J.
Gene expression studies in leiomyomata: new directions for research.
Semin Reprod Med.
2004;
22(2)
83-90
17
Pritts E A.
Fibroids and infertility: a systematic review of the evidence.
Obstet Gynecol Surv.
2001;
56(8)
483-491
18
Neuwirth R S, Amin H K.
Excision of submucus fibroids with hysteroscopic control.
Am J Obstet Gynecol.
1976;
126(1)
95-99
19
Saridogan E, Cutner A.
Endoscopic management of uterine fibroids.
Hum Fertil (Camb).
2006;
9(4)
201-208
20
Buttram Jr V C, Reiter R C.
Uterine leiomyomata: etiology, symptomatology, and management.
Fertil Steril.
1981;
36(4)
433-445
21
Verkauf B S.
Myomectomy for fertility enhancement and preservation.
Fertil Steril.
1992;
58(1)
1-15
22
Vercellini P, Maddalena S, De Giorgi O, Aimi G, Crosignani P G.
Abdominal myomectomy for infertility: a comprehensive review.
Hum Reprod.
1998;
13(4)
873-879
23
Bajekal N, Li T C.
Fibroids, infertility and pregnancy wastage.
Hum Reprod Update.
2000;
6(6)
614-620
24
Hart R, Khalaf Y, Yeong C T, Seed P, Taylor A, Braude P.
A prospective controlled study of the effect of intramural uterine fibroids on the
outcome of assisted conception.
Hum Reprod.
2001;
16(11)
2411-2417
25
Donnez J, Jadoul P.
What are the implications of myomas on fertility? A need for a debate?.
Hum Reprod.
2002;
17(6)
1424-1430
26
Bulletti C, DE Ziegler D, Levi Setti P, Cicinelli E, Polli V, Stefanetti M.
Myomas, pregnancy outcome, and in vitro fertilization.
Ann N Y Acad Sci.
2004;
1034
84-92
27
Benecke C, Kruger T F, Siebert T I, Van der Merwe J P, Steyn D W.
Effect of fibroids on fertility in patients undergoing assisted reproduction. A structured
literature review.
Gynecol Obstet Invest.
2005;
59(4)
225-230
28
Klatsky P C, Lane D E, Ryan I P, Fujimoto V Y.
The effect of fibroids without cavity involvement on ART outcomes independent of ovarian
age.
Hum Reprod.
2007;
22(2)
521-526
29
Oliveira F G, Abdelmassih V G, Diamond M P, Dozortsev D, Melo N R, Abdelmassih R.
Impact of subserosal and intramural uterine fibroids that do not distort the endometrial
cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection.
Fertil Steril.
2004;
81(3)
582-587
30
Tulandi T.
Treatment of uterine fibroids-is surgery obsolete?.
N Engl J Med.
2007;
356(4)
411-413
31
Edwards R D, Moss J G, Lumsden M A Committee of the Randomized Trial of Embolization
versus Surgical Treatment for Fibroids et al..
Uterine-artery embolization versus surgery for symptomatic uterine fibroids.
N Engl J Med.
2007;
356(4)
360-370
32
Walker W J, McDowell S J.
Pregnancy after uterine artery embolisation for leiomyomata: a series of 56 completed
studies.
Am J Obstet Gynecol.
2006;
195
1266-1271
33
Pron G, Mocarski E, Bennett J et al..
Pregnancy after uterine artery embolisation for leiomyomata: the Ontario multicentre
trial.
Obstet Gynecol.
2005;
105
67-76
34
Huang J Y, Kafy S, Dugas A et al..
Failure of uterine fibroid embolisation.
Fertil Steril.
2006;
85
30-35
35
Olive D L, Lindheim S R, Pritts E A.
Non-surgical management of leiomyoma: impact on fertility.
Curr Opin Obstet Gynecol.
2004;
16(3)
239-243
36
Deligdish L, Loewenthal M.
Endometrial changes associated with myomata of the uterus.
J Clin Pathol.
1970;
23(8)
676-680
37
Hickey M, Fraser I S.
Clinical implications of disturbances of uterine vascular morphology and function.
Baillieres Best Pract Res Clin Obstet Gynaecol.
2000;
14(6)
937-951
38
Hunt J E, Wallach E E.
Uterine factors in infertility: an overview.
Clin Obstet Gynecol.
1974;
17
44-64
39
Vollenhoven B J, Lawrence A S, Healy D L.
Uterine fibroids: a clinical review.
Br J Obstet Gynaecol.
1990;
97
285-298
40
Nakai A, Togashi K, Ueda H, Yamaoka T, Fujii S, Konishi J.
Junctional zone on magnetic resonance imaging: continuous changes on ultrafast images.
J Womens Imaging.
2001;
3
89-93
41
Lyons E A, Taylor P J, Zheng X H, Ballard G, Levi C S, Kredentser J V.
Characterization of subendometrial myometrial contractions throughout the menstrual
cycle in normal fertile women.
Fertil Steril.
1991;
55
771-774
42
Ijland M M, Evers J L, Dunselman G A, Hoogland H J.
Endometrial wavelike activity, endometrial thickness, and ultrasound texture in controlled
ovarian hyperstimulation cycles.
Fertil Steril.
1998;
70
279-283
43
Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H.
Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid
sperm transport in patients with endometriosis and infertility.
Hum Reprod.
1996;
11
1542-1551
44
de Vries K, Lyons E A, Ballard G, Levi C S, Lindsay D J.
Contractions of the inner third of the myometrium.
Am J Obstet Gynecol.
1990;
162
679-682
45
Oike K, Ishihara K, Kikuchi S.
A study on the endometrial movement and serum hormonal level in connection with uterine
contraction.
Nippon Sanka Fujinka Gakkai Zasshi.
