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Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction

Published:December 15, 2018DOI:https://doi.org/10.1016/j.rbmo.2018.11.017

      Abstract

      The pharmacological and physiological profiles of progestogens used for luteal phase support during assisted reproductive technology are likely to be important in guiding clinical choice towards the most appropriate treatment option. Various micronized progesterone formulations with differing pharmacological profiles have been investigated for several purposes. Dydrogesterone, a stereoisomer of progesterone, is available in an oral form with high oral bioavailability; it has been used to treat a variety of conditions related to progesterone deficiency since the 1960s and has recently been approved for luteal phase support as part of an assisted reproductive technology treatment. The primary objective of this review is to critically analyse the clinical implications of the pharmacological and physiological properties of dydrogesterone for its uses in luteal phase support and in early pregnancy.

      KEYWORDS

      Introduction

      Progesterone is produced by the corpus luteum after ovulation and levels rise rapidly during the early- and mid-luteal phase of the menstrual cycle (
      • Csapo A.I.
      • Pulkkinen M.
      Indispensability of the human corpus luteum in the maintenance of early pregnancy. Luteectomy evidence.
      ,
      • Baird D.D.
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      • Weinberg C.R.
      • Kamel F.
      • McConnaughey D.R.
      • Musey P.I.
      • Collins D.C.
      Preimplantation hormonal differences between the conception and non-conception menstrual cycles of 32 normal women.
      ), where it instigates secretory transformation of the endometrium, decidualization and uterine receptivity for implantation (
      • Bourgain C.
      • Devroey P.
      • Van Waesberghe L.
      • Smitz J.
      • Van Steirteghem A.C.
      Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure.
      ,
      • Segal S.
      • Casper R.F.
      Progesterone supplementation increases luteal phase endometrial thickness and oestradiol levels inin-vitro fertilization.
      ,
      • Kim M.R.
      • Park D.W.
      • Lee J.H.
      • Choi D.S.
      • Hwang K.J.
      • Ryu H.S.
      • Min C.K.
      Progesterone-dependent release of transforming growth factor-beta1 from epithelial cells enhances the endometrial decidualization by turning on the Smad signalling in stromal cells.
      ). Progesterone continues to be produced during pregnancy, where it is thought to be involved in preventing fetal rejection through immunomodulation and regulation of subendometrial blood flow (
      • Czajkowski K.
      • Sienko J.
      • Mogilinski M.
      • Bros M.
      • Szczecina R.
      • Czajkowska A.
      Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.
      ,
      • Arck P.C.
      • Hecher K.
      Fetomaternal immune cross-talk and its consequences for maternal and offspring's health.
      ,
      • Ghosh S.
      • Chattopadhyay R.
      • Goswami S.
      • Chaudhury K.
      • Chakravarty B.
      • Ganesh A.
      Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.
      ). The importance of progesterone in the establishment and maintenance of pregnancy has been proven by interventional studies in early pregnancy, which showed that progesterone deficiency caused by a lutectomy or by blocking the actions of progesterone (using a progesterone antagonist) lead to pregnancy loss (
      • Csapo A.I.
      • Pulkkinen M.
      Indispensability of the human corpus luteum in the maintenance of early pregnancy. Luteectomy evidence.
      ,
      • Couzinet B.
      • Le Strat N.
      • Ulmann A.
      • Baulieu E.E.
      • Schaison G.
      Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone).
      ,
      • Silvestre L.
      • Dubois C.
      • Renault M.
      • Rezvani Y.
      • Baulieu E.E.
      • Ulmann A.
      Voluntary interruption of pregnancy with mifepristone (RU 486) and a prostaglandin analogue. A large-scale French experience.
      ).
      Ovarian stimulation that is routinely used during IVF and assisted reproductive technology (IVF–ART) induces luteal phase deficiency, which can negatively affect implantation (
      • Macklon N.S.
      • Fauser B.C.
      Impact of ovarian hyperstimulation on the luteal phase.
      ,
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation inin vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Kolibianakis E.M.
      • Bourgain C.
      • Platteau P.
      • Albano C.
      • Van Steirteghem A.C.
      • Devroey P.
      Abnormal endometrial development occurs during the luteal phase of nonsupplemented donor cycles treated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists.
      ). As a result, luteal phase support during IVF–ART is now considered standard practice to support implantation and to improve pregnancy rates (
      Practice Committee of the American Society for Reproductive Medicine
      Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin.
      ,
      • van der Linden M.
      • Buckingham K.
      • Farquhar C.
      • Kremer J.A.
      • Metwally M.
      Luteal phase support for assisted reproduction cycles.
      ). Luteal phase deficiency has also been purportedly linked to a number of clinical conditions, including infertility and pregnancy loss (
      • Swyer G.I.
      • Daley D.
      Progesterone implantation in habitual abortion.
      ,
      • Moszkowski E.
      • Woodruff J.D.
      • Jones G.E.
      The inadequate luteal phase.
      ,
      • Blacker C.M.
      • Ginsburg K.A.
      • Leach R.E.
      • Randolph J.
      • Moghissi K.S.
      Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan.
      ); however, in these settings, luteal phase deficiency may be an epiphenomenon of other underlying disorders, such as polycystic ovary syndrome or anorexia (
      • Pirke K.M.
      • Schweiger U.
      • Lemmel W.
      • Krieg J.C.
      • Berger M.
      The influence of dieting on the menstrual cycle of healthy young women.
      ,
      • Filicori M.
      • Flamigni C.
      • Meriggiola M.C.
      • Ferrari P.
      • Michelacci L.
      • Campaniello E.
      • Valdiserri A.
      • Cognigni G.
      Endocrine response determines the clinical outcome of pulsatile gonadotropin-releasing hormone ovulation induction in different ovulatory disorders.
      ).
      Various progestogens have been investigated to support endogenous progesterone in the treatment of luteal phase deficiency. Only progesterone, dydrogesterone and 17α-hydroxyprogesterone caproate, however, are currently approved for clinical use during pregnancy (

      Abbott B.V., 8 June 2017. Duphaston 10, film-coated tablets 10 mg Summary of Product Characteristics.

      ,

      Bayer Schering Pharma AG, July 2007. Proluton® Depot 250 mg Prescribing Information.

      ,

      Besins Healthcare UK Ltd, 29 June 2017. Utrogestan vaginal 200 mg capsules.

      ). Dydrogesterone (6-dehydro-retroprogesterone) is a retroprogesterone, which was introduced for clinical use in an oral dosage form in the 1960s for the treatment of conditions associated with progesterone deficiency (
      • Backer Jr., M.H.,
      Isopregnenone (Duphaston): a new progestational agent.
      ). Dydrogesterone is a selective progesterone receptor agonist, with better oral bioavailability compared with oral micronized progesterone (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ,
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ,
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ). For luteal phase support in the context of IVF treatment, a Cochrane review reported that oral dydrogesterone may be a more effective option than progesterone (
      • van der Linden M.
      • Buckingham K.
      • Farquhar C.
      • Kremer J.A.
      • Metwally M.
      Luteal phase support for assisted reproduction cycles.
      ). This finding revived interest in the use of oral dydrogesterone for luteal phase support in this setting and prompted a large Phase III developmental programme (Lotus I and Lotus II studies), which led to the recent approval of oral dydrogesterone for luteal phase support in IVF–ART (

      Abbott B.V., 8 June 2017. Duphaston 10, film-coated tablets 10 mg Summary of Product Characteristics.

      ). An increase in global oral dydrogesterone utilization for this purpose is, therefore, foreseeable, especially as patients prefer oral administration compared with injections or vaginal application (
      • Bingham J.S.
      Single blind comparison of ketoconazole 200 mg oral tablets and clotrimazole 100 mg vaginal tablets and 1% cream in treating acute vaginal candidosis.
      ,
      • Arvidsson C.
      • Hellborg M.
      • Gemzell-Danielsson K.
      Preference and acceptability of oralversus vaginal administration of misoprostol in medical abortion with mifepristone.
      ,
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ). This review, therefore, aims to summarize the pharmacological and physiological properties of dydrogesterone, by assembling widely available published evidence as well as addressing knowledge gaps and further research needs.

