Bilateral partial oophorectomy in the management of severe ovarian hyperstimulation syndrome

An aggressive, but perhaps life-saving procedure

Z.O. Amarin1

Jordan University of Science and Technology, Irbid, Jordan

1 To whom correspondence should be addressed at: P.O.B 1572, Amman 11953, Jordan. E-mail: zoamarin{at}hotmail.com


    Abstract
 Top
 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
Two case histories are described, in which protracted courses of severe ovarian hyperstimulation syndrome (OHSS) responded poorly to conservative treatment. Each patient underwent bilateral partial oophorectomy at 14 and 16 days respectively, post oocyte retrieval. Serum albumin levels returned to normal within three days of the operation in each case and the patients, one pregnant with twins, made a rapid recovery. This seemingly ‘aggressive’ procedure is proposed as a potentially useful treatment when faced with patients who are severely or critically affected with OHSS.

Key words: bilateral/IVF/OHSS/oophorectomy/partial


    Introduction
 Top
 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
Ovarian hyperstimulation syndrome (OHSS) is a well-known iatrogenic, potentially life-threatening disease (Mozes et al., 1965Go) that complicates assisted reproduction procedures in ~10% of cases (Schenker and Ezra, 1994Go). However, severe OHSS is rare, since it complicates no more than 0.2–2% of IVF attempts (Forman et al., 1990Go; Navot et al., 1992Go; Abramov et al., 1999Go). Women suffering from polycystic ovary syndrome (PCOS) are at increased risk of OHSS (Rizk and Smitz, 1992Go). Furthermore, aggressive stimulation schemes with an exaggerated estradiol level increase the likelihood of OHSS (Asch et al., 1993Go). The risk of severe OHSS in patients undergoing IVF who develop a large number of follicles during controlled ovarian stimulation has been estimated at 30–80% (Blankstein et al., 1987Go; Enskog et al., 1990Go; Asch et al., 1991Go).

The characteristic features of severe OHSS are ovarian enlargement and massive ascites or pleural effusion in conjunction with prominent dyspnoea, haemodynamic instability (tachycardia >120/min and or systolic blood pressure <80 mmHg), oliguria, peripheral oedema, liver dysfunction, adult respiratory distress syndrome, acute renal failure, or thromboembolic phenomena (Golan et al., 1989Go; Pride et al., 1990Go; Navot et al., 1992Go; Abramov et al., 1999Go).

The pathogenesis of OHSS is thought to be an acute change in vascular permeability (Schenker, 1993Go). A key role has been attributed to arteriolar vasodilation (Balasch et al., 1998Go) and several ovarian factors, such as the ovarian cytokines, prostaglandins, histamine, serotonin, the vascular endothelial growth factor, the renin-angiotensin and the kallikrein-kinin systems (Elchalal and Schenker, 1997Go; Rizk et al., 1997Go; Kobayashi et al., 1998Go; Morris and Paulson, 1999Go).

The clinical management of the severe forms of OHSS is based on relatively small series of sporadic case reports, as a small number of cases are seen in a single unit. The syndrome lacks reliable predictive criteria, it also lacks consensus on strategy due to the imperfect understanding of the pathogenesis. Effective measures remain controversial.

We report two cases of severe OHSS who underwent bilateral partial oophorectomy on the grounds of a deteriorating clinical picture after a protracted course of poor response to conservative management.


    Patient 1
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 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
A 30-year-old woman with a 5 year history of secondary subfertility was referred for assisted conception treatment. She had no relevant past medical history or PCOS and her body mass index (BMI) was 29.6 kg/cm2. All routine investigations were within normal limits. The patient’s 37-year-old husband, who was affected by diabetes, reported the absence of ejaculate at orgasm. A urine specimen obtained after masturbation contained some spermatozoa. Colour duplex sonography of the penile cavernosal arteries revealed severe right and mild left arterial insufficiency with weak feeding artery and venous leakage. Complete retrograde ejaculation was diagnosed. Ovulation induction for IVF was achieved using pituitary down-regulation from the second day of the menstrual cycle with a GnRH analogue (Decapeptyl; Ferring Pharmaceuticals Ltd, Berks, UK), 0.1 mg by a daily subcutaneous injection, followed by 150 IU of FSH (Metrodin High Purity®; Serono Laboratories UK Ltd, Welwyn Garden City, UK) for 9 days. The cycle was monitored by vaginal ultrasound and serum estradiol (E2) levels. Human chorionic gonadotrophin (hCG, Profasi®; Serono Laboratories UK Ltd), 10 000 IU, was administered i.m. when the three leading follicles reached a minimum mean diameter of 18 mm. The peak serum E2 was 3790 pg/ml. Vaginal oocyte retrieval was carried out 36 h later. A total of eight oocytes were retrieved from 13 follicles. ICSI was performed. Of the eight metaphase II (MII) oocytes injected with the husband’s sperm, only five fertilized normally and subsequently cleaved.

