Menopause

MENOPAUSE
• The permanent cessation of menstruation that
result from loss of ovarian follicular activity .
• Natural menopause is recognized to have occurred
after 12 consecutive months of amenorrhea for
which no other obvious pathological &
physiological cause present. Menopause occurs
with the final menstrual period only known with
certainty 1 year after the event. No adequate
biological markers exists.
• Women in the UK have their menopause between
the ages of 45 and 55 years.

Premenopause
• It is refer to 1 to 2 years
immediately before the menopause
or to the whole of reproductive
period , before the menopause.
• Currently this term is
recommended to be used in the
latter sense , encompassing the
entire reproductive period from
menarche to final menstrual period.

PERIMENOPAUSE
• is the phase surrounding the
menopause.
• It is the time period from when the
ovaries start to fail (and symptoms
such as irregular periods or hot
flushes may begin) until 12 months
after the last menstrual period.

POST MENOPAUSE
• s the time after the complete
cessation of menstruation. It can
only be known with certainty after
12 months of amenorrhoea.

PREMATURE OVARIAN INSUFFICIENCY
• Menstruation cessation before the age of 40
years
• 4 months of amenorrhoea and 2 FSH>=30
iu/ml at an interval of at least 1 month before
the age of 40 years.
• The term premature ovarian failure suggests that
the state of ovarian failure is irreversible , which is
not strictly true . The ovarian follicular function
fluctuates in about 50% of women with POF and
5–10% of women with the diagnosis may eventually
conceive .

Causes of premature ovarian failure
• Primary
• Chromosome abnormalities
• FSH receptor gene polymorphism
and inhibin B mutation
• Enzyme deficiencies
• Autoimmune disease
• Secondary
• Chemotherapy & Radiotherapy
• Bilateral oophorectomy , or surgical
menopause
• Hysterectomy without
oophorectomy
• Infection

PREVALENCE
• . The average age of menopause in the UK is 51.
• However , this varies widely and 1 in 100 women experience premature
ovarian insufficiency (menopause occurring before the age of 40 years).
• Most women (8 out of 10) experience some symptoms, typically lasting
about 4 years after the last period, but continuing for up to 12 years in about
10% of women

Physiology
• Menstrual cycle and hormone
patterns begin to change many
years prior to menopause.
• The following schematic shows
the physiology of the
menopause:

Physiology continues…..
• The number of primary ovarian follicles decreases markedly after the age of
40. This results in a decrease in serum estradiol (E2) levels and a decline in
the secretion of inhibin B (a glycoprotein synthesized by granulosa cells in
the ovary). FSH normally stimulates inhibin B synthesis, which then
suppresses FSH via a negative feedback loop. After about age 45, however,
inhibin B levels fall, perhaps due to the decreased number of ovarian
follicles, causing a rise in FS
• Conti……..

• The increased FSH levels stimulate increased estradiol release from the
remaining follicles, and also prompt them to release the estradiol more
rapidly, resulting in shorter cycles. About six to twelve months before
menopause, the number of follicles is even lower, and higher FSH levels fail
to increase estradiol production. At this point, the reduced estradiol levels
can result in menopause-related symptoms.
• Conti……

• During perimenopause, estrogen production by the ovary is erratic and estradiol
levels fluctuate between normal, high, and low. Therefore, clinical history is more
reliable than measurement of FSH and estradiol for diagnoses of perimenopause.
• Without a follicular source, the larger proportion of postmenopausal estrogen is
derived from ovarian stromal and adrenal secretion of androstenedione, which is
aromatised to estrone (E1) in the peripheral tissues (fat). E1 is biologically less active
than E2. Testosterone levels also decrease with menopause but this decrease is not
as marked as the decline in E2.
• Conti……

CLINICAL MANIFESTATION
• This section of the tutorial covers:
• acute manifestations of menopause
• medium term symptoms
• long term implications.

