Menopause and Rheumatic Disease

Menopause occurs naturally in women at about 50 years of age. There is a wealth of data concerning the relationship of menopause to systemic lupus erythematosus, rheumatoid arthritis, and osteoarthritis; there are limited data concerning other rheumatic diseases. Age at menopause may affect the risk and course of rheumatic diseases. Osteoporosis, an integral part of inflammatory rheumatic diseases, is made worse by menopause. Hormone replacement therapy has been studied; its effects vary depending on the disease and even different manifestations within the same disease. Cyclophosphamide can induce early menopause, but there is underlying decreased ovarian reserve in rheumatic diseases.

Key points

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Menopause, and its treatment, may affect rheumatic diseases; rheumatic diseases may affect menopause.
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Treatment with cyclophosphamide, especially at an older age, may induce menopause.
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Decreased ovarian reserve is a feature intrinsic to disease notwithstanding treatment.
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Osteoporosis is common in several rheumatic diseases, and menopause increases the risk of osteoporosis as well as fragility fracture.
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The effect of menopause and its treatment is difficult to define in osteoarthritis because of contradictory results.

Introduction

Menopause is defined as cessation of menses retrospectively for 12 months without a pathophysiologic cause. However, age-related changes in ovarian function begin in the middle of the fourth decade of life with decreased ovarian follicles. Resultant changes in hypothalamic and pituitary hormones to compensate for the falling reserve of ovarian follicles maintain ovulation and fertility, sometimes for decades. The transition to the menopausal state demonstrates highly variable cyclic follicle development and ovulation, along with disrupted menstrual bleeding patterns. The average age at menopause is about 51 years with later age of menopause correlating with longevity.

Rheumatic illnesses include diseases with evidence of autoimmunity as well as the common, near ubiquitous, osteoarthritis (OA). These diseases are generally more common among women compared with men. There are extensive data describing the relationship of some diseases with the menopausal state, whereas the data are scant for other rheumatic diseases. In this review, the authors consider the impact of menopause on several of these diseases and the reverse, that is, the impact of the diseases on menopause.

Introduction

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is the prototype systemic inflammatory rheumatic disease. There is a wide range of serologic and clinical manifestations attributed to SLE with virtually every patient having a unique disease course. The disease affects women about 10 times more commonly than men with onset typically in the third or fourth decade of life. Despite the usual onset well before the average age of menopause, there is a wealth of data concerning menopause and SLE, with multiple aspects of this relationship to consider. Among these are whether age of onset of menopause is a risk factor for SLE and whether onset of menopause alters the course or severity of the disease or its complications, including accelerated cardiovascular disease. Hormonal therapy for menopause may also interact with the disease. Disease with onset after menopause, although uncommon, may be a distinct entity compared with premenopausal onset. Finally, cytotoxic therapy for SLE may induce an iatrogenic and early menopause. This review considers these aspects of SLE and menopause.

A recent cross-sectional study examined menopause in 961 patients with SLE, of whom 7.9% had natural menopause. Meanwhile, 4.1% had undergone a hysterectomy and 6.3% had menopause after taking cyclophosphamide. Only a small number (0.1%) had menopause associated with end-stage renal disease. The mean age at menopause was 46.4 years and the median age was 50.7 years, both similar to reported values for the general population. An early age at menopause was associated with an earlier age of SLE diagnosis, however. In Lupus in Minorities: Nature versus Nurture (LUMINA) study, a multiethnic SLE cohort from the United States, 37 of 316 women had premature menopause. In a multivariable regression analysis, age at receiving cyclophosphamide, cyclophosphamide induction therapy, higher disease activity, and Texas-Hispanic heritage were associated with a premature gonadal failure. Older studies also show age and cumulative dose of the drug as important predictors of premature menopause. Another study compared prolonged intravenous (IV) cyclophosphamide with 5 to 7 monthly doses followed by mycophenolate mofetil. In the latter group only 1 of 22 women (4%) had sustained amenorrhea, whereas in patients with prolonged cyclophosphamide treatment, 20 of 39 (51%) had sustained amenorrhea. Once again, older age at initiation of treatment was an important risk factor. Neutrophil count suppression by pulse IV cyclophosphamide as well as hypothyroidism may also predict premature ovarian failure. In the last study, 11 of 71 patients with SLE receiving cyclophosphamide developed ovarian failure: all 11 had hypothyroidism as evidenced by an elevated thyroid-stimulating hormone. Thus, treatment with cyclophosphamide can induce premature menopause in women with SLE, especially when treatment begins at an older age (>32 years), whereas hypothyroidism as a risk factor is reported but not confirmed by subsequent studies.

