Ovarian hyperstimulation syndrome and assisted reproductive technologies: why some and not others?

BACKGROUND: alpha(2)-Macroglobulin (alpha(2)M) is a multifactorial binding protein, found in follicular fluid, that is a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). The aim of this study was to determine if there is a relationship between serum VEGF levels, alpha(2)M levels and the development of OHSS in hyperstimulated subjects undergoing IVF (those with 15 or more oocytes). METHODS: Venous blood was collected at the time of oocyte retrieval from subjects who yielded 15 or more oocytes. Serum samples were analysed for VEGF and alpha(2)M concentrations. RESULTS: There was no statistically significant difference in serum VEGF levels at the time of oocyte retrieval between hyperstimulated subjects who did and did not subsequently develop OHSS [3.95 (3.3-4.4) versus 3.85 (3.3-4.5); P = 0.79]. By contrast, the serum level of alpha(2)M was statistically significantly higher in the group of subjects who did not develop OHSS [2.27 (1.91-2.58) versus 1.67 (1.45-1.73)]. CONCLUSIONS: These results suggest that elevated alpha(2)M levels are associated with a decreased risk of developing OHSS. alpha(2)M may act by 'removing and inactivating' VEGF, with higher levels providing increased protection against the syndrome. alpha(2)M measurements may help to differentiate those for whom it is safe to proceed with embryo transfer from those for whom it is not, because of the risk of OHSS.     

Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome

The receptors for follitropin (FSHR), thyrotropin (TSHR), and lutropin/chorionic gonadotropin (LHCGR) are the members of the glycoprotein hormone (GPH) receptors (GPHR) family. They present a bipartite structure with a large extracellular amino-terminal domain (ECD), responsible for high-affinity hormone binding, and a carboxyl-terminal serpentine region, implicated in transduction of the activation signal. Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare genetic condition in which human chorionic gonadotropin (hCG) promiscuously stimulates the FSHR during the first trimester of pregnancy. Surprisingly, germline FSHR mutations responsible for the disease have so far been found only in the transmembrane helices of the serpentine region of the FSHR, outside the hormone binding domain. When tested functionally, all mutants were abnormally sensitive to both hCG and thyrotropin (TSH) while displaying constitutive activity. This loss of ligand specificity was attributed to the lowering of an intramolecular barrier of activation rather than to an increase of binding affinity. Here we report the first germline mutation responsible for sOHSS (c.383C>A, p.Ser128Tyr), located in the ECD of the FSHR. Contrary to the mutations described previously, the p.Ser128Tyr FSHR mutant displayed increase in affinity and sensitivity toward hCG and did not show any constitutive activity, nor promiscuous activation by TSH. Thus, sOHSS can be achieved from different molecular mechanisms involving each functional domains of the FSHR. Based on the structure of the FSHR/FSH complex and site-directed mutagenesis studies, we provide robust molecular models for the GPH/GPHR complexes and we propose a molecular explanation to the binding characteristics of the p.Ser128Tyr mutant.     

Severe ovarian hyperstimulation syndrome after combined GnRH-agonist and low-dose human chorionic gonadotropin trigger in a patient with a single kidney

Ovarian hyperstimulation syndrome (OHSS) following gonadotropin-releasing hormone agonist (GnRH-a) trigger is rare. Here, we report a case of severe OHSS after combined GnRH-a and low-dose human chorionic gonadotropin (hCG) trigger in a patient with a single kidney. The patient is a 32-year-old women with a two-year history of infertility. The patient’s history was significant for a single kidney, that is, she had donated a kidney to a family member three years ago. The patient underwent controlled ovarian stimulation (COS) for in vitro fertilization (IVF) and received a combined 2?mg GnRH-a and 1500?IU hCG ovulatory trigger. Estradiol (E₂) levels on the day of and after the trigger were 3800?pg/mL and 4001?pg/mL, respectively. Four days after the trigger, the patient began experiencing nausea, abdominal distention and dyspnea, and her blood testing revealed hemoconcentration (hemoglobin: 16.9?g/dL; hematocrit: 51.0%) and an elevated creatinine level (1.16?mg/dL). Fresh embryo transfer was deferred. The patient was admitted to the hospital for fluid monitoring and prophylactic anticoagulation. Following inpatient management, her hemoglobin, hematocrit and creatinine levels normalized. The current report highlights that the systemic effects of OHSS can be accentuated in patients with preexisting renal disease or a single kidney.     

