Position statement of the Menopause Society of Sri Lanka on estrogen and progestogen use in peri- and post-menopausal women and some other management options M D P Gooneratne1, Hemantha Perera2 Sri Lanka Journal of Obstetrics and Gynaecology 2009; 31: 128-135 Contents
Biological identity of productsContinuous versus sequential EPT
Estrogen and progestogen Alternative and complementary therapies Management considerations
The role of local vaginal estrogen for treatment ofvaginal atrophy in postmenopausal women
The role of testosterone therapy in postmenopausal
The role of calcium in peri- and post-menopausal
Abbreviations
EPT – Combined estrogen-progestogen therapy
HT – Hormone therapy (encompassing both ET and
OsteoporosisDementia and cognitive decline
Introduction
Since the release of the position statement of the
Premature menopause and premature ovarian
Menopause Society of Sri Lanka (MSSL) in 2008, there
were many new findings and views on the Women‘s
Health Initiative (WHI) and the Million Women Study
(MWS). This has clarified some of the uncertainties
about the role of HT among health professionals andwomen. This resulted in the release of this revised
Indications for extended useQuality of life
Biological identity of products
Systemic HRT administered as EPT has the two
principal components, estrogen and progestogen. Both
1 Consultant Obstetrician and Gynaecologist, Founder
hormones may be natural or artificial in constitution. President, Menopause Society of Sri Lanka.
Therefore it may be of clinical relevance to discuss
2 Consultant Obstetrician and Gynaecologist, Sri
specific drug classes, but the results from large
epidemiological studies are in general assumed to
Corresponding author: M D P Gooneratne
apply to all systemic HRT regimens regardless of
hormonal structure or route of delivery. Sri Lanka Journal of Obstetrics and GynaecologyPosition statement of the Menopause Society of Sri Lanka
The principal difference between oral and non-
Postmenopausal women without a uterus should
oral (transdermal, subcutaneous, nasal) route of
generally not be prescribed a progestogen with
administration is the first-pass metabolism in the gut
systemic estrogen. Progestogen is generally not
and liver changing markedly the pharmacokinetics
indicated when low-dose estrogen is administered
As estrogen, natural estradiol valerate or
micronized 17- estradiol is often used in Europe
Women’s Health Initiative (WHI)
whereas the conjugated equine estrogen (CEE) derived
WHI was a combination of several randomized
from pregnant mare´s urine is the preferred product
controlled trials, designed in the early 1990s to examine
various strategies for the primary prevention andcontrol of some of the most common causes of morbidity
After oral intake the equipotent dose of 2 mg 17-
and mortality among healthy post-menopausal
estradiol corresponds to approximately 0.625mg of
conjugated estrogens and to 50 μg delivered by patchesor 1.5 mg given as percutaneous gel. Hormone Therapy Trials (HT): This component
Progesterone is not available from any natural
examined the effects of combined hormones or estrogen
source without extraction and synthesis. In contrast
alone on the prevention of coronary heart disease and
to progesterone, the progestogens used in HRT are all
osteoporotic fractures, and associated risk for breast
rapidly absorbed after oral intake. The most common
cancer. Women participating in this component took
products are those based on the C19 steroid
hormone pills or a placebo (inactive pill) until the
testosterone (i.e norethisterone, levonorgestrel), the 17-
Estrogen plus Progestin and Estrogen Alone trials
hydroxyprogesterone derivatives (i.e. medroxy-
were halted early in July 2002 and March 2004,
progesterone acetate (MPA), megestrol acetate), 19-
norprogesterone derivatives (i.e. nomegestrol,promegestone, trimegestone) or the retroprogesterone,
The Women’s Health Initiative Memory Study
dydrogesterone. Drosperinone which is a derivative
(WHIMS) is an ancillary study to the Women’s Health
of spironolactone, has the added advantage of
Initiative (WHI). WHIMS was designed to determine
preventing weight gain and possible beneficial effects
the effects of Hormone Therapy (HT) on the
development and progression of dementia symptomsin postmenopausal women. This trial too was stopped
It is not possible to extrapolate conclusions from
following the premature termination of the hormone
the study of one compound, dose, and route of
administration directly to another. However, in theabsence of clinical trial data for each estrogen and
Million Women Study (MWS): MWS was an
progestogen, the clinical trial results for one agent may
observational study of more than one million women
be generalized to all agents within the same family.