      Classification of progestogens

      Progestogens can be broadly classified into two groups: those that are structurally related to progesterone, which includes retroprogesterones such as dydrogesterone, along with 17-OH-progesterone derivatives and 19-progesterone derivatives; or those structurally related to testosterone, such as the 19-nortestosterone derivatives and the spironolactone derivative, drospirenone (
      • Druckmann R.
      Individuelle hormonsubstitution die rolle der gestagene.
      ,
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ) (Figure 1).
      Figure 1.
      Figure 1Classification of progestogens (
      • Druckmann R.
      Individuelle hormonsubstitution die rolle der gestagene.
      ,
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ), with the chemical structure of progesterone and dydrogesterone (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ). Progestogens can be classified into those structurally related to progesterone or testosterone. Progestogens that can be used during pregnancy are indicated and include progesterone, dydrogesterone, and hydroxyprogesterone caproate (

      Abbott B.V., 8 June 2017. Duphaston 10, film-coated tablets 10 mg Summary of Product Characteristics.

      ,

      Bayer Schering Pharma AG, July 2007. Proluton® Depot 250 mg Prescribing Information.

      ,

      Besins Healthcare UK Ltd, 29 June 2017. Utrogestan vaginal 200 mg capsules.

      ). Progesterone and all progestogens have a steroidal structure with three cyclohexane rings and one cyclopentane ring. Dydrogesterone has a methyl group at carbon 10 in the α-orientation rather than the β-orientation and a hydrogen at carbon 9 in the β-orientation rather than the α-orientation. Also, dydrogesterone has an additional double bond between carbons 6 and 7, which creates a ‘bent’ conformation, which is thought to mediate its key properties.
      Depending on their structure, progestogens often have agonist or antagonist effects on androgen, glucocorticoid, oestrogen and mineralocorticoid receptors that can lead to side-effects (
      • Kuhl H.
      Pharmacology of estrogens and progestogens: influence of different routes of administration.
      ). Because of cross-reactivity with other receptors (
      • Benagiano G.
      • Carrara S.
      • Filippi V.
      Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives.
      ), not all progestogens are suitable for use during pregnancy owing to the risk of potentially harmful effects to the developing fetus (
      • Kaňová N.
      • Bičíková M.
      Hyperandrogenic states in pregnancy.
      ). For example, several 19-nortestosterone derivatives have been shown to have androgenic effects (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ,
      • Benagiano G.
      • Carrara S.
      • Filippi V.
      Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives.
      ) that may lead to masculinization of the female fetus (
      • Kaňová N.
      • Bičíková M.
      Hyperandrogenic states in pregnancy.
      ). Exposure to progestogens that have potent glucocorticoid activity may alter fetal development by changing placental development and function (
      • Korgun E.T.
      • Ozmen A.
      • Unek G.
      • Mendilcioglu I.
      The Effects of Glucocorticoids on Fetal and Placental Development.
      ). Finally, exposure to progestogens that have potent oestrogenic or anti-androgenic activity may cause hypospadias in the developing fetus (
      • Wang
      • Baskin L.S.
      Endocrine disruptors, genital development, and hypospadias.
      ,
      • Blaschko S.D.
      • Cunha G.R.
      • Baskin L.S.
      Molecular mechanisms of external genitalia development.
      ). Progestogens that are approved for clinical use in pregnancy include progesterone, dydrogesterone and 17α-hydroxyprogesterone caproate (

      Abbott B.V., 8 June 2017. Duphaston 10, film-coated tablets 10 mg Summary of Product Characteristics.

      ,

      Bayer Schering Pharma AG, July 2007. Proluton® Depot 250 mg Prescribing Information.

      ,

      Besins Healthcare UK Ltd, 29 June 2017. Utrogestan vaginal 200 mg capsules.

      ) (Figure 1).
      Progesterone has a steroidal structure with three cyclohexane rings and one cyclopentane ring; progestogenic activity is mediated through the 3-keto group and the double bond between carbons 4 and 5 (
      • Kuhl H.
      Pharmacology of estrogens and progestogens: influence of different routes of administration.
      ). Dydrogesterone is a stereoisomer of progesterone with a methyl group at carbon 10 in the α-orientation rather than the β-orientation, and a hydrogen at carbon 9 in the β-orientation rather than the α-orientation (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ,
      • Colombo D.
      • Ferraboschi P.
      • Prestileo P.
      • Toma L.
      A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.
      ). Dydrogesterone also has an additional double bond between carbons 6 and 7 (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ,
      • Colombo D.
      • Ferraboschi P.
      • Prestileo P.
      • Toma L.
      A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.
      ). These unique molecular features create a ‘bent’ conformation with enhanced rigidity compared with progesterone, which is thought to account for dydrogesterone's high selectivity for progesterone receptors (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ,
      • Colombo D.
      • Ferraboschi P.
      • Prestileo P.
      • Toma L.
      A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.
      ) (Figure 1).
      Progesterone is manufactured for therapeutic use from the yam root (Dioscorea species) via Marker degradation (
      • Jasem Y.
      • Khan M.
      • Taha A.
      • Thiemann T.
      Preparation of steroidal hormones with an emphasis on transformations of phytosterols and cholesterol – a review.
      ). Initially, the therapeutic use of manufactured progesterone was hampered by its poor bioavailability, but in the 1970s it was shown that decreasing the size of progesterone particles through micronization could enhance its bioavailability (
      • de Lignières B.
      Oral micronized progesterone.
      ). Progesterone can be formulated for oral, intravaginal, subcutaneous or intramuscular administration, with vaginal progesterone now the preferred route of administration for luteal support during IVF (
      • Vaisbuch E.
      • Leong M.
      • Shoham Z.
      Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey.
      ,
      • Sator M.
      • Radicioni M.
      • Cometti B.
      • Loprete L.
      • Leuratti C.
      • Schmidl D.
      • Garhöfer G.
      Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route.
      ), despite administration-related side effects (
      • Tavaniotou A.
      • Smitz J.
      • Bourgain C.
      • Devroey P.
      Comparison between different routes of progesterone administration as luteal phase support in infertility treatments.
      ). Dydrogesterone, which is produced from progesterone (

      European Patent Office, 16 February 1993. EP0 558 119 A2.

      ), is formulated for oral intake and has higher bioavailability than oral micronized progesterone (
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ).

