A REVIEW ON RISK RELATED HORMONE REPLACEMENT THERAPY AND

CARDIOVASCULAR DISEASE

Name: Sonia Saleem

Roll no: 316-P-1115
Batch: 15
Semester: 9th
Subject: Clinical Pharmacy-Il

Subject In charge: Mam Anum Hanif

FACULTY OF PHARMACY
HAJVERY UNIVERSITY, EURO CAMPUS LAHORE

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Introduction:

Definition:
Hormone replacement therapy (HRT) is a treatment used to relieve symptoms of the menopause.
It replaces female hormone (estrogen )that is at a lower level as you approach the menopause.
Who needs hormonal replacement therapy (HRT):
 Symptomatic girls that suffer from oestrogen hormone deficiency.
 High risk cases of menopausal complications like cardiovascular illness,
osteoporosis,stroke.
 Alzheimer's disease and colonic cancer
 Premature menopause(spontaneous/post surgery)
 Gonadal sterility (therapeutic)
 Women demanding HRT therapy as prophylaxsis.
Physical symptoms:
 Irregular periods
 Hot flushes
 Night sweats
 Palpitations
 Sexual changes
 Skin and hair
 Joint pain
 Urinary symptoms
 Weight gain
 Headache
Physiological symptoms:
 Depression
 Irritability
 Tiredness
 Poor sleep
 Anxiety
 Loss of libido
 Weepiness

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  Forgetfulness loss of concentration
Drug used in hormonal replacement therapy:
1. Natural estrogens
2. Progesterone
3. Tibolone
4. Raloxifene(selective estrogen receptor modulator)
1: Natural estrogen:
Oral: -
 Conjugated equine estrogen (CEE): 0.625 mg (Estrone
 Sulphate + equilin sulphate +17 d dihydro equilin)
 Estradiol valerate (1, 2, 4 mg).
 Estrial succinate (1, 2 mg).
Transdermal (estradiol): -
 Patches: 25 micro gm, 50 micro gm / 24 hour twice weekly.
 Gel: 75 micro gm/ 24 hours daily.
Sub cutaneous implant (estradiol):
 25/50/ 100 mg. 6 monthly.
Vaginal:
 cream
2: Progesterone:
Oral route:
 Norgestrol 150 mg lday.
 Micronised progesterone 200 mg /day.
 Dydrogesterone 20 mg / day.
 Medroxy progesterone acetate 10mg/day.
 Norethisterone acetate 0.7 -2.5 mg/ day.
Hormone releasing intra uterine system:
 Levonorgestrel 20 mcg/ day.
 Progestasert 65mcg/ day.
Vaginal:
 Natural progesterone gel / pessary.
Transdermal:

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  Sequential / continuous patch.
3: Tibolone:
 Synthetic steroid, tissue specific HRT.
 2 hydroxy metabolites are estrogenic.
 D4 isomer binds to progesterone & androgen receptors.
 Addition of progesterone not required.
4: Raloxifene:
a) Raloxifene:
 Estrogen agonist - antagonist
 Dose 6omg / day orally
Advantages:
 Prevents only vertebral fractures
 Reduces LDL cholesterol( no effect on HDL)
 No endometrial hyperplasia
 Breast cancer
Disadvantages:
 Leg cramps
 Worsens vasomotor symptoms
 Venous thrombo embolism
b)Tamoxifen:
 Estrogen agonist - antagonist
 Dose 20mg/daily
Advantages:
 Protects from breast cancer
 Beneficial effect on CHD and spine bone density
Disadvantages:
 Endometrial hyperplasia.
Benefits of hormonal replacement therapy:
Vasomotor symptoms:
 Hot flushes & night sweats resulting from hyperactivity of mid brain-hypothalamic-
pituitary axis & characteristic of climacteric are relieved by HRT.
Sleep disturbances:

