Materiały źródłowe

• #1 Ovarian hyperstimulation syndrome: pathophysiology and prevention

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2842872/

  To review and discuss the pathophysiology and prevention strategies for ovarian hyperstimulation syndrome (OHSS), which is a condition that may occur in up to 20% of the high risk women submitted to assisted reproductive technology cycles. […] The role of estradiol, luteinizing hormone, human chorionic gonadotropin (hCG), inflammatory mediators, the renin-angiotensin system and vascular endothelial growth factor is discussed in the pathophysiology of OHSS. […] Increased capillary permeability and ovary enlargement are the principal characteristics of OHSS. Fluid escapes from vessels into the third space, resulting in hypovolemia. […] Some possible causal factors are listed below and summarized in Table 1. […] Estradiol level is a reliable predictor of OHSS during ART. […] High estradiol concentrations are not sufficient to induce OHSS.

• #2 Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome – UpToDate

  https://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-ovarian-hyperstimulation-syndrome/print

  Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian hyperstimulation (COH) for assisted reproduction technologies (ART). It occurs when the ovaries are hyperstimulated and enlarged due to fertility treatments (or rarely, mutations in the follicle-stimulating hormone [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 incidence of moderate and severe OHSS while undergoing IVF has decreased in the last decade due to modern approaches in prevention strategies: use of gonadotropin-releasing hormone (GnRH) agonist triggering, dopamine agonists, and others.

• #3 Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023) – practice guidance | American Society for Reproductive Medicine | ASRM

  https://www.asrm.org/practice-guidance/practice-committee-documents/prevention-and-treatment-of-moderate-and-severe-ovarian-hyperstimulation-syndrome-a-guideline/

  Ovarian hyperstimulation syndrome (OHSS) is an uncommon but serious complication associated with controlled ovarian stimulation during assisted reproductive technology (ART). […] Understanding the pathophysiology of this condition may aid in identifying measures to prevent its development and treat associated symptoms. Classic physiologic changes of OHSS include arteriolar vasodilation and an increase in capillary permeability that results in fluid shifting from intravascular to extravascular spaces. […] Vascular endothelial growth factor (VEGF) appears to be integral to the development of this condition and is involved in follicular growth, corpus luteum function, angiogenesis, and vascular endothelial stimulation. […] In response to human chorionic gonadotropin (hCG), VEGF appears to mediate the vascular permeability of OHSS, as systemic hCG levels positively correlate with the severity of the disease.

• #4

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5993897/

  Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovulation induction that usually occurs after gonadotropin stimulation, followed by human chorionic gonadotropin administration, for infertility treatment. […] The existing knowledge about the pathophysiology, risk factors, and primary and secondary methods for the prevention of OHSS is reviewed in this manuscript. […] The hallmark of OHSS is an increase in the permeability of the capillaries, resulting in a fluid shift form the intravascular space to the extravascular compartments. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of OHSS by increasing vascular permeability. VEGF is secreted by the granulosa cells, and human chorionic gonadotropin (hCG) stimulates its secretion. Severe OHSS is associated with higher levels of VEGF.

• #5

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5993897/

  Aromatase inhibitors act through the downregulation of estrogen production by inhibiting cytochrome p450 enzymes. […] The drug of choice to trigger the final maturation of follicles should be selected based on the predicted risk of OHSS development. […] GnRHa triggering during a GnRH antagonist IVF protocol virtually eliminates the risk of OHSS in a freeze-all approach for high-risk women. […] The main event in the pathogenesis of OHSS is ovarian enlargement, secretion of vasoactive substances, ascites, and hypovolemia resulting from an acute extravasation of fluid into the interstitial space. […] The clinical treatment of OHSS depends on its severity, complications, and absence or presence of pregnancy.

