SLE

Gonadotropin Releasing Hormone AgonistsMay Minimize Cyclophosphamide Associated

Gonadotoxicity in SLE and Autoimmune Diseases

Zeev Blumenfeld, MD,* Or Mischari,* Naomi Schultz, RN,†

Nina Boulman, MD,‡ and Alexandra Balbir-Gurman, MD†

Objective: Since young women undergoing cyclophosphamide pulse therapy may suffer prema-ture ovarian failure (POF) in almost 50% of cases, we examined the ability of GnRH-a adminis-tration to minimize the gonadotoxicity associated with cyclophosphamide pulse therapy (CPT).Methods: Retrospective analysis of medical charts of 44 women (age 16-38 years) who receivedCPT for autoimmune diseases. In 33 patients a monthly depot injection of GnRH-a was startedbefore the alkylating agent. The ovarian function [spontaneous menstrual bleeding, hormonalprofile, (FSH, LH, E2, progesterone) pelvic sonography, and conceptions] was evaluated, 1 to 10years after CPT.Results: In the GnRH-a group, 30 women resumed cyclic ovarian function; 1 (a 37-year-oldpatient) developed POF (3%), and 2 were lost to follow-up. In the control (no GnRH-a) group,5 of 11 patients suffered POF (45%). The mean age in the study group was 25.6 � 5.2 yearscompared with 29.3 � 5.8 years in the control group, and the mean cumulative cyclophosph-amide dose was 9.9 g compared to 10.9 g, respectively. The difference in the long-term POFremained significant even after adjusting the groups for comparable age and cumulative cyclo-phosphamide doses.Conclusion: GnRH-a decreases cyclophosphamide-associated gonadotoxicity and POF in youngwomen with systemic lupus erythematosus and other autoimmune diseases. Therefore this treat-ment should be considered and recommended to every young woman before gonadotoxicchemotherapy.© 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:346-352Keywords: connective tissue disease, systemic lupus erythematosus, systemic sclerosis, GnRH-a, gonado-

toxicity, premature ovarian failure

Life-threatening complications are not infrequentamong patients with connective tissue diseases(CTD), such as systemic lupus erythematosus

(SLE), systemic sclerosis (SSc), mixed connective tissuedisease (MCTD), and systemic vasculitis. These autoim-mune diseases are characterized by a broad spectrum of

*Reproductive Endocrinology, Rambam Health Care Campus, Rappaport Faculty ofMedicine, Technion–Israel Institute of Technology, Haifa, Israel.†The B. Shine Rheumatology Unit, Rambam Health Care Campus, Rappaport Facultyof Medicine, Technion–Israel Institute of Technology, Haifa, Israel.‡Department of Rheumatology, Bnay-Zion Med Center, Haifa, Israel.

Address reprint requests to Zeev Blumenfeld, MD, Reproductive Endocrinologyand Infertility, Department of Obstetrics and Gynecology, Rappaport Research Insti-

tute, Technion–Faculty of Medicine, Rambam Health Care Campus, Haifa, 31096,Israel. E-mail: bzeev@techunix.technion.ac.il.

346 0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserveddoi:10.1016/j.semarthrit.2011.05.008

clinical and immunological manifestations involving thevascular walls, kidneys, lungs, joints, serous surfaces, andother organs (1-5). The significantly higher prevalence ofthese disorders (for example, SLE) in women, with a fe-male-to-male ratio of 9:1, and its peak onset during child-bearing ages, accentuates the reproductive consequences(3-5). Furthermore, since the life expectancy of these pa-tients has improved from 50% 5-year survival, 60 yearsago, to over 80% 15-year survival rate at present, andsince it is prevalent in young women, the reproductiveaspects gained recent ubiquitous interest (3,6-10).

Cyclophosphamide is an effective therapy in severe life-threatening rheumatic conditions. Repeated pulsatile cy-clophosphamide courses (CPT) are standard treatment

regimens in lupus nephritis (11,12), severe MCTD (13),

.

