Ovarian function and disease activity in patients with systemic lupus erythematosus S.S. Shabanova1, L.P. Ananieva1, Z.S. Alekberova2, I.I. Guzov3

1Department of Microcirculation and Infl ammation and 2Department of Systemic Rheumatic Diseases, Institute of Rheumatology, Moscow; 3Immunology and Reproduction Center, Moscow, Russia.

Abstract Objective disturbances frequently occur during the onset or in exacerbation periods of systemic lupus erythematosus (SLE), suggesting a possible relationship. The aim of the study is to assess the ovarian function in SLE patients with active disease before the treatment with high doses of glucocorticoids (GC) and cytotoxic agents.

Methods We evaluated 94 female SLE patients (mean age of 29.2±7.0 years). The mean SLEDAI score was 11.4±8.1.8.1. Seventy-nineSeventy-nine patients had a current use of GC with a median dose of 10 mg/day (8-15). The other 15 patients were untreated. After examination and blood sample collection 40% of the patients were treated and high doses of GC (>30 mg/day); 68% from this group of patients were treated GC in combination with cyclophosphamide (CYC). Forty healthy women with the same mean age were evaluated as controls. A careful gynecological history and a gynecological examination were carried out in patients and controls. Hormonal serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol (E2) and progesterone in SLE patients and controls were measured by enzyme-linked immunosorbent assay (ELISA).

Results Menstrual cycle disorders with as dominant aspect were observed in 54% of SLE patients. The hormonal studies showed decreased progesterone level in 52% of patients, reduced E2 concentration in 25% of patients; increased levels of LH, FSH and prolactin were observed with the lower frequency (13%, 9%, 10% respectively). Menstrual cycle disorders and the hormonal unbalance such as decreased progesterone level and hyperprolactinemia were found related signifi cantly to high SLEDAI score (p<0.05, p=0.001, p<0.05). In the group of non-treated SLE patients the menstrual and hormonal disorders were observed in the same spectrum and with the same frequency as in all the examined SLE patients. SLEDAI score was found correlated signifi cantly with the frequency of menstrual cycle disorders in non-treated SLE patients (p<0.05).

Conclusion The reported study shows the disease activity as a major factor associated with menstrual cycle disorders in SLE patients before treatment with alkylating agents and high doses of GC. Therefore, SLE women might be considered as a risk group for altered ovarian function.

Key words Systemic lupus erythematosus, ovarian function, disease activity.

Clinical and Experimental Rheumatology 2008; 26: 436-441. Ovarian function and disease activity in patients with SLE / S.S. Shabanova et al.

