Menopause and Hormone Replacement Therapy Notes

Menopause and Perimenopause

  • Menopause is defined as the permanent cessation of cyclical menstruation due to loss of ovarian follicular activity, conventionally after 1 year without menstruation.
  • Perimenopause covers the menopausal transition and the first year after menopause, potentially lasting 6 years or more.
  • Perimenopause is a 4-8 year transitional stage with increasingly irregular menstrual cycles, leading up to the final menstrual period, and the first 12 months following it.
  • Postmenopause is defined as after 12 months of amenorrhea.
  • The median age for menopause is 51 years, with a normal range of 45-55 years.
  • Menopause before age 40 is premature ovarian insufficiency; between 40 and 45 is early menopause.
  • Symptoms occur in approximately 75% of females, moderate to severe in 28%, and may last 7-10 years. Vasomotor symptoms (hot flushes and night sweats) predominate in perimenopause.

Hormonal Changes During Menopause

  • Pre-menopausal: Oestrogens +++, Progesterone +++, Androgens +
  • Peri-menopausal: Oestrogens ++, Progesterone +, Androgens +
  • Post-menopausal: Oestrogens +, Progesterone -, Androgens -

Menopause Transition

  • Characterized by irregular menstrual cycles, endocrine changes, and symptoms like hot flashes.
  • Ovarian oestradiol secretion declines in the years before menopause.
  • Begins on average four years before the final menstrual period (FMP) and includes physiologic changes affecting quality of life.
  • Hormonal fluctuations are accompanied by hot flashes, sleep disturbances, mood symptoms, and vaginal dryness.
  • Changes in lipids and bone loss can occur, having implications for long-term health.

Average Age of Menopause

  • Average age is 51 years old.
  • Most women reach menopause between 45 and 55, but it can occur as early as 30s or 40s or as late as 60s.
  • Menopause in women aged 40 yrs or less is considered premature.
  • Women tend to undergo menopause at an age similar to that of their mothers.

Oestrogen Deficiency

  • After menopause, oestrogen deficiency results in increased bone resorption and rapid bone loss, increasing the risk of osteoporosis and fractures.
  • Oestrogen or androgen deficiency causes loss of bone, increasing bone remodeling rate, osteoclast and osteoblast numbers, and resorption and formation.
  • Oestrogens (or androgens) decrease bone resorption, restrain bone remodeling rate, and maintain balance between bone formation and resorption.

Symptoms of Menopause

  • Hot flushes, night sweats, vaginal dryness, mood swings, sleep disturbance, and loss of self-confidence.
  • Often begin in the perimenopausal period, even with regular bleeding.
  • Can occur in women with menstrual cycle disturbance or amenorrhoea.
  • Abnormal uterine bleeding is common due to oestradiol production fluctuations.

Diagnosis of Menopause

  • Diagnosis is usually clinical, based on menstrual bleeding pattern, menopausal symptoms and age (older than 45 years).
  • Hormone concentration assessment isn't routinely required for diagnosis in individuals older than 45 years.
  • Serum follicle stimulating hormone (FSH) and estradiol concentrations may be useful if menstrual bleeding patterns cannot be interpreted.
  • These tests also form part of the assessment of younger individuals with secondary amenorrhoea, which may be caused by premature ovarian insufficiency or early menopause.
  • Measurement of anti-Mullerian hormone (AMH) concentration is not currently recommended except by a specialist because of cost, and the variable sensitivity in diagnosing menopause.
  • Serum FSH and estradiol concentrations should not be measured if estrogen-containing hormone therapy has been taken in the preceding 4 weeks.
  • Serum FSH and estradiol concentrations are not affected by progestogen-only contraception except for depot medroxyprogesterone.

