Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome
- Cristiano E Busso, MD
Cristiano E Busso, MD
- Infertility Specialist
- Projeto ALFA, Brazil
- Sérgio Reis Soares, MD
Sérgio Reis Soares, MD
- Valencian Infertility Institute (IVI) - Lisbon, Portugal
- Antonio Pellicer, MD
Antonio Pellicer, MD
- Instituto Valenciano de Infertilidad (IVI)
Ovarian hyperstimulation syndrome (OHSS) occurs when the ovaries are hyperstimulated and enlarged due to fertility treatments (or rarely, mutations in the FSH receptor), resulting in the shift of serum from the intravascular space to the third space, mainly to the abdominal cavity. In its severe form, OHSS is a life-threatening condition because it can cause venous or arterial thromboembolic events, including stroke and loss of perfusion of an extremity.
The pathogenesis, clinical manifestations, and diagnosis of OHSS are reviewed here. The prevention and management of OHSS are discussed separately. (See "Prevention of ovarian hyperstimulation syndrome".)
Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian hyperstimulation (COH) for assisted reproduction technologies (ART). It is a broad spectrum of signs and symptoms that include abdominal distention and discomfort, enlarged ovaries, ascites, and other complications of enhanced vascular permeability [1,2]. The pathophysiology of OHSS is not fully understood, but increased capillary permeability with the resulting loss of fluid into the third space is its main feature. In the susceptible patient, hCG administration for final follicular maturation and triggering of ovulation is the pivotal stimulus for OHSS, leading to overexpression of vascular endothelial growth factor (VEGF) in the ovary, release of vasoactive-angiogenic substances, increased vascular permeability, loss of fluid to the third space, and full-blown OHSS.
OHSS is an iatrogenic and potentially life-threatening condition that affects young, healthy patients. In addition, there is an important economic burden associated with OHSS due to absence from work, bed rest, or hospitalization and intensive medical management of severe cases.
There are two clinical forms of OHSS, both hCG related: the early-onset form (occurring in the first eight days after hCG administration) and the late-onset form (occurring nine or more days after hCG administration, related to pregnancy-induced hCG production) .
- Golan A, Ron-el R, Herman A, et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44:430.
- Whelan JG 3rd, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril 2000; 73:883.
- Lyons CA, Wheeler CA, Frishman GN, et al. Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 1994; 9:792.
- Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1978; 30:255.
- Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002; 8:559.
- Papanikolaou EG, Tournaye H, Verpoest W, et al. Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile. Hum Reprod 2005; 20:636.
- Abramov Y, Elchalal U, Schenker JG. Severe OHSS: An 'epidemic' of severe OHSS: a price we have to pay? Hum Reprod 1999; 14:2181.
- Cunha-Filho JS, Samama M, Fanchin R, et al. Clinical and laboratory evaluation of hospitalized patients with severe ovarian hyperstimulation syndrome. Reprod Biomed Online 2003; 6:448.
- Binder H, Dittrich R, Einhaus F, et al. Update on ovarian hyperstimulation syndrome: Part 1--Incidence and pathogenesis. Int J Fertil Womens Med 2007; 52:11.
- Rizk B, Smitz J. Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum Reprod 1992; 7:320.
- Mozes M, Bogokowsky H, Antebi E, et al. Thromboembolic phenomena after ovarian stimulation with human gonadotrophins. Lancet 1965; 2:1213.
- Roberts WG, Palade GE. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 1997; 57:765.
- Schenker JG. Prevention and treatment of ovarian hyperstimulation. Hum Reprod 1993; 8:653.
- Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 2003; 9:275.
- Soares SR, Gómez R, Simón C, et al. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update 2008; 14:321.
- Yen SS, Llerena O, Little B, Pearson OH. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. J Clin Endocrinol Metab 1968; 28:1763.
- McClure N, Healy DL, Rogers PA, et al. Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 1994; 344:235.