in the UK, aged 50 and over. The study looked mainlyat how hormone replacement therapy affects a
Continuous versus sequential EPT
woman’s breasts and other aspects of her health. Between 1996 and 2000, women aged between 50-64
The recent RCTs were conducted with continuous
combined regimens. Cohort and case-control studies
(mean age 57) attending breast screening at 66
do not allow conclusions in favour of any regimen
participating NHS Breast Screening Centres in the UK
with regard to the breast. Concerning the cardio-
vascular risk, no information is available for thiscomparison, and there are no additional data from
Interpreting studies
other RCTs comparing other relevant clinicalendpoints during systemic sequential versus
It is essential to assess studies critically and not
to generically extrapolate the results of a single studyor trial to all menopausal women. Points to considerinclude:
Indication for progestogens
1. The appropriateness of the dose/regimen for the
Unopposed ET in women with an intact uterus
significantly increases the risk of endometrial cancer. The primary menopause-related indication for
2. The preparation and route of administration of
progestogen use is endometrial protection from
therapy since these may have different metabolic
3. The age and health profile of the population
Randomized controlled trials, albeit limited, have
shown that low-dose, local vaginal estrogen delivery
is effective and well tolerated for treating vaginal
4. The relevance of the design and duration of the
study, drop out rates and unblinding to the endpoint examined.
The choice of therapy should be guided by clinical
A significant contributor to the outcome from the
use of hormones during peri- and postmenopause is
Progestogen is generally not indicated when low-
the time of initiation of HT use in relation to
dose estrogen is administered locally for vaginal
menopause (final menstrual period). There is a real
difference between initiation of HT for symptom reliefduring perimenopause and initiation of systemic HT
Data are insufficient to recommend annual
use 5, 10, or more years beyond menopause for non-
endometrial surveillance in asymptomatic women
Evidence-based medicine implies that recom-
Vaginal ET should be continued for women as
mendations should be limited to the women for whom
long as distressful symptoms remain.
the studies are relevant. Although this goal is ideal inprinciple, it is impossible in practice, given that there
For women treated for nonhormone-dependent
will never be adequate RCTs covering all populations,
cancer, management of vaginal atrophy is similar to
that for women without a cancer history. For women
with a history of hormone-dependent cancer,management recommendations are dependent upon
Many large randomized controlled trials (RCTs)
each woman`s preference in consultation with her
and observational studies of postmenopausal women
using HT have been published in recent years. Notrial is perfect and no single trial should be used tomake public health recommendations. Coronary heart disease
The majority of observational and preclinical
Pretreatment evaluation
studies support the potential benefits of systemic ET/
EPT in reducing coronary heart disease (CHD) risk
Before considering any therapeutic regimen,
including ET/EPT, all women should have a completehealth evaluation, including a comprehensive history
When analyzed by age and time since menopause
and physical examination. Mammography should be
at initiation of HT, RCTs are in general agreement with
performed according to national guidelines and age,
observational studies indicating that HT may reduce
but preferably within the previous 12 months before
CHD risk when initiated in younger and more recently
initiation of therapy. Other specific examinations, such
as bone densitometry, should be considered on a case-by-case basis.
Analysis of the time trend in the EPT arm of the
WHI showed a significant interaction between CHD
risk and time since initiation of EPT, with an increased
Vasomotor symptoms
risk in the first year after initiation and decreased risk
Treatment of moderate to severe vasomotor
of CHD events in later years of EPT use.
symptoms (i.e., hot flushes and night sweats) remainsthe primary indication for systemic ET and EPT.
Pending additional data, the use of ET/EPT is
not recommended as a single or primary indication
for coronary protection in women of any age. Treatment of urogenital symptoms in postmeno- pausal women
It is important to note that the women enrolled in
WHI and HERS initiated EPT more than a decade after
Features of estrogen deficiency in the urogenital
menopause on average, and the majority of events that
systems include vulvar and vaginal atrophy, vaginal
produced this pattern occurred in older women.
dryness, dyspareunia, atrophic vaginitis, soreness,recurrent vaginitis, cystitis from colonic germs, postcoital cystitis, nocturia, urinary frequency and
Osteoporosis
urgency. When HT is considered solely for this
indication, local (not systemic) vaginal ET is generally
postmenopausal osteoporotic fractures, including hip
fractures, even in women without osteoporosis. Sri Lanka Journal of Obstetrics and GynaecologyPosition statement of the Menopause Society of Sri Lanka
Extended use of HT is an option in younger
increases endometrial cancer risk. This increased risk
women at risk such as premature menopause, when
persists for several years after ET discontinuation. To
alternate therapies are not appropriate or cause side
negate this increased risk, adequate concomitant
effects, or when the benefit risk ratio of the extended
progestogen use is recommended for women with an
use of alternate therapies is unknown.
