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Thou shalt luteinize, not rupture
FERTILITY AND STERILITY Copyright (t 1987 The American Fertility Society
Vol. 47 , No . 5, May 1987 Printed in U.SA.
Thou shalt luteinize, not rupture
Sezer Aksel, M.D. Professor Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of South Alabama, Mobile, Alabama
Received March 17, 1987. Reprint requests: Sezer Aksel , M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of South Alabama, College of Medicine, CC/CB 326, Mobile, Alabama 36688. 762
Aksel Editor's corner
A puzzling phenomenon is observed in cyclic women when the preovulatory follicle reaches a diameter associated with maturity and continues to grow without rupture. As if obeying an intraovarian command, the enlarging follicle, with the oocyte entrapped within its luteinized walls, maintains the integrity of its basal membrane after the luteinizing hormone (LH) surge has occurred and may reach a size that could become symptomatically uncomfortable for the patient. This continual growth of the follicle does not appear to alter the luteinizing effects of LH on its peripheral granulosa and theca cells. Progesterone (P) synthesis commences as if ovulation had occurred, and gradually rising P concentrations, in time, produce specific changes associated with the presumed ovulation, such as the biphasic shift on the basal body temperature record, secretory changes in the endometrial cells, and alteration in the quality of the cervical mucus. When a large discrepancy exists between the numb.er of presumed ovulations and the actual extrusion of the oocytes, the chances for the sperm and ovum to meet are decreased. Therefore it is no wonder that the luteinized unruptured follicle (LUF) syndrome would be more prevalent in infertile women. Ovulation is a complex process. The sequence of events starts with the selection of the dominant follicle, its maturation, and extrusion of the oocyte and terminates with the formation of the corpus luteum. There is some evidence that the primate ovary may control its own destiny. Through the interaction of several intraovarian mediators or regulators, the ovary appears to select and support the dominant follicle. 1 The ovary with a clearly identifiable preovulatory follicle is responsible for the high estradiol concentrations measurable in the venous blood draining that ovary. 2 Furthermore, the ovary in the juvenile rhesus monkey, receiving pulsatile gonadotropin-releasing hormone, appears to signal its readiness for ovulation by increasing estradiol levels into a critical range. 3 Commonly, during ovulation, the follicular responses to the ovulatory signal triggered by LH include extrusion of the oocyte, luteinization of the granulosa and theca cells, and formation of the corpus luteum. One may speculate that if these concomitantly occurring events are dissociated, luteinization without rupture may occur, although the reverse is more likely. Dissociation of LH action may be due to intra- or extraovarian factors altering the hormonal and/or chemical composition of the follicular fluid, influencing only the mechanical extrusion of the ovum without altering the luteinization process. Fertility and
Sterilit~
•
Several theories have attempted to explain the mechanism of ovum release. Activation of proteolytic enzymes in the ovary,4 initiation of ovarian contractility,5 and an increase in prostaglandin levels in the ovary or in the follicular fluid 6, 7 have been postulated as initiators of follicle rupture. It has been experimentally shown that prostaglandin F 2u (PG F 2u) is a mediator of LH action in most laboratory animals, modulating the function ofLH at the level of the follicle and causing it to rupture. Blockade of prostaglandin synthesis by systemic injection of indomethacin has resulted in ovum entrapment within the corpus luteum without disrupting the process of luteinization and normal steroidogenesis of the postovulatory phase. 7 Although PGF 2u does not mediate all LH actions, its synthesis by human follicles and its presence in the follicular fluid may playa key role in ovulation and ovum extrusion in the human being. Therefore, any pharmacologic agent that may interfere with PGF 2u dynamics at midcycle may disrupt an organized sequence of events and prevent extrusion of the oocyte. A decrease in prostaglandin production at midcycle may also be due to changes in concentrations of gonadotropin and steroid hormones both during and preceding midcycle days. Schenken and associates 8 have reported their detailed histologic and hormonal findings in a spontaneous LUF cycle in the rhesus monkey. A blunted bio- and immunoassayable LH surge was observed in this LUF cycle, which may have been responsible for a modest, but inadequate, increase in follicular PGF 2u resulting in an entrapped ovum. LUF has been observered in normally cyclic women, infertility patients with endometriosis,9 pelvic adhesive disease,lo and unexplained causes. l l The diagnoses of LUF have been based on three investigative approaches: 1. Failure to identify an ovulatory stigma on the ovaries in the early luteal phase during a laparoscopic examination. 12 2. In peritoneal fluid collected at laparoscopy or by culdocentesis, failure to measure an increased level of estradiol and P, after presumed follicular rupture. 13 Normally, in cyclic women, the steroid-rich contents of the follicle are released at the time of ovulation into the pelvis, and this results in at least a threefold increase in peritoneal fluid P concentration when compared with serum levels. 14 3. During frequent ultrasound examinations of the preovulatory follicle, failure to observe a reVol. 47, No.5, May 1987
