Benefits and risks of hormone replacement therapy

Benefits and risks of hormone replacement therapy - technical

Topics covered:

  • Essentials
  • Introduction
  • Benefits of hormone replacement therapy (HRT)
  • Side effects and risks of HRT
  • Therapeutic regimens


Hormone replacement therapy (HRT) comprises oestrogen with or without progestogen.

Benefits—HRT is the most effective treatment for the relief of menopausal symptoms and for the primary prevention of postmenopausal osteoporosis. There are also possible benefits for coronary heart disease, colorectal cancer, and neurocognitive function, but these are yet to be established.

Risks—the main risk of HRT is perhaps a small increase in incidence of breast cancer, but this risk may be confined to women with a long exposure to certain oestrogen–progestogen combinations. There is a small increased risk of stroke if HRT is initiated in older women and a small increased risk of venous thromboembolism with oral therapy.

Balance of benefits and risks—given appropriately, the benefits of HRT outweigh the risks. The choice and dose of therapeutic agents should be tailored to suit the individual case, but usually the therapy used should be the one that the patient finds most acceptable. Risks and benefits should be reviewed annually, but no limit on duration of treatment need be set.


The menopause, the time of a woman’s last spontaneous menstrual period, is a useful marker for ovarian failure and occurs naturally at an average age of around 51 years, although it may occur at any time after puberty. Symptoms arising around the time of the menopause include hot flushes and night sweats, and psychological symptoms such as mood swings, depression, anxiety and irritability, and difficulties with memory and concentration.

Later there may be genitourinary problems such as vaginal dryness and dyspareunia, and increased urinary frequency and urge incontinence. However, it is the long-term consequences of hormone deficiency, particularly osteoporosis and cardiovascular disease, which pose a major health problem.

Benefits of hormone replacement therapy (HRT)

The main indications for use of HRT are relief of menopausal symptoms and prevention of osteoporosis.

Vasomotor symptoms

HRT will abolish vasomotor symptoms, often within days of starting treatment, but psychological and genitourinary symptoms may take weeks or even months to respond. It is therefore worthwhile persisting with therapy for several months in the absence of rapid symptomatic response, and treatment should be continued for at least several months after symptomatic relief has been obtained.


HRT is well established for both the prevention and treatment of osteoporosis, and is as effective as any other agent currently available. It conserves—and to some extent increases—bone density, and results in a reduction in fracture risk. Therapy should be offered to any woman considered at increased risk of osteoporosis, and particularly those with an early menopause. When risk of osteoporosis is uncertain, bone density measurement can aid clinical decision making.

Hormone replacement may need to be given for several years when started in the early postmenopause. Benefits in reducing risk of osteoporotic fracture may persist into old age. Cessation of HRT leads to a loss of bone density, but only at the usual postmenopausal rate.

Older women are less tolerant of treatment side effects, particularly cyclical bleeding and mastalgia, hence for this age group regimens that avoid bleeding are to be preferred, and much lower doses of oestrogen than are used early after the menopause appear effective for bone conservation.

Cardiovascular disease

Observational studies have shown prevention of cardiovascular disease with HRT. There are many mechanisms, both established and potential, whereby HRT might benefit the cardiovascular system: these are summarized in Bullet list 1. The effects vary depending on the dose and type of oestrogen or progestogen and the route of administration. In general, hormone replacement produces favourable metabolic effects for lipids, and glucose and insulin metabolism, thus reversing the changes brought about by the menopause. There are also direct effects of oestrogen on arteries, which improve their function by endothelium-dependent and non-endothelium-dependent mechanisms.

In contrast to the observational studies, randomized prospective studies of HRT for both primary and secondary prevention of coronary heart disease have failed to show any overall benefit in clinical events. Although eventual reductions in events by 20 to 30% were observed by the end of the trials, these were counterbalanced by early increases in events with hormone replacement.

The doses of oestrogens used were inappropriately high for the older women in the study groups, which could result in transient increases in thrombogenesis and adverse vascular remodelling. Indeed, in these trials younger women appeared to show some benefit while older women did not. Further studies are necessary to clarify the position.

Bullet list 1 Hormone replacement therapy and the cardiovascular system: possible mechanisms of action

  • Decreased total cholesterol
  • Decreased triglycerides
  • Decreased LDL cholesterol
  • Decreased LDL cholesterol oxidation
  • Increased HDL and HDL2 cholesterol
  • Increased small dense LDL particle clearance
  • Increased postprandial lipid clearance
  • Decreased insulin resistance
  • Decreased circulating insulin concentrations
  • Decreased proportion of insulin propeptides
  • Improved glucose tolerance
  • Decreased proportion of android fat
  • Decreased NEFA flux
  • Decreased fibrinogen
  • Decreased plasminogen activator inhibitor-1
  • Increased tissue plasminogen activator
  • Decreased homocysteine
  • Increased arterial NO production 
  • Decreased endothelin-1 release 
  • Reduced calcium channel ion flux
  • Enhanced potassium channel ion flux
  • Decreased ACE activity
  • Decreased blood pressure 
  • Increased arterial blood flow
  • Improved arterial remodelling

ACE, angiotensin-1 converting enzyme; HDL, high density lipoprotein; LDL, low density lipoprotein; NEFA, nonesterified fatty acids; NO, nitric oxide.

