Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Progestogens and Schindler AE J. Reproduktionsmed. Endokrinol 2015; 12 (4), 377-379

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Wir freuen uns auf Sie! and Pregnancy

A. E. Schindler

Based upon the intensive research by E. Diczfalusy and his scholars with the concept of the “feto-placental-unit”, the development of diagnos- tic procedures by measurements in pregnancy, therapeutic and preventive effects of the use of progestogens (, dydrogesterone, 17--hydroxyprogesterone caproate) were developed and are at present to be further evaluated in order to be used for prevention and treatment of preg- nancy disorders such as threatened , recurrent (habitual) miscarriage, preterm labor and preeclampsia (hypertension in pregnancy). J Reproduk- tionsmed Endokrinol_Online 2015; 12 (4): 377–9. Key words: Pregnancy, feto-placental-unit, progesterone, dydrogesterone, 17--hydroxyprogesterone caproate, threatened miscarriage, recurrent (habitual) miscarriage, preterm labor, preeclampsia (hypertension in pregnancy)

 Introduction pregnancy regarding progesterone the The following progestogens were used: so-called luteal-placental shift occurs, – Progesterone (micronized) (i. m., Going back to the 1960s, extensive basic were some lowering of the plasma pro- oral, vaginal) and clinical studies have been done by gesterone was found after seven weeks – Dydrogesterone (oral) Egon Diczfalusy and his research team of gestation, which correlates with the –17 -hydroxy-progesterone-caproate composed of many scholars from all over manifestation of threatened miscarriage. (i. m.) the world working at Karolinska Institute Indeed a correlation of the circulating in Stockholm. The concept of the “feto- plasma progesterone values and the  Threatened Miscarriage placental-unit” had been established. probability of pregnancy disturbances and Recurrent (habitual) has been found [8]. Independently we have looked at the iso- Miscarriage lation, identification and quantitation of Parallel to these experimental situation The clinical studies started in the 1980s in human amniotic fluid [1, 2]. clinical studies have contributed to the and systematic evaluation was mainly Thereby we could establish for the first knowledge and understanding of the done with dydrogesterone. One can as- time that clinical conditions of the preg- wide range of actions of progesterone sume that similar to dydrogesterone pro- nant woman and the such as Rh- beginning preconceptional and continue gesterone has been used with limited sensibilisation did reflect its effect on throughout pregnancy: published evaluations. concentrations in amniotic fluid 1. Secretory transformation of the endo- but also in and blood such as estriol metrium and decidualisation From the prospective, randomized stud- as main product of the “feto-placental- 2. Increase of blood flow ies with dydrogesterone a recent meta- unit” [1–5]. 3. Regulation of the extravillous tropho- analysis has given the following results blast invasion with the company proposed treatment  Progestogens 4. Control of uterine contractions recommendation: in threatened miscar- 5. Maintenance of cervical rigidity and riage 40 mg p. o. at the beginning and Since the isolation, identification and closure thereafter 20 mg (2 × 10 mg) daily. The quantitation of progesterone some limit- 6. Regulating Th1-cytokines (proin- length of treatment was on average 12 ed attempts have been done to point to flammatory) and Th2-cytokines (anti- weeks. The results in 660 patients being the significant role of progesterone in inflammatory) treated with dydrogesterone in a compar- pregnancy over time. 7. Production of progesterone-induced ative way was revealing the following re- blocking factor (PIPF) controlling the sults: Dydrogesterone treatment groups Already in 1957, studies indicated a fa- immune system of the mother in order 13% ; Control groups 24% vourable influence of progesterone on to protect the semi-allogenic fetus OR 0.47; 95-CI: 0.31–0.71 [9]. the development of preeclampsia [6]. A real step forward for the peculiar levels Systematic clinical studies started in the  Recurrent (habitual) of pregnancy were done by Czapo and 1980s. The following clinical entities be- Miscarriage co-workers, who demonstrated for the came subject of investigations: first time the success of progesterone for In these cases, it was demonstrated that the proper development of pregnancy by – Threatened miscarriage and recurrent there are already low progesterone val- removing the corpus luteum around sev- (habitual) miscarriage ues in the corpus luteum phase in the en weeks of gestation, which did lead to – Preterm labor and preterm birth non-pregnant state in women with a his- miscarriage and progesterone supple- – Preeclampsia (hypertension in preg- tory of recurrent (habitual) miscarriage. mentation avoided this [7]. Indeed, in nancy) In addition, in such cases the cellular

Received and accepted: April 30th, 2015. From the Institute for Medical Research and Education, Essen, Germany Correspondence: Prof. Dr. Dr. h.c. Adolf E. Schindler, Institute for Medical Research and Education, University Clinic, D-45147 Essen, Hufelandstrasse 55; e-mail: [email protected]