After 3 days two embryos of good quality were transferred. Luteal phase support was provided using progestogen vaginal pessaries 400 mg/day (Cyclogest 400; Aventis Pharma, Kent, UK), commencing on the day of embryo replacement.

On post oocyte retrieval day 6, the patient required hospitalization because of nausea, headache, abdominal distension and colic, dyspnoea, fainting and decreasing urinary output. Examination confirmed that there had been a significant increase in both her weight (from 74 to 78 kg) and abdominal girth measurement (from 99 to 106 cm). Ultrasound assessment revealed a right ovary of 13.5 x 13.0 x 12.5 cm and left ovary of 13.2 x 12.8 x 10.5 cm with a moderate amount of fluid in the upper abdomen, and around the liver and spleen. Fundoscopy revealed no papilloedema. Serum investigations revealed haemoconcentration (haematocrit of 47%), low albumin concentrations (24 g/l), low total protein of 57 g/l. Coagulation studies, lupus anticoagulant, anticardiolipin antibody, protein C, protein S, and antithrombin III were within normal limits with a negative allele for factor V Leiden mutation. Based on clinical symptoms and the ultrasound and laboratory findings, her OHSS was categorized as severe (Golan et al., 1989Go; Navot et al., 1992Go).

Management consisted of analgesics, antiemetics and i.v. colloid solutions and an infusion of 20% human albumin solution (3 x 50 ml over 12 h) on a daily basis with careful clinical and laboratory monitoring. Prophylactic treatment with low molecular weight heparin (20 mg s.c. once daily) was started in conjunction with elasticated stockings.

On post oocyte retrieval day 9, the ascites had substantially increased and X-ray examination of the chest showed slightly elevated right diaphragmatic leaflet with left linear atelectatic band and no pleural effusion. Laboratory testing revealed normal concentrations of haemoglobin and packed cell volume but low albumin level of 22 g/l. In view of the marked ascites and the presence of respiratory distress, paracentesis was performed by a transvaginal ultrasonographic approach using the same set-up as for transvaginal oocyte retrieval under intravenous sedation. A total of 2 l of ascitic fluid were removed and a drain was left in situ for another 2 days. This was followed by rapid reaccumulation of the ascites while medically maintaining normal haematocrit, platelets, creatinine, blood urea nitrogen and liver function tests. The serum {beta}hCG was 92 IU/l. A second paracentesis was required on day 2 following the removal of the vaginal drain because of severe discomfort and pain. Another 2 l of ascitic fluid were removed and another drain was placed for the next 3 days on continuous drainage.

Sixteen days post oocyte retrieval, and despite early recognition of OHSS and prompt and vigilant attention to fluid management, daily albumin replacement, thrombosis prevention and drainage of ascitic fluid, the ovaries did not show any signs of diminishing in size. The albumin levels were constantly low (Figure 1) and the degree of ascitic fluid production remained high. It was decided to perform laparotomy and bilateral partial oophorectomy. Pregnancy termination was not an option.



