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Iatrogenic Ovarian Hyperstimulation Syndrome: Current Insights in to Therapeutic Advances
Corresponding Author(s) : Mandepudi Lakshmi Chandini
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 13 No. 3 (2025): 2025 Volume -13 - Issue 3
Abstract
Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic complication that arises due to an exaggerated ovarian response to exogenous gonadotropin administration, particularly during assisted reproductive techniques such as in vitro fertilization. Although most commonly associated with injectable gonadotropins, OHSS may also occur, albeit less frequently, with agents like clomiphene citrate or gonadotropin-releasing hormone analogues. Clinically, this manifests as abdominal distension, bloating, nausea, and ascites. In more severe presentations, patients may experience thromboembolic events, dyspnea due to pleural effusion, severe abdominal pain, hemoconcentration, dehydration, and intractable vomiting. A hallmark of OHSS is bilateral ovarian enlargement, with the degree of enlargement correlating with the severity of the syndrome. This review aims to explore the current evidence surrounding effective strategies for the prevention of ovarian hyperstimulation syndrome. Although a definitive method to completely eliminate the risk of OHSS has not yet been established, significant progress has been made by tailoring treatment protocols according to a patient’s individual risk profile. Stratifying women based on their susceptibility to OHSS has shown promise, particularly through the use of biomarkers such as Anti-Müllerian Hormone (AMH) levels and antral follicle count (AFC), which help predict ovarian response. Early identification and stratification of OHSS severity are critical in guiding management decisions, ranging from outpatient surveillance to inpatient care for moderate-to-critical cases
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- Namavar Jahromi B MD, Parsanezhad ME MD, Shomali Z MD, Bakhshai P MD, Alborzi M MD, Moin Vaziri N MD PhD, Anvar Z PhD. Ovarian Hyperstimulation Syndrome: A Narrative Review of Its Pathophysiology, Risk Factors, Prevention, Classification, and Management. Iran J Med Sci. 2018; 43(3):248-260.
- Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, Yang YS. Serum AMH and estradiol levels as predictors of OHSS in IVF. Fertil Steril. 2008; 90(4):737–743.
- Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective study of the relationship between AMH and AFC. Hum Reprod. 2010; 25(11):2723–2730.
- Homburg R. Ovulation induction in PCOS: step-up vs step-down regimens. Reprod Biomed Online. 2005; 10(5):669–675.
- Costello MF, Misso ML, Wong J, Hart R, Rombauts L, Melder AM, et al. Metformin before and during IVF or ICSI in women with PCOS. Hum Reprod. 2012; 27(1):21–29.
- Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR. Metformin for women with PCOS undergoing IVF or ICSI. Cochrane Database Syst Rev. 2020; 12(12):CD006105.
- Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM. GnRH agonist triggering reduces OHSS risk. Hum Reprod Update. 2006; 12(2):159–168.
- Alvarez C, Martinez F, Clua E, Gallego A, Sanchez R, Garcia-Velasco JA. Cabergoline reduces early signs of OHSS: a randomized study. Fertil Steril. 2007; 87(2):286–290.
- Practice Committee of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril. 2016; 106(7):1634–1647.
- Elchalal U, Schenker JG. The pathophysiology of OHSS. Hum Reprod. 1997; 12(6):1129–1137.
- Fiedler K, Ezcurra D. Predicting and preventing OHSS: the need for individualized treatment. Reprod Biol Endocrinol. 2012; 10:32.
- Gullo G, Cucinella G, Stojanovic V, et al. Ovarian Hyperstimulation Syndrome (OHSS): A Narrative Review and Legal Implications. J Pers Med. 2024; 14(9):915.
- MDPI Editorial. Ovarian Hyperstimulation Syndrome: A Narrative Review. J Pers Med. 2024; 14(9):915.
- Delbaere A, Smits G, De Leener A, Costagliola S, Vassart G. New Insights into the Pathophysiology of OHSS. Hum Reprod. 2004; 19(3):486–489.
- Elchalal U, Schenker JG. The pathophysiology of OHSS: roles of VEGF, RAS, and cytokines. Hum Reprod. 1997; 12(6):1129–1137.
- Rodien P, Beau I, Vasseur C. OHSS due to mutations in the FSH receptor. Ann Endocrinol (Paris). 2010; 71(3):206–209.