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Z. Blumenfeld et al. 347

SSc lung involvement (14), and vasculitic syndromes(Wegener’s granulomatosis, polyarteritis nodosa [PAN])(15-17).

However, whereas CPT may improve survival and re-duce end-organ damage in CTD patients, it may bringabout an unacceptable high incidence of premature ovar-ian failure (POF) (6-10,18,19).

GnRH-a may possibly provide ovarian protectionagainst the gonadotoxic effect of chemotherapy either byovarian suppression and/or by decreasing ovarian perfu-sion as it simulates a reversible prepubertal hypoestro-genic hormonal milieu, or by possible other mechanisms(6-10,18-20). We have preliminarily reported, 10 yearsago, 5 cases of POF of 8 SLE patients in the control group,while none of the 8 patients treated with GnRH-a suf-fered POF (6). Similarly, in another study, Somers andcoworkers (7) described 1 woman among 20 SLE femalepatients in the GnRH-a group who developed POF com-pared with 6/20 (30%) among the controls (P � 0.05).

Since none of the published studies was prospectivelyrandomized, it is still questioned whether young femalepatients with SLE undergoing CPT may benefit from theconcomitant addition of GnRH-a by minimizing the rateof POF (10,18).

We have therefore retrospectively evaluated themedical reports of a group of premenopausal womenwho have been treated with GnRH-a in parallel to CPTin the last 12 years and compared them to a controlgroup of CTD patients who did not receive the parallelGnRH-a treatment.

PATIENTS AND METHODS

Between February 1989 and January 2009, 44 femalepatients were treated with CPT in the rheumatology de-partments of Rambam Health Care Campus and BnayZion medical center (Haifa, Israel) for severe CTD. Di-agnosis of CTD was classified according to the AmericanCollege of Rheumatology classification (20-25) and cor-responded to SLE, SSc, MCTD, vasculitis, and otherCTD (Table 1).

Females with severe SLE manifestations World HealthOrganization class III or IV proliferative nephritis, cere-britis, or vasculitis were treated in addition to high dosesof corticosteroids with monthly CPT according to stan-dard regimen (10,24). Following 6 monthly treatments,patients who achieved satisfactory disease control wereswitched from monthly IV cyclophosphamide to addi-tional 8 CPT every 3 months. In the cases of SLE relapseor unsatisfactory disease control, patients were treatedwith an additional 4 monthly boluses of cyclophosph-amide. Completion of CPT was followed by azathioprine;most patients were on low corticosteroids doses and hy-droxychloroquine treatment at that time. Treatment ofSLE-cerebritis or -vasculitis or severe uncontrolledMCTD or systemic vasculitis (Wegener’s disease, PAN)

included CPT and different high doses of corticosteroids g

in a similar way (25,26). Patients with active SSc-relatedinterstitial lung disease were treated with low doses ofcorticosteroids (less than 15 mg/d) and 6 monthly CPT.Patients who achieved stabilization of lung function testswithout additional areas of lung involvement wereswitched to azathioprine; those who still had signs of ac-tive interstitial lung disease received an additional 3 to 6monthly CPT. Treatment of systemic vasculitis patients(Anti Neutrophilic Cytoplasmic Antibody [ANCA]-asso-ciated and non-ANCA associated) consisted of high dosesof steroids and 6 monthly CPT, during follow up patientswith signs of clinical remission were able to change thetherapy to azathioprine or methotrexate and also reducecorticosteroids doses. Relapses were re-treated with anadditional 3 to 6 monthly CPT (26). Patients whoreached a cumulative cyclophosphamide dose above 16 Gwere not allowed to continue this treatment and in a caseof uncontrolled disease were treated with other therapeu-tic options (high doses of intravenous �-globulins, biolog-ical agents, or other regimen).

