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Hormone Replacement Therapy: Recent Recommendations

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DOI: 10.5005/jp-journals-10032-1079

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REVIEW ARTICLE
Hormone Replacement Therapy: Recent Recommendations
1
Jaideep Malhotra, 2Ruchika Garg
How to cite this article: Malhotra J, Garg R. Hormone
Replacement Therapy: Recent Recommendations. J South
Asian Feder Menopause Soc 2016;4(1):17-21.
Source of support: Nil
Conflict of interest: None
Date of submission: 03 October 2015
Date of acceptance: 10 November 2015
Date of publication: January 2016
BENEFICIAL EFFECTS OF HORMONE
REPLACEMENT THERAPY
A Cochrane systematic review summarized the results
of 24 placebo-controlled randomized trials; this showed
a clear beneficial effect with estrogen replacement com-
pared with placebo.
The short-term use of hormone replacement therapy
(HRT) may improve mood and depressive symptoms
during the menopausal transition and in early meno-
pause. Women with severe depression and those who do
not respond to HRT will require psychiatric assessment.
Sexual Function
Estrogen, systemic or topical, may improve sexual func-
tion in women. It is particularly helpful in women with
dyspareunia secondary to vaginal atrophy, through its
proliferative effect on the vulval and vaginal epithelium
and by improving vaginal lubrication.
Urogenital Symptoms
Estrogen treatment has been shown to be effective in
treating symptoms related to vaginal atrophy, such as
vaginal dryness and superficial dyspareunia.
Low-dose vaginal estrogen preparations can be used
long term in symptomatic women as required, and all
1
Consultant, 2Assistant Professor
1
Rainbow IVF, Agra, Uttar Pradesh, India
2
Department of Obstetrics and Gynecology, Sarojini Naidu
Medical College, Agra, Uttar Pradesh, India
Corresponding Author: Ruchika Garg, Assistant Professor
Department of Obstetrics and Gynecology, Sarojini Naidu Medical
College, Agra, Uttar Pradesh, India, e-mail: ruchikagargagra@
gmail.com
Journal of South Asian Federation of Menopause Societies, January-June 2016;4(1):17-21
jsafoms
10.5005/jp-journals-10032-1079
Hormone Replacement Therapy: Recent Recommendations
topic estrogen preparations have been shown to be
effective in this context.
Nonhormonal preparations and lubricants can be
used as an alternative, but these are not as effective as
estrogen therapy.
Estrogen therapy has a protective effect against con-
nective tissue loss and may possibly reverse this process
in menopausal women receiving HRT.
Progestogens/Side Effects
After a minimum of 1 year of HRT, or 1 year after the last
menstrual period (2 years in premature ovarian insuffi-
ciency), women who wish to avoid a monthly withdrawal
bleed may attempt a switch to a continuous combined
regimen which aims to give bleed-free HRT; this will also
minimize the risk of endometrial hyperplasia.
Women can be switched to the tissue-selective agent
tibolone. If bleeding is heavy or erratic on a sequential
regimen, the dose of progestogen can be doubled or
duration increased to 21 days.
Persistent bleeding problems beyond 6 months
warrant investigation with ultrasound scan and/or
endometrial biopsy.
Progestogens have a Variety of Effects
Symptoms of fluid retention are produced by the sodium-
retaining effect of the renin–aldosterone system, triggered
by stimulation of the aldosterone receptors.
Androgenic side effects, such as acne and hirsutism
are a problem of the testosterone-derived progestogens
due to stimulation of the androgen receptors. Mood
swings and premenstrual syndrome-like side effects.
The dose can be halved and duration of progestogen
can be reduced to 7 to 10 days to minimize progestogenic
side effects. This may result in bleeding problems and
hyperplasia.
Progesterone and dydrogesterone generally have
less side effects due to progesterone receptor specificity;
progestogen is available in oral micronized form, vaginal
pessaries, and gel.
Long-term Effects of HRT
Initiating HRT after the age of 60 years for the sole
purpose of the prevention of osteoporotic fractures is
not recommended.
17
Jaideep Malhotra, Ruchika Garg
The bone-protective effect of estrogen is dose related.
The use of HRT for a few years around menopause
may provide a long-term protective effect many years
after stopping HRT. Bisphosphonates and other phar-
macological agents can be used as an alternative to HRT
to preserve bone density, but there can be side effects.
Long-term therapy with alendronate can predispose
to femoral shaft fragility fractures.
Cardiovascular
Data from the Danish osteoporosis trial have shown that
hormone therapy reduces the incidence of coronary heart
disease by around 50% if commenced within 10 years of
menopause; this is referred to as the “window of oppor-
tunity” for primary prevention.
The “Kronos Early Estrogen Prevention Study” ran-
domized controlled trial using lower doses of estradiol
and progesterone in women less than 3 years from their
last menstrual period reported neutral impact on cardio-
vascular risk markers, such as coronary calcium scores
and intima media thickness.
Cognition
Hormone replacement therapy should not be initiated
for the sole purpose of improving cognitive function
or reducing the risk of dementia in postmenopausal
women.
Recent critique of the Women’s Health Initiative
(WHI) and Million Women Study has clearly illustrated
a number of key flaws that limit the ability of the trials
to establish a causal association between HRT and
cancer.
Ovarian Cancer
A recent report from the Danish National Cancer Registry
revealed a small but significant increase in the incidence
of ovarian cancer following 8 years use of unopposed
estrogen and estrogen/progestogen therapy.
Endometrial Cancer
Unopposed estrogen therapy increases the incidence of
endometrial cancer by the use of combined sequential
estrogen and progestogen therapy. Long-term use of
combined HRT for more than 5 years is associated with
a small increase in risk of endometrial cancer.
Colorectal Cancer
The WHI trial showed that colorectal cancer risk was
reduced in women taking combined conjugated equine
estrogen (CEE) and medroxyprogesterone acetate, but
there was no effect of CEE only therapy.
18
Ospemifene
Ospemifene is nonhormonal and may be particularly
suited to women in whom estrogen is contraindicated.
It would also be of advantage to women with vulval and
vaginal atrophy symptoms who do not wish to administer
vaginal products of systemic estrogen.
Venous Thromboembolism (VTE) and HRT
Oral HRT increases the risk of VTE two- to fourfold, with
the highest risk in the first year of use. Venous thrombo-
embolism risk is further increased in those with a personal
or family history of VTE, advanced age, obesity, and other
risk factors, such as surgery or hospitalization.
Stroke
The WHI studies revealed an overall increased incidence
of stroke in women using estrogen and progestogen
therapy or estrogen alone. Reanalysis of the combined
data from the estrogen and progesterone study and that
of the estrogen-alone study revealed a smaller increase
in incidence of stroke in women who commenced HRT
between the ages of 50 and 59. The heart and estrogen
progestogen replacement study found no increased inci-
dence of stroke with HRT.
Premature Ovarian Insufficiency
Hormonal replacement therapy in premature ovarian
insufficiency simply replaces ovarian hormones that
should normally be produced.
Hormone therapy should generally continue at least
until the estimated age of natural menopause (on average
51 years). Hormonal replacement therapy is also impor-
tant to preserve uterine function in women planning
ovum donation.
The contraceptive pill can be used as an alternative to
control symptoms, but there are few data on long-term
benefit for protection against osteoporosis and cardio-
vascular disease.
Routes and Regimens
The vaginal route of progestogen and progesterone
administration, for example, levonorgestrel system and
progesterone gel and pessaries, provides adequate endo-
metrial protection with reduced systemic side effects.
A total of 12 to 14 days of progestogen should be
given for women with intact uterus to avoid endometrial
hyperplasia and minimize the risk of endometrial cancer
with unopposed estrogen.
Progestogen side effects may be reduced by using
natural progesterone in the form of oral capsules, transvag-
inal pessaries, or gels. The levonorgestrel-releasing intrau-
terine system provides adequate endometrial protection in

