MENOPAUSE

PRESENTED BY
AMAL ZAKI AZZAM
PROFESSOR OF OBSTETRICS AND GYNAECOLOGY
EL SHATBY MATERNITY HOSPITAL
ALEXANDRIA UNIVERSITY
 INTENDED LEARNING OBJECTIVES

• Knowledge of hormonal changes associated

with menopause
• Understand the consequent of hormonal
changes in estrogen-dependent tissues
• Understand the role of hormone
replacement therapy (HRT)
• Alternatives to HRT
 WHAT IS MENOPAUSE?
NATURAL (SPONTANEOUS) MENOPAUSE:
• Permanent cessation of menstruation
• The LAST menstrual period . End of woman”s monthly period
• No further production of estrogen & progesterone
• Average age 51
• Series of emotional & physical changes

IATROGENIC:
Surgical removal of ovary , Chemotherapy , Radiotherapy
 TERMINOLOGY
PERIMENOPAUSE (MENOPAUSAL TRANSITION):

• Begin eight to 10 years before menopause

• Ovaries gradually produce less estrogen

• Ends when women have gone 12 months without having their period.

• From the beginning of menopausal symptoms to the post-menopause

MENOPAUSE:

• A woman has gone without a menstrual period for 12 consecutive months.

POSTMENOPAUSE:
• The period of time after a woman has not bled for
an entire year (the rest of your life after going
through menopause).

PREMATURE MENOPAUSE (Premature

Ovarian Insufficiency):
Menopause that occurs before the age of 40 years
• Surgical removal of the ovaries or uterus
• A side effect of chemotherapy or radiation.
• A family history of menopause at an early age.
• Chromosomal abnormalities (Turner’s Syndrome).
• Certain infections :Mumps.
 OVARIAN FUNCTION
• Involves recruitment of follicles , selection of dominant follicle
, ovulation and corpus luteum formation

• During pre-reproductive years , GnRH (Gonadotropin

releasing hormone) from hypothalamus stimulate anterior
pituitary to produce FSH (Follicle stimulating hormone)
leading to growth of primordial follicles , one becomes
dominant & rest regress

• Granulosa cells surrounding the dominant follicle secrete:

Estrogen : acts on endometrium causing proliferative growth

Inhibin B : does the same action

• Estrogen increase negatively feedback to decrease FSH

secretion
OVARIAN FUNCTION
• After a period of time , there is LH (Luteinizing hormone) surge at
day 14.

• 36 hours later , ovulation occurs with release of ovum.

• LH stimulates the remaining follicle and Granulosa cells to form

corpus luteum (CL) which will secrete estrogen & progesterone.

Estrogen exerts:

• Negative feedback to decrease FSH

• Positive feedback to increase LH

• If pregnancy does not occur , CL degenerates , progesterone falls

and menses occur
 WHAT HAPPENS AT MENOPAUSAL AGE?
• Responsiveness of ovarian follicles will decline after the age of 40
• Decrease in estrogen and inhibin B
• Reduction in negative feedback on GnRH & FSH (increase in FSH)
• Estrogen production is erratic , levels fluctuate between normal , high &
low
• Eventually , no further responsive follicles & the negative feedback is
completely disrupted , FSH levels continue to remain high.
• LH levels are also high and will stimulate the stromal cells in the ovary to
synthesize androgens
In post-menopause , estrogen is derived from either :
• Ovarian stromal cells
• Adipose tissue
Androgens are aromatized to estrogen (Estrone)
Estrone is less active than estradiol produced from the ovary

In summary , there is:

• Increase FSH & LH levels
• Decrease estrogen , progesterone , inhibin B , testosterone & Anti-
mullerian hormone (AMH)
 ESTROGEN-DEPENDENT TISSUE
WHICH OF THESE TISSUES ARE AFFECTED BY ESTROGEN?

