STRUCTURE AND FUNCTION OF THE FALLOPIAN TUBES FOLLOWING EXPOSURE TO DIETHYLSTILBESTROL (DES) DURING GESTATION*

Transcription

1 FERTILITY AND STERILITY Copyright c 1981 The American Fertility Society Vol. 36, No. 6, December 1981 PrinU!d in U.SA. STRUCTURE AND FUNCTION OF THE FALLOPIAN TUBES FOLLOWING EXPOSURE TO DIETHYLSTILBESTROL (DES) DURING GESTATION* ALAN H. DECHERNEY, M.D.t INA CHOLST, M.D. FREDERICK NAFTOLIN, M.D. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut The association between the use of diethylstilbestrol (DES) and vaginal and cervical adenocarcinoma and adenosis in the progeny was first reported by Herbst et al. 1 in This progeny will reach a peak as far as reproduction is concerned in this decade. It is estimated that 2 million women may be involved to varying degrees. Changes in uterine and cervical contour and structure have been detailed. Thus DES exposure and anatomic changes in the Mullerian system have been documented. In this report 16 women in the reproductive age group who were exposed to DES in utero and presented with infertility are discussed. On workup for infertility they were found to have unique tubal morphologic features consisting of a foreshortened, convoluted tube with "withered" fimbria with a pinpoint os at laparoscopy. The diagnosis could not be made at the time of hysterosalpingogram. Three patients had surgery in an attempt to correct this condition; and in all cases the surgery was unsuccessful. No statistical data is offered as to epidemiologic factors or incidence rates, but the suspected increase in infertility and ectopic pregnancy rates in patients with DES. exposure may corroborate these findings. Fertil Steril36:741, 1981 The association between the use of diethylstilbestrol (DES), a nonsteroidal estrogen, in pregnancy and subsequent vaginal and cervical adenocarcinoma and adenosis in the progeny was reported by Herbst et al. 1 in Although DES is no longer used as a treatment during pregnancy, the progeny in the reproductive age group and at risk will reach a peak in this decade. It is estimated that two million women may be involved to varying degrees through exposure to DES in utero. 2 In addition to the early reports ofadenosis and cancer, changes of uterine contour and morphologic features resulting in a "T-shaped" Received April 28, 1981; revised and accepted August 5, *Presented at the Thirty-Seventh Annual Meeting of The American Fertility Society, March 14 to 18, 1981, Atlanta, Georgia. treprint requests: Alan H. DeCherney, M.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut uterus, malformed cervix, and abnormal vaginas have been detailed. 3-6 Thus, DES exposure is associated with specific anatomic changes in Mullerian derivatives which entail functional deficits leading to infertility, pregnancy wastage, and ectopic pregnancy. In this regard, we report 16 women in the reproductive age group exposed to DES during fetal life who presented with infertility and unique tubal morphologic features. MATERIALS AND METHODS Sixteen patients who had a positive history of intrauterine DES exposure were evaluated at the Yale New Haven Hospital Infertility Clinic between September 1977 and December 1980 are presented. Infertility was defined as the inability to conceive after 1 year of unprotected intercourse. The history of DES exposure was documented in all patients by hospital records or by our contacting the obstetrician who delivered the

2 DECHERNEY 742 TABLE 1. Patient Profile Average age (yrs) Primary infertility Secondary infertility Ectopic pregnancy Surgery Repeated laparoscopy Hysterographic changes Laparoscopic changes Vaginal changes or colposcopic changes patient. This history was corroborated by the patient's own recollections. Dose and timing of DES were not uniformly available, although a majority (12/16) had documented first-trimester exposure to DES. Prior to laparoscopy all patients underwent a routine infertility evaluation, including history, pelvic examination, basal body temperatures, endometrial biopsy, postcoital test, and water-soluble media hysterosalpingogram. In addition, colposcopy and Pap smears were performed. All spouses had normal semen analyses. When these procedures were completed, all patients underwent diagnostic laparoscopy. Laparoscopy was performed without