SIGNS & SYMPTOMS
This can last from a few months to several years and between
three in ten and six in ten women (30% to 60%) experience
physical and/or emotional symptoms during this time.
• The main symptoms include:
• • hot flushes and night sweats (the most common symptoms)
• • vaginal dryness
• • tiredness and sleep disturbance
• • mood swings
• • forgetfulness or lack of concentration
• • loss of interest in having sex.

UROGENITAL ATROPHY
• Thinning and shrinking of the tissues of the vulva, vagina, urethra and
bladder caused by oestrogen deficiency . This results in multiple symptoms
such as vaginal dryness, vaginal irritation, a frequent need to urinate and
urinary tract infections.

Vasomotor Symptoms
• Menopausal symptoms such as hot flushes and night sweats caused by
constriction and dilatation of blood vessels in the skin that can lead to a
sudden increase in blood flow to allow heat loss. These symptoms can have a
major impact on activities of daily living.

Menopause diagnosis
• The average age of menopause is 51 years.
• Premature ovarian failure (also known as premature ovarian insufficiency) is
diagnosed when menopause occurs before 40yrs of age.
• Menopause is diagnosed retrospectively when the last menstrual period has
occurred 1 year earlier .
• Elevated FSH/LSH level predict the menopause.
• The climacteric defines the period (most symptomatic) around the menopause
transition

DIAGNOSIS OF PERIMENOPAUSE AND
MENOPAUSE
• Diagnose the following without laboratory tests in otherwise healthy women
• aged over 45 years with menopausal symptoms:
• perimenopause based on vasomotor symptoms and irregular periods
• menopause in women who have not had a period for at least 12 months and
are not
• using hormonal contraception
• menopause based on symptoms in women without a uterus.

Do not use the following laboratory and imaging tests to diagnose the perimenopause
or menopause in women aged over 45 years:
• anti-Müllerian hormone
• inhibin A
• inhibin B
• Oestradiol
• Antral follicle count
• Ovarian volume

• Do not use a serum follicle-stimulating hormone (FSH) test to diagnose
• menopause in women using combined oestrogen and progestogen
• Contraception or high-dose progestogen.
• Consider using a FSH test to diagnose menopause only:
• in women aged 40 to 45 years with menopausal symptoms, including a
change in their menstrual cycle
• in women aged under 40 years in whom menopause is suspected

Diagnosing premature ovarian
insufficiency
• Diagnose premature ovarian insufficiency in women aged under 40 years
based on:
• menopausal symptoms, including no or infrequent periods (taking into
account whether the woman has a uterus) and elevated FSH levels on 2
blood samples taken 4–6 weeks apart.

• Do not diagnose premature ovarian insufficiency on the basis of a single blood
test.
• Do not routinely use anti-Müllerian hormone testing to diagnose premature
ovarian insufficiency .
• If there is doubt about the diagnosis of premature ovarian insufficiency , refer
the woman to a specialist with expertise in menopause or reproductive medicine.

hormonal contraceptive and continuing treatment until at least
the age of naturalmenopause (unless contraindicated)
that the baseline population risk of diseases such as breast cancer and
cardiovas disease increases with age and is very low in women aged
under 40
that HRT may have a beneficial effect on blood pressure when
compared with acombined oral contraceptive
that both HRT and combined oral contraceptives offer bone protection
that HRT is not a contraceptive.

INFORMATION & ADVICE
• Give information to menopausal women and their family members or carers (as
• appropriate) that includes:
• an explanation of the stages of menopause
• common symptoms and diagnosis
• lifestyle changes and interventions that could help general health and wellbeing
• benefits and risks of treatments for menopausal symptoms
• long-term health implications of menopause.

What is HRT…???
• HRT is a medical treatment for the menopause.
• It provides low doses of the hormone estrogen and
sometimes other hormones (progestogens and
testosterone) which your body is no longer producing.
HRT is available as tablets, skin-patches, gels or nasal
spray.
• A cream, pessary, or vaginal ring containing estrogen can
also be used to ease symptoms in the vaginal area.