      Pharmacological characteristics of progesterone and dydrogesterone

      Despite significant improvements in progesterone bioavailability through micronization (
      • de Lignières B.
      Oral micronized progesterone.
      ), the systemic bioavailability of oral and vaginal micronized progesterone is still relatively poor, with values less than 5% and between 4% and 8%, respectively (
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ,
      • Paulson R.J.
      • Collins M.G.
      • Yankov V.I.
      Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.
      ). In contrast, dydrogesterone has higher oral bioavailability (
      • Stanczyk F.Z.
      • Hapgood J.P.
      • Winer S.
      • Mishell Jr., D.R.
      Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.
      ), which together with its activity and high specificity for progesterone receptors (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ), causes endometrial transformation at a dose 10–20 times lower than that of micronized progesterone (
      • King R.J.
      • Whitehead M.I.
      Assessment of the potency of orally administered progestins in women.
      ,
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ). The apparent efficacy of oral dydrogesterone at a relatively low dose may minimize side-effects (
      • Daughton C.G.
      • Ruhoy I.S.
      Lower-dose prescribing: minimizing “side effects” of pharmaceuticals on society and the environment.
      ) and reduce the likelihood of altered liver function (
      • Ghabril M.
      • Chalasani N.
      • Björnsson E.
      Drug-induced liver injury: a clinical update.
      ). Overall, the extensive first-pass metabolism of oral progesterone limits its efficacy (
      • Paulson R.J.
      • Collins M.G.
      • Yankov V.I.
      Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.
      ) and high doses may increase the risk of intrahepatic cholestasis in predisposed women (
      • Bacq Y.
      • Sapey T.
      • Bréchot M.C.
      • Pierre F.
      • Fignon A.
      • Dubois F.
      Intrahepatic cholestasis of pregnancy: a French prospective study.
      ). To circumvent these issues, the main routes of administration for luteal phase support during IVF to date have been intravaginal and intramuscular (
      • Paulson R.J.
      • Collins M.G.
      • Yankov V.I.
      Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.
      ), with subcutaneous progesterone introduced more recently (
      • Doblinger J.
      • Cometti B.
      • Trevisan S.
      • Griesinger G.
      Subcutaneous progesterone is effective and safe for luteal phase support in IVF: an individual patient data meta-analysis of the Phase III trials.
      ).
      In addition to bioavailability, receptor binding and activity are pivotal pharmacological features. Early endocrinological studies in animal models suggested that dydrogesterone had potent progestogenic activity, but no androgenic, glucocorticoid or oestrogenic activity (
      • Reerink E.H.
      • Scholer H.F.
      • Westerhof P.
      • Querido A.
      • Kassenaar A.A.
      • Diczfalusy E.
      • Tillinger K.C.
      A new class of hormonally active steroids.
      ,
      • Aydar C.K.
      • Greenblatt R.B.
      6-dehydro-retroprogesterone (Duphaston) an interesting progesterone-like compound.
      ,
      • Vermorken A.J.
      • Sultan C.
      • Goos C.M.
      Dydrogesterone has no peripheral (anti)-androgenic properties.
      ). More recent in-vitro receptor binding and transactivation analyses support these early findings (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ). Using a GeneBLAzer assay,
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      demonstrated that dydrogesterone had no or negligible agonistic activity at androgen, glucocorticoid and mineralocorticoid receptors (Table 1). In contrast, progesterone had relatively high agonistic activity at androgen receptors, but no or negligible agonist activity at glucocorticoid or mineralocorticoid receptors (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ).
      Table 1Receptor binding affinities and activities of dydrogesterone versus progesterone
      ReceptorParameterDydrogesteroneDHDProgesterone
      Progesterone receptorRBA (%)15.915.9100
      Agonistic (RAA, %)1762100
      Antagonistic (RIA, %)<<<<<<
      Androgen receptorRBA, %10.00.8100
      Agonistic (RAA, %)0.6<<100
      Antagonistic (RIA, %)+
      RIA values were not calculated as the IC50 of the reference steroid progesterone was >10 000 nM.
      ,
      Progesterone exerted anti-androgenic effects at the pre-receptor level with over 90% inhibition of 5α-reductase type 2 (an androgen-producing enzyme), whereas dydrogesterone and its major metabolite showed only weak inhibition (up to 16%) of this enzyme. << specifies very low/negligible activity: values were not calculated if the EC50 or IC50 were >10 000 nM. DHD, 20α-dihydrodydrogesterone; EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; NR, not reported; RAA, relative agonist activity; RBA, relative binding affinity; RIA, relative inhibitory activity.
      +
      RIA values were not calculated as the IC50 of the reference steroid progesterone was >10 000 nM.
      ,
      Progesterone exerted anti-androgenic effects at the pre-receptor level with over 90% inhibition of 5α-reductase type 2 (an androgen-producing enzyme), whereas dydrogesterone and its major metabolite showed only weak inhibition (up to 16%) of this enzyme. << specifies very low/negligible activity: values were not calculated if the EC50 or IC50 were >10 000 nM. DHD, 20α-dihydrodydrogesterone; EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; NR, not reported; RAA, relative agonist activity; RBA, relative binding affinity; RIA, relative inhibitory activity.
      <<
      Progesterone exerted anti-androgenic effects at the pre-receptor level with over 90% inhibition of 5α-reductase type 2 (an androgen-producing enzyme), whereas dydrogesterone and its major metabolite showed only weak inhibition (up to 16%) of this enzyme. << specifies very low/negligible activity: values were not calculated if the EC50 or IC50 were >10 000 nM. DHD, 20α-dihydrodydrogesterone; EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; NR, not reported; RAA, relative agonist activity; RBA, relative binding affinity; RIA, relative inhibitory activity.
      Glucocorticoid receptorRBA, %17.52.0100
      Agonistic (RAA, %)<<<<<<
      Antagonistic (RIA, %)282100
      Mineralocorticoid receptorRBA, %NRNRNR
      Agonistic (RAA, %)<<<<<<
      Antagonistic (RIA, %)30.3100
      Oestrogen receptor-αRBA, %<<<<<<
      Agonistic (RAA, %)NRNRNR
      Antagonistic (RIA, %)NRNRNR
      Data shown were taken from
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ; agonist and antagonist activity were analysed using a GeneBLAzer assay.
      a RIA values were not calculated as the IC50 of the reference steroid progesterone was >10 000 nM.
      b Progesterone exerted anti-androgenic effects at the pre-receptor level with over 90% inhibition of 5α-reductase type 2 (an androgen-producing enzyme), whereas dydrogesterone and its major metabolite showed only weak inhibition (up to 16%) of this enzyme.<< specifies very low/negligible activity: values were not calculated if the EC50 or IC50 were >10 000 nM.DHD, 20α-dihydrodydrogesterone; EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; NR, not reported; RAA, relative agonist activity; RBA, relative binding affinity; RIA, relative inhibitory activity.
      Dydrogesterone also had relatively low antagonistic activity at glucocorticoid and mineralocorticoid receptors compared with progesterone (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ). Furthermore, although progesterone exerted anti-androgenic effects at the pre-receptor level with over 90% inhibition of 5α-reductase type 2 (an androgen-producing enzyme), dydrogesterone and 20α-dihydrodydrogesterone (DHD) showed only weak (up to 16%) inhibition of this enzyme (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ). Collectively, these data demonstrate that dydrogesterone, compared with progesterone, has high selectivity for progesterone receptors with low anti-androgenic effects at the pre-receptor level (
      • Rižner T.L.
      • Brožič P.
      • Doucette C.
      • Turek-Etienne T.
      • Muller-Vieira U.
      • Sonneveld E.
      • van der Burg B.
      • Bocker C.
      • Husen B.
      Selectivity and potency of the retroprogesterone dydrogesteronein vitro.
      ), thus minimizing activation of other receptors and unwanted effects (Table 1).
      Another pharmacological consideration is the quantification of progestogens after administration. Because of the structural differences with progesterone, neither dydrogesterone or DHD can be quantified by any commonly used diagnostic test for measuring progesterone levels. To specifically measure dydrogesterone or DHD levels, an instrumental chromatographic method needs to be used (
      • Abdel-Hamid M.E.
      • Sharaf L.H.
      • Kombian S.B.
      • Diejomaoh F.M.E.
      Determination of dydrogesterone in human plasma by tandem mass spectrometry: application to therapeutic drug monitoring of dydrogesterone in gynecological disorders.
      ).

