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Original Studies |
Department of Obstetrics and Gynecology (D.M., J.B., F.F., M.C., J.A.V.) Liver Unit, Institut Clínic of Digestive Diseases, Department of Medicine (V.A.) and Hormonal Laboratory (W.J., R.C.), Hospital Clínic i Provincial, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Address all correspondence and requests for reprints to: Juan Balasch, Department of Obstetrics and Gynecology, Hospital Clínic i Provincial, C/Casanova 143, 08036-Barcelona, Spain.
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Abstract |
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All patients developed a significant increase in cardiac output and decrease in arterial pressure and peripheral vascular resistance, and a marked elevation in PRA and aldosterone, all indicating the development of arteriolar vasodilation. Changes in circulatory measurements were temporarily related with the increase in E2 both being detected at study points 3–5. In contrast, there was a clear chronological dissociation between the increase in plasma E2 concentration and the stimulation of the renin-aldosterone system. PRA and aldosterone only reached abnormal levels at study point 5 in association with a significant increase in plasma norepinephrine concentration. Serum levels of nitrite/nitrate and plasma concentrations of atrial natriuretic peptide, adrenomedullin, and cyclic GMP were similar at study points 1 and 5.
It is concluded that the circulatory dysfunction that characterizes severe OHSS is a universal event in patients undergoing controlled ovarian hyperstimulation for IVF. Although the increase in E2 levels during IVF cycles is associated with significant circulatory changes, the circulatory dysfunction that characterizes severe OHSS is clearly unrelated to the onset of hyperestrogenemia. Arteriolar vasodilation during IVF cycles was not associated with an increased activity of the vasodilator substances atrial natriuretic peptide, adrenomedullin, and nitric oxide.
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Introduction |
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So far, circulatory function during IVF cycles has only been assessed in patients with severe OHSS. Therefore, it is not known whether circulatory dysfunction occurs only in the small group of patients developing severe OHSS, or whether it is a more common event among women undergoing IVF. Also, the pathogenesis of circulatory dysfunction during OHSS is unknown. Because severe OHSS is associated with dramatically increased circulating plasma estradiol (E2) concentrations, and accumulating clinical and experimental evidence exists indicating that E2 has marked systemic vasodilator effects both in pregnant and nonpregnant states that may be mediated by endothelial vasodilators (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18), it has been proposed that circulatory dysfunction is related to hyperestrogenemia (3, 4, 9, 19, 20).
In the current study, circulatory function was sequentially assessed throughout the IVF cycle in women without clinical manifestations of OHSS. The aim of the study was to investigate whether circulatory dysfunction is a general event in patients undergoing controlled ovarian hyperstimulation and is chronologically related to plasma E2 concentration, which increases in these women by more than 5- to 10-fold over values observed in spontaneous normal ovarian cycle (21). The potential role of the endogenous vasodilators atrial natriuretic peptide, adrenomedullin, and nitric oxide, was also evaluated.
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Material and Methods |
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We included 12 IVF patients aged 29–37 yr having both ovaries and regular ovulatory cycles. No patient had ovary polycystic disease. Each patient gave informed consent to be included in the study, which was approved by the Investigation and Ethics Committee of our institution. Because a woman undergoing an IVF cycle may be pregnant, no invasive procedures or tests requiring the administration of exogenous substances were performed.
Controlled ovarian hyperstimulation treatment
Multiple follicular growth for IVF was induced according to a protocol reported in detail elsewhere (22). Gonadotropin therapy (FSH and human menopausal gonadotropin) is used under pituitary suppression with a GnRH analog (leuprolide acetate started in the mid-luteal phase of previous cycle and continued until the administration of hCG). Gonadotropin stimulation of the ovaries was started 13–15 days later when serum E2 concentrations declined to <50 pg/mL, and a vaginal ultrasonographic scan showed an absence of follicles >10 mm diameter. Follicular aspiration was performed by vaginal ultrasonography 35–36 h after an hCG injection (5000 IU) under local anesthesia. Forty-eight hours later, up to four embryos were transferred into the uterus. We gave additional doses of 5000, 2500, and 2500 IU of hCG on the days of follicular aspiration and 2 and 5 later, respectively, to supplement the luteal phase in all patients.
Study design
Patients underwent blood, urine, arterial pressure, and cardiac
output measurements at five sequential study points (Fig. 1
): the midfollicular phase (cycle day 8)
of the spontaneous menstrual cycle preceding IVF (study point 1); the
day when pituitary-ovarian suppression was shown (study point 2); the
day when the hCG ovulatory injection was administered after appropriate
ovarian follicular stimulation with human menopausal gonadotropin was
accomplished (study point 3); the day after the hCG ovulatory dose was
given (study point 4); and 7 days after the administration of the
ovulatory dose of hCG (study point 5). Study point 1 was considered as
the baseline.