regard for the time of cycle in which the procedure was performed. Three patients eventually underwent laparotomy and surgery on their tubal lesions. At laparotomy a linear salpingostomy was performed on the antimesenteric side of the tube extending the incision 1 to 2 em and utilizing' microsurgical techniques. The free surface was tacked to the serosal edges with interrupted 6-0 Vicryl (Ethicon, Somerville, N.J.) in an attempt to increase the available fimbria! surface area. There were no complications in the surgery, and two patients were re-evaluated by laparoscopy 4 and 6 months after the original procedure, respectively. The study group was highly selected for DES-exposed i,nfertility patients, and therefore data on incidence and epidemiology cannot be arrived at. December 1981 cal, colposcopic, or vaginal abnormalities as well as the characteristic DES-associated changes seen by hysterosalpingography with the fallopian tubes uniformly appearing normal (Fig. 1). All patients underwent laparoscopy and were found to have "withered" tubes. The "withered" tube is described as a foreshortened, sacculated, convoluted tube with a pinpoint os and constricted fimbria (Figs. 2 and 3). Thirteen patients' tubes spilled indigo carmine dye bilaterally at the time of laparoscopy, and 3 had bilaterally occluded tubes with a predominant dimple and telangiectasia. These withered tubes were uniformly associated with multiple peritubal cysts. Three of the patients with primary infertility underwent laparotomy to correct this Mullerian change. None have conceived after 18 months, and 2 have had repeat laparoscopies 4 and 6 months, respectively, subsequent to the original procedure; 1 showed moderate improvement in fimbria! appearance and surface area, the other showed no improvement. No pregnancies have ensued. No attempt at determining the incidence of this deformity in DES-exposed women was made since laparoscopic findings were not available i~ all DES-exposed patients in our population. Pathologic specimens showed thinning of tubal epithelium, increased connective tissue and no inflammatory infiltrate (Fig..4). ' DISCUSSION Previous reports have documented Mullerian anomalies associated with intrauterine DES exposure such as cervical hoods and vaginal adenosis.1 Upper Mullerian changes have also been documented. The classic T:shaped uterus de- RESULTS After a routine infertility workup, the fallopian tubes of all 16 patients were found at the time of laparoscopy to have unique morphologic features. The average age of the 16 patients was 28 years. Ten patients had primary infertility. Six patients had secondary infertility; 2 have had second-trimester pregnancy losses; 3 have had an ectopic pregnancy; and 3 have had spontaneous first-trimester abortions. There have been three full term pregnancies in the study group (Table 1). Pelvic examination showed all16 patients to have cervi- FIG. 1. Hysterosalpingogram of at-shaped uterus and apparently normal tubes in one of the study patients.

3 Vol. 36, No.6 DIETHYLSTILBESTROL 743 In the daughter of the condition that led to the use of DES in the mother in the first place. Infertility FIG. 2. Appearance of a DES tube at the time of laparotomy in one of the study patients, showing the thinning of the wall and marked convolution, along with a pinpoint fimbrial open ing. scribed by Kaufman et al. 4 ' 5 serves as the best example. Cornual changes in the fallopian tube have also been described by Kaufman et al. 4 5 and Haney et al. 6 Changes distal to this point in the fallopian tube have not previously been reported. The tubal changes associated with DES can manifest functional as well as structural abnormalities, which, although interrelated, may be considered separately. In animals, there have been reports of abnormal tubes resulting from nonsteroidal estrogen agonist-antagonists during the perinatal period. However, the rodent's fallopian tube is capped by a furson, which covers the ovary and would retain any material shed from the tube to form "sterile abscesses" and the like. No report of "withered" tubes in DES-exposed animals has yet appeared. McCormack and Clark7 demonstrated in rats given clomiphene citrate that 14% of the offspring had degenerating epithelium. It is hypothesized by the authors that the ability of