Clomiphene, Metformin, Or Both for Infertility in the Polycystic Ovary Syndrome

8/12/2019 Clomiphene, Metformin, Or Both for Infertility in the Polycystic Ovary Syndrome

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n engl j med 356;6 www.nejm.org february 8, 2007 551

Thenew englandjournalofmedicineestablished in 1812 february 8, 2007 vol. 356 no. 6

Clomiphene, Metformin, or Both for Infertilityin the Polycystic Ovary Syndrome

Richard S. Legro, M.D., Huiman X. Barnhart, Ph.D., William D. Schlaff, M.D., Bruce R. Carr, M.D.,Michael P. Diamond, M.D., Sandra A. Carson, M.D., Michael P. Steinkampf, M.D., Christos Coutifaris, M.D., Ph.D.,

Peter G. McGovern, M.D., Nicholas A. Cataldo, M.D., Gabriella G. Gosman, M.D., John E. Nestler, M.D.,Linda C. Giudice, M.D., Ph.D., Phyllis C. Leppert, M.D., Ph.D., and Evan R. Myers, M.D., M.P.H.,

for the Cooperative Multicenter Reproductive Medicine Network*

A b s t ra c t

From Pennsylvania State University Col-lege of Medicine, Hershey (R.S.L.); DukeUniversity Medical Center, Durham, NC(H.X.B., E.R.M.); University of Colorado,Denver (W.D.S.); University of Texas South-western Medical Center, Dallas (B.R.C.);Wayne State University, Detroit (M.P.D.);Baylor College of Medicine, Houston(S.A.C.); University of Alabama, Birming-ham (M.P.S.); University of PennsylvaniaSchool of Medicine, Philadelphia (C.C.);

University of Medicine and Dentistry ofNew Jersey, Newark (P.G.M.); StanfordUniversity, Stanford, CA (N.A.C.); Univer-sity of Pittsburgh, Pittsburgh (G.G.G.);Virginia Commonwealth University Schoolof Medicine, Richmond (J.E.N.); Univer-sity of California at San Francisco, SanFrancisco (L.C.G.); and the National In-stitute of Child Health and Human De-velopment, Bethesda, MD (P.C.L.). Ad-dress reprint requests to Dr. Legro at theDepartment of Obstetrics and Gynecolo-gy, Pennsylvania State University Collegeof Medicine, M.S. Hershey Medical Cen-ter, 500 University Dr., H103, Hershey,

PA 17033, or at [email protected].

*Other members of the Cooperative Mul-ticenter Reproductive Medicine Networkare listed in the Appendix.

N Engl J Med 2007;356:551-66.Copyright 2007 Massachusetts Medical Society.

Background

The polycystic ovary syndrome is a common cause of infertility. Clomiphene andinsulin sensitizers are used alone and in combination to induce ovulation, but it isunknown whether one approach is superior.

Methods

We randomly assigned 626 infertile women with the polycystic ovary syndrome toreceive clomiphene citrate plus placebo, extended-release metformin plus placebo,or a combination of metformin and clomiphene for up to 6 months. Medication was

discontinued when pregnancy was confirmed, and subjects were followed untildelivery.

Results

The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2%(15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P


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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 356;6 www.nejm.org february 8, 2007552

The polycystic ovary syndrome af-

fects7 to 8% of women1and may be themost common cause of female infertility.2

Anovulation,2 early pregnancy loss,3 and laterpregnancy complications4have all been implicat-ed in the low fecundity of women with this dis-order. Obesity is also common in such women,5

and this condition alone appears to have an ad-verse effect on reproduction.6,7The cause of thepolycystic ovary syndrome is poorly understood,and both the diagnosis and treatment of the dis-order are controversial.5,8,9

Women with this syndrome have hyperandro-genism,10morphologic changes in the ovary (poly-cystic),10inappropriate gonadotropin secretion (ele-vated levels of circulating luteinizing hormone),11and insulin resistance with accompanying com-pensatory hyperinsulinemia.12 Targeting thesemetabolic abnormalities has been noted to im-

prove ovulation and fertility in women with thissyndrome.13-17Results from small head-to-headtrials have suggested that the efficacy of treat-ment with insulin sensitizers such as metformin(alone or in combination with clomiphene citrate)is equal or superior to that of clomiphene alonefor infertility.13,16,17

We designed a trial to test the hypothesis thattreatment of women with the polycystic ovarysyndrome with extended-release metformin ismore likely to result in a live birth than is treat-ment with clomiphene citrate and that the com-bination of the two therapies will result in thehighest live-birth rate.

