Menopause E-book

Question 1

Menstrual cycle

Answer 1

Menstruation occurs as a result of cyclic hormonal variations. During the follicular phase (the first half of the menstrual cycle) the endometrium thickens under the influence of increasing levels of oestrogen, particularly estradiol, which is secreted by the developing ovarian follicles. This increase in oestrogen triggers the anterior pituitary to release a surge of luteinising hormone, this occurs through a positive feedback loop. Following this, ovulation occurs.

After ovulation and as the luteal phase progresses, the endometrium starts to further develop due to increasing levels of progesterone released by the corpus luteum. Both progesterone and oestrogen are secreted from the corpus luteum which forms from the remaining ovarian follicle after ovulation.

If conception does not occur, luteolysis occurs and steroid levels fall, which means the endometrium cannot be maintained. Stromal fluid is lost, leucocytes infiltrate and intraglandular extravasation of blood occurs. Endometrial blood flow is reduced which leads to necrosis and sloughing which is menstruation.

Question 2

Aetiology of the menopause

Answer 2

The menopause is signalled by a woman’s last menstrual period and is defined as the permanent cessation of menstruation that results from loss of ovarian follicular activity.

There are a number of hormonal changes that occur during the menopause. This includes one part of the hypothalamic-pituitary-ovarian axis system breaking down as the ovaries become depleted of follicles which results in the lack of production of oestrogen and progesterone. Therefore the negative feedback on the hypothalamus is lost and so pituitary secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) increases resulting in high levels of these two hormones.

Question 3

Menopause can be split into three stages:

Answer 3

1. Perimenopause
2. Menopause
3. Postmenopause

Question 4

What occurs in perimenopause

Answer 4

This typically begins several years before menopause as a result of the ovaries gradually making less oestrogen. It lasts up until the menopause, when the ovaries stop releasing eggs. In the latter stages of perimenopause (the last 1-2 years) the drop in oestrogen quickens which causes women to have menopausal symptoms.

Question 5

What occurs in menopause

Answer 5

This is the point at which it has been a year since the woman last had her menstrual period. At this stage, the ovaries have stopped releasing eggs and making most of their oestrogen.

Question 6

What occurs in postmenopause

Answer 6

These are the years that follow menopause. Menopausal symptoms such as hot flushes ease for most women however health risks related to the loss of oestrogen rise as the woman ages.

Question 7

What occurs in premature menopause

Answer 7

This is a condition where menopause starts before the age of 40 years. It can be occurring naturally or due to the side effects of treatments.

Question 8

What occurs in early menopause

Answer 8

This is when menopause occurs between the age of 40 to 45 years.

Question 9

Menopausal symptoms

Answer 9

Vasomotor symptoms, commonly known as hot flushes and night sweats, are caused by dilation and constriction of blood vessels, which leads to impaired thermoregulation.
Usually this starts as a heat sensation in the chest and face but then spreads. The sensation usually only lasts a couple of minutes and is associated with sweating and skin redness. Other signs include palpitations, anxiety, and sleep disturbances.

The mechanism of these vasomotor symptoms is currently unknown however it is thought to be due to an imbalance in noradrenergic activity in the thermoregulatory centre, which is believed to be influenced by hormone level fluctuation. Increased noradrenergic activity is suspected to narrow the neutral thermoregulatory zone between sweating and shivering.

Menopause also has effects on mood. This arises via the amygdala, hippocampus and some temporal structures of the brain which are centrally involved in mood regulation and which are sensitive to fluctuating levels of sex hormones, in particular oestrogen.
Oestrogen receptors (ER) are most abundant in the amygdala and hippocampus, hence during the menopause there is decreased stimulation of ER due to less circulating oestrogen thus causing low mood.

Question 10

Recent research has also shown there to be a link between oestrogen and the serotonin system whereby:

Answer 10

● Oestrogen increases postsynaptic responsivity
● Oestrogen increases the number of serotonergic receptors
● Oestrogen enhances serotonergic transport and uptake
● Oestrogen also facilitates synthesis of serotonin and the levels of its metabolite
● Oestrogen upregulates 5-HT1 receptors and downregulates 5-HT2 receptors
● Oestrogen decreases monoamine oxidase (MAO) activity

Question 11

These urinary changes occur for two reasons:

Answer 11

● Lack of oestrogen reduces the urinary tracts ability to control urination
● Advanced age, which usually coincides with menopause, has various debilitating effects on the pelvic area organs and tissues

Question 12

Complications

Answer 12

• Osteoporosis
• Sexual dysfunction
• Insomnia
• Schizophrenia
• Bipolar disorder
• Panic disorder
• OCD

