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Menopause
I. Definitions:
A - Menopause
1 Menopause is the period in which a permanent cessation of menses occurs
because of loss of ovarian activity. The cessation of menses reflects the
reduction of ovarian estrogen production to levels insufficient to produce
proliferation of the endometrial lining.
2 Menses usually cease between 50 and 52 years of age; the median age of
menopause is 51 years, with a range of 48 to 55 years.
3 Since life expectancy is increase, so a woman with menopause now expect to
live 30 or 40 years of her age with a state of relatively profound estrogen
deficiency.
B - Climacteric (mean the change):
Is the transitional phase (from fertility to infertility) during which reproductive
function cease, usually ranging from 45 to 55 years of age and the women will
pass from her reproductive to post-reproductive years. The period reflects the
decline and loss of ovarian function and the long-term consequences of reduced
women estrogen levels.
II. Pathophysiology:
- Ovarian follicles:
Human ovary consist of an outer cortex containing follicles at
various stages of development and a central medulla, which is
heavily vascularized.
The primordial follicles numbers some 1.5 million at birth, and only
some 400- 400 000 follicles present at puberty and will progress to
ovulation. It is the cells of the developing follicles that produce the
bulk of the oestradiol circulating in the plasma of a premenopausal
women, the median level of which is 400-500 pmol /L. Synthesis of
which is principally from androstenedion and testosterone to
eostradiol in the granulosa cell which from the internal lining of the
follicle.
- Hormonal status:
The androgen to oestrogen conversion is catalyzed by the aromatase
enzyme cascade and is promoted by FSH. Theca call also produce
oestradiol from androgens whose elaborate from cholesterol is
stimulated by LH.
The first signs of approaching menopause:
1- Is a decline in fertility
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2- The first endocrine changes is fall in Inhibin production by the
ovary.
3- An increase in FSH levels results from the decreased circulating
levels of inhibin and the loss of negative feedback. This is the
earliest evidence of a change in ovarian function.
4- LH secretion escapes the negative feedback of inhibin, LH levels
rise much later than FSH levels.
5- Significant amount of androgen production is stimulated in the
ovarian stroma by FSH & LH.
6- The principle site of of oestrogen production by androstenedione
conversion to oestrone is in the adipose tissue.
- Menstruation:
May stop abruptly.
Or may cease after a prolonged stage of oligomenorrhoea.
Any bleeding more than 6 months will be classified as
postmenopuasal bleeding and will need investigations.
- Types of the menopause:
Natural or Physiological.
- Aging process.
Premature ovarian failure: due to failure of the ovary to b generate
sufficient oestrogen which cause secondary amenorrhoea, it may
associated with other autoimmune endocrinopathies, where the
antibodies attacks anywhere in the hypothalamic- pituitary- ovarian
axis:
- Premature menopause if below 45 years. It characterized by low oestradiol,
high FSH & LH with symptoms suggestive of oestrogen deficiency. The
appearances of the ovary are those of postmenopausal ovary.
- Resistant ovary syndrome: those women in which the biological appearances
of the ovary are normal with abundant primordial follicles.
Surgical menopause:
- After removal of the ovaries: menopause will supervene immediately.
- Following hysterectomy in premenopausal woman even if the ovaries are
preserved.
Drug induced:
- Use of gonadotrophin – releasing hormones agonists (GnRH analogues) in
endometriosis or fibroids treatment.
- Use of chemotherapy for malignancy treatment.
III. Symptoms of menopause: severity and its presence or absence are variable.
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The menopausal symptoms which occur due to oestrogen deficiency may occur
long before the actual cessation of menstruation. As they are triggered by
relative fall in the estradiol level before it reach the postmenopausal level that is
< 100 pmol / L.
A- General symptoms
Physical:
- Tiredness
- Hot flushes
- Night sweats
- Insomnia
- Vaginal dryness: which may associate with dyspareunia, as the vaginal skin
is dependent on oestrogen for the depth and lubrication of tis squamous
epithelium.
- Urinary frequency
Hot flushes and night sweats are the classical vasomotor symptoms. They are
a vascular response to a central disturbances of the thermoregulatory center
in the hypothalamus
Psychological: not clear if they are due to oestrogen deficiency or to
sleep deprivation.
- Mood swings
- Anxiety
- Loss of short term memory
- Lack of concentration
- Loss of self confidence
- Depression
B- Urinary Symptoms:
Common symptoms are frequency, dysuria & urgency which may mimic
UTI symptoms but with negative urine culture. Stress incontinence may be
due to oestrogen deficiency.