      Mechanisms of progesterone action

      The progestogenic potency of various progestogens can be assessed by analysing morphological and biochemical changes to the endometrium after administration.
      • King R.J.
      • Whitehead M.I.
      Assessment of the potency of orally administered progestins in women.
      showed that, in patients with oestrogen-primed endometria, 6 days of treatment with oral dydrogesterone elicited biochemical changes consistent with secretory transformation at a dose of 10 mg, whereas oral micronized progesterone required a dose of 200 mg (
      • King R.J.
      • Whitehead M.I.
      Assessment of the potency of orally administered progestins in women.
      ). In agreement with these data, biochemical analyses have shown that oral dydrogesterone doses of 10 mg and 20 mg for 12–14 days, in combination with oestrogen, were effective in inducing secretory transformation of the endometrium (
      • Siddle N.C.
      • Fraser D.
      • Whitehead M.I.
      • Jesinger D.K.
      • Endacott J.
      • Prescott P.
      • Pryse-Davies J.
      Endometrial, physical and psychological effects of postmenopausal oestrogen therapy with added dydrogesterone.
      ,
      • Rees M.
      • Leather A.
      • Pryse-Davies J.
      • Collins S.A.
      • Barlow D.H.
      • Studd J.W.
      A first study to compare two dosages of dydrogesterone in opposing the 50 mg oestradiol implant.
      ).
      More recently,
      • Fatemi H.M.
      • Bourgain C.
      • Donoso P.
      • Blockeel C.
      • Papanikolaou E.G.
      • Popovic-Todorovic B.
      • Devroey P.
      Effect of oral administration of dydrogestroneversus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept.
      analysed endometrial and endocrine profiles in six patients with premature ovarian failure treated with 20 mg oral dydrogesterone or 600 mg micronized vaginal progesterone. Using these non-equivalent doses, it was suggested that micronized vaginal progesterone was more efficient in creating an in-phase secretory endometrium compared with oral dydrogesterone (
      • Fatemi H.M.
      • Bourgain C.
      • Donoso P.
      • Blockeel C.
      • Papanikolaou E.G.
      • Popovic-Todorovic B.
      • Devroey P.
      Effect of oral administration of dydrogestroneversus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept.
      ). Reliably analysing endometrial changes by histology, however, is difficult and is, therefore, not necessarily an accurate measure of endometrial receptivity (
      • Duggan M.A.
      • Brashert P.
      • Ostor A.
      • Scurry J.
      • Billson V.
      • Kneafsey P.
      • Difrancesco L.
      The accuracy and interobserver reproducibility of endometrial dating.
      ).
      In addition to inducing secretory transformation, many progestogens have high anti-gonadotrophic activity, which may affect ovulation (
      • Guerra J.A.
      • López-Muñoz F.
      • Álamo C.
      Progestins in combined contraceptives.
      ). During the menstrual cycle, the pituitary gland releases FSH and LH, which are involved in regulating the maturation of follicles and release of oocytes, respectively (
      • Holesh J.E.
      • Lord M.
      Physiology, Ovulation.
      ). The anti-gonadotrophic actions of some progestogens suppress mid-cycle FSH and LH peaks, thereby inhibiting ovulation; as a result, these progestogens have been used in combined oral contraceptives together with oestrogen (
      • Guerra J.A.
      • López-Muñoz F.
      • Álamo C.
      Progestins in combined contraceptives.
      ).
      Most of the available evidence indicates that dydrogesterone does not inhibit ovulation at the usual therapeutic doses. Several methods are accepted for analysing ovulation, including ultrasound, urinary steroid measurement, laparoscopy and basal body temperature (BBT) measurement (
      • Endrikat J.
      • Gerlinger C.
      • Richard S.
      • Rosenbaum P.
      • Dusterberg B.
      Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.
      ). Early studies showed that oral dydrogesterone at doses between 10 mg and 40 mg did not affect the characteristic BBT pattern of the menstrual cycle and is, therefore, not hyperthermic (
      • Bishop P.M.
      • Borell U.
      • Diczfalusy E.
      • Tillinger K.G.
      Effect of dydrogesterone on human endometrium and ovarian activity.
      ,
      • Bell E.T.
      • Loraine J.A.
      Effect of dydrogesterone on hormone secretion in patients with dysmenorrhea.
      ). Similarly, oral dydrogesterone was shown to have no, or only a mild, effect on the pattern of urinary steroid excretion at doses between 4 mg and 20 mg (
      • Swyer G.I.
      Small-scale clinical trials of progestogens for control of conception.
      ,
      • Bell E.T.
      • Loraine J.A.
      Effect of dydrogesterone on hormone secretion in patients with dysmenorrhea.
      ,
      • Larsson-Cohn U.
      • Johansson E.D.
      • Wide L.
      • Gemzell C.
      Effects of daily administration of a retrosteroid on the plasma levels of progesterone and on the urinary excretion of luteinizing hormone and total oestrogens.
      ).
      Despite the lack of effect of dydrogesterone on BBT and urinary steroid excretion patterns, its effect on mid-cycle LH surges is unclear. It has been shown that oral dydrogesterone at a dose of 4 mg does not affect LH surges (
      • Larsson-Cohn U.
      • Johansson E.D.
      • Wide L.
      • Gemzell C.
      Effects of daily administration of a retrosteroid on the plasma levels of progesterone and on the urinary excretion of luteinizing hormone and total oestrogens.
      ); however, a dose of 20 mg was found to suppress LH surges (
      • Lenton E.A.
      The effect of dydrogesterone on the mid-cycle gonadotrophin surge in regularly cycling women.
      ). More recently, the effect of oral dydrogesterone (20 mg) combined with human menopausal gonadotrophin on endocrine profiles during ovarian stimulation in IVF was evaluated versus oral micronized progesterone (100 mg) or medroxyprogesterone acetate (10 mg) combined with human menopausal gonadotrophin (
      • Zhu X.
      • Ye H.
      • Fu Y.
      Duphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation duringin vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation.
      ,
      • Yu S.
      • Long H.
      • Chang H.Y.
      • Liu Y.
      • Gao H.
      • Zhu J.
      • Quan X.
      • Lyu Q.
      • Kuang Y.
      • Ai A.
      New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles.
      ). Oral dydrogesterone was similarly effective as oral micronized progesterone and medroxyprogesterone acetate in the prevention of premature LH surges (
      • Zhu X.
      • Ye H.
      • Fu Y.
      Duphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation duringin vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation.
      ,
      • Yu S.
      • Long H.
      • Chang H.Y.
      • Liu Y.
      • Gao H.
      • Zhu J.
      • Quan X.
      • Lyu Q.
      • Kuang Y.
      • Ai A.
      New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles.
      ). These results, however, need to be taken in context as LH surges are not a definite marker of ovulation (
      • Zalányi S.
      Progesterone and ovulation.
      ), and the supraphysiological oestradiol levels during ovarian stimulation may modulate the sensitivity of the pituitary gland (
      • Wang
      • Yen S.S.
      Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle.
      ). Finally, the most definitive evidence that dydrogesterone does not inhibit ovulation comes from small clinical studies investigating the use of oral dydrogesterone to treat endometriosis-associated infertility, in which a substantial proportion of patients became pregnant while undergoing oral dydrogesterone therapy (
      • Tumasian K.P.
      • Bespoiasnaia V.V.
      • Voronovskaia I.V.
      Treatment of endometriosis in female infertility [in Russian].
      ,
      • Makhmudova G.M.
      • Nazhmutdinova D.K.
      • Gafarova D.K.
      • Lukmanova Y.D.
      Efficacy of duphaston treatment in women with endometriosis after reconstructive surgery.
      ).
      Progestogens can also modulate immune responses; this is of importance in the context of pregnancy, as the embryo expresses antigens foreign to the maternal immune system (
      • Mincheva-Nilsson L.
      Pregnancy and gamma/delta T cells: taking on the hard questions.
      ). The immunomodulatory mechanisms regulating maternal tolerance to such semi-allogeneic fetal tissue have increasingly been shown to be complex; however, progesterone is thought to play a key role in mediating such immune tolerance (
      • Szekeres-Bartho J.
      • Barakonyi A.
      • Par G.
      • Polgar B.
      • Palkovics T.
      • Szereday L.
      Progesterone as an immunomodulatory molecule.
      ). Initially, it was suggested that progesterone prevents fetal rejection by favouring a T helper cell 2 (Th2) inflammatory response over a T helper cell 1 (Th1) response, e.g. via the synthesis of progesterone-induced blocking factor (PIBF) (
      • Szekeres-Bartho J.
      • Barakonyi A.
      • Par G.
      • Polgar B.
      • Palkovics T.
      • Szereday L.
      Progesterone as an immunomodulatory molecule.
      ).
