European Journal of Obstetrics & Gynecology and Reproductive Biology, 45 (1992) 187-192
187
0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01374
Severe ovarian hyperstimulation: a case report and essentials of prevention and management F. Scheele,
P.G.A. Hompes,
R.E. Bernardus
Free University Hospital, Amsterdam,
and J. Schoemaker
The Netherlands
Accepted for publication 18 March 1992
Summary
A case of ovarian hyperstimulation syndrome is presented occurring in a young woman with polycystic ovary-like disease after induction of ovulation with the combined treatment of a luteinizing hormone releasing hormone analog and human menopausal gonadotrophins. Prevention and management based on pathophysiological considerations are reviewed. Ovarian hyperstimulation
syndrome; Ovary
Introduction
With the advent of new reproductive technologies the use of super ovulation inducing agents has steadily increased. Consequently the number of patients at risk for the ovarian hyperstimulation syndrome (OH%) increases. The present paper describes a case of severe OHSS in a patient suffering from poiycystic ovary-like syndrome (PC01 after ovulation-induction with a combination of a luteinizing hormone releasing hormone (LHRH) agonist, human menopausal gonadotrophins (hMG) and human chorionic gonadotrophin (hCG). Options to prevent the OHSS and management based on the current knowledge of pathophysiology are discussed. Case report
A 2%year-old woman was referred to our outpatient clinic because of primary infertility and
Correspondence
fo: Dr. F. Scheele, Free University Hospital, De Boelelaan 1117, Amsterdam, The Netherlands.
oligomenorrhea. Menarche took place at the age of 15, followed by oligomenorrhea. Mild hirsutism had been observed since the age of 23. On physical examination a healthy woman; height 1.64 m, weight 57 kg, bloodpressure 105/70 mmHg. Except for a mild facial hirsutism no abnormalities were found. Hormonal analysis was performed on the 14th day of the menstrual cycle. Three weeks after the blood sampling menstruation had not yet occurred. The analysis showed a raised LH-level(7.1 U/l, normal values < 6.5 U/l), a normal FSH-level (6.2 U/l, normal values < 10 U/l), normal estradiol level and a progesterone level compatible with the follicular phase of the cycle. Testosterone, ACandrostenedione, dihydroepiandrosteronesulphate, pregnanetriol, proiactin and thyroxine estimations were all within the normal range. There was a diurnal rhythm of plasm-cortisol. Ultrasound showed slightly enlarged ovaries (mean diameter 3.3 and 3.4 cm) with ten to fifteen cyst-like structures ranging from 4 to 10 mm in diameter. The basal body temperature chart was monophasic. PC0 disease was diagnosed based on the clinical picture of oligomenorrhea and the raised LH level and the normal FSH level. Tubal patency
188
was assessed by hysterosalpingography and was confirmed at laparoscopy. Semen analyses were normal. Treatment with clomiphene citrate (CC) 100 mg daily for 5 days resulted in an ovulatory cycle but its use was later on rejected because of hairloss that was interpreted as a rare, reversible side effect of CC. The hair returned to normal within 3 months after discontinuation of therapy. Subsequently, it was decided to treat the patient with a combination of a LHRH-agonist (Buserelin, Hoechst, Frankfurt am Main, Germany) and hMG (Pergonal, Serono, Geneva, Switzerland). After 21 days of treatment with Buserelin 1200 pg intranasally, spread out over four daily administrations, the patient’s serum LH was 2.2 U/l, FSH was 3.7 U/l and E2 was 11 pg/ml. While Buserelin-treatment was continued, hMG was started with one ampule daily i.m. The dose was increased to two ampules daily after 1 week due to the lack of ovarian response as judged by serum estradiol and ultrasound. Seven days later hMG was discontinued and 10,000 IU hCG (Profasi, Serono, Geneva, Switzerland) was administered 24 h later, on the day the leading follicle reached 18 mm in diameter. In addition 7 other follicles, larger than 13 mm were present, while approximately another 25 follicles were visible with a diameter ranging between 8 to 13 mm. Estradiol, in retrospect, appeared to be 1770 pg/ml on the day before hCG was given. Ovulation was assessed by ultrasound and confirmed by a rise in plasma progesterone-levels. Because of the risk of OHSS hCG for luteal support was withheld. Luteal progesterone levels were 128 and 79 ng/ml, respectively, on the 4th day and the 9th day after hCG administration. On the 12th postovulatory day the patient started to complain of abdominal pain and nausea. On physical examination a woman was seen in moderate distress. Vital signs were unremarkable. There was no dyspnea. Weight had increased by 2 kg and a distended abdomen was found, tender on palpation but without signs of an acute abdomen or overt ascites. Ultrasound showed ovaries with a mean diameter of 10 cm, consisting of about ten cysts on either side, separated by very thin walls. In addition an abnormal amount of free fluid was observed in the abdomen.
