Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Dydrogesterone_PPT Slides.pptx
Similar to Dydrogesterone_PPT Slides.pptx (20)
Recently uploaded
Recently uploaded (20)
Dydrogesterone_PPT Slides.pptx
- 2. Introduction • Fertility and menstruation are largely controlled by hormones • Two main female sex hormones are estrogen and progesterone 2 Estrogens: • Responsible for female primary and secondary sexual characteristics • Estradiol promotes epithelial cell proliferation in the uterine endometrium and mammary glands of the breasts. Progesterone: • ↑ secretory actions of the endometrial lining in preparation for pregnancy • Increases secretions to nourish the rapidly developing fertilized ovum • Promotes development of breast alveoli and lobules Mc Master Pathophysiology Review. http://www.pathophys.org/sexhormones/ (as accessed on 31.07.2020 Progesterone is a steroid hormone belonging to a class of hormones called progestogens
- 3. Progesterone • It is produced in the ovaries, the placenta (when a woman gets pregnant) and the adrenal glands. • One of the most important functions of Progesterone is thickening the lining of the uterus each month • In the event of conception, progesterone is the fundamental hormone that facilitates women’s pregnancy • This lining is prepared to receive a nourished and fertilized egg. Without the thickened lining of the uterus, reproduction wouldn’t be successful 4
- 4. Progesterone In Female Reproduction • After implantation in endometrial lining, blastocyst begins to secrete human chorionic gonadotropin (hCG) • hCG promotes the maintenance of the corpus luteum (to produce both oestrogen and progesterone) • The levels of hCG are maintained for roughly 8 – 10 weeks while the placenta is being developed • After this time, the placenta becomes responsible for progesterone secretion and nourishing the embryo 5
- 5. Progesterone Level In MenstruationAnd Pregnancy Stage Progesterone Level (ng/mL) Pre-ovulation < 0.89 Ovulation ≤ 12 Post-ovulation 1.8–24 First Trimester 11–44 Second Trimester 25–83 Third Trimester 58–214 6 https://www.healthline.com/health/ progesterone-function#normal-levels-chart Semin Perinatol. 2016 Aug; 40(5): 273–280
- 6. Progesterone Actions Hormonal Actions • Endometrial changes: Induces secretory transformation, increases vascularity of the endometrial lining, stabilizes endometrium • Stimulates growth of fetus - Promotes pregnancy • Supports gestation & inhibits uterine activity (maintain uterine quiescence) Semin Perinatol. 2016 Aug; 40(5): 273–280 7 Non-hormonal Actions • Immunomodulatory or anti-inflammatory action • Progesterone along with HCG and cortisol inhibits the tissue rejection and protect the conceptus • Progesterone blocks the chemokines - transcription factor, positively regulating PIBF (Progesterone Induced Blocking Factor) • Favor shift of Th1-Th2 balance towards Th2 type
- 7. Low Progesterone levels leads to Gynecological Disorders Premenstrual Syndrome Abnormal uterine bleeding (AUB) Irregular or painful menstruation Endometriosis Pregnancy Related Disorders Vaginal bleeding in pregnancy/ Threatened Abortion Recurrent pregnancy loss/ Recurrent miscarriage 8 Obstet Gynecol Clin North Am. 2015 Mar; 42(1): 135–15 Indian J Endocr Metab 2013;17:44-9 Gynecological Endocrinology. 2016, 32:2, 97-106 Therefore, progestogens that mimic the activity of progesterone have been used extensively in an attempt to overcome progesterone deficiency
- 8. Recurrent pregnancy loss (RPL)/Recurrentmiscarriage • According to ASRM & ESHRE Recurrent pregnancy loss is defined as two or more clinical failed pregnancies before 20 weeks’ gestation • RPL constitutes for 1-5% of infertile couple and 12-15% of all pregnancies in India Rev Obstet Gynecol. 2009 Spring; 2(2): 76–83. Steven L. Bloom. Williams Obstetrics 24th edition, 2014 American Society of Reproductive Medicine (ASRM) European Society for Human Reproduction and Embryology (ESHRE) 18
