- Email: [email protected]
A case of ovarian hyperstimulation syndrome associated with the methylenetetrahydrofolate reductase mutation gene
A case of ovarian hyperstimulation syndrome associated with the methylenetetrahydrofolate reductase mutation gene Filippo Ferrara, M.D.,a Francesco Meli, M.D.,a Corrado Amato, M.D.,a Valentina Cospite, M.D.,b Francesco Raimondi, M.D.,a and Salvatore Novo, M.D.b a
Division of Angiology and b Division of Cardiology, University Medical Hospital, Palermo, Italy
Objective: To report a case of ovarian hyperstimulation syndrome with methylenetetrahydrofolate reductase (MTHFR) gene 677T homozygosis mutation and A1298C gene heterozygosis mutation. Design: Case report. Setting: A pregnant woman in an academic hospital. Patient(s): A woman with ovarian hyperstimulation syndrome. Intervention(s): Nadroparin was administered for 2 weeks at a dosage of 200 IU/kg twice per day and then once per day; also administered once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. Main Outcome Measure(s): Clinical follow-up. Result(s): Delivery was regular within the set time limits, and the fetus was born alive and in good health. Conclusion(s): We believe that MTHFR mutation research could be executed in women before ovarian stimulation treatment, but other observations are necessary to support this recommendation. (Fertil Steril威 2005;84: 217.e17– 8. ©2005 by American Society for Reproductive Medicine.) Key Words: Ovarian hyperstimulation syndrome, methylenetetrahydrofolate reductase gene 677T homozygosis mutation, methylenetetrahydrofolate reductase gene A1298C heterozygosis mutation
Ovarian hyperstimulation syndrome (OHSS) is a potential complication of treatment aimed at bringing on pregnancy. Vein thrombosis reports have recently become more frequent, even as an isolated complication of OHSS (1, 2), and they have mostly concerned patients who are carriers of coagulation genetic mutation. Few reports (3) have considered a possible relation between phlebothrombosis and homocystinemia. Although OHSS is well known to obstetricians, it often is undervalued by other specialists. For this reason and for other characteristics that will be discussed later in this article, we report here a case we have recently observed. CASE REPORT A 34-year-old pregnant woman in her 2nd week of gestation, after ovarian stimulation treatment, came to our hospital with a suspected pulmonary embolism. Remote pathologic anamnesis indicated left ovariectomy (polycystic ovary). The objective examination showed the following: respiratory rate, 24 breaths/min; pulse rate, 120 beats/ min; blood pressure, 120/70 mm Hg; no tactile vocal fremitus in the medium-base of right hemithorax; hypophonesis; vesicular sounds absent; and pain on left side of neck.
Received September 3, 2004; revised and accepted January 13, 2005. Reprint requests: Filippo Ferrara, M.D., Via Autonomia Siciliana, no. 94, 90143 Palermo, Italy (FAX: 39-091-655-45-46; E-mail: f_ferrara@ virgilio.it).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.01.108
After hospitalization, the following tests were performed: echocolordoppler on neck veins and arteries, as well as hematochemical tests. Vein echocolordoppler test showed a hypoechogenic thrombus occluding the internal left jugular and homolateral subclavian veins (Fig. 1). Abdomen echography showed presence of pleural right effusion and ascites. The hematochemical data were as follows: leukocyte growth (12,600 per mm3) and erythrocyte reduction, for a hematocrit value of 35%. Homocysteine dosage was 28 mmol/L. A genetic study showed the following: V Leiden factor mutation research was negative; prothrombin G20210A mutation research was negative; methylenetetrahydrofolate reductase (MTHFR) 677T mutation gene was homozygosis positive; and methylenetetrahydrofolate reductase A1298C gene was heterozygote positive. The diagnosis was OHSS with left internal jugular and subclavian vein thrombosis, right pleural effusion, and ascites formation in a pregnant woman in her 2nd week of gestation with homozygosis of the 677T and heterozygosis of the A1298C mutation of the MTHFR gene. Nadroparin was administered for 2 weeks at a dose of 200 IU/kg twice per day and then once per day; also given once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. On day 6 after admission to hospital, a thoracentesis was made, and 1,500 cm3 of transudate was aspirated. From day 7,
Fertility and Sterility姞 Vol. 84, No. 1, July 2005 218.e17 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
FIGURE 1 Hypoechogenic thrombus occluding the left internal jugular vein.
