Active ovulation management increases the monthly probability of pregnancy occurrence in ovulatory women who receive intrauterine insemination

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1 FERTILITY AND STERILITY Cpyright 987 The American Fertility Sciety Vl. 48, N.6, December 987 Printed in U.S.A. Active vulatin management increases the mnthly prbability f pregnancy ccurrence in vulatry wmen wh receive intrauterine inseminatin Ekkehard Kemmann, M.D.* Michael Bhrer, M.D. Rbert Shelden, Ph.D. Gary Fiascnar, M.D.t Leah Beardsley, R.N. Department f Obstetrics and Gyneclgy, University f Medicine and Dentistry f New Jersey (UMDNJ), Rbert Wd Jhnsn Medical Schl, New Brunswick, New Jersey, and Brklyn Hspital, Brklyn, New Yrk The authrs examined the hypthesis that active vulatin management wuld increase the mnthly prbability f pregnancy ccurrence (MPO) in vulatry wmen wh require intrauterine inseminatin (lui). All patients were initially treated during spntaneus vulatry cycles with lui perfrmed after the detectin f an endgenus lutenizing hrmne (LH) surge (phase ). Fr phase 2, thse patients wh had nt cnceived were ffered treatment with fertility medicatin and luis were scheduled accrdingly. Fur f 76 (5.3%) patients cnceived during 80 treatment cycles in phase ; 9 f 44 (20.5%) patients cnceived during 05 treatment cycles in phase 2. The average MPO was in phase, and in phase 2: the difference is significant (P < 0.02). The authrs cnclude that fertility medicatin imprves MPO in vulatry wmen wh underg lui fr certain infertility situatins. Fertil Steril 48:96, 987 The use f sperm-washing methds makes it pssible t deliver large numbers f active sperm int the uterine cavity. T achieve fertilizatin and pregnancy, intrauterine inseminatin (lui) has t be synchrnized with vulatin, whether spntaneus r stimulated. While vulatin stimulatin is clearly useful in patients with irregular r absent vulatin, varian stimulatin may ffer advantages even in vulatry patients wh require lui. Such advantages may include better cntrl and predictability f the vulatin sequence and an increased number f cytes available fr fertilizatin. T evaluate the hypthesis that active vula- Received April 29, 987; revised and accepted August 5, 987. * Reprint requests: Ekkehard Kemmann, M.D., Department f Obstetrics and Gyneclgy, UMDNJ-Rbert Wd Jhnsn Medical Schl, One Rbert Wd Jhnsn Place, en 9, New Brunswick, New Jersey, t Brklyn Hspital. 96 Kemmann et al. Active vulatin management and lui tin management imprves the mnthly prbability f pregnancy ccurrence (MPO) in wmen wh underg lui, we analyzed pregnancy ccurrence rates in wmen receiving lui initially during spntaneus cycles and subsequently in cnjunctin with varian stimulatin. MATERIALS AND METHODS The study ppulatin was treated between July 985 and December 986. It cnsisted f infertile cuples whse cause f infertility was either a male factr with persistent abnrmal semen analyses (semen cunt < 20 millin/ml, mtility at 2 hurs < 40%, r mrphlgic features f <50% nrmal frms) r was related t an abnrmal pstcital test (PCT) when the semen analysis was nrmal. Fr timing the PCT, patients were asked t mnitr their urine each evening fr the appearance f an endgenus luteinizing hrmne (LH) surge

2 after day f their cycle. The cuple had been instructed t have intercurse n the night f the LH surge and t return at 8 A.M. the next mrning fr the PCT. The PCT was scred n active sperm number/high-pwered field (HPF), mtility percentage, and quality f prgressive mtility! (Table 2). Patients with a ttal scre f 7 r less were treated with lui. All wmen in the study demnstrated a cyclic menstrual histry, a spntaneus midcycle LH surge, and a biphasic basal bdy temperature pattern. Mst patients had als undergne determinatin f luteal phase prgesterne levels r an endmetrial bipsy that further crrbrated the presence f nrmal vulatin. Evidence f tubal patency was btained by hystersalpinggraphy r laparscpy. Excluded frm the study were patients with ther indicatins fr lui, past expsure t lui, dnr inseminatin, r evidence f luteal dysfunctin. Previus wrk had indicated that the pregnancy rate was lw if the lui specimen cntained fewer than ne millin ttal sperm. 