1990;
42
86-92
46
Brosens J J, Barker F G, de Souza N M.
Myometrial zonal differentiation and uterine junctional zone hyperplasia in the non-pregnant
uterus.
Hum Reprod Update.
1998;
4(5)
496-502
47
Wiczyk H P, Janus C L, Richards C J et al..
Comparison of magnetic resonance imaging and ultrasound in evaluating follicular and
endometrial development throughout the normal cycle.
Fertil Steril.
1988;
49(6)
969-972
48
Noe M, Kunz G, Herbertz M, Mall G, Leyendecker G.
The cyclic pattern of the immunocytochemical expression of oestrogen and progesterone
receptors in human myometrial and endometrial layers: characterization of the endometrial-subendometrial
unit.
Hum Reprod.
1999;
14(1)
190-197
49
Brosens J, Campo R, Gordts S, Brosens I.
Submucous and outer myometrium leiomyomas are two distinct clinical entities.
Fertil Steril.
2003;
79(6)
1452-1454
50
Sampson J A.
The blood supply of uterine myomata.
Surg Gynecol Obstet.
1912;
14
215-230
51
Stewart E A, Nowak R A.
Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era.
Hum Reprod Update.
1996;
2
295-306
52
Di Lieto A, De Falco M, Pollio F et al..
Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone
analogue-treated women with uterine myomas.
J Soc Gynecol Investig.
2005;
12(2)
123-128
53
Mangrulkar R S, Ono M, Ishikawa M, Takashima S, Klagsbrun M, Nowak R A.
Isolation and characterization of heparin-binding growth factors in human leiomyomas
and normal myometrium.
Biol Reprod.
1995;
53
636-646
54
Anania C A, Stewart E A, Quade B J, Hill J A, Nowak R A.
Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal
uterine bleeding.
Mol Hum Reprod.
1997;
3(8)
685-691
55
Liu Y X, Gao F, Wei P et al..
Involvement of molecules related to angiogenesis, proteolysis and apoptosis in implantation
in rhesus monkey and mouse.
Contraception.
2005;
71(4)
249-262
56
Barbarisi A, Petillo O, Di Lieto A et al..
17-beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for
a stimulation of protein kinase-dependent pathway.
J Cell Physiol.
2001;
186(3)
414-424
57
Liang M, Wang H, Zhang Y, Lu S, Wang Z.
Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata.
Cancer Biol Ther.
2006;
5(1)
28-33
58
Jaber L, Kan F W.
Non-identical distribution pattern of epidermal growth factor and platelet-derived
growth factor in the mouse uterus during the oestrous cycle and early pregnancy.
Histochem J.
1998;
30(10)
711-722
59
Weston G, Trajstman A C, Gargett C E, Manuelpillai U, Vollenhoven B J, Rogers P A.
Fibroids display an anti-angiogenic gene expression profile when compared with adjacent
myometrium.
Mol Hum Reprod.
2003;
9(9)
541-549
60
Ingman W V, Robertson S A.
Defining the actions of transforming growth factor beta in reproduction.
Bioessays.
2002;
24(10)
904-914
61
Tamada H, McMaster M T, Flanders K C, Andrews G K, Dey S K.
Cell type-specific expression of transforming growth factor-beta 1 in the mouse uterus
during the periimplantation period.
Mol Endocrinol.
1990;
4(7)
965-972
62
Feinberg R F, Kliman H J, Wang C L.
Transforming growth factor-beta stimulates trophoblast oncofetal fibronectin synthesis
in vitro: implications for trophoblast implantation in vivo.
J Clin Endocrinol Metab.
1994;
78(5)
1241-1248
63
Irving J A, Lala P K.
Functional role of cell surface integrins on human trophoblast cell migration: regulation
by TGF-beta, IGF-II, and IGFBP-1.
Exp Cell Res.
1995;
217(2)
419-427
64
Dou Q, Zhao Y, Tarnuzzer R W et al..
Suppression of transforming growth factor-beta (TGF beta) and TGF beta receptor messenger
ribonucleic acid and protein expression in leiomyomata in women receiving gonadotropin-releasing
hormone agonist therapy.
J Clin Endocrinol Metab.
1996;
81
3222-3230
65
Leppert P C, Catherino W H, Segars J H.
A new hypothesis about the origin of uterine fibroids based on gene expression profiling
with microarrays.
Am J Obstet Gynecol.
2006;
195(2)
415-420
66
Taylor H S.
The role of HOX genes in human implantation.
Hum Reprod Update.
2000;
6(1)
75-79
67
Taylor H S, Vanden Heuvel G B, Igarashi P.
A conserved Hox axis in the mouse and human female reproductive system: late establishment
and persistent adult expression of the Hoxa cluster genes.
Biol Reprod.
1997;
57(6)
1338-1345
68
Block K, Kardana A, Igarashi P, Taylor H S.
In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing
mullerian system.
FASEB J.
2000;
14(9)
1101-1108
69
Taylor H S, Arici A, Olive D, Igarashi P.
HOXA10 is expressed in response to sex steroids at the time of implantation in the
human endometrium.
J Clin Invest.
1998;
101(7)
1379-1384
70
Cermik D, Arici A, Taylor H S.
Coordinated regulation of HOX gene expression in myometrium and uterine leiomyoma.
Fertil Steril.
2002;
78(5)
979-984
71
Rackow B W, Taylor H S.
Uterine leiomyomas affect endometrial HOXA10 expression.
J Soc Gynecol Investig.
2006;
13(2)
280A
Hilary O.D CritchleyM.D.
Division of Reproductive and Developmental Sciences, The University of Edinburgh Centre
for Reproductive Biology, The Queen's Medical Research Institute
47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom
Email: hilary.critchley@ed.ac.uk