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  Early morning awakening and inability to get back to sleep is a frequent complaint in
postmenopausal women.Estrogen receptors are present in reticular activation system,
preoptic area, and hypothalamus.Estrogen replacement improves sleep by acting at these
sites.
Atrophy of genital tract:
 Leading to vaginal dryness & postmenopausal bleeding from atrophic vaginitis / atrophic
endometrium respond to estrogen therapy.
Dyspareunea:
 Due to vaginal dryness is not a problem in menopause, but it is a problem during
climacteric.
Loss of libido:
 Also respond to estrogen replacement. Some also get benefit from testosterone.
Mood & psychological changes:
 Estrogen replacement appears to have a direct mental tonic effect on the cognitive
functions even in the absence of vasomotor symptoms .It over comes anxiety, over
sensitivity, tearfulness, irritability, aggression.However if progesterone is also given, it
may reduce the beneficial effects of estrogen on libido & mood.
Literature review:
Hormone replacement medical care (HRT) has been used for over sixty years to treat
menopausal estrogen deficiency and increase longevity in postmenopausal ladies However,
following the publication of the Women's Health Initiative (WHI) study the result of HRT on
cardiovascular risk has been the topic of abundant discussion. The initial findings of this study
incontestable an inflated risk of coronary heart condition (CHD) in older ladies, while not
increasing mortality. Various empiric studies have shown the advantages of HRT on CHD
whereas some irregular controlled trials (RCTs) have incontestable negligible effects. Since there
are clear biological effects of estrogen on the vascular system, with studies showing helpful
effects on classical risk factors for CHD (e.g. dyslipidaemia and hypoglycemic agent resistance,
still as blood vessel epithelial tissue function, it looks unlikely that HRT mustn't profit CHD in
biological time girls. However, it's been shown that unsuitably high doses of estrogen could
cause cardiovascular harm owing to transient disturbances in thrombogenesis and tube it's
attention-grabbing to notice that nearly all irregular studies mistreatment clinical outcomes failed
to show edges in older ladies. In these studies, the typical beginning age of the participants was
mid-60s, and enclosed unsuitably high doses of HRT. Conversely, there have been trends to
profit vwomen within the observational studies, comprising participants in their early 50s, the
typical onset age for climacteric, World Health Organization started on an applicable dose of
HRT. Additionally, a pilot study mistreatment older ladies on lower dose HRT failed to
demonstrate any CVS harm. While benefits appear to be shown in younger ladies on HRT early

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within the postmenopause, there could also be similar edges in older ladies with an appropriate
dose of therapy.
Coronary heart disease a battle of the sexes,cardiovascular disease (CVD) includes diseases of
the heart, and arterial and venous blood vessels. CHD is now recognised as the leading single
cause of mortality in women in northern Europe and the Americas lifestyle factors (e.g. smoking,
diet and physical inactivity) all contribute to CHD. Genetic and environmental factors also play a
part in the incidence of CHD. While mortality rates increase with age for both sexes, and the
overall incidence is similar regardless of sex, women are more likely to develop CHD at a later
age than men. Premenopausal women are at relatively low risk from the disease, but following
the menopause, the incidence of CHD in women steadily increases to a level similar to that seen
in men. It appears that female sex hormones may play a preventative role, since other risk factors
for the disease are the same in both sexes. This is further supported by the fact that early-onset
menopause leads to premature CHD.The role of oestrogen - metabolic effects estrogen clearly
has beneficial effects on the metabolic risk factors for CHD, as well as on arterial function.
Lipids and lipoproteins: Oestrogen reduces overall cholesterol levels and the effect is maintained
in the long term during treatment. This effect is considered to be beneficial in reducing the risk
of CHD. This results primarily from a decrease in low density lipoprotein (LDL) cholesterol
levels owing to an upregulation of apolipoprotein B100 (apoB100) receptor. Small dense LDL
particles are more readily cleared through scavenger mechanisms rather than by the apoB100
receptors, and are more likely to become embedded in the subendothelial space.While HRI may
increase the level of small dense LDL particles, it also increases ther clearance from the
Circulation. This may reduce the likelihood of their retention in the arterial wall. Small dense
LDL particles may be more prone to oxidative damage, leading to foam cell production and
eventual atheroma, however, oestrogen may protect LDL against oxidative damage.Estrogen also
increases high density lipoprotein (HDL) cholesterol, particularly the HDL2 subfraction. It
inhibits hepatic lipase activity and increases the hepatic synthesis of apolipoprotein Al, the main
protein component of HDL and HDL2.While the effects on LDL cholesterol levels are
unaffected by the addition of progestogen, the increase in HDL cholesterol are reversed or
greatly reduced with the addition of androgenic progestogerns owing to an increase in hepatic
lipase activity. The effects of HRT are clearly linked to the dose and route of administration,
which determine its effects on triglycerides. Oral oestrogen increases triglycerides, while this is
reduced or reversed by the addition of androgenic progestogens.Conversely,transdermal
oestradiol reduces triglycerides, which should reduce the risk of CHD.
Insulin resistance: Tissue resistance to insulin action increases the future risk of developing both
CHD and type 2 diabetes mellitus. Oestrogen has beneficial effects on the metabolism of glucose
and insulin, which results in a reduction in insulin resistance. Oral oestrogen increases the effect
more compared with transdermal oestrogen, and may help prevent the onset of diabetes.
However, the effect is impaired with the addition of androgenic progestogens (e.g. norgestrel or
medroxyprogesterone acetate Non-androgenic progestogens (e.g. dydrogesterone) do not have
this unwanted effect.

