Transvaginal ultrasound-guided follicular aspiration in the management of anovulatory infertility associated with polycystic ovaries*

Transcription

1 FERTILITY AND STERILITY Cpyright 1991 The American Fertility Sciety Vl. 56, N.6, December 1991 Printed n acid-free paper in U.S.A. Transvaginal ultrasund-guided fllicular aspiratin in the management f anvulatry infertility assciated with plycystic varies* Yasuyuki Mi, M.D., Ph.D.t Tshik Tda, M.D., Ph.D. Masahir Tanikawa, M.D. Hirhumi Terad, M.D., Ph.D. Tasuku Harada, M.D., Ph.D. Naki Terakawa, M.D., Ph.D. Department f Obstetrics and Gyneclgy, Tttri University Schl f Medicine, Ynag, Japan Study Objective: T investigate whether r nt transvaginal ultrasund (US)-guided fllicular aspiratin can effectively induce vulatin and facilitate pregnancy in anvulatry patients with plycystic varies (PCD). Design: Eight patients with plycystic varian disease (PCDD) and 1 patients with PCD were participants wh failed t vulate by the medical therapies. Mst f persistent fllicles were punctured, and their cntents were thrughly aspirated during the midluteal phase. The same varian stimulatin regimen as used in the previus cycles were administered in the cycles after the aspiratin. Main Outcme Measures: Evidence f vulatin and a subsequent pregnancy was ultrasnically mnitred after the aspiratin, and the respnsiveness f pituitary gnadtrpins t gnadtrpinreleasing hrmne was tested in these patients. Results: The vulatin rates were 87.5% per patient, 52.6% per cycle mnitred in PCDD patients and 1% per patient, 63.3% per cycle mnitred in PCD patients, respectively. Half fthe patients bth with PCDD and PCD achieved pregnancy after the aspiratin. A significant decrease (P <.5) f the basal and peak levels f serum luteinizing hrmne was bserved after the aspiratin. Cnclusins: The US-guided fllicular aspiratin seems t be a new surgical methd fr treating anvulatry patients with PCD. Fertil Steril1991;56:16-5 Plycystic varian disease (PCOD) is a wellknwn disrder assciated with anvulatin and hrmnal abnrmalities.1,2 In additin, plycystic varies (PCO) withut hrmnal abnrmalities are ften seen by ultrasngraphy in patients wh cmplain f menstrual irregularity and wh are unable t cnceive. 3-5 Mst f these patients can be treated successfully by established medical therapies, such as clmiphene citrate (CC),6 human menpausal gnadtrpin (hmg),7 pure fllicle-stimulating hrmne (FSH),S and superactive gnadtrpin-releasing hrmne analg (GnRH-a). Hwever, sme f Received February 8, 1991; revised and accepted August 6, * Presented at the 7th Wrld Cngress n Human Reprductin, Helsinki, Finland, June 26 t July 1, 199. t Reprint requests: Yasuyuki Mi, M.D., Department f Obstetrics and Gyneclgy, Tttri University Schl f Medicine, Ynag 683, Japan. 16 Mi et a1. Ultrasnic fllicle aspiratin in pe these patients fail t vulate even when fllicular develpment is detected by ultrasund (US) scanning. Ovarian wedge resectin, riginally described by Stein and Leventhal, l has been used t induce vulatin in patients with drug-resistant PCOD. It is generally accepted that althugh this strategy is very effective fr establishing vulatry menstrual cycles and pregnancies, it is assciated with an increased risk f peritubal and perivarian adhesins,lo,n which may cause infertility. Recently, varian electrcautery and laser vaprizatin via laparscpy have been reprted t be less invasive fr patients with PCOD refractry t medical therapy Althugh the beneficial effects f surgical managements fr the patients with drug-resistant PCOD is nt well established, there are several hyptheses t the pathphysilgical effects f these strategies: (1) the increased expsure f fllicles t gnadtr- Fertility and Sterility

