In leiomyoma of the uterus, both aromatase and 17β-hydroxysteroid dehydrogenase (17β-HSD)
type I are overexpressed compared with myometrium. This suggests that leiomyoma cells
convert circulating androstenedione into estrone (via aromatase), then into the active
form of estrogen, estradiol (via 17β-HSD type I). In vitro experiments and several
clinical findings support the notion that in situ estrogen plays a role in leiomyoma
growth under hypoestrogenemic conditions, such as natural menopause and therapy with
gonadotropin-releasing hormone (GnRH) agonists. GnRH agonists abolish estrogen production
both in situ in leiomyoma and in the ovary, leading to quick and profound regression
of the leiomyoma. Aromatase inhibitors also inhibit estrogen synthesis in both leiomyoma
and the ovary and may be used therapeutically. Certain doses of competitive aromatase
inhibitors would completely inhibit estrogen production in leiomyoma, whereas ovarian
production of estrogen would continue at reduced levels. This may lead to advantageous
therapeutic conditions in which leiomyoma regresses without adverse symptoms related
to estrogen depletion because levels of ovarian estrogen would be insufficient to
support leiomyoma growth but sufficient to prevent symptoms associated with deficiency.
This article discusses the potential uses of aromatase inhibitors.
KEYWORDS
Leiomyoma of the uterus - aromatase - estrogen - aromatase inhibitor
REFERENCES
- 1
Folkerd E J, Newton C J, Davidson K, Anderson M C, James V H.
Aromatase activity in uterine leiomyomata.
J Steroid Biochem.
1984;
20
1195-1200
- 2
Takamori K, Yamamoto T, Okada H.
Estrogen biosynthesis in human uterine myoma tissue: the distribution of androstenedione
aromatase activity in uterine myoma tissue.
Nippon Sanka Fujinka Gakkai Zasshi.
1984;
36
1861-1866
- 3
Yamamoto T, Takamori K, Okada H.
Estrogen biosynthesis in leiomyoma and myometrium of the uterus.
Horm Metab Res.
1984;
16
678-679
- 4
Bulun S E, Simpson E R, Word R A.
Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues
and cells in culture.
J Clin Endocrinol Metab.
1994;
78
736-743
- 5
Sumitani H, Shozu M, Segawa T et al..
In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes
cell growth probably via an autocrine/intracrine mechanism.
Endocrinology.
2000;
141
3852-3861
- 6
Gabb R G, Stone G M.
Uptake and metabolism of tritiated oestradiol and oestrone by human endometrial and
myometrial tissue in vitro.
J Endocrinol.
1974;
62
109-123
- 7
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
- 8
Eiletz J, Genz T, Pollow K, Schmidt-Gollwitzer M.
Sex steroid levels in serum, myometrium, and fibromyomata in correlation with cytoplasmic
receptors and 17 beta-HSD activity in different age-groups and phases of the menstrual
cycle.
Arch Gynecol.
1980;
229
13-28
- 9
Newton C J, James V H.
17 beta-hydroxysteroid dehydrogenase activity in leiomyoma and myometrium and its
relationship to concentrations of oestrone, oestradiol and progesterone throughout
the menstrual cycle.
J Steroid Biochem.
1985;
22
487-493
- 10
Yamamoto T, Urabe M, Naitoh K, Kitawaki J, Honjo H, Okada H.
Estrone sulfatase activity in human uterine leiomyoma.
Gynecol Oncol.
1990;
37
315-318
- 11
Van de Ven J, Donker T H, Blankenstein M A, Thijssen J H.
Differential effect of gonadotropin-releasing hormone analogue treatment on estrogen
levels and sulfatase activity in uterine leiomyoma and myometrium.
Fertil Steril.
2002;
77
1227-1232
- 12
Englund K, Blanck A, Gustavsson I et al..
Sex steroid receptors in human myometrium and fibroids: changes during the menstrual
cycle and gonadotropin-releasing hormone treatment.
J Clin Endocrinol Metab.
1998;
83
4092-4096
- 13
Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, Donnez J.
Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone
receptors A and B in leiomyomata and normal myometrium during the menstrual cycle
and under gonadotrophin-releasing hormone agonist therapy.
Hum Reprod.
1999;
14
2844-2850
- 14
Regidor P A, Schmidt M, Callies R, Kato K, Schindler A E.
Estrogen and progesterone receptor content of GnRH analogue pretreated and untreated
uterine leiomyomata.
Eur J Obstet Gynecol Reprod Biol.
1995;
63
69-73
- 15
Pasqualini J R, Cornier E, Grenier J, Vella C, Schatz B, Netter A.
Effect of decapeptyl, an agonistic analog of gonadotropin-releasing hormone on estrogens,
estrogen sulfates, and progesterone receptors in leiomyoma and myometrium.
Fertil Steril.
1990;
53
1012-1017
- 16
Otubu J A, Buttram V C, Besch N F, Besch P K.
Unconjugated steroids in leiomyomas and tumor-bearing myometrium.
Am J Obstet Gynecol.
1982;
143
130-133
- 17
Shozu M, Sumitani H, Segawa T, Yang H J, Murakami K, Inoue M.
Inhibition of in situ expression of aromatase P450 in leiomyoma of the uterus by leuprorelin
acetate.
J Clin Endocrinol Metab.
2001;
86
5405-5411
- 18
Shozu M, Sumitani H, Segawa T et al..
Over-expression of aromatase P-450 in leiomyoma tissues is driven through the promoter
I.4 of aromatase P-450.
J Clin Endocrinol Metab.
2002;
87
2540-2548
- 19
Casey M L, MacDonald P C, Mitchell M D, Snyder J M.
Maintenance and characterization of human myometrial smooth muscle cells in monolayer
culture.
In Vitro.
1984;
20
396-403
- 20
Palmberg L, Thyberg J.
Uterine smooth muscle cells in primary culture: alterations in fine structure, cytoskeletal
organization and growth characteristics.
Cell Tissue Res.
1986;
246
253-262
- 21
Dumin J, Wilcox B D, Otterness I, Melendez J A, Huang C, Jeffrey J J.
Serotonin-mediated production of interstitial collagenase by uterine smooth muscle
cells requires interleukin-1alpha, but not interleukin-1beta.
J Biol Chem.
1998;
273
25488-25494
- 22
Wilcox B D, Dumin J A, Jeffrey J J.
Serotonin regulation of interleukin-1 messenger RNA in rat uterine smooth muscle cells:
relationship to the production of interstitial collagenase.
J Biol Chem.
1994;
269
29658-29664
- 23
Zhao Y, Mendelson C R, Simpson E R.
Characterization of the sequences of the human CYP19 (aromatase) gene that mediate regulation by glucocorticoids in adipose stromal cells
and fetal hepatocytes.
Mol Endocrinol.
1995;
9
340-349
- 24
Kurose T, Hando T, Shiota A.
Clinical usefulness of GnRH agonist therapy for premenopausal women with uterine leiomyoma.
Nippon Sanka Fujinka Gakkai Zasshi.
1995;
47
35-41
- 25
Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C.
Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women.
Fertil Steril.
2001;
76
38-43
- 26
Adamson G D.
Treatment of uterine fibroids: current findings with gonadotropin-releasing hormone
agonists.
Am J Obstet Gynecol.
1992;
166
746-751
- 27
Demopoulos R I, Mesia A F.
Effects of leuprolide acetate on treatment of leiomyomata: clues to mechanisms of
action.
Adv Anat Pathol.
1998;
5
129-136
- 28
Friedman A J, Lobel S M, Rein M S, Barbieri R L.
Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing
hormone agonists: the estrogen threshold hypothesis.
Am J Obstet Gynecol.
1990;
163
1114-1119
- 29
Takeuchi H, Kobori H, Kikuchi I, Sato Y, Mitsuhashi N.
A prospective randomized study comparing endocrinological and clinical effects of
two types of GnRH agonists in cases of uterine leiomyomas or endometriosis.
