INTRODUCTION — Systemic lupus erythematosus (SLE) occurs frequently in women of childbearing age. The relationships between SLE and menstrual function, menopause, and hormone replacement therapy are discussed in this topic review. Issues related to pregnancy in women with SLE, pregnancy in patients with impaired renal function, and hormonal contraception in women with SLE are presented in detail elsewhere. (See "Pregnancy in women with systemic lupus erythematosus" and "Pregnancy in women with nondialysis chronic kidney disease" and "Approach to contraception in women with systemic lupus erythematosus".)

MENSTRUAL FUNCTION — Menstrual irregularities are common in women with systemic lupus erythematosus (SLE):

●Menstrual irregularity, especially oligomenorrhea, is a common clinical feature in women with SLE. As an example, among 94 women with SLE under the age of 45 without exposure to alkylating agents, oligomenorrhea occurred in 54 percent. Menstrual irregularities were associated with higher levels of prolactin, higher disease activity, and lower levels of progesterone [1]. These observations suggest that SLE activity may result in hormonal abnormalities that may contribute to menstrual irregularity.

●Menorrhagia has been noted in 12 to 15 percent of patients [2,3]. Thrombocytopenia, antiphospholipid antibodies, and the use of glucocorticoids and/or nonsteroidal antiinflammatory drugs (NSAIDs) may contribute to the heavy menstrual flow.

●Temporary or even permanent early (or premature) amenorrhea has been noted in 17 to 24 percent of patients. Two major mechanisms have been identified: There is an association of SLE with autoimmune ovarian injury and with the administration of immunosuppressive agents (especially cyclophosphamide [CYC]) [4,5]. A retrospective review of women treated for lupus nephritis illustrated the importance of total drug exposure with CYC [5]. Sustained early amenorrhea developed in none of 16 treated only with pulse glucocorticoids, 2 of 16 treated with seven monthly pulses of CYC, and 9 of 23 treated with 15 or more monthly pulses of CYC. Amenorrhea began within the first seven months in one-half of affected patients, occurring earlier in women over the age of 25. The amenorrhea was usually permanent, with recovery occurring only in women receiving the shorter pulse CYC regimen.

The age of the patient at which amenorrhea due to therapy with CYC occurred was examined in another study of 35 women who underwent pulse CYC therapy; the older the woman at the initiation of therapy, the more likely she was to experience ovarian failure [6]. The administration of as little as 3000 mg of CYC was associated with ovarian failure in some older patients. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity'.)

●A cross-sectional study of 196 patients with SLE compared with 90 healthy controls showed that the median age of menopausal onset was lower in SLE patients. Moreover, premature ovarian failure was more common in patients with SLE and associated with autoantibodies and exposure to certain medications [7].

●A study of 961 patients with SLE failed to show any increased prevalence of premature ovarian failure when compared with the general population [8].

In addition to these effects, the menstrual cycle can also affect SLE. In particular, patients with SLE may be more likely to flare in the premenstrual period [9,10].

MENOPAUSE — Menopause may or may not be associated with a diminution in the symptoms and signs of systemic lupus erythematosus (SLE). The amount of improvement is variable and ranges from none to substantial [11-13]. One observational study of over 300 women with SLE noted similar rates of improvement in SLE symptoms in those during the premenopausal, postmenopausal, and perimenopausal periods [14].

Menopause brings on several new concerns:

●Postmenopausal women have a greater risk of coronary disease as do women with SLE, especially those treated with glucocorticoids [15,16].

●Postmenopausal women have a greater risk of osteoporosis as do women with SLE, especially those treated with glucocorticoids [15].

HORMONE REPLACEMENT THERAPY — Hormone replacement therapy with estrogen and a progestin can decrease the risk of osteoporosis and improve the mood and sense of wellbeing and libido. However, these benefits must be weighed against the risks of breast cancer, cardiovascular disease, and stroke that are significantly increased in otherwise healthy postmenopausal women treated with estrogen and a progestin [17], as well as in those with SLE [18]. (See "Menopausal hormone therapy: Benefits and risks".)

Estrogen increases the susceptibility to SLE through uncertain mechanisms that may explain the marked female preponderance in this disorder. However, the risk of increased disease activity with estrogen replacement therapy appears to be small [18-22]. The largest study, of 351 postmenopausal women with SLE, suggested only a small increase in the risk of a disease flare in association with estrogen and intermittent progestin use [22] (see "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Hormonal factors'). A subsequent study also found that postmenopausal hormonal replacement therapy did not alter disease activity during the two years of treatment [18]. However, there appeared to be an increased risk of thrombosis in the group receiving the hormonal therapy.

It has also been suggested that estrogen replacement therapy may be associated with an increased likelihood of developing SLE. Data from the Nurses' Health Study found that, when compared with women who were never treated with estrogen replacement therapy, the relative risk of SLE was 2.5 in current users and 1.8 in past users [23]. Another large meta-analysis also showed an association between hormone replacement therapy and SLE susceptibility [24].

Estrogen therapy should be avoided in patients with a history of thromboembolic disease and/or antiphospholipid antibodies because of the increased risk of thromboembolic events. Thus, the risks and benefits of hormone replacement therapy must be carefully weighed for each individual patient.

SUMMARY AND RECOMMENDATIONS

●Menstrual irregularities, especially oligomenorrhea, are common in women with systemic lupus erythematosus (SLE), and hormonal abnormalities due to increased disease activity may contribute to menstrual irregularity. Thrombocytopenia, antiphospholipid antibodies, and the use of glucocorticoids and/or nonsteroidal antiinflammatory drugs (NSAIDs) can contribute to menorrhagia. Temporary or even permanent early (or premature) amenorrhea may result from autoimmune ovarian injury or from the administration of cytotoxic agents, particularly cyclophosphamide (CYC). Increased age and greater total drug exposure increase the risk of CYC-related ovarian failure. Hormonal effects influence disease; lupus may be more likely to flare in the premenstrual phase of the menstrual cycle. (See 'Menstrual function' above.)

●Menopause may or may not be associated with a diminution in the symptoms and signs of SLE. The amount of improvement is variable and ranges from none to substantial. (See 'Menopause' above.)

●Estrogen-containing hormonal therapy increases the risk of developing SLE through uncertain mechanisms. However, the risk of increased disease activity with postmenopausal estrogen therapy appears to be small. The risks and benefits of such therapy must be carefully weighed. We avoid estrogen therapy in patients with a history of thromboembolic disease and/or antiphospholipid antibodies. (See 'Hormone replacement therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.