• #6 Ovarian Hyperstimulation Syndrome | Doctor

  https://patient.info/doctor/ovarian-hyperstimulation-syndrome

  Ovarian hyperstimulation syndrome (OHSS) is the most serious consequence of induction of ovulation, as part of assisted conception techniques. […] The ovaries may form 20 follicles or more and swell following an increase in serum levels of hCG. OHSS is a systemic disease. Vasoactive mediators are released from the hyperstimulated ovaries, causing an increase in capillary permeability. […] This causes fluid shift from the intravascular compartment to third space compartments such as the peritoneal or thoracic cavities. Morbidity and even mortality can then be caused by effusions (pericardial, pleural, ascites), haemoconcentration (causing increased risk of thrombosis and coagulopathy) and liver or kidney dysfunction.

• #7 Ovarian hyperstimulation syndrome: pathophysiology and prevention

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2842872/

  hCG is fundamental for triggering OHSS. […] Some interleukins are associated with OHSS, and elevated concentrations are associated with increased vascular permeability, hemoconcentration, elevated plasma estradiol concentration, and inhibition of hepatic albumin production. […] There is a direct correlation between plasma renin activity and the severity of OHSS. […] VEGF expression is associated with OHSS increased vascular permeability. […] The most important aspects of OHSS prevention are sound clinical judgment with ovulation induction and acknowledgment of the risk factors. […] Coasting clearly decreases estradiol levels. […] Evidence is still insufficient to determine whether or not coasting is an effective strategy for preventing OHSS. […] The best currently available evidence shows that albumin administration does not decrease the incidence of OHSS.

• #8 Ovarian Hyperstimulation Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1343572-overview

  Vasoactive substances such as interleukins, tumor necrosis factor (TNF)-alpha, endothelin-1, and VEGF secreted by the ovaries have been implicated in increasing vascular permeability. […] Withholding hCG decreases OHSS. Hence, it plays a critical role in enhancing ovarian angiogenesis and triggering the cascade of vascular permeability in ovarian vessels that leads to third spacing and OHSS. […] Exogenous recombinant hCG precipitates OHSS more than endogenous agents (gonadotropin-releasing hormone [GnRH] analogs) do.

• #9 Ovarian hyperstimulation syndrome: pathophysiology and prevention

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2842872/

  Dopamine agonists can inhibit partially the VEGF receptor 2 phosphorylation levels and associated vascular permeability without affecting luteal angiogenesis. […] A large RCT demonstrated that low dose aspirin was associated with reduction in the OHSS incidence in a high-risk group with similar pregnancy rates. […] GnRH antagonist protocol is associated with a significant reduction in OHSS. […] A reduction in hCG dosage has been proposed, showing that reducing hCG dosage does not worsen IVF results. […] OHSS complications could be theoretically eliminated if hCG was not used. […] The safest way to prevent OHSS would be by not stimulating the ovaries. […] The occurrence of OHSS may be considered the most serious complication related to assisted reproduction techniques. […] Many strategies have been suggested to prevent OHSS. Based on current evidence, replacement of hCG by GnRH agonists in antagonist cycles and IVM are the safest approaches.

• #10 Ovarian Hyperstimulation Syndrome – Zero To Finals

  https://zerotofinals.com/obgyn/fertility/ovarianhyperstimulationsyndrome/

  Ovarian hyperstimulation syndrome (OHSS) is a complication of ovarian stimulation during IVF infertility treatment. It is associated with the use of human chorionic gonadotropin (hCG) to mature the follicles during the final steps of ovarian stimulation. […] The primary mechanism for OHSS is an increase in vascular endothelial growth factor (VEGF) released by the granulosa cells of the follicles. VEGF increases vascular permeability, causing fluid to leak from capillaries. Fluid moves from the intravascular space to the extravascular space. This results in oedema, ascites and hypovolaemia. […] OHSS is provoked by the “trigger injection” of hCG 36 hours before oocyte collection. HCG stimulates the release of VEGF from the follicles. The features of the condition begin to develop after the hCG injection. […] There is also activation of the renin-angiotensin system. A notable finding in patients with OHSS is a raised renin level. The renin level correlates with the severity of the condition.