2 pins by the increase in intravarian bld flow;15 (2) a reduced synthesis f andrgen by the drainage f atretic and persistent fllicle cntents;15 and (3) a reduced resistance f the thickened varian surface "tunica albuginea."l We cnsidered that these factrs culd arise even with US-guided fllicular aspiratin, which has been established fr cyte pickup in an in vitr fertilizatin and embry transfer (IVF-ET) prgram.16 Therefre, we investigated the effect f transvaginal US-guided fllicular aspiratin n the GnRH challenge test during menstruatin befre and after the aspiratin and n the rates f vulatin and pregnancy in patients with anvulatry infertility assciated with PCO. MATERIALS AND METHODS A ttal f 18 patients with PCO wh had failed t vulate ver three cnsecutive cycles after treatment with medical agents, despite the presence f large fllicles, were included in this study. All these patients were administered an antiestrgen (Clmid, 5 t 15 mg/d; Shingi & C., Ltd., Osaka, Japan), hmg (Humegn, 75 t 3 IU/d; N.V. Organn, Tky, Japan), r the cmbinatin in a step-up manner. Either prednislne (Prednine, 5 mg/d; Shingi & C., Ltd.) r brmcriptine (Parldel, 2.5 t 5 mg/d; Sandz Pharmaceutical C., Ltd., Tky, Japan) was added t these varian stimulatin regimens. Accrding t the criteria fr PCOD (Table 1), 8 f the 18 were diagnsed as having PCOD (grup A). Ultrasnic evidence f PCO withut a hrmnal abnrmality was fund in 1 f the 18 patients (grup B).3-5 In the cycles f attempted transvaginal US-guided fllicular aspiratin, varian stimulatins using the same medical agents were carried ut. Fllicular develpment was mnitred every ther day by ultrasngraphy (SSD-65 and 63; Alka, Tky, Japan) frm day 7 r 8 f the menstrual cycle t the day f administratin f human chrinic gnadtrpin (hcg, HCG Mchida, 5, IU; Mchida Pharmaceutical C., Ltd., Tky, Japan). When the dminant fllicle exceeded 18 mm in tw dimensins, hcg was administered intramuscularly t induce vulatin. After hcg administratin, vulatin was determined by daily varian scanning. Ultrasngraphic criteria fr vulatin were defined as fllws: (1) cllapse r disappearance f large fllicle; (2) standing fluid in the puch f Duglas; and (3) thickened endmetriumy If vulatin was nt bserved fr 3 days after hcg administratin, fllicular aspiratin was scheduled after btaining infrmed cnsent frm the patients. Table 1 Diagnstic Criteria fr PCOD Clinical signs Amenrrhea Infertility Hirsutism Obesity Endcrinlgic characteristics LH/FSH rati> 3 GnRH challenge test Peak level f LH > 1 miu/mu Peak level f FSH < 5 mid /mu T> 1. ng/mu Ovarian characteristics b Ovarian enlargement Plycystic pattern Thickened varian surface a Values were the upper limit f nrmal. b Ovarian enlargement with peripheral multicystic pattern arund a dense cre f strma was determined by transvaginal ultrasngraphy in the early fllicular phase. 4 The thickened varian surface was cnfirmed by varian bipsy perfrmed thrugh the laparscpe in sme cases. 2 During the midluteal phase (5 t 7 days after hcg administratin), mst fthe persistent fllicles, even thse <1 mm, were punctured, and their cntents were thrughly aspirated using a 16-G needle, 35 cm lng, attached t a transvaginal prbe (UST- 945, 5 MHz; Alka). This prcedure was essentially the same as that used fr cyte pick-up fr IVF ET.16 In mst patients, diazepam (Hrizn, 1 mg; Yamanuchi Pharmaceutical C., Ltd., Tky, Japan) and pentazcine (Pentagin, 3 mg; Sanky C., Ltd., Tky, Japan) were intravenusly administered fr anesthesia; in a few patients with a small number f fllicles, n anesthesia was required. Patients remained in bed fr at least 3 minutes after the aspiratin. After re-examinatin by US t rule ut intra-abdminal hemrrhage, the patient was discharged. The same varian stimulatin regimen and fllicular mnitring as used in the previus cycles were administered in the cycles after the aspiratin. In grup A, the respnsiveness f pituitary gnadtrpins t GnRH was evaluated during menstruatin befre and after the aspiratin. Evidence f vulatin and a subsequent pregnancy was mnitred by ultrasngraphy as lng as pssible (fr 12 cycles in the lngest instance). When vulatin did nt ccur in 3 cycles subsequent t the aspiratin, the same prcedure was repeated. This was required in sme patients in bth grups. Hrmne assays were perfrmed by Otsuka Pharmaceutical Cmpany, Tky, Japan (luteinizing hrmne [LH) and FSH) and by SRL, Incr- Vl. 56, N.6, December 1991 Mi et a1. Ultrasnic fllicle aspiratin in pea 161

