THE MENOPAUSE AND
HRT
Dr Jacqueline Guest
Consultant Obstetrician
and Gynaecologist
Learning Objectives
• Physiology of the Menopause and Climacteric
• Role of Hormones in the Menstrual Cycle
• Symptoms of the Climacteric
• Hormone Replacement Therapy (HRT)
• Alternatives to HRT
Definition of the Menopause
The menopause is the last menstrual
period (LMP).
The perimenopause or climacteric is the
phase encompassing the menopause.
The climacteric lasts for about two years, but
may last for 10 years or longer.
Reproductive hormone
feedback systems
H yp o th a la m us
GnRH
An te rio r
p itu ita ry
LH
FSH
O varies
Progesterone
E n d o m e trium
Oestrogen
V a g in a,u te rus
L ip o p ro te ins
B re a s ts
O s te ob la s ts
The Role of Hormones in
The Menstrual Cycle
Gonadotrophin hormones stimulate the ovaries:
follicle stimulating hormone (FSH)
luteinising hormone (LH)
At the menopause ovaries run out of oocytes and they
become resistant to the gonadotrophin hormones
Levels of FSH and LH increase throughout the latter
stages of the Climacteric and reach a peak 2 to 3
years after the menopause
A level of FSH of more than 30IU/L on 2 separate
occasions indicates Ovarian Failure
The Role of Hormones in The
Menstrual Cycle
There are 3 important oestrogens in
women: oestradiol,oestriol & oestrone
Oestradiol is predominant in
premenopausal women: produced by
the ovaries.
Oestrone is predominant in
postmenopausal women : produced by
peripheral conversion of androgens in
the adipose tissue.
E1 is less biologically active than E2.
The Menopause - Acute Symptoms
•
•
•
•
•
•
Hot flushes
Night sweats
Headaches
Panic attacks
Mood swings
Indecisiveness
• Insomnia leading
to:
• irritability
• poor short term
memory
• difficulty with
concentration
MEDIUM TERM SYMPTOMS
•
•
•
•
•
•
Vaginal dryness
Dyspareunia
Reduced libido
Thinning skin/ hair
Skin formication
Urethral syndrome (frequency, nocturia
and urge incontinence)
LONG TERM SYMPTOMS
• CARDIOVASCULAR DISEASE
• OSTEOPOROSIS
• CEREBROVASCULAR DISEASE
Rise in female life expectancy
over the last 100 years
90
80
70
60
50
Life
expectancy
Age at
menopause
40
30
20
10
0
1850
1900
1950
2000
Symptoms of the Climacteric
35-45
PRE
46-55
age range
PERI
1 yr
Last menstrual
period
56-65
POST
Average duration of
climacteric symptoms
60%
50%
40%
30%
20%
10%
0%
1-5 years
< 1 year
5+ years
Symptoms of the Menopause
At least 60% of
women have hot
flushes and
night sweats as
their main
symptom
Hormone Replacement
Therapy (HRT)
OESTROGENS
• oestradiol
• oestradiol valerate
• conjugated equine oestrogens
• oestriol
These should not be confused with the oestrogens used in the
COC. They are used at a dose which is effectively 1/6th of the
dose used in the COC.
PROGESTOGENS
19 NORTESTOSTERONE
DERIVATIVES
17 HYDROXY-PROGESTERONE
DERIVATIVES
• norethisterone
• levonorgestrel
• norgestrel
• dydrogesterone
• medroxy progesterone
acetate
Prescription of HRT: ROUTES
Transdermal:
patch or gel
Subcutaneous
(implant)
Intramuscular
(depot)
Oral
Intra-uterine
(Mirena)
Intra-vaginal
(tablets, ring
or cream)
Preparations of HRT
• Oestrogen Only HRT (tablet, patch, gel,
implant)
• Sequential Combined HRT - oestrogen
and progestogens (tablets or patch)
• Continuous Combined HRT - oestrogen
and progestogens (tablets or patch)
Oestrogen Only HRT
• Only to be used in women who have had a total
hysterectomy
• If the hysterectomy was subtotal, then may need
to use progestogens as well (some endometrium
may be left behind)
• If the hysterectomy was for endometriosis, then
progestogens continuously along with oestrogen
should be used at least initially
Sequential Combined HRT
• Sequential oestrogen and progestogen
Oestrogen for
28 days
Progestogen for
14 days
• The addition of the progestogen protects the
endometrium and leads to a regular bleed
• Single named product available as patch or
tablet but individualisation possible eg gel and
IUS
Continuous Combined HRT
• Continuous Combined HRT (CCT)
Oestrogen
combined with
progestogen for 28
days
• This should not be started until 1 year after the
LMP or aged 54. Should also be used after 2
years of cyclical therapy if under the age of 54.