Management
• Treatment should be targeted to individual women's
needs
• Types of HRT
• Routes
• Benefits
• Risk
• Uncertainities
• CVS
• Dimentia
• Ovarian cancer
• Quality of life

ROUTES of HRT
• Oral:
• usually first choice
• cost-effective
• acceptable
• beneficial effect on HDL-C, LDL-C, and total cholesterol
• high doses required
• variation in absorption
• all tablets contain lactose
• affects liver protein synthesis (increase in triglycerides).

Transdermal (Patch, gel, nasal spray)
• Avoids gut and liver breakdown; so lower dose is required
• Generally more expensive
• Avoids bolus first-pass effect on the liver (less adverse effect on gallbladder
disease and coagulation factors)
• Produces more physiological hormone levels than oral therapy
• Patch adhesive sensitivity/residue.

topical
• very little reaches systemic circulation and therefore avoids adverse systemic effects.
• Intrauterine system (Mirena coil) for urogenital symptoms
•
• licensed in the UK for delivering the progestogen part of HRT
• useful for persistent progestogenic side effects from systemic HRT
• useful when contraception is required along with HRT in the perimenopause
• useful when withdrawal bleeds on sequential HRT are heavy, after investigation if indicated.

Indication for non oral route
• patient preference
• poor symptom control with oral treatment
• side effects, e.g. nausea, with oral treatment
• history of migraine (when steadier hormone levels may be beneficial)
• risk of stroke , venous thromboembolism (when HRT should only be considered after full discussion and appropriate
investigation)
• hypertriglyceridaemia
• current hepatic enzyme inducing agent, e.g. anticonvulsant therapy
• history of gallstones
• bowel disorder that may affect absorption of oral therapy
• lactose sensitivity.

Benefits of HRT
• Vasomotor symptoms
• Estrogen is the most effective treatment for hot flushes. Improvement is usually
noted within four weeks. For all women, the lowest effective dose should be used
for the shortest time.
• Mood or sleep disturbances
• HRT will often improve sleep by alleviating night sweats. It is not known whether
HRT has a direct effect on mood, irritability, or anxiety, or whether these effects are
due solely to the alleviation of hot flushes and sleep disturbances. HRT should not
be used as monotherapy for depression. HRT is most likely to be useful if there are
other menopausal symptoms present

• Urogenital symptoms
• Symptoms of urogenital atrophy such as vaginal dryness, soreness, superficial dyspareunia, and
urinary frequency and urgency respond well to estrogens, which may be given either topically or
systemically. Maximal benefit of HRT takes between one and three months of therapy, but may
take up to one year of treatment. Symptoms can recur on cessation of therapy.
• Osteoporosis
• Evidence from randomised controlled trials (including WHI) show that HRT reduces the risk of
spine and hip as well as other osteoporotic fractures. HRT is currently not recommended as a
first line treatment for osteoporosis prevention.
• conti…….

• . While alternatives to HRT use are available for the prevention and treatment of
osteoporosis in elderly women, estrogen may still remain the best option,
particularly in younger and/or symptomatic women. It is cheaper than other
alternatives such as bisphosphonates. Unlike for HRT, there are no data suggesting
that bisphosphonates reduce fracture risk in women with normal bone density .
• Colorectal cancer
• Results from the estrogen progestogen arm of the WHI study show that HRT
reduces the risk of colorectal cancer by about one third. There is no information
about HRT in high risk populations, and current data do not allow prevention as a
recommendation.

Breast cancer
• HRT with oestrogen alone is associated with little
or no change in the risk of breast cancer
• HRT with oestrogen and progestogen can be
associated with an increase in the risk of breast
cancer.
• Any increase in the risk of breast cancer is
related to treatment duration and reduces after
stopping HRT .