Hormonal Changes

  • After the menopause, estrogen deficiency results in increased bone resorption and rapid bone loss.
  • Estrogens (or androgens) decrease bone resorption, restrain the rate of bone remodeling, and help to maintain a focal balance between bone formation and resorption.
  • Estrogen or androgen deficiency causes loss of bone associated with an increase in the bone remodeling rate, increased osteoclast and osteoblast numbers, and increased resorption and formation, albeit unbalanced.
  • Increased risk of osteoporosis and fractures

Hormone Replacement Therapy (HRT)

  • Rationale for HRT is short term relief of symptoms due to menopause or premature ovarian failure, e.g. vasomotor symptoms, vaginal dryness and dyspareunia.
  • Oestrogen relieves symptoms caused by reduced endogenous oestradiol production.
  • Progestogen reduces risk of endometrial cancer associated with unopposed oestrogen.

Before Starting Treatment

  • Lifestyle changes like stopping smoking, reducing alcohol intake, and losing weight may reduce symptoms.
  • Regular exercise and avoiding triggers may also help.

HRT Information

  • HRT is the most effective treatment for the vasomotor symptoms of menopause.
  • The use of HRT for the sole purpose of preventing chronic disease is not recommended.
  • Clinicians and women should weigh long term harms vs benefits when initiating HRT.
  • Unless contraindicated, all women with premature or early menopause should be treated with HRT.
  • The appropriate HRT regimen depends on many factors.
  • The most common regimens contain oestrogen, with or without a progestin. Tibolone is a synthetic steroid also used for HRT.

HRT Considerations

  • Alternative therapies (e.g. black cohosh, red clover isoflavones) lack evidence of benefit, and maybe harmful.
  • When a woman is using the oral contraceptive pill, it can be difficult to know when she is menopausal and whether a change to HRT is appropriate.
  • HRT does not provide contraception, so women who continue to ovulate must use nonhormonal contraception.
  • At menopause many cardiovascular risks emerge.
  • Absolute risk for cardiovascular disease should be assessed in all women aged 45 years or older, and addressed if necessary, regardless of HRT.

Hormones - Estrogens

  • Natural sources: estradiol, estriol, conjugated equine estrogen (less potent than synthetic, metabolised more rapidly, but fewer potential for liver adverse effects)
  • Synthetic: dienoestrol, mestranol, ethinylestradiol

Hormones - Progesterone

  • Progesterone included in HRT to inhibit estrogen induced endometrial proliferation, reducing the risk of endometrial cancer
    • C21 analogues: medoxyprogesterone, cyproterone
    • C19 analogues: norethisterone, levonogestrol, desogestrol
  • All women with intact uterus should use a combo of estrogen + progesterone to protect endometrium

Oestrogen/Progestin Hormone Replacement

  • Unopposed oestrogen replacement therapy is appropriate for women who have had a hysterectomy.
  • Oestrogen taken alone increases the risk of endometrial cancer, so women with an intact uterus should take a progestin as well.
  • HRT regimens containing oestrogen plus progestin are called combined HRT, and can be:
    • cyclical (oestrogen daily and progestin for 10 to 14 days of the month)
    • continuous (oestrogen and progestin throughout the month).
  • Combined HRT can be given as separate hormone preparations or a combined preparation.
  • Separate oestrogen and progestin preparations simplify dose titration to ease menopausal symptoms and minimise adverse effects.
  • Combined preparations are easier to take and improve concordance with progestin therapy.
  • Oestrogen/progestin HRT is available as oral, transdermal or intravaginal preparations.
  • If one preparation is ineffective or not tolerated, a different drug or route of administration should be tried.
  • The levonorgestrel-releasing intrauterine system can be used to deliver progestin in combination with oral or topical oestrogen.
  • Endometrial protection delivered in this manner may be particularly suitable for women with heavy menstrual bleeding leading up to the menopause.
  • Initiating therapy at a low or ultra-low dose reduces the incidence of oestrogenic adverse effects.
  • The dose should be adjusted according to symptoms. Women who have been oestrogen deficient for a significant time should start on an ultra-low dose.
  • In the short term, vaginal oestrogen preparations can be used alone in all women, whether or not they have a uterus. Women with an intact uterus on this regimen should be given progestin after 6 months to see if a withdrawal bleed occurs.
  • Women who become amenorrhoeic after an endometrial ablation need progestin as well as oestrogen, because endometrial regeneration can occur.

