Menopausal Symptoms and Hormone Therapy

Essentials

• The average age of women at menopause is 51 years, but considerable individual variation exists.
• The most typical direct symptoms of menopause are hot flushes and sleep disorders.
• The primary indication of postmenopausal hormone therapy is the treatment of menopausal symptoms.
• The physician should tell the patient the advantages and disadvantages of hormone therapy as well as the health benefits and risks of long-term use.
• The younger the patient is at the onset of menopause, the more readily the treatment should be started.
• Add progestogen to the oestrogen therapy for women with an intact uterus Postmenopausal Hormone Replacement Therapy and Risk of Endometrial Hyperplasia and Endometrial Cancer. This prevents endometrial hyperplasia and reduces the risk of cancer.

Definitions

• Climacterium (climacteric) refers to the entire period during which the function of the ovaries diminishes (ovulation and oestrogen production) and finally ceases totally.
• Menopause refers to the last menstrual bleeding induced by the woman's own hormonal activity. The criterion is amenorrhoea that has lasted for at least 12 months in a woman at menopausal age.
• Perimenopause refers to the period before menopause starting from the first menopausal symptoms and continuing for at least a year after the menopause.

Menopause

• Periods stop on average at the age of 51 (range 45-55 years of age).
• Climacterium may start earlier due to removal of the ovaries, radiotherapy or cytostatic therapy. Smoking causes menopause to occur 1-2 years earlier.
• If menstruation ceases before the age of 40 years, it may be a result of premature ovarian failure (primary ovarian insufficiency, POI), the reason of which needs to be investigated.
• About 75% of menopausal women have menopause-related symptoms of the autonomic nervous system, such as hot flushes and nocturnal sweating. The symptoms are particularly troublesome in about 20%.
• Obesity increases menopausal sweating, and hence weight control is important.
• Excessive drinking of coffee, heavily spiced foods and smoking aggravate menopausal symptoms.

Aetiology

• Along with the waning ovarian function, the oestrogen production in the ovaries ceases almost completely in the menopausal phase. At the same time, the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) is increased.
• The reduction of oestrogen production may cause symptoms of the autonomic nervous system already years before the cessation of menstrual bleedings.
• In early perimenopause, the menstrual period becomes shorter and spotting occurs often, and only at a later stage the period becomes longer.
• Great variation of both gonadotropin and oestradiol concentrations is typical of perimenopause.

Symptoms

• Symptoms of the autonomic nervous system usually persist in their bothersome form for a couple of years. On average, sweating symptoms last 7 years, and they are usually most intense in the first years. The symptoms may sometimes last up to 20 years.
• Hot flushes, redness and sweating
  • The most typical climacteric symptom
  • The subjective harm experienced because of the symptoms does not correlate to the oestrogen levels.
  • Perception of the climacteric symptoms varies greatly between women. The strongest symptoms are experienced by those whose oestrogen level drops abruptly, e.g. after removal of ovaries.
  • Often experienced as socially unpleasant
  • Often associated with heart palpitations
  • After a sweating spell, one may experience a strong sensation of freezing.
• Sleep disorders
  • Insomnia is associated with nocturnal sweating, but the quality of sleep may deteriorate also without it.
  • In many women, sleep disturbances are the most significant single symptom impairing the quality of life.
• Psychogenic symptoms
  • Tiredness, irritability, mood changes, depressive mood and lack of initiative are associated with climacteric symptoms. These are partly a result of sleep disturbances. It is important to identify real depression. The connection between the symptoms and oestrogen deficiency is unclear.
• Sexual symptoms
  • Lack of sexual desire may occur.
  • Dyspareunia may occur as a result of thinning of the vaginal mucosa.
• Gynaecological symptoms
  • In premenopause, irregularity of menstrual periods, spotting and heavy menstrual bleeding may occur due to ovulation disturbances.
  • In postmenopause, the gynaecological symptoms are primarily caused by the thinning of the vaginal mucosa and the relaxation of the tissues of the pelvic floor.
• Urological symptoms
  • The urethral syndrome entails urinary frequency and dysuria without infection.
  • Recurrent urinary tract infections may occur.
  • Bladder control is weakened.
• Musculoskeletal symptoms
  • Arthralgia and soreness of joints as well as muscular pains may increase.
  • Remember rheumatoid arthritis in the differential diagnostics.