Laboratory: The pregnancy test was positive. The hemoglobin was 9.0 mmol/l, hematocrit 0.44, sodium 138 mmol/l, potassium 4.6 mmol/l, albumin 26 g/l, creatinine 88 mmol/l, liver enzymes and cephalin time were normal. Course: The patient was admitted to the hospital and treated with bedrest. Heparin (tromboliquine, Organon, Oss, The Netherlands) 5000 IU subcutaneously twice daily and a protein rich diet were prescribed. An i.v. drip was maintained to correct fluid intake, electrolytes and colloids. After admission the patient gained 4 kg in 4 days while her abdominal circumference increased by 5 cm. Urine production decreased to less than 30 ml/h and serum albumin to 22 g/l. Pasteurized plasm to increase intravascular colloid osmotic pressure, alternating with 0.9% plasm saline solution and Ringer’s solution were titrated as such to maintain a urine production of at least 30 ml/h. Because of the progressive gain of weight and ascites, it was decided to administer Naproxene (Naprosyne, Sarva-Syntex, Rijswijk, The Netherlands) 2 g daily from the fourth day after admission onwards. During Naproxene therapy the weight gain increased and the production of urine deteriorated until below 30 ml/h. Because of the risk of acute anuria, Naproxene was discontinued 2 days later. On the seventh day after admission the patient became dyspneic. The cumulated weight gain was 10.5 kg. The increase in abdominal circumference was 10.8 cm. Marked clinical ascites was present; however, no signs of pleural effusion were found. During ultrasound guided paracentesis 2 liters of acellular ascites were aspirated on 2 consecutive days. The patient’s clinical condition improved remarkably. She recovered from dyspnea almost immediately. From the 8th day after admission urine production increased as well as serum albumin, while weight and abdominal circumference decreased. Except for the low serum albumin and the relatively high hemoglobin concentration and the hematocrit, no other serious disturbances were detected in blood chemistry during the disease. Fifteen days after admission the patient was discharged. She appeared to be pregnant of triplets and delivered at 28 weeks of gestation. Three daughters were born. After having spent some
189
months in the neonatal intensive care unit, they develop well without evident sequelae due to the premature birth. Condensed
review of the literature
The OHSS may present itself in various degrees. Golan recently proposed a new classification which, for the first time, includes the ultrasound findings [Il. Grade one is a combination of abdominal distension and discomfort. Grade two adds the features of nausea, vomiting and/or diarrhea. In grade three there is ultrasonic evidence of ascites. In grade four ascites is clinically evident and pleural effusion and breathing difficulties may occur. Grade five shows the features of the previous grades and of hypovolemia, increased blood viscosity due to hemoconcentration, coagulation-abnormalities, as well as diminished renal perfusion and function. Hypovolemia, due to extravasation of plasma or due to ovarian rupture and hemorrhage, can induce electrolyte disorders, circulatory failure and death [21. Coagulation disorders can also be life-threatening [3]. Dyspnea may be the result of mechanical obstruction due to abdominal or thoracic fluid accumulation, A case of dyspnea due to the adult respiratory distress syndrome has been reported [4]. The syndrome can be further complicated by ovarian rupture or torsion [5], hydro-ureter and ectopic pregnancy [6]. The symptoms of OHSS usually begin 3-8 days after the administration of hCG, persisting throughout the luteal phase and waning as the onset of menses approaches [2]. Cases of OHSS are more common, more severe and have a more protracted course if pregnancy occurs [2,7]. The occurrence of OHSS is associated with multiple follicular growth and ovulation [1,21. Without (multiple) ovulation OHSS rarely develops [l]. Multiple follicular growth resulting from ovulation induction is seen more often in PCO-like disease than in hypo-, normo-, and hypergonadotropic amenorrhea [2,7]. Apart from the diagnosis, the occurrence of multiple follicular growth largely depends on the method of ovulation induction [1,81. Severe OHSS during pulsatile LHRH therapy has to our knowledge never
been reported. Some cases of severe OHSS during CC therapy have been reported [l], but the majority of cases results from gonadotrophin therapy. The OHSS appears to result from a sudden and massive shift of intravascular serous fluid to the third space due to increased capillary permeability [1,2,9,10]. The pathophysiology is still a matter of controversy. It is suggested that the increased capillary permeability in cases of OHSS is due to an active substance secreted by the stimulated ovaries probably under the influence of hCG. A variety of substances have been suggested to be responsible such as prostaglandins [91, histamine [ll], renin 1121,ovarian steroids [13] and prolactin [13]. Moreover, an unknown ovarian factor has been suggested as in the Meiggs syndrome [ 101. With conservative management the disease is selflimiting [2]. Prevention
To prevent OHSS during gonadotrophin therapy, monitoring of the cycle is advocated in order to cancel when a high risk for OHSS is predicted. Haning et al. [7] used serial ultrasound observations of the ovary to detect a follicle of at least 14 mm during stimulation with hMG. If such a follicle was observed, hCG was administered. When gonadotrophins were administered between 500 and 8:00 p.m. and blood was drawn at 8:00 a.m., an upper limit for serum E, in patients with hypothalamic amenorrhea of 2417 pg/ml or an upper limit for patients with PC0 of 3778 pg/ml gave an approximate 5% risk of severe OHSS in conception cycles and a 1.3% risk of severe OHSS in nonconception cycles. Several authors advised different upper limits of estradiol. Blankstein et al. [14] used serial estradiol measurements to time the hCG administration and showed that the occurrence of ten or more follicles predominantly smaller than 9 mm was associated with moderate or severe OHSS. Whether estradiol measurements are a better prediction than ultrasound observations is unknown. Golan advises combined monitoring for gonadotrophin treatment in in vivo fertilization [l]. Van Weissenbruch showed that the growth of
190
