me LUTEINIZED UNRUPTURED FOLLICLE SYNDROME AND ENDOMETRIOSIS

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1 FERTILITY AND STERILITY Copyright c 980 The American Fertility Society Vol. 33,, JanuaEY 980 Printed in U.S.A. me LUTEINIZED UNRUPTURED FOLLICLE SYNDROME AND ENDOMETRIOSIS W. PAULDMOWSKI, M.D.,.PH.D.* RAMAA RAO, M.D. ANTONIO SCOMMEGNA, M.D. Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center, University of Chicago School of Medicine, Chicago, Illinois 6066 The identity 'of luteal.structureti was evaluated laparoscopically in 99 women. All had evidence of ovulation as judged by dated endometrial biopsies and/or elevated levels of plasma progesterone or urinary pregnanediol. Luteal structures. were identified in 9 cases. The stigma was present. in 32%, absent in 38%, and questionable in 30% of the latter. No significant differences in the distribution of thes.e findings were observed between patients with endometr.iosis and patients with male or tubal causes of infertility. However, in patients with clinically diagnosed ovulatory dysfunction, stigmata were observed significantly less frequently. The frequency of stigmata was not related to the varying severity of endometriosis. The earliest time in the menstrual cycle when the stigma was identified was on the day of the basal body temperature (BBT) dip.prior to its rise and when the endometrium was late-proliferative. The latest was days after the BBT dip and on day 26 according to endometrial histology. Uncertainty as to the presence of the stigma was frequent. The stigma was present in 33% of women with endometriosis. In some, a corpus luteum with the stigma and endometriosis were present on the same ovary. The hypothesis postulated by some investigators that the luteinized unruptured follicle (LUF) syndrome may be the cause of infertility in women with endometriosis does not appear to be accurate. However, endocrine factors probably playa role in the origin of LUF. Fertil Steril33:30,980 Several publications have recently drawn atten~ tion to the occurrence of "luteinized unruptured follicles" (LUF) in infertile women.l-3 Such a follicle is thought to contain the entrapped ovum amidst luteinized granulosa cells, which secrete progesterone. In such patients plasma progesterone levels and, accordingly, urinary pregnanediol levels, endometrial histology, and all other ovulation detection tests which depend on changes in progesterone secretion indicate the occurrence of ovulation. In actuality; however, patients with the LUF syndrome do not ovulate and remain infertile. Received June 27, 979; revised August 27,979; accepted August 30, 979. *Present address and address for reprint requests: W. Paul Dmowski, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, 430 W. Markham, Little Rock, Ark The diagnosis of the L UF syndrome has been based on visual, almost exclusively laparoscopic, examination of the surface of the luteal structure, to identify the site of the ovum release-the socalled "stigma." If the stigma is identified, a normal corpus luteum is diagnosed. If the stigma is absent, the LUF syndrome is presumed. Unfortunately, none of the authors has corroborated his visual observations with histologic identification of the entrapped ovum. Nevertheless, luteinization of the follicle without release of the ovum can be induced experimentally in animals using various endocrinologic approaches 4 and could be the cause of infertility in many patients. A frequent association between LUF and endometriosis has been reported by two independent groups.l,3 In one report,3 79% of patients with endometriosis were considered to have evidence of LUF, whereas in the other reportl this percentage

