Hemorheologic profile in healthy women undergoing controlled ovarian stimulation
Article Outline
We investigated the hemorheologic profile in 110 women undergoing controlled ovarian stimulation and provide evidence that smokers and women with body mass index >25 kg/m2 exhibit alterations of rheologic profile. A progressive increase of whole-blood viscosity throughout the ovarian stimulation cycle was observed; deformability and aggregation of erythrocytes decreased from baseline to the beginning of recombinant FSH administration, then remained unchanged throughout the next days; hematocrit mildly decreased during the last days of recombinant FSH administration; and fibrinogen and cholesterol levels decreased and increased, respectively, throughout the stimulation cycle.
Key Words: Infertility, controlled ovarian stimulation, rheological parameters, blood viscosity
Women undergoing ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI) may exhibit blood hyperviscosity, which contributes to increased risk of vascular disease (1). Whole-blood viscosity (WBV) is influenced by hematocrit, plasma viscosity, and erythrocyte aggregation and deformability, whereas plasma viscosity is dependent on protein components, particularly fibrinogen, and lipids, which may contribute to erythrocyte aggregation (2). Hormonal treatment for inducing ovulation may cause ovarian hyperstimulation syndrome, in which increased erythrocyte aggregation and blood viscosity have been observed (3).
Because no study investigating rheologic status in infertile women undergoing controlled ovarian stimulation for IVF or ICSI is available, we explored the influence of hormonal status on hemorheologic profile in otherwise healthy infertile women undergoing controlled ovarian stimulation.
We studied 110 consecutive infertile women (median age 37 years, range 20–42 years) who underwent IVF (n = 59, 53.6%) or ICSI (n = 51, 46.4%) at the Department of Gynecology, Perinatology and Reproductive Medicine, University of Florence from 2007 to 2008. Eighty-four women (76.4%) showed primary and 26 (23.6%) secondary infertility, 59 (53.6%) had undergone previous IVF/ICSI, 18 (16.4%) were overweight, and 14 (12.7%) were smokers.
All women were observed during the mid-luteal phase of the cycle (T0) and received oral contraceptive pills (Yasmin; Bayer Schering Pharma, Milan, Italy) starting on day 1 of the subsequent menses for 15–20 days. Patients received the GnRH agonist leuprolin (0.1 mg/d, SC) (Enantone; Takeda Italia, Rome, Italy) starting 5 days before discontinuation of the oral contraceptive pill. Pituitary down-regulation was confirmed by ultrasound examination. Afterward, daily SC injection of recombinant FSH (Gonal F [Serono Industrie Farmaceutiche, Rome, Italy] or Puregon [Organon Italia, Rome, Italy]) was begun. The dose of leuprolin was decreased on that day to 0.05 mg/d and continued until the day of recombinant FSH administration; the starting dose was 150–225 IU/d and was adjusted on day 5 of stimulation (T1) depending on the ovarian response, as assessed by E2 levels and ultrasound evaluation, also performed on day 7 (T2) and day 9 (T3) of stimulation.
Ovulation was triggered by hCG (250 μg) (Ovitrelle; Merck-Serono, Rome, Italy) when at least two follicles exceeded 17 mm in diameter. Oocyte recovery was performed by transvaginal ultrasound guidance after hCG administration. A maximum of three embryos was transferred on the second day after oocyte collection. The luteal phase was supported by vaginal micronized P (400 mg/d) (Prometrium; Rottapharm/Italia, Milan, Italy). Serum β-hCG measurement was performed 12 days after ET.
Informed written consent was obtained, and the study was approved by the Institutional Review Board of the Azienda Ospedaliero-Universitaria, Careggi.
Hemorheologic profile was performed by assessing WBV at low and high shear rates (WBV 0.512 s−1 [mPa·s] and WBV 94.5 s−1 [mPa·s]), plasma viscosity, erythrocyte deformability index (DI), and erythrocyte aggregation index (AI) 4, 5.
At T0 all rheologic and hematologic parameters were within the normal range of laboratory values. The WBV 0.512 s−1 and plasma viscosity remained unchanged throughout ovarian stimulation. A significant increase of WBV 94.5 s−1 at T1 and at T2 and a restoration of baseline values at T3 were observed. Erythrocyte deformability index significantly decreased at T1, remaining lower throughout the next days; AI values progressively and significantly decreased at T2, remaining unchanged from T2 to T3 (Table 1).
