This document provides information on menopause and related topics. It discusses: - The definition and causes of menopause, including natural menopause and premature menopause. - Short, intermediate, and long term effects of menopause on a woman's health, including risks of osteoporosis, cardiovascular disease, and other conditions. - Diagnosis of menopause and premature ovarian failure. - Treatment options for menopausal symptoms including hormone replacement therapy and other medications, as well as their risks and benefits. - Alternative and complementary therapies that can be used to treat menopausal symptoms.

1. MENOPAUSE
Lectures on Gynecology
Dr Magda Helmi

2. The term ‘climacteric’ (from the Greek klimakter (rung of a
ladder)) signifies a major movement on life’s ladder and is often
used synonymously with ‘perimenopause’ or ‘the change It
marks the transition from the reproductive to the non-reproductive
state, the menopause being a specific event within
that phase.

3. Menopause is the permanent cessation of menstruation resulting in the loss of
ovarian follicle development. It is considered to occur when 12 menstrual cycles
are missed. The menopause occurs as a result of loss of ovarian follicular activity
leading to a fall in oestradiol levels below the level needed for endometrial
stimulation.
Menopausal transition, or perimenopause, is the period between the
onset of irregular menstrual cycles and the last menstrual period.
Surgical menopause It occurs when functioning ovaries are removed,
such as at hysterectomy or by other treatments, such as radio- or
chemotherapy, or temporarily during treatment with GnRH analogues for a
variety of conditions.
Premature menopause A premature menopause occurs if the
menopause happens before the age of 45.
Postmenopause is the phase following the last menstrual period.

4. Causes of premature ovrian failure
Primary Chromosome anomalies, e.g. Turner’s, Fragile X
Auto-immune disease, e.g. hypothyroidism, Addison’s,
myasthenia gravis
Enzyme deficiencies, e.g. galactosaemia, 170s-hydroxylase
deficiency
Secondary Surgical menopause after bilateral oophorectomy
Chemotherapy or radiotherapy
Infections, e.g. tuberculosis, mumps, malaria, varicella

6. Menopause may only be a single event, but it
represents a significant change in a woman’s
hormonal milieu which has implications for her
future health and quality of life - hence the
importance of post-reproductive health for women.
The ovaries produce four principal steroid hormones:
oestradiol, progesterone and the androgens,
testosterone and androstenedione, when ovulation
stop the level of oestradiol production is no longer
sufficient to stimulate endometrial proliferation and
menopause ensues. Further decline in oestradiol
levels over subsequent years has effects on all
oestrogen-responsive tissues.

7. An increase in serum follicle-stimulating hormone (FSH) and
decreases in estradiol and inhibin are the major endocrine changes that
occur during the transition to menopause
FSH levels are higher than luteinizing hormone (LH) levels, and both
rise to even higher values than those seen in the surge during the
menstrual cycle
The FSH rise precedes the LH rise; FSH is the diagnostic marker for
ovarian failure, while LH is not necessary to make the diagnosis
The large cyclical variation of estradiol and estrone observed during
the menstrual years ceases, and fluctuation in levels is small and
inconsequential, with the mean value being considerably lower
No specific changes in thyroid function related to menopause have
been found

8. Patient history
Symptoms of perimenopause include the following:
Hot flashes
Cold sweats
Irregular menstrual bleeding
Urogenital atrophy and dryness with resultant
dyspareunia (see Gynecologic Pain), itching,
and urinary urge incontinence
Cognitive and affective disturbance

9. Physical examination
Physical findings associated with perimenopause include
urogenital atrophy, as well as flushing and diaphoresis
during hot flashes.
Genitourinary problems
Urogenital atrophy is a common observation in postmenopausal women which increases
with age

10. Osteoporosis
Eighty per cent of our skeleton is comprised of cortical bone, the
other 20 per cent being trabecular bone. The latter is principally
found in the vertebrae, long bones, such as femur and humerus,
and the wrist. Trabecular bone has a shock absorbing capacity
which is accomplished using its large surface area of
interconnecting trabeculae. It is constantly undergoing turnover
and is oestrogen sensitive. Oestrogen acts as an antiresorptive
agent on trabecular bone and the fall in oestrogen levels after the
menopause is characterized by an unprecedented fall in bone
density, which ultimately may lead to an increased risk of
osteoporotic fracture.