women receiving estrogen therapy. Systemic side effects
were reduced though not completely eliminated.
Continuous combined regimens avoid the need for
regular withdrawal bleeds, but may be associated with
continuous low-grade progestogen side effects. Ultra-
low-dose estradiol/progestogen continuous combined
regimens appear to maintain the benefits of higher
dose regimens while allowing minimal use of progesto-
gen to reduce side effects.
Sexual Function/Androgens
Tibolone has a weak androgenic effect that can have a
beneficial effect on mood and libido.
Testosterone gels licensed for male use are available in
50 mg, 5 mL sachets or tubed. Unlicensed prescription by
specialists is an option for female androgen replacement,
at a reduced dosage of 0.5 to 1.0 mL/day or one-fourth
sachet/tube on alternate days.
Androgenic side effects and risks are minimal and
reversible if testosterone levels are maintained within the
female physiological range. Some studies have shown
skeletal, cognitive, well-being, and vaginal benefits; these
data require confirmation.
Dehydroepiandrostenedione use requires further
research.
Pharmacological Alternatives
Evidence exists for the efficacy of selective serotonin
reuptake inhibitors, such as fluoxetine and paroxetine
in treating vasomotor symptoms; the most convincing
data for the serotonin–norepinephrine reuptake inhibitor
(venlafaxine) at a dose limits the usefulness of this agent.
Gabapentin has shown efficacy for hot flush reduction
compared with placebo.
Newer Therapies
Conjugated estrogen/bazedoxifene maintains the benefits
of traditional HRT while avoiding the need for progesto-
gen. Protection of the endometrium is achieved through
bazedoxifene, a selective estrogen receptor modulator.
This product is particularly beneficial in women with
progestogen intolerance.
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