Methods

Study Design

We have previously described the rationale forchoosing live birth as the primary outcome,18thepower analysis and main statistical methods,19the use of infert ility screening in the study,20andthe study design and baseline characteristics of the

subjects.21

The institutional review board at each centerapproved the protocol, and all subjects gave writ-ten informed consent. All subjects had receivedthe diagnosis of the polycystic ovary syndrome,which was defined as oligomenorrhea (with a his-tory of no more than eight spontaneous mensesper year) and hyperandrogenemia (with an elevat-ed testosterone level documented within the pre-vious year in an outpatient setting on the basis

of local laboratory results, with a predeterminedcutoff level set by the principal investigator at eachstudy site). Subjects were excluded if they had hy-perprolactinemia, congenital adrenal hyperplasia,thyroid disease, or other causes of amenorrhea,including premature ovarian failure. Clinicallysuspected Cushings syndrome and androgen-

secreting neoplasm were additional exclusioncriteria.21

We randomly assigned 626 infertile womenwith the polycystic ovary syndrome to one ofthree study groups by means of an interactivevoice system. The assignments were stratified ac-cording to the study site and the presence orabsence of previous exposure to either of thestudy drugs.21Subjects with other causes of in-fertility were excluded on the basis of documen-tation of a normal uterine cavity and at least onepatent fallopian tube; analysis of the semen of

each womans current partner was performedwithin 1 year before participation in the study,and a sperm concentration of at least 20 millionper milliliter was required.21All subjects were ingood health with no major medical disorders.21

Study Drugs

We used extended-release metformin because ofits increased tolerability and proven efficacy inthe treatment of type 2 diabetes.22,23Extended-release metformin (Glucophage XR) plus identicalplacebo were provided by Bristol-Myers Squibb.Overencapsulated clomiphene citrate tablets (pur-chased from Teva Pharmaceuticals) and matchingplacebo capsules were packaged and tested by acommercial pharmacy supply company (CTS) spe-cifically for the study. Neither manufacturer hadany other role in the study.

Baseline laboratory testing was performed af-ter the subjects had fasted overnight. All speci-mens were analyzed in a core laboratory.21 Insubjects without recent menses, withdrawal bleed-ing was induced with a course of oral medroxypro-

gesterone acetate before the initiation of studymedication. Each subject received a monthly med-ication package consisting of bottle M (metfor-min in 500-mg tablets or matching placebo) andblister pack C (clomiphene in 50-mg tablets ormatching placebo). The two drugs were begunconcurrently. Subjects gradually increased thedose of the study drug in bottle M until reachingthe maximum dose of four tablets (two tabletstwice a day). Subjects took one tablet a day from

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Clomiphene versus Metformin in the Polycystic Ovary S yndrome


blister pack C for 5 days, beginning on day 3 ofmenses; this dose was maintained if adequateovulation was documented. However, in subjectswho had no response or a poor response, the dosewas increased by one tablet a day on a treatment-cycle basis (either after 5 weeks of anovulationor after a menses until the maximum dose of

three tablets per day was reached).After the baseline visit, subjects returned each

month for a visit with a limited physical examina-tion, urine pregnancy test, and repeated fastingblood tests.21Subjects were instructed to have reg-ular intercourse every 2 to 3 days and to keep adiary recording intercourse, vaginal bleeding, andsymptoms. The progesterone levels in all subjectswere measured weekly or every other week in lo-cal laboratories in order to document ovulation.21If two consecutive measurements showed elevatedlevels of progesterone (above 5 ng per milliliter

[16 nmol per liter]), a weekly pregnancy test wasadministered until a positive result or mensesoccurred. Induction of withdrawal bleeding withprogestin was scheduled at the discretion of theprincipal investigator at each site. Ultrasonogra-phy for follicular and endometrial response wasnot included in the protocol, and ovulation trig-gering with human chorionic gonadotropin andintrauterine insemination were not permitted.

Subjects were treated for up to six cycles, or 30weeks. All study medication was discontinued ifa pregnancy test was positive. Pregnant subjectswere followed until ultrasonography documentedfetal viability and were then referred for prenatalcare. Investigators reviewed all obstetrical recordsto obtain data on birth outcomes. We did notcollect data on the use of other medications dur-ing pregnancy.

Outcomes

The primary outcome of the trial was the rate oflive births. Secondary outcomes included the rateof pregnancy loss, singleton birth, and ovulation

(a serum progesterone level above 5 ng per milli-liter during a cycle). A serious adverse event wasdefined as any event that was fatal, immediatelylife-threatening, or severely or permanently dis-abling; an event that required or prolonged hos-pitalization; an overdose (intentional or acciden-tal); a congenital anomaly; pregnancy loss after12 weeks of gestation; or an event that wasdeemed to be serious by the principal investigatorat each site.