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Figure 1. Serum albumin plotted against hospital stay day for the two cases

 
At operation both ovaries were grossly enlarged to 13 x 12 x 11 cm each. A wedge reaching the stromal centre of each ovary was performed. The excised wedge consisted of ~30% of each ovarian cortex extending to the centre of each ovary, thus excising ~30% of each ovary. The contents of any remaining cysts were drained. The resulting gap was obliterated using low tension absorbable ‘in and in’ sutures and the edges were closed using continuous locking stitches. Good haemostasis was achieved without undue difficulty. A pelvic drain produced a total of 400 ml of serosanguineous fluid. This was removed the following day as drainage had completely ceased. Further serum albumin estimations demonstrated marked improvement and were within normal on post-operative day 2. There was an improvement too in the total urinary output in combination with weight loss and decrease in abdominal girth. The immediate post-operative period was totally uneventful and the patient was able to go home on post-operative day 3 in a very good physical and mental state. An ultrasound scan one week later confirmed the presence of a twin pregnancy. The antenatal period was uneventful. An elective Caesarean section was performed at term for breech presentation of the first twin. Two male babies were delivered in good condition. The ovaries appeared normal in size and position, with no adhesions or obvious scarring. Mother and babies are doing well.


    Patient 2
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 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
This 21-year-old nulligravid woman with infertility secondary to oligoasthenoteratozoospermia had a regular menstrual cycle, BMI of 24.3 kg/cm2 and no past history of PCOS or any other medical or surgical problem. She underwent ovulation induction for ICSI using a similar stimulation and monitoring regime as described for the first case. Briefly, pituitary down-regulation was started on the second day of the menstrual cycle with a GnRH analogue (Decapeptyl; Ferring Pharmaceuticals Ltd), 0.1 mg by a daily s.c. injection, followed on day 3 of the cycle by 225 IU of hMG (Pergonal®; Serono Laboratories UK Ltd). After 7 days of FSH administration, ultrasound demonstrated the presence of a total of 19 follicles, of which 14 were >11 mm and the three leading follicles were >18 mm in diameter. The serum E2 concentration was 4190 pg/ml. The likelihood of OHSS was considered and the couple was counselled regarding probable risks. After coasting (Waldenström et al., 1999Go) for 2 days the serum E2 concentration was 4210 pg/ml. Ultrasound demonstrated a total of 24 follicles, of which 17 were >11 mm and six were >18 mm in diameter. It was decided to proceed with half the usual dose of hCG (5000 IU) (Navot et al., 1992Go) on day 12 and to cryopreserve all the resulting embryos (Amso et al., 1990Go). Transvaginal ultrasound guided follicular aspiration was performed 36 h later. This yielded 40 oocytes. ICSI was performed on all of them. This resulted in 28 cleaved embryos, all of which were duly cryopreserved. No embryos were transferred.

Four days following oocyte retrieval the patient complained of nausea, dyspnoea, abdominal distension and pain. Physical examination revealed stable vital signs, clear lung fields and a distended abdomen. Transvaginal ultrasound demonstrated a right ovary of 13.5 x 13.0 x 12.5 cm and left ovary of 13.5 x 12.5 x 11.5 cm with a small amount of free peritoneal fluid. The patient’s thrombophilic diathesis indices were all within normal limits. The only alteration in laboratory evaluation was a low serum albumin level of 23 g/l. The patient was admitted for observation, albumin replacement, fluid balance monitoring and prophylactic anticoagulants.

On post oocyte retrieval day 6, the patient underwent transvaginal ultrasound-guided aspiration of 2500 ml of peritoneal fluid and was subsequently transferred to the intensive care unit because of the development of prominent dyspnoea, haemodynamic instability (tachycardia and low blood pressure) and oliguria (urine output <400 ml/24 h), haemoconcentration (45%) and oedema. The drain was removed after 48 h. On post oocyte retrieval day 9, she was noted to have more pronounced dyspnoea, anxiety, tachycardia, blood pressure of 80/50 mmHg with persistent low urinary output. On physical examination she had a relapse of abdominal distension and bilateral decrease in breath sounds. Repeat paracentesis with continuous drainage was performed. Over the ensuing 3 days, the patient became lethargic with complete loss of appetite and continued to complain of shortness of breath and decreased urinary output. Arterial blood gases at ambient conditions, including PO2, PCO2, pH, base deficit, and bicarbonate concentrations were marginally abnormal (pO2 78 mmHg, PCO2 28 mmHg, pH 7.46, base deficit 4.5, HCO3 18.5 mEq/l). Serum albumin levels were persistently low (Figure 1) despite daily infusion of the maximal dose of 150 ml of 20% albumin and close monitoring of fluid balance.

