Human Reproduction vol.7 no.8 pp.1181-1182. 1992
Letters to the Editor Prophylaxis of ovarian hyperstimulation syndrome Dear Sir, We were extremely interested to read the very important article by Ferraretti et al. (1992). They found the therapeutic administration of low-dosage dopamine to be safe and effective in the management of patients with severe ovarian hyperstimulation syndrome (OHS). Dopamine produces its renal effect by increasing renal blood flow and glomerular filtration. This renovascular effect is more important in therapeutic relation, but dopamine also has endocrine effects. In our preliminary study we found that dopamine stimulated oestradiol secretion by human granulosa cells without influencing their progesterone production (Bodis et al., in preparation). We believe that this endocrine effect also has importance in the regression of symptoms of patients with severe OHS. Although little is known about the pathophysiology of the OHS, recently there are some observations on this topic. Balasch et al. (1991) demonstrated that the pathogenesis of OHS is related to a marked peripheral arteriolar vasodilation leading to underfilling of the arterial vascular compartment, arterial hypotension, compensatory increase in heart rate and cardiac ouput. This results in homeostatic stimulation of the renin—angiotensin and sympathetic nervous systems and antidiuretic hormone. Differentiating the basic pathophysiological process from the secondarily activated compensatory mechanisms is very important in therapeutic relation. From recent knowledge, platelet activating factor (PAF) has an important role in the female genital tract during human reproduction, including ovulation, fertilization, implantation, embryo development and initiation of parturition (Harper, 1989). Murdoch (1986) observed platelet aggregation and adhesion to endothelial cells in the capillaries around periovulatory ovine follicles. Li et al. (1991) reported that platelets are activated by platelet activating factor (PAF) during gonadotrophin-induced ovulation in immature rats. An increased consumption of platelets, resulting in a mild, transient thrombocytopenia, was observed as a first maternal response to pregnancy (O'Neill et al., 1985). Activated platelets can release e.g. histamine, serotonin, platelet derived growth factor, etc., which produce vasodilation and increased capillary permeability. Normally, these pathways do not require systemic compensatory mechanisms because of physiological regulation. The enormously amplified endocrine, metabolic and circulatory changes associated with platelet hyperstimulation, secondarily induce the compensatory mechanisms such as an increase in heart rate and cardiac output, stimulation of the renin—angiotensin and sympathetic nervous systems and antidiuretic hormone, which are responsible for some symptoms of OHS. In conclusion, we suggest that symptoms associated with OHS, at least in part, can be attributed to the platelet overstimulation. Consequently, aspirin application could be an effective © Oxford University Press
prophylaxis for patients susceptible to OHS. Even though further studies are needed to confirm this theory, it might be suggested that dopamine and aspirin be combined as an effective therapy in case of severe OHS. References BalaschJ., Arroyo,V., Carmona,F., LlachJ., Jimenez,W. Pare.J.C. and Vanrell,J.A. (1991) Severe ovarian hyperstimulation syndrome: role of peripheral vasodilation. Fertil. Steril., 56, 1077-1083. Ferraretti,A.P., Gianaroli.L., Diotallevi,L., Festi.C. and Trouson.A. (1992) Dopamine treatment for severe ovarian hyperstimulation syndrome. Hum. Reprod., 7, 180-183. Harper,M.J.K. (1989) Platelet-activating factor: a paracrine factor in preimplantation stages of reproduction. Biol. Reprod., 40, 907—912. Li.X.M., Sagawa,N., Diara.Y., Okagaki,A., Hasegawa,M., Inamori,K., Itoh,H., Mori,T. and Ban,C. (1991) The involvement of platelet activating factor in thrombocytopenia and follicular rupture during gonadotropin-induced superovulation in immature rats. Endocrinology, 129, 3132-3138. Murdoch,W.J. (1986) Accumulation of thromboxane B2 within periovulatory ovine follicles: relationship to adhesion of platelets to endothelium. Prostaglandins, 32, 597—604. O'Neill.C, Gidley-Baird.A.A., PokeJ.L., Porter,R.N., Sinosich,M.J. and Saunders,D.M. (1985) Maternal blood platelet physiology as a means of monitoring pre- and postimplantation embryo viability following in vitro fertilization. J. In Vitro Fertil. Embryo Transfer,
2, 87-93. Jozsef Bodis (Alexander von Humboldt Fellow) Hans-Rudolf Tinneberg Volker Hanf Attila Torok Mathias GroB University Women's Hospital of Tubingen W-7400 Tubingen 1, Schleichstrasse 4, Germany
The suggestion raised in Dr Bodis's Letter to the Editor is very important because, even if dopamine seems to be very effective as a treatment of severe OHS, the main goal in the area still remains the prevention of the syndrome. Up to now the only empiric treatment suggested to prevent the onset of OHS is the administration of indomethacin, but no significant effect has been reported in the literature. For this reason, and according to Dr Bodis's theory, we have recently started a pilot study in which picotamide monohydrate (Plactidil, Samil, Rome) is administered from the day of the embryo transfer to patients with high risk of OHS. The rationale for the use of this drug is its anticlot effect on platelets. This study is under evaluation and only preliminary data are available at the moment.