3 Therefre, we excluded cuples frm the study where a semen specimen prvided fewer than ne millin sperm fr an lui. In the first phase f the study, patients were inseminated during spntaneus cycles. On the mrning after the detected LH surge, patients delivered a fresh semen specimen t ur labratry. After sperm washing by swim-up technique, the inseminatin was perfrmed between :30 A.M. and 2:30 P.M. In a subset f phase patients, a secnd lui was dne 24 hurs later. N patients culd enter phase 2 after at least ne cmpleted treatment cycle in phase. Patients were encuraged t cmplete up t fur cycles in phase and patient chice determined the timing f the switch and the regimen (A r B) t be used in phase 2. Phase 2 used fllicular stimulatin t enhance and cntrl the vulatin prcess. Three treatment regimens were used. A. Clmiphene citrate (CC) (Serphene, Sern Labratries, Randlph, MA) 50 mg was taken by muth daily frm days 3 t 7 with patients mnitring their urine fr the endgenus LH surge, as in spntaneus cycles. A single lui was perfrmed after the detectin f the LH surge (as described previusly). B. CC 50 mg was taken daily frm days 3 t 7 fllwed by human menpausal gnadtrpin () (Perganl, Sern Labratries, Randlph, MA) n day 9 and thereafter n alternate days with individualized dsages in accrdance with serum estradil (E2) measurements. 4 E2 levels were measured using a duble antibdy kit (Leec Diagnstics Inc., Suthfield, MI). When E2 levels reached apprximately 400 pg/ml, n further was given and vulatin was triggered with 0,000 IU f human chrinic gnadtrpin (hcg; Prfasi, Sern Labratries, Randlph, MA) fllwed by a single lui 28 hurs later. C. If treatment A r B was unsuccessful, a regimen f daily with E2 mnitring was instituted until levels f apprximately 400 pg/ml were attained. 5 hcg administratin and lui were handled as in regimen B. All patients in phase 2 received nly ne lui per treatment cycle. Each patient was allwed up t fur treatment cycles in phases and 2. Sperm preparatin has been described in detail. 5 In essence, it cnsisted f a sperm wash using mdified Ham's F-I0 medium (Gibc, Grand Island, NY), fllwed by a swim-up and incubatin perid. The active sperm were suspended in a vlume f 0.5 ml and injected int the uterine fundus thrugh a transcervically placed Shepard catheter (Ck Ob/Gyn, Blmingtn, IN) in an utpatient setting. Statistical analysis included life-table methds t estimate cumulative pregnancy rates using a single parametric mdel. 6 MPO was defined as the rati f cnceptins per treatment cycles. The ut- Table PQstcital Scre Pints Subttal Mtile sperm/hpf Percent mtile sperm Quality f mvement" -4 < <40 < /3+ 3+ Ttal " Grading accrding t Macled. Vl. 48, N.6, December 987 Kemmann et al. Active vulatin management and lui 97

3 Table 2 Treatment and Mnthly Prbability f Pregnancy Occurrence (MPO) with Intrauterine Inseminatin (lui) During Spntaneus Cycles, Clmiphene Citrate (CC) Cycles, CC-/hCG Cycles, and /hcg Cycles Ovulatin Patients Cycles Pregnancy MPO Spntaneus LH " Ovulatin management " Clmiphene citrate CC-/hCG /hcg "P < cme f all treatment cycles was knwn as either pregnancy r nnpregnancy_ Pregnancy ccurrence was defined as tw increasing levels f serum hcg with the first level nt dne befre day 7 after the lui in the absence f menses. Fisher's exact test was used t cmpare MPOs in spntaneus versus stimulated treatment cycles. Patients were nt randmized fr therapy, rather all patients were initially treated during the spntaneus cycle, and subsequently entered phase 2 at their chsing. RESULTS During the study perid, 76 cuples fulfilled ur study criteria and culd be evaluated. The female patients' ages ranged frm 24 t 39 years (mean, 32.0). Duratin f infertility in this ppulatin was t 0 years (mean, 3.3). In 49 f the 76 cuples, the semen analysis was abnrmal. In the remainder, lui was perfrmed n the basis f pr PCT scring. Seventeen f the wmen had had children. Results are listed in Table 2. Seventy-six patients started in phase. Fur f these patients (5.3%) cnceived during 80 natural cycles with lui timed with the spntaneus LH surge. In phase, the average number f treatment cycles was 2.37 per patient (range, t 4). In 32 fthese patients, a secnd lui was dne 24 hurs after the initial lui in 45 treatment cycles. Thirty-eight