Colorectal cancer

There is some epidemiological evidence that oestrogen–progestogen therapy may result in a decrease in the incidence of colorectal cancer, also seen in a large randomized trial.

Side effects and risks of HRT

Oestrogenic side effects such as breast tenderness and nausea are sometimes experienced on commencing therapy, but these are transient and usually resolve by about 3 months of therapy. More commonly side effects are due to the progestogen and can include breast tenderness, abdominal and pelvic pain, backache, depression, irritability, and migraine.

Breast cancer

The main concern about HRT is the risk of breast cancer. Epidemiological evidence remains conflicting: some studies show no overall increased risk of breast cancer, whereas others show an increase with prolonged usage. The largest randomized trial showed a small increase in risk of developing breast cancer with one oestrogen–progestogen regimen, but a small decreased risk with oestrogen alone. It seems prudent to avoid HRT where possible in women with breast cancer, but previous disease need not be considered a total contraindication in all cases.

Other risks

Previous endometrial hyperplasia or neoplasia is not a contraindication, provided the disease has been eradicated. Similarly, endometriosis and uterine fibroids rarely cause a problem, although they may occasionally worsen.

HRT does not usually cause hypertension and some regimens may reduce blood pressure. There is a small but transient dose-dependent increase in venous thromboembolism risk, but this is not seen with nonoral therapy. It is prudent to exclude a pre-existing thrombophilia in patients with a relevant past or family history, and avoid oral therapy in such women. There is also a small increased risk of stroke, which may also be dose dependent.

Many women gain weight after the menopause, most commonly due to excessive calorie intake. Weight gain may occasionally occur due to fluid retention, although antimineralocorticoid progestogens prevent this. Increases in body fat are not caused by HRT.

Therapeutic regimens

HRT consists of oestrogen, which should be given continuously, with the addition of cyclical progestogen in women who have not had a hysterectomy. Low starting doses of oestrogen are now recommended. Progestogens are necessary to prevent endometrial hyperplasia and neoplasia, and to regulate any uterine bleeding that may occur.

The choice and dose of therapeutic agents should be tailored to suit the individual case. There are advantages and disadvantages of certain preparations and combinations, but usually the therapy used should be the one that the patient finds most acceptable. Annual review of risks and benefits should be undertaken, but no time limit on duration of treatment need be set.

Various types of natural oestrogens and various routes of administration can be used. The synthetic alkylated oestrogens, such as ethinyloestradiol, are not used in HRT because of their potency and unwanted side effects. The progestogens currently used are either derivatives of 19-nor-testosterone, C-21 steroids, or a spironolactone analogue. Progestogens are usually given in the minimal dose necessary for endometrial protection for 12 or more days per month, and result in a regular uterine bleed. Commonly used hormones are shown in Bullet list 2.

A major drawback to cyclical HRT regimens is the necessity of uterine withdrawal bleeding, although this is often fairly light, particularly in older women, and tends to diminish with time. With a satisfactory and regular bleeding pattern, there is usually no need for endometrial screening. However, cyclical bleeding becomes less acceptable as women get older and regimens that avoid such bleeding become preferable. Preparations giving continuous progestogen with continuous oestrogen are used to prevent endometrial stimulation and hence abolish uterine bleeding, resulting in amenorrhoea in up to 70 to 80% of women. These therapies are less successful in women close to menopause, where transient episodes of spontaneous ovarian activity may result in irregular bleeding.

Bullet list 2 Oestrogens and progestogens used in HRT

Oral preparations


  • Micronized oestradiol-17β
  • Oestradiol valerate
  • Oestrone sulphate
  • Conjugated equine oestrogens


  • dl-Norgestrel
  • Norethisterone acetate
  • Dydrogesterone
  • Medroxyprogesterone acetate
  • Micronized progesterone
  • Drospirenone


  • Tibolone
  • Raloxifene

Nonoral preparations


  • Transdermal oestradiol-17β patch
  • Percutaneous oestradiol-17β gel
  • Oestradiol-17β implant


  • Transdermal norethisterone acetate (combination patch)
  • Transdermal levonorgestrel (combination patch)

The lowest doses are often sufficient for older women; higher doses may be needed for young or acutely postmenopausal women.

Tibolone, a synthetic compound with oestrogenic, progestogenic, and androgenic properties, is an alternative that avoids cyclical bleeding. It relieves vasomotor symptoms and appears as effective as HRT for the prevention and treatment of osteoporosis, but it is not established whether it has other benefits associated with HRT, such as desirable cardiovascular effects or effects on the central nervous system. However, it has the same potential risks, for the breast and for stroke.

Raloxifene, a selective oestradiol receptor modulator (SERM), is a synthetic compound which binds to the oestrogen receptor but causes conformational changes that result in different tissue-specific actions. Thus it can act similarly to an oestrogen in the skeleton, preventing osteoporotic vertebral fractures although not hip fractures, but like an antioestrogen in the breast, causing a reduction in breast cancer incidence. It does not cause uterine bleeding, but does not relieve vasomotor or genitourinary symptoms. Its cardiovascular effects may be favourable if initiated in postmenopausal woman below age 60 years.