Choice of HRT Regimen

  1. Estrogen-only HRT
    • Recommended in women in post-hysterectomy. Estrogen is taken continuously.
  2. Vaginal estrogen
    • First choice for urogenital symptoms. Use lowest effectively dose to control symptoms. Stop treatment at least annually to see if it is still required. Progestogen is not usually necessary for endometrial protection.
  3. Combined HRT
    • Recommended in women with a uterus because of the increased risk of endometrial hyperplasia and cancer associated with estrogen-only HRT. Estrogen with progestogen regimens nay be either cyclical or continuous.
  4. Other HRT
    • Tibolone is suitable for women who are postmenopausal (at least 12 months since last menstrual period) or have had a hysterectomy.

Oestrogen and Progestogen Regimens

  • Oestrogen 28 days + progestogen 12 or 14 days, then repeat without interval (bleed every 4 weeks)
  • Oestrogen 70 days + progestogen 14 days followed by 7 days placebo tablets (bleed every 3 months)
  • Oestrogen + progesterone continuously ( no bleed)
  • Oestrogen continuously + Mirena IUS (bleed variable but levonorgestrel likely to reduce bleed and can provide amenorrhoea)

Cyclical HRT

  • Continuous oestrogen plus progestogen for 10-14 days of each month, or for 14 days every 3 months
  • Expect withdrawal bleed after stopping progestogen
  • Suitable for women in the perimenopause or early post menopause
  • Low-dose COC is a suitable alternative in selected perimenopausal women <50 years, especially those still requiring contraception; it may also give better cycle control than HRT regimens.

Continuous HRT

  • Continuous oestrogen plus continuous progestogen (generally half or quarter of the cyclical dose)
  • Suitable for postmenopausal women (at least 12 months since last menstrual period); 50% have irregular bleeding in the first 6 months of treatment; 90% are amenorrhoeic after 12 months.

HRT Dosage Forms

  • Oral: first line, cheap. Include estrogen only or combined HRT. Has to be taken every day
  • Transdermal: Patches or Gel (Sandrena®)
    • Avoids First Pass Effect, small doses can be given with reduced adverse effects including nausea.
    • Apply patches once or twice a week; apply gel daily. Skin irritation occurs in 10–20% of women using patches, <5% using gel.
    • Some patches may not stick well to some skin types.
    • Different patch size allows dose adjustment
    • Gel is applied daily to lower trunk or thigh in an area about size of your hand
  • Implants: SC usually in lower abdomen, provide depot estrogen lasting 4-12 months, estradiol levels need to be checked
  • Vaginal estrogen (Ovestin): creams, pessaries, tablets rings
    • Designed for local effect, urogenital symptoms
    • Vaginal ring lasts for 3 months
    • Use lowest effective dose to control symptoms.
    • Stop treatment at least annually to see if it is still required.
    • Progestogen is not usually necessary for endometrial protection.
    • If irregular or atypical bleeding occurs, it may indicate endometrial pathology – further investigation is warranted.

Common Adverse Effects of HRT

  • These vary according to dose and regimen
  • Breast enlargement and tenderness, abnormal mammogram, headache, depression, change in libido
  • Irregular or breakthrough bleeding, spotting, endometrial hyperplasia (oestrogen-only HRT; infrequent with combined HRT), leg cramps, dry eye syndrome

Management of HRT Adverse Effects

  • Tolerance to adverse effects may develop during the first few months; if possible, wait for 3 months before making any changes to the regimen.
  • Oestrogen-related adverse effects (e.g. breast enlargement or tenderness, fluid retention, headache, leg cramps, nausea) may occur continuously or at any time during the cycle. If persistent, consider:
    • reducing the dose
    • changing the oestrogen
    • changing the route.
    • Taking tablets with food or at night may reduce nausea.
  • Progestogen-related adverse effects (e.g. breast tenderness, fluid retention, headache, depression, premenstrual-like syndrome, acne) may occur during the progestogen phase of cyclical combined HRT. If persistent, consider:
    • changing the progestogen
    • reducing the dose (but ensure endometrium is still protected)
    • changing the route
    • reducing the duration of progestogen to 10 days/month
    • changing to a 3-monthly cyclical regimen
    • changing to continuous combined HRT if postmenopausal.