Our case deserves attention because it is an unusual example of OHSS because of the association of pleural and ascitian effusion, jugular vein thrombosis, 677T homozygosis, and A1298C heterozygosis with hyperhomocystinemia. This hyperhomocystinemia produced a vascular endothelium damage that was certainly responsible for the jugular and subclavian vein thrombosis and probably responsible for the pleural and ascitian effusion increase. Isolated phlebothrombosis with a prevailing jugular location has been recorded in patients with previous ovarian stimulation treatment who are carriers of anticoagulant C protein deficiency, Leiden V factor, or prothrombin G20210A gene (8, 9), whereas in the medical literature there are no records of OHS with deep vein thrombosis in patients with different genetic mutations.
Ferrara. MTHFR mutation gene in a woman with OHSS. Fertil Steril 2005.
there was rapid progress in the patient’s general condition, and she was dismissed on day 10. Delivery was regular within the set time limits, and the fetus was born alive and in good health. DISCUSSION Methylenetetrahydrofolate reductase polymorphism induces vascular endothelium alterations (4) because it produces an enzyme that is characterized by reduced activity and increased thermolability (5). A consequence of this polymorphism is a mild or a high hyperhomocystinemia; its effects of hyperhomocystinemia have been studied in mice with a knockout of MTHFR. Plasma homocysteine levels were 1.6- and 10-fold higher (respectively, in MTHFR⫹/⫺ and MTHFR⫺/⫺) than those in wild-type littermates. The MTHFR knockout mice showed earlier pathologic changes in their large vessel wall (6). Homocysteine is detoxified in two ways: a transsulfuration pathway (absent in the human cardiovascular system) and a remethylation pathway, which is catalyzed by methioninesynthetase. In this reaction, 5-methyltetrahydrofolate, produced in the reaction catalyzed by MTHFR, is a methyl donor. Genetic deficiency of MTHFR induces homocysteine increase, with negative effects determined by homocysteine thiolactone formation and by oxygen radical production (7). This homocysteine thiolactone can react with side-chain amino groups of lysine residues in proteins, producing their homocysteinylation. Homocysteine thiolactone production can be prevented by the S-nitrosylation reaction, which required nitric oxide and produces S-nitroso-homocysteine that can be incorporated into proteins. However, this reaction is limited by hyperhomocysteinemia, because this condition induces endothelial cell alteration and reduces nitric oxide production.
218.e18 Ferrara et al.
Our case is also singular because despite 677T homozygosis and A1298C heterozygosis with hyperhomocystinemia, both the mother and fetus had a favorable course after being treated with folate, vitamins (the only drugs capable of normalizing homocysteine), and nadroparin. We believe that mutation screening should be performed in women before starting ovarian hyperstimulation, but other observations are necessary to support this recommendation. REFERENCES 1. Lioret de Mola JR, Kiwi R, Austin C, Goldfarb JM. Subclavian deep vein thrombosis associated with the use of recombinant folliclestimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome. Fertil Stertil 2000;73:1253– 6. 2. Tacvmergen E, Ozcakir HT, Levi R, Adakan F, Ulukus M, Terek MC. Bilateral jugular vein thromboembolism and pulmonary emboli in a patient with severe ovarian hyperstimulation syndrome. J Obstet Gynaecol Res 2001;27:217–20. 3. Dulitzky M, Cohen SB, Inbal A, Seidman DS, Soriano D, Lidor A, et al. Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome. Fertil Steril 2002;77:463–7. 4. Szeklik A, Sanak M, Jankowski M, Dropoinski J, Czachor R, Musial J, et al. Mutation A1298C of methylentetraidrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Genet 2001;101:36 –9. 5. Castro R, Rivera I, Ravasco P, Jakobs C, Blom HJ, Camilo ME, et al. 5,10 –Methylentetrahydrofolate reductase 677¡T and 1298¡C mutation are genetic determinants of elevated homocysteine. Q J Med 2003; 95:1517–32. 6. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, LussierCacan S, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001;10: 433– 43. 7. Mercie P, Garnier O, Lascoste L, Renard M, Closse C, Durrieu F, et al. Homocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic feature. Apoptosis 2000;5:403–11. 8. Horstlkamp B, Lubke M, Kentenich H, Buscher U, Licthnegger W. Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in-vitro fertilization. Hum Reprod 1996;11:280 –2. 9. Curvers J, Nienhuis SJ, Nap AW, Hamulyak K, Evers JL, Rosing J. Activated protein C resistance during in vitro fertilization treatment. Eur J Obstet Reprod Biol 2001;95:222– 4.
