The Ovarian Hyperstimulation Syndrome
Infertility: new potential pathways involved

Author: Alessandro Ferrero
Date: 03/07/2012



Current epidemiological evidence suggests that 15% of couples will experience infertility. Background prevalence rates now appear to be reasonably stable, but there is evidence of an increase in the rate of referrals for medical help.
Ovarian stimulation and assisted reproduction for infertility management
After correcting the abnormalities detected during the diagnostic workup, ovulation induction is usually performed either for treatment of anovulation/oligo-ovulation,
or empirically in regularly ovulating women. This approach results in a pregnancy rate of around 8%–15% per cycle depending on the agents used for ovulation
induction and the characteristics of the couple, such as the woman's age and the presence or absence of a male factor.
Couples who do not become pregnant with ovulation induction alone then undergo more sophisticated treatment modalities including intrauterine insemination
(IUI) and in-vitro fertilization and embryo transfer (IVFET)as a treatment of last resort.
Ovarian stimulation for assisted reproduction
In most assisted reproduction programs, gonadotropins are used alone or in combination to stimulate the growth and maturation of multiple follicles. This is essential because of the need to recruit a greater number of follicles, which provides the opportunity for retrieval of a large number of oocytes. This would improve the chance for fertilization of multiple oocytes and thereby allow an increased number of embryos for transfer in order to give acceptable success rates.
The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment, 2005


The ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction and may represent a serious threat to life due to its possible complications. It is a serious potentially life-threatening physiologic complication, classically encountered in patients who undergo controlled ovarian hyperstimulation cycles for assited reproduction technology.


The incidence of moderate and severe SHO varies from 3% to 6% and 0.25% to 1.8%, respectively. And it’s more frequent in younger patients, lean with polycystic ovarian disease (SOP) with high doses of gonadotropins such as those used in the treatment of in vitro fertilization (IVF) and when you reach a serum estradiol level > 4000 pg / ml .It’s four times more frequent in cycles that lead to evolutionary pregnancy than those who do not lead to pregnancy. The use of GnRH anatagosnist decreases the risk.


There are different clinical forms depending on the severity of the framework. Depending on the moment in which it appears is identified an early form that occurs some days after collection of the oocytes and embryo transfer, and another late-onset form that usually appears between 7 and 10 days after embryo transfer, that is due to increase of betaHCG produced in the pregnancy. The clinical picture is limited and usually lasts 1 or 2 weeks if the patient is not pregnant. Symptoms resolve rapidly after menstruation. The duration is longer and the clinical picture more severe if the patient turns out to be pregnant, could last up to 60-70 days, when levels of betaHCG start to decline.
Signs and Symptoms of Mild, Moderate, Severe forme:

  • Ovarian diameter:
    • Increased: Mild
    • 6-12 cm: Moderate
    • >12cm: Severe
  • Abdominal Pain:
    • +: Mild
    • ++: Moderate
    • +++: Severe
  • Abdominal distention:
    • +: Mild
    • ++: Moderate
    • +++: Severe
  • Nausea and vomiting:
    • +: Mild
    • ++: Moderate
    • +++: Severe
  • Ascites:
    • +: Moderate
    • ++: Severe
  • Paralytic ileus:
    • +: Severe
  • Powered Ascites:
    • +: Severe
  • Hemoconcentration (HTO>45%):
    • +: Severe
  • Impaired renal function:
    • +: Severe
  • Oliguria (<500ml/d o <30 ml/h):
    • +: Severe
  • Hyponatriemia (Na <20 meq/l):
    • +: Severe
  • Impaired epatic function:
    • +: Severe
  • Thromboembolism:
    • +: Severe
      Protocol of Ovarian Hyperstimulation Syndrome of Institut Marques Barcelona

Clinical presentation

Mild OHSS is relatively common in stimulated cycles, with symptoms including lower abdominal pain and discomfort , mild weight gain, vomiting or diarrhea. Ovarian enlargement discernible on ultrasound is a key indicator of severity of condition of Ovarian Induction. Moderate OHSS is characterized by the presence of ascites on ultrasound examination, moderate hemoconcentration and elevated leukocytes. Symptoms include rapid weight gain ( >1kg/day), abdominal distension, nausea, and vomiting. In severe OHSS, increased fluid shift into the peritoneal (around the intestinal loops) and also into the pleural and pericardial cavities, leading to hypovolemia and severe hemoconcentration.
Preventing ovarian hyperstimulation syndrome: guidance for the clinician, 2010
Introduction to the pathophysiology
The ovarian hyperstimulation syndrome is a physiological response of the ovary, after an multiple ovulation using hCG or endogenous LH peak. It thus produces a release of mediators inside the ovary (among these, the endothelial growth factor VEGF) which induces an increase in capillary permeability and an increase in angiogenesis producing an extravasation of fluid in the third space, hemoconcentration, hypoalbuminemia, decreased oncotic pressure, ascites and ipercoagubility . In cases of severe hyperstimulation, it produces a marked peripheral arterial vasodilation and a subsequent hypovolemia , which activates compensatory mechanisms, like the renin-angiontesina-aldosterone system, antidiuretic hormone ADHsecretion and activation of the sympatic system. All of these mechanisms will produce an increase of absorption of water and sodium in the kidney and an increase of heart rate too. The maintenance of this pathological situation will lead to an accumulation of fluid in the third space.
Protocol of Ovarian Hyperstimulation Syndrome of Institut Marques Barcelona.