• #11 Ovarian hyperstimulation syndrome – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/ovarian-hyperstimulation-syndrome-ohss/symptoms-causes/syc-20354697

  Ovarian hyperstimulation syndrome is an exaggerated response to excess hormones. It usually occurs in women taking injectable hormone medications to stimulate the development of eggs in the ovaries. Ovarian hyperstimulation syndrome (OHSS) causes the ovaries to swell and become painful. […] The cause of ovarian hyperstimulation syndrome isn’t fully understood. Having a high level of human chorionic gonadotropin (HCG) a hormone usually produced during pregnancy introduced into your system plays a role. Ovarian blood vessels react abnormally to human chorionic gonadotropin (HCG) and begin to leak fluid. This fluid swells the ovaries, and sometimes large amounts move into the abdomen. […] During fertility treatments, HCG may be given as a „trigger” so that a mature follicle will release its egg. OHSS usually happens within a week after you receive an HCG injection. If you become pregnant during a treatment cycle, OHSS may worsen as your body begins producing its own HCG in response to the pregnancy.

• #12

  https://www.jci.org/articles/view/4814

  Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. […] Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS.

• #13 Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment | Reproductive Biology and Endocrinology | Full Text

  https://rbej.biomedcentral.com/articles/10.1186/1477-7827-10-32

  The expression of VEGF and VEGF receptor 2 (VEGFR-2) mRNA increases significantly in response to hCG, and peak levels coincide with maximum vascular permeability. […] The clinical manifestations of OHSS reflect the extent of the shift of fluid into the third space and the resulting hemoconcentration due to intravascular volume depletion. […] Symptoms range from mild abdominal distention due to enlarged ovaries alone or with an accompanying fluid shift into the abdomen, to renal failure and death as a result of hemoconcentration and reduced perfusion of organs such as the kidneys, heart and brain. […] Indeed, as the severity of OHSS increases, so does the number of organs affected. […] Several primary and secondary risk factors for OHSS have been identified. […] However, their sensitivity and specificity for predicting hyper-response/OHSS is variable.

• #14 TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-020-0396-y

  Importantly, studies in both different animal models and humans have shown that targeting VEGF or its receptor can prevent the development of OHSS. […] Altogether, these studies indicate that locally produced VEGF in the ovary is an important factor that mediates the pathogenesis of OHSS. […] In the present study, we aimed to examine the effect and the underlying molecular mechanisms of TGF-1 on VEGF expression in hGL cells. […] Our results reveal that the SMAD2/3, ERK1/2, and p38 MAPK signaling pathways are involved in TGF-1-stimulated VEGF expression and secretion. […] Importantly, for the first time, we show that the expression of TGF-1 was increased in the ovaries of OHSS mice. […] In addition, blocking TGF-1 signaling inhibited the pathogenesis of OHSS in mouse OHSS model by attenuating the expression of VEGF. […] These results provide a better understanding of the mechanisms mediating the expression of VEGF in hGL cells, which could lead to the development of alternative therapeutic approaches for OHSS.

• #14 TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-020-0396-y

  Ovarian hyperstimulation syndrome (OHSS) is one of the most serious and iatrogenic complications that can occur during in vitro fertilization treatment. […] Although the pathogenesis of OHSS is not fully understood, vascular endothelial growth factor (VEGF) has been recognized as an important mediator of the development of OHSS. […] In addition, the role of TGF-1 in the pathogenesis of OHSS remains unknown. […] Our results demonstrate that the SMAD2/3, ERK1/2, and p38 MAPK signaling pathways are involved in TGF-1-induced VEGF expression and secretion. […] Blocking TGF-1 signaling inhibits the development of OHSS by attenuating VEGF expression. […] The results of this study help to elucidate the mechanisms by which VEGF expression is regulated in hGL cells, which could lead to the development of alternative therapeutic approaches for treating OHSS.

