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Copyright Lancet Ltd. Jul 16-Jul 22, 2005
The
Million Women Study Collaborators (April 30, p 1543)1
report that tibolone therapy increases endometrial
cancer risk by an order of magnitude comparable
with unopposed oestrogen. This finding was in contrast
to that with combined oestrogen-progestogen, which
did not increase this risk. Considering the absence
of randomisation, the association between tibolone
and increased cancer risk might be due to underlying
differences between the populations studied. However,
if the risk is truly increased, a biological explanation
should be sought.
Tibolone
has oestrogenic, progestogenic, and androgenic properties.
The approved dose regimen is 2.5 mg daily, but the
dose-response relation on various sex-steroid-sensitive
target tissues would benefit from further exploration.
There are reasons to believe that the oestrogenic
activity at increasing tibolone doses overrides
the progestogenic activity on two targets characterised
by sensitivity to diverse effects of oestrogen and
progestogen-ie, the endometrium and triglycerides.
Originally,
a dose level of 5 mg tibolone daily was used to
assess the effect on bone.2 However, after only
3 months the investigators chose to reduce the regimen
to 2.5 mg because of bleeding problems. This finding
indicates that the 5 mg dose leads to overt endometrial
stimulation. The endometrial dose-response relation
has also been investigated in ovariectomised, cholesterol-fed
rabbits.3 In this study, three tibolone doses were
included. Whereas the two lower doses led to a uterine
weight comparable to that with oestrogen, the top
dose led to a uterine weight that was twice as high
as with lower doses and also twice as high as that
of unopposed oestrogen and combined oestrogen-progestogen
therapy. These data support the notion of an increasing
oestrogenic-as opposed to progestogenic-influence
on the endometrium at higher doses. The rabbit study
also explored serum triglycerides, in which sex-steroid-induced
effects are largely comparable to those seen in
human beings. Increased doses of tibolone also led
to increased serum triglyceride concentrations,
which is known to be an oestrogenic effect. In postmenopausal
women, tibolone decreases triglycerides compared
with placebo,4 but doses higher than 2.5 mg have
not been studied and might reverse the decrease,
as seen in rabbits.
Another
reason why 2.5 mg tibolone might be too oestrogenic
is the fact that 1.25 mg daily has a similar efficacy
on bone-mineral density as 2.5 mg.5 This finding
indicates that both doses are on the flat portion
of the dose-response curve. On the basis of these
data, 1.25 mg daily was chosen for a fracture intervention
study.
These
hypotheses are limited by the fact that long-term
2.5 mg tibolone treatment produces an endometrial
thickness and bleeding profile in the same order
of magnitude as continuous combined oestrogen-progestogenic
treatment. However, these markers may not be sensitive
enough to pick up a slight difference. Histology
is at present the preferred method to assess the
endometrium.
In
conclusion, a biological explanation for the increase
in endometrial cancer risk during tibolone treatment
could be that 2.5 mg is more oestrogenic with respect
to the endometrium than previously anticipated.
The ongoing 5-year fracture study in 4000 osteoporotic
women randomised to 1.25 mg tibolone or placebo
might improve our understanding of its endometrial
effects.
I
declare that I have no conflict of interest.
Nina
H Bjarnason
nina.bjarnason@rh.dk
Department
of Clinical Pharmacology Q-7642, Copenhagen University
Hospital, Rigshospitalet, Tagensvej 20, DK-2200
Copenhagen, Denmark
1
Million Women Study Collaborators. Endometrial cancer
and hormone-replacement therapy in the Million Women
Study. Lancet 2005;365:1543-51.
2
Lindsay R, Hart DM, Kraszewski A. Prospective double-blind
trial of synthetic steroid (Org OD 14) for preventing
postmenopausal osteoporosis. BMJ 1980;280:1207-09.
3
Zandberg P, Peters JLM, Demacker PNM, Smit MJ, de
Reeder EG, Meuleman DG. Tibolone prevents atherosclerotic
lesion formation in cholesterol-fed, ovariectomized
rabbits. Arterioscler Thromb Vase Biol 1998;18:1844-54.
4
Bjarnason NH, Bjarnason K, HaarboJ, Coelingh Bennink
HJT, Christiansen C. Tibolone: influence on markers
of cardiovascular disease. J Clin Endocrinol Metab
1997;82:1752-56.