1181
Letters to the Editor
Regarding the combination of dopamine and aspirin as a treatment for OHS, even if there are no data available at the moment, this treatment should be taken into consideration also because no side-effects are expected. If we consider the syndrome as the most dramatic side-effect of medically assisted conception cycles, we believe that all the trials contributing to improving die prevention or the regression of the syndrome should be strongly considered. A.P.Ferraretti L.Gianaroli L.Diotallevi C.Festi A.Trounson
Dear Sir, The very extensive and comprehensive study of Thonneau et al. (1992) provides very impressive and consistent data obtained with adequate statistical methods. I have criticism concerning the risk factor 'varicocele'. The authors found this factor in only 1% of the control group of the primary infertility and in 3% of the control group of secondary infertility. They calculated from these values a relative risk of ~26. These percentages are extremely low when compared to those found in the normal population, in which the incidence of a varicocele is reported to be between 8 and 23% (Kursh, 1987). Concerning these percentages, the relative risk of being infertile calculated for a man with varicocele would be significantly lower. The authors state themselves that there is a bias due to the way of diagnosing varicocele. It would have been better to exclude these data from the statistics, because they give some confusion to our knowledge on the role of varicocele in male fertility. The very concise study of Baker et al. (1985) has told us that infertile men with correction of varicocele have exactly the same fertility prognosis as those without correction. This indicates that varicocele seems to have no influence at all on male infertility.
References Baker.H.W.G., Burger.H.G., deKretser.D.M., Hudson,B., Remie.G.C. and Straffon,W.G.E. (1985) Testicular vein ligation and fertility in men with varicoceles. Br. Med. J., 291, 1678-1680. Kursh,E.D. (1987) What is the incidence of varicocele in a fertile population? Fend. Steril, 48, 510-511. Thonneau,P., Quesnot,S., Ducot.B., Marchand,S., Fignon,A., Lansac.J. and Spira.A. (1992) Risk factors for female and male infertility: results of a case-control study. Hum. Reprod., 7, 55 — 58.