MTHFR mutation gene in a woman with OHSS
Vol. 84, No. 1, July 2005
Division of Angiology and b Division of Cardiology, University Medical Hospital, Palermo, Italy
Objective: To report a case of ovarian hyperstimulation syndrome with methylenetetrahydrofolate reductase (MTHFR) gene 677T homozygosis mutation and A1298C gene heterozygosis mutation. Design: Case report. Setting: A pregnant woman in an academic hospital. Patient(s): A woman with ovarian hyperstimulation syndrome. Intervention(s): Nadroparin was administered for 2 weeks at a dosage of 200 IU/kg twice per day and then once per day; also administered once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. Main Outcome Measure(s): Clinical follow-up. Result(s): Delivery was regular within the set time limits, and the fetus was born alive and in good health. Conclusion(s): We believe that MTHFR mutation research could be executed in women before ovarian stimulation treatment, but other observations are necessary to support this recommendation. (Fertil Steril威 2005;84: 217.e17– 8. ©2005 by American Society for Reproductive Medicine.) Key Words: Ovarian hyperstimulation syndrome, methylenetetrahydrofolate reductase gene 677T homozygosis mutation, methylenetetrahydrofolate reductase gene A1298C heterozygosis mutation
Ovarian hyperstimulation syndrome (OHSS) is a potential complication of treatment aimed at bringing on pregnancy. Vein thrombosis reports have recently become more frequent, even as an isolated complication of OHSS (1, 2), and they have mostly concerned patients who are carriers of coagulation genetic mutation. Few reports (3) have considered a possible relation between phlebothrombosis and homocystinemia. Although OHSS is well known to obstetricians, it often is undervalued by other specialists. For this reason and for other characteristics that will be discussed later in this article, we report here a case we have recently observed. CASE REPORT A 34-year-old pregnant woman in her 2nd week of gestation, after ovarian stimulation treatment, came to our hospital with a suspected pulmonary embolism. Remote pathologic anamnesis indicated left ovariectomy (polycystic ovary). The objective examination showed the following: respiratory rate, 24 breaths/min; pulse rate, 120 beats/ min; blood pressure, 120/70 mm Hg; no tactile vocal fremitus in the medium-base of right hemithorax; hypophonesis; vesicular sounds absent; and pain on left side of neck.
Received September 3, 2004; revised and accepted January 13, 2005. Reprint requests: Filippo Ferrara, M.D., Via Autonomia Siciliana, no. 94, 90143 Palermo, Italy (FAX: 39-091-655-45-46; E-mail: f_ferrara@ virgilio.it).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.01.108
After hospitalization, the following tests were performed: echocolordoppler on neck veins and arteries, as well as hematochemical tests. Vein echocolordoppler test showed a hypoechogenic thrombus occluding the internal left jugular and homolateral subclavian veins (Fig. 1). Abdomen echography showed presence of pleural right effusion and ascites. The hematochemical data were as follows: leukocyte growth (12,600 per mm3) and erythrocyte reduction, for a hematocrit value of 35%. Homocysteine dosage was 28 mmol/L. A genetic study showed the following: V Leiden factor mutation research was negative; prothrombin G20210A mutation research was negative; methylenetetrahydrofolate reductase (MTHFR) 677T mutation gene was homozygosis positive; and methylenetetrahydrofolate reductase A1298C gene was heterozygote positive. The diagnosis was OHSS with left internal jugular and subclavian vein thrombosis, right pleural effusion, and ascites formation in a pregnant woman in her 2nd week of gestation with homozygosis of the 677T and heterozygosis of the A1298C mutation of the MTHFR gene. Nadroparin was administered for 2 weeks at a dose of 200 IU/kg twice per day and then once per day; also given once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. On day 6 after admission to hospital, a thoracentesis was made, and 1,500 cm3 of transudate was aspirated. From day 7,
Fertility and Sterility姞 Vol. 84, No. 1, July 2005 218.e17 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
FIGURE 1 Hypoechogenic thrombus occluding the left internal jugular vein.
