Endocrine gland – derived vascular endothelial growth factor concentrations in follicular fluid and Serum may predict ovarian hyperstimulation syndrome

17 03 2011

To the Editor:

We read with great interest the article of Gao et al. (1). Gao et al. (1) had 17 patients that showed only mild to moderate signs and symptoms of OHSS using Golan classification system (2). A more recent classification reclassified OHSS into two groups (moderate and severe) stressing that mild OHSS signs are seen in most cases of controlled ovarian hyperstimulation that does not require special treatments (3), further reducing their OHSS patients number. Therefore, in the absence of severe OHSS cases, it is possible that the signs and symptoms of OHSS patients in their study may be similar to the non-OHSS group.

EG-VEGF is produced mainly by steroidogenic glands and has similar biological functions to VEGF. It functions mainly to control the contractions of gastrointestinal smooth muscles. Like VEGF, EG-VEGF acts through its two G-protein coupled receptors PRK1 and PRK2. Stimulation of these receptors activates calcium mobilization leading to smooth muscles contraction and angiogenesis (4). OHSS signs and symptoms are directly due to massive fluid shift from the cells to third spaces during ovarian stimulation. Fluid movements across secretary epithelia are secondary to ion movements. The importance of ion movements across epithelia lies in their coupling with the movement of water, which is not actively transported but moves in response to osmotic gradients, largely established by the transport of ions. Rapid passage of fluid into luminal spaces, as seen in OHSS, is mediated by altered expression of transepithelial ion and water channels (5) and not through VEGF or EG-VEGF that are not ion channels but function only through G-proteins coupled receptors.

Gao et al. (1) also stated that our study demonstrated that VEGF concentrations in peripheral blood and FF may predict the occurrence, severity and progress of OHSS. On the contrary, the hypothesis was that VEGF is not a water or ion channel and could not have been directly responsible for the rapid transepithelial shift of fluids seen in severe OHSS (6).

OHSS is always associated with supraphysiological levels of estrogen (E2) as seen in the study of Gao et al. (1). Serum VEGF and EG-VEGF concentrations were also not correlated with E2 levels. However, the role of E2 in VEGF and EG-VEGF expression was not discussed either. The serum levels of E2 in donor oocyte recipients during oocyte donor programs are not as high as in OHSS. Gao et al. (1) reported that administration of high dose of extrinsic E2 dose not produce OHSS. Interestingly, Ajonuma et al. (5) demonstrated in a rat model that administration of high levels of extrinsic E2, even to ovariectomized rats, produced OHSS signs and symptoms suggesting that E2 plays important roles in OHSS. They further showed that E2 upregulates the expression of epithelial ion channels, leading to increased transepithelial transport of fluids.

In summary, the roles of E2 in EG-VEGF modulation, as well as a well-controlled prospective study with adequate sample size, is required to properly determine the involvement of EG-VEGF in OHSS pathophysiology.

Louis C Ajonuma M.D, Ph.D. a
Mary U Ajuonuma B.Pharm b
Blessing C Ajuonuma, BSc., RN a,c
Virgilus M Ogbedeagu M.D a,d
Joshua U Ajuonuma B.Pharm a,e
Chika L Chukwu M.D, FRSPH a,f
aSt Mary’s Maternity Hospital
Amakohia, Ihitte, Etiti, Imo State Nigeria
bGeneral Hospital Mina
Niger State, Nigeria
cImo State University
Owerri, Imo State, Nigeria
dUniversity of Abuja Teaching Hospital
Gwagwalada, Abuja, Nigeria
e College of Pharmacy
Lyceum Northwestern University
Dagupan City, The Philippines
f Specialist Hospital
Port Harcourt, Rivers State, Nigeria

References
1. Min-Zhi Gao, Xiao-Ming Zhao, Yan Hong, Zhao-Gui Sun, Lei-Wen Zhao, Hui-Qin Zhang. Endocrine gland–derived vascular endothelial growth factor concentrations in follicular fluid and serum may predict ovarian hyperstimulation syndrome in women undergoing controlled ovarian hyperstimulation. Fertility and Sterility, 2011, 95, 673-678.

2. Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gnecol Surv. 1989, 44, 430-40.