- Kamat BR, Brown LF, Manseau EJ, et al. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol 1995; 146:157.
- Yan Z, Weich HA, Bernart W, et al. Vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) expression in luteinized human granulosa cells in vitro. J Clin Endocrinol Metab 1993; 77:1723.
- Neulen J, Yan Z, Raczek S, et al. Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 1995; 80:1967.
- Wang TH, Horng SG, Chang CL, et al. Human chorionic gonadotropin-induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor. J Clin Endocrinol Metab 2002; 87:3300.
- Yamamoto S, Konishi I, Tsuruta Y, et al. Expression of vascular endothelial growth factor (VEGF) during folliculogenesis and corpus luteum formation in the human ovary. Gynecol Endocrinol 1997; 11:371.
- Pellicer A, Albert C, Mercader A, et al. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor. Fertil Steril 1999; 71:482.
- Rizk B, Aboulghar M, Smitz J, Ron-El R. The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome. Hum Reprod Update 1997; 3:255.
- Chen CD, Wu MY, Chen HF, et al. Prognostic importance of serial cytokine changes in ascites and pleural effusion in women with severe ovarian hyperstimulation syndrome. Fertil Steril 1999; 72:286.
- Agrawal R, Tan SL, Wild S, et al. Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation syndrome. Fertil Steril 1999; 71:287.
- Abramov Y, Barak V, Nisman B, Schenker JG. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome. Fertil Steril 1997; 67:261.
- Alvarez C, Martí-Bonmatí L, Novella-Maestre E, et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. J Clin Endocrinol Metab 2007; 92:2931.
- Pau E, Alonso-Muriel I, Gómez R, et al. Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome. Hum Reprod 2006; 21:1453.
- Villasante A, Pacheco A, Ruiz A, et al. Vascular endothelial cadherin regulates vascular permeability: Implications for ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 2007; 92:314.
- Bates DO, Lodwick D, Williams B. Vascular endothelial growth factor and microvascular permeability. Microcirculation 1999; 6:83.
- Villasante A, Pacheco A, Zúñiga A, Pellicer A, Garcia-Velasco JA. Ovarian hyperstimulation syndrome: the role of vascular endothelial cadherin. Hum Reprod 2003;18:35 (Abstract).
- Chae HD, Park EJ, Kim SH, et al. Ovarian hyperstimulation syndrome complicating a spontaneous singleton pregnancy: a case report. J Assist Reprod Genet 2001; 18:120.
- Smits G, Olatunbosun O, Delbaere A, et al. Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med 2003; 349:760.
- Vasseur C, Rodien P, Beau I, et al. A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med 2003; 349:753.
- Montanelli L, Delbaere A, Di Carlo C, et al. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 2004; 89:1255.
- Abir R, Fisch B. Invited commentary: a single nucleotide polymorphism in BMP15 is associated with high response to controlled ovarian hyperstimulation. Reprod Biomed Online 2011; 23:77.
- Hanevik HI, Hilmarsen HT, Skjelbred CF, et al. A single nucleotide polymorphism in BMP15 is associated with high response to ovarian stimulation. Reprod Biomed Online 2011; 23:97.
- Morón FJ, de Castro F, Royo JL, et al. Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenet Genomics 2006; 16:485.
- Cappa F, Pasqua C, Tobia M, Ventura T. [Ascites and hydrothorax due to endogenous hyperstimulation of H.C.G. in a case of hydatidiform mole destruens with secondary irreversible kidney insufficiency due to disseminated intravascular coagulation]. Riv Ital Ginecol 1976; 56:363.
- Guvenal F, Guvenal T, Timuroglu Y, et al. Spontaneous ovarian hyperstimulation-like reaction caused by primary hypothyroidism. Acta Obstet Gynecol Scand 2006; 85:124.
- Borna S, Nasery A. Spontaneous ovarian hyperstimulation in a pregnant woman with hypothyroidism. Fertil Steril 2007; 88:705.e1.