intact uterus. No increased risk of endometrial cancerhas been found with continuous combined regimens. Venous thromboembolism Colorectal cancer
Observational studies and RCTs have found a
significant increase in the risk of venous
Results from the oestrogen progestogen arm, but
thromboembolism (VTE) in postmenopausal women
not the oestrogen alone arm, of the WHI study were
consistent with data from case control and cohortstudies that HRT reduces the risk of colorectal cancer
Lower doses of oral estrogens may be safer than
by about a third. However little is known about
higher doses. Growing evidence suggests that women
colorectal cancer risk when treatment is stopped. There
with a prior history of VTE or women who possess
is no information about HRT in high risk populations
factor V Leiden are at increased risk for VTE with HT
and current data do not allow prevention as a
use. There are limited observational data suggesting
lower risks of VTE with transdermal than with oralET, but there are no RCT data on this subject. Ovarian cancer
This issue is unresolved and requires further
examination and there is currently insufficient
Both ET and EPT appear to increase the risk of
evidence to recommend alterations in HRT prescribing
ischemic stroke in postmenopausal women, but RCT
data have not been fully consistent in this regard. TheWHI EPT and ET arms demonstrated an increased
Diabetes mellitus
risk, whereas some other large trials have not.
Large RCTs suggest that HT reduces new onset
Women with prevalent cardiovascular disease
(CVD) have a high baseline risk of stroke. No HTregimen should be used for the primary or secondary
There is inadequate evidence to recommend
prevention of stroke, and HT should be particularly
combined EPT for a sole indication of the prevention
avoided for women who have an elevated baseline
of DM in perimenopausal women. This is a promising
Breast cancer Gallbladder disease
Breast cancer risk increases with EPT use beyond
WHI confirmed the observation of the Heart and
5 years. In absolute terms, this increased risk was rare
Estrogen/progestin Replacement Study published in
in the WHI, being 4 to 6 additional invasive cancers
1998 that HRT increases the risk of gallbladder
per 10,000 women per year who used EPT for 5 or
disease. Gallbladder disease increases with ageing
and with obesity, and as confounder HRT users mayhave silent pre-existing disease.
Women in the ET arm of the WHI demonstrated
no increase in risk of breast cancer after an average of
Dementia and cognitive decline
7.1 years of use, with 8 fewer cases of invasive breastcancer per 10,000 women per year of ET use.
HT cannot be recommended at any age for the
sole or primary indication of preventing cognitive
Irrespective of the type of HT prescribed, breast
cancer risk falls after cessation of use, risk being nogreater than that in women who have never been
Depression
Although HT might have a positive effect on mood
and behavior, evidence is insufficient to support the
Endometrial cancer
use of ET/EPT for the treatment of depression in
Premature menopause and premature ovarian
of age and duration of ET/EPT use. The decision to
continue HT should be individualized on the basis of
Premature menopause and premature ovarian
severity of symptoms and current risk-benefit ratio
failure are conditions associated with a lower risk of
considerations, provided the woman in consultation
breast cancer and earlier onset of osteoporosis and
with her healthcare provider believes that continuation
CHD, but there are no clear data as to whether ET or
EPT will affect morbidity or mortality from theseconditions. Indications for extended use
The risks attributable to HT use by these young
Extended use of the lowest effective dose for
women receiving HT are likely smaller and the benefits
treatment goals of ET or EPT is acceptable under the
potentially greater than those in older women who
following circumstances, provided that the woman is
commence HT at or beyond the typical age of
well aware of the potential risks and benefits and that
menopause, although no trial data exist.
For the woman for whom, in her own opinion, the
Lower doses
benefits of menopause symptom relief outweigh
risks, notably after failing an attempt to stop HT.
should be considered (i.e., daily doses of 0.3 mg oralconjugated estrogens, 0.25-0.5 mg oral micronized
For women who are at high risk of osteoporotic
17A-estradiol, 0.025 mg transdermal 17A-estradiol
fracture and also have moderate to severe
patch, or the equivalent). However, lower doses have
not been tested in long-term trials. Some women may
For further prevention of bone loss in the woman
require additional local therapy for persistent vaginal
with established reduction in bone mass when
alternate therapies are not appropriate for thatwoman or cause side effects or when the outcomes
Non-oral therapy
of the extended use of alternate therapies areunknown.