2 Vol. 33, LUTEINIZED UNRUPTURED FOLLICLE SYNDROME AND ENDOMETRIOSIS 3 was only 6. Is the LUF syndrome the primary cause of infertility in patients with endometriosis? In the present study, we attempted to examine such a possibility. MATERIALS AND METHODS The subjects in this retrospective study were 99 infertile women from the authors' medical practice, which is limited exclusively to reproductive endocrinology and infertility. All subjects underwent a laparoscopic examination during ofthe 6 consecutive years between 973 and 979 in the luteal phase of the cycle. All had evidence of ovulation as judged by dated endometrial biopsies and! or plasma progesterone levels > ng/ml and/or urinary pregnanediol levels >2 mg/24 hours (Table ). Endometrial biopsies were performed at the time of laparoscopy and were dated according to the criteria ofn oyes et al. Plasma progesterone levels were determined using a specific radioimmunoassay technique 6 on 3 consecutive days-the day before, the day of, and the day after laparoscopy-and the average value was calculated. Urinary pregnanediol levels prior to 97 were determined in 24~hour urine samples collected during hospitalization for laparoscopy, using an assay technique previously described. 7 Laparoscopywas performed by one of the authors in each case. In all 99 patients, both ovaries were well visualized. Patients with pelvic adhe" sions or other lesions preventing adequate visualization of the gonads were excluded from the study. The presence or absence ofthe luteal structure and its location were noted and charted on the special form.8 The luteal structure was examined for the presence of the stigma, and an appropriate note was made. In some patients, laparoscopic photographs were obtained. In tabulating the data, we recorded the presence or absence of the luteal structure and the presence or absence of the stigma. The presence of the stigma was considered questionable when recorded as such by the laparoscopist or when no mention regarding this structure was made. Basal body temperature (BBT) was recorded during the hospitalization cycle in 2 of 99 patients. All data on the identity of the luteal structure and its presence or absence were tabulated separately in patients with endometriosis, male or tubal causes of infertility, and in patients with evidence of ovulatory dysfunction. Endometriosis was diagnosed and classified as mild, moderate, or severe on the basis oflaparoscopic findings. 9 Other infer- TABLE. General Patient Information of patients Laparoscopic examination showing evidence of ovulation and well-visualized ovaries Secretory endometrial changes Plasma progesterone > ng/ml Urinary pregnanediol >2 mg/24 hours 8 9 Secretory endometrium and elevated plasma progesterone or urinary pregnanediol Secretory endometrium and < ng/ml plasma 29 progesterone (pregnanediol <2 mg/24 hours) Plasma progesterone > ng/ml (pregnanediol 4 2 >2 mg/24 hours) and proliferative endometrium Laparoscopic findings Luteal structures identified 9 00 Stigma present 2 32 Stigma absent 6 38 Stigma questionable tility-causing disorders were identified through a complete infertility and endocrine work-up. The term "ovulatory dysfunction" as used here describes a heterogeneous group of disorders in patients with evidence of various ovulatory problems (e.g., short or poor luteal phase, anovulation, or oligo-ovulation) based on the BBTs, endometrial biopsies, and endocrine studies. The data were analyzed for statistical significance using the X 2 test. RESULTS Presumptive evidence of ovulation was present at the time of laparoscopy in all 99 patients included in the study (Table ). In all of them, the ovaries were accessible to laparoscopic examination. In 40, both endometrial histology and the plasma progesterone level (urinary pregnanediol) were indicative of ovulation. However, in 29 women a low plasma progesterone concentration (urinary pregnanediol) was associated with secretory changes in the endometrium; in 4 women the endometrium was proliferative in the presence of an elevated plasma progesterone level (urinary pregnanediol). The luteal structure was identified in 9 patients (80%) and in 40 it was not seen in spite of an elevated plasma progesterone level and. secretory endometrium. Interestingly, in of 40 patients with "absent luteal structure," conception occurred during the cycle of laparoscopy, which was performed days after the BBT dip. About onethird of the luteal structures had identifiable stigmata(table ). The stigma was absent in 38% and '*

3 32 January 980 D-MOWSKI ET AL. TABLE 2. Luteal Structures and Their Identity in Women with Endometriosis Corpus luteum not seen Corpus luteum identified with stigma Extent of endometriosis of patients Present Questionable Absent 0/, 'if 0/, lj;' Mild Moderate U Severe b Total USignificantly different bsignificantly different (P (P < 0.00) from mild endometriosis findings. < 0.0) from mild endometriosis findings. questionable in 30% of cases. In of 46 patients with a questionable stigma, conception occurred during the hospitalization cycle. Laparoscopy in this patient was performed 7 days after the BBT dip. The earliest time during the menstrual cycle when the stigma was observed was the day of the BBT dip. On that day, late-proliferative endometrium was diagnosed on the endometrial biopsy report. The latest time during the cycle when the stigma was noted occurred days after the BBT dip and on day 26 according to endometrial histology. The frequency with which various luteal structures were or were not identified in patients with mild, moderate, or severe endometriosis is summarized in Table 2. Over-all, the stigma was present in 33% of patients with endometriosis, absent in %, and questionable in 2%. In approximately % of women with this condition, a luteal structure could not be identified in spite of elevated plasma progesterone levels and secretory endometrium. In many patients, the stigma could be positively identified even if endometriosis and corpus luteum involved the same ovary (Fig. ). However, in one of every four women with endometriosis, the stigma was not present on the luteal structure and the LUF syndrome could be diagnosed (Fig. 2). When evaluated statistically, all findings in patients with mild endometriosis were distributed differently from those in patients with moderate or severe disease (P < 0.00 and P < 0.0, respectively). This difference, however, is related primarily to the fact that in patients with moderate or severe disease luteal structures were noted much less frequently. There was no significant difference in the presence or absence of the stigma in patients with varying severity of endometriosis. These observations made in patients with endometriosis were compared with the corresponding data in patients with male or tubal causes of infertility and in patients with ovulatory dysfunction (Table 3). There was no significant difference FIG.. Laparoscopic photograph demonstrating corpus luteum with the stigma (a) and endometriotic plaque (b) involv ing the same ovary. FIG. 2. Laparoscopic photograph of the pelvic organs. Note luteal structures on the left ovary (a) and right ovary (b) and multiple endometriotic implants (cl.