5
Bjarnason NH, Bjarnason K, Haarbo J, Rosenguist
C, Christiansen C. Tibolone: prevention of bone loss in late postmenopausal women.
J Clin Endocrinol Metab 1996;81: 2419-22.
The
Million Women Study Collaborators1 report that postmenopausal
women exposed to tibolone for at least 3 years have
a relative risk of endometrial cancer of 2.03 compared
with untreated women. The risk was three-fold higher
in women with normal weight, but was unchanged in
obese women. These results suggest a scenario in
which the endometrium is subject to the proliferative
influence of a potent oestrogenic metabolite in
the absence of a strong progestogenic counterbalance
(unlike, for example, in postmenopausal women on
continuous hormone replacement therapy, in whom
the progestin effectively antagonises the proliferative
effects of oestradiol or conjugated equine oestrogens,
and the risk of endometrial cancer is not increased).
Oral
administration of tibolone results in the rapid
formation of the Δ4-isomer (7α-methylnorethisterone).
This metabolite exerts relatively weak progestogenie
activities (13% of that of norethisterone) and strong
androgenic effects (similar to testosterone).2 The
oestrogenic activity of tibolone, in turn, has been
mostly ascribed to metabolites with weak oestrogenic
potency-ie, 3α-hydroxytibolone and 3β-hydroxytibolone
(table).
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Table: Prodrugs noretynodrel and tibolone and some of
their hormonally active metabolites
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We
have shown that, similarly to norethisterone which
is rapidly aromatised to ethinylestradiol in the
liver after oral administration,3 treatment with
tibolone (2.5 mg daily) results in the formation
of 7α-methylethinylestradiol, which reaches peak
serum concentrations of 120 ng/L within 2 h after
oral administration.4 This oestrogen has a potency
comparable with that of ethinylestradiol.5 Thus
the development of endometrial cancer during treatment
with tibolone could be explained by the relatively
weak progestogenic activity of the Δ4-isomer of
tibolone, which might be insufficient to inhibit
the proliferative effect of 7α-methylethinylestradiol
in all patients.
The
formation of 7α-methylethinylestradiol during use
of tibolone has been questioned because the normal
adult human liver does not express aromatase cytochrome
P450 (CYP 19), and CYP 19 converts testosterone
into oestradiol, but does not aromatise the nandrolone
derivatives norethisterone and tibolone (or tibolone
metabolites). However, the key reaction of CYP 19
is the oxidation of the 19-methyl group, which is
lacking in nandrolone derivatives. Therefore, other
hepatic CYP mono-oxygenases may oxidise ring A of
norethisterone and tibolone metabolites, resulting
in the formation of an aromatic ring A with oestrogenic
properties. The results of clinical studies with
norethisterone and tibolone have clearly confirmed
the formation of ethinylestradiol and 7α-methylethinylestradiol,3,4
and the manufacturer of tibolone (Organon), who
has done a study similar to ours,4 to our knowledge
has not yet published the results.
We
declare that we have no conflict of interest.
Inka
Wiegratz, *Herbert Kuhl
H.Kuhl@em.uni-frankfurt.de
Department
of Obstetrics and Gynecology, J W
Goethe
University of Frankfurt, D-60590 Frankfurt am Main,
Germany
1
Million Women Study Collaborators. Endometrial cancer
and hormone-replacement therapy in the Million Women
Study. Lancet 2005; 365:1543-51.
2
Schoonen WGEJ, Deckers GH, de Gooijer ME, de Ries
R, Kloosterboer HJ. Hormonal properties of norethisterone,
7α-methyl-norethisterone and their derivatives.
J Steroid Biocbem Mol Biol 2000;74:213-22.
3
Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis
K. In vivo conversion of norethisterone and norethisterone
acetate to ethinyl estradiol in postmenopausal women.
Contraception 1997; 56:379-85.
4
Wiegratz I, Sänger N, Kuhl H. Formation of
7αmethyl-ethinyl estradiol during treatment with
tibolone. Menopause 2002; 9: 293-95.
5
Bodine PVN, Harris HA, Lyttle CR, Komm BS. Estrogenic
effects of 7α-methyl-17α-ethynylestradiol: a newly
discovered tibolone metabolite. Steroids 2002; 67:681-86.
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Endometrial cancer and hormone-replacement
therapy(子宫内膜癌与雌激素替代治疗)
