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Selective progesterone
1. Selective progesterone receptor modulators and their use
within gynaecology
Megan Murdoch MBChB MRCOG,a,
* Mark Roberts MD MRCOG
b
a
Specialty Trainee in Obstetrics and Gynaecology Women’s Services, University Hospital of North Tees, Stockton on Tees TS19 8PE, UK
b
Consultant Gynaecologist, Women’s Directorate, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
*Correspondence: Megan Murdoch. Email: meganmurdoch@doctors.org.uk
Accepted on 24 September 2013
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
Please cite this paper as: Murdoch M, Roberts M. Selective progesterone receptor modulators and their use within gynaecology. The Obstetrician Gynaecologist
2014;16:46–50.
Introduction
Mifepristone, a progesterone receptor (PR) and glucocorticoid
receptor (GR) antagonist, was discovered in 1981 in the course of
attempts to develop glucocorticoid receptor ligands.1
The effects
it had on menstruation and the ability to interrupt pregnancy
eventually led to the development of further compounds with
both agonist and antagonist properties on the PR and fewer
antiglucocorticoid properties. These compounds are classified as
selective progesterone receptor modulators (SPRMs).2
SPRMs
have been shown to have an antagonistic effect on endometrial
andbreasttissuePRswithoutinfluencingtheeffectofestrogenon
endometrial and breast tissue.3
Mifepristone and ulipristal acetate are the only SPRMs
currently licensed for use in the UK, however, other SPRMs have
been or are currently being developed and undergoing trial.4
There have been several review articles on the clinical uses of
SPRMs.1,2,4
The authors summarise the currentlicensed uses and
potential uses of SPRMs in gynaecology.
Mechanism of action
Progesterone is a steroid hormone synthesised by the corpus
luteum of the ovary, the placenta, and also by theadrenal 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.3,4
The mechanism of action of SPRMs is not clearly
understood.1
It is known that SPRMs bind to both isoforms
of the PR producing a mixed agonist and antagonist effect via
the combined activation of co-activators and co-repressors
46 ª 2014 Royal College of Obstetricians and Gynaecologists
DOI: 10.1111/tog.12072
The Obstetrician Gynaecologist
http://onlinetog.org
2014;16:46–50
Review
2. (Figure 1).1,4
This is thought to be as a result of the structure of
the specific SPRM, the ratio of PR isoforms and tissue
concentrations of co-activators and co-repressors.4
Uterine fibroids and SPRMs
Uterine fibroids (leiomyomas or myomas) are benign
tumours of smooth muscle cells and fibrous tissue that
develop within the wall of the uterus.6
They are the
most common tumours of the female genital tract present
in 20–40% of women in the reproductive age group.5
There is
increasing evidence that progesterone and the PR have a
major role in the growth and development of uterine
fibroids.7
In the management of fibroids an SPRM is
required that selectively acts as a progestogen on the
endometrium and an anti-progestin within the fibroid.8
Fibroids can be asymptomatic or result in abnormal
uterine bleeding, urinary incontinence or frequency, pelvic
pressure or pain, infertility, miscarriage and pregnancy
complications.5,9
Treatment is often only required if the
woman is symptomatic and is dependent on symptoms. If the
woman has heavy menstrual bleeding, the National Institute
for Health and Care Excellence (NICE) recommends
consideration of pharmaceutical treatment when fibroids
are less than 3 cm in diameter and causing no distortion of
the uterine cavity.10
The management of heavy menstrual
bleeding is well documented elsewhere and therefore not
covered in this article.
Medical management of fibroids
Gonadotrophin-releasing hormone analogues (GnRH-a) are
an effective treatment but long-term use is limited due to
adverse side effects.11
These include hot flushes, vaginitis,
sweating, change in breast size and bone density loss.11,12
The
sole use of GnRH-a is generally only considered when all
other treatment options, including surgery or uterine artery
embolisation (UAE), are contraindicated.10
SPRMs could provide a pharmacological treatment option
for the long-term management of uterine fibroids if safety
and efficacy is confirmed. Within this context, the SPRM of
choice should be one that selectively acts as a progestogen on
the endometrium and an anti-progestogen within the
fibroid.9
The PEARL group is currently conducting a Phase
III multicentre, randomised, double-blind clinical study,
investigating the efficacy and safety of repeated 12-week
courses of daily ulipristal acetate for this purpose. The study
is due to be completed late 2014.