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Laboratory methods and hemodynamic measurements
Blood samples were collected between 0800–0930 h after overnight fasting from food and after 1 h of bedrest. PRA and plasma concentrations of aldosterone, atrial natriuretic peptide, adrenomedullin, norepinephrine, E2, and cGMP were measured following methods previously described (22, 23, 24). Serum concentration of nitrite/nitrate was determined by the fluorometric method of Misko et al. (25). Arterial pressure and cardiac output were measured by sphygmomanometry and Doppler echocardiography, respectively, according to methods previously reported (22). Mean arterial pressure was calculated as diastolic blood pressure plus one third of the difference between the systolic and diastolic blood pressures. We used the following formula to estimate peripheral vascular resistance: mean arterial pressure - right atrial pressure ÷ cardiac output x 80. Because we did not measure right atrial pressure, we considered it to be zero in this calculation.
For this study, normal values for PRA, and plasma concentrations of aldosterone and norepinephrine were obtained from 10 normally ovulating women (mean age 32 yr, range 27–35) who underwent blood sampling on the 7th postovulatory day according to ultrasonographic detection of ovulation. Values for these measurements in these control women were: PRA, 0.57 ± 0.21 ng/mL•h (range 0.1–1.6); plasma aldosterone, 21.9 ± 4 ng/dL (range 9.6–35); and plasma norepinephrine, 182 ± 17.9 pg/mL (range 114–246). Mean midluteal plasma progesterone level in these women was 13.1 ng/mL (range 8.9–17.1).
Statistical analysis
The paired and unpaired Student’s t test, two-variable regression analysis, ANOVA, Kruskal-Wallis test, and Bonferroni tests were used for the analysis of the results. Data are presented as mean ± SEM.
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Results |
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All patients had multiple follicular development and successful oocyte retrieval. The mean peak plasma E2 level during ovarian stimulation (study point 3, day of hCG injection) was 2430 ± 428 pg/mL (range 1630–3840 pg/mL). The mean number of follicles observed by transvaginal ultrasonography on the day of hCG administration was 17 (range 8–24); the mean number of oocytes obtained was 10 (range 4–19). By definition, all patients remained asymptomatic throughout the study. The absence of ascites was confirmed by ecography. Three patients became pregnant and carried successfully to term.
Changes in systemic hemodynamics and renin-aldosterone system. Relationship with plasma E2 levels
Figure 2 shows sequential changes of
hemodynamic and neurohormonal parameters. Mean plasma E2
levels throughout the study reproduced the expected standard pattern in
IVF cycles. After GnRH-agonist administration, there was a significant
fall of plasma E2 to levels equivalent to those observed in
the postmenopause (study point 2). Gonadotropin ovarian stimulation was
associated with a dramatic increase in plasma E2
concentration (study point 3), which persisted during the luteal phase
after hCG administration (study points 4 and 5).
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). Cardiac output measurement showed similar values at points 1 and 2
but it was increased at points 3, 4 and 5.
The most remarkable change in the activity of the renin angiotensin
system was observed at study point 5. At this time of the IVF cycle
there was a marked increase in PRA, reaching mean values 18.4 times
higher than baseline levels (study point 1) (Fig. 2) and 8.1 times
higher than midluteal values in normal controls (P <
0.005). Figure 3 shows the individual
values of PRA and norepinephrine concentration at baseline and study
point 5. PRA increased in all patients and occurred in association with
an activation of the sympathetic nervous system. Plasma norepinephrine
concentration at study point 5 (307 ± 23 pg/mL) was significantly
increased with respect to baseline (228 ± 32 pg/mL) and values
observed in controls (P < 0.005 for both
comparisons).
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). Changes in vasorelaxant factors
Table 1 shows serum nitrite/nitrate
levels and plasma concentration of atrial natriuretic peptide, cGMP,
and adrenomedullin at study points 1 and 5 in the 12 patients. There
was no significant change in any of these parameters.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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Recent studies from our group have shown that the pathogenesis of severe OHSS is more complex, and that marked peripheral arteriolar vasodilation is a major event in the development of the syndrome (22, 26, 27). These patients present a hyperdynamic circulation characterized by arterial hypotension, high cardiac output, and low peripheral vascular resistance, indicating the existence of peripheral arteriolar vasodilation. In addition, the increased activity of the renin-angiotensin-aldosterone system in this condition is associated with a marked stimulation of other endogenous vasoconstrictor mechanisms, such as the sympathetic nervous system, antidiuretic hormone, and endothelin, indicating that renin-angiotensin system hyperactivity is a component of a generalized homeostatic response to maintain circulatory function. The increased activity of the renin-angiotensin and sympathetic nervous systems and the high plasma levels of antidiuretic hormone and endothelin would counteract an unknown vasodilator mechanism, thus maintaining arterial pressure within normal or near normal limits. However, renal sympathetic overactivity and increased antidiuretic hormone and aldosterone would promote sodium and water retention, which contribute to ascites and edema formation. Arteriolar vasodilation, by altering microvascular hemodynamics and permeability, could also contribute to the escape of fluid from the intravascular to the extravascular compartment (28). The observation that patients developing hemoconcentration were those with more intense peripheral arteriolar vasodilation (22) supports this contention.
