Menopause

Lifestyle advice for menopause

- Hot flushes and night sweats: regular exercise, weight loss, wearing light clothing, sleeping in cool room, reducing stress, avoiding triggers (spicy food, caffeine, smoking, EtOH) - Sleep disturbances: avoiding exercise late in the day and maintaining a regular bedtime - Mood and anxiety disturbance: adequate sleep, regular physical activity, and relaxation exercises - Cognitive symptoms: exercise and good sleep hygeine

What is it?

- Menopause refers specifically to the last menstrual period. This diagnosis can only be made retrospectively after 1 year of absent cycles. - Women may experience symptoms and irregular periods before their last period when they are said to be 'perimenopasal'. This period of time is also referred to as the 'climacteric'. - The menopause generally occurs between the ages of 45 and 55 with the average age being 51 years. - Premature is < 40 - Perimenopausal is the period when you start getting menopausal symptoms and erratic menstruation

HRT pathway

1) Combined or estrogen alone; estrogen if intact uterus 2) Cyclical r continuous - Women should be prescribed sequential combined HRT if their LMP was < 12 months ago - Women can be prescirbed continuous combined HRT if they have received sequential for at least one year; or if it has been at least one year since LMP, or 2 years if they had premature menopause 3) oral or transdermal - by avoiding first pass metabolism through the liver, non-oral preparations are more suitable for women at risk of embolism 4) Low dose vaginal estrogen (tablet, cream, pessary or ring) - may be preferred if symptoms are primarily urogenital 5) Mirena + estrogen component - if progestogen side effects are experienced

Complications of HRT

1) Malignancy - There is no evidence of any increase in malignancy of the cervix or ovary . - Neoplasia of the endometrium may follow unopposed oestrogen; the risk increases with the duration of use: • 3- 6-fold after five years of use. • 10-fold after ten years. - Adding cyclical progestogens virtually eliminates this risk. - Breast cancer is stimulated by higher oestrogen levels. But estrogen alone is fine, estrogen and prostestogen is risky for breast cancer. - Meta-analysis indicates that the relative risk of breast cancers is about ¥ 1.3 up to ten years and exceeds this with longer-term therapy. - Continuous combined preparations have been shown to increase the risk of breast cancer two-fold after 5 years and three-fold after 10 years of use. The increased risk declines back to baseline within 5 years of stopping treatment. - Obviously, a woman with a family history of breast cancer should be counselled before starting HRT. 2) Continued periods The risk rates of cancer of the ovary and cervix are unaffected. Regular monthly bleeding going on into the 60 s is a nuisance. It often reduces in amount but still occurs. In an attempt to prevent this, progestogens may be given in a wider spread but lower dose throughout the cycle. Tibolone (2.5 mg daily), a gonadomimetic, possesses weak oestrogenic, progestational and androgenic properties. It can be used to treat flushes, psychological and libido problems and is not accompanied by regular withdrawal bleeding symptoms though it is not absolute especially if used on women early in the menopause. Some women have a weight gain due to water retention when they start the oestrogens but this settles after a few months. Some women get a depression like premenstrual tension during the progestogen phase. Changing the dose of added progestogens will help this. 3) Uterine enlargement Hyperplasia of the uterus may lead to an increase of bleeding. Any pre-existing fibroids may rarely continue their growth, whereas normally after the menopause their growth stops. 4) VTE - risk is increased by oral HRT so consider transdermal - patch: most people use it for 3-5 years? 5) CVD - estrogen alone is okay, E+P a bit more - oral is more risky than transdermal - if started in women <60 risk is low