patients decided nt t cntinue with lui therapy after ne r mre unsuccessful treatments in spntaneus cycles and discntinued the study. Patients wh did nt enter phase 2 did nt differ significantly frm thse wh cntinued in regard t age, duratin f infertility, and indicatin fr lui. Thirty-fur patients entered phase 2 fthe study (active management f vulatin): 9 wmen were treated with regimen A (CC), 34 with regimen B (CC fllwed by /hcg), and 4 with regimen C (/hcg); several wmen underwent mre than ne methd f vulatry therapy. In phase 2, the average number f treatments per patient was Nine patients cnceived (20.5%) during 05 treatment cycles. In the vulatin managed grup, the average MPO was This is significantly higher than the average MPO in the spntaneus cycle, which was (P < 0.02, Fisher's exact test). Within the vulatin managed grup, patients n CC r CCI had a mnthly prbability f and 0.063, respectively; patients n withut CC shwed the highest MPO with The cumulative pregnancy rates fr phase and 2 are listed in Table 3. Overall, 3 patients (7.%) cnceived during phase and 2 f the study during 285 treatment cycles. The pregnancy rate in phase was 4 f 76 patients and in phase 2, 9 f 44 patients: the difference is significant at P < 0.02 (Fisher's exact test). Spntaneus abrtins ccurred in ne patient in phase and in ne patient in phase 2 fr an abr- Table 3 Life-Table Analysis f Cumulative Pregnancy Occurrence in Patients in Phase Treatment (IUI Timed in the Spntaneus Cycle) and Phase 2 Treatment (IUI Timed with Active Ovulatin Management) Treatment Prprtin mnth n nt pregnant Pregnancy Censred Cumulative pregnancy rate Phase " 0.039" b Phase " 0.59" b Phase versus phase 2: " P < 0.05, bp < Kemmann et al. Active vulatin management and lui

4 Table 4 Data n Pregnant Patients Indicatin Patient Age Duratin fr lui yr Phase 29 2 OS OS PCT b OS Phase OS OS PCT PCT OS OS 34 2 PCT 2 36 OS OS yr Methd f varian stimulatin CC' CC- d CC- CC- CC- Pregnancy utcme Mle, spntaneus abrtin Twins (male, female), delivered Spntaneus abrtin 6 weeks Induced abrtin, 9 weeks OS, ligspermia. b PCT, lw scre n pstcital testing (see text). ' CC, clmiphene citrate. d, human menpausal gnadtrpin. tin rate f 7%. One patient in phase 2 underwent an abrtin fr medical reasns; all ther patients either delivered r are clse t term (Table 4). In the 63 patients wh did nt cnceive during the study perid, 6 pregnancies ccurred either subsequent t censring r after December 986. The breakdwn f these pregnancies is as fllws. Tw pregnancies ccurred in 36 patients independent f treatment, n pregnancies ccurred in 24 patients wh cntinued phase therapy, 8 pregnancies ccurred with cntinued phase 2 therapy in 29 patients, and 6 pregnancies ccurred in 8 patients with dnr inseminatin. (Sme patients used mre than ne treatment ptin). DISCUSSION Our study analyzed MPO in a patient ppulatin whse infertility was diagnsed t be due t a male factr r a "pr" PCT. In this ppulatin, we shwed that lui in cnjunctin with active vulatin management significantly increased the MPO when cmpared with the spntaneus cycle. All female patients had demnstrated evidence f spntaneus LH surges and vulatin. At the utset, we were reluctant t stimulate nrmally vulating wmen fr the purpse f lui and thus did nt frmulate a randm experimental design. Instead, all female patients were initially treated with luis during their spntaneus cycle. Only patients failing t cnceive fllwing lui in spntaneus cycles became eligible fr active vulatin management. The study design therefre favred phase Vl. 48, N.6, December 987 regimens, as all patients were initially expsed t this treatment mdality, and, in additin, multiple inseminatins were allwed in 45 f 80 treatments. Hwever, we did nt find that multiple lui increased MPO and therefre have discntinued multiple inseminatins. 7 Because the wmen cnsistently demnstrated evidence f nrmal vulatin, it is dubtful that the primary benefit f vulatin management was the crrectin f an vulatry prblem. Rather, it appears that vulatin management was effective as the result f stimulating an increased number f develping fllicles. Such cytes may nt be released simultaneusly, but ver a prtracted time span, thereby increasing the windw fr fertilizatin.s With lui, a sudden blus f active sperm becmes available in the viduct. 