Serum oestradiol and progesterone concentrations during prolonged coasting in 15 women at risk of ovarian hyperstimulation syndrome following ovarian stimulation for assisted reproduction treatment

Serum oestradiol and progesterone concentrations were examined for up to 7 days after withholding gonadotrophins whilst continuing pituitary down-regulation in 15 women at serious risk of severe ovarian hyperstimulation syndrome (OHSS) (serum oestradiol >6000 pg/ml and >15 follicles per ovary). Serum oestradiol concentrations rose on day 1 of coasting in all but two of the 15 women before falling, the decrement being in the order of 40% on each day. This observation permits a rational basis for the estimation of frequency of serum oestradiol measurements and duration of coasting. The trends and rates of fall of serum oestradiol do not seem to predict the occurrence of moderate and severe OHSS, being similar in the six women who developed OHSS compared with nine women without OHSS. The trends in progesterone concentrations were unrelated to any aspects of the clinical outcome.     

Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome

BACKGROUND: Elevated estradiol (E(2)) levels predispose to development of ovarian hyperstimulation syndrome (OHSS). Since GnRH antagonist is associated with a reduction in E(2) levels, we hypothesized that GnRH-antagonist treatment of women down-regulated with GnRH agonist who are at risk of OHSS might reduce E(2) levels and avoid cycle cancellation. METHODS: Retrospective study in a university-based assisted reproduction technology (ART) programme in 87 patients treated with long luteal (LL) or microdose flare (MDF) with ovarian hyperresponse and 87 control patients without ovarian hyperresponse. GnRH-antagonist (ganirelix acetate) treatment was started and leuprolide acetate discontinued in women who failed to respond to a reduction in gonadotrophin dosage. RESULTS: In the treatment group, there was a significant, reproducible reduction in serum E(2) levels. Mean E(2) at the start of ganirelix treatment was 4219.8 pg/ml and decreased in 24 h to 2613.7 pg/ml (36.7%; P < 0.001). An average of 24.9 +/- 8.8 oocytes were obtained at retrieval and an average of 19.1 +/- 8.0 were metaphase II (79.2%). Fertilization occurred in 13.9 +/- 8.1 embryos (72.8%). In this high risk group, two cases of severe OHSS (2.3%) occurred. The ongoing pregnancy rate was 51.8%. Compared with the control group, there were no statistically significant differences in the rate of oocyte recovery, oocyte maturity, 2PN rate, fertilization, cancellation, OHSS or pregnancy. CONCLUSIONS: GnRH-antagonist treatment of women pretreated with GnRH agonist rapidly reduced circulating serum E(2) without adversely affecting oocyte maturation, fertilization rates or embryo quality and resulted in a high pregnancy rate in this subgroup of patients at risk of OHSS.     

Serum inhibin A, VEGF and TNFalpha levels after triggering oocyte maturation with GnRH agonist compared with HCG in women with polycystic ovaries undergoing IVF treatment: a prospective randomized trial

