128-135 jog 11 review.pmd

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
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 Gynaecology Position 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 Gynaecology Position 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 Gynaecology Position 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

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 Gynaecology Position statement of the Menopause Society of Sri Lanka The role of calcium in peri- and post-menopausal
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 Menopause Society 2008; 15: 584-603.

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