follicles occurs when FSH is higher than a certain threshold value [151. FSH and hMG therapy resulted in equal FSH levels and follicular growth patterns as well as an equal risk for OHSS. Persistent high levels of FSH resulted in more growing follicles [16]. Low dose and slow step up administration of gonadotrophins aiming at FSH just to surpass the threshold value show more monofollicular cycles and less risk for OHSS [17,181. Whether the use of LHRH agonists as an adjuvants for gonadotrophin therapy will increase cumulative pregnancy rates during ovulation induction in the PCO-like syndrome is a matter of controversy [ 19,201. However, it is established that the response to gonadotrophins of a medically hypophysectomized PCO-patient is not the same as in hypogonadotropic amenorrhea: the diagnosis dependent predisposition to multifollicular growth persists [20,21]. The use of LHRH analogs in IVF seems to stimulate multifollicular growth in gonadotrophin treatment of women with a normal cycle [22]. There is evidence that this effect of LHRH analog treatment will also be seen in ovulation induction of PCO-patients [20,21]. If estrogen or ultrasound monitoring shows a high risk for the development of OHSS [7,141, it can usually be avoided by withholding the hCG [2]. The patient should be considered at risk and a more moderate mode of stimulation should be used in a next treatment cycle 1231.Another option is to observe the overstimulated ovaries without further gonadotrophin stimulation until the estradiol value is < 1700 pg/ml and the ultrasound shows a leading follicle of 17-22 mm, before administering hCG [24]. Furthermore, it is possible to puncture the follicles. In that case 34 h after hCG all follicles, except two large ones, are punctured: two ovulations may occur [25]. The risk for OHSS and multiple pregnancy is reduced to a large extent by follicular puncture and oocyte retrieval Cl]. If the risk for OHSS seems to be too high to accept an hCG producing pregnancy, it is possible to puncture all follicles and freeze the embryos after IVF and perform embryo transfer in a subsequent cycle [26]. The protection against OHSS provided by follicular
puncture and removal of follicular fluid and granulosa cells is not well understood. Whether the use of prostaglandin-synthetase inhibitors is of value for the prevention or treatment of OHSS is unknown. Schenker et al. prevented OHSS in rabbits with the prostaglandin-synthetase inhibitor indomethacin [91. However, treatment was started before ovulation and the number of ovulations was significantly reduced in the indomethacin treated group compared to the group treated with gonadotrophins alone. Prostaglandin synthetase inhibitors may acutely induce anuria in the oliguric patient due to the deterioration of prostaglandin dependent renal bloodflow which is maintained during the hypovolemic state [27]. Their use is, therefore, dangerous. The use of exogenous hCG for luteal support may increase the risk of OHSS [28]. For the purpose of early detection, patients treated with gonadotropins should be advised to check their bodyweight daily after ovulation. A weight gain of more than 1 kg per day or a cumulative weight gain after hCG-injection of over 2 kg is considered an early sign of moderate to serious OHSS. Treatment of the manifest OHSS Admission to the hospital is advised when the OHSS has reached grade four of the score of Golan [l]. The OHSS is selflimiting, but complications must be recognized and treated. Puncture of large cysts several days after ovulation as well as a surgical approach have been reported [29], but may induce the risk of bleeding and rupture of the ovaries. Abdominal surgery may be extremely difficult in OHSS because of the friable ovarian tissue and may result in bilateral oophorectomy. Therefore a conservative approach is generally preferred. In OHSS, complications may be divided in four main groups: 1, acute abdomen; 2, coagulation disorders; 3, hypovolemia; and 4, severe dyspnea. The acute abdomen may become a major problem because of the risks of surgery. Venous as well as arterial thrombosis have been reported [3]. It is unknown whether coagulation disorders in OHSS are merely dependent
191
on hemoconcentration and although most thromboembolic cases in the literature showed a raised hematocrit, prophylaxis by heparin 2 X 5000 IU s.c./day might be suitable in all cases of admission. The prophylaxis, however, has not been validated by appropriate research. Hypovolemia is managed by infusion of crystalloid fluid replacements and colloid fluids until production of urine is at least 30 ml/h. It is suggested that exogenous colloids might leak through the permeable bloodvessels and increase accumulation to the third space. Even if this were the case, it is not a reason to avoid their use in the treatment of hypovolemia. The majority of the accumulated extravascular fluid may be easily removed from the abdominal or thoracic cavity by paracentesis. Fluid restriction to avoid ascites has been advocated [30], but may aggravate hypovolemia and hemoconcentration, while paracentesis is a rather simple method to solve the problem of ascites. The paracentesis is best performed guided by ultrasound to prevent damage of intraabdominal or intra-thoracic structures [31]. Large amounts of fluid may be required due to rapid leakage to the third space. Therefore electrolytes must be monitored carefully. Diuretics increase urine production but do not increase renal bloodflow and aggravate hypovolemia. Dyspnea is most often the result of a massive ascites and/or hydrothorax. It should be treated by paracentesis [32]. Dyspnea may be due to pulmonary embolism complicating the OHSS. Hypovolemia induced shock and acidosis may also induce dyspnea and tachypnea. A rare reason for dyspnea is the adult respiratory distress syndrome [4] which requires assisted ventilation with continuous positive pressure. Discussion
In retrospect, the reversible hairloss during CC therapy in this case report was a negligible side effect in comparison to the grade five OHSS and the pregnancy and premature delivery of triplets which resulted from gonadotrophin therapy. The use of an LHRH agonist [20,21] and a step-up schedule of hMG increasing one ampule per week [17,18] have contributed to the risk of multifollicular growth and OHSS in this patient already
predisposed by diagnosis [7]. At the time of administration of hCG, the excessive number of follicles predicted the risk for OHSS according to the criteria of Blankstein et al. [14]. Favorable experience with other patients receiving the same treatment and the expectation of some protective effect from the low value of serum LH accounted for the decision to continue the treatment without measures which might have prevented OHSS, e.g., selective oocyte retrieval [25]. The estradiol values were only available in retrospect and also would have predicted the OHSS [7]. The availability of a double warning might have directed to a more preventive management. During admission 2 of the 4 main problems of OHSS were encountered: hypovolemia, expressed by oliguria and dyspnea. During the oliguric period, treatment with Naproxene was discontinued because of the,risk of anuria [27]. The use of prostaglandin synthetase inhibitors is dangerous during massive fluid leakage to the extravascular space. Probably this medication does not deserve the benefit of the doubt. The dyspnea reacted favorably to paracentesis. Moreover, paracentesis coincided with recovery from OHSS. Whether this coincidence is causative is unknown. Our experience as well as reports from the literature indicate that paracentesis is easily performed and an important tool in the treatment of OHSS [31,32]. It is concluded that the serious OHSS in the discussed patient was not prevented by the hypogonadal state induced by Buserelin. A viable pregnancy, however, was achieved. Management based on_ the knowledge of pathophysiology may usually prevent complications of manifest OHSS. Still, serious problems such as ovarian rupture may be encountered even when treatment seems to be optimal. Serious neonatal problems resulting from multiple pregnancies as well as maternal complications due to OHSS indicate that gonadotropins must be handled with care in a way that combines a maximal success rate with a minimal chance for complications. References 1 Golan A. Ron-El R, Herman A et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Survey 1989;44:430-440.