Physical changes

• The vaginal and urethral mucosa become atrophic, which is manifested by drying and thinning.
• The skin becomes thinner and loses its elasticity: wrinkles develop as a result of collagen loss.
• Breasts become smaller.
• As a result of oestrogen deficiency, age-related bone fragility is accelerated.

Indications of hormone therapy (HT)

• Menopausal symptoms (hot flushes, sweating, sleep disturbances) Oestrogen and Combined Oestrogen/Progestogen Replacement Therapy for Hot Flushes
• Osteoporosis prophylaxis and treatment Menopausal Hormone Therapy in the Prevention Fractures in patients who have concomitant menopausal symptoms requiring treatment.
  • Hormone therapy may also be used if other bone drugs are not suitable and there are no contraindications for hormone therapy, even if the menopausal symptoms as such do not necessarily require treatment.
• Urogenital symptoms are treated with topical agents Local Oestrogen for Genitourinary Syndrome of Postmenopause.

Initiation of treatment

• In general, oestrogen therapy should not be introduced too early, preferably not until the menstrual cycles are infrequent, or have ceased, or there are disturbing menopausal symptoms.
• At least in symptomatic women below the age of 45, other menstrual disturbances than the menopause should be considered. Following tests are useful in differential diagnosis: serum prolactin, TSH and FSH (> 30 IU means declining ovarian function and consequent oestrogen deficiency). Determination of serum oestradiol level alone is not valuable.
• Progestogen challenge test, e.g. medroxyprogesterone acetate (MPA) 10 mg daily for ten days gives a picture of the ovarian oestrogen production. If the patient has withdrawal bleeding (which normally occurs within a week after discontinuing therapy), the ovaries produce enough oestrogen.
• Absence of bleeding or very scant bleedings mean deprivation of endogenous oestrogen production and oestrogen can be added to the treatment for symptomatic women.
• Before starting treatment
  • a gynaecological examination is always indicated if any of the following symptoms has occurred: irregular bleeding, lower abdominal pain or a feeling of pressure in the lower abdomen, troublesome mucous membrane symptoms, abnormal vaginal discharge or urinary incontinence
  • during the gynaecological examination, it is also advisable to assess the condition of the mucous membranes and pelvic floor muscles
  • examine the breasts and measure blood pressure and weight
  • check that the pap smear and mammogram results from the screening programme are normal
  • identify risk factors for osteoporosis and cardiovascular diseases
  • find out if there are any contraindications (remember family history).

Contraindications for HT

• Breast cancer
• Gynaecological cancer
• History of deep vein thrombosis or pulmonary embolism, or known thrombotic tendency
• Difficulty to manage heart failure
• Treatment-resistant hypertension (antihypertensive medication as such is not a contraindication)
• Systemic lupus erythematosus (SLE) when blood antiphospholipid antibodies are present (risk of thrombosis)
• Severe liver disease
• Undiagnosed vaginal bleeding
• In all the above-mentioned situations, hormone replacement therapy may be considered if there are weighty indications (severe symptoms, young age of the patient) but the initiation of treatment requires evaluation by a gynaecologist.

The choice of hormone product and mode of administration

Principles of treatment

• Sole oestrogen is to be used in hysterectomized women only. In others, progestogen is always to be added in order to prevent endometrial hyperplasia Postmenopausal Hormone Replacement Therapy and Risk of Endometrial Hyperplasia and Endometrial Cancer.
• If a Mirena^® IUD is used, oestrogen alone can be started alongside it.
• If less than a year has passed since the menopause, treatment is started with a cyclical combined oestrogen/progestogen preparation as tablets or patch. An alternative therapy consists of oestrogen alone orally or through the skin continuously on a daily basis combined with progestogen (e.g. dydrogestrone 10 mg or medroxyprogesterone acetate 10 mg) for the first 12-14 days of each calendar month.
• If the woman wants to avoid uterine bleeding, continuous combined regimens may be used where both oestrogen and progestogen are given daily. However, it is recommended that this treatment form is not prescribed until 12 months after the menopause, when cyclic therapy has reduced uterine bleeding.
  • The therapy is started with a low dose of oestrogen, (e.g. 1 mg oestrogen tablet, a 25 µg patch, or 1 mg dose of oestrogen gel), combined with a low oral dose of progestogen (dydrogestrone 10 mg or medroxyprogesterone acetate 5 mg), or a progestogen-releasing intrauterine device (Mirena^® ). The doses can be tailored at a later stage according to response or adverse effects.
• See table T1.

