Aust N Z J Obstet Gynaecol 2017; 57: 12–15

DOI: 10.1111/ajo.12583

REVIEW ARTICLE

The endometrial and breast safety of menopausal

hormone therapy containing micronised
progesterone: A short review

John Eden1,2,3,4

1
Medical Officer Royal Hospital for For a significant minority of women, menopausal symptoms can be very unpleas-
Women, Sydney, Australia
2
ant; however, many are worried about taking menopausal hormone therapy
Barbara Gross Research Unit Royal
Hospital for Women, Sydney, Australia (MHT) for fear of causing breast cancer. Micronised progesterone (mP4) has been
3
Sydney Menopause Centre Royal available in Europe since the 1990s and clinical trials have shown that 100 mg
Hospital for Women, Sydney, Australia
oral daily, 200 mg oral sequentially or 100 mg vaginal every second day effec-
4
Women’s Health and Research
Institute of Australia, Sydney, Australia
tively protect the endometrium from the stimulatory effects of oestrogen. MHT
containing mP4 has a significantly lower breast cancer risk than those containing
Correspondence: Dr John Eden, Medical
Officer Royal Hospital for Women,
progestins. Micronised progesterone does not appear to attenuate the cardio-
Sydney, Australia. vascular benefits of oestrogen. Pharmaceutical grade, body identical MHT is now
Email: j.eden@unsw.edu.au
available in Australia.
Received: 8 September 2016;
Accepted: 28 November 2016
KEYWORDS
breast cancer, endometrium, menopause, progesterone

INTRODUCTION that are identical to the human hormones.4 In Australia, oestradiol

Australian women can expect to spend 30–40 years of their life
in the postmenopausal phase. For some, problems such as vul-
vovaginal dryness, painful intercourse, recurrent urinary tract
infections, severe frequent flushes and night sweats can be very
problematic. Menopausal hormone therapy (MHT) is highly ef-
fective for these, but many women are reticent to use MHT for
fear of causing breast cancer. This was confirmed in a recent
Australian survey showing that fewer than one in eight women
suffering severe vasomotor symptoms were being treated with
any therapy (including antidepressants) and only 5% of women
aged 60–65 years were using vaginal oestrogens.1
Over the last few decades many new MHTs have become
available and as such guidelines have changed. The International
Menopause Society (IMS) recently revised its guidelines.2,3 The
IMS guidelines point out that ‘the increased risk of breast cancer
thus seems primarily, but not exclusively, associated with the use
of a progestin with oestrogen therapy in women without hysterec-
tomy and may be related to duration of use’ (page 3143).
The term, ‘body-­identical hormone replacement’ (bHT) has
been used to refer to pharmaceutical grade hormone therapies
has been available as tablets, patches and a gel for many years (and
oestriol vaginal cream). Micronised progesterone (mP4) became
available in Australia from 1 September 2016 (Prometrium 100 mg
cap; Besins Healthcare, Sydney, NSW, Australia) and so it seemed
timely to review the safety profile of oestrogen-­mP4 as a MHT.
AIMS
This narrative review aims to examine the endometrial, breast
and cardiovascular safety of mP4, when used with oestrogen re-
placement and MHT.
MATERIALS AND METHODS
A systematic review was made using the University of NSW Library
search engine (which uses many databases including Scopus,
Medline, Web of Science) between the years 1980 and 2016 using the
keywords – ‘progesterone,’ ‘menopause,’ ‘endometrium,’ ‘breast can-
cer,’ ‘heart,’ ‘lipids,’ ‘endothelium’ and ‘cardiovascular.’ Preference was

