Menopause

Question 1

Definition of the menopause

Answer 1

A biological stage in a woman’s life that occurs when she stops menstruating and reaches the end of her natural reproductive life.

When a woman has not had a period for 12 consecutive months (for women reaching menopause naturally)

Question 2

What is the physiology of the menopause

Answer 2

Changes associated with menopause occur due to loss of ovarian follicular activity and absence of oestrogen and progesterone secretion (high LH and FSH).
* The process begins with a decline in the development of ovarian follicles, without which there is reduced production of oestrogen
* As the level of oestrogen falls, there is an absence of negative feedback (reduced inhibin B) on the pituitary gland, resulting in increased GnRH pulsatility and levels of LH and FSH
* Ovulation does not occur, leading to amenorrhoea
* Lower levels of oestrogen cause perimenopausal symptoms
* After menopause oestrone becomes the prominent oestrogen (peripheral adipose conversion)
* Ovaries also produce 30-50% of circulating androgen levels (rest in adipose tissue and adrenals)

Question 3

Normal hormone levels during perimenopause, early and late menopause

Answer 3

Question 4

Normal course of presentation in menopause

Answer 4

• Symptoms typically last up to 7 years
• (symptoms by time of onset)
• Immediate (0-5 years): Vasomotor symptoms (hot flushes, night sweats), psychological symptoms (labile mood, anxiety, tearfulness), cognitive symptoms (loss of concentration, poor memory), musculoskeletal symptoms (dry hair, itchy skin, joint aches), loss of libido
• Intermediate (3-10 years): Vaginal dryness, dyspareunia, urgency of urine, recurrent UTI, urogenital prolapse
• Long term (>10 years): Osteoporosis, cardiovascular disease and stroke, dementia

Question 5

Common CNS symptoms of menopause

Answer 5

• Vasomotor symptoms (occur in 80%- severe impact on life in 25%) including hot flushes and night sweats are some of the earliest symptoms seen in menopause.
• Occur due to the loss of the modulating effect of oestrogen on serotoninergic receptors in the thermoregulatory centre of the brain- leads to an exaggerated peripheral vasodilatory response to slight changes in environmental temperature
• Night sweats can disrupt sleep and cause exhaustion- triggers include alcohol, caffeine and smoking
• Menopause is also associated with a low mood, lack of energy, tiredness and impaired QOL.
• Many women additionally complain of some change in memory/ global cognitive function

Question 6

Common genital tract symptoms of menopause

Answer 6

• An initial scanty or irregular vaginal bleeding is due to the reduction in oestrogenic endometrial stimulation with failing ovarian function (eventually results in secondary amenorrhoea)
• Irregular heavy bleeding can occur due to episodic infrequent ovulation with fluctuations in oestrogen and unpredictable progesterone levels
• Loss of oestrogenic support to the vaginal epithelium leads to reduced cellular turnover and reduced glandular activity -> vaginal dryness, irritation, dyspareunia
• The urogenital system also becomes more susceptible to infection due to increased pH

Question 7

Common bone health symptoms in menopause

Answer 7

• Bone density reaches a peak at 20-30 years- after this peak is reached, there is a steady decline in BMD until menopause- after this point bone loss is accelerated (until 60 years) due to loss of oestrogenic protective function
• Leads to development of osteoporosis: characterised by compromised bone strength predisposing an increased fracture risk
• Risk factors: FH, Smoking, alcohol, long-term steroid use, immobility, malnutrition and liver disease

Question 8

Common cardiovascular disease presentations in menopause

Answer 8

• Oestrogen has a protective effect on cardiovascular system → supportive effect on the vessel wall favouring vasodilation and preventing atherogenesis
• In menopause there is a change from a gynaecoid (breast and hip fat) to android (abdominal fat) pattern of fat distribution, rise in triglycerides, total cholesterol and LDLs + reduction in HDLs

Question 9

Investigations for menopause

Answer 9

The following diagnoses can be made without laboratory testing in otherwise healthy women aged over 45 years with menopausal symptoms:
* Perimenopause, based on vasomotor symptoms and irregular periods
* Menopause, in women who have not had a period for at least 12 months and are not using hormonal contraception
* Menopause, based on symptoms in women without a uterus