Professor W. Krause Klinikum der Philipps-Universitat Marburg D-3550 Marburg Germany
1182
Dear Sir, We thank Dr Krause for his careful consideration of the results of our case-control study on the risk factors for infertility, particularly those concerning varicocele. We agree that the measurement of varicocele in a fertile or an infertile population is very subjective, and is essentially dependent on the clinical and paraclinical criteria (Doppler) used by the authors. Indeed in the 'Discussion' section we mentioned that we may have underestimated the prevalence of varicocele in the control group. However an underestimate is not the same as an exclusion, and it is quite rational in statistical terms (R = 28; 4—280) to assume that variococele is a risk factor for primary infertility. Finally, it seems to us misplaced to mention G.Baker's article on the effect on fertility of testicular vein ligation in the context of our research. The identification and measurement of a risk factor for infertility (such as variococele or infection) with appropriate methodology (case-control) has no relation to the degree of effectiveness of surgery which is involved in correcting the variococele. It would be unfortunate to confuse measurement of a risk factor for infertility with evaluation of a surgical technique (in our study, no surgical corrections had been made on the patients). Dr Patrick Thonneau and Dr Beatrice Ducot Hopital de Bicetre France
Letters to the Editor Prophylaxis of ovarian hyperstimulation syndrome Dear Sir, We were extremely interested to read the very important article by Ferraretti et al. (1992). They found the therapeutic administration of low-dosage dopamine to be safe and effective in the management of patients with severe ovarian hyperstimulation syndrome (OHS). Dopamine produces its renal effect by increasing renal blood flow and glomerular filtration. This renovascular effect is more important in therapeutic relation, but dopamine also has endocrine effects. In our preliminary study we found that dopamine stimulated oestradiol secretion by human granulosa cells without influencing their progesterone production (Bodis et al., in preparation). We believe that this endocrine effect also has importance in the regression of symptoms of patients with severe OHS. Although little is known about the pathophysiology of the OHS, recently there are some observations on this topic. Balasch et al. (1991) demonstrated that the pathogenesis of OHS is related to a marked peripheral arteriolar vasodilation leading to underfilling of the arterial vascular compartment, arterial hypotension, compensatory increase in heart rate and cardiac ouput. This results in homeostatic stimulation of the renin—angiotensin and sympathetic nervous systems and antidiuretic hormone. Differentiating the basic pathophysiological process from the secondarily activated compensatory mechanisms is very important in therapeutic relation. From recent knowledge, platelet activating factor (PAF) has an important role in the female genital tract during human reproduction, including ovulation, fertilization, implantation, embryo development and initiation of parturition (Harper, 1989). Murdoch (1986) observed platelet aggregation and adhesion to endothelial cells in the capillaries around periovulatory ovine follicles. Li et al. (1991) reported that platelets are activated by platelet activating factor (PAF) during gonadotrophin-induced ovulation in immature rats. An increased consumption of platelets, resulting in a mild, transient thrombocytopenia, was observed as a first maternal response to pregnancy (O'Neill et al., 1985). Activated platelets can release e.g. histamine, serotonin, platelet derived growth factor, etc., which produce vasodilation and increased capillary permeability. Normally, these pathways do not require systemic compensatory mechanisms because of physiological regulation. The enormously amplified endocrine, metabolic and circulatory changes associated with platelet hyperstimulation, secondarily induce the compensatory mechanisms such as an increase in heart rate and cardiac output, stimulation of the renin—angiotensin and sympathetic nervous systems and antidiuretic hormone, which are responsible for some symptoms of OHS. In conclusion, we suggest that symptoms associated with OHS, at least in part, can be attributed to the platelet overstimulation. Consequently, aspirin application could be an effective © Oxford University Press
prophylaxis for patients susceptible to OHS. Even though further studies are needed to confirm this theory, it might be suggested that dopamine and aspirin be combined as an effective therapy in case of severe OHS. References BalaschJ., Arroyo,V., Carmona,F., LlachJ., Jimenez,W. Pare.J.C. and Vanrell,J.A. (1991) Severe ovarian hyperstimulation syndrome: role of peripheral vasodilation. Fertil. Steril., 56, 1077-1083. Ferraretti,A.P., Gianaroli.L., Diotallevi,L., Festi.C. and Trouson.A. (1992) Dopamine treatment for severe ovarian hyperstimulation syndrome. Hum. Reprod., 7, 180-183. Harper,M.J.K. (1989) Platelet-activating factor: a paracrine factor in preimplantation stages of reproduction. Biol. Reprod., 40, 907—912. Li.X.M., Sagawa,N., Diara.Y., Okagaki,A., Hasegawa,M., Inamori,K., Itoh,H., Mori,T. and Ban,C. (1991) The involvement of platelet activating factor in thrombocytopenia and follicular rupture during gonadotropin-induced superovulation in immature rats. Endocrinology, 129, 3132-3138. Murdoch,W.J. (1986) Accumulation of thromboxane B2 within periovulatory ovine follicles: relationship to adhesion of platelets to endothelium. Prostaglandins, 32, 597—604. O'Neill.C, Gidley-Baird.A.A., PokeJ.L., Porter,R.N., Sinosich,M.J. and Saunders,D.M. (1985) Maternal blood platelet physiology as a means of monitoring pre- and postimplantation embryo viability following in vitro fertilization. J. In Vitro Fertil. Embryo Transfer,
2, 87-93. Jozsef Bodis (Alexander von Humboldt Fellow) Hans-Rudolf Tinneberg Volker Hanf Attila Torok Mathias GroB University Women's Hospital of Tubingen W-7400 Tubingen 1, Schleichstrasse 4, Germany
The suggestion raised in Dr Bodis's Letter to the Editor is very important because, even if dopamine seems to be very effective as a treatment of severe OHS, the main goal in the area still remains the prevention of the syndrome. Up to now the only empiric treatment suggested to prevent the onset of OHS is the administration of indomethacin, but no significant effect has been reported in the literature. For this reason, and according to Dr Bodis's theory, we have recently started a pilot study in which picotamide monohydrate (Plactidil, Samil, Rome) is administered from the day of the embryo transfer to patients with high risk of OHS. The rationale for the use of this drug is its anticlot effect on platelets. This study is under evaluation and only preliminary data are available at the moment.