• #15

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5993897/

  The other suggested factors that may act directly or indirectly on the development or severity of OHSS are angiotensin II, insulin-like growth factor, epidermal growth factor, transforming growth factor alpha and beta, basic fibroblast growth factor, platelet-derived growth factor, interleukin-1B, and interleukin-6. […] The intra-ovarian renin-angiotensin system (RAS) is another pathophysiological mechanism implicated in OHSS. Furthermore, hCG activates the RAS, which is confirmed by the association of high renin activity in the follicular fluid of women with OHSS. High levels of the VEGF and the RAS seem to play a role in the development of OHSS. […] The prevention of OHSS is based on its prediction. There is no method that can completely abolish OHSS. However, its prevention can be lifesaving and is principally preferred over its treatment.

• #16 Prevention of OHSS – Walter Bushnell Healthcare Foundation

  https://wbhf.walterbushnell.com/publications/fertility-blaze/item/350-prevention-of-ohss

  The renin-angiotensin system has implications in new vessel formation while angiogenesis is associated with an increase in capillary permeability. Therefore, high plasma renin-like activity in human FF suggests a role of the renin-angiotensin system in ovarian enlargement and extracellular fluid accumulation in OHSS. […] Vascular endothelial growth factor (VEGF) is crucial for the development of OHSS. The expression of VEGF and VEGFR-2 mRNA has been noted to increase significantly following hCG administration. The maximum levels have been noted to coincide with peak vascular permeability.

• #17 Prevention of OHSS – Walter Bushnell Healthcare Foundation

  https://wbhf.walterbushnell.com/publications/fertility-blaze/item/350-prevention-of-ohss

  Ovarian hyperstimulation syndrome (OHSS), an iatrogenic complication of controlled ovarian stimulation (COS) with follicle-stimulating hormone (FSH) medications, first came into the limelight in 1943 while the initial evidence of fatal consequences of the condition surfaced in 1951. […] Despite extensive investigations, the pathophysiology of OHSS still remains obscure. When ovaries stimulated with FSH/leuteinizing hormone (LH) are subsequently exposed to human chorionic gonadotropin (hCG), OHSS ensues. The fundamental feature underlying OHSS includes increased vascular permeability that leads to a shift in fluid from the intravascular space to third space compartments. […] Several cytokines and growth factors including interleukins (IL)-2, IL-6, IL-8, IL-10 and IL-18 have been implicated in the pathogenesis of OHSS. Their role has been suggested in the inflammatory processes associated with late follicular maturation, ovulation, corpus luteum function and embryo implantation. A recent study by Wei and colleagues revealed that IL-6 trans-signaling is activated during the ovarian stimulation process and this may induce vascular leakage in OHSS.

• #18 Ovarian Hyperstimulation Syndrome (OHSS): A Narrative Review and Legal Implications

  https://www.mdpi.com/2075-4426/14/9/915

  OHSS pathophysiology has been shown to be closely linked to an increased vascular permeability of the ovarian and peritoneal capillaries, brought about by ovarian VEGF hypersecretion. Treatment relying on a dopamine-receptor agonist such as cabergoline has been hypothesized to potentially cause a reduction in VEGF production, with ensuing OHSS mitigation. Strong evidence links OHSS to stimulation-related factors, such as a large amount of mature range follicles at the trigger, elevated estradiol at the trigger, and an increased number of oocytes retrieved. […] Elevated serum estradiol levels, usually detected over the course of a robust response to ovarian stimulation, are closely linked to a higher risk of developing OHSS in a moderate to severe form. High serum estradiol suppresses the expression of the KISS1 receptor and increases both VEGF and nitric oxide secretion via estrogen receptor modulation. It has been proposed that the administration of an aromatase inhibitor such as letrozole after the administration of the hCG trigger injection will decrease serum estradiol levels and may reduce the incidence of OHSS.