      It is now known that the Th1/Th2 paradigm is too simplistic and maternal–fetal tolerance involves complex interplay between a variety of immune cells and signalling molecules (
      • Arck P.C.
      • Hecher K.
      Fetomaternal immune cross-talk and its consequences for maternal and offspring's health.
      ) (Figure 2). Regulatory T (Treg) cells have been shown to have an important role in maternal–fetal immune tolerance (
      • Mao G.
      • Wang J.
      • Kang Y.
      • Tai P.
      • Wen J.
      • Zou Q.
      • Li G.
      • Ouyang H.
      • Xia G.
      • Wang B.
      Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice.
      ). In mice, progesterone expands the number of systemic and local uterine Treg cells during mid-term pregnancy and enhances their immunosuppressive functions (
      • Mao G.
      • Wang J.
      • Kang Y.
      • Tai P.
      • Wen J.
      • Zou Q.
      • Li G.
      • Ouyang H.
      • Xia G.
      • Wang B.
      Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice.
      ). The mechanism by which progesterone exerts its effects on Treg cells, however, remains to be determined.
      • Engler J.B.
      • Kursawe N.
      • Solano M.E.
      • Patas K.
      • Wehrmann S.
      • Heckmann N.
      • Luhder F.
      • Reichardt H.M.
      • Arck P.C.
      • Gold S.M.
      • Friese M.A.
      Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy.
      suggested that progesterone expands the numbers of Treg cells by promiscuous binding to glucocorticoid receptors on T cells.
      • Areia A.
      • Vale-Pereira S.
      • Alves V.
      • Rodrigues-Santos P.
      • Moura P.
      • Mota-Pinto A.
      Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy.
      found that about 8% of Treg cells in pregnant women express the membrane progesterone receptor-α (mPRα). As nuclear progesterone receptors (PR-A and PR-B) have not been consistently identified in human T cells (
      • Dosiou C.
      • Hamilton A.E.
      • Pang Y.
      • Overgaard M.T.
      • Tulac S.
      • Dong J.
      • Thomas P.
      • Giudice L.C.
      Expression of membrane progesterone receptors on human T lymphocytes and jurkat cells and activation of G-proteins by progesterone.
      ), activation of mPRα could be important in mediating the immunomodulatory functions of progesterone (
      • Areia A.
      • Vale-Pereira S.
      • Alves V.
      • Rodrigues-Santos P.
      • Moura P.
      • Mota-Pinto A.
      Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy.
      ).
      Figure 2.
      Figure 2The potential immunomodulatory effects of progesteroneª. Progesterone has multiple immunomodulatory effects, including expanding the number of local Treg cells (
      • Mao G.
      • Wang J.
      • Kang Y.
      • Tai P.
      • Wen J.
      • Zou Q.
      • Li G.
      • Ouyang H.
      • Xia G.
      • Wang B.
      Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice.
      ), and arresting dendritic cells in a tolerogenic state (
      • Blois S.M.
      • Ilarregui J.M.
      • Tometten M.
      • Garcia M.
      • Orsal A.S.
      • Cordo-Russo R.
      • Toscano M.A.
      • Bianco G.A.
      • Kobelt P.
      • Handjiski B.
      • Tirado I.
      • Markert U.R.
      • Klapp B.F.
      • Poirier F.
      • Szekeres-Bartho J.
      • Rabinovich G.A.
      • Arck P.C.
      A pivotal role for galectin-1 in fetomaternal tolerance.
      ). Progesterone increase the expression of the immunosuppressive molecule Galectin-1, which promotes the generation of tolerogenic dendritic cells (
      • Blois S.M.
      • Ilarregui J.M.
      • Tometten M.
      • Garcia M.
      • Orsal A.S.
      • Cordo-Russo R.
      • Toscano M.A.
      • Bianco G.A.
      • Kobelt P.
      • Handjiski B.
      • Tirado I.
      • Markert U.R.
      • Klapp B.F.
      • Poirier F.
      • Szekeres-Bartho J.
      • Rabinovich G.A.
      • Arck P.C.
      A pivotal role for galectin-1 in fetomaternal tolerance.
      ). Progesterone may also epigenetically silence chemokine genes, thereby preventing homing of effector T cells to the decidua (
      • Nancy P.
      • Tagliani E.
      • Tay C.S.
      • Asp P.
      • Levy D.E.
      • Erlebacher A.
      Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.
      ). ªThe above immunomodulatory effects of progesterone have been investigated in murine models and remain to be proven in humans. DSC, decidual stromal cells; EVT, extravillous trophoblasts; Gal, galectin; tDC, tolerogenic dendritic cell; Teff, effector T cell; Th, T helper cell; Treg, regulatory T cell.
      Dendritic cells are also key in regulating maternal–fetal tolerance as demonstrated in murine models. Pre-implantation, depletion of dendritic cells is associated with implantation failure (
      • Krey G.
      • Frank P.
      • Shaikly V.
      • Barrientos G.
      • Cordo-Russo R.
      • Ringel F.
      • Moschansky P.
      • Chernukhin I.V.
      • Metodiev M.
      • Fernandez N.
      • Klapp B.F.
      • Arck P.C.
      • Blois S.M.
      In vivo dendritic cell depletion reduces breeding efficiency, affecting implantation and early placental development in mice.
      ). After implantation, dendritic cells are arrested in a tolerogenic state in successful pregnancies; these cells are expanded, recruited, or both, by the decidual expression of Galectin-1 and promote the expansion of Treg cells and Th2 immune responses (
      • Blois S.M.
      • Ilarregui J.M.
      • Tometten M.
      • Garcia M.
      • Orsal A.S.
      • Cordo-Russo R.
      • Toscano M.A.
      • Bianco G.A.
      • Kobelt P.
      • Handjiski B.
      • Tirado I.
      • Markert U.R.
      • Klapp B.F.
      • Poirier F.
      • Szekeres-Bartho J.
      • Rabinovich G.A.
      • Arck P.C.
      A pivotal role for galectin-1 in fetomaternal tolerance.
      ). Dydrogesterone has been shown to up-regulate Galectin-1 expression in mice, whereas Galectin-1 up-regulates PIBF expression, indicating that Galectin-1 is linked with the progesterone-PIBF axis (
      • Blois S.M.
      • Ilarregui J.M.
      • Tometten M.
      • Garcia M.
      • Orsal A.S.
      • Cordo-Russo R.
      • Toscano M.A.
      • Bianco G.A.
      • Kobelt P.
      • Handjiski B.
      • Tirado I.
      • Markert U.R.
      • Klapp B.F.
      • Poirier F.
      • Szekeres-Bartho J.
      • Rabinovich G.A.
      • Arck P.C.
      A pivotal role for galectin-1 in fetomaternal tolerance.
      ). Collectively, these data suggest that systemic progestogens could be important in tailoring the maternal immune adaption towards the promotion of fetal tolerance; however, some of the immunomodulatory effects are yet to be investigated in humans and the clinical implications, therefore, remain speculative.
      Appropriate immunomodulatory signals are key for maintaining pregnancy; however, subendometrial blood flow may also play a role by providing an adequate oxygen and nutrient supply to the developing embryo (
      • Czajkowski K.
      • Sienko J.
      • Mogilinski M.
      • Bros M.
      • Szczecina R.
      • Czajkowska A.
      Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.
      ). This has been supported by evidence that elevated uterine arterial resistance and reduced blood flow is associated with recurrent pregnancy loss (
      • Abdel-Razik M.
      • El-Berry S.
      • Mostafa A.
      The effects of nitric oxide donors on uterine artery and sub-endometrial blood flow in patients with unexplained recurrent abortion.
      ). Both micronized vaginal progesterone and oral dydrogesterone have been shown to lower the uterine arterial systolic–diastolic ratio and vascular resistance in women with threatened or recurrent miscarriage, suggesting improved endometrial blood flow (
      • Czajkowski K.
      • Sienko J.
      • Mogilinski M.
      • Bros M.
      • Szczecina R.
      • Czajkowska A.
      Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.
      ,
      • Ghosh S.
      • Chattopadhyay R.
      • Goswami S.
      • Chaudhury K.
      • Chakravarty B.
      • Ganesh A.
      Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.
      ). Nitric oxide plays a role in increasing uterine blood flow during the luteal phase and in early pregnancy (
      • Abdel-Razik M.
      • El-Berry S.
      • Mostafa A.
      The effects of nitric oxide donors on uterine artery and sub-endometrial blood flow in patients with unexplained recurrent abortion.
      ), and progesterone has been shown to increase nitric oxide synthesis in human vascular endothelial cells in vitro, mainly mediated through mPRα (
      • Pang Y.
      • Dong J.
      • Thomas P.
      Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α.
      ). Although dydrogesterone itself has a minimal effect on nitric oxide synthesis in human vascular endothelial cells, its main metabolite DHD elicits a consistent increase in nitric oxide synthesis from these cells (
      • Simoncini T.
      • Caruso A.
      • Giretti M.S.
      • Scorticati C.
      • Fu X.D.
      • Garibaldi S.
      • Baldacci C.
      • Mannella P.
      • Fornari L.
      • Genazzani A.R.
      Effects of dydrogesterone and of its stable metabolite, 20-alpha-dihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells.
      ). The clinical implications of these effects of progesterone and dydrogesterone in early pregnancy or luteal phase support, however, remain to be determined.