12wileyonlinelibrary.com/journal/anzjog
© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
J. Eden13
given to reviews, especially systematic reviews and meta-­analyses.
Only English language articles and human studies were used.
Results are presented in three main sections reviewing
the safety of mP4 when used as MHT, on endometrium, heart
and breast.
MICRONISED PROGESTERONE AND
ENDOMETRIAL PROTECTION
The largest randomised controlled trial (RCT) examining the en-
dometrial safety of oestrogen-­mP4 was the Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial.5 This was a three
year, placebo controlled RCT of daily 0.625 mg conjugated equine
oestrogens (CEE) used alone or in combination with medroxy-
progesterone acetate (MPA) or mP4 200 mg given for 12 days per
month. Two thousand four hundred and eighteen endometrial
biopsies were obtained from 596 subjects. After three years of
treatment, the three progestin regimens -­ cyclic or continuous
MPA and cyclical mP4 200 mg – all effectively prevented endo-
metrial hyperplasia and carcinoma. No carcinomas were found
in the treatment groups (one was found in the placebo group).
The complex endometrial hyperplasia rates are shown in Table 1.
6
Cicinelli and colleagues performed a three year prospective
trial of oestradiol (E2) gel daily and alternative day vaginal mP4
100 mg. At the end of the study, the sonographic endometrial
thickness was significantly reduced when compared with baseline
and endometrial biopsy showed atrophy in all cases. Ninety-­three
percent were amenorrhoeic.
Jondet and colleagues7 performed a RCT on 336 postmeno-
pausal women who received percutaneous oestradiol 1.5 mg/
day from days 1–24 and either chlomadinone (CA) 10 mg daily or
oral mP4 200 mg daily from days 10–24. The primary endpoint
was endometrial assessment by biopsy. All subjects had normal
endometrium prior to receiving treatment. Treatment time was
18 months. No cases of endometrial hyperplasia were seen in ei-
ther treatment.
8
Fernandez-­Murga and colleagues performed an open-­label
study of 64 moderately symptomatic postmenopausal women.
T A B L E   1   Rates of complex endometrial hyperplasia in the
PEPI study
Risk of complex endome-
trial hyperplasia (cases /
Therapy (over 3 years) subjects in each group)
CEE alone 27/119
CEE and MPA cyclic 2/118
CEE and MPA continuous 0/120
CEE and mP4 200 mg 12 days per 0/120
month
CEE, conjugated equine oestrogen; MPA, medroxy-progesterone ace-
tate; mP4, micronised progesterone; PEPI, Postmenopausal Estrogen/
Progestin Interventions trial
T A B L E   2   Recommended dosage of mP4 for endometrial
protection
Oral route
Cyclical: 200 mg mP4 for 12–14 days per month
Continuous: 100 mg mP4 daily
Vaginal route
Alternate day: 100 mg mP4
Sequential: 45–100 mg for at least 10 days a month
Minimal dose: 100 mg twice a week (more research needed;
endometrial monitoring may be required)
Transdermal route
Not recommended
mP4, micronised progesterone
They were given 25 μg/day E2 as patches changed twice weekly
and on the day that the patch was changed they used intravag-
inal mP4 100 mg (i.e. twice weekly) for up to 12 months. The au-
thors reported no apparent endometrial stimulation based on
no change from baseline in endometrial thickness as assessed
by transvaginal ultrasound (backed up by biopsy if endometrial
thickness was increased).
One meta-­analysis was found.9 They reviewed 40 studies
using oestrogen-­mP4 as MHT and assessed the endometrium by
transvaginal ultrasound, endometrial sampling and / or endome-
trial carcinoma incidence. They found that oral and vaginal mP4
were effective endometrial protections, but transdermal mP4 was
not adequate. Their main conclusions are summarised in Table 2.
THE VAGINA AS A DELIVERY SYSTEM
Cicinelli has reviewed the intravaginal administration of progester-
one (and oestrogens).10 The vaginal route has several advantages
over oral. ‘Uterine first-­pass’ allows hormones such as progester-
one to concentrate in the uterus with low systemic levels. In vitro
fertilisation doctors have been using vaginal mP4 for decades as
luteal phase support. As a delivery system, the vagina functionally
comprises two sections. The anterior compartment has vascular
and lymphatic connections with the bladder (and so topical oes-
trogens are best delivered here). In contrast, the posterior vagina