- 9. CausesofRPL/RepeatedMiscarriage 19 In almost 50% of the cases no cause is identified (Idiopathic) Reasons • Heterogenous condition • Pathogenesis is multifactorial, complex and poorly understood • In the cases of idiopathic recurrent miscarriage (IRM), several preventive treatment options are used to avoid further pregnancy failures Aust N Z J Obstet Gynaecol 2019; 59: 36–44
- 10. ThreatenedAbortion • WHO - Pregnancy-related bloody vaginal discharge or frank bleeding during the first half of pregnancy without cervical dilatation • Symptoms • Early pregnancy with lower abdominal pain, and/or vaginal bleeding • Nearly 25% of pregnant women have some degree of vaginal bleeding BJOG. 2010;117(3): 245-257 Mouri MI, Rupp TJ. Threatened Abortion. [Updated 2019 May 6]. In: StatPearls [Internet]. BMJ. 2004 Jul 17; 329(7458): 152–155. 21
- 11. ThreatenedAbortion Causes: BJOG. 2010;117(3): 245-257 Mouri MI, Rupp TJ. Threatened Abortion. [Updated 2019 May 6]. In: StatPearls [Internet]. BMJ. 2004 Jul 17; 329(7458): 152–155. Diagnosis: • Fetal cardiac activity on ultrasound • Complete blood count • Beta-hCG level • Progesterone level Management: • Bed rest • Progesterone treatment for women with symptoms of threatened miscarriage 22
- 12. Luteal Phase Deficiency (LPD) • It is a condition of insufficient progesterone exposure to maintain a normal secretory endometrium and allow for normal embryo implantation and growth. • Seen in women with PCOS, thyroid disorders and prolactin disorder • Luteal phase insufficiency is one of the reasons for implantation failure and has been responsible for miscarriages and unsuccessful assisted reproduction (infertility treatment) • Diagnosed in 3-20% of patients who are infertile and in 5-60% of patients experiencing recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2015 Mar; 42(1): 135–15 Indian J Endocr Metab 2013;17:44-9 Luteal Phase Dysfunction. https://emedicine.medscape.com/article/254934-overview#a5
- 13. LPD In Assisted Reproduction Technique (ART) • ART - Include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of establishing a pregnancy. • Low progesterone environment is created iatrogenically due to interventions in assisted reproductive technology (ART) • To correct the luteal phase defect in stimulated IVF/ICSI cycles, progesterone and /or human chorionic gonadotrophin (hCG) can be administered • ART cycles involving use of a GnRH agonists or antagonists, hCG, progesterone supplementation yields higher pregnancy rates • Progesterone supplementation is beneficial in women with history of recurrent miscarriages Indian J Endocr Metab 2013;17:44-9
- 14. Classification of Progestogens 26 • Only certain progestogens are to be used for pregnant women. The following progestogens had been studied: 1. Dydrogesterone (oral) 2. Micronized progesterone (vaginal) 3. 17- Hydroxyprogesterone caproate (intramuscular)
- 15. 27 Dydrogesterone versus Micronized Progesterone Receptor Selectivity Biological activity Dydrogesterone Progesterone Progestogenic + + Anti-gonadotropic – + Anti-estrogenic + + Estrogenic – – Androgenic – – Anti-androgenic ±* ± Glucocorticoid – + Anti-mineralocorticoid ± + Dydrogesterone is selective for the progesterone receptor, avoiding other receptor-related side effects *Dydrogesterone has less pronounced anti-androgenic effects than progesterone; + effective; ± weakly effective; – not effective Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. Dydrogesterone CCDS. 23 June 2015. Rižner TL, et al. Steroids 2011; 76(6):607-615.