Factors predisposing to the development of the circulatory dysfunction associated with severe OHSS (only 2% of women undergoing gonadotropin ovarian stimulation for IVF develop the syndrome) are unknown. Two possible explanations may be raised. Because severe OHSS is usually associated to enlarged multifollicular ovaries and very high plasma levels of E2, it has been proposed that it develops in those patients having a more intense ovarian response to gonadotropin treatment. According to this concept, in the remaining cases, the ovarian response would be insufficient to alter circulatory function. However, a second possibility exists, which is that circulatory dysfunction would be a universal event during IVF cycles, with symptoms developing only in those very few patients with a profound impairment in circulatory function.
Several findings in the present study are in keeping with the latter hypothesis: 1) all our patients, which were asymptomatic throughout the IVF, developed the circulatory dysfunction that characterizes the OHSS, namely decreased mean arterial pressure and peripheral vascular resistance, increased cardiac output, and a marked increase in PRA and plasma norepinephrine concentrations (22, 26), 7 days after the administration of hCG; 2) the degree of activation of the renin-aldosterone and sympathetic nervous system observed in the cases included in the current study, although intense, was much lower than that observed in patients with severe OHSS studied by our group using identical laboratory techniques (22, 26); and 3) circulatory dysfunction after hCG injection in patients included in the present study occurred at the time when clinical manifestations of severe OHSS usually develop (3, 5, 6).
Even further, it could be postulated that the circulatory and neurohormonal events occurring during IVF cycles, represent an exaggeration of the normal process of follicular development and ovulation. In fact, variations in ovarian size, changes in peritoneal fluid volume, ovarian neovascularization, amplification of steroidogenesis, and modest increase in PRA and aldosterone with corpus luteum rescue by endogenous hCG are normal physiological processes that may be magnified by induction of ovulation and present as the hallmark features of OHSS in extreme cases (19, 29). Also, changes in cardiovascular parameters seen in very early pregnancy in spontaneous cycles result in the stimulation of the renin-angiotensin system to maintain blood pressure (8, 30).
The low prevalence of severe OHSS is a major limiting factor for investigating the syndrome. The demonstration in our study that circulatory dysfunction, as manifested by the development of hyperdynamic circulation and marked increase in PRA and norepinephrine concentration, consistently develops in asymptomatic patients undergoing gonad-otropin therapy for IVF, is important in this respect. Investigations in these patients may throw light on the pathogenesis of severe OHSS, which would represent the extreme expression of the circulatory dysfunction associated with ovarian hyperstimulation treatment.
Hyperestrogenemia was chronologically related with changes in circulatory function as indicated by a significant decrease in mean arterial pressure and peripheral vascular resistance and increase in cardiac output at study point 3, in coincidence with a marked increase in plasma E2 levels. However, this circulatory response was not intense enough to stimulate the renin-angiotensin-aldosterone system above normal levels. In fact, PRA and plasma aldosterone concentration were within the normal range at study points 3 and 4 in all patients despite very high plasma levels of E2. The circulatory dysfunction that characterizes severe OHSS, namely an arteriolar vasodilation with a more severe impairment of circulatory function leading to a compensatory hyperactivation of endogenous vasoconstrictor systems, was not detected until the study point 5, 7 days after the administration of hCG and peak plasma E2 level. These findings suggest that, although hyperestrogenemia during IVF cycles induces circulatory changes, it cannot fully explain the circulatory dysfunction associated with OHSS. Isolated reported cases of OHSS in the setting of very low plasma E2 concentration in patients with congenital enzymatic deficiencies for ovarian steroidogenesis (31, 32) are in agreement with this contention. An alternative explanation, as proposed by Sealey et al. (19), for the activation of the renin-aldosterone system could be the marked elevation of luteal progesterone associated with IVF cycles.
Circulatory dysfunction in IVF cycles was associated neither with significant changes in plasma concentrations of nitrite/nitrate and atrial natriuretic peptide nor in plasma concentration of cGMP, the second messenger of both nitric oxide and atrial natriuretic peptide. Taken together, these data suggest that arteriolar vasodilation during IVF cycles is not mediated by these endogenous vasodilators. Similarly, adrenomedullin, a recently described vasodilator peptide synthesized by the endothelial and vascular smooth muscle cells and whose vasodilator effect is mediated in part by nitric oxide (33, 34, 35, 36), showed no significant changes.
In summary, our results indicate that circulatory dysfunction is a universal event in patients undergoing IVF, and suggest that severe OHSS is the extreme expression of this abnormality. Neither hyperestrogenemia nor the endogenous vasodilators nitric oxide, atrial natriuretic peptide, and adrenomedullin, seem to play a major role in the pathogenesis of this problem.
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Footnotes |
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2 Recipient of a grant (01/1996) from the Hospital Clinic i
Provincial of Barcelona.
Received October 15, 1997.
Revised December 31, 1997.
Accepted January 26, 1998.
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References |
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