[Pathophysiology and current clinical approach of ovarian hyperstimulation syndrome]. / Az ovarialis hiperstimulációs szindróma kórélettana és korszeru klinikuma.

During assisted reproduction technologies, controlled hyperstimulation of the ovaries occurs. Ovarian hyperstimulation syndrome is an excessive overreaction of the ovaries complicating pharmacological ovulation induction. Rarely other causes, such as the mutation of the follicle-stimulating hormone receptor may also be in the background. Ovarian hyperstimulation syndrome is clinically characterized by a massive ovarian enlargement associated with an acute third-space fluid shift responsible for the development of ascites, and sometimes pleural or pericardial effusion. Associated arterial or venous thromboembolic symptoms are also common. Ovarian hyperstimulation syndrome is an iatrogenic and potentially life-threatening condition in the form of ischemic stroke or circulatory insufficiency of the limbs. Recently some new methods have been developed for the prevention of the disease. The syndrome affects young, healthy patients. It also has an important economic burden due to the absence from work, bed rest, or hospitalization and intensive medical management of more severe cases. Supportive therapy, anticoagulant prophylaxis and close monitoring are the main approach for the syndrome. However, hospitalization or intervention should not be delayed for patients with severe or critical conditions. Orv Hetil. 2018; 159(34): 1390-1398.

Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.

STUDY QUESTION: What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER: The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY: OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION: An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE: One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION: This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS: The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS: Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. REPORTS: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: Not applicable.

Consensus statement on prevention and detection of ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome is an important condition with considerable morbidity and a small risk of mortality, which most commonly results as an iatrogenic condition following follicular stimulation of the ovaries. AIM: To produce evidence-based and consensus statements on the prevention and detection of ovarian hyperstimulation syndrome (OHSS). METHOD: The CREI Consensus Group met in 2008 and identified issues for inclusion and review. Review of the available evidence was conducted and consensus statements prepared. Areas of dissent of expert opinion and for further research were noted. RESULTS: The group considered that there is a need for standardisation of the definition and classification of the clinical syndrome of OHSS to allow further conclusive research. Interventions with evidence of effect in reducing OHSS include the use of metformin in women with PCOS, use of GnRH antagonist rather than GnRH agonist and use of GnRH agonist triggers in GnRH antagonist stimulation cycles. The consensus view was that reducing the dose of FSH, freezing all embryos and transferring a single embryo were appropriate interventions to reduce OHSS. Agreement could not be reached on coasting, the lowest number of oocytes to consider freezing all embryos and management after cancellation of oocyte collection. CONCLUSION: OHSS is a serious condition for which there are a number of proven preventative strategies. OHSS is an area requiring ongoing research and development of a universally agreed definition will allow development of optimal prevention strategies and facilitate improved early detection of women at risk.

Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation.

Spontaneous ovarian hyperstimulation syndrome (OHSS) is an extremely rare event. Normally OHSS is seen in the context of IVF. In 2003 a mutation of the FSH receptor (FSHR D567N) was identified for the first time as a cause of spontaneous OHSS. In most FSHR mutations, a hypersensitivity to human chorionic gonadotrophin (HCG) or thyroid-stimulating hormone (TSH) is described. This clinical case presents for the first time two occurrences of spontaneous OHSS in a single woman with a FSHR mutation and two different entities. Pathophysiology of both pregnancies was completely different. During the first pregnancy, elevated HCG and androgen concentrations led to spontaneous OHSS and finally to miscarriage. The second pregnancy with spontaneous OHSS was dominated by a latent hypothyroidism and normal HCG concentrations and ended in a delivery of a healthy female newborn. Due to the unusual courses of the pregnancies, the study looked for a mutation in the FSHR and surprisingly identified the same mutation previously described. This report confirms for the first time the in-vitro findings in a single clinical case that TSH as well as HCG leads to spontaneous OHSS in patients with FSHR D567N mutation. Hypothyroidism has to be treated or ruled out.