Preoperative medical treatment for fibroids
The current nonpharmacological treatment options include
UAE, myomectomy (including transcervical resection) and
hysterectomy.9
Other treatments such as magnetic resonance
(MR) image guided percutaneous laser ablation and MR
image guided transcutaneous focused ultrasound for uterine
fibroids may be available under research conditions.
Preoperative treatment with GnRH-a is recommended in
women with a greatly enlarged uterus, preoperative anaemia,
or where reduction in fibroid volume may result in a low
transverse rather than midline incision. There is evidence
demonstrating a significant reduction in uterine volume and
fibroid size, a slight improvement in haematological indices,
and a possible reduction in intraoperative blood loss and
operating time with the preoperative use of GnRH-a.10,11
These advantages, along with a reduction in analgesia
requirements and length of hospital stay, may also be seen
if the use of GnRH-a allows a laparoscopic rather than open
procedure. The use of GnRH-a is contraindicated prior to
UAE due to the effect it has on blood vessels which
complicates the procedure.10
SPRMs currently offer an
alternative preoperative treatment option and are possibly
suitable for use prior to UAE.
A recent randomised, parallel group, double blind, placebo
controlled phase III trial (PEARL I) evaluated the efficacy and
safety of oral ulipristal acetate versus placebo for the
treatment of symptomatic uterine fibroids before surgery.13
Patients eligible for surgical treatment of fibroids were
randomised to receive up to 13 weeks of treatment with
ulipristal acetate, 5 mg or 10 mg, or a placebo. The primary
end points were a reduction in uterine bleeding and fibroid
volume. Menstrual bleeding was controlled in 91% and 92%
of women who received 5 mg and 10 mg of ulipristal
respectively and with only 19% in those who received placebo
(P 0.001). Median changes in total fibroid volume were –
21%, –12% and +3% (P = 0.002 ulipristal acetate 5 mg versus
placebo, and P = 0.006 ulipristal acetate 10 mg versus placebo).
Although the most common side effects were headache and
breast pain, there was no significant difference between
ulipristal and placebo groups for discomfort or tenderness in
those areas. A low rate of hot flushes was reported in all
groups.13
In contrast to that seen in women treated with
GnRH-a, there was no suppression of estradiol in the women
treated with ulipristal acetate.13
The same group conducted a
double-blind, double-dummy phase III trial comparing
Figure 1. Suggested sites of action of SPRMs.
ª 2014 Royal College of Obstetricians and Gynaecologists 47
Use of progesterone receptor modulators in gynaecology
3. ulipristal acetate with leuprolide acetate (injectable GnRH-a)
(PEARL II). They reported moderate to severe hot flushes in
11% and 10% of those receiving 5 mg and 10 mg of ulipristal
acetate respectively and in 40% of those receiving leuprolide
acetate.14
These trials demonstrated ulipristal acetate to be an
effective alternative to GnRH-a as a preoperative treatment for
women undergoing surgery for uterine fibroids with a reduced
side-effect profile.
Although 3-monthly intramuscular preparations of
GnRH-a are available, the lack of enteric options is a
disadvantage which is overcome by the SPRM ulipristal
acetate, which is effective as an oral medication.