- Miras AD, Mogford JT, Wright J, et al. Ovarian hyperstimulation from ectopic hypersecretion of follicle stimulating hormone. Lancet 2015; 385:392.
- Practice Committee of American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril 2008; 90:S188.
- Delvigne A, Dubois M, Battheu B, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. II. Multiple discriminant analysis for risk prediction. Hum Reprod 1993; 8:1361.
- Soave I, Marci R. Ovarian stimulation in patients in risk of OHSS. Minerva Ginecol 2014; 66:165.
- Navot D, Relou A, Birkenfeld A, et al. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988; 159:210.
- Asch RH, Li HP, Balmaceda JP, et al. Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum Reprod 1991; 6:1395.
- Tummon I, Gavrilova-Jordan L, Allemand MC, Session D. Polycystic ovaries and ovarian hyperstimulation syndrome: a systematic review*. Acta Obstet Gynecol Scand 2005; 84:611.
- Delvigne A. Symposium: Update on prediction and management of OHSS. Epidemiology of OHSS. Reprod Biomed Online 2009; 19:8.
- Enskog A, Henriksson M, Unander M, et al. 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 1999; 71:808.
- Lewis CG, Warnes GM, Wang XJ, Matthews CD. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertil Steril 1990; 53:1097.
- Ocal P, Sahmay S, Cetin M, et al. Serum anti-Müllerian hormone and antral follicle count as predictive markers of OHSS in ART cycles. J Assist Reprod Genet 2011; 28:1197.
- Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992; 58:249.
- Delvigne A, Rozenberg S. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 2003; 9:77.
- Abramov Y, Elchalal U, Schenker JG. Pulmonary manifestations of severe ovarian hyperstimulation syndrome: a multicenter study. Fertil Steril 1999; 71:645.
- Fábregues F, Balasch J, Ginès P, et al. Ascites and liver test abnormalities during severe ovarian hyperstimulation syndrome. Am J Gastroenterol 1999; 94:994.
- Elchalal U, Schenker JG. The pathophysiology of ovarian hyperstimulation syndrome--views and ideas. Hum Reprod 1997; 12:1129.
- Practice Committe of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril 2003; 80:1309.
- Grossman LC, Michalakis KG, Browne H, et al. The pathophysiology of ovarian hyperstimulation syndrome: an unrecognized compartment syndrome. Fertil Steril 2010; 94:1392.
- Abramov Y, Elchalal U, Schenker JG. Febrile morbidity in severe and critical ovarian hyperstimulation syndrome: a multicentre study. Hum Reprod 1998; 13:3128.
- Mashiach S, Bider D, Moran O, et al. Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil Steril 1990; 53:76.
- Aboulghar MA, Mansour RT, Serour GI, Amin YM. Moderate ovarian hyperstimulation syndrome complicated by deep cerebrovascular thrombosis. Hum Reprod 1998; 13:2088.
- Stewart JA, Hamilton PJ, Murdoch AP. Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum Reprod 1997; 12:2167.
- Cluroe AD, Synek BJ. A fatal case of ovarian hyperstimulation syndrome with cerebral infarction. Pathology 1995; 27:344.
- Phillips LL, Gladstone W, vande Wiele R. Studies of the coagulation and fibrinolytic systems in hyperstimulation syndrome after administration of human gonadotropins. J Reprod Med 1975; 14:138.
- Tang OS, Ng EH, Wai Cheng P, Chung Ho P. Cortical vein thrombosis misinterpreted as intracranial haemorrhage in severe ovarian hyperstimulation syndrome: case report. Hum Reprod 2000; 15:1913.
- Arya R, Shehata HA, Patel RK, et al. Internal jugular vein thrombosis after assisted conception therapy. Br J Haematol 2001; 115:153.
- Dulitzky M, Cohen SB, Inbal A, et al. Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome. Fertil Steril 2002; 77:463.