- Email: [email protected]
Prevention and treatment of pregnancy-induced hypertension (preeclampsia) with progestogens
Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 439–440
Prevention and treatment of pregnancy-induced hypertension (preeclampsia) with progestogens M.B. Sammour a , H. El-Kabarity a , M.M. Fawzy a , A.E. Schindler b,∗ b
a Department Obstretrics and Gynecology, Ain Shams University, Cairo, Egypt Institute of Medical Research and Education, Hufelandstrasse 55, D-45147 Essen, Germany
Abstract Available data indicate that progesterone is able to treat pregnancy-induced hypertension (preeclampsia). Dydrogesterone and 17␣hydroxyprogesterone caproate might also be used for this purpose. Prevention of hypertensive disorders in preeclampsia also seems possible, but studies are needed to confirm this. © 2005 Elsevier Ltd. All rights reserved. Keywords: Progesterone; 17␣-Hydroxyprogesterone caproate; Dydrogesterone; Hypertension in pregnancy; Preeclampsia; HELLP-syndrome
1. Introduction Pregnancy-induced hypertension (preeclampsia) remains a relevant complication in pregnancy, not only endangering the pregnant women but also the fetus. Two distinct clinical entities have to be differentiated. In the first group of pregnant women, hypertension in pregnancy (preeclampsia) is initiated and maintained during pregnancy, is manifested by hypertension, oedema and proteinuria, and finally can lead to convulsions and coma [1]. Among this group of pregnant women, there is a subgroup that develops a symptom complex and specific laboratory changes during pregnancy; this is termed the Hemolysis, Elevated Liver, Low Platelet (HELLP) syndrome and was first described in 1982 by Weinstein [2]. The second group comprises women suffering from essential hypertension or specific renal disease who also became pregnant [1]. In this group, the pathological effects are always evident before the 24th week of gestation and are not relieved after parturition. Blood pressure associated with renal hypertension improves during pregnancy. Studies in animals showed that there was a tendency for blood pressure to decline during pregnancy in renal hypertensive dogs, rabbits and rats [3–5]. Such a decline in blood pressure was also seen in pregnant ∗
Corresponding author. Tel.: +49 21 7991833; fax: +49 21 7499533. E-mail address: [email protected] (A.E. Schindler).
0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.08.014
women with renal hypertension [1]. Higher concentrations of progesterone in early pregnancy were related to lower systolic blood pressure [6] and the blood pressure reducing effect of progesterone in humans with hypertension has been demonstrated [7]. In a placebo-controlled, double-blind, crossover study in which oral progesterone was given to men and postmenopausal women with mild to moderate hypertension, there was a significant reduction in blood pressure in both the men and the women [8]. It is therefore possible that treatment, or even prevention, of hypertensive disorders in pregnancy might be achieved with progesterone or progestins, such as 17␣-hydroxyprogesterone caproate and dydrogesterone.
2. Treatment of pregnancy-induced hypertension (preeclampsia) 2.1. Progesterone A group of 40 pregnant women, between the 34th and 40th week of gestation, with preeclampsia were treated with 200 mg/day progesterone given intramuscularly in four doses of 50 mg. There were 19 cases of mild preeclampsia, 16 of severe preeclampsia and five of fulminating preeclampsia with a short duration of symptoms and blood pressure over
440
M.B. Sammour et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 439–440
180 mmHg systolic and 110 mmHg diastolic; three women had essential hypertension before pregnancy. A group of 10 normal pregnant women between the 34th and 38th week of gestation were treated as controls [1]. Overall, 32 of 36 evaluable pregnant women with preeclampsia showed a clinical response to progesterone. The three cases with essential hypertension failed to show any relevant response [1]. A full effect on both systolic and diastolic blood pressure was obtained in 80% of preeclamptic women. All cases showed a mild increase in urinary output, a fall in uric acid and improvement in urea clearance [1]. Treatment did not affect blood pressure in the normal pregnant women, although diuresis was increased and this was accompanied by less weight gain [1]. In a further study, treatment with 50 mg progesterone in oil four times daily intramuscularly for 1–6 weeks induced a significant decrease of both systolic and diastolic blood pressure, associated with a marked increase in urinary output, a decrease in oedema and some body weight reduction in patients with severe pregnancy-induced hypertension [9]. 2.2. 16α-,17α-Dihydroxyprogesterone acetophenide Synthetic 16␣-,17␣-dihydroxyprogesterone acetophenide was used in 10 preeclamptic women and five normal pregnant women [1]. Neither group showed a reduction in blood pressure. There was also no change in urine volume or other laboratory parameters [1]. 3. Conclusion Progesterone causes a hypotensive reaction in animals and humans, and lowers blood pressure in hypertensive
patients [1,7,8,10]. In women with preeclampsia, progesterone appears to be effective, but other compounds such as 16␣-,17␣-dihydroxyprogesterone acetophenide have shown no beneficial effects [1]. The data obtained so far indicate that further studies should be encouraged in order to verify the therapeutic effect of progesterone, and perhaps also dydrogesterone and 17␣-hydroxyprogesterone caproate, in the treatment and prevention of preeclampsia.