Among patients treated with CPT, 33 patients(73.3%) also received concomitantly a monthly injectionof depot, controlled release GnRH-a (Decapeptyl CR,3.75 mg; Ferring, Switzerland), releasing 0.1 mg/d,started before the alkylating agent, and continued duringthe CPT treatment, up to 6 monthly injections. The pro-tocol was approved by the institutional ethical committee.Each patient referred to the reproductive endocrinologyoutpatient clinic of the Rambam Health Care Campuswas offered the option of fertility preservation, includingcryopreservation of embrya, ova, or ovarian tissue beforestaring the gonadotoxic chemotherapy, and GnRH-ago-nists in parallel to cyclophosphamide pulses. Those whodid not receive the GnRH-a were either not interested orreferred to us after the gonadotoxic chemotherapy treat-ment (6,19).

The ovarian function was evaluated, 1 to 10 years afterthe end of treatment by the existence of monthly sponta-neous menstrual bleeding, hormonal profile (FSH, LH,E2, progesterone), ultrasound of the ovaries and endome-rium, and conceptions.

tatistical Analysis

ata are presented as means (SD) for continuous vari-bles and percentages for qualitative variables. The Mann-

hitney test was used to compare continuous variables. Avalue of 0.05 or less was considered significant.

ESULTS

edical data were available in 42 patients; 2 patients leftsrael. Therefore, follow-up data on these 2 patients werencomplete. Treatment of 30 of the 31 evaluable women’secords in the GnRH-a group resumed in preserved cyclicvarian function (COF), and in 1, a 37-year-old patient,esulted in POF (3%). In the control (no GnRH-a)

roup, 5 of 11 patients developed POF (45%). The mean

348 GnRH-a in CTD

Table 1 Characteristics of Patients Treated with Chemotherapy for Connective Tissue Diseases, with or without GnRH-a

Serial Number Age Diagnosis Ethnicity Prednisone MTP CYC

GnRHa�1 21 SLE AR 10 1 142 27 MCTD AR 7.5 1 83 30 SLE AR 10 1 104 26 SLE AJ 10 35 23 SLE AR 10 126 29 SLE AJ 10 1 3.57 26 SLE AR 10 1 128 16 SLE AJ 10 129 32 SLE AR 10 1 1210 30 SLE AJ 10 911 17 SLE SJ 10 1 7.512 25 SLE,APLA AR 10 1 1213 26 SLE,SSC AR 10 1 914 33 SLE SJ 15 1 1115 22 SLE AR 15 1 1216 30 MCTD AR 20 1217 25 NS AR 10 718 21 SLE AR 10 1219 18 SLE AJ 5 620 25 SLE AR 2.5 621 18 SLE AR 10 1 1222 27 SLE AR 0 1 1223 38 SSC SJ 12.5 624 23 SLE AR 15 14.425 23 SLE AJ 10 1226 31 SSC AJ27 28 SLE AJ 5 1428 37 SSC AJ 0 1229 26 SLE AR 10 1 3.7530 21 PAN AR 20 1 12.531 24 SLE SJ 10 1032 26 SLE SJ 10 1233 22 SLE AR 10 1 9

Mean 25.6 AR 19 Mean 9.92 16High 38 AJ 9 High 20Low 16 SJ 5 Low 0SD 5.25 SD 4.37

Serial Number Age Diagnosis Ethnicity Prednisone [gr] MTP CYC

GnRHa�34 31 BD AR 10 635 23 SLE AR 10 1 1036 33 SLE AR 15 1 837 22 SLE AJ 10 1 1038 33 SLE AJ 10 1 1239 32 SLE AJ 10 1 340 25 SLE AJ 10 1 941 36 SSC AR 10 842 39 SLE�APLA AR 5 1 1443 23 SLE SJ 15 1 2544 26 JRA AJ 15 9

Mean 29.36 No GnRH-a [n � 11] Mean 10.9 8High 39 AR- 5 High 15Low 23 AJ- 5 Low 5

SD 5.82 SJ- 1 SD 3.0

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Z. Blumenfeld et al. 349

age in the study group was 25.6 � 5.25 years (median 26ears, range 16 to 38 years), versus 30.1 � 5.5 years (me-ian 31.5, range 23 to 39) in the control group (P �.04), and the mean cumulative cyclophosphamide was.92 g versus 10.52 g, respectively. Overall, the mean agef 5 patients who suffered POF was 32.2 � 7.2 yearsompared with 26.35 � 4.75 years of those who returnedo cyclic ovarian function (COF) (P � 0.08) (Table 1).

