Menopause is that time in the reproductive
phase of a woman where by the levels of circulating estrogen diminishes to such
low levels as to cause physical, psychological and sexual disturbances. At or
around menopause (between 48 to 52 years) there is a decline in the ovarian
functions and in the amounts of hormones produced by hypothalamus-FSH and LH
which results in decrease in the ovarian hormones. While cessation of periods
can be welcome to many a women, the wide ranging effects of lack of estrogen
can be discomforting to an equal many. One alternative to overcome the hazards
of menopausal syndrome is the use of Hormone Replacement Therapy (HRT).
Many trials on the use of hormone replacement
therapy during the past two decades have provided contradictory results on its
risks and benefits in post-menopausal women that has consequently put the
medical community in quandary in decision making about use of HRT. The use of
HRT declined globally following publication of the first data from the Women’s
Health Initiative (WHI) trial in 2002, with the revelation that there was an increased
risk of breast cancer and coronary heart disease (CHD) in postmenopausal women
taking HRT. Following this, Heart and Estrogen/Progestin Replacement Study
& its follow-up (HERS I & II), WHI Memory Study (WHIMS), Women’s
international study of long duration oestrogen after menopause (WISDOM) and the
Million Women Study (MWS) published results that were consistent with the
findings of the WHI study. This reduced enthusiasm for HRT use, and many health
professionals and patients considered the use of such hormones as ‘unsafe’,
leading to reduction in HRT prescribing1.
However, recent publications from the International Menopause Society13,14 indicate that HRT is the first-line and most effective treatment for menopausal symptoms. Moreover when the full results of the WHI trial were subsequently published it appeared that HRT may confer benefit for CHD prevention below age 60. The 2013 British Menopause Society & Women’s Health Concern recommendations2 on hormone replacement therapy and European guidance3 for the diagnosis and management of osteoporosis in postmenopausal women published in 2013 also supported this opinion. These revelations renew interest in realms of HRT use among post-menopausal women.
The differences in age at initiation and the
duration of HRT are key points. The intention dose and regimen of HRT need to
be individualized based on the principle of choosing the lowest appropriate
dose in relation to the severity of the symptoms and the time and age. HRT
appears to decrease coronary artery disease in younger women, near menopause
yet, in older women, HRT increases risks of coronary event. New findings also
showed that the additional benefits of
HRT use for those initiating HRT in the 50-59 age group, or for those less than
10 years past the menopause – trends to a lower risk from heart disease; a
lower risk of death from any cause; no clear increased risk from stroke. They
also showed a general increased risk for those starting HRT after the age of 604. This article reviews the
current body of evidence on HRT use among post-menopausal women in light of the
consensus statement published by International Menopause Society in 2013 and
revised recently in 2016.
In
1975, estrogen only was found to be associated with an increased risk of
endometrial cancer. In November 2015, NICE guidelines on hormone therapy were
published that did not take this risk into account. A systematic literature
review of 28 published studies assessing the safety of estrogen plus progestin
therapy according to the risk of endometrial cancer, while considering both
regimen and type of progestin concluded that use of unopposed estrogen,
tibolone and sequential combined therapy increases the risk of endometrial
cancer. Continuous combined therapy might provide a lower risk than never use,
even when treatment lasts less than 5 years, and therapy for more than 10 years
does not increase risk; micronized progesterone increases the risk of
endometrial cancer, regardless of regimen5.
Global consensus statement on menopausal
hormone therapy
The past one and a half decade has witnessed
much confusion regarding the use of menopausal hormone therapy (MHT). New
evidence challenged previously accepted clinical guidelines, especially on
aspects of safety and disease prevention. This led to many women unnecessarily being
denied the use of MHT. Detailed revised guidelines were published and regularly
updated by the major regional menopause societies. The confusion was initially
escalated by significant differences amongst published guidelines. In recent revisions,
the differences have become much less. In view of this, The International
Menopause Society (IMS) took the initiative to arrange a round-table
discussion, in November 2012, between representatives of the major regional
menopause societies to reach consensus on core recommendations regarding MHT.