- 16. Limitation with Available Progesterone • Drowsiness • Pruritis (itching) Oral natural micronized progesterone • Results in higher uterine concentrations, but often uncomfortable in presence of vaginal bleeding, or may be washed out if bleeding is severe • Vaginal irritation and discharge Vaginal natural micronized progesterone suppositories • Need specific applicator • In India due to social reasons use of vaginal preparation is not preferred Vaginal progesterone gel • Provides optimal blood levels but can induce abscesses formation & extremely painful Injectable Howard Carp. Gynecological Endocrinology, 2012; Early Online: 1–8 Open Acc J Repro & Sexual Disord 1(4) - 2018. OAJRSD.MS.ID.000119 J Reprod Med. 1995 Jul;40(7):521-4.. 28
- 17. Dydrogesterone Class: Synthetic progesterone • Dydrogesterone is retroprogesterone, stereoisomer of progesterone, with additional double bond between carbons 6 and 7 (bent confirmation) which is thought to mediate its key properties Progesterone Dydrogesterone 1. Schindler AE et al. Maturitas 2009; 65(Suppl 1): S3-S11. 29 Small changes can make a difference Enhances the progestogenic effects (improved bioavailability, and specificity and affinity for the progesteronereceptor)
- 18. MechanismofAction Menstrual disorders/Dysmenorrhea • Works by regulating the healthy growth and normal shedding of the womb lining by acting on progesterone receptors in the uterus • Pelvic pain in dysmenorrhea is due to increase production of prostaglandins. • Dydrogesterone exert its beneficial effects through a decrease in the rate of prostaglandin synthesis, since this rate has been shown to be inversely proportional to levels of progesterone. Endometriosis • initial decidualisation of endometrial tissue and eventual atrophy. • Decrease production of prostaglandins and inflammatory cytokines In Recurrent miscarriage/threatened abortion • Anti-abortive effect: Increase production of PIBF and inducing T-helper 2 (Th2) cell dependent cytokines, thereby shifting the balance towards a Th2- dominated, cyto-protective immune response • Relaxes uterine muscles Luteal Phase Support • Elicit biochemical changes consistent with secretory transformation of endometrium https://doi.org/10.1101/603720. Reprod Biomed Online. 2019 Feb;38(2):249-259 Dydrogesteone monograph). 30
- 19. Pharmacokinetics Parameters Absorption • Rapidly absorbed after oral administration • Tmax : 0.5 Hrs • Half life: 5 to 7 Hrs • AUC: 40 • Cmax: 25 Distribution • The plasma protein binding is unknown Metabolism • Completely metabolized • Metabolite : 20-dihydrodydrogesterone, another potent progestogen Excretion • After oral administration of labelled dydrogesterone on average 63% of the dose is excreted into the urine. • Within 72 hours excretion is complete Prescribing information of Innovator. 31
- 20. Indications&Dosage Indication Dosage Dysmenorrhoea 10 or 20mg per day from day 5 to day 25 of the menstrual cycle. Endometriosis 10 to 30 mg per day from day 5 to day 25 of the cycle or continuously Dysfunctional Uterine Bleeding Treatment is started to arrest a bleeding episode, 20 or 30 mg dydrogesterone per day is to be given for up to 10 days For continuous treatment, 10 or 20 mg dydrogesterone per day should be given during the second half of the menstrual cycle Secondary Amenorrhoea 10 or 20 mg dydrogesterone per day, to be given daily for 14 days during the second half of the theoretical menstrual cycle to produce an optimum secretary transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen. Pre-menstrual syndrome 10 mg dydrogesterone twice daily starting with the second half of the menstrual cycle until the first day of the next cycle. The starting day and the number of treatment days will depend on the individual cycle length. Irregular cycles 10 or 20 mg dydrogesterone per day starting with the second half of the menstrual cycle until the first day of the next cycle. The starting day and the number of treatment days will depend on the individual cycle length. Prescribing information of Innovator. Monograph. Dydrogesterone