Data Management

All data entry, data management, and analyseswere performed at the Data Coordinating Centerat the Duke Clinical Research Institute. Subjectswere enrolled in the study from November 2002to December 2004. The last conception was inJune 2005, the last subject finished medicat ion

in August 2005, and the last birth was reportedin February 2006. Data were analyzed according tothe intention-to-treat principle.

Statistical Analysis

We assumed a dropout rate of 15% and the follow-ing rates of live birth: 45% in the combination-therapy group, 30% in the metformin group, and25% in the clomiphene group. On the basis ofthese assumptions, we needed to enroll 678 sub-jects19for the study to have a power of 80% witha type I error rate of 0.05 to detect a 15% absolute

difference in live-birth rates for the followingtwo primary comparisons: the combination-ther-apy group versus the next best group and themetformin group versus the clomiphene group.

Because of limitations in the supply of metfor-min and matching placebo, the number of sub-jects was reduced to 626 after the data safety andmonitoring board reviewed blinded data in Novem-ber 2004. Because the live-birth rate was lowerthan projected, the final number of subjects pro-vided adequate power (80%) to detect the same15% absolute difference in live-birth rates for theoriginal two primary comparisons because of theincreased power for detecting the same differ-ence in proportions when the magnitude of theproportion was decreased.

Either a chi-square test or Fishers exact testwas used for testing differences among the threestudy groups for categorical variables. A Wilcoxonrank-sum test was used for testing differencesbetween two groups, and a KruskalWallis testwas used for testing differences among groupsof three or more. KaplanMeier curves were used

for time-to-event analyses. Generalized estimat-ing equations were used for analysis of the ovu-lation rate to account for correlation of multipleovulation cycles for each subject. Post hoc strat-ification of outcomes was performed on the basisof the body-mass index (BMI; the weight in kilo-grams divided by the square of the height inmeters) and presence or absence of previous ex-posure to medication. All analyses were performedwith SAS software, version 8.2 (SAS Institute).





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Results

Study Population

There were no significant differences in baselinevariables among the study groups (Table 1).21The numbers of subjects who dropped out of thestudy were 55 of 209 (26.3%) in the clomiphene

group, 72 of 208 (34.6%) in the metformin group,and 49 of 209 (23.4%) in the combination-therapygroup (P = 0.07 for the metformin group vs. theclomiphene group, and P = 0.01 for the metformingroup vs. the combination-therapy group) (Fig. 1).The reasons for dropout were similar among thethree groups, except that the metformin grouphad a higher rate of loss to follow-up than did theother two groups (P = 0.03 for the comparison withthe clomiphene group, and P = 0.01 for the com-parison with the combination-therapy group).

Primary Outcome

The rate of live birth was significantly lower inthe metformin group than in the clomiphene groupand the combination-therapy group (P


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before pregnancy was documented or at the f inalstudy visit, whichever came first (Table 3). As com-pared with the baseline values, the clomiphenegroup had a signif icant increase in BMI (P = 0.05),levels of insulin (P = 0.01), insulin resistance asdetermined by homeostasis model assessment(HOMA) (P = 0.01), and levels of sex hormone

binding globulin (P


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The combination-therapy group had changes sim-ilar to those in the metformin group, includinga significant decrease in BMI, levels of testoster-one, and the free androgen index and a signifi-cant increase in sex hormonebinding globulinlevels (P


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Table 2.Rates of Ovulation, Pregnancy, and Pregnancy Loss.*

VariableClomiphene Group

(N = 209)Metformin Group

(N = 208)

Combination-Therapy Group

(N = 209)

Absolute Differencebetween Combination

Therapy and Metformin

no./total no. (%) % (95% CI)

Ovulation 462/942 (49.0) 296/1019 (29.0) 582/964 (60.4) 31.4 (24.7 to 38.0)

Conception 62/209 (29.7) 25/208 (12.0) 80/209 (38.3) 26.3 (18.4 to 34.2)Pregnancy 50/209 (23.9) 18/208 (8.7) 65/209 (31.1) 22.4 (15.0 to 29.8)

Singleton 47/50 (94.0) 18/18 (100.0) 63/65 (96.9) 3.1 (7.3 to 1.1)

Twins 2/50 (4.0) 0 2/65 (3.1) 3.1 (10.1 to 16.3)

Triplets 1/50 (2.0) 0 0 0 (12.7 to 12.7)

Other 0 0 0 0 (12.7 to 12.7)

Live birth 47/209 (22.5) 15/208 (7.2) 56/209 (26.8) 19.6 (12.6 to 26.6)

Pregnancy loss

Total losses among subjects who conceived 16/62 (25.8) 10/25 (40.0) 24/80 (30.0) 10.0 (31.7 to 11.7)

Loss in first trimester 14/62 (22.6) 10/25 (40.0) 20/80 (25.0) 14.5 (35.9 to 6.9)