has lymphatic and vascular networks with the uterus.
Cicinelli performed a proof-­of-­concept study on six volunteers
undergoing abdominal hysterectomy.11 In three, he sealed their
cervix with surgical glue. In all six, 0.2 mL of 99mTc-­pertechnetate
was introduced vaginally. Six women having thyroid nucleotide
scans were controls. In the group who received the vaginal ra-
dionucleotide, uterine radioactivity appeared after 60 min and
peaked between 120 to 210 min. Results were the same, whether
or not the cervix was sealed. In the group having thyroid scans, the
intravenous nucleotide did not appear in the uterus. He postulated
that there is probably a countercurrent mechanism that preferen-
tially delivers the nucleotide from the upper vagina to the uterus.
14
A large randomised controlled trial of vaginal P4 versus oral
P4 is unfortunately lacking at the moment. However, based on
the data presented, oral mP4 given as 200 mg cyclically or 100 mg
daily appears adequate as endometrial protection for oestrogen
replacement. The vaginal route may offer a low dose, infrequent
dosage and even lower systemic exposure than oral, but further
studies are needed.
MICRONISED PROGESTERONE AND
CARDIOVASCULAR SAFETY
CEE-­MPA and tibolone have both been shown in RCTs to have ad-
12,13
verse cardiovascular impact in older women (60 years and older).
CEE-­MPA usage increased the risk of heart disease, thrombosis and
stroke; tibolone increased risk of stroke only (all in the range 6–10
per 10 000 / year). Canonico14 has performed a meta-­analysis of
thrombosis risk associated with different delivery systems for oes-
trogen. Oral oestrogen increases the risk of thrombosis and stroke,
whereas transdermals such as E2 patches and gels do not.
Canonico and colleagues, in a separate study,15 reviewed
thrombosis risk with progestins and mP4. They concluded that
MPA and the norpregnane-­derived progestins were significantly
associated with increased risk of venous thromboembolism. With
regard to mP4 they concluded that it ‘could be safe’ with reference
to venous thrombosis risk.
RCTs using mP4 containing MHT with heart disease end-­points
have not yet been performed and so for the moment all that are
available are surrogate studies examining lipids, metabolic syn-
drome and vascular function.
Casanova and colleagues performed a RCT of 40 patients and
measured lipids, metabolic and endothelial function markers.16
Twenty received oral E2 1 mg and drospirenone 2 mg daily for
2 months and another group received E2 3 mg daily intranasally
with vaginal mP4 200 mg for 14 days out of 28. In both groups,
total and non-­high-­denity lipoprotein-­cholesterol decreased
below basal levels and fasting glucose, insulins, endothelian-­1, fi-
brinogen and C-­reactive protein levels remained unchanged.
Cuadros performed a retrospective analysis of women who used
MHT for more than 10 years.17 Twenty-­two used a 50 μg/day E2
patch alone; 83 used a 50 μg/day E2 patch plus 14 days per month
200 mg oral mP4; and 46 used a 50 μg/day E2 patch plus 100 mg oral
mP4 daily. There were 35 controls not using MHT. The frequency
of the metabolic syndrome was unchanged by treatment. Glucose
levels were significantly higher in the group receiving the sequential
regimen; otherwise no changes were seen in lipid profiles.
Finally, Simon has published an interesting intellectual exer-
cise entitled, ‘What if the Women’s Health Initiative [WHI] has used
transdermal oestradiol and oral progesterone instead?’18 He com-
pared and contrasted WHI data with the available information
on transdermal E2 combined with oral mP4. He concluded that
women treated with transdermal E2 (rather than oral CEE) and
mP4 (rather than MPA) ‘would probably have fared better with
Breast safety of progesterone
regard to CVD [cardiovascular disease] risk, stroke risk, VTE [ve-
nous thromboembolism] risk and breast cancer risk’ (page 781).
MICRONISED PROGESTERONE AND
BREAST SAFETY
Only three useful studies were found examining breast cancer
risk;19–21 nevertheless, they do supply some compelling data. The
E3N-­EPIC Study is a French prospective cohort study investigating
cancer risk factors in nearly 100 000 women born between 1925
and 1950.19This is easily the largest study examining MHT regi-
mens containing mP4. Since June 1990, every two years subjects