- Delvigne A, Rozenberg S. VEGF in OHSS pathophysiology. Hum Reprod Update. 2003; 9(6):77–96.
- Ferrara N. VEGF biology and OHSS. Angiogenesis. 2004; 7(2):113–116.
- Hugues JN, Schaitz JL. RAS involvement in OHSS. Fertil Steril. 2001; 75(2):280–286.
- Homburg R. LOD and OHSS prevention. Reprod Biomed Online. 2005; 10(5):669–675.
- Abramov Y, Fatum M, Abrahamov D, Schenker J. Hydroxyethyl starch versus human albumin for the treatment of severe ovarian hyperstimulation syndrome: a preliminary report. Fertil Steril. 2001; 75(6):1228–1230.
- Ovarian Hyperstimulation Syndrome: Current Views on Pathophysiology, Prevention, and Management. McGill Journal of Medicine. 2003; 6(1):11–17.
- Gerli S, Fabris C, Restelli L, Scarselli G, Ferrari S, Pagliardini L. Outpatient management of severe OHSS: paracentesis and pigtail catheter use. Hum Reprod. 2008; 23(2):613–621.
- Navot D, Fasouliotis SJ, Rosenwaks Z. Paracentesis in outpatient OHSS management reduces disease severity. Fertil Steril. 2003; 80(1):164–168.
- Rizk B, Aboulghar M, Mansour RT. Therapeutic paracentesis relieves symptoms and normalizes renal function in severe OHSS. Fertil Steril. 2002; 77(2):235–239.
- Practice Committee of the ASRM. OHSS Guidelines: Diagnosis and Management. Fertility and Sterility. 2016; 106(7):1634–1647.
- Predictive value of AMH and AFC in OHSS risk stratification. Hum Reprod Update. 2010; 16(2):113–130.
- Pundir J, Sunkara SK, El‑Toukhy T, Khalaf Y. Meta-analysis of GnRH antagonist versus agonist protocols: OHSS risk and outcomes in PCOS patients. Reprod Biomed Online. 2012; 24(1):6–17.
- Patel RS, Thompson LJ, Williams CE. Multidisciplinary approaches and hemodynamic management in OHSS: a 2023–2024 review. Int J Women’s Health. 2024; 16:321–333.
- Chen HY, Al-Inany H, Tzur T. Patient education and protocol-directed management significantly improve outcomes in high-risk stimulation cycles. Fertil Steril. 2025; 133(2):215–224.
- Rizk B, Aboulghar M. Modern management of ovarian hyperstimulation syndrome. Hum Reprod. 1991; 6(8):1082-1087.
- Corbett S, Shmorgun D, Claman P. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014; 36(11):1024-1033.
- Budev MM, Arroliga AC, Falcone T. Ovarian hyperstimulation syndrome. Crit Care Med. 2005; 33(10 Suppl):S301-6.
- Bangsbøll S. Ovarian hyperstimulation syndrome--a risk of treatment for infertility. Nord Med. 1997; 112(7):236-239.
- Engmann LL, Maslow BS, Kaye LA, Griffin DW, DiLuigi AJ, Schmidt DW, Grow DR, Nulsen JC, Benadiva CA. Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome - a prospective randomized double-blind clinical trial. J Ovarian Res. 2019; 12(1):8.
- Singh N, Dogra Y, Saini M, Govindarajan M. Severe early-onset ovarian hyperstimulation syndrome with liver dysfunction in an IVF segmentation cycle. BMJ Case Rep. 2020; 13(1):e233379.
- Nikfarjam E, Eftekhar M, Fatehi H, Arabian S. Letrozole and ovarian hyperstimulation syndrome: Retrospective cross-sectional study. Int J Reprod Biomed. 2024; 22(3):211-218.
- Daolio J, Sperduti S, Casarini L, Falbo A, Materazzo C, Aguzzoli L, Villani MT. Spontaneous and iatrogenic ovarian hyperstimulation syndrome in the absence of FSHR mutations: a case report of two unexpected cases. BMC Med Genomics. 2023; 16(1):45.
- Mathur RS, Akande AV, Keay SD, Hunt LP, Jenkins JM. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril. 2000; 73:901–907.
- Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. 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; 71:482–489.
- Whelan JG, 3rd, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril. 2000; 73:883–896.
- Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: Guidance for the clinician. Fertil Steril. 2010; 94:389–400.
- Naredi N, Talwar P, Sandeep K. VEGF antagonist for the prevention of ovarian hyperstimulation syndrome: Current status. Med J Armed Forces India. 2014; 70:58–63.
- Mathur RS, Tan BK. British Fertility Society Policy and Practice Committee: Prevention of ovarian hyperstimulation syndrome. Hum Fertil (Camb) 2014; 17:257–268.
- Pérez CN, Sainz MA, Camacho SAE. Ovarian hyperstimulation syndrome: iatrogenic complication associated with assisted reproductive techniques. Revista Médica Sinergia. 2019; 4(06):40-52.
References
Namavar Jahromi B MD, Parsanezhad ME MD, Shomali Z MD, Bakhshai P MD, Alborzi M MD, Moin Vaziri N MD PhD, Anvar Z PhD. Ovarian Hyperstimulation Syndrome: A Narrative Review of Its Pathophysiology, Risk Factors, Prevention, Classification, and Management. Iran J Med Sci. 2018; 43(3):248-260.
Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, Yang YS. Serum AMH and estradiol levels as predictors of OHSS in IVF. Fertil Steril. 2008; 90(4):737–743.
Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective study of the relationship between AMH and AFC. Hum Reprod. 2010; 25(11):2723–2730.
Homburg R. Ovulation induction in PCOS: step-up vs step-down regimens. Reprod Biomed Online. 2005; 10(5):669–675.
Costello MF, Misso ML, Wong J, Hart R, Rombauts L, Melder AM, et al. Metformin before and during IVF or ICSI in women with PCOS. Hum Reprod. 2012; 27(1):21–29.
Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR. Metformin for women with PCOS undergoing IVF or ICSI. Cochrane Database Syst Rev. 2020; 12(12):CD006105.
Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM. GnRH agonist triggering reduces OHSS risk. Hum Reprod Update. 2006; 12(2):159–168.
Alvarez C, Martinez F, Clua E, Gallego A, Sanchez R, Garcia-Velasco JA. Cabergoline reduces early signs of OHSS: a randomized study. Fertil Steril. 2007; 87(2):286–290.
Practice Committee of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril. 2016; 106(7):1634–1647.
Elchalal U, Schenker JG. The pathophysiology of OHSS. Hum Reprod. 1997; 12(6):1129–1137.
Fiedler K, Ezcurra D. Predicting and preventing OHSS: the need for individualized treatment. Reprod Biol Endocrinol. 2012; 10:32.
Gullo G, Cucinella G, Stojanovic V, et al. Ovarian Hyperstimulation Syndrome (OHSS): A Narrative Review and Legal Implications. J Pers Med. 2024; 14(9):915.
MDPI Editorial. Ovarian Hyperstimulation Syndrome: A Narrative Review. J Pers Med. 2024; 14(9):915.
Delbaere A, Smits G, De Leener A, Costagliola S, Vassart G. New Insights into the Pathophysiology of OHSS. Hum Reprod. 2004; 19(3):486–489.
Elchalal U, Schenker JG. The pathophysiology of OHSS: roles of VEGF, RAS, and cytokines. Hum Reprod. 1997; 12(6):1129–1137.
Rodien P, Beau I, Vasseur C. OHSS due to mutations in the FSH receptor. Ann Endocrinol (Paris). 2010; 71(3):206–209.
Delvigne A, Rozenberg S. VEGF in OHSS pathophysiology. Hum Reprod Update. 2003; 9(6):77–96.
Ferrara N. VEGF biology and OHSS. Angiogenesis. 2004; 7(2):113–116.
Hugues JN, Schaitz JL. RAS involvement in OHSS. Fertil Steril. 2001; 75(2):280–286.
Homburg R. LOD and OHSS prevention. Reprod Biomed Online. 2005; 10(5):669–675.
Abramov Y, Fatum M, Abrahamov D, Schenker J. Hydroxyethyl starch versus human albumin for the treatment of severe ovarian hyperstimulation syndrome: a preliminary report. Fertil Steril. 2001; 75(6):1228–1230.