• #19 TGF-β1 upregulates secreted protein acidic and rich in cysteine expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01123-2

  Ovarian hyperstimulation syndrome (OHSS) is a serious complication during in vitro fertilization (IVF) treatment. The upregulation of ovarian transforming growth factor-beta 1 (TGF-1) is involved in the development of OHSS. The secreted protein acidic and rich in cysteine (SPARC) is a secreted multifunctional matricellular glycoprotein. […] The expression of SPARC is induced by TGF-1 in different types of cells. However, whether the expression of SPARC is regulated by TGF-1 in hGL cells is unknown. […] Our results also revealed that SPARC was upregulated in the OHSS rat ovaries and in the follicular fluid of OHSS patients. […] By illustrating the potential physiological and pathological roles of TGF-1 in the regulation of SPARC in hGL cells, our results may serve to improve current strategies used to treat clinical infertility and OHSS.

• #20 TGF-β1 upregulates secreted protein acidic and rich in cysteine expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01123-2

  The knockdown of SPARC decreased Slug expression. […] The knockdown of SPARC attenuated the TGF-1-stimulated expression of vascular endothelial growth factor (VEGF) and aromatase, two markers of OHSS. […] The results suggest that the upregulation of SPARC in the ovaries could contribute to the pathogenesis of OHSS by increasing the expression of VEGF and E2 levels. […] Our results also reveal that TGF-1 treatment induces expressions of transcription factors, Snail and Slug. However, only Slug is involved in TGF-1-induced SPARC expression. […] The knockdown of SPARC decreases SMAD4 expression, indicating the involvement of SPARC in the development of OHSS.

• #21

  https://omim.org/entry/608115?search=NOT%20prefix%3A/%5E&highlight=not

  A number sign (#) is used with this entry because of evidence that spontaneous ovarian hyperstimulation syndrome (OHSS) is caused by heterozygous mutation in the follicle-stimulating hormone receptor gene (FSHR; 136435) on chromosome 2p16. […] Kaiser (2003) reviewed the pathogenesis of ovarian hyperstimulation syndrome and the mechanism by which mutations in the FSH receptor result in the disorder, with explanatory diagrams.

• #22 SciELO Brazil – Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy

  https://www.scielo.br/j/eins/a/6zP5SVNrNTKGw887bf5VMxg/

  The loss of fluid and protein into the abdominal cavity generates hypovolemia and hemoconcentration responsible for blood circulation disorders and renal function. The most severe complications are the result of hypercoagulability and decreased renal perfusion. […] The cause of spontaneous ovarian hyperstimulation appears to be a permittivity of ovarian follicle-stimulating hormone (FSH) receptor for hCG and/or TSH. Three mechanisms are described in the genesis of spontaneous OHSS. There have been reports of spontaneous OHSS associated with high levels of hCG in particular molar pregnancies and multiple births. This mechanism is related with the hyperactivation of the FSH receptor in granulosa cells of the ovary by hCG, with consequent ovarian hyperstimulation. Similarly, spontaneous elevated TSH by hyperactivation of FSH from the TSH receptor, as occurs in hypothyroidism, could cause the syndrome. The third mechanism is based on the mutation of the FSH receptor, with consequent decrease of its specificity and increased sensitivity to hCG and TSH.

• #23 SciELO Brazil – Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy

  https://www.scielo.br/j/eins/a/6zP5SVNrNTKGw887bf5VMxg/

  Activating mutations of the FSHR gene that cause ovarian hyper-responsiveness for circulating FSH or even cross-responsiveness of FSHR to hormones with similar structure to FSH, such as hCG or TSH, and hCG/LH receptor gene mutation claimed increased response to normal hCG levels and, therefore, ovarian hyper responsiveness. […] In our case, the values of TSH and hCG were normal. The most likely mechanism is the mutation of the FSH receptor gene. This diagnosis is possible by genetic sequencing, because several mutations in the gene have been described. The presence of mutation has implications regarding the recurrence of the syndrome in future pregnancies.