      Luteal phase support in IVF and assisted reproductive technology

      Ovarian stimulation during IVF–ART involves the use of gonadotrophin-releasing hormone (GnRH) analogues (both agonists and antagonists), which prevent premature luteinization and ovulation (
      Practice Committee of the American Society for Reproductive Medicine
      Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin.
      ). Although it is well established that ovarian stimulation can lead to a defective luteal phase, the mechanisms behind this effect have been debated for many years. It is thought that supraphysiological levels of steroids secreted during the follicular phase or early luteal phase after ovarian stimulation may inhibit LH secretion from the pituitary gland (
      • Edwards R.G.
      • Steptoe P.C.
      • Purdy J.M.
      Establishing full-term human pregnancies using cleaving embryos grownin vitro.
      ,
      • Sungurtekin U.
      • Jansen R.P.
      Profound luteinizing hormone suppression after stopping the gonadotropin-releasing hormone-agonist leuprolide acetate.
      ,
      • Fauser B.C.
      • Devroey P.
      Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.
      ,
      • Fatemi H.M.
      Assessment of the luteal phase in stimulated and substituted cycles.
      ). This may result in a lack of support for the corpus luteum, thereby shortening the luteal phase and causing luteolysis (
      • Duffy D.M.
      • Stewart D.R.
      • Stouffer R.L.
      Titrating luteinizing hormone replacement to sustain the structure and function of the corpus luteum after gonadotropin-releasing hormone antagonist treatment in rhesus monkeys.
      ,
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation inin vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Fauser B.C.
      • Devroey P.
      Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.
      ). As a result, luteal phase support using progestogens has been recommended when GnRH analogues are used during IVF–ART (
      Practice Committee of the American Society for Reproductive Medicine
      Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin.
      ). These recommendations are supported by a recent systematic review that demonstrated that luteal phase support with progesterone was associated with higher live birth and pregnancy rates compared with placebo or no treatment (
      • van der Linden M.
      • Buckingham K.
      • Farquhar C.
      • Kremer J.A.
      • Metwally M.
      Luteal phase support for assisted reproduction cycles.
      ).
      Oral micronized progesterone is not commonly used for luteal phase support as there is some evidence that it may not be as effective as vaginal or intramuscular formulations, although this has not been proven (
      • Friedler S.
      • Raziel A.
      • Schachter M.
      • Strassburger D.
      • Bukovsky I.
      • Ron-El R.
      Luteal support with micronized progesterone followingin-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration.
      ,
      • Licciardi F.L.
      • Kwiatkowski A.
      • Noyes N.L.
      • Berkeley A.S.
      • Krey L.L.
      • Grifo J.A.
      Oralversus intramuscular progesterone forin vitro fertilization: a prospective randomized study.
      ,
      • Paulson R.J.
      • Collins M.G.
      • Yankov V.I.
      Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.
      ,
      • van der Linden M.
      • Buckingham K.
      • Farquhar C.
      • Kremer J.A.
      • Metwally M.
      Luteal phase support for assisted reproduction cycles.
      ). Although no single progesterone formulation or regimen has been identified as superior in efficacy (
      • van der Linden M.
      • Buckingham K.
      • Farquhar C.
      • Kremer J.A.
      • Metwally M.
      Luteal phase support for assisted reproduction cycles.
      ), the vaginal route is generally preferred at IVF–ART centres as it avoids injection-site pain and the abscesses associated with progesterone injections (
      • Tavaniotou A.
      • Smitz J.
      • Bourgain C.
      • Devroey P.
      Comparison between different routes of progesterone administration as luteal phase support in infertility treatments.
      ,
      • Vaisbuch E.
      • Leong M.
      • Shoham Z.
      Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey.
      ,
      • Beltsos A.N.
      • Sanchez M.D.
      • Doody K.J.
      • Bush M.R.
      • Domar A.D.
      • Collins M.G.
      Patients' administration preferences: progesterone vaginal insert (Endometrin®) compared to intramuscular progesterone for luteal phase support.
      ). Vaginally administered progesterone, however, is associated with its own administration-related side-effects, such as interference with coitus, vaginal bleeding, irritation and discharge (
      • Lockwood G.
      • Griesinger G.
      • Cometti B.
      European Centers
      Subcutaneous progesteroneversus vaginal progesterone gel for luteal phase support inin vitro fertilization: a noninferiority randomized controlled study.
      ,
      • Tomic V.
      • Tomic J.
      • Klaic D.Z.
      • Kasum M.
      • Kuna K.
      Oral dydrogesteroneversus vaginal progesterone gel in the luteal phase support: randomized controlled trial.
      ). Micronized vaginal progesterone for luteal phase support can be administered either as suppositories, tablets, or as an 8% gel (
      Practice Committee of the American Society for Reproductive Medicine
      Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin.
      ).
      Dydrogesterone is an alternative to progesterone for luteal phase support in IVF–ART. Numerous small-scale clinical studies and a meta-analysis have indicated that oral dydrogesterone is at least as efficacious as micronized vaginal progesterone in supporting pregnancy rates after luteal phase support (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ,
      • Patki A.
      • Pawar V.C.
      Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone.
      ,
      • Ganesh A.
      • Chakravorty N.
      • Mukherjee R.
      • Goswami S.
      • Chaudhury K.
      • Chakravarty B.
      Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoingin vitro fertilization: a randomized clinical study.
      ,
      • Salehpour S.
      • Tamimi M.
      • Saharkhiz N.
      Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support inin vitro fertilization (IVF): a randomized clinical trial.
      ,
      • Tomic V.
      • Tomic J.
      • Klaic D.Z.
      • Kasum M.
      • Kuna K.
      Oral dydrogesteroneversus vaginal progesterone gel in the luteal phase support: randomized controlled trial.
      ,
      • Barbosa M.W.
      • Silva L.R.
      • Navarro P.A.
      • Ferriani R.A.
      • Nastri C.O.
      • Martins W.P.
      Dydrogesteronevs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials.
      ,
      • Saharkhiz N.
      • Zamaniyan M.
      • Salehpour S.
      • Zadehmodarres S.
      • Hoseini S.
      • Cheraghi L.
      • Seif S.
      • Baheiraei N.
      A comparative study of dydrogesterone and micronized progesterone for luteal phase support duringin vitro fertilization (IVF) cycles.
      ,
      • Zargar M.N.S.
      • Ejtahed M.