Question 13

Osteoporosis

Answer 13

This is characterised by backache, fractures with minimal trauma, decreased height and mobility. This is caused by decreasing levels of oestrogen in the body that help to protect bone strength. Modifiable risk factors include: low dietary intake of calcium or vitamin D, smoking and a sedentary lifestyle. Osteoporosis can be a risk factor for developing: hyperthyroidism, hyperparathyroidism, CKD and diseases requiring systemic corticosteroid use. HRT is effective in treating and preventing osteoporosis, as well as the use bisphosphonates like alendronate. Selective estrogen receptor modulators lie raloxifene have also demonstrated some effectiveness in the treatment of osteoporosis

Question 14

Sexual dysfunction

Answer 14

often results from depression or anxiety disorders and symptoms which make sexual activity uncomfortable like vaginal dryness. Treatment of the underlying depression or vaginal dryness is usually effective. In some cases treatment with androgens may be indicated

Question 15

Insomnia

Answer 15

occurs in 40-50% of women during the menopausal transition. This may be a result of the oestrogen deficiency as it has been shown that exogenous oestrogen improves both subjective and objective sleep. HRT may help some cases of insomnia

Question 16

Schizophrenia

Answer 16

There is a higher incidence of schizophrenia in women aged 45-50 compared to men in the same age bracket. This suggests that oestrogen may play a modulatory role in the pathophysiology of schizophrenia. Referral to a specialist is necessary in this patient population

Question 17

Bipolar disorder

Answer 17

there is evidence to show that women with pre diagnosed bipolar disorder experience a higher amount of depressive episodes during the menopausal transition

Question 18

Panic disorder

Answer 18

this is common during perimenopause, especially among women who experience many physical symptoms of menopause. Panic attacks in menopausal women are mostly associated with negative life events, medical comorbidity and functional impairment

Question 19

OCD

Answer 19

The onset of OCD is more common in menopausal women than other patient populations. Hormone levels in menopause have been correlated with a worsening of
the disorder, suggesting that oestrogen may play role in the development of the disorder

Question 20

Non-pharmacological management options

Answer 20

Many women will benefit from lifestyle changes, smoking cessation, improving diet, and regular exercise, although these factors do no necessarily reduce menopausal symptoms, they do improve overall well being and can make symptoms easier to tolerate.

• CBT
• Herbal remedies (however these are not recommended as their safety is unknown)
• Vaginal lubricant

General lifestyle modifications are also recommended to reduce menopausal symptoms. For symptoms of hot flushes and night sweats: regular exercise, weight loss, wearing light clothing, sleeping in a cooler room, reducing stress and avoiding possible triggers such as spicy foods, caffeine, smoking, and alcohol is recommended.

Question 21

Non-hormonal management for vasomotor symptoms

Answer 21

2 week trial of:
- fluoxetine 20mg OD
or 
- Citalopram 20mg OD
or 
Venlaflaxine 37.5mg BD

Question 22

Non-hormonal management for vaginal dryness

Answer 22

Vaginal lubricant/ moisturiser

Question 23

Non-hormonal management for psychological symptoms

Answer 23

• Self groups
• CBT
• Antidepressants

Question 24

Pharmacological options for vasomotor symptoms

Answer 24

HRT with small doses of oestrogen (together we a progesterone in women with a uterus) is appropriate for alleviating vasomotor instability. Tibolone combines oestrogenic and progestogenic activity with weak androgenic activity it is given continuously without cyclical progestogen. Clonidine hydrochloride may be used to reduce vasomotor symptoms in women who cannot take an oestrogen, but may cause unacceptable side-effects. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine should not be given as first-line treatment for vasomotor symptoms alone

Question 25

Pharmacological options for psychological symptoms

Answer 25

HRT should be considered to alleviate low mood that arises as a result of the menopause. There is no clear evidence for the use of SSRIs or SNRIs to ease low mood
in menopausal women who have not been diagnosed with depression.

Question 26

Pharmacological options for altered sexual function

Answer 26

Testosterone supplementation for menopausal women with low sexual desire should be considered if HRT alone is not effective

Question 27

Pharmacological options for urogenital therapy

Answer 27

HRT with small doses of an oestrogen is appropriate for alleviating urogenital atrophy.
Vaginal oestrogen may be offered to women with urogenital atrophy and treatment may be continued for as long as needed to relieve symptoms. The dose may be increased if symptoms do not resolve after seeking advice from a healthcare professional with expertise in menopause

Question 28

Pharmacological options for Postmenopausal osteoporosis

Answer 28

Oestrogen given systemically in the perimenopausal and postmenopausal period or tibolone given in the postmenopausal period also diminish postmenopausal osteoporosis but other drugs are preferred.