On day 14 post oocyte collection and in view of this protracted course of OHSS and severe anxiety associated with invasive monitoring and multiple medical therapies in the intensive care unit, deteriorating respiratory status, oliguria and haemodynamic instability, it was decided to perform laparotomy and bilateral partial oophorectomy. At operation both ovaries were grossly enlarged to 12 x 12 x 11 cm each. Wedge resection reaching the stromal centre of each ovary was performed on the opposite side to the tubes. The excised wedge consisted of ~30% of each ovarian cortex extending to the centre of each ovary, thus excising ~30% of each ovary. Any remaining cysts were punctured and drained. The resulting gap was closed in a similar fashion to that for the first patient.

Post-operatively, the patient made a remarkable recovery. There was a marked improvement in serum albumin levels (Figure 1) and urinary output. There was also a very dramatic decrease in the amount of ascitic fluid drainage, coming to a virtual halt within 24 hours. This was combined with weight loss and reversal of abdominal girth. She was able to go home on post-operative day 3 in a very good physical and mental state.


    Discussion
 Top
 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
In superovulation induction, one of the main concerns of physicians is OHSS prevention. This is a dramatic and potentially lethal complication of fertility treatment. There is no consensus on strategy, and effective measures remain controversial. Various methods have been suggested to prevent OHSS, or to reduce its severity, such as cycle abandonment, the use of low doses of gonadotrophin during the follicular phase (Asch et al., 1991Go), partial follicular aspiration in the follicular phase or after hCG triggering but before oocyte retrieval (Vrtovec and Tomazevic, 1995Go), early unilateral follicular aspiration (Egbase et al., 1999Go), triggering of ovulation with low doses of HCG (Navot et al., 1992Go), administration of recombinant LH (Rizk and Smitz, 1992Go) or GnRH analogue (Casper, 1996Go) instead of hCG, i.v. albumin or hydroxyaethyl starch solutions during oocyte retrieval, or administering glucocorticoids (Tan et al., 1992Go; Asch et al., 1993Go; Graf et al., 1997Go). In view of the increased risk of OHSS associated with pregnancy, cryopreservation of all embryos has also been advocated (Amso et al., 1990Go) and avoiding hCG administration in the luteal phase (Araujo et al., 1994Go). Coasting, i.e. withholding gonadotrophins whilst continuing GnRH agonist administration for pituitary down-regulation, is being increasingly employed to prevent or minimize the incidence of severe OHSS (Waldenström et al., 1999Go). One more regimen that seems effective, particularly in ‘high responders’, is combining GnRH antagonist-based ovarian stimulation with GnRH agonist-driven ovulation triggering (Itskovitz-Eldor et al., 2000Go).

The second concern facing physicians is the management of the severe forms of OHSS. The clinical acumen is supported by, and based on, relatively small series of sporadic case reports. In a review of severe OHSS (Abramov et al., 1999Go), the main signs and symptoms recorded in 209 patients were ascites (99%), dyspnoea (92%), haemoconcentration (95%) and gastrointestinal disturbances (54%). Oliguria was reported in 62 patients (30%), whereas massive pleural effusion appeared in 19%. Peripheral oedema occurred in 13% and thromboembolism in 2%.

Some unusual reported complications include benign intracranial hypertension (Lesny et al., 1999Go), spontaneous OHSS and deep vein thrombosis (Todros et al., 1999Go), OHSS complicated by peritonitis due to perforated appendicitis (Fujimoto et al., 2002Go), recurrent cholestasis (Midgley et al., 1999Go), hepatic dysfunction (Elter et al., 2001Go), internal jugular vein thrombosis (Belaen et al., 2001Go), cortical vein thrombosis misinterpreted as intracranial haemorrhage (Tang et al., 2000Go), subclavian deep vein thrombosis (Loret de Mola et al., 2000Go), myocardial infarction (Ludwig et al., 1999Go), superior vena cava thrombosis (Lamon et al., 2000Go), pericardial and pleural effusions complicated by supraventricular arrhythmia (Sovova et al., 1999Go), deep cerebrovascular thrombosis (Aboulghar et al., 1998Go), perforated duodenal ulcer (Uhler et al., 2001Go), massive pulmonary oedema, pleural effusion and death (Cluroe and Synek, 1995Go; Semba et al., 2000Go). These case reports illustrate that OHSS can be a serious and life-threatening complication of controlled ovarian stimulation.

