FERTILITY AND STERILITY Copyright c 1978 The American Fertility Society Vol. 29, No.3, March 1978 Printed in U.S.A. LUTEINIZED UNRUPTURED FOLLICLE SYNDROME: A SUBTLE CAUSE OF INFERTILITY* JAROSLA V MARIK, M.D. JAROSLA V HULKA, M.D.t The Tyler Clinic, Los Angeles, California 90024, and Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2714 A clinical description of luteinized unruptured follicles is presented, This abnormality in ovulation is characterized by normal endocrinologic presumptive signs of ovulation: biphasic basal body temperature curves, secretory endometrium, and laboratory evidence of progesterone production by elevated urinary pregnanediol or plasma progesterone levels. In a group of 102 such infertile women, laparoscopy performed 3 to days after apparent ovulation revealed the absence of a corpus hemorrhagicum in women, and the absence of a stigma on a corpus hemorrhagicum in an additional women. These findings were evidence that a follicle had not ruptured and an ovum had not escaped. Of 28 patients undergoing follicular stimulation with clomiphene citrate or human menopausal gonadotropin after this diagnosis, 1 conceived. Ovulation is defined anatomically as the rupture of a follicle and the release of an ovum. Clinically, however, this process has been observed only once in the human.! The clinical diagnosis of ovulation is based on presumptive signs of the formation of luteinization: basal body temperature elevations, the presence of a secretory endometrium, and increased blood progesterone levels. Recent careful observations of the ovaries of patients with apparent ovulation but with infertility problems have revealed that in some instances changes characteristic ofluteinization occur in the absence of rupture of a follicle and release of an egg. The purpose of this paper is to describe this syndrome and to suggest its diagnosis and management. GROSS ANATOMICAL CHANGES Normal Ovulation. If a patient is selected for diagnostic laparoscopy 2 to days after elevation Received April 6, 1977; revised September 12, 1977, and October 10, 1977; accepted October 18, 1977. * Presented at the Mott Center Symposium on Human Ovulation, April 21, 1977, Detroit, Mich. treprint requests: Jaroslav Hulka, M.D., Department of Obstetrics and Gynecology, University of North Carolina, Old Clinic Building, Chapel Hill, N. C. 2714. of the basal body temperature, one ovary should contain a vascularized structure (corpus hem orrhagicum) at the surface of the ovary or protruding from it (Fig. 1). Somewhere on the surface of this structure there will be an opening 1 to 2 mm in diameter, indicative of the site of follicular escape-the so-called "stigma." This stigma can become re-epithelialized within a few days of rupture of the follicle, so that timing of laparoscopic observation to coincide closely following the date of suspected ovulation is important. The red corpus hemorrhagicum is that month's "corpus luteum." If the red "in vivo" structure is removed and drained of blood, as happens in pathology and anatomy laboratories, the yellow lipid-laden cells remain to give the structure a yellow appearance. Other yellow corpora lutea may be seen in vivo in the same or opposite ovary, representing previous months' structures undergoing involution. These corpora lutea should not be confused with the current month's active vascularized structure, but are helpful in documenting that corpora lute a had developed in recent months as well. Abnormal Luteinization. In some patients, examination of the ovaries 2 to days after elevation of the basal body temperature, in the pres- 270
LUTEINIZED UNRUPTURED FOLLICLE SYNDROME Vol. 29, No.3 271 FIG. 1. Normal corpus hemorrhagicum with stigma. Notice the clearly defined crater in the middle of the vascularized structure on the surface of the ovary. This is the normal finding in a follicle which has ruptured, released an ovum, and is undergoing active luteinization and vascularization. ence of secretory endometrium by biopsy and the presence of elevated blood progesterone levels, will sometimes reveal that there is no corpus hemorrhagicum on the surface of the ovary. If one is present, careful inspection of the surface of this structure will fail to reveal any sign of a stigma, but a smooth, glistening surface will be apparent (Fig. 2). In these situations, unruptured follicles have been luteinized. MATERIALS AND METHODS Patient Selection. At the Tyler clinic, 20 consecutive laparoscopies for infertility from January 197 to March 1977 were reviewed. At the time of surgery, planned for 3 to days after ovulation, most patients had maintained basal body temperature records and had had urinary pregnanediol studies (in 197) or plasma progesterone levels analyzed (in 1976) on the day of admission for laparoscopy. Dilatation and curettage were routinely performed at laparoscopy unless this procedure was irrelevant (e.g., the patient had massive, inoperable adhesions). Patients whose ovaries could not be completely inspected because of adhesions or pelvic pathology or whose curettings failed to reveal secretory endometrium were not included in the study (see Table 1). RESULTS Secretory endometrium was found and ovaries were visualized in 102 patients. In 62 of these, either a corpus hemorrhagicum was visualized with no stigma ( patients) or no corpus hemorrhagicum was visualized ( patients) (Table 1). The distribution of data confirmatory for progestational activity according to elevated pregnanediol levels (in 197) or plasma progesterone levels (in 1976) and basal body temperatures (BBTs) is presented in Table 2. Proliferative endometrium with a freshly ruptured corporus hemorrhagicum was seen in three patients not included in the above analysis.
