Cabergoline Reduces OHSS
Condition: Ovarian Hyperstimulation Syndrome
MeSH terms: Ovarian Hyperstimulation Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      The present study was designed to provide clinical confirmation of Cb2's value as a new
      approach in the prevention of increased vascular permeability and hemoconcentration, both
      signs of OHSS in humans, and in order to explore its mechanism of action. To this end, a
      prospective, randomized, placebo-controlled study was designed in which Cb2 was employed in
      women at risk of OHSS after gonadotropin administration for ART. Simultaneously, ovarian
      perfusion was assessed in these patients using MR pharmacokinetic modeling.
    

Detailed description: 
      Patients and Study design This study was performed in 82 oocyte donors between April 2004 and
      July 2006. The study protocol was approved by our institution's Ethical Committee and all
      participants signed a written consent form. The protocol for COH has previously been
      described (23). Only patients at risk of developing OHSS were included. The definition of
      risk was the development of 20-30 follicles >12 mm in diameter, and retrieval of >20 oocytes.
      Once the decision to administer hCG was taken, patients were immediately allocated into two
      groups based on a computer randomization: the study group initially consisted of 41 patients,
      but 6 of these were discarded after randomization because <20 oocytes were retrieved despite
      the development of >20 follicles >12 mm. Thus, a remaining total of 35 patients received one
      0.5 mg tablet of Cb2 daily for eight days. The control group was also initially composed of
      41 women. However, 7 of these did not meet the criteria of number of oocytes retrieved, and 2
      donors decided to withdraw themselves from the study. This left a remaining total of 32
      women, all of whom completed the study, and who received a placebo tablet daily for 8 days.
      Women were monitored every 48 hours from the day of hCG (day 0) until day 8.

      On day hCG+4, in order to define ascites, and provided that there was a certain degree of
      fluid in the pouch of Douglas after ovum pick-up, we employed transvaginal ultrasound (TVU)
      to measure two major perpendicular diameters of fluid pockets in 15 donors who showed no risk
      of OHSS. We observed 3.5±2.8 cm2 of fluid in the pelvis in normal conditions. Therefore, the
      existence of ascites was confirmed when a pocket of peritoneal fluid >9 cm2 was observed when
      the patient was in lithotomy position (with the gynecological table always at 45º from the
      floor of the room), which is the result of the mean± 2 standard deviations (SD) of the value
      found in non-OHSS candidates. TVU scans were performed by the same researcher (CA), who was
      blind to the treatment to which the patient was submitted. A 6.5 MHz vaginal probe (Voluson
      730 Pro V, General Electric, Madrid, Spain) was employed for all TVU scans.

      To evaluate the biochemical risk of hemoconcentration, we evaluated hemoglobin, hematocrit,
      and leukocyte count. Moreover, renal (creatinine) and liver [transaminases: aspartate
      aminotransferase (AST); alanine aminotransferase (ALT)] functions, and electrolytes (Na, K)
      were analyzed to ascertain the severity of the syndrome.

      Since all women undergoing ART experience a certain degree of discomfort and enlarged ovaries
      (known as mild OHSS), we centered our attention on analyzing the incidence of moderate and
      severe OHSS, which were identified according to our modified (24) classification of Golan et
      al (25). Moderate OHSS was confirmed when a patient presented ultrasonographic evidence of
      ascites, while diagnosis of severe OHSS required clinical evidence of ascites and/or
      hydrothorax and breathing difficulties, or one of the following criteria: a) increased blood
      viscosity due to hemoconcentration (hemoglobin ≥15 g/dl, hematocrit ≥45%, or leukocyte count
      ≥20,000/mm3); b) coagulation abnormality; c) diminished renal perfusion and function (serum
      creatinine levels >1.2 mg/dl); d)liver dysfunction: defined when transaminases (AST or ALT)
      were >40 U/ml (24, 25).

      Additionally, serum PRL levels were measured and adverse drug reactions recorded. An
      end-of-study assessment was scheduled 7-10 days after the last dose of Cb2/placebo.

      Moreover, in the first 8 patients included in the study, follicular fluid aspirates without
      obvious blood contamination were collected, pooled and and mRNA extracted to quantify the
      amount of Dp-r2 in human ovaries, employing two different molecular techniques.

      To further objectively analyze changes in vascular permeability and fluid shifts,
      confirmatory studies were performed on six women in the study group and four controls,
      employing magnetic resonance (MR) as described below. Dynamic contrast-enhanced MR was
      performed at three different stages of the study: at baseline, before gonadotropin
      administration was initiated; just before hCG injection; and on day hCG+5, after oocyte
      pick-up.
    

Intervention name(s): Cabergoline; MR; Ultrasound; Blood Analysis
Intervention type(s): Drug; Procedure; Procedure; Procedure
Intervention MeSH terms: Cabergoline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Prevention
Keywords: Ovarian hyperstimulation syndrome, dopamine agonists, cabergoline, hemoconcentration, ascites, ovarian perfusion, dopamine receptor 2