The pathogenesis of OHSS may be explained by an increase in vascular permeability leading to leakage of protein rich intravascular fluid into the peritoneal, pleural and pericardial cavities and a consequent reduction in circulating fluid volume. A number of vasoactive mediators that alter the permeability of capillaries have been identified in serum, follicular fluid and in cultured human luteinizing granulosa cells (Elchalal and Schenker, 1997Go; Rizk et al., 1997Go; Balasch et al., 1998Go; Doldi et al., 1999Go; Morris and Paulson, 1999Go). The severity of the syndrome is directly related to the extent of ovarian response to stimulation. The biochemical link between the ovary and OHSS remain unclear. Transvaginal ultrasound guided aspiration of the multiple corpora lutea as a therapeutical approach to severe OHSS has been reported (Fakih and Bello, 1992Go). The authors suggest that bilateral partial oophorectomy was effective not only due to the emptying of the contents of the corpora lutea, but also to the total excision of some luteal cysts where the walls closely incorporate most of the granulosa cells that are the likeliest origin of most vasoactive mediators. This procedure gives some insight into the possible aetiology of OHSS and suggests that the main, or perhaps the sole producer of vasoactive substances in OHSS is the ovary. Although transvaginal ultrasound guided aspiration of the multiple corpora lutea as a therapeutical approach to severe OHSS may seem less aggressive compared with laparotomy, it is the author’s opinion that it is less effective as the contents do re-accumulate and is difficult as most of the content of the corpora lutea constitutes a thick coagulum; especially in the later forms of OHSS, which is not very amenable to aspiration. This was observed in the above two cases, both at the ultrasound evaluation of the ovaries and during the surgical interventions.

Although the pathophysiology of OHSS remains unclear, the appearance of its features and symptoms are always associated with the presence of hCG. Therefore, pregnancy may aggravate early OHSS and may induce late OHSS. In the case of the first multiparous patient described, the option of partial oophorectomy was by far the preferred one as opposed to terminating the pregnancy, having in mind that she did not have any plans for future pregnancies. Even if she had such plans, her ovarian reserve, arguably, would have been adequate. In cases of successful assisted reproductive technology outcome, it is the author’s view that this procedure is preferable to pregnancy termination.

In the second case described, the patient developed critical OHSS despite the avoidance of pregnancy and lack of further luteal exposure to hCG. Close vigilance for potential OHSS, as well as for the variable appearance of its possible sequelae, was imperative in providing care to this otherwise young and healthy woman. Coasting, hCG dose reduction and cryopreservation of all resulting embryos were three OHSS prevention modalities that were adopted in the case of this patient with no success. The natural course of OHSS is eventually to improve over time, and the marked worsening in status prompted an aggressive search for secondary complications and ways to avoid them, hence the decision to perform bilateral partial oophorectomy. Treatment resulted in complete resolution of symptoms within 3 days.

The procedure of bilateral partial oophorectomy in severe OHSS may seem aggressive as it aims to excise a given volume of the ovaries. There is a plethora of commonly practised procedures that similarly aim at reducing the functional volume of ovaries, albeit for other indications and under different circumstances. Examples are bipolar electrocoagulation (Merchant, 1996Go), argon laser ovarian capsule drilling and vaporization (Heylen et al., 1994Go), laparoscopic ovarian resection (Campo et al., 1993Go) for the treatment of PCOS per se, and laparoscopic ovarian electrocautery to prevent the cancellation of IVF cycles due to risk of OHSS in women with polycystic ovaries (Rimington et al., 1997Go). The long-term anatomical and physiological sequelae are perhaps similar in all those procedures. Alteration of the tubo-ovarian relationship may be expected in some cases. While this may not make a difference to some patients, such as those requiring IVF and ICSI, it would probably affect the fecundity of others. Research into the long-term ovarian reserve implications of procedures that diminish the overall ovarian mass is needed.