11. While coronary heart disease (CHD) is the single
most common cause of death in women in the
United Kingdom, it is relatively uncommon
before the menopause. There is a large body of
evidence suggesting that oestrogen has a
protective influence against CHD. Early
menopause without additional oestrogen is
associated with a two» to four-fold increased risk
in CHD

12. Short term (0-5 years) Vasomotor symptoms, eg. Hot flushes, night sweats
Psychological symptoms, e.g. labile mood, anxiety, tearfulness
Loss of concentration, poor memory
Joint aches and pains
Dry and itchy skin
Hair changes
Decreased sexual desire
Intermediate (3-10 years) Vaginal dryness, soreness
Dyspareunia
Sensory urgency
Recurrent urinary tract Infections
Urogenital prolapse
Long term (>10 Years) Osteoporosis
Cardiovascular disease
Dementia

13. The risk of depression appears to be higher during
perimenopause, when hormone levels are
changing, than during postmenopausal, when
estrogen and progesterone levels are low but
stable.
 Life stressors
 Depression
 Problems with sleep
 Schizophrenia
 Obsessive-compulsive disorder
 Bipolar disorder

14. FSH measurements are the most useful for confirming the
diagnosis. A level of >30 IU/L is considered diagnostic of
menopause. However, there is significant daily variation of
FSH levels throughout the cycle and the results should be
interpreted with caution and repeated if necessary. The
tests are best done on day 3-5 of the cycle when FSH levels
are usually at their lowest. To confirm that a woman with
amenorrhea or who has been hysterectomized is
menopausal, two measurements at least 2 weeks and up to
three months apart are recommended.

15. The diagnosis of POF is usually confirmed by the combination of a
6-month period of amenorrhea or oligomenorrhoea and two
measurements of follicle-stimulating hormone (FSH) above 30 IU/l
taken at least 4 weeks apart. Oestradiol measurement is typically
very low, although ovarian function can resume on an unpredictable
basis and produce detectable oestradiol. FSH is not an ideal
diagnostic tool: it rises only in the later stages of follicle depletion,
has marked cycle-to-cycle variability and is poor at predicting
reproductive status. There has been interest in more direct markers
of ovarian reserve such as anti-Müllerian hormone (AMH), which
closely follows the reduction in follicle number over time in healthy
women and falls to very low levels prior to menopause. In
assessment of amenorrhea, AMH or transvaginal ultrasound scan
will exclude polycystic ovarian syndrome as a cause. In POF, the
antral follicle count is very low, and seeing this as a 'direct' marker
of ovarian function may help some women understand the
diagnosis. However, even in POF, the intermittent ovarian function
means that follicular activity is seen in the majority of women.

16. Genetic Tests
A karyotype should be offered to women with POF if the onset of
amenorrhea or oligomenorrhoea is before age 25. A karyotype is also
indicated in women of any age in whom Turner's syndrome mosaicism is
suspected.
Women with POF should be offered FMR1 (fragile X) permutation
testing. Overall the permutation is found in 4–5% of women with POF;
amongst those with a family history of POF, 14% have a positive result.
Autoimmune Tests
Thirty per cent of cases of POF are estimated to be owing to
autoimmunity.
Associated Medical Conditions
A wide range of medical conditions may be associated with POF.
Thyroid dysfunction is common; women should have initial thyroid
function tests (TFT) and antibody testing.

17. Alternative and complementary
Lifestyle changes Diet and exercise
Complementary
therapies
Acupuncture, Reflexology, Magnetism.
Herbal remedies Black cohosh (Actaea racemosa), Dong quai (Angelica sine.nsis), Evening
primrose oil (Oenothera biennis),
Gingko (Gingko biloba), Ginseng (Panax ginseng), Kava kava (Piper
methysticurn), St John’s wort (Hypericum perforatum)
‘Bio-identical’ Natural progesterone gel hormones DHEA, Phytoestrogens, e.g. isoflavones,
red clover
Alpha-adrenergic
agonists
Clonodine
Beta-blockers Propanolol
Selective serotonin
reuptake inhibitor
Venlafaxine, fluoxetine, paroxetine, citalopram, gabapentin
Hormone replacement,
therapy (HRT)
Oestrogen alone, Oestrogen and progestogen combined, Progestogen alone

18. the bisphosphonates are the principle class of
drug used. Alternatives include strontium and
Raloxifene®, which is a type of SERM (see below
under New developments). However, all these
can have significant side effects and should
usually only be prescribed to women over 60
who are at high risk of osteoporosis.
Para-thyroid hormone is reserved for women
with a very high risk.