3 F, Table 2 Clinical Prfiles f Tw Grups Parameter Grup A (n = 8) Grup B (n = 1) Prbability Age" Infertility perid" Obesity (BMI) " Hirsutism (%) LH (miu/ml)c FSH (miu/ml)c LH/FSH ratic PRL (ng/ml)c T (ng/ml)c A (ng/ml)c DHEAS (ng/ml)c DHEA (ng/ml)c 27.7 ± ± ± ± ± ± ± ± ±.2 2,698.5 ± ± ± ± ± ± ± ± ± ±.1.7 ±.1 2,864.2 ± ± 1.1 b p<.q1 P<.1 P<.5 P<.5 "Values are means ± SD. b, nt significant. C Values are means ± SEM. prated, Tky, Japan (teststerne [T], andrstenedine [A], dehydrepiandrsterne [DHEA], dehydrepiandrsterne sulfate [DHEAS]). Sperm cncentratin and mtility f all husbands whse wives participated in this study were within the nrmal range, accrding t the Wrld Health Organizatin classificatin. IS Statistical analysis f the data was perfrmed using Student's t-test r X2 test, with ~ P <.5 accepted as significant. RESULTS Clinical and Hrmnal Prfiles There were n significant differences in the mean age and perid f infertility between grups A and B. Bdy mass index (BMI) in grup A was significantly higher than that in grup B (P <.1). Higher, rates f hirsutism was als bserved in grup A as cmpared with grup B. ',;::.) Althugh the difference in the serum levels flh ;l!~~ and FSH between gr~ps A a~d ~ was nt. signi~ '. ljit! cant, the LH/FSH rati was slgnlficantly hlgher m grup A cmpared with grup B (P <.1). Serum levels f T and A in grup A were significantly higher than in grup B (P <.5), althugh A levels in ',. mst patients in grup A did nt exceed the upper i~; limit f nrmal (2.4 ng/ml). There were n signif,jt icant differences in serum levels f prlactin (PRL), tj DHEA, and DHEAS between the tw grups (Table 2). Clinical Outcmes After Aspiratin Overall clinical utcmes after the aspiratin are shwn in Table 3. All patients experienced spntaneus menstruatin 7 t 14 days later. Of the Mi et al. Ultrasnic fllicle aspiratin in pea patients with PCOD in grup A, 7 (87.5%) had at least 1 vulatry cycle during 8 cycles subsequent t the aspiratin. The verall vulatin rate per cycle mnitred was 52.6% (2/38). One PCOD patient subsequently had a successful pregnancy after the first menstruatin after the aspiratin; 3 f the 7 patients wh vulated achieved pregnancy n the 2nd, 4th, r 5th cycle after the aspiratin (Fig. 1). In grup B, at least 1 vulatry cycle was bserved in all 1 patients (1%); 5 f the 1 patients cnceived n the 2nd, 4th, 5th, 7th, r 1th cycle. The verall vulatin rate per cycle mnitred was 63.3% (5/79) in grup B (Fig. 2). Gnadtrpin-releasing Hrmne Challenge Test inpcod Serum cncentratins f LH and FSH accrding t the GnRH challenge test befre and after the aspiratin appear in Figure 3. Befre the aspiratin, the mean (±SEM) serum LH level befre GnRH injectin was 35. ± 8.3 miu /ml; the mean peak level was 252. ± 44.5 miu /ml. These results bviusly indicate an elevated basal level f serum LH and an exaggerated reactivity t GnRH. A signifi- Table 3 Grup A B Overall Results" Patients b 87.5 (7/8) 1 (1/1) Ovulatin CyclesC 52.6 (2/38) 63.3 (5/79) Pregnancy 5. (4/8) 5. (5/1) " Values are percents. b Denminatrs in parentheses are number f patients. C Denminatrs in parentheses are number f cycles mnitred. Fertility and Sterility