Symposium: Update on prediction and management of OHSS. A modern classification of OHSS.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication of ovarian stimulation using fertility medications. OHSS classification presents the different severity categories and grades of OHSS and optimizes management schemes and prognosis. An initial classification system, which grouped OHSS into mild, moderate and severe categories, was based on patients' symptomatology plus manual estimation of ovarian enlargement and urinary excretion of sex steroids. A revised classification system then also incorporated the use of transvaginal sonography for both estimation of ovarian enlargement and detection of even small amounts of ascitic fluid. The detection of ascites establishes the diagnosis of moderate OHSS which may deteriorate to a severe form and is therefore of major importance. Subsequent modifications defined a group of critical or complicated OHSS in which grave complications have already developed. A consensus on the classification of OHSS should be reached by professional societies. As the revised classification system is very valid and widely used, it should form the basis for a modern classification, with the addition of critical or complicated OHSS to the severe category of the syndrome.

Update on ovarian hyperstimulation syndrome: Part 1--Incidence and pathogenesis.

Ovarian hyperstimulation syndrome (OHSS) is a rare and potentially life-threatening complication during controlled ovarian stimulation. It can be associated with severe morbidity and may even be fatal. The etiology of the condition and predisposing factors are still not fully understood. Data concerning pathophysiology in patients with OHSS were searched using PubMed and other medical data bases. The incidence of severe OHSS, as calculated by World Health Organization (WHO), is 0.2-1% of all stimulation cycles in assisted reproduction. Considerations on OHSS classifications and forms of manifestations are discussed in detail. New insights concerning genetics and altered FSH receptor are given. OHSS may involve, according to its grade of severity, elevated or decreased levels of growth factors, cytokines, mediators, changes in hormones, renin-angiotensin and kinin-kallikrein system. There are massive electrolytic imbalances and changes in hemodynamic and fluid metabolism. Furthermore, liver and pulmonary dysfunction is observed as well as increased coagulation with subsequent thromboembolism. The influence of OHSS on the pregnancy rate and outcome of pregnancy is a matter of controversy. Patients with OHSS have high pregnancy rates with a tendency to an increased incidence of abortion.

[The ovarian hyperstimulation syndrome--diagnostic criteria, management procedures]. / Zespól hyperstymulacji jajników--kryteria rozpoznania, sposoby postepowania.

The ovarian hyperstimulation syndrome (OHSS) is still a difficult diagnostic and therapeutic problem. OHSS is associated with significant hypertrophy of the ovaries associated with the loss of the intravascular fluid to the third space which results in hypovolaemia, oliguria, electrolyte imbalance, and a rise in haematocrit. The endogenous OHSS is rare. Most often OHSS appears as a complication of induction of ovulation. The fundamental issue in pathophysiology of OHSS is an increase of capillary permeability which results in the leakage of fluid to the third space. The vascular endothelial growth factor--VEGF--is considered to be the factor directly responsible for the processes involved. The most common are the mild and moderate forms of the syndrome. The severe form of OHSS is a life-threatening condition. The following symptoms may be present: ascites, pleural and pericardial effusion, oliguria, dyspnoea with tachypnoe, tachycardia, adult respiratory distress syndrome, renal failure, venous thrombosis, ischaemic stroke, haemorrhage from a ruptured ovary. Therapy should be based on the correction of hypovolaemia, hypotension and oliguria. Antithrombotic prophylaxis is an integral part of the OHSS management. Some interesting attempts have been undertaken to re-infuse the protein-rich ascites fluid directly to the systemic circulation, so called continuous auto-transfusion system of the ascites (CATSA).

The continuum of high ovarian response: a rational approach to the management of high responder patient subgroups.

Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between individual patients, and even from cycle to cycle for the same patient. High responder patients are characterized by an exaggerated response to gonadotropin administration, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In spite of its importance, the literature regarding high responders is characterized by heterogeneous classification methodologies. A clear separation should be drawn between risk factors for a high ovarian response and the actual response exhibited by a patient to stimulation. Similarly, it is important to distinguish between high ovarian response and development of clinically significant OHSS. In this article we: (1) review recent publications pertaining to the identification and clinical management of high responders, (2) propose an integrated clinical model to differentiate sub-groups within this population based on this review, and (3) suggest specific protocols for each sub-group. The model is based on a chronological patient assessment in an effort to target treatment based on the specific clinical circumstances. It is our hope that the algorithm we have developed will assist clinicians to supply targeted and precise treatments in order to achieve a favorable reproductive outcome with minimum complications for each patient.

Ovarian hyperstimulation syndrome (OHSS): diagnosis and management.

OBJECTIVE: To present our experience and the current knowledge about pathophysiology, diagnosis, and management of the ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective study concerning clinical and laboratory findings of severe OHSS. SETTING: General ICU at a maternity-surgical hospital. PATIENTS: Ten patients suffering from severe OHSS. INTERVENTIONS: Supportive and preventive therapeutic measures applied are described. MEASUREMENTS AND RESULTS: Admission and discharge data as well as worst values during disease course were recorded. Clinical and laboratory findings showed third space fluid shift leading to weight gain, generalized tissue edema, ascites, hydrothorax, abdominal distension and pain, chest discomfort, hypovolemia, dehydration, ovaries enlargement, electrolyte disturbances, hypoalbuminemia, high hematocrit, urea, and WBC. CONCLUSIONS: OHSS is an iatrogenic complication of assisted conception of unknown pathogenesis, with potentially life-threatening sequelae due to hemoconcentration such as circulatory shock, ARDS, hepato-renal failure, thromboembolic phenomena, and multi-organ dysfunction syndrome. Gynecologists and intensivists must be aware of the diagnosis and management of the syndrome because of the widely used reproductive techniques for assisted conception.

Ovarian hyperstimulation syndrome: facts and fallacies.

Severe or critical ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian hyperstimulation for assisted reproduction techniques (ART). The syndrome is characterized by cystic enlargement of the ovaries and fluid shifts from the intravascular to the third space. The morbidity in OHSS is mainly determined by the hemodynamic changes caused by increased capillary permeability. The incidence of OHSS depends on definitions, risk factors, ovarian stimulation protocols, luteal support and conception. Currently, research on the pathogenesis of OHSS is focused on increased capillary permeability. Several theories are reviewed. Until the pathogenesis of OHSS becomes clear, treatment is restricted to supportive therapy. The various proposals for management of OHSS are discussed and, based on the available data, directions for the management of various grades of OHSS are summarized. However, prevention and early recognition are still the most important tools to handle OHSS. A flowchart with preventive measures for OHSS is presented derived from the available literature.

Clinical aspects of ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is characterized by massive transudation of protein-rich fluid (mainly albumin) from the vascular space into the peritoneal pleural and to a lesser extent to the pericardial cavities. The intensity of the syndrome is related to the degree of the follicular response in the ovaries to the ovulation inducing agents. OHSS is still a threat to every patient undergoing ovulation induction. The pathophysiology of OHSS is of extreme importance in the face of the increased use of ovulation induction agents as well as the development of sophisticated assisted reproductive techniques. The correlation found between plasma cytokine activities and the severity of OHSS suggests that plasma cytokines may be involved in the pathogenesis of OHSS and may serve as a means of monitoring the syndrome during the acute phase and throughout convalescence. The interactions between cytokine and non-cytokine mediators of the syndrome, such as the renin-angiotensin system and vascular endothelial growth factor were recently clarified. Awareness of possible mechanisms and factors in the pathophysiology of OHSS will hopefully provide opportunities to design specific treatment regimens effective for both prevention and treatment of this potentially fatal iatrogenic condition. Among IVF patients with severe and critical OHSS, pregnancy rates, multiple gestations, miscarriage, preterm premature rupture of the membranes, prematurity, and low birth weight rates are significantly higher than those reported previously for pregnancies after assisted conception. The incidence of other obstetrical complications, as well as congenital malformations and Cesarean section rates are not significantly different.