Table 1. Hemorheologic and hematologic parameters in infertile women according to ovarian stimulation phases (T0–T3).
| Group | Parameter | T0 | T1 | P valuea (T1 vs. T0) | T2 | P valuea (T2 vs. T0) | T3 | P valuea (T3 vs. T0) |
|---|---|---|---|---|---|---|---|---|
| All women (n = 110) | WBV 0.512 s−1 (mPa·s) | 21.41 (20.67–22.15) | 21.37 (20.64–22.10) | .8 | 20.43 (19.62–21.24) | .08 | 21.22 (20.21–22.23) | .7 |
| WBV 94.5 s−1 (mPa·s) | 4.05 (3.69–4.40) | 4.18 (3.83–4.53) | .003 | 4.53 (4.14–4.92) | .02 | 4.04 (3.55–4.52) | .5 | |
| Plasma viscosity (mPa·s) | 1.41 (1.39–1.42) | 1.42 (1.41–1.44) | .09 | 1.41 (1.39–1.43) | .8 | 1.39 (1.37–1.41) | .1 | |
| DI | 9.41 (8.46–10.37) | 7.89 (6.95–8.83) | .01 | 7.56 (6.52–8.61) | .01 | 7.56 (6.26–8.86) | .06 | |
| AI | 2.77 (2.64–2.91) | 2.66 (2.53–2.79) | .09 | 2.54 (2.39–2.69) | .003 | 2.50 (2.32–2.68) | .002 | |
| Hematocrit (%) | 39.4 (38.9–39.9) | 39.8 (39.3–40.2) | .2 | 39.4 (38.9–39.9) | .7 | 38.5 (38.8–39.2) | .001 | |
| White blood cells (×109/L) | 6.2 (5.9–6.5) | 5.6 (5.3–5.9) | <.0001 | 5.9 (5.6–6.2) | .02 | 6.6 (6.3–7.0) | .1 | |
| Platelets (×109/L) | 249 (239–259) | 254 (244–264) | .1 | 254 (243–265) | .7 | 257 (243–270) | .8 | |
| Fibrinogen (mg/dL) | 375 (363–387) | 318 (308–329) | <.0001 | 320 (309–332) | <.0001 | 319 (305–334) | <.0001 | |
| Total cholesterol (mg/dL) | 169 (163–176) | 219 (212–225) | <.0001 | 216 (209–223) | <.0001 | 196 (187–204) | <.0001 | |
| BMI (kg/m2) >25 (n = 18) | WBV 94.5 s−1 (mPa·s) | 4.18 (4.02–4.34)b | 4.29 (4.10–4.49)b | .09 | 4.25 (4.04–4.46)b | .4 | 4.16 (3.93–4.40)b | .9 |
| DI | 8.55 (5.76–11.35)b | 6.42 (4.12–8.72)c | .07 | 7.00 (4.41–9.59)b | .2 | 7.47 (4.25–10.68)b | .4 | |
| BMI (kg/m2) <25 (n = 92) | WBV 94.5 s−1 (mPa·s) | 4.03 (3.95–4.11) | 4.12 (4.02–4.22) | .1 | 4.11 (4.00–4.22) | .06 | 3.98 (3.86–4.10) | .3 |
| DI | 9.45 (8.05–10.86) | 8.70 (7.52–9.89) | .2 | 8.39 (7.07–9.71) | .4 | 7.52 (5.89–9.15) | .09 | |
| Smoking habit (n = 14) | WBV 94.5 s−1 (mPa·s) | 4.17 (3.99–4.35)b | 4.25 (4.02–4.48)b | .4 | 4.47 (4.28–4.66)d | .02 | 4.09 (3.84–4.34)b | .6 |
| DI | 7.60 (4.54–10.66)b | 7.76 (5.13–11.38)b | .9 | 5.89 (3.14–8.63)b | .4 | 6.79 (3.48–10.10)b | .6 | |
| Nonsmoking habit (n = 96) | WBV 94.5 s−1 (mPa·s) | 4.04 (3.94–4.13) | 4.14 (4.02–4.26) | .07 | 4.07 (3.97–4.17) | .4 | 3.93 (3.79–4.07) | .2 |
| DI | 8.96 (7.39–10.54) | 7.96 (6.64–9.28) | .2 | 8.16 (6.71–9.61) | .7 | 7.02 (5.21–8.82) | .1 |
aWilcoxon test; Mann-Whitney test (To vs. To; T1 vs. T1; T2 vs. T2; T3 vs. T3). |
bP>.05. |
cP=.08. |
dP=.001. |
No difference in hemorheologic behavior between primary (n = 84) and secondary (n = 26) infertility was observed throughout the ovarian stimulation cycle.