have filled in a questionnaire. Breast cancer risk was then assessed
in 54 548 postmenopausal women who had never used HRT be-
fore entering into the study. Over six years, 958 primary breast
cancers were detected. Subjects who took HRT used it on average
for 2.8 years. The results are shown below. Those using oestrogen
and synthetic progestins had a significantly higher breast cancer
risk than those using E2 and mP4 (P < 0.001; Table 3).
Asi et al. recently performed a systematic review and meta-­
analysis on the breast cancer risk associated with progestins and
mP4.20 They found two more smaller studies to use in their analy-
sis as well as the EPIC study. The included studies enrolled 86 881
postmenopausal women with mean age 59 years and follow up
ranging from three to 20 years. MHT regimens using mP4 (mostly
E2 and mP4) were associated with a significantly lower risk of
breast cancer than those using MHT therapies which included a
synthetic progestin (relative risk 0.67; 95% CI: 0.55–0.81).
Campognoli and colleagues reviewed clinical trial and labora-
tory data on progestins and mP4 and breast cancer risk.21 They
point to the differences in breast cancer risks with different regi-
mens (as above). There is also abundant laboratory data suggest-
ing that progestins have adverse effects on breast and hepatic
enzyme and protein systems that make it likely that MHT therapies
containing synthetic progestins will slightly increase breast cancer
risk. However, Campognoli concludes that ‘progesterone does not
have cancer-­promoting effects on breast tissue’ (page 104).
SIDE EFFECTS
Around 5–10% of patients will have side effects from proges-
tins such as mood swings, depression and fluid retention.22 In
T A B L E   3   Relative risk of breast cancer from the E3N-­EPIC
Study19
Hormone replacement therapy used Relative risk (95% CI)
Oestrogen alone (mostly E2) (0.8–1.6)
Oestrogen and progestin 1.4 (1.2–1.7)
Oestrogen and mP4 0.9 (0.7–1.2)
mP4, micronised progesterone
J. Eden15
contrast side effects from oral mP4 are infrequent, although a few
develop dizziness or moodiness when initiating therapy; this can
be minimised by taking the treatment at night.22 Vaginal mP4 is
very well tolerated, since most of the progesterone is delivered to
the uterus, rather than systemically.
CONCLUSIONS
Clearly more research is required. Ideally a large RCT (like WHI)
is needed using transdermal E2 in combination with oral or vagi-
nal mP4. At the moment, we can conclude that mP4 given orally
(100 mg daily or 200 mg sequentially) or vaginally (100 mg every
second day) offers adequate endometrial protection for women
using oestrogen therapy to manage menopausal symptoms. With
regard to metabolic and cardiovascular safety, most of the data to
date is surrogate and reassuring. Micronised progesterone does
not seem to attenuate the cardiovascular benefits of oestrogens
and is likely safer than progestins.
For most women, the breast cancer issue is of greatest con-
cern. Unlike WHI, EPIC was not a RCT and so does have limitations.
Nevertheless, EPIC is easily the largest cohort study of MHT con-
taining mP4 yet performed and in combination with the Asi et al.
meta-­analysis20 would suggest that MHT regimens containing
mP4 are associated with a significantly lower risk of breast cancer
than those containing progestins.
Oral P4 appears to have fewer side effects than synthetic
progestins, although a small number may develop dizziness or
moodiness. For these patients, the vaginal route may be superior,
although more studies are needed, ideally randomised trials com-
paring progestins, oral P4 and vaginal P4.
Many women want to use body identical MHT. It would seem
that transdermal oestradiol in combination with oral or vaginal mP4
may offer those Australian women having moderately severe meno-
pausal symptoms an effective ‘natural’ MHT that has a lower throm-
bosis and breast risk than standard oral MHT containing synthetic
progestins. At the moment, we can conclude that mP4 given orally
(100mg daily or 200mg sequentially) or vaginally (100mg every sec-
ond day) offers adequate endometrial protection for women using
low to medium dosage oestrogen therapy (equivalent to transdermal
patches 25-50mcg/day) to manage menopausal symptoms.
ACK NO WLEDGEM E N TS
Nil.
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