Since both the age and dose differences may possiblyffect the rate of POF, we adjusted the groups for bothhese parameters. Therefore, to minimize the age differ-nce, we did a second comparison, comparing only theatients up to the age of 31. Thus, the mean age in bothroups was 25.6 (range 17 to 31) years. The POF rate inhe control group remained 40%, significantly higherhan in the treatment group (P � 0.05). Thus, the differ-nce in the long-term POF remained significant even afterdjusting the groups for comparable age.

The COF patients received lower cumulative doses ofyclophosphamide (8.73 � 3.4G; range 3-14.4), whereashose who suffered POF received a higher cumulativeose (13.75 � 6.8 g; range 8-25) (P � 0.08) (Table 1).owever, the mean cumulative dose of cyclophosph-

mide was 9.9 � 2.9 g in the treatment group (range 3 to5 g) versus 10.4 g in the controls. Therefore, we adjustedhe groups for a new comparison, including only the patientsho received up to 15 g cumulative dose of cyclophosph-

mide. The mean cumulative dose in the GnRH-a groupas 8.92 G versus 8.72 g in the control group. Even after

djusting the cumulative doses of cyclophosphamide be-ween the groups, the POF remained different, 4.35%, inhe GnRH-a group versus 37.5% in the controls (P � 0.05).

Thus, the difference in the long-term POF remainedignificant even after adjusting the groups for comparablege and cumulative cyclophosphamide. Patients in bothreated subgroups experienced adverse events related toyclophosphamide treatment: nausea, vomiting, fatigue,nd leucopenia. Neither serious adverse events (severe cy-openia, sepsis, or dyspnea) nor mortality were seen dur-ng cyclophosphamide therapy. The only additional ad-

Table 1 Continued

Total

NumberPatients

Age (yr)

Mean (SD)

Total 44 26.6 (5.6) 1Received GnRH 33 25.6 (5.3) 1No GnRH 11 29.4 (5.8) 2

GnRH, gonadotropin releasing hormone agonist; SD, standard demethylprednisolone (1 G pulses, 3 consequent days); SLE, systemjuvenile inflammatory arthritis; PAN, polyarteritis nodosa.

erse event in the GnRH-a group was hot flashes in a o

inority of the patients; all were mild and did not de-and additional therapy.Eight pregnancies and 7 deliveries took place in the

reatment group, generating 7 healthy neonates (1 mis-arriage of a twin gestation) versus 3 pregnancies in theontrols.

ISCUSSION

e are aware of the limitations and inferiority of a non-andomized study, as compared with a prospective ran-omized controlled (RCT) trial. Indeed Manger and co-orkers (8) started such a RCT (the PREGO study) a fewears ago, and we are all looking forward to its results.ach patient referred to the reproductive endocrinologyutpatient clinic of the Rambam Health Care Campusas offered the option of fertility preservation, including

ryopreservation of embrya, ova, or ovarian tissue beforetaring the gonadotoxic chemotherapy, and GnRH-ago-ists in parallel to cyclophosphamide pulses. Those whoid not receive the GnRH-a were either not interested oreferred to us after the gonadotoxic chemotherapy treat-ent was given at another hospital (6,19,27).Recently, 3 prospective RCTs have found a statistically

ignificant advantage of the GnRH-a co-treatment in pre-erving ovarian function in patients with malignant breastumors and aggressive chemotherapy (28-30). The first ofhese 3 peer-reviewed, RCTs (28) has found 11.4% POFn the GnRH-a group versus 66% POF in controls (P �.001). Similarly, the second RCT (29) has concludedhat: “Among women treated with goserelin, there was atatistically significant increase in the proportion of men-truating women,” and the “. . .protective effect of gosere-in on ovarian function in Cyclophosphamide, Metho-rexate, and Fluorouracil (CMF) treated women.” Thehird (30), the largest, and the most recent and convincingulticenter prospective RCT started in 2003 and ended

n 2008, was a multicenter, open-label, randomized,hase III trial of 281 breast cancer patients (median age9) treated with chemotherapy alone or chemotherapynd GnRH-a. One year after chemotherapy, POF was

ary

Ethnicity

axian) Arab (%)