The aim was to produce a short document, only containing the points of
consensus. It is acknowledged that, in view of the global variance of disease
and regulatory restrictions, these core recommendations do not replace the more
detailed and fully referenced recommendations prepared by individual national and
regional societies6,7,8,9,12.
IMS document serves to emphasize international consensus regarding MHT and is
aimed at empowering women and health-care practitioners in the appropriate use
of MHT. The publication of the Global Consensus on Menopausal Hormone Therapy
in 201310,11 by leading
global menopause societies succeeded in presenting guidelines in a troubled
therapeutic area that are helpful to both health-care providers and potential
users of menopausal hormone therapy.
In June, 2016, a Revised Global Consensus
Statement on menopausal hormone therapy13,14
has been endorsed by The International Menopause Society, The North
American Menopause Society, The Endocrine Society, The European Menopause and
Andropause Society, The Asia Pacific Menopause Federation, The International
Osteoporosis Foundation and The Federation of Latin American Menopause
Societies. This statement has been simultaneously published in the journals
Climacteric and Maturitas, on behalf of the International Menopause Society and
The European Menopause and Andropause Society, respectively. Statement reads as
under:
The revised statement aims at updating and
expanding the areas of consensus. The revised statement contains only areas of
consensus and does not replace the more detailed and fully referenced
recommendations of the individual societies. This statement is expected to
enable health-care providers to offer those women in midlife, who may benefit
from MHT, the opportunity to make an informed decision.
Benefit/risk
profile of MHT13,14
MHT, including tibolone and the combination of conjugated equine
estrogens and bazedoxifene (CE/BZA), is the most effective treatment for
vasomotor symptoms (VMS) associated with menopause at any age, but benefits are
more likely to outweigh risks if initiated for symptomatic women before the age
of 60 years or within 10 years after menopause.
If MHT is contraindicated or not desired for treatment of VMS, selective
serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors
such as paroxetine, escitalopram, venlafaxine and desvenlafaxine, which have
been shown to be effective in randomized controlled trials (RCTs), may be
considered. Gabapentin may also be considered.
Quality of life, sexual function and other menopause-related complaints,
such as joint and muscle pains, mood changes and sleep disturbances, may
improve during MHT.
MHT, including tibolone and CE/BZA, is effective in the prevention of
bone loss in postmenopausal women.
MHT has been shown to significantly lower the risk of hip, vertebral and
other osteoporosis-related fractures in postmenopausal women.
MHT is the only therapy available with RCT-proven efficacy of fracture
reduction in a group of postmenopausal women not selected for being at risk of
fracture and with mean T-scores in the normal to osteopenic range.
MHT, including tibolone, can be initiated in postmenopausal women at
risk of fracture or osteoporosis before the age of 60 years or within 10 years
after menopause.
Initiation of MHT after the age of 60 years for the indication of
fracture prevention is considered second-line therapy and requires individually
calculated benefit/risk, compared to other approved drugs. If MHT is elected,
the lowest effective dose should be used.
MHT, including tibolone, is effective in the treatment of vulvovaginal
atrophy (VVA), now also considered as a component of the genitourinary syndrome
of menopause (GSM). Local low-dose estrogen therapy is preferred for women
whose symptoms are limited to vaginal dryness or associated discomfort with
intercourse or for the prevention of recurrent urinary tract infections.
Ospemifene, an oral selective estrogen receptor modulator, is also licensed in
some countries for the treatment of dyspareunia attributed to VVA.
RCTs and observational data as well as meta-analyses provide evidence
that standard-dose estrogen-alone MHT may decrease the risk of myocardial
infarction and all-cause mortality when initiated in women younger than 60
years of age and/or within 10 years of menopause.
Data on estrogen plus progestogen MHT initiated in women younger than
age 60 years or within 10 years of menopause show a less compelling trend for
mortality benefit, and evidence on cardioprotection is less robust with
inconsistent results compared to the estrogen-alone group.