1181
Letters to the Editor
Regarding the combination of dopamine and aspirin as a treatment for OHS, even if there are no data available at the moment, this treatment should be taken into consideration also because no side-effects are expected. If we consider the syndrome as the most dramatic side-effect of medically assisted conception cycles, we believe that all the trials contributing to improving die prevention or the regression of the syndrome should be strongly considered. A.P.Ferraretti L.Gianaroli L.Diotallevi C.Festi A.Trounson
Dear Sir, The very extensive and comprehensive study of Thonneau et al. (1992) provides very impressive and consistent data obtained with adequate statistical methods. I have criticism concerning the risk factor 'varicocele'. The authors found this factor in only 1% of the control group of the primary infertility and in 3% of the control group of secondary infertility. They calculated from these values a relative risk of ~26. These percentages are extremely low when compared to those found in the normal population, in which the incidence of a varicocele is reported to be between 8 and 23% (Kursh, 1987). Concerning these percentages, the relative risk of being infertile calculated for a man with varicocele would be significantly lower. The authors state themselves that there is a bias due to the way of diagnosing varicocele. It would have been better to exclude these data from the statistics, because they give some confusion to our knowledge on the role of varicocele in male fertility. The very concise study of Baker et al. (1985) has told us that infertile men with correction of varicocele have exactly the same fertility prognosis as those without correction. This indicates that varicocele seems to have no influence at all on male infertility.
References Baker.H.W.G., Burger.H.G., deKretser.D.M., Hudson,B., Remie.G.C. and Straffon,W.G.E. (1985) Testicular vein ligation and fertility in men with varicoceles. Br. Med. J., 291, 1678-1680. Kursh,E.D. (1987) What is the incidence of varicocele in a fertile population? Fend. Steril, 48, 510-511. Thonneau,P., Quesnot,S., Ducot.B., Marchand,S., Fignon,A., Lansac.J. and Spira.A. (1992) Risk factors for female and male infertility: results of a case-control study. Hum. Reprod., 7, 55 — 58.
Professor W. Krause Klinikum der Philipps-Universitat Marburg D-3550 Marburg Germany
1182
Dear Sir, We thank Dr Krause for his careful consideration of the results of our case-control study on the risk factors for infertility, particularly those concerning varicocele. We agree that the measurement of varicocele in a fertile or an infertile population is very subjective, and is essentially dependent on the clinical and paraclinical criteria (Doppler) used by the authors. Indeed in the 'Discussion' section we mentioned that we may have underestimated the prevalence of varicocele in the control group. However an underestimate is not the same as an exclusion, and it is quite rational in statistical terms (R = 28; 4—280) to assume that variococele is a risk factor for primary infertility. Finally, it seems to us misplaced to mention G.Baker's article on the effect on fertility of testicular vein ligation in the context of our research. The identification and measurement of a risk factor for infertility (such as variococele or infection) with appropriate methodology (case-control) has no relation to the degree of effectiveness of surgery which is involved in correcting the variococele. It would be unfortunate to confuse measurement of a risk factor for infertility with evaluation of a surgical technique (in our study, no surgical corrections had been made on the patients). Dr Patrick Thonneau and Dr Beatrice Ducot Hopital de Bicetre France