the one injection of clomiphene citrate to stimulate long-term estrogen stimulation to the Mullerian system during early fetal life effected changes similar to DES _exposure in the uterus. McLachlan et al., 8 in a study of female mice exposed in utero to DES, described a dose-related increase in oviductal abnormalities with abnormalities of anatomic relation to the ovary and decreased convolution noted at the highest dose. Boylan, 9 in a study of similarly exposed female rats, describes 3 animals (of 32) in which the oviducts were distended with viscous fluid. In humans, judgment must be tempered with the fact that some of the changes we report may not be due to DES exposure but to the inheritance Herbst et al. 3 studied 226 DES daughters and compared them with 203 exposed daughters whose mothers participated in a double-blind evaluation of gestational DES therapy 27 years before. They found that 86% of the unexposed and 67% of the exposed were able to achieve a pregnancy. Bibbo et al. 10 confirmed an increased rate of infertility, along with Berger and Goldstein, 11 who found only a 27% pregnancy rate, and Schmidt et al., 12 a 29.2% infertility rate. Barnes et al. 13 and Cousins et aly found no decrease in the fertility rate in exposed progeny. Rosenfeld and Bronson15 have pointed out the importance of the cervical factor as a cause for infertility in these patients, as well as the fact that the distorted uterine cavity possibly plays some role. Finally, the impact of timing and dose remain compounding factors. Assessment of infertility in these patients presents a problem, because incidence rates are difficult to obtain due to the lack of an appropriate control population. This is true of other studies cited as well, "12 14 since some are based on chart review and others had skewed patient selection procedures. Hysterosalpingogram The classic findings in DES-exposed daughters are changes within the uterus. 4 5 Forty of60 DES patients studied by Kaufman et al. 4 had uterine anomalies, such as the classic T -shaped uterus, and infertility, as illustrated in Figure 1. Thirty- FIG. 3. Appearance of a DES tube showing marked decreases in fimbrial tissue and almost total occlusion.

4 744 DECHERNEY FIG. 4. Pathologic slide of a human fallopian tube exposed to DES during gestation. six of these women had associated cervical and vaginal changes. In a second study, 267 exposed women were studied. 5 Sixty-nine percent of the patients studied had uterine anomalies, the occurrence of which could be correlated with the time in gestation that the DES was given. In those women given DES at less than 12 weeks, 71% of the daughters had an abnormality, as opposed to 40% whose mothers were given DES after 12 weeks of gestation. Hendricks et al. 16 was unable to show a correlation between the time of exposure in utero with outcome in macaca mulatta. Berger and Goldstein 11 found that of their patients had a uterine anomaly, and Haney et al., 6 using the planimeter, found when calculating these gross changes in the uterus no associated changes in the fallopian tubes distal to the cornual portion. In our hands it appears that the hysterosalpingogram is a crude way of establishing information about tubal structures other than patency. Ectopic Pregnancy A four- to fivefold increase over the normal incidence of ectopic pregnancy has been reported in DES-exposed women, " compared with a normal incidence of approximately 1%. 19 Clinically this increased ectopic rate suggests a corroboration of our findings of an anatomic distortion of the tube with alteration in function. The spontaneous abortion rate, in comparison, is only slightly increased in the first trimester and possibly due to a uterine factor (Table 2). We report on 16 women who have a unique finding on laparoscopy, who are DES-exposed December 1981 daughters, and who are infertile. The tubal anatomic change noted is the so-called "withered" tube. All the patients in this study had the classic hysterosalpingography findings, i.e., a T-shaped uterus, but no significant findings in terms of tubal changes were noted on the hysterosalpingogram. The diagnosis was made at laparoscopy. This observation, coupled with the increased rate in ectopic pregnancy, bespeaks the fact that DES in utero does have an effect on the fallopian