duction in the size of the follicle and free fluid in the cul-de-sac. 15 All these methods that identify continual enlargement of follicles in the luteal phase with no evidence of ovum release are acceptable for diagnosis of LUF syndrome and are easy to perform in an outpatient setting. However, before a definitive diagnosis is made, the inability to identify a stigma on the ovary during laparoscopic examination because of adhesions preventing clear observation of the bilateral ovarian poles, or reepithelialization of these surfaces before the laparoscopic procedure, must be taken into account. There are also a few drawbacks to diagnosing LUF by ultrasound. Although a reduction in size of the preovulatory follicle may occur and fluid may be easily identified in the cul-de-sac, ovum release may not occur. There is evidence that ovum retention inside an obviously ruptured follicle has been observed. 16 If ultrasound follow-up of a growing follicle is not performed at frequent intervals, a corpus luteum cyst may easily be mistaken for a L UF if the midcycledays were missed. 10 Controversy still prevails regarding the recurrence of LUF in the same patient in subsequent cycles. In this issue, Killick and associates have pharmacologically produced the LUF syndrome in women by administering prostaglandin synthetase inhibitors. This experimental approach to the midcycle hormonal dynamics opens many possibilities and some concerns. The authors propose that the obvious potential of administering prostaglandin synthetase inhibitors may be used as a form of nonhormonal contraception. This indeed should be a valuable addition to the currently available contraceptive choices, which have dwindled significantly after removal of several types of intrauterine devices from the market. Also, prevention of follicle rupture before oocyte recovery by these agents will be intriguing to try in in vitro fertilization programs with the hopes of in~ creasing ova harvest. Last, in view of the alarming effect of prostaglandin synthetase inhibitors at midcycle by producing LUFs, physicians working with infertility patients should educate them about the numerous over-the-counter products that inhibit formation of prostaglandins and caution them against using these compounds before or at midcycle.
Aksel Editor's corner
763
REFERENCES 1. diZerega GS, Hodgen GD: Folliculogenesis in the primate ovary. Endocr Rev 2:27, 1981 2. Baird DT, Fraser IS: Concentration of estrone and estradiol in follicular fluid and ovarian venous blood of women. Clin Endocrinol 4:259, 1975 3. Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G: Control ofthe rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science 207:1371, 1980 4. Espey LL: Ovarian proteolytic enzymes and ovulation. BioI Reprod 10:216, 1974 5. Walles B, Edvinsson L, Falck B, Nybell G, Owmann C, Sjoberg NO, Svensson KG: Modifications of ovarian and follicular contractility by amines: a mechanism involved in ovulation. Eur J Obstet Gynecol Reprod BioI (Suppl 1) 4:8103, 1974 6. Channing CP: The interrelationship of prostaglandins, cyclic 3'-5'-AMP and ovarian function. Res Prostaglandins 2:1, 1973 7. Plunkett ER, M{)on YS, Zamecnik J, Armstrong DT: Preliminary evidence of a role for prostaglandin F in human follicular function. Am J Obstet Gynecol 123:391, 1975 8. Schenken RS, Werlin LB, Williams RF, Prihoda JJ, Hodgen GD: Histologic and hormonal documentation of the luteinized upruptured follicle syndrome. Am J Obstet Gynecol 154:839, 1986
764
Aksel Editor's corner
9. Dmowski WP, Rao R, Scommega A: The luteinized unruptured follicle syndrome and endometriosis. Fertil Steril 33:30,1980 10. Hamilton CJCM, Wetzels LCG, EversJLH, Hoogland HJ, Muijtjens A, de Haan J: Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome. Fertil Steril 43:541, 1985 11. Daly DC, Soto-Albors C, Walters C, Ying Y, Riddick DH: Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility. Fertil Steril 43:62,1985 12. Marik J, Hulka J: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, 1978 13. Koninckx PR, DeMoor P, Brosensia XX: Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br J Obstet Gynaecol 87:929, 1980 14. Lesorgen PR, Wu CH, Green PJ, Gocial B, Lerner LJ: Peritoneal fluid and serum steroids in infertility patients. Fertil Steril 42:237, 1984 15. Coulam CB, Hill LM, Breckle R: Ultrasonic evidence for luteinization of unruptured preovulatory follicles. Fertil Steril 37:524, 1982 16. Craft I, Shelton K, Yovich J, Smith D: Ovum retention in the human. Fertil Steril 34:537, 1980
Fertility and Sterility
Vol. 47 , No . 5, May 1987 Printed in U.SA.