Sabina S. Shabanova, MD, PhD, Research Introduction demonstrated as markers of autoim- Associate; Lidia P. Ananieva, MD, Systemic lupus erythematosus (SLE) mune ovarian failure in SLE (21-23). Professor of Rheumatology; Zemfi ra S. is an acute and chronic autoimmune Menstrual cycle disturbances frequent- Alekberova, Professor of Rheumatology; infl ammatory disease known for its fe- ly occur during the onset or in exacerba- Igor I. Guzov, MD, PhD, Gynecologist. male predilection and peak incidence tion periods of SLE, suggesting a pos- Please address correspondence and during the reproductive years (1). sible relationship. Nevertheless, there reprint requests to: Dr. Sabina S. Shabanova, Kravchenko Altered neuroendocrine immune in- are different opinions about the disease Street 4-1-54, 119313, Moscow, Russia. teractions could pay an important role activity infl uence on ovarian function. E-mail: [email protected] in the pathogenesis in SLE and might Some studies stressed the relationship Received on April 12, 2007; accepted in predispose to an increased susceptibil- between SLE activity and menstrual revised form on October 5, 2007. ity to the development of the disease. cycle disturbances in the other studies © CopyrightCopyright CLINICAL AND In additional, regardless of the premor- this fact was not confi rmed (12-16). EXPERIMENTAL RHEUMATOLOGY 2008.2008. bid reactivity of the hypothalamic-pi- Furthermore, the distinct role of the tuitary-adrenal (HPA) axis, chronic in- disease activity and the GC therapy in fl ammation itself could alter HPA axis menstrual cycle disorders has not been responses (2). Infl ammation is accom- properly evaluated, because these two panied by raised levels of cytokines factors usually occur concomitantly. like interleukin IL6, interleukin IL1, Having a suppressive effect on the hy- tumor necrosis factor TNF-α that can pothalamic-pituitary-ovarian system, activate HPA axis (3). The stimulated GC induce a decrease of LH and FSH HPA axis regulates immune responses levels (24, 25). Most likely, the ovarian through the immunosuppressive ef- failure in SLE has a diffi cult genesis. fects of glucocorticoids (4, 5). Cutolo The aim of the study is to assess the et al. showed that complex interactions ovarian function of SLE patients with occur between the endocrine, nervous active disease before treatment with and immune systems during synovi- high doses of GC and cytotoxic agents, tis that will potentially uncover new since the above-mentioned relationship mechanisms in the pathophysiology was not thoroughly investigated. also of rheumatoid arthritis (6, 7). In addition, SLE and polymyalgia rheu- Patients and methods matica might also be characterized by We evaluated 94 consecutive patients impaired function of the HPA axis, in- with the mean age of 29.2±7.0 years cluding its altered negative-feedback (age range 16-45 years), who had four regulation or reduced cortisol effects or more American College of Rheuma- owing to glucocorticoid receptor defect tology (ACR) criteria for SLE (26), at- (8, 9). tending the Institute of Rheumatology Despite the fact that fertility in the most from Russia during the period from patients is preserved, the gonadal func- 2001 to 2004. tion of women with SLE can be altered The exclusion criteria for the study by several factors such as: autoimmuni- were: , lactation, meno- ty, disease activity, hyperprolactinemia, pause, primary , previous dysfunction of the hypothalamic-pi- history of , oophorectomy tuitary-ovarian axis and thyroid, using and a current use of oral contraceptive very high doses of immunosuppressive agents. agents, particularly cyclophosphamide The mean disease duration was 7.3±6.2 (CYC) and glucocorticoids (GC). years. The disease activity was meas- Recent reports suggest that menstrual ured by the SLEDAI (Systemic Lupus disturbances varying from menorrh- Erythematosus Disease Activity Index) agia to amenorrhea are common in (27). The mean SLEDAI score was SLE women (10-18). Most of the stud- 11.4±8.1 (range 2-41 balls). All the pa- ies are devoted to the infl uence of CYC tients were examined in the period of on the gonadal function, since ovarian SLE fl are or at the disease onset before failure is a well-known side effect of the treatment of CYC and high dose CYC therapy, with older patients being of GC. At the time of investigation 79 more susceptible (18-20). Anti-ovary (84%) patients had a current use of GC autoantibodies, including anti-corpus with a median dose of 10 mg/day (8- Competing interests: none declared. luteum antibody have recently been 15). The other 15 (16%) patients were

437 Ovarian function and disease activity in patients with SLE / S.S. Shabanova et al. untreated. After examination and blood sample collection 40% of all the pa- tients were treated and high doses of GC (>30 mg/day), 68% of this group of patients were treated with GC in com- bination with CYC. Forty healthy women with the same mean age of 28.7±4.4 years (age range 19-41 years) were evaluated as controls. A careful gynecological history (ac- cording to the special questionnaire) and physical examination by an attend- ing gynecologist were carried out in patients and controls.

Determination of hormonal serum levels Fig. 1. Frequency of menstrual disturbances in SLE patients. Blood samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) were collected at the (on days 3-7 of menstrual cycle) and for estradiol (E2) and progesterone at the (on days 20-22 of menstrual cycle). Hormonal levels in patients and con- trols were measured by enzyme linked immunosorbent assay (ELISA). E2 was measured using a commercial kit from DRG Diagnostics (USA); the other hormones were determined by an ALKOR-BIO kit (Russia).