J Reproduktionsmed Endokrinol_Online 2015; 12 (4) 377 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Progestogens and Pregnancy progesterone receptors were very low These results were recently confirmed in preeclampsia (hypertension in pregnan- [10]. a large meta-analysis [21]. Two indica- cy) could be obtained (p < 0.001) [28]. tions have been investigated: The treatment scheme with dydrogester- 1. History of previous preterm birth  Conclusion one is the same as with threatened mis- 2. Short cervix carriage. The significant clinical effect Egon Diczfalusy and his scholars have could be accomplished. Most recent More recently also dydrogesterone has laid the ground work on the understand- studies have confirmed this [11, 12]. been studied for stopping preterm labor ing of the endocrinology of pregnancy [22]. including the concept of the “feto-pla-  Preterm Labor cental-unit”. This was followed by using Our own unpublished results point to hormone measurements in urine and Delivery before the beginning of week two indications for the effective use of blood to evaluate functional integrity of 37 of gestation is defined as preterm dydrogesterone in case of labor: pregnancy. birth. The frequency differs from coun- 1. Prevention starting dydrogesterone at try to country, but even be > 12% like in week 16 of gestation with 40 mg dy- At present, the use of progesterone and the USA [13]. The incidence of preterm drogesterone and thereafter 2 × 20 mg dydrogesterone have gained great clini- birth in the developing countries is even daily up to week 37 of gestation. cal importance creating for reproductive higher than in the developed countries 2. Treatment in case of established labor, medicine, obstetricians and perinatology [14]. perhaps with short cervix but intact the possibility to prevent or treat preg- membranes 40 mg p.o.; thereafter 2 × nancy disorders such as threatened mis- Nationally and internationally preterm 20 mg daily up to week 37 of gesta- carriage, recurrent (habitual) miscar- birth rate has a trend to rise, it is most tion or preterm delivery [23]. riage, preterm labor and preeclampsia. costly and is the main problem in obstet- rics [15]. It also has been suggested to use tocolyt-  Conflict of Interest ics together with progestogens, which Preterm birth is associated with: saves finally the amount of tocolytics to The author declares no conflict of inter- 1. Main cause of perinatal mortality be used. est. 2. Main cause of perinatal morbidity 3. High care costs.  Preeclampsia/Hyperten- sion in Pregnancy The causes for preterm labor/preterm References: birth are manifold: stress caused by dif- It is know that progesterone with its anti- 1. Schindler AE, Siiten PK.. Isolation and quantitation of steroids ferent entities (death of relatives, family action can lower the from normal human amniotic fl uid. JCEM 1968; 28: 1189–98. struggles, financial problems etc [16]. systolic and diastolic blood pressure and 2. Schindler AE. in human amniotic fl uid. Monographs The stress situation seems to go along this effect was demonstrated in women on Endocrinology 1982; 21: 1–158. 3. Schindler AE, Ratanasopa V, Herrmann WL, Lee Ty. Estriol in with a decrease of circulating progester- and men alike [24]. Indeed, clinically es- Rh-isoimmunization: A new approach to the management of one, which was found to be associated tablished preeclampsia could be con- severely affected . Obstet Gynec 1967; 29: 62531. with low progesterone throughout preg- trolled with intramuscular progesterone 4. Schindler AE, Herrmann WL. Estriol in pregnancy urine and amniotic fl uid. Am J Obstet Gynecol 1966; 95: 301–7. nancy [17]. Up to now, studies have [24, 25]. 5. Ratanasopa V, Schindler AE, Lee TY, Herrmann WL. Measure- clearly demonstrated the possible effect ments of estriol in plasma by gas-liquid chromatography. Its signifi cance in the treatment of high-risk pregnancies. Am J of 17-hydroxy-progesterone-caproate Before the first reported trial with pro- Obstet Gynecol 1967; 99: 295–302. 250 mg i. m. weekly starting around gesterone in women developing signs of 6. Dalton K. Toxaemia of pregnancy treated with progesterone week 16–37 of pregnancy [18]. hypertension in pregnancy intramuscular during the symptomatic stage. Brit Med J 1957; 2: 378–81. progesterone was used and published in 7. Csapo AI, Pulkinen MO, Ruttner B, Sauvage JP, Wiest WG. The signifi cance of the human corpus luteum in pregnancy A metaanalysis looking at papers using 1957. There was less weight gain and the maintenance. Am J Obstet Gynecol 1972; 112: 1061–7. 17-hydroxy-progesterone-caproate incidence of preeclampsia decreased 8. McCord ML, Arheart KL, Muran D, Stovall Tg, Buster JE, has already been published in 1990, considerably [26]. This was confirmed Carson SE. Single serum progesterone as a screen for ectopic pregnancy, enhancing specifi city and sensitivity to obtain opti- showing significant reduction of pre- by a later study [27]. mal test performance. Fert Steril 1996; 66: 513–6. term birth compared with the control 9. Carp H. A systematic review of dydrogesterone for the treat- ment of threatened miscarriage. Gynecol Endocrinol 2012; 28: group [19]. Thirteen years later a large In 2014 it was first time published the 983–90. randomized, placebo-controlled investi- possibility of prevention of preeclampsia 10. Salazar El, Calzada L. The role of progesterone in endometri- gation showed similar significant re- (hypertension in pregnancy) using dy- al - and synthesis in women with menstrual disorders and habitual abortion. Gynecol sults [20]. Further details are described drogesterone in women under ART-pro- Endocrinol 2007; 23: 22–225. elsewhere [18]. cedures receiving 30 mg dydrogesterone 11. Kumar A, Beguin N, Prasat S,Aggarwal S, Sharma SH. Oral p. o. daily starting day 1–5 after ovum dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine Also in 2003 the use of vaginal proges- pick-up and continued after positive production: a double-blind, randomized, placebo-controlled trial. terone for prevention of preterm labor HCG-test up to week 16 of gestation. It Fertil Steril 2014; 102: 1354–7. 12. Carp H. A systematic review of dydrogesterone for the treat- with 100 mg/200 mg vaginally daily has was demonstrated in this randomized ment of . Gynecol Endocrinol 2015; 31: been published [20]. study that a significant reduction of 422–30.