References [1] M.I. Ragab, M.B. Sammour, H. El-Kabarity, R. Hegazi, Progesterone a treatment for pre-eclamptic toxaemia, Ain-Shams Med. J. 22 (1971) 9–24. [2] L. Weinstein, Syndrome of haemolysis, elevated liver enzymes and low platelet count: a severe consequence of hypertension in pregnancy, Am. J. Obstet. Gynecol. 142 (1982) 159–167. [3] J.D. Corbit, The effect of pregnancy upon experimental hypertension in the rabbit, Am. J. Med Sci. 201 (1941) 876–884. [4] P.P. Foa, N.L. Foa, M.M. Peet, Effect of pregnancy on experimental hypertension in rats, Am. J. Med. Sci. 204 (1942) 350–356. [5] A. Grollmann, Effect of pregnancy on the course of experimental hypertension, Am. J. Physiol. 151 (1947) 373–379. [6] P. Christianson, J.X. Wang, Reproductive hormones and blood pressure during pregnancy, Hum. Reprod. 16 (2001) 13–17. [7] J.G. Armstrong, Hypertensive action of progesterone in experimental and human hypertension, Proc. Soc. Exp. Biol. Med. 102 (1959) 452–455. [8] P.B. Rylance, M. Brincat, K. Lafferty, J.C. de Trafford, S. Brincat, V. Parson, J.W. Studd, Natural progesterone and antihypertensive action, Br. Med. J. (Clin. Res. Ed.) 290 (1985) 13–14. [9] M.B. Sammour, M.N. Makhzangy, M.N. Fawzy, A.E. Schindler, Progesterone therapy in pregnancy induced hypertension: Therapeutic value and hormonal profile, Clin. Exp. Hypertens., Part B: Hypertens. Pregnancy 1 (1982) 475–478. [10] W. Genest, E. Nowaczynski, E. Koiw, P. Sandor, P. Biron, Ciba International Symposium on Essential Hypertension, Bern, 1960, pp. 126–146.
Prevention and treatment of pregnancy-induced hypertension (preeclampsia) with progestogens M.B. Sammour a , H. El-Kabarity a , M.M. Fawzy a , A.E. Schindler b,∗ b
a Department Obstretrics and Gynecology, Ain Shams University, Cairo, Egypt Institute of Medical Research and Education, Hufelandstrasse 55, D-45147 Essen, Germany
Abstract Available data indicate that progesterone is able to treat pregnancy-induced hypertension (preeclampsia). Dydrogesterone and 17␣hydroxyprogesterone caproate might also be used for this purpose. Prevention of hypertensive disorders in preeclampsia also seems possible, but studies are needed to confirm this. © 2005 Elsevier Ltd. All rights reserved. Keywords: Progesterone; 17␣-Hydroxyprogesterone caproate; Dydrogesterone; Hypertension in pregnancy; Preeclampsia; HELLP-syndrome
1. Introduction Pregnancy-induced hypertension (preeclampsia) remains a relevant complication in pregnancy, not only endangering the pregnant women but also the fetus. Two distinct clinical entities have to be differentiated. In the first group of pregnant women, hypertension in pregnancy (preeclampsia) is initiated and maintained during pregnancy, is manifested by hypertension, oedema and proteinuria, and finally can lead to convulsions and coma [1]. Among this group of pregnant women, there is a subgroup that develops a symptom complex and specific laboratory changes during pregnancy; this is termed the Hemolysis, Elevated Liver, Low Platelet (HELLP) syndrome and was first described in 1982 by Weinstein [2]. The second group comprises women suffering from essential hypertension or specific renal disease who also became pregnant [1]. In this group, the pathological effects are always evident before the 24th week of gestation and are not relieved after parturition. Blood pressure associated with renal hypertension improves during pregnancy. Studies in animals showed that there was a tendency for blood pressure to decline during pregnancy in renal hypertensive dogs, rabbits and rats [3–5]. Such a decline in blood pressure was also seen in pregnant ∗
Corresponding author. Tel.: +49 21 7991833; fax: +49 21 7499533. E-mail address: [email protected] (A.E. Schindler).