Nonetheless, factors unrelated to cyclophosphamide can affect ovarian reserve in patients with SLE. Using levels of anti-Müllerian hormone (AMH) as a measure of ovarian function in a study of 33 premenopausal women with SLE (without past cyclophosphamide use) and 33 age- and ethnicity-matched healthy controls, Lawrenz and colleagues found lower mean AMH in SLE (2.15 ± 1.64 vs 3.17 ± 2.29); however, there was no difference in number of pregnancies or spontaneous abortions between the groups. Another study confirmed this result but found AMH levels did not predict early menopause. The factors intrinsic to SLE that affect ovarian function and reserve have not yet been identified. And, although antiovarian antibodies have been described in patients with SLE, there is no evidence of premature menopause among patients with SLE apart from the effects of cyclophosphamide. Pharmacologic suppression of ovarian function by gonadotropin-releasing hormone agonists may protect women from premature ovarian failure caused by this drug, and there are several other strategies to preserve fertility after cyclophosphamide, including oocyte preservation.

Whether or not menopause, natural or otherwise, affects the course of SLE has been investigated. This investigation includes the study of SLE with onset at an older, postmenopausal age. A study of SLE with average age of onset at 55 years among 20 postmenopausal and 70 premenopausal women showed the postmenopausal women were statistically less likely to have malar rash (55% vs 80%), renal disease (30% vs 69%), leukopenia (25% vs 56%), or positive antinuclear antibody (70% vs 93%). Other studies find low incidence of anti–double-stranded DNA (dsDNA) and hypocomplementemia among postmenopausal SLE onset. Thus, absence of these characteristic features, along with older age, may make diagnosis difficult.

Menopause may also affect the course of SLE. In a study of 34 postmenopausal patients with SLE with premenopausal onset compared with patients with SLE continuing to have menstrual periods, Mok and colleagues found fewer (0.5/y vs 0.14/y) and less severe flares. Mean and maximum disease activity were both decreased in 30 patients with SLE not receiving sex hormone therapy followed for an average of 1.7 years before and 3.3 years after menopause.

Surgical menopause before SLE onset was associated with less renal involvement and lower anti-dsDNA seropositivity, an effect independent of ethnicity. However, the Toronto Lupus Group has shown a constant rate of improvement in disease activity over time since diagnosis regardless of onset of menopause, concluding that menopause is not a proximate cause of improved SLE disease activity. That is, the evidence suggests that SLE improves after menopause but a cause and effect relationship has not been established.

The relationship of menopause to disease activity in SLE begs the controversial question of whether postmenopausal sex hormone replacement is safe in patients with SLE. This topic has been studied and reviewed extensively. Evidence from the Nurses’ Health Study, a large prospective cohort study, shows a 2-fold increased risk of SLE for women treated with postmenopausal hormone replacement. However, these data were collected at a time when such therapy was much more common than now. Estrogen or combined estrogen-progesterone therapy is associated with increased mild to moderate flares of SLE but not with severe flares. New data are available that may suggest possible mechanisms of SLE flares with hormonal therapy. In a recent study of 35 patients with SLE and 15 controls, investigators found increased expression of toll-like receptor (TLR) 3, 7, and 9 on peripheral blood mononuclear cells when comparing patients with controls. Postmenopausal status among the patients was associated with a higher percentage of cells expressing TLRs. Another study reported decreased tumor necrosis factor production by estrogen-treated peripheral blood mononuclear cells from patients with SLE.