Types of HRT

1) Orally this is the commonest and the most convenient. Compliance may be patchy and patients may forget, rendering the therapy ineffective. 2) Transdermal patches and gels Oestrogen and progestogens are readily absorbed through the skin. There is the advantage of the oestrogen not having to pass through the portal system after absorption, where much would be destroyed. Hence, higher tissue levels of the oestrogens are achieved. The patches only need to be changed every third/seventh day and so compliance is higher. More recently, sprays have been developed. 3) Implants Oestrogens can be given in a retard preparation by implantation under local anaesthesia. The pellets can be inserted into the abdominal wall or the thigh under the fascia lata. They last up to six months and are easily replaced so compliance is not relevant. Occasionally the oestrogens are given with testosterone to provide some stimulus to the libido but this reduces the cardioprotective effect of oestrogen. Repeated use of oestrogen implants can lead to very high levels of oestrogen. As the implant wears off the woman may experience menopausal symptoms even though the serum oestradiol levels are still within or above physiological levels. This may lead to women requesting their implants more and more often leading to dangerous levels of oestradiol with an increased risk of thrombosis. Early replacement of implants should therefore be avoided. Progesterones should be taken by mouth during the second half of each cycle in order to get a withdrawal bleed and prevent build-up of the endometrium in women with a uterus. This method is most commonly used by women who have had a hysterectomy. 4) Vaginally Steroids are absorbed through the vaginal epithelium, but a large dose is needed in the vagina to get a reasonable dose inside the body. However, if vaginal dryness is the main symptom, this is a good route Estrogen only for people who have had hysterectomies.

Preparations

1) Orally — Progynova, oestradiol or Premarin (oestrone). Progestogen — norethisterone 1 mg a day for last 10 days. 2) Subcutaneous implant — 50- 100 mg oestradiol (with 100 mg testosterone). 3) Patches of oestradiol 25 or 50 m g with norethisterone acetate 1 mg (12 days). 4) Vaginal application — oestriol or oestradiol as a cream or pessary high in the vagina twice a week. 5) Non-bleed preparations. These can be either oestrogen with continuous progestogen or nonoestrogenic compounds (Tibolone) that mimic oestrogen's effect on menopausal symptoms and bone. All treatments should be given for two years or to the age of 55. If the uterus has been removed previously, the supplementary progestogen is not required. Unless treatment is stopped for an interval, the doctor and the patient will never know if the treatment is still required.

Causes of premature menopause

A premature menopause (<45 years of age) can occur for a number of reasons, e.g. surgery, chemo/radiotherapy or, indeed, naturally. - A small percentage of women (1%) will experience premature ovarian failure below the age of 40 years. - TB, mumps & other infections

Osteoporosis

Although it is not a first-line treatment for osteoporosis prophylaxis in older age groups (due to the risk profile), HRT is still recommended for women under the age of 50 undergoing menopause for bone protection. Once they reach the age of 51, HRT should be reviewed and other methods to prevent osteoporosis considered. Other pharmacological agents include bisphospho- nates, and Selective oEstrogen Receptor Modulators (SERMs). Calcium and vitamin D supplementation, ces- sation of smoking and regular weight-bearing exercises are also important.

Investigating menopausal symptoms

FSH should only be considered in women - Over 45 with atypical symptoms - Between 40 and 45 with menopausal symptoms including a change in menstrual cycle - Younger than 40 if premature suspected FSH test should not be used to diagnose menopause in women using COCP or high dose progestogen.

Non-hormonal agents

If hormonal agents are not tolerated or contraindicated for vasomotor symptoms, consider: • clonidine - a centrally active alpha-2 agonist. • selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs).

Ix PM bleeding

Investigation of postmenopausal bleeding • Inspection of vulva and urethra. • Cervical smear. • Bimanual vaginal examination. • Transvaginal ultrasound scan. • Hysteroscopy and endometrial biopsy. Intrauterine pathology is best excluded by hystero- scopic examination of the uterine cavity with endome- trial biopsy, although ultrasound estimation of the endometrial thickness combined with endometrial sampling can be used. The endometrial thickness in a postmenopausal woman should be less than 5 mm. Although a negative endometrial sample is reassuring, the commonest method of taking the sample in the out- patient setting is by using the 'pipelle' endometrial sampler, which samples only 4% of the uterine cavity. Ultrasound with biopsy can, therefore, miss early focal pathology. The ovaries can be assessed using ultrasound and if an oestrogen-secreting tumour is suspected, circulating oestradiol levels should be measured.

Long term symptoms

Most of the above symptoms disappear within a year or two but those on the skeleton stay for ever. The calcium part of the skeleton is reabsorbed, whilst the collagen framework stays the same. This leads to osteoporosis (Fig. 21.1). Women lose calcium at different rates and so the need for replacement oestrogens differs from one woman to another. Those with established osteoporosis should be treated with biphosphonates. In reproductive life, while oestrogen synthesis is high, women are protected from heart disease and coronary occlusion. After the menopause, this does not occur and ten years later, the rate of coronary thrombosis is as high in women as men. There has been some evidence that hormone replacement therapy (HRT) may decrease the incidence of ischaemic heart disease (IHD), but a more recent study amongst women at high risk of IHD has not demonstrated a protective effect. HRT does alter the lipid profile with a higher level of high density lipoproteins and lower cholesterol, but there is no definitive evidence that HRT reduces the risk of IHD in low-risk women.