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4
5
6
7
8
9
10
11
12 13
14
15
16
17
18
Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1987;30:255-268. Mazes M, Bogokowsky H, Antebi E et al. Thromboembolic phenomena after ovarian stimulation with human gonadotropins. Lancet 1965;ii:1213-1215. Zosmer A, Katz Z, Lancet M et al. Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome. Fertil Steril 1987;47:524-526. Chin NW, Friedman HK, Awadalla SG et al. Adnexal torsion as a complication of superovulation for ovum-retrieval. Fertil Steril 1987;48:149-151. Paulson RJ, Lobo RA. Ovarian hyperstimulation complicating the clinical presentation of a pre-existing ectopic pregnancy. Fertil Steril 1988;50:670-671. Haning RV, Boehnlein LN, Carbon IH et al. Diagnosisspecific serum 17P-estradiol (E,) upper limits for treatment with menotropins using a 1251 direct E, assay. Fertil Steril 1984;42:882-889. Borenstein R, Ashkenazy M, Rosenman D et al. Ovarian hyperstimulation syndrome after different treatment schedules. Int J Fertil 1981;26:279-282. Schenker JG, Polishuk WZ. The role of prostaglandins in ovarian hyperstimulation syndrome. Eur J Gynecol Reprod Biol 1976;6:47-52. Haning RV, Strawn EY, Nolten WE. Pathophysiology of the ovarian hyperstimulation syndrome. Obstet Gynecol 1985;66:220-224. Knox GE. Antihistamine blockade of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1974;118:992-994. Itskovitz J, Sealy JE. Ovarian prorenin-renin-angiotensin system. Obstet Gynecol Surv 1987;42:545-551. Yuen BH, McComb P, Lewis J et al. Plasma prolactin, human chorionic gonadotropin, estradiol, testosterone and progesterone in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1987;133;316-320. Blankstein J, Shalev J, Saadon T et al. Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil Steril 1987;47:597-602. Weissenbruch van M. Gonadotropins for induction of ovulation. Thesis, 1990, Vrije Universiteit, Amsterdam, The Netherlands. Ben-Raphael Z, Strauss JF, Mastroianni L et al. Differences in ovarian stimulation in human menopausal gonadotropin treated woman may be related to follicle stimulating hormone accumulation. Fertil Steril 1986;46:586592. Polson DW, Mason HD, Saldahna MBY et al. Ovulation of a single dominant follicle during treatment with low dose pulsatile follicle stimulating hormone in women with polycystic ovary syndrome. Clin Endocrin 1987;26:205-212. Buvat J, Buvat-Herbaut M, Marcolin G et al. Purified follicle stimulating hormone in polycystic ovary syndrome: slow administration is safer and more effective. Fertil Steril 1989;52:553-559.
19 Fleming R, Haxton MJ, Hamilton MPR et al. Combined gonadotropin releasing hormone analog and exogenous gonadotropins for ovulation-induction in infertile women: efficacy related to ovarian function assessment. Am J Obstet Gynecol 1988;159:376-381. 20 Homburg R, Eshel A, Kilborn J et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotropins for the treatment of infertility associated with polycystic ovaries. Human Reproduction 1990;5:3235. 21 Lanzone A, Fulghesu AM, Spina MA et al. Successful induction of ovulation and conception with combined gonadotropin releasing hormone agonist plus highly purified follicle stimulating hormone in patients with polycystic ovarian disease. J Clin Endocrinol Metab 1987;65:12531258. 22 Neveu S, Hedon B, Bringer J et al. Ovarian stimulation by a combination of a gonadotropin-releasing hormone agonist and gonadotropins for ovulation induction. Fertil Steril 1987;47:639-643. 23 Forman RG, Frydman R, Egan D et al. Severe ovarian hyperstimulation using agonists of gonadotropin releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990;53:502-509. 24 Rabinovici J, Kushnir 0, Shalev J et al. Rescue of menotrophin cycles prone to develop ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1987;94:1098-l 102. 25 Belaisch-Allart J, Belaisch J, Hazout A et al. Selective oocyte retrieval: a new approach to ovarian hyperstimulation. Fertil Steril 1988;50:654-656. 26 Amso NN, Ahuja KK, Morris N et al. The management of predicted ovarian hyperstimulation involving gonadotropin-releasing analog with elective cryopreservation of all pre-embryos. Fertil Steril 1990;53:1087-1090. 27 Demey HE, Daelemans R, Galdermans D et al. Acute oligo-anuria during ovarian hyperstimulation syndrome Acta Obstet Gynecol Stand 1987;66:741-743. 28 Herman A, Ron-El R, Golan A et al. Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins. Fertil Steril 1990;53:92-96. 29 Narita 0, Shimosuka Y, Suzuki M et al. Induction of ovulation with human menopausal gonadotropin; with special reference to ovarian hyperstimulation syndrome and hormone excretion. Nagoya J Med Sci 1980;43:7-13. 30 Shapiro AG, Thomas T, Epstein M. Management of hyperstimulation syndrome. Fertil Steril 1977;28:237-239. 31 Abdoulghar MA, Mansour RT, Serour GI et al. Ultrasonically guided vaginal aspiration of ascites in the treatment of severe ovarian hyperstimulation syndrome. Fertil Steril 1990;53:933-935. 32 Thaler I, Yoffe N, Kaftory JK et al. Treatment of ovarian hyperstimulation syndrome: the physiologic basis for a modified approach. Fertil Steril 1981;36:110-113.
