MENOPAUSELectures on Gynecology

Dr Magda Helmi

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.

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.

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

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.

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 menopauseFSH levels are higher than luteinizing hormone (LH) levels, and both rise to even higher values than those seen in the surge during the menstrual cycleThe FSH rise precedes the LH rise; FSH is the diagnostic marker for ovarian failure, while LH is not necessary to make the diagnosisThe 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 lowerNo specific changes in thyroid function related to menopause have been found

Patient history

Symptoms of perimenopause include the following:

Hot flashesCold sweatsIrregular menstrual bleedingUrogenital atrophy and dryness with resultant dyspareunia (see Gynecologic Pain), itching, and urinary urge incontinenceCognitive and affective disturbance

Physical examinationPhysical findings associated with perimenopause include urogenital atrophy, as well as flushing and diaphoresis during hot flashes.

Genitourinary problemsUrogenital atrophy is a common observation in postmenopausal women which increases

with age

OsteoporosisEighty 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.

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

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

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

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.

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.

Genetic TestsA 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 TestsThirty per cent of cases of POF are estimated to be owing to autoimmunity. Associated Medical ConditionsA 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.

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

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.

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.

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.

Oestradiol (transderrnal, gel, implant)

Oestradiol valerate

Conjugated equine oestrogens

Oestrone sulphate

Oestriol (vaginal only)

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)

Progestogens used

Benefits Risks Uncertainties

Vasomotor

symptoms

Urogenital symptoms

and sexual function

Stroke

Osteoporosis

Colon cancer

Breast cancer

VTE

Endometrial

cancer

Cardiovascular

disease and stroke

Alzheimer’s

Ovarian cancer

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.

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.

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.

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.

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.

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.

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

Drugs used to treat perimenopausal depression include antidepressants and hormones.

And Improvement of mood and quality of life