      Comparison the effectiveness of oral dydrogesterone, vaginal progesterone suppository and progesterone ampule for luteal phase support on pregnancy rate during ART cycles.
      ). More recently, the randomized, double-blind, double-dummy, Phase III Lotus I clinical study, conducted in 1031 patients, compared oral dydrogesterone (30 mg [10 mg three times daily]) with micronized vaginal progesterone capsules (600 mg [200 mg three times daily) for luteal phase support in fresh cycle IVF (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). In this double-blind, double-dummy study, non-inferiority of oral dydrogesterone to micronized vaginal progesterone capsules was demonstrated, with pregnancy rates at 12 weeks of gestation in the full analysis set of 37.6% and 33.1% in the oral dydrogesterone and micronized vaginal progesterone capsule treatment groups, respectively (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). The second study in the Phase III Lotus clinical trial program (Lotus II), although being an open-label, randomized study, followed a similar overall design to Lotus I, and compared oral dydrogesterone (30 mg [10 mg three times daily]) with 8% micronized vaginal progesterone gel (90 mg once daily) (
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ). Lotus II demonstrated non-inferiority of oral dydrogesterone to micronized vaginal progesterone gel for luteal phase support in fresh cycle IVF, with pregnancy rates at 12 weeks gestation in the full analysis set of 38.7% and 35.0% in the oral dydrogesterone and micronized vaginal progesterone gel treatment groups, respectively (
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ).
      The results of a prospective, randomized, comparative study demonstrated that the percentage of patients satisfied with the tolerability of treatment was significantly higher in the oral dydrogesterone group versus the micronized vaginal progesterone group (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ). No patients in the oral dydrogesterone group experienced vaginal pain or irritation, but these administration-related side-effects were reported in 10.5% of patients in the micronized vaginal progesterone group (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ). Moreover, another randomized clinical study demonstrated that perineal irritation, vaginal bleeding, vaginal discharge and interference with coitus were significantly lower in the oral dydrogesterone group compared with the micronized vaginal progesterone gel group (
      • Tomic V.
      • Tomic J.
      • Klaic D.Z.
      • Kasum M.
      • Kuna K.
      Oral dydrogesteroneversus vaginal progesterone gel in the luteal phase support: randomized controlled trial.
      ). These data are supported by studies that compared oral versus vaginal formulations of non-progestogen drugs, which showed that women preferred to use oral formulations compared with vaginal ones (
      • Bingham J.S.
      Single blind comparison of ketoconazole 200 mg oral tablets and clotrimazole 100 mg vaginal tablets and 1% cream in treating acute vaginal candidosis.
      ,
      • Arvidsson C.
      • Hellborg M.
      • Gemzell-Danielsson K.
      Preference and acceptability of oralversus vaginal administration of misoprostol in medical abortion with mifepristone.
      ).
      The efficacy of oral dydrogesterone for luteal phase support in fresh cycle IVF is well established (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ;
      • Patki A.
      • Pawar V.C.
      Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone.
      ;
      • Ganesh A.
      • Chakravorty N.
      • Mukherjee R.
      • Goswami S.
      • Chaudhury K.
      • Chakravarty B.
      Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoingin vitro fertilization: a randomized clinical study.
      ,
      • Salehpour S.
      • Tamimi M.
      • Saharkhiz N.
      Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support inin vitro fertilization (IVF): a randomized clinical trial.
      ,
      • Tomic V.
      • Tomic J.
      • Klaic D.Z.
      • Kasum M.
      • Kuna K.
      Oral dydrogesteroneversus vaginal progesterone gel in the luteal phase support: randomized controlled trial.
      ,
      • Barbosa M.W.
      • Silva L.R.
      • Navarro P.A.
      • Ferriani R.A.
      • Nastri C.O.
      • Martins W.P.
      Dydrogesteronevs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Saharkhiz N.
      • Zamaniyan M.
      • Salehpour S.
      • Zadehmodarres S.
      • Hoseini S.
      • Cheraghi L.
      • Seif S.
      • Baheiraei N.
      A comparative study of dydrogesterone and micronized progesterone for luteal phase support duringin vitro fertilization (IVF) cycles.
      ,
      • Zargar M.N.S.
      • Ejtahed M.
      Comparison the effectiveness of oral dydrogesterone, vaginal progesterone suppository and progesterone ampule for luteal phase support on pregnancy rate during ART cycles.
      ,
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ); however, limited data are available about its use in artificial frozen-thawed cycles, which have different underlying endocrinological issues. The lack of ovulation in artificial frozen-thawed cycles causes an absence of endogenous corpora lutea, meaning that the endometrial changes necessary for implantation and early pregnancy are totally dependent on exogenous progestogen supplementation (
      • Ghobara T.
      • Gelbaya T.A.
      • Ayeleke R.O.
      Cycle regimens for frozen-thawed embryo transfer.
      ). The use of oral dydrogesterone in artificial frozen-thawed cycles has been investigated in two small randomized clinical studies (
      • Rashidi B.H.
      • Ghazizadeh M.
      • Tehrani Nejad E.S.
      • Bagheri M.
      • Gorginzadeh M.
      Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial.
      ,
      • Zarei A.
      • Sohail P.
      • Parsanezhad M.E.
      • Alborzi S.
      • Samsami A.
      • Azizi M.
      Comparison of four protocols for luteal phase support in frozen-thawed Embryo transfer cycles: a randomized clinical trial.
      ).
      • Rashidi B.H.
      • Ghazizadeh M.
      • Tehrani Nejad E.S.
      • Bagheri M.
      • Gorginzadeh M.
      Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial.
      reported comparable pregnancy rates between the oral dydrogesterone and micronized vaginal progesterone groups, using equivalent doses of 40 mg and 800 mg, respectively (
      • Rashidi B.H.
      • Ghazizadeh M.
      • Tehrani Nejad E.S.
      • Bagheri M.
      • Gorginzadeh M.
      Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial.
      ) Conversely,
      • Zarei A.
      • Sohail P.
      • Parsanezhad M.E.
      • Alborzi S.
      • Samsami A.
      • Azizi M.
      Comparison of four protocols for luteal phase support in frozen-thawed Embryo transfer cycles: a randomized clinical trial.
      reported a lower pregnancy rate in the oral dydrogesterone group compared with the micronized vaginal progesterone group, using non-equivalent doses of 20 mg and 800 mg, respectively. Overall, further studies are needed to investigate the efficacy and optimal dosing schedule of oral dydrogesterone during artificial frozen-thawed cycle IVF.