187
0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01374
Severe ovarian hyperstimulation: a case report and essentials of prevention and management F. Scheele,
P.G.A. Hompes,
R.E. Bernardus
Free University Hospital, Amsterdam,
and J. Schoemaker
The Netherlands
Accepted for publication 18 March 1992
Summary
A case of ovarian hyperstimulation syndrome is presented occurring in a young woman with polycystic ovary-like disease after induction of ovulation with the combined treatment of a luteinizing hormone releasing hormone analog and human menopausal gonadotrophins. Prevention and management based on pathophysiological considerations are reviewed. Ovarian hyperstimulation
syndrome; Ovary
Introduction
With the advent of new reproductive technologies the use of super ovulation inducing agents has steadily increased. Consequently the number of patients at risk for the ovarian hyperstimulation syndrome (OH%) increases. The present paper describes a case of severe OHSS in a patient suffering from poiycystic ovary-like syndrome (PC01 after ovulation-induction with a combination of a luteinizing hormone releasing hormone (LHRH) agonist, human menopausal gonadotrophins (hMG) and human chorionic gonadotrophin (hCG). Options to prevent the OHSS and management based on the current knowledge of pathophysiology are discussed. Case report
A 2%year-old woman was referred to our outpatient clinic because of primary infertility and
Correspondence
fo: Dr. F. Scheele, Free University Hospital, De Boelelaan 1117, Amsterdam, The Netherlands.
oligomenorrhea. Menarche took place at the age of 15, followed by oligomenorrhea. Mild hirsutism had been observed since the age of 23. On physical examination a healthy woman; height 1.64 m, weight 57 kg, bloodpressure 105/70 mmHg. Except for a mild facial hirsutism no abnormalities were found. Hormonal analysis was performed on the 14th day of the menstrual cycle. Three weeks after the blood sampling menstruation had not yet occurred. The analysis showed a raised LH-level(7.1 U/l, normal values < 6.5 U/l), a normal FSH-level (6.2 U/l, normal values < 10 U/l), normal estradiol level and a progesterone level compatible with the follicular phase of the cycle. Testosterone, ACandrostenedione, dihydroepiandrosteronesulphate, pregnanetriol, proiactin and thyroxine estimations were all within the normal range. There was a diurnal rhythm of plasm-cortisol. Ultrasound showed slightly enlarged ovaries (mean diameter 3.3 and 3.4 cm) with ten to fifteen cyst-like structures ranging from 4 to 10 mm in diameter. The basal body temperature chart was monophasic. PC0 disease was diagnosed based on the clinical picture of oligomenorrhea and the raised LH level and the normal FSH level. Tubal patency
188
was assessed by hysterosalpingography and was confirmed at laparoscopy. Semen analyses were normal. Treatment with clomiphene citrate (CC) 100 mg daily for 5 days resulted in an ovulatory cycle but its use was later on rejected because of hairloss that was interpreted as a rare, reversible side effect of CC. The hair returned to normal within 3 months after discontinuation of therapy. Subsequently, it was decided to treat the patient with a combination of a LHRH-agonist (Buserelin, Hoechst, Frankfurt am Main, Germany) and hMG (Pergonal, Serono, Geneva, Switzerland). After 21 days of treatment with Buserelin 1200 pg intranasally, spread out over four daily administrations, the patient’s serum LH was 2.2 U/l, FSH was 3.7 U/l and E2 was 11 pg/ml. While Buserelin-treatment was continued, hMG was started with one ampule daily i.m. The dose was increased to two ampules daily after 1 week due to the lack of ovarian response as judged by serum estradiol and ultrasound. Seven days later hMG was discontinued and 10,000 IU hCG (Profasi, Serono, Geneva, Switzerland) was administered 24 h later, on the day the leading follicle reached 18 mm in diameter. In addition 7 other follicles, larger than 13 mm were present, while approximately another 25 follicles were visible with a diameter ranging between 8 to 13 mm. Estradiol, in retrospect, appeared to be 1770 pg/ml on the day before hCG was given. Ovulation was assessed by ultrasound and confirmed by a rise in plasma progesterone-levels. Because of the risk of OHSS hCG for luteal support was withheld. Luteal progesterone levels were 128 and 79 ng/ml, respectively, on the 4th day and the 9th day after hCG administration. On the 12th postovulatory day the patient started to complain of abdominal pain and nausea. On physical examination a woman was seen in moderate distress. Vital signs were unremarkable. There was no dyspnea. Weight had increased by 2 kg and a distended abdomen was found, tender on palpation but without signs of an acute abdomen or overt ascites. Ultrasound showed ovaries with a mean diameter of 10 cm, consisting of about ten cysts on either side, separated by very thin walls. In addition an abnormal amount of free fluid was observed in the abdomen.