AshkenaziJew (%)

SephardicJew (%)

26) 24 (54.5) 14 (31.8) 6 (13.7)26) 19 (57.6) 9 (27.3) 5 (15.1)31.5) 5 (45.5) 5 (45.5) 1 (9)

; Min, minimal dose; Max, maximal dose; PR, prednisone; MTP,s erythematosus; SSc, systemic sclerosis; BD, Behcet disease; JIA,

summ

Min-M(Med

6-39 (6-38 (3-39 (

viationic lupu

bserved in 32.3% in the chemotherapy alone arm versus

350 GnRH-a in CTD

13.5% in the chemotherapy and GnRH-a arm (P �0.0002), with a 19% absolute reduction (95% CI �8-29). Cyclic menstrual function and premenopausal E2levels resumed in 58% of the patients in the chemother-apy alone arm versus 77% in the chemotherapy andGnRH-a arm (P � 0.006) (30). Logistic regression anal-ysis showed that GnRH-a was independently associatedwith a higher probability of COF preservation (P �0.001), concluding that temporary ovarian suppressionwith GnRH-a during gonadotoxic chemotherapy is asso-ciated with a significant increase in preserving cyclic ovar-ian function (30).

A recent meta-analysis (31) of the published Englishliterature on this controversial issue has found a signifi-cant beneficial role for the agonists on both preservationof ovarian function and conception during chemotherapyfor malignant conditions, concluding: “The use of aGnRHa during chemotherapy was associated with a 68%increase in the rate of preserved ovarian function com-pared with women not receiving a GnRHa” (RR � 1.68,95% CI � 1.34-2.1). Among the GnRHa-treatedwomen, 22% achieved pregnancy following treatmentcompared with 14% of women without GnRHa therapy(RR � 1.65, CI � 1.03-2.6) (31). This meta-analysis(31) also concluded that women facing chemotherapyshould be counseled about ovarian preservation options,including the use of GnRHa therapy.

Table 1 Continued

Total

Diagnosis CY

SLE SScOther (BD, JIA,

PAN)Mean(SD)

33 (75.0) 7 (15.9) 4 (9.1) 9.8 (4.2)25 (75.6) 6 (18.3) 2 (6.1) 9.9 (2.9)

8 (72.7) 1 (9.1) 2 (18.2) 10.4 (6.3)

Table 2 Premature Ovarian Failure in All the Published StuCyclophosphamide Pulses with or without Concomitant G

AuthorsAge, yr

(mean � SD)

Somers et al, US 2005 24 � 4 SLELiang et al, China 2008 35.3 � 2.4 [30-39] SLEManger et al, Germany

200630-40 SLE

Blumenfeld et al, Israel 2011 17-39 SLE, RTotal 17-40 CTD

GnRH-a, gonadotropin releasing hormone agonist; SD, standard defailure; SLE, systemic lupus erythematosus; SS, systemic sclerosis;

CTD; NM, not mentioned.

Another (32) meta-analysis concluded that GnRH-asare effective in reducing amenorrhea rates in all patients(RR � 0.26, 95% CI � 0.14-0.49), and that pregnancyrate was higher in the GnRH-a arm.

The third meta-analysis (33) also concluded thatGnRH-a co-treatment during chemotherapy can protectovarian function and decrease gonadotoxicity. The re-cently published fourth meta-analysis of RCTs (34) sim-ilarly concluded that the incidence of POF or resumptionof ovulation both demonstrated a statistically significantdifference in favor of the GnRH co-treatment.