5 Als, with hcg administratin, the timing f lui becmes mre predictable. The bservatin that a single lui is as effective as multiple luis n separate days supprts this view. 9 Als f interest is the experience in the ppulatin after the study perid had clsed. Only tw patients cnceived withut vulatin management while anther eight cnceived using active vulatin management. Patients wh changed t dnr inseminatin achieved pregnancies in a majrity f cases. While a number f vulatin regimens were used, it has been ur experience that lui in cnjunctin with a regimen f /hcg results in the highest MPO. Ovulatin regimens that use CC are less cstly, but als appear t be less efficacius. In this Kemmann et al. Active vulatin management and lui 99

5 study, the MPO fr a cmbinatin f CC and lui is based n nly a small sample. Generally, it has been ur experience that MPO is abut 0.06 fr luis dne in CC cycles with LH timing. A regimen f CC/ cmbined with lui appears t prduce a MPO that is between that f CC and /hcg. Our data suggest that the efficacy f lui during the spntaneus cycle is relatively lw. A number f reprts have indicated that lui is f little value in the treatment f male infertility, but it appears that these bservatins have been btained during the spntaneus cycle. lo,l These bservatins therefre d nt cnflict with ur experience cncerning the efficacy f lui during the spntaneus cycle. Our experience with lui suggests that vulatin management is an imprtant cmpnent in the full use f the ptential f lui. Frm a practical pint f view, it may be useful t use active vulatin management in vulatry wmen in whm lui is indicated, specifically if lui has been unsuccessful during spntaneus cycles. We als suggest the cnsideratin f the use f active vulatin management with gnadtrpins in cnjunctin with lui befre the use f gamete intrafallpian transfer r in vitr fertilizatin in thse infertility situatins where the wman appears vulatry and t have nrmal pelvic structures and the infertility is deemed t be related t ligspermia r pr PCT results. Our data supprt ur hypthesis that active vulatin management significantly increases MPO in these defined infertility situatins. Acknwledgment. We wuld like t thank Ms. Natalie Tsignis fr her help in cmpiling the data. REFERENCES. Macled J: Semen quality in ne thusand men f knwn fertility and in eight hundred cases f infertile marriage. Fertil Steril 2:5, Skaf RA, Kemmann E: Pstcital testing in wmen during mentrpin therapy. Fertil Steril 37:54, Bhrer M, Kemmann E, Pasquale S, Shelden RM: The significance f the ttal number f mtile sperm delivered with intrauterine inseminatin in mentrpin treated wmen (Abstr). Presented at the furth-secnd annual meeting f The American Fertility Sciety and the eighteenth annual meeting f the Canadian Fertility and Andrlgy Sciety, September 27 t Octber 2, 986, Trnt, Ontari, Canada. Birmingham, The American Fertility Sciety, 986, p Kemmann E, Jnes JR: Sequential clmiphene-citratementrpin therapy fr inductin r enhancement f vulatin. Fertil Steril 39:772, Cruz RI, Kemmann E, Brandeis VT, Becker KA, Beck M, Beardsley L, Shelden R: A prspective study f intrauterine inseminatin f prcessed sperm frm males with ligasthenspermia in supervulated wmen. Fertil Steril 46:673, Olive DL: Analysis f clinical fertility trials: a methdlgic review. Fertil Steril 45:57, Kemmann E, Bhrer M: Unpublished data 8. Abbasi R, Kenigsberg D, Danfrth D, Falk RJ, Hdgen GD: Cumulative vulatin rate in human menpausal/human chrinic gnadtrpin treated mnkeys: "step up" versus "step dwn" dse regimens. Fertil Steril 47:09, Bhrer M, Kemmann E: Frequency f intrauterine inseminatin in wmen under mentrpin therapy (Abstr). Presented at the frty-secnd annual meeting f The American Fertility Sciety, September 27 t Octber 2, 986, Trnt, Ontari, Canada. Birmingham, The American Fertility Sciety, 986, p Hull ME, Magyar DM, Vasques JM, Hayes MF, Mghissi KS: Experience with intrauterine inseminatin fr cervical factr and ligspermia. Am J Obstet Gynecl 54:333, 986. Cnfin E, Friberg J, Dudkiewicz AB, Gleicher N: Intrauterine inseminatin with washed human spermatza. Fertil Steril 46:55, Kemmann et al. Active vulatin management and lui