3. Rizk B and Aboulghar M. Classification, Pathophysiology and management of ovarian hyperstimulation syndrome. In Brisden P et al., A textbook of In vitro Fertilization and Assisted Reproduction 2nd Edition Lancaster, United Kingdom, Partheron Publishing 1999, 131-155.

4. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. “Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins / endocrine gland vascular endothelial growth factor”. J. Biol. Chem. 2002, 277, 19276–80.

5. Ajonuma LC, Tsang LL, Zhang GH, Wong CH, Lau MC, Ho LS, Rowlands DK, Zhou CX, Ng CP, Chen J, Xu PH, Zhu JX, Chung YW, Chan HC. Estrogen-induced abnormally high cystic fibrosis transmembrane conductance regulator expression results in ovarian hyperstimulation syndrome. Mol. Endocrinol. 2005, 19, 3038-44.

6. Ajonuma LC. Is vascular endothelial growth factor (VEGF) the main mediator in ovarian hyperstimulation syndrome (OHSS)? Med Hypotheses. 2008, 70, 1174-8.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.051

The Authors Respond:

Despite the small sample in this study, statistical difference was seen in FF EG-VEGF concentrations among non-OHSS and OHSS groups. In fact, mild OHSS is classified as grades 1 and 2 according to the Golan classification system. We selected grade 2 for the mild OHSS group in our study, and these may be more inclined to signs. Besides, the number of patients in the mild OHSS group is small (n=5) and most OHSS patients belonged to the moderate group (n=12), so the effect might not be as great. It is very important and helpful to elucidate the role of EG-VEGF in OHSS whether severe cases can be included. However, with the improvement of prevention measures such as careful COH and ET cancellation, severe OHSS cases are rare in our clinic.

The characteristic sign of OHSS is massive body fluid shift from the intravascular compartment into the third space during ovarian stimulation, which is mainly due to the ion channel function in controlling passive fluid transport. However, the pathomechanism of OHSS remains unclear and other pathophysiologic pathways, such as vascular permeability change, may also play an important role during the process. EG-VEGF acts, through its two G-protein coupled receptors, PKR1 and PKR2, together with VEGF, in mediating the dysregulated vascular permeability that occurs in OHSS by acting on the endothelial cells (Trends EndocrinolMetab 2007;18:66–72).
As mentioned above, other factors may also be involved in this process. In the present report we speculate that EG-VEGF, not VEGF, may predict the occurrence, severity and progress of OHSS if multiple time-point measurements of EG-VEGF are conducted to determine the dynamic change of serum EG-VEGF concentration during the luteal phase.

So far, the results from studies on the role of estradiol (E2) in OHSS are inconsistent. Most studies revealed that E2 is not as important as hCG. Patients with high levels of E2 rarely develop OHSS if hCG administration is cancelled. However, our results showed that the serum E2 levels on the hCG day were significantly higher in the OHSS group than in the non-OHSS group. This had a negative association with FF EG-VEGF, serum EG-VEGF and FF VEGF concentrations. Thus, we think E2 may play an indirect role in OHSS by inhibiting the synthesis of EG-VEGF and VEGF. We also speculated in the discussion that the presence of high E2 levels in COH cycle may promote EG-VEGF to bind to its tissue receptors, resulting in decreased detectable EG-VEGF in FF and serum.

Certainly, further study on the function of EG-VEGF in vascular permeability by using animal models and in vitro experiments, such as human uterine microvascular endothelial cells culture, will be helpful in clarifying the role of EG-VEGF in the process of OHSS. These methods will overcome any ethical issues limiting human study.

We totally agree with this opinion, and to this end we are considering carry out a further prospective study, together with the animal study and in vitro experiments, to determine the involvement of EGVEGF in OHSS pathophysiology.

Min-zhi Gao, M.D.a,b
Xiaoming Zhao, M.D.a
Zhao-gui Sun, Ph.D.c
a Department of Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University
b Shanghai Medical College of Fudan University
c Key Laboratory of Contraceptive Drugs and Devices of NPFPC
Shanghai Institution of Planned Parenthood Research
Shanghai, People’s Republic of China

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.050

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