[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.

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: definition, incidence, and classification.

Ovarian hyperstimulation syndrome (OHSS) is a iatrogenic complication of controlled ovarian stimulation. Although considered uncommon, the severe form is potentially fatal. Different clinical classifications have been developed through the years. No matter whether it is termed "grade C" or "critical" OHSS, life-threatening events may develop. Hence it is prudent to recognize the population at risk. Several risk factors for OHSS have been identified; some are considered major risk factors such as polycystic ovary syndrome; others are less well defined. Preventive measures could be taken before and during the treatment cycle while taking into consideration the patient's characteristics and the various treatment options and approaches that currently exist.

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.

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.

Comparison of clinical characteristics between early and late patterns in hospitalized patients with ovarian hyperstimulation syndrome.

OBJECTIVE: To clarify the differences in clinical characteristics between early and late ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective study. SETTING: Tertiary university hospital. PATIENT(S): Ninety-four patients/cycles hospitalized for moderate-to-severe OHSS after controlled ovarian hyperstimulation (COH) for IVF/intracytoplasmic sperm injection (ICSI); early type (n = 69) and late type (n = 25). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The COH and pregnancy outcomes, preclinical and clinical miscarriage rate, and hospital courses. RESULT(S): Serum E(2) levels (4,955.5 +/- 3,268.5 pg/mL vs. 2,340.8 +/- 960.6 pg/mL) and the number of follicles > or =11 mm on day of hCG administration (15.9 +/- 6.0 vs. 13.0 +/- 4.0), and the number of oocytes retrieved (21.9 +/- 9.7 vs. 13.2 +/- 5.9) were significantly higher in the early OHSS group compared with the late OHSS group. Clinical pregnancy rate (PR) was significantly higher in the late OHSS group (23.6% [13/55] vs. 92.0% [23/25]). There were no significant differences in multiple PR and disease severity between the two groups. CONCLUSION(S): Early OHSS is associated with excessive ovarian response to gonadotropin stimulation, whereas late OHSS is closely associated with conception cycle. Our findings do not support that late OHSS is more severe and closely associated with multiple pregnancies compared with early OHSS.

Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate the effect of low-dose aspirin therapy on ovarian hyperstimulation syndrome (OHSS) in an unselected group of patients undergoing in vitro fertilization (IVF). DESIGN: Randomized clinical trial. SETTING: Division of Reproductive Medicine at the Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, Pécs, Hungary. PATIENT(S): Patients who underwent IVF between 2000 and 2006. INTERVENTION(S): Initiation of 3154 IVF cycles, for which gonadotropin-releasing hormone agonist was used in 2425 cycles; 1503 cycles randomly selected for low-dose aspirin treatment starting from the first day of controlled ovarian hyperstimulation compared with no treatment in the remaining 922 cycles. MAIN OUTCOME MEASURE(S): The incidence of severe or critical OHSS and the rate of clinical pregnancy. RESULT(S): During this time period, 45 cases of severe OHSS were detected. Only two of the OHSS patients had received aspirin previously. CONCLUSION(S): Based on our preliminary results, introduction of low-dose aspirin therapy during ovulation induction for the prevention of OHSS in high-risk patients should be considered.

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).

Síndrome de hiperestímulo ovariano: fisiopatologia, abordagem clínica, prevenção e tratamento / Ovarian hyperstimulation syndrome: physiopathology, management, prevention and treatment

A síndrome de hiperestímulo ovariano é uma importante complicação das técnicas de reprodução assistida devido a sua grande morbidade. O mecanismo patogênico básico é o aumento da permeabilidade capilar levando ao extravasamento de líquidos do espaço intravascular para o extravascular, com desenvolvimento de ascite e outros tipos de sufusões, além de hemoconcentração e hipovolemia. A fisiopatologia ainda é motivo de controvérsia. Evidências recentes apontam para o papel de vários mediadores neste processo, sendo que o vascular endothelial growth factor vem sendo envolvido como principal responsável pelo desenvolvimento da síndrome do hiperestímulo ovariano. O presente estudo tem como objetivo revisar sua fisiopatologia e avaliar os recentes avanços descritos na literatura sobre a profilaxia e tratamento da síndrome de hiperestímulo ovariano

Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures.

The aim of this review was to summarize previously published classifications for ovarian hyperstimulation syndrome (OHSS), as well as to analyse the available methods for preventing OHSS. Withholding hCG and cycle cancellation--once the main methods of preventing OHSS--are now seldom used. There is a growing body of evidence to support the use of coasting to prevent OHSS, without cycle cancellation. However, most studies on coasting are retrospective, and well-designed prospective randomized studies are lacking. There is no current consensus as to how coasting should be carried out. A serum estradiol level of 3000 pg/ml is generally considered optimum for administration of hCG. It appears that intravenous albumin or hydroxyethyl starch at the time of oocyte retrieval is beneficial in preventing OHSS, but does not offer complete protection. There is insufficient evidence to support routine cryopreservation of all embryos for the later transfer of frozen-thawed embryos in high-risk patients. Several uncontrolled studies have reported the protective effect of GnRH agonist to trigger ovulation in preventing OHSS, though the method is applicable solely for gonadotrophin-only or GnRH antagonist cycles. A single dose of recombinant LH to trigger ovulation significantly reduced OHSS as compared with hCG. The possible role of GnRH antagonist protocols in reducing the incidence of OHSS is debatable. The above measures to prevent OHSS were successful in reducing the incidence of the syndrome, but complete prevention is not as yet possible.

Ovarian hyperstimulation syndrome: distinction between local and systemic disease.

The ovarian hyperstimulation syndrome (OHSS) is an iatrogenic, unpredictable and potentially life-threatening complication in patients submitted to pharmacological ovarian stimulation. Information on risk factors, etiopathogenetic mechanisms, prevention strategies and therapeutic management is continuously updated. The present study retrospectively analyzed 123 women affected by different grades of OHSS as a result of pharmacological ovulation induction. Hospital admission was suggested in 14 patients with severe OHSS, whereas patients with moderate or mild OHSS were followed in the out-patient section of our department. The results confirmed the efficacy of the therapeutic scheme adopted. The syndrome is localized to the ovaries at the time that the condition is triggered; when organs different from the ovaries become involved, OHSS assumes systemic aspects. The different clinical signs are the basis of a proposal of a local and systemic classification.

[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.