March 1978 MARIK AND HULKA 272 FIG. 2. Luteinized unruptured follicle. On the surface of the ovary, a vascularized structure is visible, but it has a continuous, smooth surface and no pattern suggestive of rupture or stigma formation. Although luteinization and vascularization are occurring, causing progestational changes characteristic of the normal luteal phase, no ovum has been released from this ovary. Pathology. Pathology associated with luteinized unruptured follicles is summarized in Table 3. Except for the absence of visible corpora hemorrhagica associated with endometriosis in 37% of these patients, adhesions and endometriosis appeared to be similarly distributed among women with normal and abnormal morphology. Pregnancies. Pregnancies were studied by chart review. Not all patients with a discrepancy between ovarian morphology and progestational activity received therapy, because of other factors (obstructed tubes, absent tubes, or extensive tubal adhesions) or because they failed to return for TABLE 1. Tyler Clinic Infertility Laparoscopies, January 197 to February 1977 Total no. of diagnotic laparoscopies performed Secretory endometrium, ovaries visualized Corpus hemorrhagicum, normal stigma Corpus hemorrhagicum, no stigma 20 102 40 continuing care. Of those suitable for treatment, received treatment and 18 conceived. Patients initially received 0 or 100 mg of clomiphene citrate (Clomid) from day to day 9 of the menstrual cycle. (Four patients received 100 mg ofclomid plus 10,000 units of human chorionic gonadotropin (RCG) on day 14 or day 1.) When this regimen did not result in pregnancy in 2 or 3 months the patients received Pergonal from day TABLE 2. Confirmatory Evidence of Progesterone Secretion in Abnormal Ovaries Diagnostic procedure Corpora hemorrhagica, no stigma Biopsy only Biopsy and BBTs Biopsy, BBTs, and progesterone Biopsy and progesterone No corpora hemorrhagica Biopsy only Biopsy and BBTs Biopsy, BBTs, and progesterone Biopsy and progesterone No. of patients 10 12 10 7 8
Vol. 29, No.3 LUTEINIZED UNRUPTURED FOLLICLE SYNDROME 273 Laparoscopic finding Normal corpus hemorrhagicum with stigma Normal corpus hemorrhagicum, no stigma TABLE 3. Pathology Associated with Luteinized Unruptured Follicle Total no. of patients 40 Adhesions Endometriosis No. of patients % No. of patients % 23 7 12 20 6 3 9 18 60 11 37 to day 13. The dose was adjusted from one to three vials per day depending on frequent evaluations of cervical mucus secretion or vaginal cytology, and was carried to a maximum oftwentytwo vials per cycle. The patients then received 10,000 units of HCG on day 14. Twelve patients underwent such a course. These treatments are summarized in Table 4, separated according to pathology found and results. Only of the 28 women became pregnant with Clomid therapy alone, whereas 8 of 12 treated with Pergonal became pregnant. Two patients with no corpora hemorrhagica conceived, aborted, and conceived again to carry to term after Pergonal therapy. DISCUSSION Other workers in this field have alluded to the possibility that an egg can become "entrapped" and thus resulted in infertility.2. 3 The term "luteinized unruptured follicle" was first used by Jewelewicz 4 in describing the management of anovulatory conditions. To our knowledge, however, no one has documented the incidence of this condition in an infertility population. Physiologic processes do not occur with absolute predictability. Rather, they occur at high frequency with a predictable pattern, but with differing degrees of deviation around that pattern. The complex process of ovulation, involving maturation of a particular follicle, rupture of the follicle, and subsequent luteinization and produc- TABLE 4. Pregnancies in Women with Luteinized Unruptured Follicles following Ovarian Stimulation No. of patients No. of patients Laparoscopic finding and treatment treated pregnant CorpUS hemorrhagicum, no stigma Clomid 7 3 Clomid + HCG 2 2 Pergonal + HCG 2 Endometriosis suppression 2 2 No treatment (3) Clomid 2 Clomid + HCG 2 0 Pergonal + HCG 7 6 Endometriosis suppression 2 1 No treatment (1) Total 18 tion of progesterone, has an orderly ideal sequence. However, these