19. HRT is the principal medical treatment available for
troublesome menopausal symptoms and simply acts
by replacing the hormones that are normally produced
by the human ovary at physiological levels. Oestrogen
is the main hormone and is either given alone or in
combination with a progestogen, which should be
given to all non-hysterectomized women. A third
hormone, testosterone, can also be given in
conjunction with oestrogen. Most HRT treatments
come in prepared combinations, but it is important to
understand the component parts.

20. There are a variety of different types of oestrogen,
which can be given at varying doses and by
different routes. For the vast majority of women,
the type and route of administration are not
important and, provided an adequate dose of
oestrogen is given, it is likely to be effective.
As with any treatment, the lowest possible dose
should be used.
Different routes of oestrogen administration have
different pharmacokinetic profiles.

21. Oestradiol (transderrnal, gel,
implant)
Oestradiol valerate
Conjugated equine
oestrogens
Oestrone sulphate
Oestriol (vaginal only)
Progestogens used
 C-19 nortestosterone derivatives:
 Norethisterone (transdermal)
 Levonorgestrel (transdermal,
intrauterine)
 C-21 progesterone derivatives:
 Dydrogesterone
 Medroxyprogesterone acetate
 Cyproterone acetate (not
available in UK)
 C-17 derivatives:
 Progester
 Drospirenoneone: Micronized
progesterone (vaginal gel,
pessary, suppository)

22. Benefits Risks Uncertainties
Vasomotor
Breast cancer
symptoms
VTE
Urogenital symptoms
Endometrial
and sexual function
cancer
Stroke
Osteoporosis
Colon cancer
Cardiovascular
disease and stroke
Alzheimer’s
Ovarian cancer

23. From British Menopause Society Consensus Statement,
currently advise that HRT should not be used as a first-line
treatment for osteoporosis prevention as the potential risks
outweigh the benefits. However, they also emphasize that
HRT is the most appropriate treatment for osteoporosis
prevention in women with premature ovarian failure under
the age of SU and for women in whom the standard
osteoporosis treatments are not tolerated or are unsuitable.
While there is convincing evidence that HRT started around
the menopause does have a protective effect against
cardiovascular disease, this is not an indication for
considering HRT. Similarly, despite consistent evidence of
reduced rates of colon cancer with HRT, this is not
considered an indication.

24. Controversy continues to surround the true
effect of HRT on breast cancer risk.
More recently, a large randomized trial on HRT
(the Women’s Health Initiative (WHI)),
reported a broadly similar risk to that seen in
the epidemiological studies for combined
oestrogen and progestogen treatment after five
years, but also found no increase in risk over
seven years with oestrogen-only treatment.
Thus, the increase in risk seems to be more
associated with the progestogen component.

25. Unopposed oestrogen replacement
therapy increases endometrial cancer
risk which is why all non-hysterectomized
women should also
receive a progestogen. These are usually
given cyclically to mimic the natural
menstrual cycle.

26. Most of the limited data relate to
oestrogen alone and suggest a small
increase in risk with very long term
(>10 years) treatment. This increase
does not seem apparent with combined
therapy.

27. HRT increases the risk of venous
thromboembolism (VTE) twofold, with the
highest risk occurring in the first year of use. The
background risk of VTE in women over 50 years
not taking HRT is small (1.7/ 1000), so the overall
impact of this increase is very low.
Yet, despite the recent controversies, HRT remains
the clinically most effective and cost-effective
strategy for women with menopausal symptoms.
For the majority of healthy symptomatic
menopausal women, the potential benefits will
outweigh any small risks.

28. Absolute and relative contraindications to taking HRT
Absolute Relative
 Suspected pregnancy
 Breast cancer
 5 Endometrial cancers
 Active liver disease
 Uncontrolled hypertension
 Known VTE
 Known thrombophilia (e.g.
Factor V ‘leiden)
 Otosclerosis
 Uninvestigated abnormal
bleeding V
 Large uterine fibroids
 Past history of benign breast
disease
 Unconfirmed personal
history or a strong family
history of VTE
 Chronic stable liver disease
 Migraine with aura.

29. Oestrogen related Progestogen related
Fluid retention
Nausea
Headaches
Breast enlargement
Leg cramps
Dyspepsia
Irritability
Fluid retention
Breast tenderness
Headaches
Acne
Mood swings
Depression
Bloating
Constipation
Increased appetite

30. Drugs used to treat perimenopausal
depression include antidepressants and
hormones.
And Improvement of mood and quality of
life