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13. Armstrong J. 17-Progesterone for preterm birth prevention: 18. Schindler AE. Progestogens for treatment and prevention of 23. Hudic H, Skekeres-Bartho J, Fatusic Z, et al. Dydrogesterone a potential US§ 2 billion opportunity. Am J Obstet Gynecol pregnancy disorders. Horm Mol Biol Clin Invest 2010; 3: 453–60. supplementation in women with threatened preterm delivery 2007; 196: 194–5. 19. Keirse MJ. administration in pregnancy may – the impact on cytokine profi le, hormone profi le and progester- 14. Da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Pro- prevent preterm delivery. Br J Obstet Gynecol 1990; 9: 149–54. one induced blocking factor. J Reprod Immunol 2011; 92: 103–7. phylactic administration of progesterone by vaginal suppository 20. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, et 24. Schindler AE. Unpublished results. to reduce the incidence of spontaneous preterm birth in women al, for the National Institute of Child Health and Human De- 25. Ragab MI, Sammour MB, ElKabarity H, Hegazy MR. Pro- at increased risk: a randomized placebo-controlled double-blind velopment Maternal-Fetal Medicine Units Network Prevention study. Am J Obstet Gynecol 2003; 188: 419–24. gesterone: a treatment for preeclamptic toxaemia. Ain Shams of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Med J 1971; 22: 9–24. 15. Hensen MC. Pregnancy maintenance and the regulation of Caproate. N Engl J Med 2003; 348: 2374–85. 26. Sammour MB, ElMakhzangy MN, Fawzy MM, Schindler A. placental progesterone biosynthesis in the baboon. Human 21. Romero R, Nicoleides K, Conde-Agudelo A, et al. Vaginal Reprod Update 1998; 4: 389–409. Progesterone therapy in pregnancy induced hypertension: Progesterone in women with an asymptomatic sonographic Therapeutic value and hormonal profi le. Clin Exp Hypertens B 16. Khashani AS, McNamee R, Abel KM. Rates of preterm birth short cervix in the midtrimester decreases preterm delivery and 1982; 1: 455–78. for antenatal exposure to score life events: a population-based neonatal morbidity: A systematic review and metaanalysis of cohort study. Human Reprod 2009; 24: 429–37. individual based data. Am J Obstet Gynecol 2012; 206: 124e1– 27. Dalton K. Toxaemia of pregnancy treated with progesterone during the symptomatic stage. Brit Med J 1957; 2: 378–81. 17. Blois SM, Joachim R, Kandel I, et al. Depletion of CD8+ 124. Cells Abolishes the Pregnancy Protective Effect of Progesterone 22. Polgar B, Hadziehudic B, Fatusik J. Maternal serum proges- 28. Dalton K. Controlled trials in the prophylactic value of pro- Substitution with Dydrogesterone in Mice by Altering the Th1/ terone induced blocking factor (PIBF) in the prediction of pre- gesterone in the treatment of preeclamptic toxaemia. Brit Th2 Cytokine Profi le. J Immunol 2004; 172: 5893–9. term birth. J Reprod Immunol 2015; 109: 36–40. Commonw 1962; 69: 463–8.

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