      Safety data related to progestogen use

      It is estimated that 113 million women and about 20 million fetuses have been exposed to dydrogesterone since 1960 (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). Overall, clinical studies have demonstrated that oral dydrogesterone has a good benefit–risk profile comparable to that of micronized vaginal progesterone during luteal phase support (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ,
      • Tomic V.
      • Tomic J.
      • Klaic D.Z.
      • Kasum M.
      • Kuna K.
      Oral dydrogesteroneversus vaginal progesterone gel in the luteal phase support: randomized controlled trial.
      ,
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). In maternal populations, liver function analyses (
      • Chakravarty B.N.
      • Shirazee H.H.
      • Dam P.
      • Goswami S.K.
      • Chatterjee R.
      • Ghosh S.
      Oral dydrogesteroneversus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.
      ,
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ), as well as the incidence of vascular, gastrointestinal and nervous system disorders (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ), were comparable between the oral dydrogesterone and micronized vaginal progesterone capsule groups. Furthermore, the Lotus I study demonstrated that the incidence of maternal serious treatment emergent adverse events was similar between the oral dydrogesterone and micronized vaginal progesterone capsule groups, occurring in 10.8% and 13.3% of participants, respectively (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). In the newborn population, the incidence of serious adverse events was low, occurring in 4.2% and 5.7% of participants in the oral dydrogesterone and micronized vaginal progesterone capsule groups, respectively (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). Overall, newborn safety data, including the incidence of congenital, familiar and genetic disorders, were comparable between the oral dydrogesterone and micronized vaginal progesterone capsule groups in the Lotus I study (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ).
      In the Lotus II study, the incidence of maternal serious treatment emergent adverse events was similar between the oral dydrogesterone and micronized vaginal progesterone gel groups, occurring in 13.7% and 13.1% of participants, respectively (
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ). Furthermore, in the fetal and newborn population, the incidence of serious treatment emergent adverse events was comparable between the oral dydrogesterone and micronized vaginal progesterone gel groups, occurring in 12.7% and 11.4% of participants, respectively; the incidence of congenital, familial and genetic disorders were also similar between the oral dydrogesterone and micronized vaginal progesterone gel groups (
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ).
      A recent retrospective case-controlled study in 202 children that investigated the use of oral dydrogesterone in early pregnancy to prevent miscarriage reported a positive association between congenital heart malformations and oral dydrogesterone treatment (
      • Zaqout M.
      • Aslem E.
      • Abuqamar M.
      • Abughazza O.
      • Panzer J.
      • De Wolf D.
      The impact of oral intake of dydrogesterone on fetal heart development during early pregnancy.
      ). However, this study did not implement three key principles in their study design to reduce selection, confounding and information bias. To reduce selection bias, the groups should have only included offspring whose mother had experienced miscarriage, as oral dydrogesterone is indicated in early pregnancy for the treatment or prevention of miscarriage as well as, more recently, luteal support in ART–IVF (

      Abbott B.V., 8 June 2017. Duphaston 10, film-coated tablets 10 mg Summary of Product Characteristics.

      ). There is strong evidence that previous miscarriages are an important risk factor for congenital heart defects (
      • Tikkanen J.
      • Heinonen O.P.
      Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy.
      ,
      • Liu S.
      • Liu J.
      • Tang J.
      • Ji J.
      • Chen J.
      • Liu C.
      Environmental risk factors for congenital heart disease in the Shandong Peninsula, China: a hospital-based case-control study.
      ,
      • Shi H.
      • Yang S.
      • Liu Y.
      • Huang P.
      • Lin N.
      • Sun X.
      • Yu R.
      • Zhang Y.
      • Qin Y.
      • Wang L.
      Study on environmental causes and SNPs of MTHFR, MS and CBS genes related to congenital heart disease.
      ); as such, confounding bias could have been avoided by choosing offspring whose mother had experienced miscarriages as a study base. Finally, they did not confirm oral dydrogesterone exposure in medical records, but relied on the mother's recollection of oral dydrogesterone usage, which is no guarantee of comparable drug exposure. As a result of these weaknesses in the study design, no association of a causal relationship can be concluded.
      In the Lotus II study, the of incidence congenital heart malformations was low, occurring in six cases and 10 cases of fetuses and newborns in the oral dydrogesterone and micronized vaginal progesterone gel groups, respectively (
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ). The Lotus I study reported three congenital heart disease events in each treatment group (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ).
      Of note, the 2017 European Society of Human Reproduction and Embryology guidelines for the prevention of recurrent pregnancy loss (miscarriage) state that vaginal progesterone use during early pregnancy has no beneficial effect in women with unexplained recurrent pregnancy loss. There is some evidence that oral dydrogesterone treatment, initiated when fetal heart action can be confirmed, may be effective but more trials are needed (

      ESHRE Early Pregnancy Guideline Development Group. Recurrent pregnancy loss: guideline of the European Society of Human Reproduction and Embryology. 2017

      ).
      Overall, oral dydrogesterone has a well-established safety profile; the results of the large and robust Lotus I and Lotus II Phase III clinical trials revealed no new safety concerns related to oral dydrogesterone use during early pregnancy for either the mother or the developing fetus, and no increased risk of congenital heart disease has been identified (
      • Mirza F.G.
      • Patki A.
      • Pexman-Fieth C.
      Dydrogesterone use in early pregnancy.
      ,
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ,
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ).

      Conclusions

      Overall, dydrogesterone has a favourable pharmacological profile. Dydrogesterone is a selective progesterone agonist, allowing specific progestogenic effects in relevant cell types. As shown in clinical studies, the benefits of oral dydrogesterone treatment in luteal support outweigh the risks if it is used as recommended.
      The pharmacological profile of dydrogesterone enhances its progestogenic effects versus progesterone, indicated by the fact that an equivalent dose of oral dydrogesterone is 10–20-fold lower than that of oral micronized progesterone (
      • Schindler A.E.
      • Campagnoli C.
      • Druckmann R.
      • Huber J.
      • Pasqualini J.R.
      • Schweppe K.W.
      • Thijssen J.H.
      Classification and pharmacology of progestins.
      ). Although an equivalent dose versus micronized vaginal progesterone remains to be accurately determined, the Lotus I study demonstrated that a 20-fold lower dose of oral dydrogesterone (30 mg) is non-inferior to micronized vaginal progesterone (600 mg) for luteal phase support (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ). Although the implications of some of the immunomodulatory features of progesterone remain to be proven in the clinical setting, it is likely that dydrogesterone mimics the effects of progesterone through binding to progesterone receptors. It will be interesting to determine whether oral dydrogesterone is a more effective systemic immunomodulator than vaginal progesterone owing to its administration route; further studies are required in this area.
      The unique structure of dydrogesterone results in enhanced oral bioavailability versus progesterone, allowing for effective oral administration and circumventing the inconvenience and discomfort related to intravaginal or intramuscular progesterone applications. The Lotus I and Lotus II Phase III studies demonstrated that oral dydrogesterone is a well-tolerated and efficacious treatment during luteal phase support; as a result, oral dydrogesterone may replace micronized vaginal progesterone as the standard of care owing to its patient-friendly oral administration route (
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ,
      • Griesinger G.
      • Blockeel C.
      • Sukhikh G.T.
      • Patki A.
      • Dhorepatil B.
      • Yang D.Z.
      • Chen Z.J.
      • Kahler E.
      • Pexman-Fieth C.
      • Tournaye H.
      Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial.
      ). Oral dydrogesterone may induce a paradigm shift in the treatment of the estimated 1.5 million women worldwide undergoing IVF each year (
      • Chambers G.M.
      • Hoang V.P.
      • Zhu R.
      • Illingworth P.J.
      A reduction in public funding for fertility treatment–an econometric analysis of access to treatment and savings to government.
      ,
      • Tournaye H.
      • Sukhikh G.T.
      • Kahler E.
      • Griesinger G.
      A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization.
      ).

      Acknowledgements

      Editorial support was provided by Josh Lilly of Alpharmaxim Healthcare Communications.

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      Biography

      Georg Griesinger is a Professor at Lübeck University and chair at the Department of Gynecological Endocrinology and Reproductive Medicine at University Hospital of Schleswig-Holstein, Lübeck, Germany. His research interests include endocrinology of ovarian stimulation, evidence-based medicine in reproductive health care, epidemiological studies in IVF, folliculogenesis and cryopreservation of ovarian tissue.
      Key message
      Dydrogesterone is a selective progesterone receptor agonist with high oral bioavailability. These key pharmacokinetic features allow for effective oral administration and may limit the risk of side-effects. Clinical studies have shown that oral dydrogesterone has a good benefit–risk profile, comparable to that of micronized vaginal progesterone, during luteal phase support.