Nonoral routes of administration of ET/EPT may
offer advantages and disadvantages, but the long-termrisk-benefit ratio has not been demonstrated. Quality of life
There is some evidence that transdermal 17A-
An improvement in health-related QOL (HQOL)
estradiol may be associated with lower risk of deep
can result with HT through decreased menopausal
venous thrombosis than oral estrogen.
symptoms and possible elevation of mood that leadsto a feeling of well-being. Long-term therapy in symptomatic women
While some studies have shown improvement in
The effects of ET/EPT on risk of breast cancer,
both symptomatic and asymptomatic women, others
CHD, stroke, total CVD, and osteoporotic fracture in
have not. This lack of effect seen in WHI is hardly
perimenopausal women with moderate to severe
surprising, since the study participants were largely
menopause symptoms have not been established in
asymptomatic. This area is difficult to evaluate
because of the different measures used, varying levelsof menopausal symptomatology, a large placebo effect
Data from large studies such as the WHI and
and extrinsic factors which may alter women's
HERS should not be extrapolated to symptomatic
postmenopausal women younger than 60 years of agewho initiate HT at that time as these women were notstudied in those trials. Summary of the position statement of the Menopause Society of Sri Lanka
The data should also not be extrapolated to
women experiencing premature menopause (?40 y)
necessarily relevant to younger postmenopausalwomen taking appropriate doses of different regimens
Symptom recurrence
Giving one HT regimen to women in WHI who
Symptoms have an approximate 50% chance of
had no particular indication to take it resulted in
recurring when therapy is discontinued, independent
neither harm nor benefit to over 99%. Sri Lanka Journal of Obstetrics and GynaecologyPosition statement of the Menopause Society of Sri Lanka
The oestrogen alone arm of WHI found a reduced
effects similar to those of estrogens. Preparations vary
risk of breast cancer and coronary heart disease in
from enriched foods, such as bread or drinks (e.g. soy
milk), to more concentrated tablets.
HT should currently not be prescribed solely for
The most important groups are called isoflavones
possible prevention of cardiovascular disease and
The results from recent papers have thus far given
daidzein. The major lignans are enterolactone and
no reason to make any change in current clinical
Isoflavones are found in soybeans, chickpeas, red
Summary practice points
clover and probably other legumes (beans and peas).
(i) Most women who request HT do so for symptom
relief which is the main indication for HT use in
Lignans are found in oil seeds such as flaxseed,
peri and postmenopausal women. Treatment for
and they also are found in cereal bran, whole cereals,
up to five years does not add significantly to
lifetime risk of breast cancer, but significantlydecreases bone loss and risk of osteoporotic
The role of phytoestrogens has stimulated
considerable interest, as people from populations thatconsume a diet high in isoflavones, such as the
(ii) Women with a premature menopause should
Japanese, are claimed to have lower rates of:
normally be offered HT until the average age of
menopausal vasomotor symptoms; cardiovascular
disease; osteoporosis; and breast, colon, endometrial
(iii) Some women may be susceptible to early
thrombotic risk, but when appropriate HRT isgiven after individual clinical evaluation, the
benefits will far outweigh any potential risks and
evidence from randomized placebo-controlled trials
the treatment should be recommended.
in Western populations is conflicting for soy and
(iv) The merits of long term use need to be assessed
derivatives of red clover. Similarly, debate also
for each individual at regular intervals, such as
surrounds the effects on lipoproteins, endothelial
function, blood pressure, cognition, the endometriumand the breast.