BREAST HAIR OVARY

ENDOMETRIUM TESTES COLON

BONE BLOOD
FAT
VESSELS
 ESTROGEN-DEPENDENT TISSUES
• All of these tissues are affected by estrogen even the testes.

• Estrogen receptors are present in all kinds of tissues.

• Estrogen is composed of 2 receptors : ER α and ER β , nuclear receptors ,

act as transcription factors to modulate transcription of target genes as
well as membrane receptors
 ACUTE CLINICAL SYMPTOMS OF MENOPAUSE

• Cessation of menses

• Vasomotor symptoms : Hot flushes & Night sweats

• Mood swings , depression , forgetfulness

• Headaches
 HOT FLUSHES
• Sudden , subjective sensation of intense heat
perceived in head , neck & upper chest (Red blotchy
skin)
• Lasts 1-5 minutes may recur any time of the day at
any frequency
• Associated with sweating , irritability , anxiety ,
palpitations & panic
• Triggered by small elevations in core body
temperature & hormonal fluctuations
• Increased sensitivity of relatively narrow
hypothalamic thermal regulatory center to internal
environmental triggers
 MEDIUM-TERM CLINICAL SYMPTOMS
Urogenital Problems:
• Vulval , vaginal , urethral & bladder tissues are estrogen-dependent
• Epithelium thins & atrophies
• Raised vaginal pH increases bacterial growth & contributes to recurrent
urinary infections /urinary incontinence &/or urgency
Sexual Problems:
• Vaginal dryness & atrophy
• Painful intercourse (dyspareunia)
• Loss of libido
 LONG-TERM HEALTH IMPLICATIONS
1-Osteoporosis (weak fragile bone due to increase bone loss)
2-Metabolic consequences:
• Obesity
• Type 2 diabetes & dyslipidemia
3-Cardiovascular consequences:
• Endothelial dysfunction
• Hypertension
• Atherosclerosis
4-Mood & cognition disorders , insomnia (Neurotransmitters)
 DIAGNOSIS OF MENOPAUSE
Women > 45 years:
• Perimenopause : Irregular periods , vasomotor symptoms
• Menopause: No period for 12 months (Not on hormonal contraception)
It is more difficult to make a diagnosis when :
1- A woman had a hysterectomy but the ovaries are conserved
2-The woman is on hormonal contraception
• In younger women think about polycystic ovary syndrome , hypothalamic / pituitary
problems or uterine problems
 DIAGNOSIS OF MENOPAUSE

Women <45 years:

• FSH test: 2 blood samples 4-6 weeks apart

• AMH test: Not used in UK to diagnose menopause . It is used in fertility

setting to predict the possibility of fertility & timing of menopause

• Antral follicle count on USS : Useful in assessing fertility status but not
actually diagnosing menopause
 HORMONE REPLACEMENT THERAPY

• Menopausal symptoms can be treated by pharmacological & non pharmacological

measures.
Hormones used as HRT are:
• Estradiol
• Conjugated equine estrogen
• Progesterone
• Norethisterone
 WHICH OF THESE CANCERS IS MOST LIKELY TO BE
CAUSED BY ESTROGEN-ONLY HRT?
• Womb cancer

• Breast cancer

• Ovarian cancer

• Liver cancer

• Colon cancer
 ENDOMETRIAL CANCER

• Endometrial cancer occur when we give estrogen-only HRT

• Million women study recruited over 300,000 women and found that
women taking estrogen-only HRT have 4-5% increased risk compared with
non-users of HRT.