Similarly, 2 recent human reproductive update reviewshave summarized all the published studies on this debate(27,35). Both these reviews have found a 9% to 11% rateof POF in the young women receiving aggressive chemo-therapy for malignancy and treated with concomitantGnRH-a versus 55% to 59% in controls (27,35). All thesepublications concluded that using GnRH-a concomi-tantly with chemotherapy is associated with a higher rateof ovarian function preservation (6,7,27-35). A recentAmerican Society of Clinical Oncology educational pub-lication (36) similarly found the rates of POF to be 0% to6% with GnRH-a versus 32% to 47% without it. How-ever, some investigators are still unconvinced regardingthe effectiveness of this treatment (10,35).

Cyclophosphamide gonadotoxicity in CTD patients isa well-recognized drawback; the rate of POF may develop

ary

e (G) Corticosteroids Dose (mg)

Min-Max(Median) MTP (%)

PR

Mean(SD)

Min-Max(Median)

6-25 (10.5) 24 (54.5) 10.1 (4.3) 0-20 (10)7-14.4 (10) 16 (48.5) 9.7 (4.7) 0-20 (10)

3-25 (9) 8 (72.7) 10.9 (3.0) 5-15 (10)

f Patients with Autoimmune Diseases Treated with(Combined Studies on GnRH-a in SLE/CTD)

aseCumulativeCTX Dose

GnRH-a �POF GnRH-a� POF

13 � 7 g 1/20 (5%) 6/20 (30%)NM 3/28 (11%) —NM — 60%

MCTD, GN 9.5 � 4.4 g 1/31 (3.3%) 5/11 (45%)8-20 g 5/79 (6.3%) 11/31 (35.5%)

; Min, minimal dose; Max, maximal dose; POF, premature ovarianlomerulonephritis; CTD, connective tissue disease; MCTD, mixed

summ

C dos

3.

dies onRH-a

Dise

A, SS,

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ymGade(2(inb(mGG(

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

Z. Blumenfeld et al. 351

in one half of treated patients (6-10). Similarly, Liang andcoworkers (9) treated 28 SLE women, aged 35.3 � 2.4ears (range, 30-39 years), with cyclophosphamide, 200g IV, every other day for 4 months and monthlynRH-a, 3.75 mg from the beginning of CTX. Menstru-

tion recovered in 25/28 of their patients. One patienteveloped amenorrhea after 2 normal menses. Three oth-rs were persistently amenorrheic 6 months after GnRH-a9). Estradiol levels increased after the last GnRH-a in4 patients, to normal baseline level within 6 months9). They (9) concluded that GnRH-a treatment dur-ng cyclophosphamide therapy is associated with a sig-ificant reduction of POF in most SLE women. Com-ining the rates of POF from the 4 published studies6-9), in SLE patients receiving cyclophosphamide (cu-ulative dose ranging from 8 to 20 g) with or withoutnRH-a, results in a POF rate of 6.3% (5/79) in thenRH-a � group versus 35.5% (11/31) in the controls

no GnRH-a) (Table 2).In addition, GnRH-a administration can effectively

prevent the chemotherapy-associated menorrhagia andanemia in those patients who experience thrombocyto-penia (37).

We conclude, therefore, that GnRH-a decreases cyclo-phosphamide-associated gonadotoxicity and POF inyoung women with SLE and other autoimmune diseaseswho are receiving alkylating agents. If the published re-sults of the prospective randomized PREGO study (8) aresimilar, this treatment should be recommended to everyyoung woman with SLE or other CTD, before CPT oranother alkylating agent.

REFERENCES

1. American College of Rheumatology Ad Hoc Committee on Sys-temic Lupus Erythematosus Guidelines. Guidelines for referraland management of systemic lupus erythematosus in adults. Ar-thritis Rheum 1999;42:1785-96.