Consider using an FSH test to diagnose menopause:
* In women aged 40 to 45 with menopausal symptoms, including change in menstrual cycle
* In women aged under 40, in whom menopause is suspected

MUST DO A PREGNANCY TEST

Question 10

How can a diagnosis of Premature menopause be made

Answer 10

Diagnose premature menopause in women < 40 years based on
* Menopausal symptoms AND elevated FSH on 2 blood samples 4-6 weeks apart
* Do not if taking COCP or high-dose progestogen
* If doubt about diagnose: consider AMH testing after seeking specialist advice

Question 11

Causes of premature menopause

Answer 11

• Primary: Chromosomal abnormalities (Turner’s syndrome, fragile X), autoimmune disease (hypothyroidism, Addison’s, myasthenia gravis), enzyme deficiencies (galactosaemia, 17a-hydroxylase-deficiency)
• Secondary: Chemotherapy, radiotherapy, infections (TB, mumps, malaria, varicella)
• Idiopathic (most common)

The risk of premature or early menopause may be increased in women with a history of early menarche, nulliparity or low parity, smoking (dose-response effect), being underweight

Question 12

Menopause differentials

Answer 12

• Irregular vaginal bleeding: during the perimenopause possible causes include endometrial polyps; uterine fibroids; adenomyosis; endometrial hyperplasia or cancer; and vulval, vaginal, or cervical lesions
• Hot flushes: Endocrine (hyperthyroidism and phaeochomocytoma), tumours (carcinoid syndrome, pancreatic cancer, medullary thyroid cancer, RCC), excess alcohol consumption, anxiety and panic disorder, TB, drugs (opiates, nitrates, selective serotonin reuptake inhibitors (SSRIs), calcium-channel blockers, levodopa, GnRH agonists)

Question 13

Does a woman require contraception during the menopause (for how long are they fertile?)

Answer 13

• Although natural decline in fertility occurs with age and spontaneous pregnancy is rare after age 50, effective contraception is required until menopause. Additionally women should be advised about condom use and protection against STIs (should also be asked about urogenital issues and sexual dysfunction)
• A woman is potentially fertile for 2 years after her last menstrual period if she is younger than 50 years of age, and for 1 year if she is over 50 years of age
• In general, all women can cease contraception at age 55 as spontaneous conception after this age is exceptionally rare even in women still experiencing menstrual bleeding.

Question 14

Does contraception effect the onset of menopause. Which contraceptives are appropriate in older women

Answer 14

• Contraception does not affect duration or onset of menopause, but may mask its symptoms
• CU-IUD is recommended until menopause (when inserted at age 40 or over)
• LNG-IUS is supported until age 55, if inserted at age 45 or over
• Women should not use the DMPA depot aged over 50 (initial bone loss)
• Progesteone-only implant and POP are safe until menopause
• Women opting for the COCP should use levonorgestrel or norethisterone and ethinylestradiol when aged over 40, due to lower VTE risk, but should use an alternative contraceptive after 50

Question 15

How should women be advised on contraceptive use when taking HRT

Answer 15

Women using sequential HRT should be advised not to rely on this for contraception
* All progesterone-only methods of contraception are safe to use as contraception alongside sequential HRT
* CHC can be used in eligible women under 50 as an alternative to HRT for relief of menopausal symptoms and prevention of loss of BMD

Question 16

What lifestyle advice should be given to perimenopausal women

Answer 16

• Vasomotor- regular exercise, weight loss, lighter clothing, reducing stress, cooler room, avoiding potential triggers (caffeine, alcohol, spicy food)
• Low mood and anxiety- adequate sleep, regular physical activity, relaxation exercises
• Cognitive symptoms- exercise and good sleep hygeine

Question 17

Management of vasomotor symptoms

Answer 17

Likely to resolve after 2-5 years without any treatment (management depends on severity, personal circumstance.) Offer women HRT for vasomotor symptoms after discussing the short-term (up to 5 years) and longer-term benefits and risks. Offer:
* Oestrogen and progestogen to women with a uterus
* Oestrogen alone to women without a uterus
* DO NOT routinely offer SSRIS, SNRIs or clonidine as fist-line treatment for vasomotor symptoms alone.
* Isoflavones or black cohosh may relieve vasomotor symptoms