Laboratory: The pregnancy test was positive. The hemoglobin was 9.0 mmol/l, hematocrit 0.44, sodium 138 mmol/l, potassium 4.6 mmol/l, albumin 26 g/l, creatinine 88 mmol/l, liver enzymes and cephalin time were normal. Course: The patient was admitted to the hospital and treated with bedrest. Heparin (tromboliquine, Organon, Oss, The Netherlands) 5000 IU subcutaneously twice daily and a protein rich diet were prescribed. An i.v. drip was maintained to correct fluid intake, electrolytes and colloids. After admission the patient gained 4 kg in 4 days while her abdominal circumference increased by 5 cm. Urine production decreased to less than 30 ml/h and serum albumin to 22 g/l. Pasteurized plasm to increase intravascular colloid osmotic pressure, alternating with 0.9% plasm saline solution and Ringer’s solution were titrated as such to maintain a urine production of at least 30 ml/h. Because of the progressive gain of weight and ascites, it was decided to administer Naproxene (Naprosyne, Sarva-Syntex, Rijswijk, The Netherlands) 2 g daily from the fourth day after admission onwards. During Naproxene therapy the weight gain increased and the production of urine deteriorated until below 30 ml/h. Because of the risk of acute anuria, Naproxene was discontinued 2 days later. On the seventh day after admission the patient became dyspneic. The cumulated weight gain was 10.5 kg. The increase in abdominal circumference was 10.8 cm. Marked clinical ascites was present; however, no signs of pleural effusion were found. During ultrasound guided paracentesis 2 liters of acellular ascites were aspirated on 2 consecutive days. The patient’s clinical condition improved remarkably. She recovered from dyspnea almost immediately. From the 8th day after admission urine production increased as well as serum albumin, while weight and abdominal circumference decreased. Except for the low serum albumin and the relatively high hemoglobin concentration and the hematocrit, no other serious disturbances were detected in blood chemistry during the disease. Fifteen days after admission the patient was discharged. She appeared to be pregnant of triplets and delivered at 28 weeks of gestation. Three daughters were born. After having spent some
189
months in the neonatal intensive care unit, they develop well without evident sequelae due to the premature birth. Condensed
review of the literature
The OHSS may present itself in various degrees. Golan recently proposed a new classification which, for the first time, includes the ultrasound findings [Il. Grade one is a combination of abdominal distension and discomfort. Grade two adds the features of nausea, vomiting and/or diarrhea. In grade three there is ultrasonic evidence of ascites. In grade four ascites is clinically evident and pleural effusion and breathing difficulties may occur. Grade five shows the features of the previous grades and of hypovolemia, increased blood viscosity due to hemoconcentration, coagulation-abnormalities, as well as diminished renal perfusion and function. Hypovolemia, due to extravasation of plasma or due to ovarian rupture and hemorrhage, can induce electrolyte disorders, circulatory failure and death [21. Coagulation disorders can also be life-threatening [3]. Dyspnea may be the result of mechanical obstruction due to abdominal or thoracic fluid accumulation, A case of dyspnea due to the adult respiratory distress syndrome has been reported [4]. The syndrome can be further complicated by ovarian rupture or torsion [5], hydro-ureter and ectopic pregnancy [6]. The symptoms of OHSS usually begin 3-8 days after the administration of hCG, persisting throughout the luteal phase and waning as the onset of menses approaches [2]. Cases of OHSS are more common, more severe and have a more protracted course if pregnancy occurs [2,7]. The occurrence of OHSS is associated with multiple follicular growth and ovulation [1,21. Without (multiple) ovulation OHSS rarely develops [l]. Multiple follicular growth resulting from ovulation induction is seen more often in PCO-like disease than in hypo-, normo-, and hypergonadotropic amenorrhea [2,7]. Apart from the diagnosis, the occurrence of multiple follicular growth largely depends on the method of ovulation induction [1,81. Severe OHSS during pulsatile LHRH therapy has to our knowledge never
been reported. Some cases of severe OHSS during CC therapy have been reported [l], but the majority of cases results from gonadotrophin therapy. The OHSS appears to result from a sudden and massive shift of intravascular serous fluid to the third space due to increased capillary permeability [1,2,9,10]. The pathophysiology is still a matter of controversy. It is suggested that the increased capillary permeability in cases of OHSS is due to an active substance secreted by the stimulated ovaries probably under the influence of hCG. A variety of substances have been suggested to be responsible such as prostaglandins [91, histamine [ll], renin 1121,ovarian steroids [13] and prolactin [13]. Moreover, an unknown ovarian factor has been suggested as in the Meiggs syndrome [ 101. With conservative management the disease is selflimiting [2]. Prevention
To prevent OHSS during gonadotrophin therapy, monitoring of the cycle is advocated in order to cancel when a high risk for OHSS is predicted. Haning et al. [7] used serial ultrasound observations of the ovary to detect a follicle of at least 14 mm during stimulation with hMG. If such a follicle was observed, hCG was administered. When gonadotrophins were administered between 500 and 8:00 p.m. and blood was drawn at 8:00 a.m., an upper limit for serum E, in patients with hypothalamic amenorrhea of 2417 pg/ml or an upper limit for patients with PC0 of 3778 pg/ml gave an approximate 5% risk of severe OHSS in conception cycles and a 1.3% risk of severe OHSS in nonconception cycles. Several authors advised different upper limits of estradiol. Blankstein et al. [14] used serial estradiol measurements to time the hCG administration and showed that the occurrence of ten or more follicles predominantly smaller than 9 mm was associated with moderate or severe OHSS. Whether estradiol measurements are a better prediction than ultrasound observations is unknown. Golan advises combined monitoring for gonadotrophin treatment in in vivo fertilization [l]. Van Weissenbruch showed that the growth of