• #24 Severe primary hypothyroidism and ovarian hyperstimulation syndrome in a spontaneous pregnancy: a case report – Guerra – AME Case Reports

  https://acr.amegroups.org/article/view/8658/html

  Ovarian hyperstimulation syndrome (OHSS) is a rare ovulation induction therapy side effect. Nevertheless, it can occur in spontaneous ovulation cycles linked to multiple gestation, molar pregnancy, polycystic ovarian syndrome, and hypothyroidism. The pathogenesis of OHSS remains poorly understood. However, in recent studies, it has been observed that increased concentrations of thyroid-stimulating hormone (TSH) can potentially have stimulatory effects on the ovaries due to the homologous structure shared between TSH and gonadotropins. […] The pathophysiological mechanism of OHSS is not fully understood. It appears to be dependent on exposure of the ovaries to beta-human chorionic gonadotropin (b-HCG), which induces the production and release of vasoactive substances (like vascular endothelium growth factor, renin-angiotensin, several pro-inflammatory cytokines, and endothelin-1). These substances increase the permeability of capillaries, resulting in the extravasation of fluid from the intravascular space into the extravascular space and its accumulation in the peritoneal, pleural, and pericardial cavities. This process results in hypovolemia and hemoconcentration, which interfere with renal filtration and excretion by promoting hypercoagulability.

• #25 Ovarian hyperstimulation syndrome: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/007294.htm

  Ovarian hyperstimulation syndrome (OHSS) is a problem that is sometimes seen in women who take fertility medicines that stimulate egg production. […] If these medicines stimulate the ovaries too much, the ovaries can become very swollen. Fluid can leak into the belly and chest area. This is called OHSS. This occurs only after the eggs are released from the ovary (ovulation). […] OHSS affects 3% to 6% of women who go through in vitro fertilization (IVF). […] Other risk factors for OHSS include: Having a very high estrogen level during fertility treatments. […] If your provider diagnoses severe OHSS before transferring embryos in an IVF, they may decide to cancel the embryo transfer. […] In the rare case that you develop severe OHSS, you will probably need to go to a hospital. Your provider will give you fluids through a vein (intravenous fluids). They will also remove fluids that have collected in your body, and monitor your condition. […] In rare cases, OHSS can lead to fatal complications. These can include: Severe electrolyte imbalance. […] If you are getting injections of fertility medicines, you will need to have regular blood tests and pelvic ultrasounds to make sure that your ovaries aren’t over-responding.

• #26 Spontaneous bacterial peritonitis complicating ovarian hyperstimulation syndrome-related ascites | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-spontaneous-bacterial-peritonitis-complicating-ovarian-S1807593222019317

  Ovarian hyperstimulation syndrome (OHSS) is a life-threatening iatrogenic complication of in vitro fertilization (IVF). One of the characteristic features of OHSS is increased vascular permeability due to the overproduction of vasoactive mediators from hyperstimulated and enlarged ovaries. Such altered permeability leads to fluid shifts from intravascular to interstitial or third-space compartments. Clinical manifestations, therefore, include hemoconcentration, hypovolemia, decreased renal perfusion, hypotension, electrolyte imbalance, and in severe forms (0.5%5% of cases), tense ascites. In addition, lower-than-normal levels of plasma immunoglobulin have been detected in patients with severe OHSS, which may predispose patients to serious infections. […] Ovarian hyperstimulation syndrome is an iatrogenic complication of the ovarian stimulation commonly used for IVF. The condition is potentially life-threatening; therefore, it represents one of the most serious complications of assisted reproduction treatments. In this case report, we describe SBP as a new infectious complication of OHSS.