Ulipristal acetate (5 mg daily Esmyaâ
[Gedeon Richter,
Budapest, Hungary]) is currently licensed for the
preoperative treatment of uterine fibroids, with treatment
duration limited to 3 months. The Faculty of Sexual and
Reproductive Healthcare advise against the use of
concomitant progestogens, as the competitive action on the
PR is likely to reduce efficacy. Although most women will be
amenorrhoeic, for the same reasons as for those on GnRH-a,
nonhormonal contraception is advised.15,16
Contraception and SPRMs
SPRMs inhibit or delay ovulation by blocking the luteinising
hormone (LH) surge and follicular rupture whilst
maintaining plasma estrogen levels.1,17
These effects have
been demonstrated with the SPRMs asoprisnil, mifepristone
and ulipristal acetate.1,4
SPRMs also have a direct effect on
the endometrium (discussed below) which may have an effect
on implantation.1
In the UK, mifepristone, in combination with a
prostaglandin, has been licensed for use in medical
termination of pregnancy (TOP) since 1991, with a
complete TOP rate of at least 95%.18
A double-blind randomised control trial of 2 mg and 5 mg
of mifepristone taken for 120 days showed that it inhibited
ovulation, induced amenorrhoea and potentially prevented
pregnancy.2,19
A randomised non inferiority trial comparing
the efficacy and safety of ulipristal acetate with that of the
progesterone levonorgestrel (LNG) for emergency
contraception concluded that ulipristal acetate is an
effective alternative which can be used for up to 120 hours
after unprotected sexual intercourse (UPSI).20
A significantly
lower pregnancy rate was observed in women given ulipristal
acetate when compared to the LNG in all time periods up to
120 hours. A Cochrane systematic review concluded that
mid-dose mifepristone (25–30 mg) is superior to LNG and
that ulipristal acetate may be more effective than LNG.21
There are three methods of emergency contraception
licensed for use in the UK; ulipristal acetate, LNG and the
copper-bearing intrauterine device (Cu-IUD). Ulipristal
acetate (30 mg single dose Ellaoneâ
[HRA Pharma, Paris,
France]) and the Cu-IUD can both be used up to 120 hours
after UPSI or contraceptive failure. Ulipristal acetate is the
only oral method licensed for use between 72 and 120 hours
of UPSI.17
Whereas LNG can be used to cover UPSI more than once
in a cycle ulipristal acetate is only licensed to be given once.17
Both LNG and ulipristal acetate may interfere with the
efficacy of hormonal contraceptive methods. It is
recommended that subsequent acts of unprotected sexual
intercourse be protected with barrier methods until the next
menstrual period starts.15
Due to the anovulatory effects of SPRMs they also have the
potential to be used as long term contraceptives potentially
suitable for use in women in whom estrogen containing
contraceptives are contraindicated. Irregular bleeding is
experienced in up to 70% of women taking the progesterone
only pill (POP) and between 10% and 25% discontinue POPs
within a year due to this side effect.22
SPRM induce
amenorrhoea, although the exact mechanism behind this is
unknown.1
Amenorrhoea rates of up to 70% with ulipristal,
70% with asoprisnil and 90% with mifepristone have been
observed.13,19,23
Preliminary data from ongoing trials of
ulipristal acetate have suggested a higher amenorrhoea rate.
SPRMs may offer an effective long-term contraceptive
without the undesirable side effect of irregular bleeding.
Mifepristone has been considered and researched for use as a
long-term contraceptive for many years but it is not
established or licensed for this use within the UK.24
Endometriosis and SPRMs
Endometriosis is defined as the presence of endometrial like
tissue outside the uterus, which induces a chronic,
inflammatory reaction.25
It is a common condition causing
symptoms such as dysmenorrhoea, dyspareunia, pelvic pain,
dyschezia and infertility.25
One of the current pharmacological
treatment options is based on the suppression of ovulation,
which is shown to reduce pain associated with endometriosis.
These include the combined oral contraceptive pill, danazol,
gestrinone, medroxyprogesterone acetate and GnRH-a.25
The
LNG–IUS has also been shown to reduce pain associated to
endometriosis.25
All have various contraindications, side
effects and limitations, which have been discussed previously.