To our knowledge, this is the first report on the use of partial oophorectomy in the management of severe OHSS. The seriousness of this worrying clinical condition and the lack of any definitive therapy to date justify considering new approaches. Although clear scientific evidence is lacking to justify ovarian surgery in OHSS, dramatic changes as evidenced by serial estimations of serum albumin, urinary output, ascitic fluid drainage, daily weight and abdominal girth measurements before and after surgery strengthen the argument that it was the ovarian surgery that was therapeutic and that recovery was not just part of the natural disease process. It has been found that those indirect but reliable indices seem to correlate well with reversal of OHSS (Whelan III and Vlahos, 2000Go).

The authors propose that this seemingly ‘aggressive’ procedure is a potentially useful treatment when faced with severely or critically affected patients with OHSS. Further research is needed to provide guidelines for its judicial implementation.


    References
 Top
 Abstract
 Introduction
 Patient 1
 Patient 2
 Discussion
 References
 
Aboulghar, M.A., Mansour, R.T., Serour, G.I. and Amin, Y.M. (1998) Moderate ovarian hyperstimulation syndrome complicated by deep cerebrovascular thrombosis. Hum. Reprod., 13, 2088–2091.[Abstract]

Abramov, Y., Elchalal, U. and Schenker, J.G. (1999) Severe OHSS. An epidemic of severe OHSS: a price to pay? Hum. Reprod., 14, 2181–2185.[Free Full Text]

Amso, N.N., Ahuja, K.K, Morris, N. and Shaw, R.W. (1990) The management of predicted ovarian hyperstimulation involving gonadotropin-releasing hormone analog with elective cryopreservation of all pre-embryos. Fertil. Steril., 53, 1087–1090.[ISI][Medline]

Araujo, E. Jr, Bernardini, L., Frederick, J.L., Asch, R.H. and Balmaceda, J.P. (1994) Prospective randomized comparison of human chorionic gonadotropin versus intramuscular progesterone for luteal-phase support in assisted reproduction. J. Assist. Reprod. Genet., 11, 74–78.[ISI][Medline]

Asch, R.H., Li, H.P., Balamceda, J.P. Weckstein, L.N. and Stone, S.C. (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum. Reprod., 6, 1395–1399.[Abstract]

Asch, R.H., Ivery, G., Goldsman, M., Frederick, J.L., Stone, S.C. and Balmaceda, J.P. (1993) The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome. Hum. Reprod., 8, 1015–1020.[Abstract]

Balasch, J., Fabregues, F. and Arroyo, V. (1998) Peripheral arterial vasodilation hypothesis: a new insight into the pathogenesis of ovarian hyperstimulation syndrome. Hum. Reprod., 13, 2718–2730.[Abstract/Free Full Text]

Belaen, B., Geerinckx, K., Vergauwe, P. and Thys, J. (2001) Internal jugular vein thrombosis after ovarian stimulation. Hum. Reprod., 16, 510–512.[Abstract/Free Full Text]

Blankstein, J., Shalev, J., Saadon, T., Kukia, E.E., Rabinovici, J., Pariente, C., Lunenfeld, B., Serr, D.M. and Mashiach, S. (1987) Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597–602.[ISI][Medline]

Campo, S., Felli, A., Lamanna, M.A., Barini, A. and Garcea, N. (1993) Endocrine changes and clinical outcome after laparoscopic ovarian resection in women with polycystic ovaries. Hum. Reprod., 8, 359–363.[Abstract]

Casper, R.F. (1996) Ovarian hyperstimulation: effects of GnRH analogues. Does triggering ovulation with gonadotrophin-releasing hormone analogue prevent severe ovarian hyperstimulation syndrome? Hum. Reprod., 1, 1144–1146.

Cluroe, A.D. and Synek, B.J. (1995) A fatal case of ovarian hyperstimulation syndrome with cerebral infarction. Pathology, 27, 344–346.[ISI][Medline]

Doldi, N., Destefani, A., Gessi, A., Grossi, D., Ferrari, A. and Egbase, P.E. (1999) Human albumin enhances expression of vascular endothelial growth factor in cultured human luteinizing granulosa cells: importance in ovarian hyperstimulation syndrome. Hum. Reprod., 14, 1157–1159.[Abstract/Free Full Text]

Egbase, P.E., Sharhan, M. A. and Grudzinskas, J.G. (1999) Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized trial. Hum. Reprod., 14, 1421–1425.[Abstract/Free Full Text]