tube, which is a Mullerian structure. This effect is perhaps dose-related, but specific evidence is not available. The management of these infertile patients is not at the present time surgical. Three of these patients were operated on to improve fimbria! surface area, but none of them have conceived, and two patient~? at the time of repeat laparoscopy had no significant improvement in the previous condition of the fallopian tube. Up to the present time, there has been no description of abnormal tubes in DES patients. However, the widespread nature of DES association with Mullerian abnormalities, the suspected increase of unexplained infertility, and particularly the increased incidence of tubal pregnancy all indicate that there may be an associated abnormality of the tubes, either morphologic or functional, or both. The patients described in this paper all had similar unique tubal morphologic features, consisting of foreshortened thin-walled, convoluted "withered" tubes with absent or minimal fimbria! tissue and a pinpoint os. This "withered" tube is unlike any known spontaneously occurring tubal anomaly. Three of the patients in this study did achieve intrauterine pregnancies; thus the "withered" tube is not an absolute impediment to conception but rather a relative one. Since it is not possible to perform a case-controlled study, the results of this report cannot be extrapolated to the general DES-exposed population. TABLE 2. Ectopic Pregnancy Rate and Spontaneous Abortion Rate in Patients Exposed to DES in Utero Ectopic al. 13 Barnes et Berger and Goldstein11 Cousins et al. 14 Herbst et al. 3 Kaufman et al. 4 Schmidt et al. 12 (8/220) (3/69) (2/43) (4189) (2/60) (7/129) 3.6% 4.3% 4.6% 4.4% 3.3% 5.4% Abortion 25.9% 30.6% 13.8% 18.0% 32.0% 17.3% ) I \

5 Vol. 36, No.6 DIETHYLSTILBESTROL 745 REFERENCES 1. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878, Glebatis DM, Janerich DT: A statewide approach to diethylstilbestrol-the New York Program. N Engl J Med 304: 47, Herbst AL, Hubby MM, Blough RR, Azizi F: A comparison of pregnancy experience in DES-exposed and DES-unexposed daughters. J Reprod Med 24:62, Kaufman RH, Binder GL, Gray PM, AdamE: Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Am J Obstet Gynecol 128:51, Kaufman RH, Adam E, Binder GL, Gerthoffer E: Upper genital tract changes and pregnancy outcome in offspring exposed in utero to diethylstilbestrol. Am J Obstet Gynecol 137:299, Haney AF, Hammond CB, Soules MR, Creasman MT: Diethylstilbestrol-induced upper genital tract abnormalities. Fertil Steril 31:142, McCormack S, Clark JH: Clomid administration to pregnant rats causes abnormalities of the reproductive tract in offspring and mothers. Science 204:629, McLachlan JA, Newbold RR, Bullock BC: Long term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 40:3988, Boylan ES: Morphological and functional consequences of prenatal exposure to diethylstilbestrol in the rat. Bioi Reprod 19:854, Bibbo M, Gil WB, Azizi F, Blough R, Fang VS, Rosenfeld RL, Schumacher GF, Sleeper K, Sonek,MG, Wied GL: Follow-up study of male and female offspring of DES exposed mothers. J Obstet Gynecol 49:1, Berger MJ, Goldstein DP: Impaired reproductive performance in DES exposed women. Obstet Gynecol 55:25, Schmidt G, Fowler WC, Talbert LM, Edelman DA: Reproductive history of women exposed to diethylstilbestrol in utero. Fertil Steril 33:21, Barnes AB, Colton T, Gundersen J, Noller KL, Tilley BC, Strama T, Townsend DE, Hatab P, O'Brien PC: Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med 302:609, Cousins L, Karp W, Lacey C, Lucas W: Reproductive outcome of women exposed to diethylstilbestrol in utero. Obstet Gynecol 56:70, Rosenfeld DL, Bronson RA: Reproductive problems in the DES-exposed female. Obstet Gynecol 55:453, Hendricks AG, Benirschke K, Thompson RS, Ahern JK, Lucas WE, Oi RH: The effects of prenatal diethylstilbestrol (DES) exposure on the genitalia of pubertal macaca mulatta. J Reprod Med 22:233, Barnes AB: Menstrual history of young women exposed in utero to diethylstilbestrol. Fertil Steril 32:148, Siegler AM, Wang CF, Friberg J: Fertility of the diethylstilbestrol-exposed offspring. Fertil Steril 31:601, DeCherney AH, Minken MJ, Spangler S: Contemporary management of ectopic pregnancy throughout ultrasound. J Reprod Med 26:519, 1981