Post-menopausal bleeding

Postmenopausal bleeding is bleeding from the genital tract occurring six months or more (or is it 12) after the menopause. It is a serious symptom which may indicate the presence of malignant disease in the genital tract. Every woman with postmenopausal bleeding should be assumed to have a carcinoma until a full investigation has proved to the contrary. 9% of women with PMB have an underlying malignancy.

Premature ovarian failure

Premature ovarian failure occurs in 1% of women. It is diagnosed in patients under the age of 40 with second- ary amenorrhoea, with a high FSH on two separate occa- sions. Causes include chemo or radiotherapy or viral infections such as mumps. Diagnosis is based on FSH and LH levels, whilst treatment is primarily HRT and dietary advice to prevent osteoporosis. Women affected by premature ovarian failure must be counselled on the need for IVF, together with the possibility of devel- oping other autoimmune disorders such as thyroid disorders. Once again, although it is not a first-line treatment for osteoporosis prophylaxis in older age groups (due to the risk profile), HRT is still recommended.

Alternatives

SSRIs for hot flushes Alternative therapies like acupuncture for hot flushes Climodone Raloxifene Tipolone Clonidine Stuff to treat depression, osteoporosis etc Gabapentin for hot flushes - For vasomotor consdier a 2 week trial of fluoxetine (20 mg OD), citalopram (20mg OD) or venlafaxine (37.5 mg OD) - For vaginal dryness, prescribe a lubricant - For psych symptoms, consider CBT or antidepressants.

Side effects

Side effects described are nausea, fluid retention, hirsutism, leg cramps and breast discomfort. Modifying the preparation, as well as reducing the dose, can be beneficial. The progestogen component must be altered particularly carefully as there is a risk of not adequately protecting the endometrium. The Mirena® IUS can be beneficial as it secretes the progestogen locally with low systemic levels. Over the past 20 years the use of HRT has come under intense scrutiny due to some studies showing an increased risk of cardiovascular disease, breast cancer and stroke in patients taking combined forms of HRT. In breast cancer it is thought that the risk increases with the duration of use, but this increased risk is not seen in those patients taking HRT for an early menopause. Evi- dence around cardiovascular risk is somewhat conflicting, although there appears to be a protective effect in the younger age group of patients taking HRT (50-59) and a detrimental effect in older patients (70-79 years).

Other genital changes

The breasts become atrophic and the nipples flatten. The uterus becomes smaller. There is less support from the cardinal ligament, uterosacral and uteropubic ligaments so prolapse may occur.

Vaginal dryness

The cervix and vagina are oestrogen dependent. Secretions from the cervix and the surface glands are diminished and the vaginal epithelium becomes thinner, less elastic with a reduced blood supply; atrophic vaginitis follows. Dryness and, therefore, dyspareunia are common. Extra lubrication may be required or oestrogen cream.

Other symptoms

The lower oestrogen levels lead to atrophy of the urethra causing frequency of micturition, dysuria and urgency (urethral syndrome). This is commonly confused with symptoms of urinary tract infection but does not improve with antibiotics. The weakness of the supporting muscles and the cardinal ligaments allows stress incontinence to start at this age. The pulling back of the posterior wall of the urethra often exposes the sensitive anterior wall which becomes inflamed. A small polyp or caruncle may occur on the posterior wall. The reduction of oestrogens leads to an increase in the levels of low density lipoproteins, cholesterol and triglycerides. This is accompanied by a catch-up rate for women of coronary heart disease.