data serve to illustrate that in some individuals the failure to conceive could be due to a subtle deviation from this orderly sequence. Three patients had visible corpora hemorrhagic a with a stigma, but their endometrial biopsies revealed proliferative endometrium. In these women, follicular rupture was out of phase with luteinization. Forty patients in this series had the ideal ovulatory sequence- evidence of a ruptured follicle on the surface of the ovary together with evidence of progesterone production. Some patients, however, deviated from this orderly pattern in that some follicles did not rupture ( patients) and a luteinizing structure did not appear at all on the surface of the ovary ( patients) (see Table 1). The failure of a follicle to rupture is probably due to an "inadequate" follicular phase. This premise is supported by the greater pregnancy rate following direct follicular stimulation with Pergonal (8 pregnancies in 12 women) than following indirect ovarian stimulation with clomiphene citrate ( pregnancies in 28 women). The relationship between this "inadequate" follicular phase problem and the "inadequate" luteal phase problem cannot be determined from these data, since dilatation and curettage at the time of laparoscopy rendered the subsequent mentrual pattern impossible to evaluate. It is always possible that seeing one event in a patient's monthly activity may not be representative of all cycles. This indeed must have been true for the four patients who became pregnant spontaneously without therapy (see Table 4) and can be used as a criticism of our therapeutic assumption that one laparoscopic observation was representative of an individual woman's pattern of ovulation. It is equally as valid to assume that infertile women with normal ovulatory mechanisms may undergo laparoscopy in an occasional cycle with an abnormal ovulatory pattern as it is to assume that infertile women with abnormal ovulatory mechanisms may undergo laparoscopy in an occasional cycle with a normal ovulatory pattern. The distribution of abnormalities in this group of endocrinologic ally ovulating infertile
274 MARIK AND HULKA March 1978 women (40 normal ovaries, 62 abnormal) indicates that abnormalities of follicular rupture may be more frequent than has been appreciated until now. Thus our assumption that the presence of a normal stigma establishes a woman as normal may be just as erroneous as our therapeutic assumption that the absence of a stigma requires ovarian stimulation. Despite this problem inherent in a one-look surgical diagnosis, of 28 previously infertile patients with no other obvious infertility factor, the administration of ovarian stimulatory agents such as Clomid or Pergonal resulted in subsequent pregnancy in 1 (Table 4, excluding patients with endometriosis). It is difficult to draw any conclusion other than a causal relationship between the administration of these agents and subsequent pregnancy. It is therefore difficult to deny the possibility that these patients had abnormal ovulatory mechanisms which resulted in unruptured luteinized follicles and caused their infertility. REFERENCES 1. Frangenheim H: Movie of human ovulation. Presented at the First American Association of Gynecologic Laparoscopist's Symposium, Las Vegas, November 14, 1972 2. Kistner RW: Personal communication: "... the late Dr. Mike Leventhal who felt that some patients with polycystic ovarian syndrome did not really ovulate subsequent to the administration of Clomid. Mike felt that a good number of the follicles were brought almost to maturation by the administration of the Clomid and that perhaps one, or more, of these follicles would rupture beneath the cortex of the ovary and thus produce either luteinized follicles, or a corpus luteum, without release of the ovum from the ovary. He, thus, used the term 'entrapped ovum' and, if I have used it somewhere or you have seen it, which undoubtedly you have, that is the source." 3. El-Fouly MA, Cook B, Nekola M, Nalbandov AV: Role of the ovum in follicular luteinization. Endocrinology 87: 288, 1970 4. Jewelewicz R: Management of infertility resulting from ovulation. Am J Obstet Gynecol 122:909, 197