The risk of venous thromboembolism (VTE) and ischemic stroke increases
with oral MHT, although the absolute risk of stroke with initiation of MHT
before age 60 years is rare. Observational studies and a meta-analysis point to
a probable lower risk of VTE and possibly stroke with transdermal therapy
(0.05 mg twice weekly or lower) compared to oral therapy.
The risk of breast cancer in women over 50 years of age associated with
MHT is a complex issue with decreased risk reported from RCTs for estrogen
alone (CE in the Women's Health Initiative (WHI)) in women with hysterectomy
and a possible increased risk when combined with a progestin
(medroxyprogesterone acetate in the WHI) in women without hysterectomy. The
increased risk of breast cancer thus seems to be primarily, but not
exclusively, associated with the use of a progestin with estrogen therapy in
women without hysterectomy and may be related to the duration of use.
The risk of breast cancer attributable to MHT is rare. It equates to an incidence of women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and particularly before 40 years are at a higher risk for cardiovascular disease and osteoporosis and may be at increased risk of affective disorders and dementia. In such women, MHT reduces symptoms and preserves bone density. Observational studies that suggest MHT is associated with reduced risk of heart disease, longer lifespan, and reduced risk of dementia require confirmation in RCTs. MHT is advised at least until the average age of menopause.
The risk of breast cancer attributable to MHT is rare. It equates to an incidence of women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and particularly before 40 years are at a higher risk for cardiovascular disease and osteoporosis and may be at increased risk of affective disorders and dementia. In such women, MHT reduces symptoms and preserves bone density. Observational studies that suggest MHT is associated with reduced risk of heart disease, longer lifespan, and reduced risk of dementia require confirmation in RCTs. MHT is advised at least until the average age of menopause.
MHT initiated in early menopause has no substantial effect on cognition,
but, based on observational studies, it may prevent Alzheimer’s disease in
later life. In RCTs, oral MHT initiated in women aged 65 or older also has no
substantial effect on cognition and increases the risk of dementia.
MHT may be beneficial in improving mood in early postmenopausal women
with depressive and/or anxiety symptoms. MHT may also be beneficial for
perimenopausal women with major depression but antidepressant therapy remains
first-line treatment in this setting.
General principles governing the use of MHT13,14
The option of MHT is an individual decision in terms of quality of life
and health priorities as well as personal risk factors such as age, time since
menopause and the risk of VTE, stroke, ischemic heart disease and breast
cancer. MHT should not be recommended without a clear indication for its use.
Consideration of MHT for symptom relief or osteoporosis prevention
should be a part of an overall strategy including lifestyle recommendations
regarding diet, exercise, smoking cessation and safe levels of alcohol
consumption for maintaining the health and quality of life of peri- and
postmenopausal women.
MHT includes a wide range of hormonal products and routes of administration,
including tibolone (where available) or CE/BZA, with potentially different
risks and benefits. However, evidence regarding differences in risks and
benefits between different products is limited.
The type and route of administration of MHT should be consistent with
treatment goals, patient preference and safety issues and should be
individualized. The dosage should be titrated to the lowest appropriate and
most effective dose.
Duration of treatment should be consistent with the treatment goals of the
individual, and the benefit/risk profile needs to be individually reassessed
annually. This is important in view of new data indicating longer duration of
VMS in some women.
Estrogen as a single systemic agent is appropriate in women after
hysterectomy but concomitant progestogen is required in the presence of a
uterus for endometrial protection with the exception that CE can be combined
with BZA for uterine protection.
The use of continuous testosterone therapy, either alone or with MHT, is
supported in carefully selected postmenopausal women with sexual
interest/arousal disorder (in countries with regulatory approval).
The use of custom-compounded hormone therapy is not recommended because
of lack of regulation, rigorous safety and efficacy testing, batch
standardization, and purity measures.
