Menopausal hormone replacement therapy (hrt)

Estrogen/progestogen regimens

Estrogens combined with progestogens in women who have uterus are the mainstays of menopausal therapy. Estrogens normally promote growth of the endometrium. A two to ten fold increase in the risk of cancer of the endometrium has been recorded after constant long-term hormonal stimulation of unopposed estrogen. This potential increase in the risk of endometrial cancer can however be eliminated by concurrent administration of a progestogen.

The duration of exposure to progestogen each month is critical, the endometrial response to progestogens being more dependent on duration than on the dose of a particular progestogen. The minimum requirement is a monthly exposure of at least 10 days and the optimum 12-14 days. Addition of progestogen in a sequential regimen generally ensures an acceptable bleeding pattern. Regular withdrawal bleeding occurs in 80-90% of women on a sequential regimen. The doses needed in sequential regimens are higher than those, which are sufficient in continuous combined regimens.

The only documented beneficial effect of progestogens is their effect on the endometrium and bleeding patterns. Other effects are either unwanted side effects (e.g. depression, lethargy, mood changes, bloating) or potential hazards. Hence progestogens should not be given to women who have undergone hysterectomy except in those with a history of pelvic endometriosis or stage I carcinoma of the endometrium.

Continuous combined estrogen/progestogen combinations have been developed, in an attempt to avoid vaginal bleeding and thereby make HRT more acceptable at older ages. Irregular bleeding however is common during the first three to four months of treatment and may continue irregularly thereafter. The closer the woman is to menopause the more likely she is to experience spotting and bleeding on a continuous combined regimen. The use of continuous combined preparations should therefore be avoided during the first two to three years after the menopause.

Endometrial stimulation can also be avoided by local administration of progestogens into the uterine cavity, with an intrauterine device releasing progestogen (Mirena IUS).

Doses and routes of administration

The dose of estrogen should take into account expected benefits and known risks of such therapy. The aim of oestrogen replacement should be to achieve blood levels, which correspond to those of the early follicular phase in pre-menopausal women. Indeed, blood levels of estradiol associated with the standard dose of HRT (1 mg of oral estradiol or 50 mcg estradiol patch) are between 150-370 pmol/L. It is therefore accepted that blood levels greater than 700 pmol/L should be avoided.

Oral preparations undergo metabolic conversion in the liver and principally increase levels of estrone which is three to four times less potent than 17-beta estradiol. Only a small amount of the hormone taken orally reaches the systemic circulation. Because of this effect comparatively high doses are required orally for a therapeutic effect. At the same time as estrogens are metabolized by the liver they affect metabolism of several protein and lipids in the liver and therefore can affect adversely coagulation and blood pressure.

The choice with non-oral estrogen includes the estradiol patch, estradiol gel, or subdermal pellet and also various vaginal estrogen preparations (pessaries, creams and rings). All routes of administration are effective for the relief of menopausal symptoms. The vaginal route is often neglected but has much to commend it. Estrogens (cream, pessary or ring) are well absorbed from the vagina, reaching the systemic circulation and relieving symptom. This route of application is particularly effective for the relief of local vaginal and urethral atrophy.

Discontinuing HRT

In approximately 25 percent of women who experience vasomotor symptoms (hot flushes & sweats) they persist for longer than five years and therefore could be present after discontinuation of HRT. Most of these women will have symptoms less frequent and less severe than at the time of the menopause. In a small minority of postmenopausal women, however, symptoms could be frequent, severe and lifelong.

Whether the recurrence of menopausal symptoms after discontinuing HRT is the result of underlying menopause or is purely a withdrawal effect is unclear. There is some evidence that women who used HRT for longer than 10 years have more problems after discontinuing treatment than those who used HRT for a short while. There is no evidence that gradual discontinuation of HRT reduces the recurrence of hot flushes compared with sudden discontinuation.