• #27

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5993897/

  The primary risk factors for OHSS are young age, low body mass index, polycystic ovarian syndrome (PCOS), and history of previous OHSS. […] Serum anti-Mullerian hormone (AMH) is a biomarker that may predict the risk of OHSS. […] The secondary risk factors depend on ovarian response to COS. […] The risk of OHSS should be assessed individually based on the history, physical examination, ultrasound results, and the AFC. […] The minimum gonadotropin dose should be used for ovulation induction in patients with PCOS, and step-up regimens are considered superior to step-down regimens. […] A recent Cochrane Review, which was based on 8 randomized controlled trials with 798 cases, concluded that metformin significantly reduced the risk of OHSS by 63% and increased the clinical pregnancy rates, with no effect on live birth rates.

• #28 Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023) – practice guidance | American Society for Reproductive Medicine | ASRM

  https://www.asrm.org/practice-guidance/practice-committee-documents/prevention-and-treatment-of-moderate-and-severe-ovarian-hyperstimulation-syndrome-a-guideline/

  Ovarian hyperstimulation syndrome is staged (mild, moderate, severe, or critical) by the severity of symptoms and laboratory findings. […] A systematic search of the literature was performed to answer 3 questions about OHSS: who is at high risk, how can it be prevented, and what is the treatment for it? […] There is strong evidence that factors associated with a robust response to ovarian stimulation predispose to OHSS. This includes baseline characteristics such as younger age and the diagnosis of PCOS, in addition to elevated ovarian reserve markers, including AFC and AMH levels. […] There is strong evidence associating OHSS with stimulation-related factors such as a heightened number of mature range follicles at the trigger, elevated estradiol at the trigger, and an increased number of oocytes retrieved.

• #29 Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment | Reproductive Biology and Endocrinology | Full Text

  https://rbej.biomedcentral.com/articles/10.1186/1477-7827-10-32

  If iCOS is not correctly applied then patients are more likely to experience OHSS. […] To minimize the risk of severe complications, secondary preventative measures are normally applied. […] Various preventative protocols have been proposed to reduce or minimize the risk of developing OHSS during COS, including in vitro oocyte maturation, coasting, decreasing the hCG trigger dose, and using a gonadotropin-releasing hormone agonist (GnRHa) trigger. […] However, despite the widespread use of these preventative techniques, supporting evidence is limited. […] A recent Cochrane review concluded that there was no evidence to suggest a benefit of coasting to prevent OHSS compared with no coasting or other interventions. […] The risk of OHSS can be reduced by using a GnRHa trigger, instead of an hCG trigger, in patients undergoing COS with a GnRH-antagonist protocol.

• #30 Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023) – practice guidance | American Society for Reproductive Medicine | ASRM

  https://www.asrm.org/practice-guidance/practice-committee-documents/prevention-and-treatment-of-moderate-and-severe-ovarian-hyperstimulation-syndrome-a-guideline/

  There is strong evidence to recommend the use of a GnRH agonist to trigger oocyte maturation before oocyte retrieval to reduce the risk of OHSS. […] The pathophysiology of OHSS is largely attributed to an increased vascular permeability of the ovarian and peritoneal capillaries caused by ovarian hypersecretion of VEGF. […] It has been postulated that treatment with a dopamine-receptor agonist such as cabergoline may result in a reduction of VEGF production and a subsequent reduction in OHSS. […] There is strong evidence that dopamine agonist administration near the time of the hCG trigger reduces the incidence of moderate-to-severe OHSS. […] There is weak evidence that the use of an aromatase inhibitor such as letrozole does not prevent OHSS on the basis of a few studies with contradictory findings.