• Also tiboloneEffects of Tibolone in Postmenopausal Women may be used as a bleeding-free treatment form (not within 12 months of last menstrual period). Tibolone is a synthetic steroid hormone that the body converts into metabolites that have oestrogenic, androgenic and progestogenic properties (i.e. a progestogen is thus not used concomitantly with tibolone). Tibolone has been shown to reduce osteoporotic vertebral fractures. In healthy women over 60 years of age tibolone reduces both fractures and breast cancer but increases the risk of stroke.
• Other treatments
  • SSRIsand SNRIs seem to have some effect on hot flushes, and they may be tried in women for whom oestrogen is not suitable Non-Hormonal Interventions for Hot Flushes in Women with a History of Breast Cancer.
    • E.g. venlafaxine 37.5-75 mg (depot), paroxetine 20 mg, citalopram 10-20 mg
  • Gabapentin 900 mg a day is one alternative.
  • The newest drug for the treatment of hot flashes is fezolinetant. It inhibits neurokinin B, reducing the number and intensity of hot flashes and night sweats mediated through the hypothalamic thermoregulatory centre Fezolinetant for Menopausal Vasomotor Symptoms.
  • Physical exercise does not directly influence menopausal symptoms, but it may improve quality of life Exercise for Vasomotor Menopausal Symptoms. Weight control, smoking cessation and reduced consumption of coffee and spices are worthwhile changes.
  • Soy and other phyto-oestrogens Phytoestrogens for Vasomotor Menopausal Symptoms, black cohosh Black Cohosh (Cimicifuga Spp.) for Menopausal Symptoms or acupuncture Acupuncture for Menopausal Hot Flushes do not seem to be effective in the treatment of menopausal symptoms.

Adverse effects of HT

• During the first few months of HT, adverse effects, such as bloating and breast tenderness, are common.
• There is no evidence that HT causes weight gain Effect of Peri- and Postmenopausal Hormone Replacement Therapy on Body Weight.
• Progestogenic adverse effects include headache and psychogenic symptoms.
• If the subjective side effects are disturbing or persist for more than 3 months the progestogenic preparation should be changed or the dose should be reduced.
• The ways to reduce progestogenic adverse effects include the use of the lowest effective dose and the change of the mode of administration to an intrauterine system.
• When the patient is treated for hypothyroidism, oestrogen replacement therapy may increase the need for thyroxin.

Uterine bleeding

• The aim is for the bleeding to occur during the treatment-free week, or after the end of the progestogen phase in cyclical treatment. The amount and duration of bleeding should be normal. During treatment of several years duration, the amount of bleeding will diminish in many women, or cease altogether.
• With bleeding-free regimens the bleeding should cease totally within 4-6 months from the start of the therapy.
• Irregular bleeding always calls for consideration of the need for investigations (Pap smear, ultrasonography Pap (Cervical) Smear and Endometrial Biopsy, endometrial biopsy, see Gynaecological Ultrasound Examination).
• Transvaginal ultrasonography is a good method for detecting endometrial hyperplasia, submucous myomas and polyps. Abnormal thickness of the endometrium warrants histological examination.
• Endometrial biopsy is easy to obtain during a general appointment.

Follow-up of the treatment

• A follow-up visit is recommended within 12 months of starting HT.
• During the first year attention should be paid to the disappearance or persistence of the symptoms, occurrence of any adverse effects and to the patient's satisfaction with the treatment.
• Follow-up visits are recommended every couple of years. It is most important to assess the need for and suitability of the therapy and to ensure that there are no changes in the patient's overall state of health and other medication.
• Mammography and a Pap smear are taken as planned within the national screening programme, unless there are clinical symptoms or signs that warrant further investigations.
• During the follow-up visit an assessment is made whether the dosage could be decreased or the treatment discontinued.