C- Skeletal symptoms:
20% of the bony part in the body are trabecular in structure which are highly
oestrogen sensitive. They are present in the vertebrae, distal radius, the
femoral neck and calcaneus. Oestrogen play an important role in holding the
balance between bone resorption and bone formation and with the loss of
oestrogen after menopause there will be greater bone resorption than
formation. The net result is that after menopause there will be progressive
rise in the incidence of fracture of the trabecular sites as the bones become
more liable to fracture after minimal or moderate trauma. Traumatic fracture
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affect the distal radius and femoral neck, whereas non traumatic fracture
affects the vertebrae.
D- Cardiovascular system:
The function of the heart and the great vessels is now known to be affected
by the presence and by the relative absence of oestradiol.
The decline in plasma oestrogen is attended by system changes in the lipid
profile that are conductive to atherogenesis. With decrease in oestradiol there
will be:
- Increase in total cholesterol
- Decrease in HDL
- Increase in LDL cholesterol
- Equivocal triglycerides.
In addition to its direct effect on the vessels wall. Loss of oestrogen can thus
result in a promotion of both atherogenesis and vasoconstriction. However many
respected studies had shown that HRT is not indicated for the treatment or
prevention of cardiovascular disease.
E- Central nervous system:
Possible role of HRT in the prevention and treatment of Alzheimer’s disease
and other related neurodegenerative disorders and that could be due to known
action of oestrogen by enhance cerebral blood flow.
VI. Hormone Replacement Therapy:
Benefits and indications. Currently, the best reason to use hormone or estrogen
replacement in the menopause is related to quality of life. If a woman feels better
using these medications, the risks may be justified.
1.
Pretreatment assessment:
- History & examination:
Full history is needed looking to the symptoms of menopause, with
special concerned to the symptoms of oestrogen deficiency, family
history of cardiovascular disease, skeletal disease especially
osteoporosis and low trauma fracture to wrist, hip and other sites,
presence of Alzheimer’s or other neurodegenerative disease in the
family. Also to exclude family history of liver or gastrointestinal
disease that may interfere with oestrogen absorption.
Gynecological disease to exclude previous history of fibroids or
endometriosis.
History of benign or malignant breast disease
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Pelvic and breast examination to exclude oestrogen sensitive tumors
and blood pressure management.
Follow up of the women on HRT include:
= Any abnormal vaginal bleeding need to be investigated.
= Annual blood pressure measurement.
= Regular mammographic and breast examination need to be
ascertain
2.
Hormones used:
A. Modes of treatment:
- Estrogens, for the purpose of replacement, are administered orally (the most
widely use method) or transdermal patch or gel (avoid the hepatic first pass)
or subcutaneous implantation (in hysterectomies patients). Oral rout is the
preferred method. The current trend is to give the lowest dose of estrogen
necessary to relieve menopausal symptoms and to continue estrogen only as
long as is necessary for relief of symptoms. Transdermal and subcutaneous
root may be appropriate for bone built.
Conjugated equine estrogens are the preparation that has been used
for the longest time for hormone replacement. The most commonly
used dose is 0.625 mg. Low-dose therapy is 0.3 mg.
Estrone sulfate is administered in dosages of 1.25 mg.
Oestradiol valerate 1 mg or 2 mg.
Estradiol can be administered orally or transdermally.
A combination estrogen-progestin patch is available.
Local oestrogen may be suitable treatment for relieving symptoms in
the lower genital tract in the bladder and urethra, in the form of
pessary, cream or vaginal tablets. Or it is suitable for those women
who have contraindication for systemic oestrogen as previous history
of breast cancer.
- Progestogens, administered according to the regimens described for the
purpose of prevention of endometrial hyperplasia and endometrial carcinoma
in woman who have a uterus.
The most commonly used agent is medroxyprogesterone acetate.
Other progestins are used, including norethindrone acetate. Though
they are a testosterone derivative and carry many side effects.
Natural oral micronized progesterone is also used in 100- or 200- mg
doses.
Progestogens usually given in a continuous form or cyclical for 12
days per months.
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Progestin intrauterine devices (Mirena) are being used as a way to
provide endometrial protection and avoid the side effects of systemic
progestin.
It’s unnecessary in hysterectomized women.
Progestins alone are less effective than conjugated estrogen, estrone,
or estradiol, but they may provide relief in women who have
contraindications to estrogen use.