(v) Women whose uterus is present should be offered
appropriate progestogen therapy as oestrogen
It is clear that foods or supplements that contain
alone will increase the risk of endometrial cancer
isoflavones have some physiologic effects. Cliniciansmay wish to recommend that menopausal women
Alternative and complementary therapies
consume whole foods that contain isoflavones,
Tibolone
especially for the cardiovascular benefits of thesefoods; however, a level of caution needs to be observed
Tibolone is a synthetic steroid that has oestro-
genic, progestogenic and androgenic properties. It iseffective in treating menopausal symptoms. It
Further well designed, randomized clinical trials
conserves bone mass, and preliminary data have
are needed before specific recommendations can be
demonstrated a reduction in vertebral fractures. Further fracture data will be forthcoming.
made regarding increased consumption of foods orsupplements that contain high amounts of isoflavones
Tibolone shares some of the risks of oestrogen
and to determine the role and safety of phytoestrogen
based HRT. The MWS showed an increased risk of
supplements in perimenopausal and postmeno-
breast cancer and endometrial cancer. However, it is
probable that the level of risk is overestimated in this
study and the actual level is uncertain. Again data
Herbalism
from randomised controlled trials are awaited.
Herbal remedies need to be used with caution in
women with a contraindication to estrogen, as some
Phytoestrogens
herbs have estrogenic properties. Herbs used by
Phytoestrogens are plant substances that have
The role of testosterone therapy in postmenopausal women
Endogenous testosterone levels have not been
clearly linked to sexual function in postmenopausal
women. Published evidence from randomizedcontrolled trials, although limited, indicates that
exogenous testosterone, both oral and nonoral
formulations, has a positive effect on sexual function,primarily desire, arousal, and orgasmic response, in
Others – wild yam cream, St John's wort, Vitexagnus-castus, liquorice root, Valerian root.
women after spontaneous or surgically inducedmenopause.
Interaction with conventional therapies is a major
concern as the consequences are potentially fatal.
Postmenopausal women with decreased sexual
desire associated with personal distress and with no
The consequences of herb-drug interactions
other identifiable cause may be candidates for
Bleeding when combined with warfarin or aspirin
Testosterone treatment without concomitant
estrogen therapy cannot be recommended because of
Hypertension, coma and mild serotonin syndromewhen combined with serotonin reuptake
therapy, recommendations are to rule out causes not
Reduces the blood concentrations of cyclosporin,
related to testosterone levels (eg, physical and
midazolam, tacrolimus, amitriptyline, digoxin,
psychosocial factors, medications) and to ensure that
there is a physiologic cause for reduced testosteronelevels (eg, bilateral oophorectomy).
There is also concern about interactions withanticancer drugs.
Laboratory testing of testosterone levels should
be used only to monitor for supra-physiologic levels
Furthermore, little control over the quality of the
before and during therapy, not to diagnose testosterone
products exists, so it is unusual to know what is
actually present in individual herbal preparations anddietary supplements.
Monitoring should also include subjective
assessments of sexual response, desire, and
Severe adverse reactions, including renal and
satisfaction as well as evaluation for potential adverse
liver failure and cancer, have been reported. Moreover,
some preparations contain high levels of heavy metals,such as arsenic, lead and mercury.
Transdermal patches and topical gels or creams
are preferred over oral products because of first-pass
Liver toxicity has been reported with black
hepatic effects documented with oral formulations.
Testosterone products formulated specifically for
Summary practice points
men have a risk of excessive dosing, although some
(i) Evidence from randomized trials that alternative
clinicians use lower doses of these products in women.
and complementary therapies improve meno-pausal symptoms or have the same benefits as
Testosterone therapy is contraindicated in
hormone replacement therapy is poor.
women with breast or uterine cancer or in those withcardiovascular or liver disease.
(ii) There is concern about interactions with other
treatments, as these may have potentially fatal
It should be administered at the lowest dose for
the shortest time that meets treatment goals.
(iii) Some preparations may contain estrogenic
compounds and this is a concern for women with
Counselling regarding the potential risks and
benefits should be provided before initiating therapy. Sri Lanka Journal of Obstetrics and GynaecologyPosition statement of the Menopause Society of Sri LankaThe role of calcium in peri- and post-menopausal References
1. British Menopause Society: Consensus Statement on
Hormone replacement therapy 27 June 2007.
The most definitive role for calcium in peri- and
postmenopausal women is in bone health, but, like
2. European Menopause and Andropause Society (EMAS) 2004/
2005 position statements on peri- and post-menopausal
most nutrients, calcium has beneficial effects in many
hormone replacement therapy. Maturitas 2005; 51.
body systems. Based on the available evidence, there
3. Menopause: The Journal of The North American Menopause
is strong support for the importance of ensuring
Society 2005; 12: 496.
adequate calcium intake in all women, particularly
4. Menopause: The Journal of The North American MenopauseSociety 2008; 15: 584-603.
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