J Obstet Gynaecol Res.
2000;
26
325-331
- 30
Friedman A J, Daly M, Juneau-Norcross M, Gleason R, Rein M S, LeBoff M.
Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of
leuprolide acetate depot plus either oestrogen-progestin or progestin “add-back” for
2 years.
Hum Reprod.
1994;
9
1618-1625
- 31
Andersen J.
Growth factors and cytokines in uterine leiomyomas.
Semin Reprod Endocrinol.
1996;
14
269-282
- 32
Shozu M, Sumitani H, Murakami K, Segawa T, Yang H-J, Inoue M.
Regulation of aromatase activity in bone-derived cells: possible role of mitogen-activated
protein kinase.
J Steroid Biochem Mol Biol.
2001;
79
61-65
- 33
Chegini N, Verala J, Luo X, Xu J, Williams R S.
Gene expression profile of leiomyoma and myometrium and the effect of gonadotropin
releasing hormone analogue therapy.
J Soc Gynecol Investig.
2003;
10
161-171
- 34
Iveson T J, Smith I E, Ahern J, Smithers D A, Trunet P F, Dowsett M.
Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal
patients with advanced breast cancer.
Cancer Res.
1993;
53
266-270
- 35
Lee M J, Kazer R R.
Massive ascites after leuprolide acetate administration for the treatment of leiomyomata
uteri.
Fertil Steril.
1992;
58
416-418
- 36
Harding S G, Pesce A, McMillan L.
Symptomatic ascites complicating GnRH analogue use for myoma shrinkage.
Br J Obstet Gynaecol.
1993;
100
1054-1056
- 37
Moudgal N R, Shetty G, Selvaraj N, Bhatnagar A S.
Use of a specific aromatase inhibitor for determining whether there is a role for
oestrogen in follicle/oocyte maturation, ovulation and preimplantation embryo development.
J Reprod Fertil Suppl.
1996;
50
69-81
- 38
Palter S F, Tavares A B, Hourvitz A, Veldhuis J D, Adashi E Y.
Are estrogens of import to primate/human ovarian folliculogenesis?.
Endocr Rev.
2001;
22
389-424
- 39
Mitwally M F, Casper R F.
Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate
response to clomiphene citrate.
Fertil Steril.
2001;
75
305-309
- 40
Selvaraj N, Bhatnagar A S, Moudgal N R.
Is there a role for estrogen in follicular maturation in the primate?.
Endocrine.
1995;
3
245-249
- 41
Shozu M, Akasofu K, Harada T, Kubota Y.
A new cause of female pseudohermaphroditism: placental aromatase deficiency.
J Clin Endocrinol Metab.
1991;
72
560-566
- 42
Conte F A, Grumbach M M, Ito Y, Fisher C R, Simpson E R.
A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic
ovaries associated with missense mutations in the gene encoding aromatase (P450arom).
J Clin Endocrinol Metab.
1994;
78
1287-1292
- 43
Morishima A, Grumbach M M, Simpson E R, Fisher C, Qin K.
Aromatase deficiency in male and female siblings caused by a novel mutation and the
physiological role of estrogens.
J Clin Endocrinol Metab.
1995;
80
3689-3698
- 44
Shozu M, Zhao Y, Simpson E R.
Estrogen biosynthesis in THP1 cells is regulated by promoter switching of the aromatase
(CYP19) gene.
Endocrinology.
1997;
138
5125-5135
- 45
Shozu M, Simpson E R.
Aromatase expression of human osteoblast-like cells.
Mol Cell Endocrinol.
1998;
139
117-129
- 46
Shozu M, Murakami K, Segawa T, Kasai T, Inoue M.
Successful treatment of symptomatic uterine leiomyoma with a non-steroidal aromatase
inhibitor in a perimenopausal woman.
Fertil Steril.
2003;
79
628-631
Makio ShozuM.D.
Department of Obstetrics and Gynecology, Kanazawa University School of Medicine
13-1 Takara-machi, Kanazawa 920-0934, Japan