- Tibolone: it is a synthetic steroid exhibits oestrogenic, progestogenic and
androgenic activity.
- Raloxifene: SERMs (selective estrogen receptors modulators) newly
available which is selectively acting on the skeleton estrogen receptors so it
will not affecting the endometrium or the breast. So use for prevention and
treatment of bone loss. It behaves like estrogen.
B.
Risks and contraindications.
1.
Absolute contraindications.
1)
Confirmed venous thromboembolism.
2)
Neuro-ophthalmologic vascular disease.
3)
Suspicion of endometrial carcinoma.
4)
Suspicion of breast cancer.
5)
Undiagnosed vaginal bleeding.
6)
Presence or suspicion of pregnancy.
7)
Acute active hepatic disease.
1)
Uncontrolled hypertension.
2.
Relative contraindications.
1)
Seizure disorders.
2)
Presence of uterine fibroid.
3)
History of benign breast disease.
4)
Chronic stable liver disease.
5)
Unconfirmed venous thromboembolism.
6)
Migraine.
3.
Endometrial cancer. Estrogen therapy increases the risk of
endometrial hyperplasia and carcinoma when used without progestin.
4.
Cardiovascular disease. It was recommended that hormone
replacement therapy not be given for prevention of cardiovascular
disease.
5.
Breast cancer. The controversy surrounding the risk of breast cancer
in women who use estrogen replacement therapy continues. Fear of
breast cancer is one of the most common reasons women choose not
to use estrogen after the menopause. It had been shown a
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significantly increased risk of invasive breast cancer in women who
used conjugated estrogen and medroxyprogesterone.
6.
Uterine bleeding. The return of periods is another common reason
women avoid estrogen replacement therapy after the menopause.
a.
Progestin is added to estrogen therapy to prevent endometrial
hyperplasia and carcinoma.
b.
Abnormal bleeding that occurs during hormone replacement
therapy must be evaluated with endometrial sampling to rule
out endometrial disease.
V. Recommendations for Care of the Menopausal Women:
A.
Health risk assessment and physical examination.
1.
Identification of risk factors for cardiovascular disease and cancer in
medical, social, family, lifestyle history.
2.
Annual determination of height, weight and blood pressure.
3.
Annual physical examination, including breast and pelvic
examination.
B.
Age-risk appropriate screenings. Screening tests are performed to
detect risk factors and early disease in asymptomatic patients.
1.
Cholesterol screening according to age and prior values.
2.
Fasting blood sugar screening according to risk and age.
3.
Mammography every 1 to 2 years from 40 to 50 years of age,
annually after 50 years of age, and in women taking hormone
replacement therapy.
4.
Pap smear every 1 to 3 years depending on age, risk, and previous
results.
5.
Bone density screening for osteoporosis beginning at age 65 years,
earlier in women with risk factors.
C.
Healthy lifestyle promotion.
1.
Smoking cessation and alcohol limitation.
2.
Nutritional assessment and recommendations about fat, cholesterol,
calcium, and caloric intake.
3.
Exercise recommendations, especially weight bearing excersis.
4.
Screening for symptoms of depression.
5.
Counseling about prevention of falls.
D.
Menopause management.
1.
Hormone replacement therapy counseling if indicated.
2.
Non hormonal management of symptoms.
3.
Problem-related evaluation and management.
4.
Osteoporosis prevention and treatment:
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- Prevention involves hormone or estrogen replacement after the menopause.
Estrogen acts through an antiresorptive effect. Although estrogen is not
approved for the treatment of osteoporosis, it does appear to decrease the
fracture risk in women with osteoporosis.
- Accelerated bone loss that occurs after the menopause can be prevented with
early estrogen replacement therapy. Transdermal and oral preparations
effectively reduce bone loss.
- Adequate calcium intake must also be ensured through diet or
supplementation; 1000 to 1500 mg of elemental calcium plus vitamin D is
required daily.
- A regular program of weight-bearing exercise is necessary to stimulate bone
formation and to ensure maintenance of muscle tone.
- Other antiresorptive agents used to treat osteoporosis include calcitonin and
bisphosphonates (Non hormonal agent, as Etidronate and Alendronate,
inhibitors of bone turnover and slow down or prevent bone loss. Need to be
taken on an empty stomach. Treatment of choice for older women and those
with contra-indications to HRT).
- Selective estrogen receptor modulators, such as raloxifene. Use for
prevention and treatment of bone loss.
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