Question 29

Pharmacological options for hot flushes

Answer 29

Strong evidence suggested that transdermal oestradiol plus progestogen greatly reduces the frequency of hot flushes in women with a uterus

Question 30

Benefits and Risks of HRT

Answer 30

The benefits of HRT include reduction of vasomotor symptoms; improved sleep, joint pain and quality of life; improved psychological symptoms; relief of vaginal dryness and improved sexual function; improved bone mineral density and reduced fracture risk; reduced risk of colon cancer, dementia, prevention of diabetes, macular degeneration and cataract formation, improved skin healing.
The risk of VTE associated with HRT is greater for oral than transdermal preparations.
The risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline risk. HRT with oestrogen alone is associated with no, or reduced, risk of CHD; HRT with oestrogen and progestogen is associated with little or no increase in the risk of CHD. Oral oestrogen is associated with a small increase in the risk of stroke and HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer.

Question 31

Side effects of HRT include

Answer 31

● Breast tenderness
● Headaches
● Nausea
● Indigestion
● Abdominal pain
● Vaginal bleeding
● Some types of HRT can also cause a small increase in your risk of certain serious problems, such as blood clots and breast cancer

Question 32

Cautions and contraindications for HRT

Answer 32

For women at increased risk of VTE, avoid oral HRT and consider transdermal HRT. For women with cardiovascular risk factors, HRT can be considered, however cardiovascular risk factors should be managed. For women with hypothyroidism, monitor thyroid function regularly to ensure that thyroid hormone levels remain in the acceptable range.

Question 33

Premature menopause HRT

Answer 33

In premature menopause, there is an increased risk of osteoporosis and ischaemic heart disease due to early loss of oestrogens. In premature menopause HRT should be taken at least until the age of normal menopause and for 5-10 years after the age of 50.
It should be taken until the age of 52 and for 5-10 years after this age in surgically-induced menopause

Question 34

Perimenopause HRT

Answer 34

Perimenopausal women may still need contraception. Contraception should continue to be used until 1 year after the last period if over the age of 50, and for 2 years if under the age of 50

Question 35

Tibolone

Side effects

Answer 35

● Breast abnormalities
● Cervical dysplasia
● Endometrial thickening
● Gastrointestinal discomfort
● Genital abnormalities
● Abnormal hair growth
● Increased risk of infection
● Pelvic pain
● Postmenopausal haemorrhage
● Vaginal discharge
● Vaginal haemorrhage
● Increased weight

Question 36

Contraindications - Tibolone

Answer 36

Contraindications include active or recent thromboembolic disease, history of breast cancer, liver disease, and history of thromboembolism

Question 37

Cautions - Tibolone

Answer 37

Tibolone should be used with caution in: diabetes, history of endometrial hyperplasia, history of fibrocystic disease, history of liver disease, and risk of stroke

Question 38

Interactions - Tibolone

Answer 38

Bleomycin, cyclophosphamide, lenalidomide, methotrexate, and raloxifene all interact with tibolone

Question 39

Clonidine

Side effects

Answer 39

● Constipation
● Depression
● Dizziness
● Dry mouth
● Fatigue
● Headache
● Nausea
● Postural hypotension
● Salivary gland pain
● Sedation
● Sexual dysfunction
● Sleep disorders
● Vomiting

Question 40

Clonidine - CI

Answer 40

Contraindications include severe bradyarrhythmia secondary to second- or third-degree AV block or sick sinus syndrome

Question 41

Clonidine - Interactions

Answer 41

acebutolol, amlodipine, bendroflumethiazide, and chlorpromazine

Question 42

Clonidine - cautions

Answer 42

Caution should be taken when using clonidine in: cerebrovascular disease, constipation, heart failure, history of depression, mild to moderate bradyarrhythmia, polyneuropathy, Raynaud’s syndrome, or other occlusive peripheral vascular disease

Question 43

Antidepressants

Side effects

Answer 43

SSRIs and SNRIs:
● Feeling agitated, shaky or anxious
● Feeling and being sick
● Indigestion and stomach aches
● Diarrhoea or constipation
● Loss of appetite
● Dizziness
● Insomnia or feeling very sleepy
● Headaches
● Low sex drive

Question 44

Antidepressants - cautions

Answer 44

SSRIs may not be suitable if you have: bipolar disorder, a bleeding disorder or if you’re taking medicines that can increase bleeding risk, type 1 diabetes and type 2 diabetes, epilepsy, and kidney disease.

Question 45

Antidepressants - CI

Answer 45

Poorly controlled epilepsy, mania

Question 46

Antidepressants - interactions

Answer 46

St John’s wort, monoamine oxidase inhibitors, and other serotonergic drugs, NSAIDs, anticoagulants, drugs that prolong QT interval