[The ovarian hyperstimulation syndrome]. / La sindrome da iperstimolazione ovarica.

The ovarian hyperstimulation syndrome is the most important iatrogenic complication of ovarian stimulation. Every drug used in the treatment of infertility such as FSH, HMG, CC, GnRHa, can lead to the syndrome. The authors of the article report the incidence of OHSS in their patients treated for an assisted conception program; the role of oestrogens, HCG and renin-angiotensin system; the classification, the therapy and how to prevent the syndrome.

Massive unilateral hydrothorax as the only clinical manifestation of ovarian hyperstimulation syndrome.

We describe the case of a 36 old woman with a right massive hydrothorax resulting from Controlled Ovarian Hyperstimulation (COH) for infertility. This complication is defined as Ovarian Hyperstimulation Syndrome (OHSS) which usually includes abdominal pain, nausea and ascites, rarely involving the respiratory apparatus. The usual determining factors of OHSS are the presence of high serum estradiol levels and pregnancy. In the case that we describe the serum estradiol levels during COH were monitored and were slightly higher than the COH alarm threshold and the patient was not pregnant.

[Isolated pleurisy revealing ovarian hyperstimulation syndrome]. / Pleurésie isolée révélant un syndrome d'hyperstimulation ovarienne.

Ovarian hyperstimulation is a rare but serious iatrogenic complication following induction of ovulation cycles. Release of vasoactive substances by the stimulated ovaries leads to leakage of intravascular fluid into the extracellular and serous spaces due to enhanced capillary permeability. Pleural effusion is a classical finding in the most severe forms, often associated with ascitis and signs of hemoconcentration. We report the case of a women who presented pleural effusion as the sole inaugural sign of ovarian hyperstimulation.

[The lung and benign diseases of the ovary]. / Poumon et pathologie bénigne de l'ovaire.

Two main benign diseases of the ovary which can simulate advanced stage cancer of the ovary are described. The first is Meigs' syndrome, a triad of benign ovarian tumor, usually an ovarian fibroma, ascitis, and pleural effusion with complete disappearance of serous exsudative effusions with surgical resection of the ovarian tumor. The second is ovarian hyperstimulation syndrome following ovulation induction with exogenous gonotropins for the treatment of infertility. This syndrome associates significant ovarian enlargement, hyperestrogenism and latent or clinically patent serous exsudative effusions; it usually resolves with suggestive measures and rest.

[The ovarian hyperstimulation syndrome in pregnancy after IVF-ET]. / Ovarialen khiperstimulatsionen sindrom pri bremennost sled IVF-ET.

The authors present 3 cases of OHSS in 85 patients (3.5%), treated with long stimulation protocol. They propose an original grading of the severity of the syndrome as well as prophylactic and therapeutic measures.

Treatment of ovarian hyperstimulation syndrome.

Mild forms of ovarian hyperstimulation syndrome (OHSS) do not require treatment. Moderate OHSS should be followed up on an outpatient basis with no specific treatment. Severe OHSS requires proper evaluation. Investigations are done to evaluate hematocrit, electrolytes, and kidney and liver function. Conservative treatment with intravenous (i.v.) fluids and close monitoring is usually done. Intensive care admission is indicated in cases with severe respiratory distress or major electrolyte imbalance with elevated serum creatinine. Crystalloids in the form of i.v. saline and colloids as albumin or hydroxyethyl starch are commonly used to expand intravascular volume. Dopamine can be used to improve diuresis, and prophylactic heparin is administered to prevent venous thrombosis. Diuretics are generally contraindicated because they may further contract intravascular volume. Abdominal or vaginal aspiration of ascitic fluid results in marked improvement of symptoms, improved diuresis, and shortened hospital stay. The current trend to treat patients with i.v. fluids, albumin, and to perform aspiration of ascitic fluid on an outpatient basis has been found to be a more cost-effective protocol of treatment.