4 Vol. 33, LUTEINIZED UNRUPTURED FOLLICLE SYNDROME AND ENDOMETRIOSIS 33 TABLE 3. Luteal Structures and Their Identity in Women with Endometriosis or Other Causes of Infertility Corpus luteum identified with stigma Corpus luteum not seen Diagnostic entity of Present Absent Questionable patients (k % 'Ii 'Ii Endometriosis Male or tubal fac to~ Ovulatory dys functionb a Findings not significantly different from endometriosis. bfindings significantly different (P < 0.00) from endometriosis. in the distribution ofthe findings between patients with endometriosis and patients with male or tubal causes of infertility. However, the stigma was observed less frequently in patients with ovulatory dysfunction than in patients with endometriosis (P < 0.00) and patients with male or tubal causes of infertility (P < 0.0). DISCUSSION The hypothesis postulated by Brosens et ai. 3 that LUF may be the cause of infertility in women with endometriosis, although attractive, does not appear to be accurate. The authors themselves were able to identify the stigma in 2% of their patients with endometriosis. In another report by Marik and Hulka,l 26% of women with endometriosis showed stigmata, whereas in the present study this percentage was 33. To allow a meaningful comparison, we tabulated our data, excluding patients with questionable stigmata, along with the results published previously (Table 4). The frequency of stigmata present on the luteal structure in patients with endometriosis was not different statistically in our study and that of Marik and Hulka. Results in both studies, however, differed significantly from the data reported by Brosens et ai. 3 Furthermore, the latter study differed from the other two significantly in the incidence of stigmata it reported in a control population. Of 6 patients with tubal or male factor studied by Brosens et ai., 3 (94%) had evidence of a stigma. Marik and Hulka, on the other hand, reported only a 38% incidence of stigmata among their patients with pelvic adhesions. The latter figure is close to that observed in the present study; that is, a 0% incidence of stigmata among patients with male or tubal factors. There is no question that recognition of the stigma is directly related to the experience of the laparoscopist, the quality of his instruments, his ability to manipulate the ovaries and examine them thoroughly, and perhaps the time in the cycle. In our study, we were not able to identify the corpus luteum in at least one patient who underwent laparoscopy days after the BBT dip and who conceived in the same cycle. In another patient who also conceived during the laparoscopy cycle, we were uncertain of the presence of a stigma 7 days after the BBT dip. Similarly, in as many as 7% of patients, we were unable to state without a doubt whether the stigma was present. There is no information available as to the time in the cycle when the stigma should be seen ini tial- TABLE 4. Endometriosis and LUF Syndrome: Laparoscopic Identification of Ovulation Stigmata corpus luteum with No corpus luteum Investigator Diagnostic group of eases Stigmata present Stigmata absent 'Ii 'Ii 'Ii Marik and Hulka Endometriosis Adhesions Koninckx et al. 2 Tubal or male factor Unexplained infertility Brosens et al. 3 Endometriosis Tubal or male factor Present study Endometriosis Tubal or male factor ~ Ovulatory dysfunction

5 34 DMOWSKI ET AL. ly and when it should be seen no longer. In some of our patients, the stigma could be detected on the day of the BBT dip, when the endometrium was still late-proliferative and the plasma progesterone concentration was at the beginning of its rise.. On the other hand, the stigma still could be clearly noted as late as days after the BBT dip, when the endometrium was dated histologically as day 26. Since all of our patients had infertility problems we cannot be sure whether similar findings are demonstrable in normal women. There was no significant difference in the incidence of the stigma among patients with differing severity of endometriosis (Table 2), although such a finding was reported by Brosens et al. 3 It appears, however, that "absence" of the corpus luteurn was more frequent in patients with more advanced ovarian endometriosis. The possibility exists that some corpora lutea or luteal cysts in these patients may have been mistaken for small endometriomas. A relatively low percentage (2) of recognizable stigmata among patients with apparent endocrine dysfunction and ovulatory problems is confirmatory of the clinical impression in that group (Table 3). We may therefore conclude that in women as in January 980 animals endocrine factors may play a role in the LUF syndrome. REFERENCES. Marik J, Hulka J: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, Koninckx PR, Heyns WJ, Corvelyn PA, Brosens IA: Delayed onset of luteinization as a cause of infertility. Fertil Steril 29:266, Brosens la, Koninckx PR, Corvelyn PA: A study of plasma progeste'rone, oestradiol-7~, prolactin and LH levels, and of the luteal phase appearance of the ovaries in patients with endometriosis and infertility. Br J Obstet Gynaecol 8:246, Litwack G: Biochemical Actions of Hormones, Vol 4, New York, Academic Press, 977, p 0. Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril:3, Auletta FJ, Agins H, Scommegna A: Prostaglandin F mediation of the inhibitory effect of estrogen on the corpus luteum of the rhesus monkey. Endocrinology 03:83, Scommegna A, Chattoraj SC: Automated analysis of urinary steroids. Obstet Gynecol 32:277, Cohen MR: Endoscopic evaluation of the ovary. In Human Ovulation, Edited by ESE Hafez. New York, Elsevier North Holland Publishing Co, 979, p Dmowski WP, Cohen MR: Treatment of endometriosis with an antigonadotropin, danazol. Obstet Gynecol46: 47, 97