4 E :J C.l!l 5 c Q) ~ 6 7 p p ND ND 8 P (FA) (FA) Mnitred cycles after the aspiratin p ND ND ND 8 9 Figure 1 Clinical utcme in the cycles mnitred by ultrasngraphy after the aspiratin in patients with PCOD (grup A). Open circle () indicates the cycle in which vulatin was cnfirmed ultrasnically. Clsed circle (.) indicates the cycles in which vulatin was nt cnfirmed ultrasnically. P, pregnancy; ND, nt determined; FA, repeated fllicular aspiratin. (FA) (Ft) ND.8 ND E 5 ND ND ND :J C.l!l 6 ai ~ 7.. (Ft) 1 P I II 12 Mnitred cycles after the aspiratin Figure 2 Clinical utcme in the cycles mnitred by sngraphy after the aspiratin in patients withut hrmnal abnrmalities (grup B). Open circle () indicates the cycles in which vulatin was cnfirmed ultrasnically. Clsed circle (.) indicates the cycles in which vulatin was nt cnfirmed ultrasnically. P, pregnancy; ND, nt determined; FA, repeated fllicular aspiratin. cant decrease (P <.5) fthe basal and peak levels f serum LH ccurred after the aspiratin: basal level: 16.8 ± 4.2 miu /ml; peak level: 96.8 ± 3.5 miu /ml. In cntrast, FSH respnses t GnRH befre and after the aspiratin shwed n significant change, indicating that these levels remained within the nrmal range. DISCUSSION This is the first reprt n the use f transvaginal US-guided fllicular aspiratin during the midluteal phase in the patients with PCO refractry t medical agents. In a preliminary study, we perfrmed ultrasnic fllicular puncture withut aspiratin t develped fllicles 36 hurs after hcg administratin, aiming t achieve artificial vulatin. Only 1 f 1 patients with PCOD achieved pregnancy in subsequent cycles. 19 This result did nt satisfy us. The methd perfrmed in the present study has several benefits: (1) the effect f varian stimulatin n achieving vulatin can be illustrated; (2) diameters f fllicles failed t vulate becme largest during the midluteal phase; and (3) fllicular drainages can be successfully achieved as being in traditinal surgical prcedures. Therefre, we thught that the ptimal time fr ultrasnic fllicular aspiratin must be during the midluteal phase. Surprisingly, the rates f bth vulatin and pregnancy were quite high after fllicular aspiratin.'~j. The vulatin rate in patients with PCOD (grup If, A) was 87.5% per patient and 52.6% per fllw-up cycle. After the aspiratin, fur f the eight patients achieved pregnancy. Chen 2 reprted that 75% f PCOD patients wh had varian wedge resectin experienced regular menses after surgery with a crrected live birth rate f 56% r---'---_..j.~ Time (min) ~5 " : Time (min) Figure 3 Changes in serum levels f LH and FSH by GnRH challenge test befre ( - ) and after (. -.) ultrasnic fllicular aspiratin in PCOD. Pints and bars are means ± SEM. Each hatched area indicates nrmal range f bth gnadtrpins. Differences are significant befre (basal level) and 3 minutes (peak level) after the GnRH challenge test (P <.5). Vl. 56, N.6, December 1991 Mi et al. Ultrasnic fllicle aspiratin in pea 163

5 Recent reprts have indicated that electrcautery and laser vaprizatin t varies via laparscpy can prduce results cmparable with traditinal varian wedge resectin in terms f btaining vulatin and pregnancy.12-i4 The vulatin and pregnancy rates in the present study were equal t r higher than thse in previus methds. Mrever, we bserved a significant decrease in bth basal and peak levels f serum LH in the GnRH challenge test after the aspiratin in patients with PCOD, althugh n remarkable change was bserved in the serum FSH levels. Judd et aly reprted that althugh a reductin in serum T after surgery was bserved, the serum levels f LH and FSH after varian wedge resectin in CC-resistant patients with PCOD remained stable up t the time f LH surge in the cycle after surgery. These investigatrs cncluded that an intravarian mechanism may be respnsible fr vulatin after surgery. Gj6nnaess and Nrman21 demnstrated an increased respnsiveness f serum LH t GnRH after electrcautery in PCOD