Cristiano Busso

Obesity and assisted reproductive technology outcomes

Obesity is a rising health problem in Western societies. It has been related to increased morbidity and mortality rates due to several pathologies. In the field of gynaecology and reproduction, obesity is associated with menstrual disorders, hirsutism, infertility, miscarriage and obstetric complications. It is known to impair human reproduction through different mechanisms such as insulin resistance, hyperandrogenism and elevated leptin levels. Weight management and dietary intervention can reverse this situation and improve reproductive function. Obesity can also impair the outcome of assisted reproductive technologies. The lower probability of a healthy live birth described in obese women seems to be the result of a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and increased complications during pregnancy for both mother and fetus. Studies performed in infertile women undergoing assisted reproduction technologies indicate that the ovary plays a leading, but not exclusive, role in the fertility prognosis of these patients. The endocrine and metabolic environment may affect oocyte quality and, therefore, embryo development, implantation and pregnancy outcome. The endometrium seems to play a subtle role in the more negative reproductive outcome of obese women, according to recent studies based on the ovum donation model.

Physiology and pathology of ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) occurs when ovaries primed with follicle-stimulating hormone/leuteinizing hormone (LH) are subsequently exposed to human chorionic gonadotropin (hCG). The ultimate pathophysiological step underlying this clinical picture is increased vascular permeability (VP). With the administration of hCG, the expression vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) mRNA increases significantly rising to a maximum coinciding with peaked VP. Immunohistochemistry shows the presence of VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the entire corpus luteum. These findings suggest that the syndrome can be prevented by inducing ovulation with LH or gonadotropin-releasing hormone analogs, which prevent VEGF overexpression. Also, coadministration of a dopamine agonist inhibits phosphorylation of the receptor VEGFR-2. In a trial of 69 oocyte donors, the incidence of moderate OHSS was 20% with the dopamine agonist cabergoline and 44% with a placebo ( P = 0.04). Another dopamine agonist, quinagolide, was also effective in nonpregnant patients, but those pregnant did not benefit from dopamine agonist administration. In conclusion, the pathophysiological mechanisms involved in OHSS show that targeting VEGF/VEGFR2 is an effective preventive approach to treat the syndrome. Pharmaco-prevention through dopamine agonists is effective only in nonpregnant high-risk OHSS women. Embryo cryopreservation plus dopamine agonist administration might be the most appropriate way to prevent OHSS in high-risk patients.

The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) seems to be induced by the ovarian release of vascular endothelial growth factor (VEGF), which increases vascular permeability. Dopamine agonists inhibit VEGF receptor phosphorylation and thereby decrease vascular permeability. METHODS A randomized, double-blind, placebo-controlled, multicentre study assessing three oral doses (50, 100, 200 µg/day) of the non-ergot derived dopamine agonist quinagolide started on the day of human chorionic gonadotrophin (hCG) and continued for 17–21 days without dose-titration in comparison to placebo in preventing moderate/severe early OHSS (onset ≤9 days after hCG administration) in 182 IVF patients with ≥20 but less than 30 follicles ≥10 mm. RESULTS The incidence of moderate/severe early OHSS was 23% (12/53) in the placebo group and 12% (6/51), 13% (7/52) and 4% (1/26) in the quinagolide 50, 100 and 200 µg/day groups, respectively. The moderate/severe early OHSS rate was significantly lower with all quinagolide groups combined compared with placebo [P = 0.019; OR = 0.28 (0.09–0.81)]. The incidence of ultrasound evidence of ascites among patients with no clinical pregnancy was significantly reduced from 31% (8/26) with placebo to 11% (8/70) with all quinagolide groups combined [P = 0.033; OR = 0.29 (0.10–0.88)], although there was no difference for those with clinical pregnancy. Quinagolide did not have a detrimental effect on pregnancy or live birth rates. The incidence of gastrointestinal and central nervous system adverse events increased with increasing doses of quinagolide. CONCLUSIONS Quinagolide appears to prevent moderate/severe early OHSS while not affecting treatment outcome. The effect is more marked in patients who did not achieve a clinical pregnancy. Quinagolide administered in high doses without dose-titration is associated with poor tolerability. ClinicalTrials.gov Identifier: NCT00329693.

Prevention of OHSS – dopamine agonists

Abstract Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction, which may seriously affect the patients health, with 0.1–2.0% of the patients developing severe forms of the syndrome. OHSS signs and symptoms are direct consequences of fluid shift from capillaries to the third space due to increased vascular permeability. The mechanisms of OHSS pathophysiology remain unknown but evidence obtained in animal models prove that vascular endothelial growth factor (VEGF) is directly involved and the inhibition of the VEGF system could prevent OHSS from occurring. Dopamine agonists impede the phosphorylation of the VEGF receptor 2 and reduce the incidence and severity of OHSS with a safe clinical profile. As far as is known, this is the first pathophysiological approach for treatment and prevention of OHSS.