- 21. Indications&Dosage Indication Dosage Threatened abortion Starting dose: 4 tablets of Dydrogesterone at once followed by 1 tablet of Dydrogesterone mg every 8 hours. Dosages of 10 mg several times a day should be spread over the day. It is recommended that treatment should start at the highest dose. If the symptoms persist or recur during the treatment, the dose should be increased by 1 tablet of Dydrogesterone every 8 hours. The effective dose should be maintained for one week after symptoms have ceased; it can then be gradually reduced. If the symptoms recur, the treatment should be resumed immediately at the effective dose. Habitual abortion 1 tablet of Dydrogesterone a day up to the 20th week of pregnancy; the dose can then be gradually reduced. Treatment should preferably be started before conception. If the symptoms of threatened abortion occur during treatment, treatment should be continued as described for that indication. Infertility due to luteal insufficiency 1 tablet of Dydrogesterone a day from the 14th to the 25th day of the cycle. Treatment should be continued for at least 6 consecutive cycles. It is advisable to continue this treatment for the first months of any pregnancy at dosages as indicated for habitual abortion. Prescribing information of Innovator. There is no relevant use of dydrogesterone before the menarche. The safety and efficacy of dydrogesterone in adolescents aged from 12 to 18 years has not been established
- 22. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization 34 LOTUS 1 Trial • Study Type: International Phase III randomized controlled trial, performed across 38 sites • N= 1031 premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF • Participants: Subjects received either oral dydrogesterone (n = 520) or MVP (n = 511) • Primary end point: Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer Hum Reprod. 2017 May 1;32(5):1019-1027
- 23. 35 Pregnancy status post-treatment • Dydrogesterone was as effective as the current standard of care in women undergoing IVF. • Owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment. Hum Reprod. 2017 May 1;32(5):1019-1027
- 24. 36 LOTUS 2 Trial • Study Type: Randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide • N= 1034 premenopausal women (>18 to <42 years of age) undergoing IVF • Participants: Subjects received either 30mg oral dydrogesterone (n = 520) or 8% MVP gel 90mg (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation • Primary end point: Presence of fetal heart beats at 12 weeks of gestation, as determined by transvaginal ultrasound. Tournaye H et al. Hum Reprod. 2017;32(5):1019-1027. doi:10.1093/humrep/dex023
- 25. 37 • Oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. • Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF. Pregnancy and live birth rates post-treatment FAS, full analysis sample; IVF, in vitro fertilization; MVP, micronized vaginal progesterone; PPS, per-protocol sample. Non-inferiority of oral dydrogesterone was demonstrated Tournaye H et al. Hum Reprod. 2017;32(5):1019-1027. doi:10.1093/humrep/dex023
- 26. A RandomizedTrial of Progesterone in Womenwith Recurrent Miscarriages Total: 522 participants • Dydrogesterone: N=175 • Placebo: N=173 • Healthy controls: N=174 Active Drug: Dydrogesterone Dosage: 10 mg BID (20 mg daily) tablet Treatment initiation: Confirmation of pregnancy, preferably at 4–8 weeks of gestation (enrolled after fetal heart activity confirmed) End of treatment: Treatment ended at 20 weeks of gestation 3.5% 16.8% 6.9% 18 16 14 12 10 8 6 4 2 0 Healthy controls, no RM (N=174) Placebo (N=173) Dydrogesterone (N=175) Miscarriage rate, % Risk of miscarriage was 2.4times higher in the placebo than the dydrogesterone group The present study supports the use of dydrogesterone in women with recurrent abortions to improve pregnancy outcome, such as a reduction in abortions and improved gestational age and baby weight at delivery. Fertil Steril. 2014 Nov;102(5):1357-1363.e3. 38
- 27. Dydrogesterone In Threatened Abortion • Study Duration: 2 year • N = 154 • Age: Majority <30 years old, only 32 patients ≥35 years old • Dose: Initial dose: 40 mg followed by 10 mg twice a day for 1 week or conservative treatment Corpus luteal support with dydrogesterone has been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion 86.3% 95.9% Dydrogesterone Control Grp J Steroid Biochem Mol Biol . 2005 Dec;97(5):421-5. 39