Current safety data do not support the use of systemic MHT in breast
cancer survivors, although discussions, in selected women and in conjunction
with each woman’s oncologist, may occur for compelling reasons after
non-hormonal or complementary options have been unsuccessful.
On continuing use of systemic hormone therapy
after age 65, The North American Menopause Society Statement has provided that if
a woman has been advised of the increase in risks associated with continuing HT
beyond age 60 and has clinical supervision, extending HT use with the lowest
effective dose is acceptable under some circumstances, such as for the woman
who has persistent bothersome menopausal symptoms and for whom her clinician has
determined that the benefits of menopause symptom relief outweigh the risks.
Use of HT should be individualized and not discontinued solely based on a woman’s
age. The decision to continue or discontinue HT should be made jointly by the
woman and her healthcare provider15.
Conclusion
Body of evidence on HRT use suggests that all
interventions to relieve menopausal symptoms should be individually tailored to
the specific needs and concerns of each woman to provide an optimal quality of
life. Menopause – the natural event in every woman’s life should be treated
keeping in view the symptoms experienced by many women in milder or severe
form. For relief of hot flushes and vaginal dryness HRT remains the most
effective pharmacologic intervention. The benefits of HRT include protection
from osteoporotic fracture and colon cancer but evidences show that the risk of
CHD is reduced in younger women (less than 60 years) and women beginning HRT near menopause (within 10 years). HRT for
the treatment of menopausal symptoms and prevention of osteoporosis is
suggestive because studies support that estrogens and estrogen plus progestins
increase bone density and reduce risk of fractures by preventing bone loss in
both young and older postmenopausal women. The decision to use HRT should be a
joint one between a woman and her doctor with consideration to her need for
treatment, her age, history, risk factors and personal preferences. For all
women the lowest effective dose should be used for the shortest time. The need
to continue the HRT should be reviewed every 6 to 12 months taking into consideration
the change risk-benefit balance. Recent literature review suggests that the use
of HRT in management of menopause in specific age groups, regimens, dosage
forms is safe as the benefits in such patterns outweigh the risks associated
with the HRT usage.
References:
- Geer MI, Hussain PT, Mir JI. Risk-benefit analysis of combination versus unopposed HRT in post-menopausal women. International Journal of User-Driven Healthcare 2011;1(4):61-76.
- Panay N, Hamoda H, Arya R. The 2013 British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause International: The Integrated Journal of Postreproductive Health 2013; 0(0):1–10.
- Kanis JA, McCloskey EV, Johansson H. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23–57.
- Palacios S. Advances in hormone replacement therapy: making the menopause manageable. BMC Women’s Health 2008;8:22.
- Sjogren LL, Morch LS, Lokkegaard E. Hormone replacement therapy and the risk of endometrial cancer: A systematic review. Maturitas 2016;91:25-35.
- Baber RJ, Panay N, Fenton A, and the IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2015;19:109–50.
- Shifren JL, Gass ML; NAMS Recommendations for Clinical Care of Midlife Women Working Group. The North American Menopause Society recommendations for clinical care of midlife women. Menopause 2014;21:1038–6.
- Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100:3975–4011.
- Neves-e-Castro M, Birkhäuser M, Samsioe G, et al. EMAS position statement: The ten point guide to the integral management of menopausal health. Maturitas 2015;81:88–92.
- de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Climacteric 2013;16:203–4.
- de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Maturitas 2013;74:391–92.
- Wierman M, Arlt W, Basson R, et al. Androgen therapy (testosterone and DHEA) in women: a reappraisal: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014;99:3489–510.
- de Villiers TJ, Hall JE, Pinkerton JV, et al. Revised global consensus statement on menopausal hormone therapy. Climacteric 2016;19(4):313-5.
- de Villiers TJ, Hall JE, Pinkerton JV, et al. Revised global consensus statement on menopausal hormone therapy. Maturitas 2016;91;153-55.
- NAMS: The North American Menopause Society Statement on continuing use of systemic hormone therapy after age 65. Menopause 2015; 22(7):1.