OHSS and VEGF, biochemical pathways

OHSS is characterized by massive cystic enlargement of the ovaries associated with third space fluid shift, resulting in the formation of ascites and pleural effusion. Ascites develops because of increased peritoneal capillary permeability. With some studies it was examined the role of vascular endothelial growth factor (VEGF) and interleukins in the pathogenesis of increased capillary permeability. It has been reported that VEGF might increase vascular permeability by reducing tight junction occludin expression and disrupting ZO-1 and occludin organization, leading to tight junction disassembly. It was demonstrated that VEGF was the follicular fluid factor responsible for increased endothelial cell permeability in OHSS.Rearrangement of the actin cytoskeleton and disruption of ZO-1 protein are likely primary mechanisms by which VEGF in the follicular fluid disrupts endothelial cell tight junctions and increases permeability.
VEGF is a member of the family of heparin binding proteins that act directly on endothelial cells to induce proliferation and angiogenesis. VEGF mRNA and protein are expressed by human ovarian granulosa and theca cells late in follicular development and subsequent to ovulation by granulosa and theca cells.
Therefore, VEGF is ideally positioned to provoke the increased permeability of theca blood vessels that occurs shortly before ovulation. Hybridization studies in the rat and primate ovary have demonstrated VEGF mRNA expression predominantly after the luteinizing hormone (LH) surge known to be essential for OHSS.
The GnRH antagonist results in a decreased mRNA expression, expression that is dependent on LH level. The expression of VEGF mRNA has been recently shown to be enhance also by human chorionic gonadotrophin (HCG) in a dose and time-dependent mode. Using the rat OHSS model,it was showed that ovarian hyperstimulation increased ovarian levels of the mRNAs encoding VEGF.They also showed that VEGF mRNA expression in the ovaries of OHSS rats reached its highest level 48 hours after hCG administration(needed to obtain the ovulation). It was observed similar significant increases in peritoneal vascular permeability and ovarian expression of VEGF mRNA.
Studies confirm the timely association between VEGF and HCG that has been clinically known for many years to be integral in the development of OHSS. VEGF concentrations in serum, peritoneal fluid and follicular fluid of patients at risk for OHSS have been shown to be significantly related to the development of the syndrome.
Interleukin-2 (IL-2) is the first of a series of lymphocytotrophic hormones to be recognized as pivotal role for the regulation of immune response.
IL-6 is a mediator of the acute phase response to injury, a systemic reaction characterized by leukocytosis, increased vascular permeability and increased synthesis of acute phase proteins by the liver.
Significantly higher serum and ascitic liquid IL-6 concentrations were seen in OHSS patients. The immunohistochemical localization pattern suggested that IL-6 is LH or HCG dependent, like the VEGFmRNA. However, the use of IL-6 as a predictor for the occurrence of OHSS has not been successful. The kinetics of IL-6 in patients with severe OHSS are correlated with the clinical symptoms and the biochemical parameters known to be associated with the severity of the syndrome, suggesting a possible role for IL-6.
In conclusion, molecular biology and clinical studies strongly suggest that VEGF is the principal mediator by which HCG might increase capillary permeability in OHSS.
The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome, 1997

Effects of gonadotropin-releasing hormone antagonist on the expression of vascular endothelial growth factor and its receptors in a rat model of ovarian hyperstymulation syndrome, 2008


Most of OHSS can be managed on an outpatient basis, with oral analgesic and patient education regarding indicators of worsening illness that may require more aggressive intervention. Symptomatic relief of moderate OHSS with antiemetics and stronger analgesics should be accompanied by careful monitoring, including physical examination, ultrasound, weight measurement and laboratory determination of hematocrit, electrolytes, and serum creatinine, ideally on a daily basis. In non conceptions cycles, mild or moderate OHSS is likely to resolve spontaneously after menstruation. However in patient who become pregnant, rising serum levels of beta HCG developing severe OHSS, which generally requires hospitalizatio, ascites puncture, and prophylactic measures to prevent thromboembolism.
Preventing ovarian hyperstimulation syndrome: guidance for the clinician, 2010


Primary prevention is essential and consists in devising appropriate protocols for each patient to avoid excessive ovarian stimulation. It 's very important to keep it into account in

  1. young and lean women
  2. in patients with polycystic ovary syndrome
  3. with estradiol levels> 4000
  4. when using HCG as ovulation inductor

Secondary prevention consists in taking measures to prevent that a mild or moderate form will convert into a severe one:

  1. Consider suspending the administration of HCG in patients with E2 levels> 4000
  2. Suspend the administration of gonadotropins
  3. Cancel the transference of embryos and embryo cryopreservation
  4. Administer Cabergoline and GnRH antagonists

Cabergoline is an dopaminergic agonist that has demonstrated prevent the increase in capillary permeability, inhibiting the phosphorylation of VEGFR2.
The Ganarelix Cetrorelix and GnRH antagonists are two that produce a rapid inhibition of the release of LH at the pituitary level. It has been shown that the granulosa cells under stimulation of LH and cultured with GnRH antagonists, decrease the secretion of VEGF.
Protocol of Ovarian Hyperstimulation Syndrome of Institut Marques Barcelona.

Alessandro Ferrero
Filippo Gatti

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