Question 18

Management of psychological sumptoms

Answer 18

Consider HRT to alleviate low mood that arises as a result of menopause. Additionally consider CBT- there is no clear evidence that SSRIs or SNRIs alleviate low mood

Question 19

Management of sexual function

Answer 19

Consider testosterone supplementation for women with low sexual desire if HRT alone is not adequate

Question 20

Management of urogenital atrophy

Answer 20

• Offer vaginal oestrogen to women with urogenital atrophy (including those on systemic HRT) and continue treatment for as long as needed to relieve symptoms. Explain to women that symptoms may come back, adverse effects are very rare and that they should report unscheduled bleeding to their GP
  Can alternatively offer oral ospemifene

Question 21

When should treatment be reviewed

Answer 21

• At 3 months to assess efficacy and tolerability
• Annually thereafter unless there are clinical indicators for an earlier review

Question 22

What are some non-hormonal treatments for perimenopausal symptoms

Answer 22

Can be given where a woman chooses not to take HRT, or it is not tolerated or contraindicated:
* First advise on lifestyle measures for menopause symptom relief
* For vasomotor symptoms, consider a trial of:
o SSRIs or SNRIs for 2 weeks initially- Fluoxetine, citalopram, paroxetine, venlafaxine modified release
o Clonidine (alpha-2 adrenergic receptor agonist)
o Gabapentin (off-label)
o CBT
* For mood disorders, consider:
o Self-help resources and a trial of CBT for low mood and/or anxiety
o Antidepressant treatment for a confirmed diagnosis of depression and/or anxiety
* For urogenital symptoms:
o Vaginal moisturizers, such as Replens MD®, to be used at least twice weekly.
o Vaginal lubricants if there are insufficient vaginal secretions for comfortable sexual activity.
* Arrange to review the woman after 3 months, then at least annually thereafter.

Question 23

What is the indication for using combined HRT

Answer 23

Used in women with uteri since progesterone needs to be given to prevent endometrial hyperplasia and endometrial cancer secondary to unopposed oestrogen

Question 24

What are the indications for HRT

Answer 24

• Replacing hormones in premature ovarian insufficiency, even without symptoms
• Reducing vasomotor symptoms such as hot flushes and night sweats
• Improving symptoms such as low mood, decreased libido, poor sleep and joint pain
• Reducing risk of osteoporosis in women under 60 years old

Question 25

Benefits of HRT

Answer 25

* In women under 60 years old the **benefits generally outweigh the risks** * Improved perimenopausal symptoms, improved quality of life, reduced risk of osteoporosis and fractures

Question 26

Risks of HRT

Answer 26

The risks of HRT are more significant in older women and increase with a longer duration of treatment. **VTE**: The risk of VTE is increased by oral HRT compared with the baseline population risk and is greater than in transdermal preparations (risk if given transdermally is no greater than baseline) * Consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a **BMI over 30Kg/m2** * Consider referring to a haematologist if at high risk of VTE **Cardiovascular disease**: HRT does not increase cardiovascular risk when started in women **aged under 60 years** (does not increase the risk of dying from CVD)- presence of cardiovascular risk factors is not a risk factor (if managed optimally) * HRT with oestrogen alone is associated with no, or reduced, risk of coronary heart disease * HRT with oestrogen and progestogen is associated with little or no increase in the risk of coronary heart disease. * Oral oestrogen use is associated with a small increase in the risk of stroke T2DM: not associated with increased risk of developing T2DM **Breast cancer**: The baseline risk of breast cancer for women around menopausal age varies from one woman to another (depending on risk factors) * HRT with oestrogen alone is associated with little change in risk of breast cancer * HRT with oestrogen and progestogen can be associated with **an increase in the risk of breast cancer** (risk is associated with duration of use) * SSRIs paroxetine and fluoxetine **should not** be offered to women with breast cancer who are taking tamoxifen **Ovarian cancer**: Increased risk even with less than five years use (one extra ovarian cancer per 1000 users)