Ovarian Hyperstimulation Syndrome: Current Views on Pathophysiology, Prevention, and Management. McGill Journal of Medicine. 2003; 6(1):11–17.
Gerli S, Fabris C, Restelli L, Scarselli G, Ferrari S, Pagliardini L. Outpatient management of severe OHSS: paracentesis and pigtail catheter use. Hum Reprod. 2008; 23(2):613–621.
Navot D, Fasouliotis SJ, Rosenwaks Z. Paracentesis in outpatient OHSS management reduces disease severity. Fertil Steril. 2003; 80(1):164–168.
Rizk B, Aboulghar M, Mansour RT. Therapeutic paracentesis relieves symptoms and normalizes renal function in severe OHSS. Fertil Steril. 2002; 77(2):235–239.
Practice Committee of the ASRM. OHSS Guidelines: Diagnosis and Management. Fertility and Sterility. 2016; 106(7):1634–1647.
Predictive value of AMH and AFC in OHSS risk stratification. Hum Reprod Update. 2010; 16(2):113–130.
Pundir J, Sunkara SK, El‑Toukhy T, Khalaf Y. Meta-analysis of GnRH antagonist versus agonist protocols: OHSS risk and outcomes in PCOS patients. Reprod Biomed Online. 2012; 24(1):6–17.
Patel RS, Thompson LJ, Williams CE. Multidisciplinary approaches and hemodynamic management in OHSS: a 2023–2024 review. Int J Women’s Health. 2024; 16:321–333.
Chen HY, Al-Inany H, Tzur T. Patient education and protocol-directed management significantly improve outcomes in high-risk stimulation cycles. Fertil Steril. 2025; 133(2):215–224.
Rizk B, Aboulghar M. Modern management of ovarian hyperstimulation syndrome. Hum Reprod. 1991; 6(8):1082-1087.
Corbett S, Shmorgun D, Claman P. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014; 36(11):1024-1033.
Budev MM, Arroliga AC, Falcone T. Ovarian hyperstimulation syndrome. Crit Care Med. 2005; 33(10 Suppl):S301-6.
Bangsbøll S. Ovarian hyperstimulation syndrome--a risk of treatment for infertility. Nord Med. 1997; 112(7):236-239.
Engmann LL, Maslow BS, Kaye LA, Griffin DW, DiLuigi AJ, Schmidt DW, Grow DR, Nulsen JC, Benadiva CA. Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome - a prospective randomized double-blind clinical trial. J Ovarian Res. 2019; 12(1):8.
Singh N, Dogra Y, Saini M, Govindarajan M. Severe early-onset ovarian hyperstimulation syndrome with liver dysfunction in an IVF segmentation cycle. BMJ Case Rep. 2020; 13(1):e233379.
Nikfarjam E, Eftekhar M, Fatehi H, Arabian S. Letrozole and ovarian hyperstimulation syndrome: Retrospective cross-sectional study. Int J Reprod Biomed. 2024; 22(3):211-218.
Daolio J, Sperduti S, Casarini L, Falbo A, Materazzo C, Aguzzoli L, Villani MT. Spontaneous and iatrogenic ovarian hyperstimulation syndrome in the absence of FSHR mutations: a case report of two unexpected cases. BMC Med Genomics. 2023; 16(1):45.
Mathur RS, Akande AV, Keay SD, Hunt LP, Jenkins JM. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril. 2000; 73:901–907.
Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. 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; 71:482–489.
Whelan JG, 3rd, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril. 2000; 73:883–896.
Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: Guidance for the clinician. Fertil Steril. 2010; 94:389–400.
Naredi N, Talwar P, Sandeep K. VEGF antagonist for the prevention of ovarian hyperstimulation syndrome: Current status. Med J Armed Forces India. 2014; 70:58–63.
Mathur RS, Tan BK. British Fertility Society Policy and Practice Committee: Prevention of ovarian hyperstimulation syndrome. Hum Fertil (Camb) 2014; 17:257–268.
Pérez CN, Sainz MA, Camacho SAE. Ovarian hyperstimulation syndrome: iatrogenic complication associated with assisted reproductive techniques. Revista Médica Sinergia. 2019; 4(06):40-52.