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Body composition: Central body fat accumulation is an important risk factor for CVD. It is a
common misconception that HRT results in weight gain; it has Iittle overall effect on body
weight. In fact, as many women lose weight with HRT as gain weight. Central distribution is
linked to insulin resistance and the metabolic syndrome and, therefore, is an increased risk for
CHD. The menopause contributes to an increase incentral fat distribution, but HRT reverses the
changes in body fat distribution associated with menopause. This resulits in a reduction in central
fat accumulation.
Vascular remodelling:The abnormal deposition and remodelling of vascular extracellular matrix
are important processes involved in the pathogenesis and progression of atheroma. The
normalisation of these processes may inhibit atherogenesis. The matrix
metalloproteinases(MMPs)and their tissue inhibitors are central to vascular remodelling and may
contribute to the development of cardiovascular disease. A study has shown that oestradiol
increase the release of MMPs in a dose-dependent manner. Therefore, increases in MMPs
induced by low dose oestrogen may normalise vascular remodelling, while high doses of
oestrogenmay produce large increases in MMPs and produce excessive remodelling. Therefore,
the oestrogen dose at the onset of therapy is vital in terms of beneficial or harmful effects on
vascular remodelling.
Randomised trials:The WHI conducted a prospective RCT of HRT, using either conjugated
equine oestrogens alone or conjugated with MPA in more than 27,000 (16,608 in the oestrogen
plus MPA arm) postmenopausal women aged 50-79 demonstrated no overall difference between
treatments and placebo in outcomes of CHD. The study has sub"evidence that HRT does not
lower the risk of CHD, however, there are problems with the results of this study possible initial
adverse cardiovascular effects, perhaps owing to the high dose of oestrogen in the older women
eventual benefit. This appeared to be greater in those women on oestrogen alone than in those on
combined adverse effect of MPA. Benefits were seen in women aged 50-59 years taking
oestrogen alone. This was stay composite outcome of myocardial infarction, death and coronary
interventions. With 13 years post-trial obsessed reduction in myocardial infarction in these
oestrogen users became statistically significant compared with the benefits were seen in women
aged 70-79 years. The results suggested a "window of opportunity" to reduce early
postmenopausal years using HRT. Further analyses have shown no decreased risk of CHD in the
first two possible cardioprotective effect in women initiating oestrogen plus progestogen after six
years, with a halving this age-dependency is supported by the findings of the Danish
Osteoporosis Prevention Study (DOPS) age of menopause were randomised to oral oestradiol,
with or without cyclical norethisterone acetate (NETA years, with a further six years
observational follow-up. This showed a significant reduction in a composite out infarction, death
or hospital admission for heart failure in the HRT users compared with placebo users. One of
that the number of events was very small owing to the young age of the women involved - there
were five randomised trial (one on HRT), which increased to 16 in the observational follow-up
(five on HRT).Studies of cynomolgus macaques have also shown an age-dependency
relationship between HR CHD. Intervention with HRT at the time of menopause in the macaques
resulted in a 70% reduction of dietary compared with placebo, but a delay in initiating HRT
resulted in a loss of this effect.At the onset of menopause, women still have relatively healthy

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arteries, but arterial disease increases with a clinical evidence for the repair of already diseased
arteries in reponse to oestrogen. As a result, any preventative including HRT, is more effective
for younger women with less established atheroma. However, this does not receive no benefit.
Some studies have demonstrated that older women can still benefit from an appropriate with
established CHD. Evidence for this comes from the Women's Hormone Intervention Secondary
Preventive with low dose oral oestradiol plus NETA was given to older women with established
CHD. The results demo decreased CHD events over 12 months compared with placebo.
Consequently, the benefits of HRT may still be window of opportunity. Women with CHD
should not be denied HRT if there is a good clinical indication, but the dose at initiation is
crucial.
Conclusion:
Hormone replacement therapy (HRT) has a profound impact on the cardiovascular system in
postmenopausal women, achieved through its effects on metabolic risk factors for coronary heart
disease (CHD) and on arterial function. Observational studies have consistently shown an
association between postmenopausal HRT use and a reduced incidence of CHD. However, the
largest randomised trial initially reported no overall benefit on CHD risk. Subsequent analyses
and follow-up of the study have demonstrated a significant benefit for CHD risk in healthy
women initiating oestrogen therapy soon after the onset of menopause. This benefit of early
initiation of HRT has been confirmed in more recent trials and in meta-analyses. The dose and
type of hormones at initiation of therapy appears crucial to obtaining CHD benefit.
Reference:
1.

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