BACKGROUND: We aimed to examine the serum levels of inhibin A, vascular endothelial growth factor (VEGF), tumour necrosis factor alpha (TNFalpha), estradiol (E2) and progesterone levels after triggering of final oocyte maturation with GnRH agonist compared with HCG in patients with polycystic ovaries (PCO) and to investigate the relationship between these markers and ovarian hyperstimulation syndrome (OHSS). METHODS: Twenty-eight patients with PCO, undergoing controlled ovarian hyperstimulation with FSH and GnRH antagonist for IVF-embryo transfer treatment, were randomized for triggering of final oocyte maturation with GnRH agonist (GnRH agonist group, n = 15) or HCG (HCG group, n = 13). Blood samples were obtained on the day of randomization and thereafter every 2-7 days. Serum levels of inhibin A, VEGF, TNFalpha, E2 and progesterone, the incidence of OHSS, ovarian size and pelvic fluid accumulation were evaluated. RESULTS: Serum inhibin A, E2 and progesterone levels were significantly lower in the GnRH agonist group compared with the HCG group, particularly on the day of embryo transfer (P < 0.0001). Serum VEGF and TNFalpha levels were similar between the two groups. Four patients in the HCG group developed severe OHSS, whereas no patient had any symptoms or signs of OHSS in the GnRH-agonist group (P < 0.05). CONCLUSIONS: In patients with PCO treated with FSH/GnRH antagonist, final oocyte maturation with GnRH agonist instead of HCG reduces significantly inhibin A, E2 and progesterone levels during the luteal phase. This phenomenon reflects the inhibition of the corpus luteum function and may explain, at least in part, the mechanism of OHSS prevention in high-risk patients. Our results do not support a crucial role for VEGF or TNFalpha in OHSS.     

The influence of urinary versus recombinant gonadotropin on serum P-selectin levels in vivo

Objective.?To determine the levels of serum P-selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles with urinary (uGn) versus recombinant gonadotropins (rGn) and their possible correlation with COH variables.

Methods.?This study was carried out in a large university-based infertility and in vitro fertilization unit. A total of 14 consecutive patients underwent our routine COH protocol for unexplained infertility with either uGn or rGn. Blood was drawn three times during the COH cycle: on day 2 or 3 of the menstrual cycle and before gonadotropin treatment (day-0); on the day of or prior to human chorionic gonadotropin (hCG) administration (day-hCG); and on the day of ovulation (day-OVU). Levels of sex steroids and serum P-selectin were compared among the three time points between the uGn and rGn subgroups. P-selectin was measured with a commercial quantitative sandwich immunoassay technique.

Results.?In both Gn subgroups, there was a non-significant increase in P-selectin level between day-hCG and day-0. In the rGN subgroup, no significant difference was observed in P-selectin levels between day-OVU and day-hCG. In the uGn subgroup, P-selectin levels were significantly lower in day-OVU as compared to day-hCG (p?<?0.04) and day-0 (p?<?0.04). No differences were noted between the uGn and rGn subgroups in patient age, number of gonadotropin ampules used or estradiol and progesterone levels during the COH cycle or P-selectin on day-0 or day-hCG. However, on day-OVU, P-selectin levels were significantly lower in the uGn than the rGn subroups (p?<?0.01).

Conclusion.?The increase in serum P-selectin level during COH until the peak of estradiol level was significantly attenuated after hCG administration in patients pretreated with uGn, but not rGN. It would therefore be prudent in patients at risk of developing thromboembolism undergoing COH to use uGN rather than rGN in order to attenuate platelet activation.     

Successful pregnancy outcomes after preimplantation genetic diagnosis (PGD) for carriers of chromosome translocations

Reciprocal translocations are found in about 1 in 500 people, whereas Robertsonian translocations occur with a prevalence of 1 in 1000. Balanced carriers of these rearrangements, although phenotypically normal, may present with infertility, recurrent miscarriage, or offspring with an abnormal phenotype after segregation of the translocation at meiosis. Once the translocation has been identified, prenatal diagnosis can be offered, followed by termination of pregnancies with chromosome imbalance. Couples who have suffered repeated miscarriage or those who have undergone termination of pregnancy as a result of the translocation carrier status of one partner are looking increasingly to preimplantation genetic diagnosis (PGD) as a way of achieving a normal pregnancy. Similarly, infertile couples in which one partner is a translocation carrier may request PGD to ensure transfer of normal embryos after in vitro fertilization. Translocation PGD has been applied successfully in several centres worldwide and should now be considered as a realistic treatment option for translocation carriers who do not wish to trust to luck for a successful natural outcome.