Key content
Mifepristone, a progesterone receptor antagonist, was
initially discovered in the 1980s and has been licensed for use
in medical termination since 1991. Subsequently, selective
progesterone receptor modulators (SPRM), which have
both agonist and antagonist properties, have been
developed and have therapeutic advantages over
alternative therapies.
Ulipristal acetate, a SPRM, was licensed as
emergency contraception in 2009 and, in May 2012, as a
preoperative treatment for fibroids. There is ongoing
research on its use for the long-term management of
uterine fibroids.
Learning objectives
History of the development of SPRM.
Mechanism of action of SPRM.
Summary of research on ulipristal acetate for the management
of fibroids.
Potential advantages of SPRM over the current medical treatments
for uterine fibroids.
Current licensed uses for ulipristal acetate.
Potential uses of SPRM in other gynaecological conditions.
Risks and side effects of SPRM.
Keywords: emergency contraception / selective progesterone
receptor modulators / ulipristal acetate / uterine fibroids
Introduction
Mechanism of action
Progesterone is a steroid hormone synthesised by the corpus
luteum of the ovary, the placenta, and also by the adrenal cortex and testes. It prepares the endometrium for pregnancy,
maintains the uterus throughout pregnancy and promotes
breast development.5 PRs are present, but not exclusively, in
endometrial, myometrial and breast tissue. Progesterone
enters the cytoplasm of the cell where it binds to the PR.
Dimerisation results in formation of the progesterone receptor
complex. This complex then binds to the basal transcription
apparatus in the nucleus via co-activators and initiates
transcription of the target gene.4 PR agonists initiate
transcription via co-activators and PR antagonists inhibit
transcription via co-repressors.1,4 There are two isoforms of
the PR, human progesterone receptor A (hPR-A) and human
progesterone receptor B (hPR-B). They differ in that the hPR-B
has an extended N-terminal region.3,4 Research in mice has
demonstrated the different biological effects of activation of
these two isoforms.
Activation of the hPR-A counteracts estrogen induced
endometrial proliferation whilst activation of the hPR-B
principally relates to proliferation and differentiation in the
mammary gland.
Uterine fibroids and SPRMs
Contraception and SPRMs
Endometriosis and SPRMs
Other potential uses of SPRMs in
gynaecology
The role of SPRMs in the management of dysfunctional
uterine bleeding is yet to be defined. As discussed earlier
SPRMs induce amenorrhoea with very few reports of
breakthrough bleeding.2
Limitations of SPRMs
Risk of endometrial cancer
Unopposed estrogen is a well documented risk factor for
endometrial cancer and therefore the effects of endometrial PR
antagonists in premenopausal women are a safety concern.27
Endometrial changes unique to progesterone receptor
modulators (PRM) are described and referred to as
PRM-associated endometrial changes (PAEC).27 These newly
described non-physiological changes are generic and not
specific to a single PRM. SPRMs have different agonist and
antagonist properties and therefore variable effects on the
endometrium. Although glandular changes consistent with
concurrent estrogen and progesterone stimulation
are distinctive they are not always present. It is therefore not
always possible to identity patients taking PRM on histology
alone and it is therefore important to inform the pathologist
when sending a hysterectomy or an endometrial
biopsy specimen.
Breast tissue and SPRMs
The Women’s Health Initiative study and the Million
Women Study have both demonstrated an increased risk of
breast cancer in women taking both combined and
estrogen-only hormone replacement therapy. SPRMs may
have a potential role in the treatment of women with breast
cancer and possibly a preventative role in the development of
breast cancer in high risk groups such as those with BRCA
gene mutations. This is being actively researched.
Conclusion
We are still in the early days of realising the full potential of
SPRMs. The benefits of mifepristone are widely appreciated
and it has thus been accepted in gynaecological practice.
Ulipristal acetate is readily available as an emergency
contraception and within the last year, it has been licensed
for preoperative use in the management of uterine fibroids.
The science behind the progesterone receptor is still being
explored and the development of further SPRMs is likely to
continue with exciting prospects for use within gynaecology.
It is also important to remember that progesterone receptors
are present in other tissues in the body and therefore their use is
not just limited to those within gynaecology