Post-menopausal therapy

The treatment for postmenopausal symptoms is: 1) acute oestrogen replacement for women who have symptoms, principally hot flushes and dry vagina; 2) more chronic replacement therapy for women who are losing oestrogen in order to prevent osteoporosis. Oestrogen is a potent factor in the maintenance of bone mineralization. Low oestrogen levels lead to a thinning of trabecular bone and eventually osteoporosis. This leads to an increased risk of fractures of the hip and wrist and compression fractures of the vertebrae resulting in a dowager hump. The giving of symptomatic oestrogen replacement is the more straightforward therapy. The aim should be to use the lowest effective dose of oestrogen for the shortest period of time. It is usual to give it in a cyclical fashion of 28 days. This causes remission of symptoms in most women, once the correct dose is achieved. Progestogens are added in the second half of the cycle in all women who have a uterus to prevent a build up of endometrium with possible hyperplasia, or atypical hyperplasia and then malignancy. Owing to the cyclical nature of the treatment, the endometrium which develops during the oestrogen phase is shed after withdrawal and so there appears to be a continuation of menstrual periods (usually light).

Chief causes of post-menopausal bleeding

The vulva • Carcinoma. • Urethral caruncle. • vulvitis • dystrophies The vagina • Carcinoma. • Vaginitis, especially atrophic vaginitis. • Foreign bodies, especially pessaries. The cervix • Carcinoma of the ectocervix. • Carcinoma of a cervical canal polyp. • Benign cervical polyp. • Atrophic changes The Uterine body • Carcinoma. • Sarcoma. • Mixed mesodermal tumours. • Polyp. • Atrophic endometritis. • Myometrium: submucous fibroid The fallopian tube • Carcinoma. The ovary • Feminizing tumours. • Granulosa cell tumour. • Theca cell tumour.

Hot flushes

These are the feeling of heat over the face and upper part of the body usually lasting for half to one minute. They are followed by perspiration of this area, which may render the woman wringing wet. These flushes usually last for a year or so and in up to a quarter of women at least four years. This is probably due to an increase in the sympathetic nervous system drive mediated through the central neurotransmitters. They come on more at night when in bed and can wake a woman up.

Rx of PMB

Withdrawal bleeding may follow administration of oestrogens for menopausal symptoms. This should not be assumed to be the cause of any postmenopausal bleeding until a full investigation including cytology and curettage has excluded more sinister causes Treatment depends on the pathology. The most com- mon cause of PMB is atrophic change and, therefore, oestrogen replacement is indicated not only to prevent a recurrence of PMB, but also to treat other symptoms associated with oestrogen deficiency (e.g. dyspareunia). Most women in this situation prefer to use topical oes- trogen. The newer 17b oestradiol-releasing creams, rings and vaginal tablets avoid the risk of endometrial hyperplasia by minimizing systemic absorption. If sys- temic HRT is requested then oestrogen therapy must be combined with a progestogen in women who have a uterus. The treatment of urethral caruncle is by surgical exci- sion of the prolapsed urethral mucosa and is a painful and unpleasant procedure. It should, therefore, be reserved for those cases in which recurrent PMB or pain occur. Small caruncles might recede with oestrogen cream

Contraception

Women in the climacteric remain at risk of pregnancy. Women should continue contraception for 1 year after their last menstrual period if they are >50 years old and for 2 years if they are <50 years old.

Physiology of menopause

• At the end of reproductive life, the ovaries become less able to produce oocytes due to: - A lack of primordial follicles, because all have been used; - More refractory receptor function in the granulosa and thecal cells. • The falling oestrogen levels result in a large increase in follicular stimulating hormone (FSH). The endometrium does not proliferate. • The ovarian stroma produces androstenedione which converts in peripheral fat to oestrone, a weaker oestrogen than oestradiol, the steroid on which the woman has depended for much of her reproductive life. Menstruation stops due to a lack of cyclical oestrogen and progesterone - In the peri-menopausal patient anovulatory cycles become more common and oestrogen secretion can continue without the progesterone opposition required to protect the endometrium. - These patients are at risk of endometrial hyperplasia and, rarely, endometrial cancer.

Symptoms of menopause

• At the menopause 60% of women are relatively asymptomatic, 25% of women have mild symptoms and 15% have moderate to severe symptoms. The two commonest symptoms are: hot flushes and dryness of the vagina. • There is often a loss of libido, part of which is hormonal. • Mood swings, nervousness, anxiety, irritability and depression are all measured in this group of women. The decrease of oestrogens may reduce their modulatory role on brain monoamine synthesis. • Symptoms are found more commonly in those who had premenstrual tension or dysmenorrhoea. The symptoms are less frequent in Asian and African women, possibly associated with better maintenance of oestrogen levels by peripheral conversion in these groups. • Loss of collagen leads to uterovaginal prolapse and wrinkling of the skin.