0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.08.014
women with renal hypertension [1]. Higher concentrations of progesterone in early pregnancy were related to lower systolic blood pressure [6] and the blood pressure reducing effect of progesterone in humans with hypertension has been demonstrated [7]. In a placebo-controlled, double-blind, crossover study in which oral progesterone was given to men and postmenopausal women with mild to moderate hypertension, there was a significant reduction in blood pressure in both the men and the women [8]. It is therefore possible that treatment, or even prevention, of hypertensive disorders in pregnancy might be achieved with progesterone or progestins, such as 17␣-hydroxyprogesterone caproate and dydrogesterone.
2. Treatment of pregnancy-induced hypertension (preeclampsia) 2.1. Progesterone A group of 40 pregnant women, between the 34th and 40th week of gestation, with preeclampsia were treated with 200 mg/day progesterone given intramuscularly in four doses of 50 mg. There were 19 cases of mild preeclampsia, 16 of severe preeclampsia and five of fulminating preeclampsia with a short duration of symptoms and blood pressure over
440
M.B. Sammour et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 439–440
180 mmHg systolic and 110 mmHg diastolic; three women had essential hypertension before pregnancy. A group of 10 normal pregnant women between the 34th and 38th week of gestation were treated as controls [1]. Overall, 32 of 36 evaluable pregnant women with preeclampsia showed a clinical response to progesterone. The three cases with essential hypertension failed to show any relevant response [1]. A full effect on both systolic and diastolic blood pressure was obtained in 80% of preeclamptic women. All cases showed a mild increase in urinary output, a fall in uric acid and improvement in urea clearance [1]. Treatment did not affect blood pressure in the normal pregnant women, although diuresis was increased and this was accompanied by less weight gain [1]. In a further study, treatment with 50 mg progesterone in oil four times daily intramuscularly for 1–6 weeks induced a significant decrease of both systolic and diastolic blood pressure, associated with a marked increase in urinary output, a decrease in oedema and some body weight reduction in patients with severe pregnancy-induced hypertension [9]. 2.2. 16α-,17α-Dihydroxyprogesterone acetophenide Synthetic 16␣-,17␣-dihydroxyprogesterone acetophenide was used in 10 preeclamptic women and five normal pregnant women [1]. Neither group showed a reduction in blood pressure. There was also no change in urine volume or other laboratory parameters [1]. 3. Conclusion Progesterone causes a hypotensive reaction in animals and humans, and lowers blood pressure in hypertensive
patients [1,7,8,10]. In women with preeclampsia, progesterone appears to be effective, but other compounds such as 16␣-,17␣-dihydroxyprogesterone acetophenide have shown no beneficial effects [1]. The data obtained so far indicate that further studies should be encouraged in order to verify the therapeutic effect of progesterone, and perhaps also dydrogesterone and 17␣-hydroxyprogesterone caproate, in the treatment and prevention of preeclampsia.
References [1] M.I. Ragab, M.B. Sammour, H. El-Kabarity, R. Hegazi, Progesterone a treatment for pre-eclamptic toxaemia, Ain-Shams Med. J. 22 (1971) 9–24. [2] L. Weinstein, Syndrome of haemolysis, elevated liver enzymes and low platelet count: a severe consequence of hypertension in pregnancy, Am. J. Obstet. Gynecol. 142 (1982) 159–167. [3] J.D. Corbit, The effect of pregnancy upon experimental hypertension in the rabbit, Am. J. Med Sci. 201 (1941) 876–884. [4] P.P. Foa, N.L. Foa, M.M. Peet, Effect of pregnancy on experimental hypertension in rats, Am. J. Med. Sci. 204 (1942) 350–356. [5] A. Grollmann, Effect of pregnancy on the course of experimental hypertension, Am. J. Physiol. 151 (1947) 373–379. [6] P. Christianson, J.X. Wang, Reproductive hormones and blood pressure during pregnancy, Hum. Reprod. 16 (2001) 13–17. [7] J.G. Armstrong, Hypertensive action of progesterone in experimental and human hypertension, Proc. Soc. Exp. Biol. Med. 102 (1959) 452–455. [8] P.B. Rylance, M. Brincat, K. Lafferty, J.C. de Trafford, S. Brincat, V. Parson, J.W. Studd, Natural progesterone and antihypertensive action, Br. Med. J. (Clin. Res. Ed.) 290 (1985) 13–14. [9] M.B. Sammour, M.N. Makhzangy, M.N. Fawzy, A.E. Schindler, Progesterone therapy in pregnancy induced hypertension: Therapeutic value and hormonal profile, Clin. Exp. Hypertens., Part B: Hypertens. Pregnancy 1 (1982) 475–478. [10] W. Genest, E. Nowaczynski, E. Koiw, P. Sandor, P. Biron, Ciba International Symposium on Essential Hypertension, Bern, 1960, pp. 126–146.