• Those who had combined HRT (adding progestogen) had 30% decreased
risk of endometrial cancer
 HORMONE REPLACEMENT THERAPY
1-Advice and information:
• Symptoms are mild & short duration
• Life style measures
2-Medical therapy:
• Symptoms disturbs the quality of life
• Best agent to treat estrogen deficiency is estrogen
• For vasomotor symptoms , combined E/P HRT is used
• (E alleviates the symptoms , progesterone protects uterus from cancer)
 REGIMENS FOR HRT
1-Estrogen-only regimen: (Unopposed)

• Increase risk of endometrial hyperplasia and cancer

• Likely to cause irregular vaginal bleeding

2-Continuous combined regimen : Progesterone added to estrogen and taken continuously

3-Sequential combined regimen : Progesterone is added to estrogen but given for 10-14 days only.
Withdrawal bleeding resembling a period occurs

4-Synthetic Steroid Alternatives : Tibolone

• Selective estrogen receptor modulator which binds to ER to relieve vasomotor symptoms &
prevent bone loss
 HRT ROUTES
1-ESTROGEN:
• Transdermal patch or gel : Most physiological/gut & liver are avoided/lower
thromboembolism/local skin irritation/expensive
• Oral :most acceptable/metabolized in liver/higher doses are required/cost effective/increase
synthesis of coagulation factors
• Vaginal : creams/tablets/rings/local delivery/effective in urogenital symptoms ( dryness &
painful intercourse)

2-PROGESTERONE:
• Micronized (oral easily absorbed version)
• Mirena coil: progesterone-released intrauterine coil (5 years )
 BENEFITS AND RISKS OF HRT
BENEFITS RISKS
VASOMOTOR SYMPTOMS BREAST CANCER
MOOD & SLEEP DISTURBANCES STROKE
UROGENITAL ATROPHY VENOUS THROMBOSIS
OSTEOPOROSIS OVARIAN CANCER

Heart diseases depends on

what age the HRT is started
 BREAST CANCER

• Progesterone increase breast cancer risk compared with estrogen alone.

• The risk of breast cancer increase with duration of use

• There is no increased risk in women who start HRT because of premature

menopause
 BREAST CANCER
• When sequential & combined HRT are used ,
5 years use 10 years use
there is 7/10 extra cases for 1000 women after Extra Extra
cases/1000 W cases/1000 w
5 years use.
SEQUENTIAL +7 +17
• After 10 years there is a rise up to 17/25 extra HRT
cases for 1000 women COMBINED +10 +25
HRT
• obesity also increases the risk of breast cancer
ESTROGEN- +3 +7
and so is alcohol ONLY HRT

• HENCE someone who is obese and drinks is OBESE (BMI +15

>35)
probably at higher risk of getting breast cancer
ALCOHOL (>2 +8-15
on adding HRT , than another one who is slim U/d)

and doesn’t drink alcohol

 VENOUS THROMBOEMBOLISM
• Venous thromboembolism (Pulmonary emboli or
deep venous thrombosis)
Increase risk with age:
• Incidence is 100-200/100,000 w/year
5 years use 10 years use
• RR is 1.6-2.7 in HRT users Extra cases Extra cases
Other risk factors : Obesity , smoking , varicose veins , /1000 W /1000 W
family or personal history
HRT +7 +13
➢ Risk is highest with oral estrogen
➢ No risk with micronized progesterone & non-oral Estrogen-only +2 +3
estrogen
➢ Strong family history or thrombophilia : Refer to
Haematologist for advice
 UNCERTAINTIES: CARDIOVASCULAR DISEASE
• Estrogen or HRT seems to be cardioprotective
• HRT should not be used as primary or secondary prevention of cardiovascular
disease
A-Coronary Heart Disease (CHD):
1-RCTs : Increased risk of CHD if combined HRT was started > 10 years after the
menopause . Starting HRT > 60 years is generally not recommended
2-Trend towards reduction in CHD risk if estrogen-only HRT was started under 60
years and within 10 years from menopause
 UNCERTAINTIES : CARDIOVASCULAR DISEASE

B-STROKE :

1. Combined HRT increases the risk of stroke

2. Tibolone increases the risk of ischemic stroke

Counselling :