Elchalal, U. and Schenker, J.G. (1997) The pathophysiology of ovarian hyperstimulation syndrome – views and ideas. Hum. Reprod., 12, 1129–1137.[CrossRef][ISI][Medline]

Elter, K., Scoccia, B. and Nelson, L.R. (2001) Hepatic dysfunction associated with moderate ovarian hyperstimulation syndrome. A case report. J. Reprod. Med., 46, 765–768.[ISI][Medline]

Enskog, A., Henriksson, M., Unander, M., Nilsson, L. and Brannstrom, M. (1990) Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil. Steril., 71, 808–814.[CrossRef]

Fakih, H. and Bello, S. (1992) Ovarian cyst aspiration: a therapeutic approach to ovarian hyperstimulation syndrome. Fertil. Steril., 58, 829–832.[ISI][Medline]

Forman, R.G., Frydman, R., Egan, D. Ross, C. and Barlow, D.H. (1990) Severe hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502–509.[ISI][Medline]

Fujimoto, A., Osuga, Y., Yano, T., Kusumi, M., Kurosawa, T., Fujii, T. and Taketani, Y. (2002) Ovarian hyperstimulation syndrome complicated by peritonitis due to perforated appendicitis: Case Report. Hum. Reprod., 17, 966–967.[Abstract/Free Full Text]

Golan, A., Ron-El, R., Herman, A., Soffer, Y., Weinraub, Z. and Caspi, E. (1989) Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv., 44, 430–440.

Graf, M.A., Fisher, R., Naether, O.G.J., Baukloh, V., Tafel, J. and Nuckel, M. (1997) Reduced incidence of ovarian hyperstimulation syndrome by prophylactic infusion of hydroxyaethyl starch solution in an in-vitro fertilization programme. Hum. Reprod., 12, 2599–2602.[Abstract]

Heylen, S.M., Puttemans, P.J. and Brosens, I.A. (1994) Polycystic ovarian disease treated by laparoscopic argon laser capsule drilling: comparison of vaporization versus perforation technique. Hum. Reprod., 9, 1038–1042.[Abstract]

Itskovitz-Eldor, J., Kol, S. and Mannaerts, B. (2000) Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication. Hum. Reprod., 15, 1965–1968.[Abstract/Free Full Text]

Kobayashi, H., Takeda, S., Fukuda, J., Gotoh, J. and Terao, T. (1998) The kallikrein-kinin system, but not vascular endothelial growth factor, plays a role in the increased vascular permeability associated with ovarian hyperstimulation syndrome. J. Mol. Endocrinol., 20, 363–374.[Abstract/Free Full Text]

Lamon, D., Chang, C.K., Hruska, L., Kerlakian, G. and Smith, J.M. (2000) Superior vena cava thrombosis after in vitro fertilization: case report and review of the literature. Ann. Vasc. Surg., 14, 283–285.[CrossRef][ISI][Medline]

Lesny, P., Maguiness, S.D., Hay, D.M., Robinson, J., Clarke, C.E. and Killick, S.R. (1999) Ovarian hyperstimulation syndrome and benign intracranial hypertension in pregnancy after in-vitro fertilization and ET: Case report. Hum. Reprod., 14, 1953–1955.[Abstract/Free Full Text]

Loret de Mola, J.R., Kiwi, R., Austin, C. and Goldfarb, J.M. (2000) Subclavian deep vein thrombosis associated with the use of recombinant follicle-stimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome. Fertil. Steril., 73, 1253–1256.[ISI][Medline]

Ludwig, M., Tolg, R., Richardt, G., Katus H. A. and Diedrich, K. (1999) Myocardial infarction associated with ovarian hyperstimulation syndrome. J. Am. Med. Assoc., 282, 632–633.[Free Full Text]

Merchant, R.N. (1996) Treatment of polycystic ovary disease with laparoscopic low-watt bipolar electrocoagulation of the ovaries. J. Am. Assoc. Gynecol. Laparosc., 4, 503–508.[ISI]

Midgley, D.Y., Khalaf, Y., Braude, P.R. and Nelson-Piercy, C. (1999) Recurrent cholestasis following ovarian hyperstimulation syndrome: case report. Hum. Reprod., 14, 2249–2251.[Abstract/Free Full Text]