Thou shalt luteinize, not rupture
Sezer Aksel, M.D. Professor Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of South Alabama, Mobile, Alabama
Received March 17, 1987. Reprint requests: Sezer Aksel , M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of South Alabama, College of Medicine, CC/CB 326, Mobile, Alabama 36688. 762
Aksel Editor's corner
A puzzling phenomenon is observed in cyclic women when the preovulatory follicle reaches a diameter associated with maturity and continues to grow without rupture. As if obeying an intraovarian command, the enlarging follicle, with the oocyte entrapped within its luteinized walls, maintains the integrity of its basal membrane after the luteinizing hormone (LH) surge has occurred and may reach a size that could become symptomatically uncomfortable for the patient. This continual growth of the follicle does not appear to alter the luteinizing effects of LH on its peripheral granulosa and theca cells. Progesterone (P) synthesis commences as if ovulation had occurred, and gradually rising P concentrations, in time, produce specific changes associated with the presumed ovulation, such as the biphasic shift on the basal body temperature record, secretory changes in the endometrial cells, and alteration in the quality of the cervical mucus. When a large discrepancy exists between the numb.er of presumed ovulations and the actual extrusion of the oocytes, the chances for the sperm and ovum to meet are decreased. Therefore it is no wonder that the luteinized unruptured follicle (LUF) syndrome would be more prevalent in infertile women. Ovulation is a complex process. The sequence of events starts with the selection of the dominant follicle, its maturation, and extrusion of the oocyte and terminates with the formation of the corpus luteum. There is some evidence that the primate ovary may control its own destiny. Through the interaction of several intraovarian mediators or regulators, the ovary appears to select and support the dominant follicle. 1 The ovary with a clearly identifiable preovulatory follicle is responsible for the high estradiol concentrations measurable in the venous blood draining that ovary. 2 Furthermore, the ovary in the juvenile rhesus monkey, receiving pulsatile gonadotropin-releasing hormone, appears to signal its readiness for ovulation by increasing estradiol levels into a critical range. 3 Commonly, during ovulation, the follicular responses to the ovulatory signal triggered by LH include extrusion of the oocyte, luteinization of the granulosa and theca cells, and formation of the corpus luteum. One may speculate that if these concomitantly occurring events are dissociated, luteinization without rupture may occur, although the reverse is more likely. Dissociation of LH action may be due to intra- or extraovarian factors altering the hormonal and/or chemical composition of the follicular fluid, influencing only the mechanical extrusion of the ovum without altering the luteinization process. Fertility and
Sterilit~
•
Several theories have attempted to explain the mechanism of ovum release. Activation of proteolytic enzymes in the ovary,4 initiation of ovarian contractility,5 and an increase in prostaglandin levels in the ovary or in the follicular fluid 6, 7 have been postulated as initiators of follicle rupture. It has been experimentally shown that prostaglandin F 2u (PG F 2u) is a mediator of LH action in most laboratory animals, modulating the function ofLH at the level of the follicle and causing it to rupture. Blockade of prostaglandin synthesis by systemic injection of indomethacin has resulted in ovum entrapment within the corpus luteum without disrupting the process of luteinization and normal steroidogenesis of the postovulatory phase. 7 Although PGF 2u does not mediate all LH actions, its synthesis by human follicles and its presence in the follicular fluid may playa key role in ovulation and ovum extrusion in the human being. Therefore, any pharmacologic agent that may interfere with PGF 2u dynamics at midcycle may disrupt an organized sequence of events and prevent extrusion of the oocyte. A decrease in prostaglandin production at midcycle may also be due to changes in concentrations of gonadotropin and steroid hormones both during and preceding midcycle days. Schenken and associates 8 have reported their detailed histologic and hormonal findings in a spontaneous LUF cycle in the rhesus monkey. A blunted bio- and immunoassayable LH surge was observed in this LUF cycle, which may have been responsible for a modest, but inadequate, increase in follicular PGF 2u resulting in an entrapped ovum. LUF has been observered in normally cyclic women, infertility patients with endometriosis,9 pelvic adhesive disease,lo and unexplained causes. l l The diagnoses of LUF have been based on three investigative approaches: 1. Failure to identify an ovulatory stigma on the ovaries in the early luteal phase during a laparoscopic examination. 12 2. In peritoneal fluid collected at laparoscopy or by culdocentesis, failure to measure an increased level of estradiol and P, after presumed follicular rupture. 13 Normally, in cyclic women, the steroid-rich contents of the follicle are released at the time of ovulation into the pelvis, and this results in at least a threefold increase in peritoneal fluid P concentration when compared with serum levels. 14 3. During frequent ultrasound examinations of the preovulatory follicle, failure to observe a reVol. 47, No.5, May 1987