2. Madhok R, Wu O. Systemic lupus erythematosus. Am PhamPhysician 2007;76:1351-3.

3. Bellver J, Pellicer A. Ovarian stimulation for ovulation inductionand in vitro fertilization in patients with systemic lupus erythem-atosus and antiphospholipid syndrome. Fertil Steril 2009;92:1803-10.

4. Mackillop LH, Germain SJ, Nelson-Piercy C. Systemic lupuserythematosus. BMJ 2007;335:933-6.

5. Rahman A, Isenberg DA. Systemic lupus erythematosus. N EnglJ Med 2008;358:929-39.

6. Blumenfeld Z, Shapiro D, Shteinberg M, Avivi I, Nahir M. Pres-ervation of fertility and ovarian function and minimizing gonado-toxicity in young women with systemic lupus erythematosustreated by chemotherapy. Lupus 2000;9:401-5.

7. Somers EC, Marder W, Christman GM, Ognenovski V, McCuneWJ. Use of a gonadotropin-releasing hormone analog for protec-tion against premature ovarian failure during cyclophosphamidetherapy in women with severe lupus. Arthritis Rheum 2005;52:2761-7.

8. Manger K, Wildt L, Kalden JR, Manger B. Prevention of gonadaltoxicity and preservation of gonadal function and fertility inyoung women with systemic lupus erythematosus treated by cy-clophosphamide: the PREGO-Study. Autoimmun Rev 2006;5:

269-72.

9. Liang LQ, Qiu Q, Yang XY, Xu HS, Ye YJ, Zhan ZP, et al. Roleof gonadotropin releasing hormone analogues for ovarian protec-tion in systemic lupus erythematosus patients treated with cyclo-phosphamide [in Chinese]. Zhonghua Yi Xue Za Zhi 2008;88:1009-11.

0. Mersereau J, Dooley MA. Gonadal failure with cyclophosph-amide therapy for lupus nephritis: advances in fertility preserva-tion. Rheum Dis Clin North Am 2010;36:99-108.

1. Grootscholten C, Ligtenberg G, Hagen EC, van den Wall BakeAW, de Glas-Vos JW, Bijl M, et al. Azathioprine/methylpred-nisolone versus cyclophosphamide in proliferative lupus nephritis.A randomized controlled trial. Kidney Int 2006;70:732-42.

2. Grootscholten C, Bajema IM, Florquin S, Steenbergen EJ, Peutz-Kootstra CJ, Goldschmeding R, et al. Treatment with cyclophos-phamide delays the progression of chronic lesions more effectivelythan does treatment with azathioprine plus methylprednisolonein patients with proliferative lupus nephritis. Arthritis Rheum2007;56:924-37.

3. Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immu-nosuppressive therapy in connective tissue diseases-associated pul-monary arterial hypertension. Chest 2006;130:182-9.

4. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS,et al. A multicenter, prospective, randomized, double blind, pla-cebo-controlled trial of corticosteroids and intravenous cyclo-phosphamide followed by oral azathioprine for the treatment ofpulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54:3962-70.

5. Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I,et al. A prospective, multicenter, randomized trial comparing ste-roids and pulse cyclophosphamide versus steroids and oral cyclo-phosphamide in the treatment of generalized Wegener’s granulo-matosis. Arthritis Rheum 1997;40:2187-98.

6. Jayne D. Review article: Progress of treatment in ANCA-associ-ated vasculitis. Nephrology 2009;14:42-48.

7. de Groot K, Adu D, Savage CO. The value of pulse cyclophosph-amide in ANCA-associated vasculitis: Meta-analysis and criticalreview. Nephrol Dial Transplant 2001;16:2018-27.

8. Sinha R, Dionne JM. Should gonadotropin releasing hormoneanalogue be administered to prevent premature ovarian failure inyoung women with systemic lupus erythematosus on cyclophos-phamide therapy? Arch Dis Child 2008;93:444-5.

9. Blumenfeld Z. Gynaecologic concerns for young women exposedto gonadotoxic chemotherapy. Curr Opin Obstet Gynecol 2003;15:359-70.