Cardiovascular Disease
• Ensure that menopausal women and healthcare professionals
involved in their care understand that HRT :
• does not increase cardiovascular disease risk when started in
women aged under 60 years
• does not affect the risk of dying from cardiovascular disease.
• Be aware that the presence of cardiovascular risk factors is
not a contraindication to HRT as long as they are optimally
managed.

Osteoporosis
• HRT with oestrogen alone is associated with
little or no change in the risk of breast
cancer
• HRT with oestrogen and progestogen can be
associated with an increase in the risk of breast
cancer
• Any increase in the risk of breast cancer is
related to treatment duration and reduces
after stopping HRT .

Type 2 diabetes
• Explain to women that taking HRT (either orally or
transdermally) is not associated with an increased risk of
developing type 2 diabetes.
• Ensure that women with type 2 diabetes and all
healthcare professionals involved in their care are aware
that HRT is not generally associated with an
adverse effect on blood glucose control.
• Consider HRT for menopausal symptoms in women
with type 2 diabetes after taking comorbidities into
account and seeking specialist advice if needed.

Dementia
• Explain to menopausal women that the likelihood of HRT affecting their
risk of dementia is unknown.

ENDOMETRIAL CANCER
• Unopposed estrogen therapy increases the risk of endometrial cancer in
women with a uterus. Adding a progestogen to estrogen therapy (combined
HRT) for at least 12 days per month greatly reduces this risk.
• Endometrial cancer risk is not completely eliminated with monthly sequential
progestogen addition, especially when continued for more than five years
and also with long cycle HRT . No increased risk of endometrial cancer has
been found with continuous combined regimens. Tibolone has also been
reported to increase the risk of endometrial cancer (MWS).

Venous thromboembolism
• Oral HRT has been associated with an increased risk of
venous thromboembolism (VTE) (i.e., deep vein
thrombosis or pulmonary embolism) in the first year of
use.
• The level of risk may be lower with transdermal HRT
even in women with predisposing factors. The risk is
higher with combined HRT than with estrogen-only
HRT. Limited data do not suggest an increased risk of
thromboembolism with tibolone compared with
combined HRT or women not taking HRT.

Gallbladder Disease
• HRT increases the risk of
gallbladder disease; the risk might
be lower with transdermal
preparations. Gallbladder disease
increases with ageing and with
obesity.

Assessment prior to start HRT
1) Assess menopausal state and symptoms Stage of menopause (peri-, postmenopausal)
Time of the last menstrual period
Bleeding pattern
Presence or absence of acute menopausal symptoms

2) Current contraception – if the woman requires contraception Continue contraception for one year after the last menstrual period in
women over 50 years old, or for two years in women under 50 years old
Women taking HRT should use barrier methods, an intra-uterine device, or the
levonorgestrel-releasing intra-uterine system (IUS)
Women taking combined oral contraception do not need to have HRT added

3) Check for contraindications Hormone-dependent malignancy (e.g. endometrial cancer, current or past breast cancer)
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction or stroke)
Venous thromboembolic disease
Current pregnancy
Severe active liver or renal disease
Uninvestigated abnormal vaginal bleeding
Acute intermittent porphyria
4) Ask about family history of... Cardiovascular disease
Osteoporosis
Venous thromboembolism

5) Check risk factors for coronary heart disease Hypertension, diabetes mellitus
A family history of premature myocardial infarction or stroke
Cigarette smoking, sedentary lifestyle, and obesity
6) Check risk factors for osteoporosis
7) What does the patient want? Does she want to take HRT?
If not, what alternatives would she prefer?
8) Discuss healthy lifestyle options to prevent osteoporosis and cardiovascular disease

Follow up of a woman taking HRT
• The recommended follow up schedule for HRT is:
• three months
• six months
• yearly – BP, breast examination, vaginal examination (three-yearly smears
and three-yearly mammography aged 50–64).

Management of side effects with HRT
• Adverse effects account for almost 35% of HRT discontinuations. Women
should be encouraged to persist with HRT for at least three months, as most
adverse effects resolve with increased duration of use.