Alterations of WBV 94.5 s−1 and DI were present in smokers and in women with a body mass index (BMI) >25 kg/m2, in comparison with those observed in nonsmoking and nonoverweight women (Table 1). Nonsignificant differences of WBV 94.5 s−1 and DI values according to age (>35 vs. <35 years) were observed (data not shown).
Fibrinogen values from T1 to T3 were constantly lower than T0 concentrations (Table 1) and correlated with AI (R = 0.26, P<.0001) and plasma viscosity (R = 0.32, P<.0001); cholesterol levels significantly increased throughout the stimulation cycle (Table 1). Hematocrit slightly but significantly decreased at T3. Progesterone and E2 levels did not correlate with any rheologic or hematologic parameters.
In this study we observed a mild increase of WBV and a reduction of DI and AI, possibly related to reduced fibrinogenemia, throughout the stimulation cycle.
Changes of plasma viscosity, which mainly depends on plasma fibrinogen, lipoproteins, and total serum proteins, were not observed; these findings might be related to the opposite behavior of fibrinogen concentrations, which decreased, and cholesterol values, which increased.
When we considered the rheologic profile in relation to BMI, smoking habit, and age, we observed a slight increase of WBV 94.5 s−1 and a decrease of DI in women with BMI >25 kg/m2 and smokers, whereas no influence of age on rheologic parameters was found.
A role of female hormones in regulating the rheologic properties of blood has been previously reported (6); in particular, decreased DI during follicular and ovulatory compared with mid- and late luteal phases has been described (7); indeed, we observed a reduction of DI under estroprogestin stimulation.
To the best of our knowledge, no information concerning the effect of drospirenone and GnRH on blood viscosity is available; nevertheless, our findings of increased WBV and decreased DI at T1 after drospirenone administration and GnRH treatment suggest their role in influencing the rheologic profile. The effect on DI might be related to the role of GnRH in inhibiting the synthesis of nitric oxide (8), which acts as a determinant of erythrocyte mechanical behavior and deformability.
In the present study we have found an unexpected decrease of fibrinogen concentrations during controlled ovarian stimulation. This datum is difficult to explain: we can rule out possible determinants able to influence its concentration, such as lifestyle changes (i.e., smoking cessation), seasonal variations (fibrinogen baseline determination was performed at different times of the enrollment period), and interlaboratory variability. Nevertheless, this decrease might be related to drospirenone, which has been found associated with reduced fibrinogen concentrations (9).
The mild increase of cholesterol concentrations, observed during ovarian stimulation, may be related to the effect of both drospirenone and GnRH treatment on lipid profile 10, 11.
Limitations of this study are the lack of information concerning triglycerides values, which are known to influence plasma viscosity, and serum protein electrophoresis able to identify the presence of monoclonal gammopathies, as well as a lack of adequately matched fertile women as a control group.
In conclusion, this study provides evidence that healthy female smokers and overweight women undergoing controlled ovarian stimulation exhibit alterations of rheologic parameters. This suggests that a rheologic profile, obtained with a clinical algorithm including parameters such as fibrinogen and lipids, may be useful to better frame women with a potential vascular risk related to obesity and smoking habit.
Acknowledgments
The authors thank Brunella Bandinelli and Maria Costanzo for their skillfulness in technical assistance.
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F.C. has nothing to disclose. L.M. has nothing to disclose. E.S. has nothing to disclose. M.N.M. has nothing to disclose. G.C. has nothing to disclose. A.A.L. has nothing to disclose. R.A. has nothing to disclose. I.N. has nothing to disclose.
PII: S0015-0282(10)02204-1
doi:10.1016/j.fertnstert.2010.07.1078
© 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