• If you are in early menopause , have moderate to severe hot flushes , and
are otherwise healthy then the benefits of HRT likely outweigh any
potential risks of heart disease
 OTHER AREAS OF UNCERTAINTY
Some observational studies have shown:
1- Delay or reduce the risk of Alzheimer’s Disease:
• Insufficient evidence
• Combined HRT & Estrogen-only therapy may increase the risk of dementia if initiated
> 65 years
2-Ovarian Cancer:
• One study (Women’s Health Initiative): No increased risk
• Another study (Million Women Study) : +1 extra case / 2500 users after 5 years use
• Overall , the risk of having ovarian cancer because of HRT is accepted to be small
 CONTRINDICATIONS FOR HRT
• Pregnancy

• Undiagnosed vaginal bleeding

• Active/Recent venous thromboembolism or heart attack

• Suspected or active breast or endometrial cancer

• Acute liver disease

• Porphyria cutanea tarda (caused by liver enzyme defect)

 WHEN TO STOP HRT?
HRT FOREVER?
• Increased risk of breast cancer +25 extra cases/1000 W > 10 years of use /
Cost implications / Living for longer & working for longer
• Apply the medical principle of “First do no harm”
• Decision to stop depends on consultation between physician and patient : Is
there particular biological justifications to stop HRT after 5 years
• Each woman individual risk is screened annually , risks are reassessed
• Women should be offered therapy if she needs it provided she understand
the potential risks
 ALTERNATIVE THERAPIES
1. Life style measures : Exercise , lighter clothing , stress reduction , trigger avoidance ,
sleeping in a cooler room ( may be enough )
2. Non-hormonal therapy : Antidepressants
3. Non-pharmacological therapy: vaginal moisturizers before intercourse
4. Complementary therapy:
• Phytoestrogens (SOY products , beans , Isoflavones)
• Herbal Remedies (Ginseng)
• However , effectiveness , safety , quality & purity of many of these is not known /No
sufficient Randomized controlled studies
 HRT AFTER GYNECOLOGICAL SURGERY
Hysterectomy is done for benign or malignant causes:

1. Benign : Heavy menstrual bleeding /prolapse /

endometriosis

2. Malignant : endometrial / ovarian / cervical / breast

cancers

Salpingo-ophrectomy : Removal of ovaries & fallopian tubes

One or both ovaries may be removed if they are carriers of

genetic mutations
 HRT AFTER GYNECOLOGICAL SURGERY
• In hysterectomy for benign causes in young women < 45 , one or both
ovaries may be conserved .
• In many cases of ovarian conservation , they continue to function normally
however sometimes the blood supply to the ovary is affected & ovary may
stop producing hormones
• In hysterectomy for malignant cases , the ovaries are removed. The patient
will experience sudden hot flushes . HRT should be considered for
symptom control & bone health .
• If the entire uterus has been removed the patient may be treated with
estrogen-only HRT
 PREMATURE OVARIAN INSUFFICIENCY
Affects :

1 : 100 < 40

1 :1000 < 30

1 :10,000 < 20

HRT is recommended until age of natural menopause (unless

contraindicated ) for bone and cardiovascular health
 HRT AFTER CANCER
1-BREAST CANCER:

• Avoid systemic HRT

• Use topical estrogen

• Consider clonidine (alpha-2 adrenergic agonist) or paroxetine

(antidepressant , SSRI (selective serotonin reuptake inhibitor).

2-CERVICAL CANCER:

• If young & early , ovarian conservation is recommended

• HRT can be used ( Not hormonal driven)

 HRT AFTER CANCER
3- ENDOMETRIAL CANCER:

• If stage 1 and young female: consider ovarian conservation or HRT

• If later stage , HRT is usually contraindicated

4- OVARIAN CANCER:

• HRT not usually contraindicated unless the tumour has estrogen receptors
 SUMMARY : TOPICS COVERED

• Hormonal changes associated with menopause

• Consequences of hormonal changes in estrogen-dependent

tissue

• Role of hormone replacement therapy (HRT) in menopause and

special conditions

• Alternatives to HRT
For any questions or inquiries, please contact me via e-mail:
amalazzam2768@gmail.com