Our case deserves attention because it is an unusual example of OHSS because of the association of pleural and ascitian effusion, jugular vein thrombosis, 677T homozygosis, and A1298C heterozygosis with hyperhomocystinemia. This hyperhomocystinemia produced a vascular endothelium damage that was certainly responsible for the jugular and subclavian vein thrombosis and probably responsible for the pleural and ascitian effusion increase. Isolated phlebothrombosis with a prevailing jugular location has been recorded in patients with previous ovarian stimulation treatment who are carriers of anticoagulant C protein deficiency, Leiden V factor, or prothrombin G20210A gene (8, 9), whereas in the medical literature there are no records of OHS with deep vein thrombosis in patients with different genetic mutations.
Ferrara. MTHFR mutation gene in a woman with OHSS. Fertil Steril 2005.
there was rapid progress in the patient’s general condition, and she was dismissed on day 10. Delivery was regular within the set time limits, and the fetus was born alive and in good health. DISCUSSION Methylenetetrahydrofolate reductase polymorphism induces vascular endothelium alterations (4) because it produces an enzyme that is characterized by reduced activity and increased thermolability (5). A consequence of this polymorphism is a mild or a high hyperhomocystinemia; its effects of hyperhomocystinemia have been studied in mice with a knockout of MTHFR. Plasma homocysteine levels were 1.6- and 10-fold higher (respectively, in MTHFR⫹/⫺ and MTHFR⫺/⫺) than those in wild-type littermates. The MTHFR knockout mice showed earlier pathologic changes in their large vessel wall (6). Homocysteine is detoxified in two ways: a transsulfuration pathway (absent in the human cardiovascular system) and a remethylation pathway, which is catalyzed by methioninesynthetase. In this reaction, 5-methyltetrahydrofolate, produced in the reaction catalyzed by MTHFR, is a methyl donor. Genetic deficiency of MTHFR induces homocysteine increase, with negative effects determined by homocysteine thiolactone formation and by oxygen radical production (7). This homocysteine thiolactone can react with side-chain amino groups of lysine residues in proteins, producing their homocysteinylation. Homocysteine thiolactone production can be prevented by the S-nitrosylation reaction, which required nitric oxide and produces S-nitroso-homocysteine that can be incorporated into proteins. However, this reaction is limited by hyperhomocysteinemia, because this condition induces endothelial cell alteration and reduces nitric oxide production.
218.e18 Ferrara et al.
Our case is also singular because despite 677T homozygosis and A1298C heterozygosis with hyperhomocystinemia, both the mother and fetus had a favorable course after being treated with folate, vitamins (the only drugs capable of normalizing homocysteine), and nadroparin. We believe that mutation screening should be performed in women before starting ovarian hyperstimulation, but other observations are necessary to support this recommendation. REFERENCES 1. Lioret de Mola JR, Kiwi R, Austin C, Goldfarb JM. Subclavian deep vein thrombosis associated with the use of recombinant folliclestimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome. Fertil Stertil 2000;73:1253– 6. 2. Tacvmergen E, Ozcakir HT, Levi R, Adakan F, Ulukus M, Terek MC. Bilateral jugular vein thromboembolism and pulmonary emboli in a patient with severe ovarian hyperstimulation syndrome. J Obstet Gynaecol Res 2001;27:217–20. 3. Dulitzky M, Cohen SB, Inbal A, Seidman DS, Soriano D, Lidor A, et al. Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome. Fertil Steril 2002;77:463–7. 4. Szeklik A, Sanak M, Jankowski M, Dropoinski J, Czachor R, Musial J, et al. Mutation A1298C of methylentetraidrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Genet 2001;101:36 –9. 5. Castro R, Rivera I, Ravasco P, Jakobs C, Blom HJ, Camilo ME, et al. 5,10 –Methylentetrahydrofolate reductase 677¡T and 1298¡C mutation are genetic determinants of elevated homocysteine. Q J Med 2003; 95:1517–32. 6. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, LussierCacan S, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001;10: 433– 43. 7. Mercie P, Garnier O, Lascoste L, Renard M, Closse C, Durrieu F, et al. Homocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic feature. Apoptosis 2000;5:403–11. 8. Horstlkamp B, Lubke M, Kentenich H, Buscher U, Licthnegger W. Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in-vitro fertilization. Hum Reprod 1996;11:280 –2. 9. Curvers J, Nienhuis SJ, Nap AW, Hamulyak K, Evers JL, Rosing J. Activated protein C resistance during in vitro fertilization treatment. Eur J Obstet Reprod Biol 2001;95:222– 4.
MTHFR mutation gene in a woman with OHSS
Vol. 84, No. 1, July 2005