• No monthly bleed
Continuous Combined HRT
• This preparation leads to no bleeding after the
first 6 months of use
• Single named product available as tablets or
patches
• Any oestrogen continuously + any progestogen
continuously
The Mirena is now licensed for use with
Oestrogen only HRT for 4 years. The
advantage is that it can be used in younger
women to induce a no-bleed regime.
Tibolone or Livial
• This is an alternative CC HRT
• It is a gonadomimetic containing oestrogen,
progestogens and androgens
• Licensed for vasomotor symptoms and osteoporosis
• The risk:benefit ratio similar to HRT in women under 60,
but over 60 increased risk of stroke
• Slightly increased risk for endometrial cancer
• Less risk of breast cancer compared with CCT but
increased over E2 only HRT
• May help libido due to androgen content
How long with sequential HRT?
• There are now several papers * that show
that prolonged use of sequential HRT can
increase the risk of endometrial cancer
• Relative risk of endometrial cancer rose
from 1.3 to 2.9 for 5 years use
• For CCT HRT relative risk fell to 0.2
*Beresford et al. Lancet 1997.
Wiederpass et al. J. of the National Cancer Institute 1999.
The advice is therefore
 Do not keep women on cyclical
therapies longer than 5 years
 If the woman is over 54 or her
periods have stopped for a year at
any age start with CCT
 Under the age of 54 continue on
cyclical therapy for 2 years and
then change to CCT
Local oestrogen preparations
• For women with vaginal and bladder
symptoms who do not need systemic HRT
local oestrogens can be used
• Vaginal creams and tablets are available
• There has been some concern that long
term use without progestogens may cause
endometrial hyperplasia or cancer
Long term treatment of atrophic vaginitis
with low-dose oestradiol vaginal tablets*
• Women treated with
twice weekly Vagifem
tablets had an
atrophic endometrium
after 2 years
• Licensed for long
term use as required
*L.Mettler and P.G.Olsen
Maturitas.14(1991) 23-31
MANAGEMENT OF HRT
• Initial visit
• 3 months
• 6 months
• Yearly: BP, breast examination and
vaginal examination (3 yearly
smears to age 60 and 3 yearly
mammography aged 50-64)
• Invite earlier visit for specific
problems
July 2002
HRT
Risks and benefits
www.mhra.gov.uk
Vol 1. Issue 2. September 2007
Benefits of
HRT
Benefits and HRT:
Menopausal Symptoms
• HRT effectively relieves vasomotor
symptoms
• In most cases, 2-3 years therapy is
sufficient, but some women may need
longer
• Symptoms may recur for a short time after
stopping it.
Benefits and HRT:
Coronary Heart Disease
• Re-analysis of WHI study suggests a cardioprotective effect if HRT taken in the early
menopausal years
• No increased risk of CHD has been identified to
date with oestrogen-only HRT
• RCT’s have shown an increased risk of CHD in
women who started combined HRT more than
10 years after the menopause.
Healthcare professionals
should assess carefully
every woman’s risk of CHD
before prescribing HRT,
irrespective of her age or
time since menopause
Benefits and HRT:
Colorectal Cancer
• HRT reduces the
risk of colorectal
cancer
• This is likely to be
the anti-oxidant
effect of oestrogen
Benefits and HRT: Osteoporosis
• “osteoporosis is a skeletal disorder
characterised by compromised bone
strength predisposing to an increased
risk of fracture”
Schematic representation of
lifetime changes in bone mass
Attainment of
80
Consolidation
peak bone mass
Age related
bone loss
70
60
50
Women
Men
40
30
20
10
0
0
25
40
Climacteric
70
RISK FACTORS FOR
OSTEOPOROSIS
MINOR
• Cigarette smoking
• Sedentary lifestyle
• Low Calcium intake
MODERATE
• FH of osteoporosis
• Underweight
• High C2H5OH
consumption
MAJOR
• Early menopause
• Prolonged steroid
therapy
• Prolonged
amenorrhoea
Management of patients at
risk from osteoporosis
• Early diagnosis and treatment critical
• Bone density screening
• Recommend lifestyle factors for self
help
Benefits and HRT: Osteoporosis
• HRT is effective for the prevention of
osteoporosis but its beneficial effect on bone
diminishes soon after stopping treatment
• Because of the risks associated with long term
use of HRT, it should only be used for prevention
in women who are unable to use other
medicines that are authorised for this purpose
• However HRT remains the treatment of choice in
women with premature ovarian failure
Bone mineral content as a function of
time and treatment in women soon after
the menopause (Christiansen et al.