0. Hochberg MC. Updating the American College of Rheumatologyrevised criteria for the classification of systemic lupus erythemato-sus [letter]. Arthritis Rheum 1997;40:1725.

1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Meds-ger TA Jr, et al. Scleroderma (systemic sclerosis): classification,subsets and pathogenesis. J Rheumatol 1988;15:202-5.

2. Alarcon-Segovia D, Cardiel MH. Comparison between 3 diag-nostic criteria for mixed connective tissue disease: study of 593patients. J Rheumatol 1989;16:328-334.

3. Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, KoldingsnesW, et al. Development and validation of a consensus methodologyfor the classification of the ANCA-associated vasculitides and pol-yarteritis nodosa for epidemiological studies. Ann Rheum Dis2007;66(2):222-7.

4. McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox D.Clinical and immunologic effects of monthly intravenous cyclo-phosphamide in severe systemic lupus. N Engl J Med 1988;318:1423-31.

5. Trevisani VFM, Castro AA, Ferreira Neves Neto JJFNN, AtallahÁN. Cyclophosphamide versus methylprednisolone for treatingneuropsychiatric involvement in systemic lupus erythematosus.Cochrane Database of Systematic Reviews 2006(2): CD002265.

6. Yazici Y. Systemic vasculitis treatment and monitoring update,

2008. Bull NYU Hosp Jt Dis 2008;66:228-30.

3

3

3

3

3

352 GnRH-a in CTD

27. Blumenfeld Z, von Wolff M. GnRH-analogues and oral contra-ceptives for fertility preservation in women during chemotherapy.Hum Reprod Update 2008;14:543-552 [review].

28. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-in-duced ovarian damage: prospective randomized study. Fertil Steril2009;91:694-7.

29. Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvantgoserelin and ovarian preservation in chemotherapy treated pa-tients with early breast cancer: results from a randomized trial.Breast Cancer Res Treat 2009;117:561-7.

30. Del Mastro L, Boni L, Michelotti A, Gamucci T, Olmeo N,Giordano M, et al. Role of luteinizing hormone-releasing hor-mone analog (LH-RHa) triptorelin in preserving ovarian functionduring chemotherapy for early breast cancer patients: results of amulticenter phase III trial of Gruppo Italiano Mammella (GIM)group. J Clin Oncol 2010;28(suppl):15s [abstract 528].

31. Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ,Leppert PC, et al. Ovarian preservation by GnRH agonists duringchemotherapy: A meta-analysis. J Womens’ Health (Larchmt)2009;18:311-39.

32. Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Phar-

macological interventions for fertility preservation during chemo-

therapy: a systematic review and meta-analysis. Breast Cancer ResTreat 2010;122:803-11.

3. Kim SS, Lee JR, Jee BC, Suh CS, Kim SH, Ting A, et al. Use ofhormonal protection for chemotherapy-induced gonadotoxicity.Clin Obstet Gynecol 2010;53:740-52.

4. Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D,El-Nashar SA, et al. Gonadotropin-releasing hormone analog co-treatment for preservation of ovarian function during gonado-toxic chemotherapy: a systematic review and meta-analysis. FertilSteril 2011;95:906-14.

5. Beck-Fruchter R, Weiss A, Shalev E. GnRH agonist therapy asovarian protectants in female patients undergoing chemotherapy:A review of the clinical data. Hum Reprod Update 2008;14:553-61.

6. Moore HC. Ovarian failure after chemotherapy for breast cancerand the role of gonadotropin-releasing hormone analogs in pro-tection of ovarian function. ASCO, Alexandria (VA): AmericanSociety of Clinical Oncology Educational Book; 2008; pp. 39-42.

7. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben-YehudaD. Prevention of severe menorrhagia in oncology patients withtreatment-induced thrombocytopenia by luteinizing hormone-re-leasing hormone agonist and depo-medroxyprogesterone acetate.

Cancer 2006;107:1634-41.