hormone replacement therapy is prescribed to women whose ovarian cycles have ceased (due to the menopause or bilateral oophorectomy), or as part of ‘add-back’ therapy with GnRH analogs. The benefits of hormone replacement therapy for postmenopausal women are well known. The use of progesterone in hormone replacement therapy is essential to protect the endometrium from stimulation induced by estrogen use. Progestogens prevent endometrial hyperplasia and cancer. However, during the progesterone phase of therapy, a significant percentage of women develop physical and psychological symptoms that are indistinguishable from premenstrual syndrome.
Women known to suffer from premenstrual syndrome and who had undergone hysterectomy and bilateral salpingo-oophorectomy, and who were commenced on cyclical hormone replacement therapy, remained asymptomatic during the estrogen-only phase. However, they started with premenstrual syndrome-like symptoms while on progestogen. This demonstrates fairly clearly that the patients remained sensitive to the effects of ovarian hormones and that the ovarian hormones were directly responsible for the premenstrual syndrome.
Magos and colleagues demonstrated the influence of progestogens on mood and behavior. A total of 58 postmenopausal hysterectomized women were treated with subcutaneous estradiol and testosterone implants. There was a dose-dependent increase in depression, loss of energy, loss of libido and mastalgia when norethisterone was added. Severity of symptoms was related to duration of progestogen therapy. Moreover, different progestogens cause different adverse symptoms. Norethisterone is less likely to cause negative-affect complex symptoms, and is possibly more likely to cause pain complex symptoms than either medroxyprogesterone acetate or dydrogesterone.
hormone replacement therapy-induced premenstrual symptoms, or even premenstrual syndrome, seem to be a major cause of decreased compliance in hormone replacement therapy users. In studies looking at the reasons for not taking prescribed hormone replacement therapy among menopause clinic attendees, 35-39% of the women on hormone replacement therapy reported premenstrual syndrome-like symptoms. These symptoms were severe enough for some of them to discontinue the treatment. The potential severity of the problem is highlighted by a long-term study in which such symptoms led to hysterectomy in 10% of the patients. However, there are few clinical studies addressing this common and important issue.
There are many strategies that could be adopted to decrease the risk of hormone replacement therapy-induced premenstrual syndrome. These include the following:
- (1) Continuous progestogen therapy was introduced in an attempt to improve compliance and acceptability of hormone replacement therapy. The advantages of the continuous regimen include reduction of bleeding and the possible reduction of progestogen-related subjective and metabolic side effects. This is because of lower overall progestogen doses than those used in sequential regimens.
- (2) Local progestogen delivery via a levonorgestrel-releasing intrauterine system (LNG-IUS) has been found to be effective in suppressing the endometrium and reversing hyperplasia, in addition to being well accepted by patients. This effect is, most probably, secondary to the low serum concentration of levonorgestrel in women using the LNG-IUS, despite the high concentration in the endometrium. Barrington and Bowen-Simpkins found the device to be useful in avoiding premenstrual syndrome symptoms in 56% of the study population.
- (3) If the patient is sufficiently beyond the menopause that bleeding will not be a problem, then tibolone may be a suitable option. There is evidence from randomized controlled trials of its benefit in premenstrual syndrome, particularly when used as add- back therapy with GnRH analogs. However, the occasional patient complains of premenstrual syndrome symptoms continuously in the first few months of treatment.
- (4) Three-monthly-bleed hormone replacement therapy could potentially decrease the frequency of occurrence of hormone replacement therapy-induced premenstrual syndrome, because this will only happen during the progestogenic phase of each 3-monthly cycle. However, this advantage should be balanced against the possibility of increased bleeding problems.
- (5) Selective estrogen receptor modulators (selective estrogen receptor modulators) have virtually no effect on menopausal symptoms. However, if the aim of hormone replacement therapy is to protect bone, then selective estrogen receptor modulators can be used without development of premenstrual syndrome.
- (6) Given the known beneficial response to SSRIs in premenstrual syndrome, a parallel effect may arise in the hormone replacement therapy scenario, although such an approach has not been published.
hormone replacement therapy-induced premenstrual symptoms remain difficult to treat. There have been no large randomized controlled trials to study their prevention or treatment. As this is a major cause of limited compliance in hormone replacement therapy users, attempts should be made to individualize hormone replacement therapy prescribing following careful assessment and counselling.