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follicles occurs when FSH is higher than a certain threshold value [151. FSH and hMG therapy resulted in equal FSH levels and follicular growth patterns as well as an equal risk for OHSS. Persistent high levels of FSH resulted in more growing follicles [16]. Low dose and slow step up administration of gonadotrophins aiming at FSH just to surpass the threshold value show more monofollicular cycles and less risk for OHSS [17,181. Whether the use of LHRH agonists as an adjuvants for gonadotrophin therapy will increase cumulative pregnancy rates during ovulation induction in the PCO-like syndrome is a matter of controversy [ 19,201. However, it is established that the response to gonadotrophins of a medically hypophysectomized PCO-patient is not the same as in hypogonadotropic amenorrhea: the diagnosis dependent predisposition to multifollicular growth persists [20,21]. The use of LHRH analogs in IVF seems to stimulate multifollicular growth in gonadotrophin treatment of women with a normal cycle [22]. There is evidence that this effect of LHRH analog treatment will also be seen in ovulation induction of PCO-patients [20,21]. If estrogen or ultrasound monitoring shows a high risk for the development of OHSS [7,141, it can usually be avoided by withholding the hCG [2]. The patient should be considered at risk and a more moderate mode of stimulation should be used in a next treatment cycle 1231.Another option is to observe the overstimulated ovaries without further gonadotrophin stimulation until the estradiol value is < 1700 pg/ml and the ultrasound shows a leading follicle of 17-22 mm, before administering hCG [24]. Furthermore, it is possible to puncture the follicles. In that case 34 h after hCG all follicles, except two large ones, are punctured: two ovulations may occur [25]. The risk for OHSS and multiple pregnancy is reduced to a large extent by follicular puncture and oocyte retrieval Cl]. If the risk for OHSS seems to be too high to accept an hCG producing pregnancy, it is possible to puncture all follicles and freeze the embryos after IVF and perform embryo transfer in a subsequent cycle [26]. The protection against OHSS provided by follicular
puncture and removal of follicular fluid and granulosa cells is not well understood. Whether the use of prostaglandin-synthetase inhibitors is of value for the prevention or treatment of OHSS is unknown. Schenker et al. prevented OHSS in rabbits with the prostaglandin-synthetase inhibitor indomethacin [91. However, treatment was started before ovulation and the number of ovulations was significantly reduced in the indomethacin treated group compared to the group treated with gonadotrophins alone. Prostaglandin synthetase inhibitors may acutely induce anuria in the oliguric patient due to the deterioration of prostaglandin dependent renal bloodflow which is maintained during the hypovolemic state [27]. Their use is, therefore, dangerous. The use of exogenous hCG for luteal support may increase the risk of OHSS [28]. For the purpose of early detection, patients treated with gonadotropins should be advised to check their bodyweight daily after ovulation. A weight gain of more than 1 kg per day or a cumulative weight gain after hCG-injection of over 2 kg is considered an early sign of moderate to serious OHSS. Treatment of the manifest OHSS Admission to the hospital is advised when the OHSS has reached grade four of the score of Golan [l]. The OHSS is selflimiting, but complications must be recognized and treated. Puncture of large cysts several days after ovulation as well as a surgical approach have been reported [29], but may induce the risk of bleeding and rupture of the ovaries. Abdominal surgery may be extremely difficult in OHSS because of the friable ovarian tissue and may result in bilateral oophorectomy. Therefore a conservative approach is generally preferred. In OHSS, complications may be divided in four main groups: 1, acute abdomen; 2, coagulation disorders; 3, hypovolemia; and 4, severe dyspnea. The acute abdomen may become a major problem because of the risks of surgery. Venous as well as arterial thrombosis have been reported [3]. It is unknown whether coagulation disorders in OHSS are merely dependent
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on hemoconcentration and although most thromboembolic cases in the literature showed a raised hematocrit, prophylaxis by heparin 2 X 5000 IU s.c./day might be suitable in all cases of admission. The prophylaxis, however, has not been validated by appropriate research. Hypovolemia is managed by infusion of crystalloid fluid replacements and colloid fluids until production of urine is at least 30 ml/h. It is suggested that exogenous colloids might leak through the permeable bloodvessels and increase accumulation to the third space. Even if this were the case, it is not a reason to avoid their use in the treatment of hypovolemia. The majority of the accumulated extravascular fluid may be easily removed from the abdominal or thoracic cavity by paracentesis. Fluid restriction to avoid ascites has been advocated [30], but may aggravate hypovolemia and hemoconcentration, while paracentesis is a rather simple method to solve the problem of ascites. The paracentesis is best performed guided by ultrasound to prevent damage of intraabdominal or intra-thoracic structures [31]. Large amounts of fluid may be required due to rapid leakage to the third space. Therefore electrolytes must be monitored carefully. Diuretics increase urine production but do not increase renal bloodflow and aggravate hypovolemia. Dyspnea is most often the result of a massive ascites and/or hydrothorax. It should be treated by paracentesis [32]. Dyspnea may be due to pulmonary embolism complicating the OHSS. Hypovolemia induced shock and acidosis may also induce dyspnea and tachypnea. A rare reason for dyspnea is the adult respiratory distress syndrome [4] which requires assisted ventilation with continuous positive pressure. Discussion
In retrospect, the reversible hairloss during CC therapy in this case report was a negligible side effect in comparison to the grade five OHSS and the pregnancy and premature delivery of triplets which resulted from gonadotrophin therapy. The use of an LHRH agonist [20,21] and a step-up schedule of hMG increasing one ampule per week [17,18] have contributed to the risk of multifollicular growth and OHSS in this patient already
predisposed by diagnosis [7]. At the time of administration of hCG, the excessive number of follicles predicted the risk for OHSS according to the criteria of Blankstein et al. [14]. Favorable experience with other patients receiving the same treatment and the expectation of some protective effect from the low value of serum LH accounted for the decision to continue the treatment without measures which might have prevented OHSS, e.g., selective oocyte retrieval [25]. The estradiol values were only available in retrospect and also would have predicted the OHSS [7]. The availability of a double warning might have directed to a more preventive management. During admission 2 of the 4 main problems of OHSS were encountered: hypovolemia, expressed by oliguria and dyspnea. During the oliguric period, treatment with Naproxene was discontinued because of the,risk of anuria [27]. The use of prostaglandin synthetase inhibitors is dangerous during massive fluid leakage to the extravascular space. Probably this medication does not deserve the benefit of the doubt. The dyspnea reacted favorably to paracentesis. Moreover, paracentesis coincided with recovery from OHSS. Whether this coincidence is causative is unknown. Our experience as well as reports from the literature indicate that paracentesis is easily performed and an important tool in the treatment of OHSS [31,32]. It is concluded that the serious OHSS in the discussed patient was not prevented by the hypogonadal state induced by Buserelin. A viable pregnancy, however, was achieved. Management based on_ the knowledge of pathophysiology may usually prevent complications of manifest OHSS. Still, serious problems such as ovarian rupture may be encountered even when treatment seems to be optimal. Serious neonatal problems resulting from multiple pregnancies as well as maternal complications due to OHSS indicate that gonadotropins must be handled with care in a way that combines a maximal success rate with a minimal chance for complications. References 1 Golan A. Ron-El R, Herman A et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Survey 1989;44:430-440.