Menstrual disorders were classifi ed as: - Amenorrhea: the absence of menstru- al periods for six and more months - Oligomenorrhea: menstrual periods occuring at intervals of greater than Fig. 2. SLEDAI score in SLE patients with normal menstrual cycle (group 1) and with menstrual 35 days. disorders (group 2). - Polymenorrhea: menstrual periods occuring at interval of 21 days or fewer. characteristics. The Mann-Whitney U- The mean length of menstrual cycle - : a diminution of the test was used to compare two independ- and blood fl ow in SLE patients with fl ow or a shortening of the duration ent groups, and Wilcoxon test to de- preserved menstrual cycle were such of . pendent groups. Spearman criterion was as in the general population (28±3 and - Hypermenorrhea: heavy or pro- used to establish the correlation between 5±2 days, respectively). longed menstruation. the two characteristics. Fisher exact test, Nevertheless, menstrual cycle disor- - Metrorrhagia: bleeding at irregular Yates corrected χ2, McNemar χ2 were ders with oligomenorrhea dominant intervals, particularly between the used to compare the binary characteris- were observed in 54% of SLE patients, expected menstrual period. tics. In all the statistical tests the level of mainly at the periods of SLE fl are or - : painful menstruation. signifi cance was set at p<0.05. at the disease onset (Fig. 1). There were found associations of menstrual Statistical analysis Results disorders with disease activity. Figure The data were analyzed by Statistica Menstrual function 2 shows that SLEDAI score was sig- (StatSoft - Russia, 1999). To determine The mean age of in SLE pa- nifi cantly higher in the patients with the average criteria we used M±s in nor- tients was 13.2±1.3 years (range 10-17 menstrual disorder than in the patients mal dissemination and Me (LQ-UQ) in years); in 77% of patients, menarche with normal menstrual cycle (14.0±8.9 the dissemination different from normal was between 12 and 14. versus 8.4±5.8 balls, p<0.001).

438 Ovarian function and disease activity in patients with SLE / S.S. Shabanova et al.

Table I. The mean hormone levels of and SLEDAI score.

LH (mIU/ml) FSH (mIU/ml) PRL (mIU/ml) E2 (nmol/l) Progesterone (nmol/l)

SLE patients 3.8 (2.4-5.5) 5.15 (4-7) 374 (272-563) 0.37 (0.23-0.57) 10.9 (2.34-25)* n=94

Group I (SLEDAI <11) 4.1 (3.2-6.5) 5.3 (4.0-8.9) 347 (263-486)** 0.35 (0.25-0.56) 16.2 (4.6-30.9)** n=48

Group II (SLEDAI ≥11) 3.5 (2.1-4.9) 5.0 (3.7-6.0) 450 (275-675)** 0.39 (0.23-0.57) 7.3 (1.1-18.6)** n=46

Control group 3.5 (2.8-6.5) 6.0 (5.0-7.0) 344 (227-438) 0.53 (0.30-0.70) 24.9 (12.6-60)* n=40

*Differences between SLE pts and the control group (p<0.05) **Differences between group I and group II (p<0.05) Normal levels of hormones: LH = 1.1-8.7 mIU/ml, FSH = 1.8-11.3 mIU/ml, PRL = 67-726 mIU/ml (follicular phase); E2 = 0.2-0.8 nmole/l and progesterone = 12.7-79.5 nmol/l (luteal phase).