Bleeding as a side effect of HRT
• Nearly 50% of previous HRT users discontinue treatment because of bleeding problems. Unpredictable or
unacceptable bleeding may be due to non-adherence to therapy, drug interactions, or gastrointestinal upset
(or malignancy if not already excluded).
• Endometrial assessment is required if:
• for sequential regimens
• it is heavy or prolonged at the end of or after the progestogen phase, or
• occurs at any time (breakthrough bleeding)
• for continuous combined regimens
• if it occurs after the first six months of treatment (irregular breakthrough bleeding or spotting is common in the first 3–
6 months), or
• it occurs after amenorrhoea.

Estrogen-related adverse effects
• Estrogen-related adverse effects tend to occur continuously or randomly through
the cycle. They include fluid retention (more likely due to the progestin component),
bloating, breast tenderness/enlargement, nausea, dyspepsia, headaches and leg
cramps:
• leg cramps can improve with lifestyle changes, including exercise and regular
stretching of the calf muscles
• nausea/gastric upset may be helped by taking with food or switching to transdermal
preparations
• migraine triggered by fluctuating estrogen levels may respond to transdermal
therapy as this produces more stable estrogen levels.

Progestogen-related adverse effects of
HRT
• Progestogen-related adverse effects tend to occur in a cyclical pattern during the progestogen phase of cyclical HRT. The
effects include fluid retention, breast tenderness, headaches/migraine, mood swings, depression, acne, lower abdominal
pain, and backache.
• For persistent symptoms the following options can be considered:
• reduce the duration – swapping from a 14-day to a 12-day product may provide benefit
• reduce the dosage – but not below the recommended levels for endometrial protection
• change the type – e.g. from more androgenic ones to less androgenic ones
• change the route – e.g. from oral to transdermal or intra-uterine progestogen
• change to continuous combined therapy – as these products contain lower dosages of progestogen, but this option is
only suitable for postmenopausal women.
• Fluid retention and headache may be related to either estrogen or progestin; modifying the progestogen first is usually the
better strategy.
• Breast tenderness is more likely to be alleviated with lower estrogen dosages, although adjusting the progestogen may
occasionally be effective if the symptoms seem to have a cyclic quality.

• All women should be reviewed annually as the risks and benefits of HRT will
alter with time. Women who choose to take HRT for more than five years
should be counselled about the long term risks.
• Many women do not notice any symptoms even with abrupt cessation of
HRT, while others will have recurrent vasomotor symptoms. However, there
is insufficient evidence to support the assumption that tapering hormone
therapy lowers the risk of recurrent symptoms.
• conti……

• If symptoms are severe after HRT is stopped, or persist for several months
after stopping, the woman may wish to restart HRT after reassessment and
counselling. Often a lower dose of HRT can be used (e.g. estradiol 1 mg) if
HRT is restarted.
• The implications of stopping HRT, besides recurrence of menopausal
symptoms, include resumption of bone loss. Therefore, risk factors for
osteoporosis should be assessed and alternatives for preventing or treating
osteoporosis (including diet and lifestyle advice) should be discussed at this
time.

Stopping HRT
• All women should be reviewed annually as the risks and benefits of HRT will alter
with time. Women who choose to take HRT for more than five years should be
counselled about the long term risks.
• Many women do not notice any symptoms even with abrupt cessation of HRT,
while others will have recurrent vasomotor symptoms. However, there is insufficient
evidence to support the assumption that tapering hormone therapy lowers the risk
of recurrent symptoms.
• Conti…..

What are alternatives to HRT..???
• The alternatives to HRT can be broadly classified as:
• Herbal medicine – a practice based on the use of plants or plant extracts to relieve
symptoms – for example, evening primrose oil or St John’s Wort
. • Alternative medicine – a range of therapies used instead of conventional medicine,
such as acupressure, acupuncture and homeopathy.
• Complementary therapy – interventions which tend to be used alongside
conventional medicine, for example, aromatherapy with HRT.
• Medical treatments – prescribed by your doctor, such as antidepressants.