Lancet 1981)
Treatment
group
% bone
mineral
content
Placebo
group
0
12
24
36
months
Interventions for prevention and
treatment of osteoporosis
Spine
Hip
Etidronate
A
B
Alendronate
A
A
Risendronate
A
A
Ibandronate
A
ND
Calcium and Vitamin D
ND
A
Calcium
A
B
Calcitrol
A
ND
Calcitonin
A
B
Oestrogen
A
A
Raloxifene
A
ND
Strontium ranelate
A
A
Parathyroid hormone peptides
A
ND
Bisphosphonates
A: Evidence
from RCT ‘s or
well designed
controlled trial
B: Evidence
from other well
designed trial
(CCT or
comparative)
ND: not
demonstrated
Risks and HRT: Stroke
• In RCT’s HRT increased the risk of stroke
(mostly ischaemic) compared with placebo
• Older women have a greater absolute risk
of stroke
• Risk may depend on oestrogen dose
Risks and HRT: Stroke
Risks and HRT:
Venous Thromboembolism
• Oral HRT has been associated with an
increased risk of DVT and PE in RCT’s and
observational studies.
• Evidence suggests that it is higher with
combined HRT than oestrogen-only HRT and
that these events are more likely in the first year
of use
• One study suggests that risk may be lower with
a non-oral route
Risks and HRT: VTE
Risks and HRT:
Endometrial Cancer
• In women with a uterus, use of
oestrogen-only HRT
substantially increases the risk
of endometrial hyperplasia and
cancer in a way that depends
on dose and duration
• Addition of progestogen
cyclically for at least 10 days
per 28 day cycle reduces the
risk and progestogen
continuously eliminates risk
Risks and HRT: Endometrial Ca
Risks and HRT: Ovarian Cancer
• Observational studies suggest that
long-term use of all HRT’s may be
associated with a small increased risk
of ovarian cancer which returns to
baseline a few years after stopping it.
Risks and HRT: Ovarian Ca
Risks and HRT: Breast Cancer
Risks and HRT: Breast Cancer
• The risk is increased in women who take HRT
for several years
• Combined HRT has the highest risk
• For oestrogen-only HRT the risk is lower
• Some studies have not shown an increase for
oestrogen-only HRT
• Risk increases with duration of use and returns
to baseline within a few years of stopping
treatment
Standard HRT increases breast density in up to 50% of women which
may adversely affect radiological detection of Br CA. TIBOLONE increases
it by only 5%.
Risks and HRT: Breast Ca
Are there any alternatives to
HRT?
SERMS
Specific
Estrogen
Receptors
Modulators
THE IDEAL ‘SERM’
WOULD:
• Give oestrogen agonism where it is needed
ie. skeleton, CVS and CNS
• Give oestrogen antagonism where it is
needed ie. breast and uterus
TAMOXIFEN
• BONE probably favourable but no
large trials
• CVS favorable effect on lipids but no
effect on mortality
• UTERUS increase risk of endometrial
proliferation, endometrial polyps and
Ca body
RALOXIFENE
• Approved for the prevention of
non-traumatic vertebral
fractures in post menopausal
women at increased risk of
osteoporosis
Summary of Raloxifene
•
•
•
•
•
•
Prevents bone loss
Favourable effect on lipid mechanism
Minor side effects
VTE risk similar to HRT
No endometrial stimulation
No increase in breast or endometrial
cancer risk
BUT
• Does not help menopausal symptoms
Alternatives to HRT:
PHYTOESTROGENS
Phytoestrogens are plant substances that have effects
similar to oestrogen
ISOFLAVONES
• red clover
• soy beans
• soy products
• legumes
LIGNANS
• whole cereals
• oilseeds
• cereals
• berries
• Where isoflavones are an
integral part of the diet,
menopausal symptoms,
CHD, osteoporosis, cancers
of breast, colon, endometrium
and ovary are significantly
lower
• The isoflavone red clover is
the only alternative treatment
to have some trial evidence
of benefit for menopausal
symptoms
Annual Breast Cancer Rates*
19-20/100,000
60-90/100,000
*Similar patterns also for colon, endometrial and prostate CA
Other alternatives
• Herbalism: eg. Black cohosh, ginseng
• Homeopathy
• DHEA
• Acupuncture, magnets
None of these have definitively proven to be of
benefit and drug interactions can occur
Read more: www.thebms.org.uk
Premature Ovarian Failure
(Dysfunction)
• Cessation of menses before the age of 45
• Definition varies with the reference
population (2SD below mean)
• Affects 1% women under 40
• Primary and secondary causes
Premature Ovarian Dysfunction
• Primary due to chromosome
abnormalities eg Turner’s (XO);
autoimmune disorders; enzyme defects
• Secondary due to chemotherapy,
radiotherapy, surgery
• Spontaneous ovulation may occur with
pregnancy rates up to 5-10%
Premature Ovarian Dysfunction
• Hormone replacement required to keep tissues
healthy including bones and heart
• HRT (higher doses) or COCP to age 52
• Testosterone as patch or implant
• Risks are none use of HRT rather than use at
this age. On HRT same risk as age equivalent
population for breast Ca, VTE etc