When using GnRH-a, a regime of ‘add back’ hormone therapy
is recommended.10
Surgical excision or bilateral salpingo
oophorectomy (+/– hysterectomy) is not always appropriate,
especially for women who wish to retain fertility.1
SPRMs may offer a pharmacological therapeutic alternative
potentially improving the symptoms of endometriosis by the
suppression of ovulation, antiproliferative effects on the
endometrium and suppression of endometrial bleeding.2
Small studies on the effects of mifepristone have
demonstrated improvement in pelvic pain and uterine
48 ª 2014 Royal College of Obstetricians and Gynaecologists
Murdoch and Roberts
4. cramping associated with endometriosis, along with a
regression of endometriosis.1,4,26
Short courses of asoprisnil
versus placebo have been shown to be effective in reducing
nonmenstrual pain and dysmenorrhoea in women with a
laparoscopic diagnosis of endometriosis.1–3
The effects of
SPRMs on the endometrium limit their long-term use and are
currently being evaluated. The effects on ectopic endometrium
are unknown.1, 4
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.17,27
PAEC were evaluated in women taking short courses of
SPRMs (asoprisnil, ulipristal acetate and telapristone acetate)
and no hyperplasia, premalignant or malignant lesions were
identified in these specimens.4,13,27
Due to the theoretical
concerns, however, the use of ulipristal acetate is currently
limited to 3 months. The effects of ulipristal acetate on the
endometrium were assessed in the PEARL trials.13,28
Although nonphysiological changes were seen frequently in
the ulipristal group, these changes had resolved 6 months
after treatment demonstrating reversibility of these changes
and safety in this respect of their short-term use.13
Further
research on the long term PAEC are required before they can
be safely used for a prolonged duration.
At present, there do not appear to be any significant side
effects of ulipristal acetate but it is recommended that they be
used with caution in those with severe asthma uncontrolled by
oral glucocorticoids and in those with hepatic dysfunction,
hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption.4, 17
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.1
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.
Disclosure of interests
Mark Roberts is a Principle Investigator for the PEARL IV
study sponsored by PregLem S.A. a member of the Gedeon
Richter Group.
References
1 Chabbert-Buffet N, A Pintiaux A, Bouchard P. The imminent dawn of SPRMs
in obstetrics and gynecology. Mol Cell Endocrinol 2012;358:232–43.
2 Wilkens J, Critchley H. Progesterone receptor modulators in gynaeco-
logical practice. J Fam Plann Reprod Health Care 2010;36:87–92.
3 Chwalisz K, Perez MC, DeManno D, Winkel C, Schubert G, Elger W.
Selective progesterone receptor modulator development and use in the
treatment of leiomyomata and endometriosis. Endocr Reviews
2005;26:423–38.
4 Bouchard P, Chabbert-Buffet N, Fauser BC. Selective progesterone receptor
modulators in reproductive medicine: pharmacology, clinical efficacy and
safety. Fertil Steril 2011;96:1175–89.
5 Concise Medical Dictionary. 8th ed. Oxford: Oxford University Press; 2010.
6 National Institute for Health and Care Excellence. Uterine artery
embolisation for fibroids (IPG367). London: National Institute for Health
and Care Excellence; 2010.
7 Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial cancer,
endometriosis, uterine fibroids, and breast cancer. Endocr Rev.
2013;34:130–62.
8 Catherino WH, Malik M, Driggers P, Chappel S, Segars J, Davis J. Novel,
orally active selective progesterone receptor modulator CP8947 inhibits
leiomyoma cell proliferation without adversely affecting endometrium or
myometrium. J Steroid Biochem Mol Biol 2010;122:279–86.
ª 2014 Royal College of Obstetricians and Gynaecologists 49
Use of progesterone receptor modulators in gynaecology
5. 9 The Royal College of Radiologists and the Royal College of Obstetricians and
Gynaecologists. Clinical recommendations on uterine artery embolisation in
the management of fibroids Second edition. London: The Royal College of
Radiologists, 2009 [http://www.rcr.ac.uk/docs/radiology/pdf/BFCR%2809%
291_Embolisation.pdf].