Question 27

For how long should HRT be continued

Answer 27

HRT should be continued for **as long as benefits of symptom control and improved QOL outweigh any risks**, there is no arbitrary limit for duration of HRT use * For vasomotor symptoms, most women require 2-5 years of treatment (some need longer) * Women with POI should take HRT **up to the age of natural menopause** (51 in the UK)- after which their need should be reassessed * HRT can be gradually reduced over 3-6 months, or stopped suddenly depending on the woman’s preference (increases the chance of symptom recurrence) * **Stop HRT immediately if there is**: sudden severe chest pain, breathlessness, calf tenderness, abdominal pain, serious neurological effects, HTN, prolonged immobility * Stop oestrogen-containing contraceptives or HRT 4 weeks before major surgery * It takes *3-6 months* for treatment to gain its full effect

Question 28

How can we decide which formulation of HRT to use (three step process)

Answer 28

THREE steps for deciding formulation: 1. Do they have local or systemic symptoms? * Local symptoms: use topical treatments such as topical oestrogen cream or tablets 2. Does the woman have a uterus? * No uterus: use continuous oestrogen-only HRT * Has uterus: add progesterone (combined HRT) 3. Have they had a period in the past 12 months? * Perimenopausal: give cyclical combined HRT * Postmenopausal (more than 12 months since last period): give continuous combined HRT

Question 29

How is cyclical HRT given

Answer 29

Cyclical progesterone is given for **10-14 days per month** (at the end of the month), this is used for women that have had a period *within the past 12 months*. Cycling the progesterone allows patients to have a monthly breakthrough bleed during the oestrogen-only part of the cycle, similar to a period. * sequential tablets or patches containing continuous oestrogen with progesterone added for specific periods during the cycle.

Question 30

When is continuous progesterone used in HRT

Answer 30

Continuous progesterone is used when the woman has not had a period in the **past 24 months if under 50** or **12 months if over 50 years** (can switch from cyclical to continuous regimens)

Question 31

For how long is the Mirena coil liscenced for endometrial protection

Answer 31

4 years, after which it needs replacing. The Mirena coil has the added benefits of contraception and treating heavy menstrual periods. It can cause irregular bleeding and spotting in the first few months after insertion. This usually settles with time and many women become amenorrhoeic

Question 32

Definition of progestogens, progesterone and progestins

Answer 32

* Progestogens- any chemical that targets and stimulates progesterone receptors * Progesterone- the hormone produced naturally in the body * Progestins- synthetic progesterone

Question 33

WHat are the two classes of progesterone in HRT

Answer 33

Can be described as **C19** (derived from testosterone- norethisterone, levonorgestrel and desogestrel) an **C21** progestogens (progesterone, dydrogesterone and medroxyprogesterone) If a woman experiences side effects using one consider switching to the other.

Question 34

What is tibolone

Answer 34

A synthetic steroid that stimulates both oestrogen and progesterone receptors (also weakly stimulates androgen receptors meaning it can be used in patients with low libido). Tibolone is a form of continuous combined HRT (no breakthrough bleed)

Question 35

HRT side effects

Answer 35

* Oestrogenic side effects: Nausea and bloating, Breast swelling, Breast tenderness, Headaches, Leg cramps * Progestogenic side effects: Mood swings, bloating, fluid retention, weight gain acne and greasy skin

Question 36

Management of premature menopause

Answer 36

* Offer sex steroid replacement with a choice of **HRT or a combined hormonal contraceptive** to women with premature ovarian insufficiency, unless contraindicated (for example, in women with hormone-sensitive cancer). * Explain to women: * The importance of starting hormonal treatment either with HRT or a combined hormonal contraceptive and continuing treatment until at least the age of natural menopause (unless contraindicated) * That the baseline population risk of diseases such as breast cancer and cardiovascular disease increases with age and is very low in women aged under 40 * That HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive * That both HRT and combined oral contraceptives offer bone protection * That HRT is not a contraceptive.