Menopause has been studied in relationship to complications of SLE, especially premature atherosclerosis and osteoporosis. Low bone density is associated with disease activity and damage accrual: osteoporosis is an intrinsic part of SLE that is not induced purely by treatment. Menopause is a risk factor for more severe osteoporosis as well as fragility fracture. Postmenopausal patients with SLE were significantly more likely to have a vertebral compression fracture than premenopausal patients. Further, the 10-year risk of osteoporotic fracture is greater among women with SLE compared with matched controls, despite comparable bone mineral density values. This risk was predicted by premature menopause as well as cumulative glucocorticoid dose. Treatment with either estrogen or selective estrogen agonists, such as raloxifene, maintain bone density in postmenopausal patients with SLE. Newer data suggest that raloxifene does not worsen lupus flares, alter disease activity, or increase inflammatory markers in postmenopausal patients with SLE. But the study is small (n = 62) and relatively short (12 months).

Women with SLE have dramatically increased rates of cardiovascular disease such that, beginning about 10 years after diagnosis, this is the most common cause of death. Interestingly, a correlate of premature cardiovascular disease, as measured by coronary artery calcification, is low bone mineral density. There are several studies of vascular function, which may serve as a surrogate of vascular disease, in women with SLE. Pulse wave velocity measured at peripheral large arteries determines arterial elasticity. Postmenopausal patients with SLE (n = 96) had worsened pulse wave velocity compared with premenopausal patients (n = 124), but most of this difference was explained by age in a multivariate analysis. But higher cumulative organ damage and worsened renal function were associated with stiffer arteries in the postmenopausal group. A more traditional measure of arterial function is flow-mediated dilatation, usually determined at the brachial artery. A meta-analysis of these studies found that although endothelium-dependent flow-mediated dilatation was impaired in patients with SLE, menopause was not an important determinate in multivariate analysis.

Rheumatoid arthritis

Rheumatoid arthritis (RA) affects about 1% of the worldwide population with a ratio of women to men of up to 6 to 1 in young adults, but the sex ratio approaches 1 as age of onset increases. The onset of disease is substantially older than that seen in SLE such that initial disease among women is common in postmenopausal years. Extra-articular disease may rarely lead to life-threatening complications; but patients with RA have excess mortality from several causes, including cardiovascular, infectious, and hematological disease. Similar to SLE and OA, there are multiple aspects of the disease potentially related to menopause.

First among these to consider is whether menopause increases the risk or severity of RA. In fact, the results of observational studies of both menopause and estrogenic hormones, either postmenopausal or contraception, are variable and discrepant. A study from Belgium showed that first symptoms of RA had a mean time from onset of menopause of zero. The investigators suggested these data indicate that the average woman with RA has the onset of symptoms concurrent with menopause. A recent study showed that menopause before 45 years of age (early menopause) was associated with milder RA. Meanwhile, another study found early menopause was associated with postmenopausal onset of RA. Thus, a definite conclusion about the effects of menopause on RA cannot be made.

Some observational studies, but not all, show hormone replacement therapy (HRT) or oral contraception improves disease among postmenopausal women. Similar to cardiovascular disease risk of HRT, studies of RA risk may be confounded by the use of estrogen alone versus estrogen plus progesterone. A recent population-based epidemiologic study from Sweden showed a decreased risk of anti–cyclic citrullinated peptide-positive RA among postmenopausal women older than 50 years with most of this reduction occurring in women on combination HRT (odds ratio 0.3). But in a 2-year study of HRT in 88 postmenopausal women with RA, there were no changes in autoantibodies. In addition, a 6-month, randomized, single-blinded, placebo-controlled trial showed no improvement in RA. But this last trial likely has no bearing on whether or not HRT reduces the risk of developing RA.