Hormonal status score was signifi cantly higher than in tendency to decrease of E2 levels, in- The mean levels of LH, FSH, PRL and the patients with normal progesterone crease of LH, FSH and prolactin levels E2 were comparable among patients concentration (14.0±9.0 vs. 8.5±5.7 in patients without GC therapy were and controls. The progesterone levels balls, p=0.001). The SLEDAI score in noted with the same frequency as in all in SLE patients were signifi cantly low- the patients with hyperprolactinemia the investigated SLE patients. er than in controls (p<0.05) (Table I). (10%) was signifi cantly higher that in Thus, the ovarian function in SLE pa- The hormonal studies showed in 52% the patients with the normal PRL lev- tients is more correlated to the disease patients reduced progesterone, in 25% els (16.0±7.4 vs. 10.7±7.9, p<0.05). No activity, than to the GS therapy. reduced E2 levels. Increased levels of statistically signifi cant difference be- LH, FSH and PRL were observed with tween the other hormone levels and the Discussion the lower frequency (13%, 9%, 10% SLEDAI score was observed. The reported study shows the disease respectively) and only 2% of patients Therefore, the frequency of menstrual activity as a major factor associated had increased E2 concentration. The disorders in the SLE patients correlated with menstrual cycle disorders in SLE SLE duration was correlated with LH with decreased progesterone (r=0.47, patients before the treatment of alkylat- (r=0.35, t=3.58, p<0.05) and FSH lev- t=5.0, p<0.001) and E2 levels (r=0.23, ing agents and high doses of GC. els (r=0.21, t=2.1, p<0.05). t=2.2, p<0.05). It is noteworthy that patients over 45 The patients were divided into two As most of the SLE patients (84%) were years old were systematically exclud- groups according to the SLEDAI score; taking GC, it is necessary to stress the ed. Moreover, other gynecological the fi rst group with the score <11 and the infl uence of this therapy on the ovarian causes of menstrual disturbances such second group with the score ≥11, as the function. Mean daily GC doses were as previous history of oophorectomy, mean SLEDAI score was 11.4±8.1. The similar in the patients with and with- hysterectomy and recent uterine curet- average meanings of the age, disease out menstrual disturbances (12 (8-24) tage were avoided by our selection cri- duration and daily steroidal doses were versus 8 (8-12) mg/day). LH and FSH teria. Likewise, patients with hormonal compared in both groups. As shown lowering which may be due to GC ther- changes due to pregnancy or in the in Table I, we observed signifi cantly apy was not confi rmed in our study. lactation period and those consequent decreased progesterone and increased The state of ovarian function in non- to the use of oral contraceptive agents prolactin in patients with SLEDAI treated SLE patients is of great signifi - were not included. Importantly, that in score ≥11 compared with patients hav- cance, because it allows us to evaluate our study the patients’ examination was ing activity <11 balls and controls. properly the distinct role of the disease performed before giving them adequate Thus, the decrease of progesterone con- activity on menstrual cycle disorders. immunosuppressive therapy. centration was the most frequent among In our study, 9 out of 15 (60%) patients Different menstrual disorders were ob- the other disorders of hormonal profi le. without GC therapy had menstrual served in 54% of SLE women, and most We compared the activity according to disturbances. SLEDAI score correl- of them showed progesterone defi cien- SLEDAI score in patients with the nor- ated signifi cantly with the frequency cy (52%). In fact, mean progesterone mal (n=45) and the decreased progester- of menstrual disorders in non-treated level in SLE patients was signifi cantly one levels (n=49). In the patients with a SLE patients (r=0.75, t=4.1, p=0.001). lower than in the controls. Our results low level of progesterone the SLEDAI Moreover, progesterone defi ciency, are similar to the other studies con-

439 Ovarian function and disease activity in patients with SLE / S.S. Shabanova et al. cerning decreased progesterone level, our study the elevation of FSH and LH 3. DUNN AJ: Cytokine activation of the HPA which might exert an immunosuppres- concentration that is an early marker of axis. Ann N Y Acad Sci 2000; 917: 608-17. 4. STERNBERG EM: Neuroendocrine regulation sive effect in SLE patients (28-31). ovarian damage was revealed with low of autoimmune/infl ammatory disease. J En- It is well known, the feature of sexual frequency – 13 and 9%, which may be docrinol 2001; 169: 429-35. hormone metabolism in SLE having a result of the ovarian functional reserve 5. CUTOLO M, BIJLSMA JW, LAHITA RG, MASI hyperestrogenic trend. (32-35). In pa- reduction. AT, STRAUB RH, BRADLOW HL: Altered neuroendocrine immune (NEI) networks in tients with SLE the aromatic hydroxy- The prolonged use of GC therapy is rheumatology. 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HARBUZ MS, CHOVER-GONZALEZ AJ, JES- estrogens (37-39). Concerning E2, its effect on ovarian function. Pasoto et al. SOP DS: Hypothalamic-pituitary-adrenal axis levels were reported to be in increased, obtained similar results; in that study and chronic immune activation. Ann N Y Acad Sci 2002; 992: 99-106. normal, or low in SLE patients (1, 28, the use of non-high prednisone doses 9. VAN ROSSUM EF, LAMBERTS SW: Glucocor- 31). In our study, the decrease of E2 (10-20 mg/day) in SLE patients did not ticoid resistance syndrome: A diagnostic and level was dominant and only in 2% of cause signifi cant disorders of ovarian therapeutic approach. Best Pract Res Clin patients its increase was observed. An function and suppression of gonadotro- Endocrinol Metab 2006; 20: 6-26. 10. BUYON JP, WALLACE DJ: The use of ex- investigation from Munoz et al. 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