Counselling Information

  • Tell doctor immediately if:
    • Symptoms of blood clot (red swollen or painful leg, difficulty breathing, chest pain)
    • Change in breasts (skin or nipple, lumps)
    • Change in vaginal bleeding a few months after starting HRT (heavy or irregular bleeding or bleeding after sex)

HRT Risks vs Benefits

  • HRT maintains or improves Bone mineral density and reduces fracture risk in postmenopausal women; these benefits do not appear to outweigh the risks (e.g. VTE, stroke, breast cancer), even in those at high risk of fracture, unless vasomotor symptoms are troublesome
  • The Women's Health Initiative was a large study to find out if hormone therapy would reduce the risk of heart attacks after menopause.
  • The study found that taking estrogen-progestin in combination increases the risk of heart attacks, breast cancer, blood clots, and strokes in older postmenopausal women.
  • Women who took estrogen alone had a small increase in the risk of stroke and blood clots, but there was no increased risk of heart attacks or breast cancer.
  • RossouwJE,AndersonGL,PrenticeRL,etal.Risksandbenefitsofestrogenplusprogestininhealthypostmenopausalwomen:principalresultsFromtheWomen′sHealthInitiativerandomizedcontrolledtrial.JAMA2002;288:321.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women:principal results From the Women'sHealth Initiative randomized controlled trial. JAMA2002; 288:321.

Summary of HRT

  • Consider HRT for women who have troublesome vasomotor symptoms, taking into account their individual risks and benefits
  • Use HRT at the lowest effective dose for the shortest time possible to relieve these symptoms; short-term treatment (2–3 years) is sufficient in most women
  • Review treatment regularly (at least annually); the risks and benefits will change with time
  • Choose vaginal products for women who only have urogenital symptoms.
  • Stop smoking, eat a healthy diet, manage cholesterol levels

Postmenopausal Osteoporosis

  • HRT maintains or improves BMD and reduces fracture risk in postmenopausal women; these benefits do not appear to outweigh the risks (e.g. VTE, stroke, breast cancer)
  • Reduction in fracture risk appears to be lost within a few years of stopping HRT
  • Therefore, short-term use of HRT for menopausal symptoms is unlikely to have a significant effect on fracture risk after age 70
  • Vaginal oestrogens do not appear to offer any protection against osteoporosis

Tibolone 2.5mg Tablets (Livial)

  • Synthetic steroid hormone
  • Acts as an oestrogen on vagina, bone and thermoregulatory centres in brain.
  • Has progestogenic and anti-oestrogenic effects on breast and endometrium (androgenic effects include decrease in HDL, triglycerides and lipoprotein(a).
    • Indicated for relief of menopausal symptoms, e.g. hot flushes (short-term treatment)
    • Indicated for prevention of postmenopausal osteoporosis when there is a high risk of fractures and alternative treatment is inappropriate

Other Treatment Options

  • Phyto-oestrogens eg isoflavones from soy or red clover, have some oestrogenic properties. A systematic review concluded that phyto-oestrogens have no additional effect on frequency of hot flushes, or other menopausal symptoms, compared with placebo. Long-term treatment (up to 5 years) has been associated with the development of endometrial hyperplasia.
  • Black cohosh - efficacy is in doubt as results from randomised controlled trials are mixed. Safety (>6 months) has not been assessed but there are reports of hepatic failure.
  • Wild yam or natural progesterone creams - have not been shown to improve menopausal symptoms and are not effective in the prevention or treatment of osteoporosis. They should not be used as the progestogen component of HRT as they do not protect against oestrogen-induced endometrial hyperplasia.