Similar to other inflammatory rheumatic illnesses, osteoporosis is caused in part by the disease itself with specific effects on bone remodeling and not simply a result of glucocorticoid therapy. In a study of 343 postmenopausal and 100 premenopausal women with RA, 56% of the former but only 18% of the latter had osteoporosis. Of course, study of healthy women before and after menopause might find similar numbers. However, there is clearly excess osteoporosis among women with RA compared with controls with postmenopausal status an important predictor. Excess bone loss seen in RA occurs early in the disease. Recent studies from the era of biologics (and low prevalence of postmenopausal HRT) continue to show excess osteoporosis in patients with RA compared with age-matched controls (30.0% vs 17.4%) and an association with menopause. HRT reduces bone resorption regardless of glucocorticoid therapy in postmenopausal patients with RA ; but there are, of course, other potential health concerns with postmenopausal HRT.

Osteoarthritis

OA is highly prevalent in postmenopausal women. The Women’s Health Initiative showed that 44% of the participating postmenopausal women reported OA. Risk factors in this study include higher body mass index and older age. American Indian and African American women in the extreme obesity category have significant odds of OA compared with non-Hispanic white women.

Estrogen receptors are present in joint tissues. Estrogen has chondro-protective roles in part due to glycosaminoglycan synthesis, which is an important part of connective tissue. Estrogen also inhibits cyclooxygenase 2 messenger RNA expression in bovine articular chondrocytes as well as other tissues, leading to protection against reactive oxygen species induced chondrocyte damage. Estrogens decrease cartilage damage. Coincubation of chondrocytes with interleukin (IL)-1b and raloxifene led to a dose-dependent increase in proteoglycans and reduction of matrix metalloproteinase-3 and nitric oxide induced by IL-1b. Polymorphism in the estrogen receptor (ER) alpha gene may be associated with risk of severe OA of large, lower limb joints in a sex-specific manner suggesting that estrogen activity may influence the development of large joint OA. The same study concluded that variation in aromatase gene CYP19A1 and ER alpha gene is associated with risk of severe OA. Influence of the CYP19A1 single nucleotide polymorphism is more important in women than in men and in knee OA than in hip OA. A recent meta-analysis by Ma and colleagues reported rs9340799 and rs2228480 polymorphisms, rather than the rs2234693 polymorphism, in the ER alpha gene are associated with the incidence of OA.

It has been demonstrated that C-telopeptide of type II collagen (CTX II), a marker of collagen degradation, increases in the urine of asymptomatic postmenopausal women and ovariectomized rats, suggesting that estrogen deprivation leads to cartilage breakdown. No association has been found for urinary Helix II and estrogen deprivation leading to cartilage breakdown. A study of 860 women in China noted that menopause is associated with cartilage degeneration of the knee joint compared with premenopausal and perimenopausal women. Knee cartilage showed progressive severe degeneration on MRI in the first 2.5 years since menopause. However, although the investigators reported controlling for age, the study did not achieve much overlap in age across the menopause status group. The investigators concluded that estrogen deficiency is a risk factor for cartilage degeneration, and further studies are needed to clarify whether age or menopause plays a more important role in progression of cartilage degeneration. The study could not definitely differentiate between the effects of menopause and age in our opinion.

Gao and colleagues studied endogenous estrogens and estrogen metabolites in premenopausal and postmenopausal Chinese women with OA. The study showed that serum concentration of free estradiol and total 2-hydroxyestrone were significantly lower in premenopausal women with OA compared with the levels in controls (RA and healthy women). In postmenopausal women, serum concentration of free and total estradiol was significantly decreased compared with controls, and 2-hydroxyestradiol was significantly increased in postmenopausal women. The investigators reported that apart from free and total estradiol deficiency, a decreased serum level of total 2-hydroxyestrone in premenopausal women and an increased total 2-hydroxyestradiol level in postmenopausal women with OA may correlate with the pathogenesis of OA.