• #31 Ovarian Hyperstimulation Syndrome (OHSS): A Narrative Review and Legal Implications

  https://www.mdpi.com/2075-4426/14/9/915

  The following features point to the risk of developing OHSS: young age, low body weight, polycystic ovarian syndrome (PCOS), profound hyperstimulation protocols with gonadotropin-releasing hormone (GnRH) agonist long protocol cotreatment, high number of preovulatory follicles, high serum E2 levels, high (5000 IU) dose of hCG for final oocyte maturation, hCG use for luteal phase supplementation, and a state of pregnancy. Prevention strategies for this condition include cessation of exogenous gonadotropins for several days (referred to as “coasting”), cancellation of the in vitro fertilization (IVF) cycle, and withholding hCG. […] The complexities inherent in OHSS require absolute compliance with guidelines and evidence-based recommendations, both for the sake of patient welfare and the medicolegal tenability of all procedures. OHSS is characterized by arteriolar vasodilation and increased capillary permeability, causing a shift of the intravascular volume to the extravascular space. Moreover, it leads to significant ovarian enlargement and overproduction of pro-inflammatory and vasoactive cytokines. OHSS onset has been linked to hCG administration as an ovulatory trigger, in light of the ability of hCG to foster vascular endothelial growth factor (VEGF) production, which promotes angiogenesis and increased vascular permeability. The severity of OHSS is directly related to the levels of VEGF.

• #32 Pharmacologic Interventions in Preventing Ovarian Hyperstimulation Syndrome: A Systematic Review and Network Meta-Analysis | Scientific Reports

  https://www.nature.com/articles/srep19093

  Because VEGF is the most predominant mediator of the OHSS process, by targeting the VEGF receptor directly, it is possible to arrest this dangerous complication. […] Theoretically, cabergoline, which is a dopamine agonist, can inhibit phosphorylation of the VEGFR-2 receptor and, therefore, reduce the vascular leakage into the third space and alleviate various presentations of OHSS after the COS cycle.

• #33 Severe primary hypothyroidism and ovarian hyperstimulation syndrome in a spontaneous pregnancy: a case report – Guerra – AME Case Reports

  https://acr.amegroups.org/article/view/8658/html

  The pathophysiology association between OHSS and hypothyroidism is still unknown and requires further study. TSH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) all have well-known alpha chains. The high levels of TSH observed in hypothyroidism and their cross-reactivity with certain gonadotropins appears to increase the concentration of FSH and LH, thereby causing hyperstimulation of the ovaries. […] This case report aims to demonstrate the rarity of this condition and the causal connection between hypothyroidism and ovarian hyperstimulation, as suggested by the consistent regression of ovarian tumors following the initiation of thyroid hormone replacement therapy. […] In conclusion, this case study illustrates the rare but important occurrence of spontaneous OHSS in the context of severe hypothyroidism during pregnancy. It emphasizes the need for clinical vigilance, early diagnosis, and comprehensive care in managing such cases, as well as the significance of thyroid management in pregnancy. Additionally, it suggests potential avenues for future research in this field.

• #34

  https://link.springer.com/article/10.1177/107155769800500301

  To relay the current knowledge on the interaction between cytokines, growth factors, and ovarian hyperstimulation syndrome (OHSS) and to propose a new insight into the pathogenesis of OHSS. […] Several cytokines, as well as vascular endothelial growth factor, were found to have a role, either in the prediction or pathogenesis of OHSS. […] Current knowledge indicates a close interaction between cytokines, growth factors, and OHSS. Further understanding of these interactions may lead to different understanding of ovarian hyperstimulation syndrome.

• #35 Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment | Reproductive Biology and Endocrinology | Full Text

  https://rbej.biomedcentral.com/articles/10.1186/1477-7827-10-32

  Importantly, the use of a GnRHa trigger completely eliminated OHSS in the 375 women randomized to receive it across all nine RCTs. […] The use of AMH, as a biomarker to individualize COS protocols, has been evaluated in a retrospective study of women undergoing ART. […] The study also reported a fall in the incidence of OHSS and failed fertilization. […] If the risk factors and biomarkers for OHSS are recognized and patients are correctly treated with iCOS, OHSS may no longer be an issue.

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