duction in the size of the follicle and free fluid in the cul-de-sac. 15 All these methods that identify continual enlargement of follicles in the luteal phase with no evidence of ovum release are acceptable for diagnosis of LUF syndrome and are easy to perform in an outpatient setting. However, before a definitive diagnosis is made, the inability to identify a stigma on the ovary during laparoscopic examination because of adhesions preventing clear observation of the bilateral ovarian poles, or reepithelialization of these surfaces before the laparoscopic procedure, must be taken into account. There are also a few drawbacks to diagnosing LUF by ultrasound. Although a reduction in size of the preovulatory follicle may occur and fluid may be easily identified in the cul-de-sac, ovum release may not occur. There is evidence that ovum retention inside an obviously ruptured follicle has been observed. 16 If ultrasound follow-up of a growing follicle is not performed at frequent intervals, a corpus luteum cyst may easily be mistaken for a L UF if the midcycledays were missed. 10 Controversy still prevails regarding the recurrence of LUF in the same patient in subsequent cycles. In this issue, Killick and associates have pharmacologically produced the LUF syndrome in women by administering prostaglandin synthetase inhibitors. This experimental approach to the midcycle hormonal dynamics opens many possibilities and some concerns. The authors propose that the obvious potential of administering prostaglandin synthetase inhibitors may be used as a form of nonhormonal contraception. This indeed should be a valuable addition to the currently available contraceptive choices, which have dwindled significantly after removal of several types of intrauterine devices from the market. Also, prevention of follicle rupture before oocyte recovery by these agents will be intriguing to try in in vitro fertilization programs with the hopes of in~ creasing ova harvest. Last, in view of the alarming effect of prostaglandin synthetase inhibitors at midcycle by producing LUFs, physicians working with infertility patients should educate them about the numerous over-the-counter products that inhibit formation of prostaglandins and caution them against using these compounds before or at midcycle.
Aksel Editor's corner
763
REFERENCES 1. diZerega GS, Hodgen GD: Folliculogenesis in the primate ovary. Endocr Rev 2:27, 1981 2. Baird DT, Fraser IS: Concentration of estrone and estradiol in follicular fluid and ovarian venous blood of women. Clin Endocrinol 4:259, 1975 3. Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G: Control ofthe rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science 207:1371, 1980 4. Espey LL: Ovarian proteolytic enzymes and ovulation. BioI Reprod 10:216, 1974 5. Walles B, Edvinsson L, Falck B, Nybell G, Owmann C, Sjoberg NO, Svensson KG: Modifications of ovarian and follicular contractility by amines: a mechanism involved in ovulation. Eur J Obstet Gynecol Reprod BioI (Suppl 1) 4:8103, 1974 6. Channing CP: The interrelationship of prostaglandins, cyclic 3'-5'-AMP and ovarian function. Res Prostaglandins 2:1, 1973 7. Plunkett ER, M{)on YS, Zamecnik J, Armstrong DT: Preliminary evidence of a role for prostaglandin F in human follicular function. Am J Obstet Gynecol 123:391, 1975 8. Schenken RS, Werlin LB, Williams RF, Prihoda JJ, Hodgen GD: Histologic and hormonal documentation of the luteinized upruptured follicle syndrome. Am J Obstet Gynecol 154:839, 1986
764
Aksel Editor's corner
9. Dmowski WP, Rao R, Scommega A: The luteinized unruptured follicle syndrome and endometriosis. Fertil Steril 33:30,1980 10. Hamilton CJCM, Wetzels LCG, EversJLH, Hoogland HJ, Muijtjens A, de Haan J: Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome. Fertil Steril 43:541, 1985 11. Daly DC, Soto-Albors C, Walters C, Ying Y, Riddick DH: Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility. Fertil Steril 43:62,1985 12. Marik J, Hulka J: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, 1978 13. Koninckx PR, DeMoor P, Brosensia XX: Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br J Obstet Gynaecol 87:929, 1980 14. Lesorgen PR, Wu CH, Green PJ, Gocial B, Lerner LJ: Peritoneal fluid and serum steroids in infertility patients. Fertil Steril 42:237, 1984 15. Coulam CB, Hill LM, Breckle R: Ultrasonic evidence for luteinization of unruptured preovulatory follicles. Fertil Steril 37:524, 1982 16. Craft I, Shelton K, Yovich J, Smith D: Ovum retention in the human. Fertil Steril 34:537, 1980
Fertility and Sterility