Morris, R. and Paulson, R.J. (1999) Increased angiotensin-converting enzyme activity in a patient with severe ovarian hyperstimulation syndrome. Fertil. Steril., 71, 562–563.[CrossRef][ISI][Medline]

Mozes, M., Bogokowsky, H., Antebi, E., Lunenfeld, B., Rabou, E., Serr, D.M., David, A. and Salomy, M. (1965) Thromoembolic phenomena after ovarian stimulation with human gonadotrophin. Lancet, 2, 1213–1215[CrossRef][Medline]

Navot, D., Bergh, P.A. and Laufer, N. (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil. Steril., 58, 249–261.[ISI][Medline]

Pride, S.M., James, C.S.I. and Yuen, B.H. (1990) The ovarian hyperstimulation syndrome. Semin. Reprod. Endocrinol., 8, 247–260.[ISI]

Rimington, M.R., Walker, S.M. and Shaw, R. (1997) The use of laparoscopic ovarian electrocautery in preventing cancellation of in-vitro fertilisation treatment cycles due to risk of ovarian hyperstimulation syndrome in women with polycystic ovaries. Hum. Reprod., 12, 1443–1447.[Abstract]

Rizk, B. and Smitz, J. (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum. Reprod., 7, 320–327.[Abstract]

Rizk, B., Aboulghar, M., Smitz, J. and Ron-El, R. (1997) The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome. Hum. Reprod. Update, 3, 255–266.[Abstract/Free Full Text]

Schenker, J.G. (1993) Prevention and treatment of ovarian hyperstimulation. Hum. Reprod., 8, 653–659.[ISI][Medline]

Schenker, J.G. and Ezra, Y. (1994) Complications of assisted reproductive techniques. Fertil. Steril., 61, 411–422.[ISI][Medline]

Semba, S., Moriya, T., Youssef, E.M. and Sasano, H. (2000) An autopsy case of ovarian hyperstimulation syndrome with massive pulmonary edema and pleural effusion. Pathol. Int., 50, 549–552.[CrossRef][ISI][Medline]

Sovova, E., Oborna, I., Dostal, J., Marek, D., Lukl, J. and Talas, M. (1999) The ovarian hyperstimulation syndrome with pericardial and pleural effusions complicated by supraventricular arrhythmia. Cas. Lek. Cesk., 138, 730–733.[Medline]

Tan, S.L., Balen, A., El Hussein, E., Campbell, S. and Jacobs, H.S. (1992) The administration of glucocorticoids for the prevention of ovarian hyperstimulation syndrome in in-vitro fertilization: a prospective randomized study. Hum. Reprod., 58, 378–383.

Tang, O.S., Ng, E.H., Wai Cheng, P. and Chung Ho, P. (2000) Cortical vein thrombosis misinterpreted as intracranial haemorrhage in severe ovarian hyperstimulation syndrome: case report. Hum. Reprod., 15, 1913–1916.[Abstract/Free Full Text]

Todros, T., Carmazzi, C.M., Bontempo, S., Gaglioti, P., Donvito, V. and Massobrio, M. (1999) Spontaneous ovarian hyperstimulation syndrome and deep vein thrombosis in pregnancy: case report. Hum. Reprod., 14, 2245–2248.[Abstract/Free Full Text]

Uhler, M.L., Budinger, G.R., Gabram, S.G. and Zinaman, M.J. (2001) Perforated duodenal ulcer associated with ovarian hyperstimulation syndrome: Case Report. Hum. Reprod., 16, 174–176.[Free Full Text]

Vrtovec, H.M. and Tomazevic, T. (1995) Preventing severe ovarian hyperstimulation syndrome in an in vitro fertilization/ET program. Use of follicular aspiration after human chorionic gonadotropin administration. J. Reprod. Med., 40, 37–40.[ISI][Medline]

Waldenström, U., Kahn, J., Marsk, L. and Nilsson, S. (1999) High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by ‘prolonged coasting’ of very hyperstimulated patients: a multicentre study. Hum. Reprod., 14, 294–297.[Abstract/Free Full Text]

Whelan, J.G. III and Vlahos, N.F. (2000) The ovarian hyperstimulation syndrome. Fertil. Steril., 73, 883–896.[CrossRef][ISI][Medline]