Are these alternatives safe and do they work?
• Overall, the evidence shows that the alternatives to HRT discussed in this
document are much less effective at easing the symptoms of the menopause
compared with HRT. The best ones can reduce the severity of symptoms by
50% to 60%, compared with a reduction of 80% to 90% with HRT.

. Treatments that work and are safe
• There is evidence that the treatments below work and are safe:
• Lifestyle choices
• Regular aerobic exercise such as running and swimming.
• You should avoid infrequent, high-impact exercise as this may make your symptoms worse.
• Low-intensity exercise such as yoga may help hot flushes and general wellbeing.
• Reducing your intake of caffeine/caffeinated drinks and alcohol can help to reduce hot flushes and night
sweats.
• Vaginal lubricants and moisturisers replace vaginal secretions and can help with vaginal dryness.
• St John’s Wort appears to be effective in treating depression during the menopause but it can interfere with other medications
so it is important to speak with your GP before taking it. It has not been proven to help with hot flushes.

.
• Why would I choose an alternative to HRT?
• Not every woman chooses HRT for the menopause.
• For you, this may be because:
• • Your GP has advised you not to take HRT because of your own, or your family’s, medical
history of (for example) breast cancer or deep venous thrombosis (blood clot in a deep
vein).
• • You want a treatment that works especially well for one particular symptom that you have.
• • You have concerns about the safety and side effects of HRT and believe that other
treatments are safer.
• • You would prefer a non-medical treatment.

Treatments where more evidence is needed to
know if they work and are safe
• More evidence is needed to know if the treatments below work, what the
side effects may be and whether there are long-term risks. If there are safety
concerns about a specific treatment

Non-prescribed treatments
• Acupuncture
• Black cohosh
• Chasteberry (agnus castus), selenium, vitamin C and herbs such as ginkgo biloba,
hops, sage leaf, liquorice and valerian root
• Dehydroepiandrosterone (DHEA)
• Homeopathy
• Magnetism in the form of bracelets/insoles

• Phytoestrogens are plant substances that have similar effects to estrogen and are found in the
following:
• foods such as soya beans, chickpeas, beans and peas.
• phytoestrogen supplements
• Soy products
• Red clover (trifolium pratense)
• Progesterone skin creams studies of whether these help with hot flushes and night
sweats are conflicting and more studies are needed.
• Reflexology

Treatment prescribed by a DOCTOR
NON-HORMONAL
• Antidepressants such as fluoxetine, paroxetine, citalopram and venlafaxine have been
used to treat hot flushes and night sweats. More studies are needed to see whether they work
since many of the studies only lasted a few weeks. However, venlafaxine appeared to have
the most benefit. Antidepressants can cause nausea and other side effects.
• • Clonidine may help for hot flushes but the number of studies is small. Clonidine
patches may be more effective than the tablets.
• Gabapentin, an anti-epileptic medication, appears to help hot flushes but may cause
tiredness and other side effects. More studies are needed to confirm it helps and that it is
safe.

Managing premature ovarian insufficiency
• Offer sex steroid replacement with a choice of HRT or a combined hormonal
contraceptive to women with premature ovarian insufficiency , unless
contraindicated (for example, in women with hormone-sensitive cancer).
• Explain to women with premature ovarian insufficiency:
• the importance of starting hormonal treatment either with HRT or a combined
• that HRT may have a beneficial effect on blood pressure when compared with
acombined oral contraceptive
• that both HRT and combined oral contraceptives offer bone protection that
HRT is not a contraceptive.
• Continue…………

• Give women with premature ovarian insufficiency and contraindications to
hormonal treatments advice, including on bone and cardiovascular health,
and symptom management
• Consider referring women with premature ovarian insufficiency to
healthcare professionals who have the relevant experience to help them
manage all aspects of physical and psychosocial health related to their
condition.

Menopause

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