Studies on hormonal therapy in postmenopausal women with OA have shown conflicting evidence ( Table 1 ). The Women’s Health Initiative study showed that there are 29% greater odds of OA with past HRT use and 38% greater odds of OA for current HRT. American Indian women who reported current HRT use had an odds ratio of greater than 2 for arthritis (presumably OA) than the population as a whole. In contrast, an Italian study showed HRT is associated with 27% lower odds ratio of physician-diagnosed OA. In a cohort study of 1001 postmenopausal women (mean age 71 years) the effect of postmenopausal estrogen therapy was examined on hand, knee, and hip OA. A total of 638 women had used estrogen after menopause for greater than 1 year, and 71% were current users. Postmenopausal estrogen use for greater than 1 year was associated with higher prevalence of OA compared with no use of estrogen (34.5% compared with 30.9%, P = .02). Women using estrogen had significantly higher prevalence of hip and hand OA (15.8% vs 13.5%, P = .02 for hip, 4.1% compared with 1.1%, P = .002 for hand). Knee OA was slightly higher with estrogen use; however, the difference was not statistically significant. Unfortunately, this study did not report radiographic evidence of OA. In contrast, a large cross-sectional study evaluated 4366 postmenopausal women for osteoporotic fractures. Women currently using estrogen had 40% lower prevalence of radiologic and symptomatic hip OA. Reduction was greater for estrogen use greater than 10 years. In the Framingham OA study, estrogen use was not associated with increased risk of radiographic OA of the knees. In fact, estrogen use had a modest but nonsignificant protective effect in the study. In the Heart and Estrogen/Progestin Replacement Study, older postmenopausal women with cardiac disease (n = 969) were assessed for knee pain. There was no significant effect of 4 years of estrogen plus progestin therapy compared with placebo on knee pain and related disability, indicating that HRT is not associated with more prevalent or severe knee pain. The Chingford cross-sectional study demonstrated an inverse association of current postmenopausal HRT use and radiologic knee OA, suggesting protective effects. There was a nonsignificant protective effect for distal interphalangeal OA but no clear effect on carpometacarpal joints, leading to the conclusion that the effect was weaker in the hand joints. Further studies are needed to evaluate the true effect of estrogen replacement on OA considering the current contradictory evidence. Consideration of the site of OA may be critical in any such study.

Table 1

Effect of postmenopausal hormone replacement on osteoarthritis

Study	Type of Study	Population	Results
Women’s Health Initiative	Observational study	N = 146,494 Postmenopausal women	• HRT use associated with increased odds of OA • 29% increase odds of OA with current use and 38% with past use of HRT
Parazzini & Progretto Menopausa Italia Study Group, 2003	Cross-sectional study	N = 42,464 Italian postmenopausal women	• Increase odds of OA with menopause • Natural menopause associated with increased OR of 1.13 for OA (95% CI 1.07, 1.21) • Surgical menopause OR of 1.18 for OA (95% CI 1.09, 1.28) • HRT: 27% lower odds of physician-diagnosed OA compared with those not on HRT
Von Mühlen et al, 2002	Cross-sectional study	N = 1001 Postmenopausal women	• Postmenopausal estrogen use: 34% higher prevalence of OA compared with nonusers • Higher prevalence of subjects with hip and hand OA using estrogen replacement therapy compared with nonusers (15.8% compared with 13.5%, P = .02 for hip, 4.1% compared with 1.1%, P = .002 for hand)
Nevitt et al, 1996	Cross-sectional study	N = 4366 Postmenopausal women	• 40% Lower prevalence for radiologic and symptomatic OA of hip with estrogen use
Framingham OA Study	Cohort study	N = 831	• Nonsignificant protective effect for radiographic knee OA (OR 0.71, 95% CI 0.42, 1.20) or severe radiographic OA (OR 0.66, 95% CI 0.33,1.32) with estrogen use
Heart Estrogen/Progestin Replacement Study	Randomized control trial	N = 969 Postmenopausal women	• No difference between women on HRT vs placebo on knee pain and related disability
Chingford Study	Cross-sectional study	N = 606 Postmenopausal women	• Current HRT use was protective for knee OA (OR 0.31, 95% CI 0.11, 0.93) • Nonsignificant protective effect for OA of DIP joint with HRT use; OR 0.48 (95% CI 0.17, 1.42) • No effect on carpometacarpal joint (OR 0.94, 95% CI 0.44, 2.03)