patients. Hwever, Sumiki et al.22 reprted that the mean LH level and the respnsiveness f LH t GnRH were markedly reduced after multiple-punch resectin f the vary perfrmed via laparscpy. Furthermre, Sakata et al.14 demnstrated that nt nly the level f biactive LH but als that f immunreactive LH fell significantly after laparscpic varian electrcautery. These studies imply that laparscpic methds that inflict limited damage n the varies significantly nrmalize the heightened pituitary sensitivity t GnRH. A similar result was btained in the present study with fllicular aspiratin. It is generally accepted that the secretin f excessive amunts f andrgen is the basis fr the anvulatin in PCOD patients.15 It is als thught that varian wedge resectin can reduce the andrgen level by either the resectin f sme amunt f varian tissue r trauma t the sterid-prducing tissue.15 Althugh transvaginal US-guided fllicular aspiratin des less extensive damage t the varian surface and is unlikely t affect the varian strmal tissue, this methd prduces a significant imprvement in the rates f vulatin and pregnancy and in endcrinlgic abnrmalities. Therefre, drainage f the fllicular cntents seems t be a key factr in releasing patients frm an endcrinlgicallymediated vicius cycle that may disturb nrmal fllicular grwth and vulatin in drug-resistant PCOD. Further studies f these endcrine changes are required. 164 Mi et al. Ultrasnic fllicle aspiratin in pca We als perfrmed transvaginal US-guided fllicular aspiratin in anvulatry patients with ultrasnic evidence f PCO withut hrmnal abnrmalities (grup B). In sme f these patients, degenerated cyte-crna-cumulus cmplexes were cllected frm persistent fllicles; thus the luteinized unruptured fllicle, first described by Jewelewicz,23 shuld have been included in the categry f "plycystic vary withut hrmnal abnrmality." Kerin et al. 24 reprted that luteinized unruptured fllicle was uncmmn with nly a spradic incidence in infertile patients. Hwever, Tda25 recently reprted that 13.5 % f 384 cycles in patients with unexplained infertility and wh had apparent vulatry cycles shwed luteinized unruptured fllicle n daily ultrasnic scanning. Mst patients with luteinized unruptured fllicle failed t vulate despite the administratin f medical therapy t induce vulatin. Furthermre, the severity f PCOD is nt necessarily related t its respnsiveness t medical treatment,3 and it may be difficult t differentiate patients wh have PCO frm thse with luteinized unruptured fllicle. Our experience in these patients was encuraging. The aspiratin f persistent fllicles prduced vulatin in all 1 patients with PCO withut hrmnal abnrmalities. The rate per fllw-up cycle f vulatin was 63.3%, and 5 f the 1 patients subsequently cnceived. These results were cmparable with thse btained in patients with PCOD. Because transvaginal US-guided fllicular aspiratin is cmmnly accepted as a much less invasive and simpler methd fr cyte pick-up in an IVF ET prgram, we believe that this methd is preferable fr treating anvulatry patients with PCOD r with PCO withut hrmnal abnrmalities. This methd is als helpful in clarifying the pathphysilgy f anvulatin such as PCOD and luteinized unruptured fllicle. Investigatins n hrmnal changes in serum and fllicular cntents befre and after the aspiratin will ffer sme answers fr the hyptheses cncerning the mechanism f the effect f US-guided fllicular aspiratin in patients assciated with PCO. REFERENCES 1. Stein IF, Leventhal ML: Amenrrhea assciated with bilateral plycystic varies. Am J Obstet Gynecl 29:181, Yen SSC: The plycystic vary syndrme. Clin Endcrinl (Oxf) 12:177, Swansn M, Sauerbrei EE, Cperberg PL: Medical implicatins f ultrasnically detected plycystic varies. J Clin Ultrasund 9:219, 1981 Fertility and Sterility

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