Biochemical factor or no fetal heart motion 10/62 (16.1) 7/25 (28.0) 13/80 (16.2) 11.7 (31.1 to 7.7)

Ectopic pregnancy 2/62 (3.2) 0 2/80 (2.5) 2.5 (7.8 to 12.8)Loss after observed heart motion 2/62 (3.2) 3/25 (12.0) 5/80 (6.2) 5.7 (19.5 to 8.1)

Loss in second or third trimester 2/62 (3.2) 0 4/80 (5.0) 5.0 (5.7 to 15.7)

Events among ovulated cycles

Conception 62/462 (13.4) 25/296 (8.4) 80/582 (13.7) 5.4 (1.2 to 9.6)

Singleton pregnancy 47/462 (10.2) 18/296 (6.1) 63/582 (10.8) 4.7 (1.0 to 8.4)

Singleton live birth 47/462 (10.2) 15/296 (5.1) 56/582 (9.6) 4.5 (1.0 to 8.0)

Events among subjects who ovulated

Conception 62/157 (39.5) 25/115 (21.7) 80/174 (46.0) 24.3 (13.7 to 34.9)

Singleton pregnancy 47/157 (29.9) 18/115 (15.7) 63/174 (36.2) 20.5 (10.7 to 30.3)

Singleton live birth 47/157 (29.9) 15/115 (13.0) 56/174 (32.2) 19.2 (9.9 to 28.5)

Ovulation per monthly visit

Visit 1 90/209 (43.1) 45/208 (21.6) 109/209 (52.2) 30.6 (21.8 to 39.4)

Visit 2 90/181 (49.7) 72/189 (38.1) 114/185 (61.6) 23.5 (13.6 to 33.4)

Visit 3 86/159 (54.1) 44/169 (26.0) 97/163 (59.5) 33.5 (23.5 to 43.5)

Visit 4 70/141 (49.6) 49/153 (32.0) 92/144 (63.9) 31.9 (21.1 to 42.7)

Visit 5 58/119 (48.7) 38/138 (27.5) 81/125 (64.8) 37.3 (26.1 to 48.5)

Visit 6 55/99 (55.6) 38/120 (31.7) 74/106 (69.8) 38.1 (26.0 to 50.2)

After Visit 6 13/34 (38.2) 10/42 (23.8) 15/32 (46.9) 23.1 (1.5 to 44.7)

Live birth per monthly visit

Visit 1 10/209 (4.8) 3/208 (1.4) 9/209 (4.3) 2.9 (0.3 to 6.1)

Visit 2 10/199 (5.0) 3/205 (1.5) 5/200 (2.5) 1.0 (1.7 to 3.7)

Visit 3 9/189 (4.8) 1/202 (0.5) 11/195 (5.6) 5.1 (1.7 to 8.5)

Visit 4 10/180 (5.6) 2/201 (1.0) 8/184 (4.3) 3.3 (0.1 to 6.5)

Visit 5 2/170 (1.2) 4/199 (2.0) 6/176 (3.4) 1.4 (1.9 to 4.7)

Visit 6 6/168 (3.6) 2/195 (1.0) 15/170 (8.8) 7.8 (3.3 to 12.3)

After Visit 6 0 0 2/155 (1.3) 1.3 (1.5 to 4.1)

* Ovulation was defined as a serum progesterone level of more than 5 ng per milliliter. Conception was defined as any positive serum level ofhuman chorionic gonadotropin. Pregnancy was defined as an intrauterine pregnancy with fetal heart motion, as determined by transvaginalultrasonography. Live birth was defined as the delivery of a viable infant.





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P Value

Absolute Differencebetween Combination

Therapy and Clomiphene P Value

Absolute Differencebetween Clomiphene

and Metformin P Value

% (95% CI) % (95% CI)


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receive either clomiphene alone or a combinationof metformin and clomiphene for up to six ovu-latory cycles, there were no significant differencesin ovulation rates or pregnancy rates between thecombination-therapy group and the group thatreceived clomiphene alone, with a cumulativepregnancy rate of 40% in the combination-therapy

group and 46% in the clomiphene group (abso-lute change in the combination-therapy group,6%; 95% confidence interval [CI], 20 to 7).28

Although we found no significant benefit ofthe combination of metformin and clomiphene,as compared with clomiphene alone, the possibil-ity of some benefit cannot be excluded. On thebasis of the 95% CIs, plausible differences in thelive-birth rate between groups range from a 12.6%absolute increase to a 4.2% absolute decrease in

Rate

ofLive

Birth

0.3

0.4

0.2

0.1

0.00 150 200 250 300 350 400 450 500

Days from Randomization to Live Birth

Clomiphene

Metformin

Combined

0.5

P


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SHBGnmol/liter

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Clomiphene, Metformin, Or Both for Infertility in the Polycystic Ovary Syndrome