10 National Institute for Health and Care Excellence. Heavy Menstrual Bleeding.
(CG44) London: National Institute for Health and Care Excellence;2007.
11 Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy
before hysterectomy or myomectomy for uterine fibroids. Cochrane
Database Syst Rev 2000;(2):CD000547.
12 Leather AT, Studd JW, Watson NR, Holland EF. The prevention of bone loss
in young women treated with GnRH analogues with “add-back” estrogen
therapy. Obstet Gynecol 1993;81:104–7.
13 Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T,
et al. Ulipristal acetate versus placebo for fibroid treatment before surgery.
N Engl J Med 2012;366:409–20.
14 Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baro F, et
al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J
Med 2012;366:421–32.
15 Faculty of Sexual and Reproductive Healthcare. Statement on drug
interactions between hormonal contraception and ulipristal products:
ellaOneâ
and Esmya â
. London: Faculty of Sexual and Reproductive
Health;2012 [http://www.fsrh.org/pdfs/CEUstatementEsmya.pdf].
16 Electronic Medicines Compendium (ePC). Summary of product
characteristics: Esmya 5 mg tablets (ulipristal acetate) [http://
www.medicines.org.uk/EMC/medicine/26068/SPC/2012].
17 Faculty of Sexual and Reproductive Healthcare. Emergency contraception:
clinical guidance. London: Faculty of Sexual and Reproductive Healthcare;
2012 [http://www.fsrh.org/pdfs/
CEUguidanceEmergencyContraception11.pdf].
18 Kulier R, Kapp N, G€ulmezoglu AM, Hofmeyr GJ, Cheng L, Campana A.
Medical methods for first trimester abortion. Cochrane Database Syst Rev
2011;(11):CD002855.
19 Brown A, Cheng L, Lin S, Baird DT. Daily low-dose mifepristone has
contraceptive potential by suppressing ovulation and menstruation: a
double-blind randomized control trial of 2 and 5 mg per day for 120 days.
J Clin Endocrinol Metab 2002;87:63–70.
20 Glasier AF, Cameron ST, Fine PM, Logan SJ, Casale W, Van Horn J, et al.
Ulipristal acetate versus levonorgestrel for emergency contraception: a
randomised non-inferiority trial and meta-analysis. Lancet 2010;375:555–
62.
21 Cheng L, Che Y, G€ulmezoglu AM. Interventions for emergency
contraception. Cochrane Database Syst Rev 2012;(8):CD001324.
22 Faculty of Sexual and Reproductive Healthcare. Progesterone-only pills:
clinical guidance London: Faculty of Sexual and Reproductive Healthcare;
2009 [http://www.fsrh.org/pdfs/CEUGuidanceProgestogenOnlyPill09.pdf].
23 Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA.
A randomized, controlled trial of asoprisnil, a novel selective progesterone
receptor modulator, in women with uterine leiomyomata. Fertil Steril
2007;87:1399–412.
24 Hapangama DK, Brown A. Glasier AF, Baird DT. Feasibility of administering
mifepristone as a once a month contraceptive pill. Hum Reprod
2001;16:1145–50.
25 Royal College of Obstetricians and Gynaecologists. The Investigation and
management of endometriosis. Green-top guideline No.24. London: RCOG;
2008
26 Kettel LM, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen SS. Treatment
of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril
1996;65:23–8.
27 Mutter GL, Bergeron C, Deligdisch L, Ferenczy A, Glant M, Merino M, et al.
The spectrum of endometrial pathology induced by progesterone receptor
modulators. Mod Pathol 2008;21:591–8.
28 Williams AR, Bergeron C, Barlow DH, Ferenczy A. Endometrial
morphology after treatment of uterine fibroids with the selective
progesterone receptor modulator, ulipristal acetate. Int J Gynecol Pathol
2012;31:556–69.
50 ª 2014 Royal College of Obstetricians and Gynaecologists
Murdoch and Roberts