Benefits and harms of HT Hormone Therapy for Sexual Function in Perimenopausal and Postmenopausal Women

• The benefits of hormone therapy (HT) in the treatment of menopausal symptoms are well established Oestrogen and Combined Oestrogen/Progestogen Replacement Therapy for Hot Flushes.
• Topical vaginal oestrogen treatment reduces urogenital symptoms Local Oestrogen for Genitourinary Syndrome of Postmenopause, e.g. dryness of the mucous membranes, urinary tract infections and urinary incontinence. The effect of systemic treatment on incontincence is controversial.
• Oestrogen treatment prevents the development of menopause-related osteoporosis and osteoporotic fractures Menopausal Hormone Therapy in the Prevention Fractures.
• Oestrogens have both direct and indirect (lipids) effects on the vascular system. The effect of oestrogen and oestrogen-progestogen therapy on the risk of coronary heart disease depends on the age of the patient and her phase in relation to menopause at the time when the therapy was started.
• Hormone replacement therapy, if started in a healthy woman less than 10 years after the menopause, reduces cardiac events, but the therapy is not recommended for the prevention of cardiovascular diseases as the primary indication.
  • During a controlled study (the HERS study), in which the combination of oestrogen and progestogen was used for secondary prevention of CHD, the number of cardiovascular events in the treatment group increased during the first twelve months, but decreased towards the end of the follow-up period.
  • HT is associated with an increased risk of ischaemic stroke Menopausal Hormone Therapy and the Risk of Stroke, Transdermal and Oral Hormone Replacement Therapy and the Risk of Stroke.
• Both orally administered oestrogen and oestrogen/progestogen therapies are associated with an increased risk of venous thromboembolism Menopausal Hormone Therapy and Risk of Venous Thromboembolism. The extra risk per year is calculated to be 1 per 10 000 oestrogen users aged 50 to 59 years and the annual risk of death from pulmonary emboli is calculated to be 1 per 100 000. The risk increases with age. The risk of thromboemboli appears to be greatest at the start of treatment Menopausal Hormone Therapy and Risk of Venous Thromboembolism. Family history and previous thromboembolic episodes, severe obesity and immobilization should be taken into consideration when planning the introduction of HT.
• HT is associated with an increased risk of cerebral infarction after the 60th year of life. It would seem that this risk is associated with a large oestrogen dose in particular.
• The scientific evidence of how HT affects dementia is conflicting. It seems that the effect of oestrogen on vascular dementia is similar to its effect on coronary artery disease. HT does not, however, reduce the risk of developing Alzheimer's disease.
• HT increases the risk of breast cancer, less if oestrogen alone is used as compared to oestrogen-progestogen combination therapy Menopausal Hormone Therapy and Breast Cancer.
  • According to meta-analyses, the relative risk of breast cancer is 1.35 in women who have used HT for at least 5 years. Between 50 and 65 years of age the cumulative incidence of breast cancer is 45 per 1 000 women who have never used HT. Use of HT for ten years causes an excess risk (attributable risk) of six cases per 1 000 women. According to the WHI study, using oestrogen alone appears not to increase the risk of breast cancer in hysterectomized patients at least during 7 years' follow-up.
• According to epidemiological studies, prolonged use (> 10 years) of oestrogen therapy may be associated with an increased risk of developing ovarian cancer Ovarian Cancer and Hormone Replacement Therapy. The risk is increased both in oestrogen therapy and in oestrogen-progestogen combination therapy. The route of administration has no effect on the risk.
• The risk of endometrial cancer is not increased if sufficient dose of progestogen is added to the therapy Postmenopausal Hormone Replacement Therapy and Risk of Endometrial Hyperplasia and Endometrial Cancer.
• HT may be beneficial for the treatment of menopausal depressed mood The Effect of Hormone Replacement Therapy Upon Depressed Mood, but it does not improve cognitive function in asymptomatic women Hormone Replacement Therapy for Cognitive Function in Postmenopausal Women.
• HT reduces the risk of developing type 2 diabetes.
• Postmenopausal HT increases the risk of cholelithiasis Hormone Therapy and Risk of Gallbladder Disease and is also associated with a 1.8-fold increase in the risk of cholecystitis.