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Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1987;30:255-268. Mazes M, Bogokowsky H, Antebi E et al. Thromboembolic phenomena after ovarian stimulation with human gonadotropins. Lancet 1965;ii:1213-1215. Zosmer A, Katz Z, Lancet M et al. Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome. Fertil Steril 1987;47:524-526. Chin NW, Friedman HK, Awadalla SG et al. Adnexal torsion as a complication of superovulation for ovum-retrieval. Fertil Steril 1987;48:149-151. Paulson RJ, Lobo RA. Ovarian hyperstimulation complicating the clinical presentation of a pre-existing ectopic pregnancy. Fertil Steril 1988;50:670-671. Haning RV, Boehnlein LN, Carbon IH et al. Diagnosisspecific serum 17P-estradiol (E,) upper limits for treatment with menotropins using a 1251 direct E, assay. Fertil Steril 1984;42:882-889. Borenstein R, Ashkenazy M, Rosenman D et al. Ovarian hyperstimulation syndrome after different treatment schedules. Int J Fertil 1981;26:279-282. Schenker JG, Polishuk WZ. The role of prostaglandins in ovarian hyperstimulation syndrome. Eur J Gynecol Reprod Biol 1976;6:47-52. Haning RV, Strawn EY, Nolten WE. Pathophysiology of the ovarian hyperstimulation syndrome. Obstet Gynecol 1985;66:220-224. Knox GE. Antihistamine blockade of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1974;118:992-994. Itskovitz J, Sealy JE. Ovarian prorenin-renin-angiotensin system. Obstet Gynecol Surv 1987;42:545-551. Yuen BH, McComb P, Lewis J et al. Plasma prolactin, human chorionic gonadotropin, estradiol, testosterone and progesterone in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1987;133;316-320. Blankstein J, Shalev J, Saadon T et al. Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil Steril 1987;47:597-602. Weissenbruch van M. Gonadotropins for induction of ovulation. Thesis, 1990, Vrije Universiteit, Amsterdam, The Netherlands. Ben-Raphael Z, Strauss JF, Mastroianni L et al. Differences in ovarian stimulation in human menopausal gonadotropin treated woman may be related to follicle stimulating hormone accumulation. Fertil Steril 1986;46:586592. Polson DW, Mason HD, Saldahna MBY et al. Ovulation of a single dominant follicle during treatment with low dose pulsatile follicle stimulating hormone in women with polycystic ovary syndrome. Clin Endocrin 1987;26:205-212. Buvat J, Buvat-Herbaut M, Marcolin G et al. Purified follicle stimulating hormone in polycystic ovary syndrome: slow administration is safer and more effective. Fertil Steril 1989;52:553-559.
19 Fleming R, Haxton MJ, Hamilton MPR et al. Combined gonadotropin releasing hormone analog and exogenous gonadotropins for ovulation-induction in infertile women: efficacy related to ovarian function assessment. Am J Obstet Gynecol 1988;159:376-381. 20 Homburg R, Eshel A, Kilborn J et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotropins for the treatment of infertility associated with polycystic ovaries. Human Reproduction 1990;5:3235. 21 Lanzone A, Fulghesu AM, Spina MA et al. Successful induction of ovulation and conception with combined gonadotropin releasing hormone agonist plus highly purified follicle stimulating hormone in patients with polycystic ovarian disease. J Clin Endocrinol Metab 1987;65:12531258. 22 Neveu S, Hedon B, Bringer J et al. Ovarian stimulation by a combination of a gonadotropin-releasing hormone agonist and gonadotropins for ovulation induction. Fertil Steril 1987;47:639-643. 23 Forman RG, Frydman R, Egan D et al. Severe ovarian hyperstimulation using agonists of gonadotropin releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990;53:502-509. 24 Rabinovici J, Kushnir 0, Shalev J et al. Rescue of menotrophin cycles prone to develop ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1987;94:1098-l 102. 25 Belaisch-Allart J, Belaisch J, Hazout A et al. Selective oocyte retrieval: a new approach to ovarian hyperstimulation. Fertil Steril 1988;50:654-656. 26 Amso NN, Ahuja KK, Morris N et al. The management of predicted ovarian hyperstimulation involving gonadotropin-releasing analog with elective cryopreservation of all pre-embryos. Fertil Steril 1990;53:1087-1090. 27 Demey HE, Daelemans R, Galdermans D et al. Acute oligo-anuria during ovarian hyperstimulation syndrome Acta Obstet Gynecol Stand 1987;66:741-743. 28 Herman A, Ron-El R, Golan A et al. Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins. Fertil Steril 1990;53:92-96. 29 Narita 0, Shimosuka Y, Suzuki M et al. Induction of ovulation with human menopausal gonadotropin; with special reference to ovarian hyperstimulation syndrome and hormone excretion. Nagoya J Med Sci 1980;43:7-13. 30 Shapiro AG, Thomas T, Epstein M. Management of hyperstimulation syndrome. Fertil Steril 1977;28:237-239. 31 Abdoulghar MA, Mansour RT, Serour GI et al. Ultrasonically guided vaginal aspiration of ascites in the treatment of severe ovarian hyperstimulation syndrome. Fertil Steril 1990;53:933-935. 32 Thaler I, Yoffe N, Kaftory JK et al. Treatment of ovarian hyperstimulation syndrome: the physiologic basis for a modified approach. Fertil Steril 1981;36:110-113.