- 28. Dydrogesterone Usage Pattern In India – India Gynecologist Survey • Total 1168 gynaecologists across India 40 Dydrogesterone 10 mg twice daily was the most commonly preferred dosage 73% Doctors 70 76 85 36 1007 0 200 400 600 800 1000 1200 RPL LPS Threatened miscarriage Habitual miscarriage All of the abvoe Doctors Count Most Suitable Condition for use of Dydrogesterone Poor tolerability, compliance and lower efficacy as major limitations of micronized progesterone 68% Doctors Noted more than 40% of clinical pregnancy rate after dydrogesterone usage 30% Doctors Int J Reprod Contracept Obstet Gynecol. 2021 Oct;10(10):3793-3798 The effectiveness and the tolerability of dydrogesterone is valued by Indian gynaecologists which accounts for its robust clinical utility
- 29. Dydrogesterone versus Micronized Progesterone Bioavailability and OralAdministration Oral bioavailability 28% <5% 10mg 100 – 300mg Dose Micronized Progesterone Dydrogesterone has ~5.6 times better oral bioavailability than progesterone Dydrogesterone requires a 10–20 times lower oral dose than micronized progesterone Endocr Rev. 2013 Apr;34(2):171-208. Dydrogesterone 41
- 30. Guidelines and Recommendations Recommendations 1. For women presenting with a clinical diagnosis of threatened miscarriage, there is a reduction in the rate of spontaneous miscarriage with the use of Dydrogesterone 2. For women presenting with a clinical diagnosis of recurrent miscarriage, 3 or more, there is a reduction in the rate of miscarriage with the use of Dydrogesterone European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens Gynecol Endocrinol. 2015 Jun;31(6):447-9.ar 42
- 31. ESHREguideline: ovarian stimulationfor IVF/ICSI 43 Human Reproduction Open, pp. 1–13, 2020 doi:10.1093/hropen/hoaa009
- 32. Dydrogesterone Clinical Benefits Indications Advantages PMS • Reduces physical symptoms Dysmenorrhea • Relieves the pain associated with incapacitating dysmenorrhea • ↓ the need for analgesics Secondary amenorrhea • Adequately induces bleeding when the endometrium is sufficiently primed with oestrogens DUB and irregular cycles • Reduce heavy menstrual bleeding in patients with ovulatory cycles Endometriosis • Reduces pelvic pain • Does not inhibiting ovulation, so that patients are able to become pregnant during treatment HRT • Effectively guard against the development of endometric hyperplasia. Provide excellent cycle control in sequentially combined HRT • No clinical significant interaction with oestrogen • Does not cause changes in body weight, blood pressure, glucose tolerance or blood lipid ratios. Luteal insufficiency • Almost doubles pregnancy rates compared to placebo Threatened and habitual abortion • Restores luteal function & exerts anti-abortive effects • No inhibitory effect on ovulation • Higher success rate 70% 44
- 33. Safety of Oral Dydrogesterone • 113 million women and about 20 million foetuses have been exposed to dydrogesterone since 1960 • It is not chemically related to testosterone and has a low affinity for the androgen receptor • Even at high doses and prolonged treatment, it does not cause unwanted androgenic side-effects such as voice changes, hirsutism and acne in the adult female • It does not interfere with normal ovulation • Clinical studies have demonstrated a good benefit risk profile comparable to that of micronized vaginal progesterone during luteal phase support • Large and robust Lotus - Phase 3 clinical trials revealed no new safety concerns of its use during early pregnancy for either the mother or the developing fetus 45
- 34. Summary Dydrogesterone is a selective progesterone agonist No estrogenic, no androgenic, no thermogenic, & no corticoid activity It has been used to treat a variety of conditions related to progesterone deficiency since the 1960s Available in more than 100 countries Enhanced oral bioavailability - circumventing the inconvenience and discomfort related to intravaginal or intramuscular progesterone applications Equivalent dose of oral dydrogesterone is 10–20-fold lower than that of oral micronized progesterone At recommended doses, no effect on ovulation Recently approved in luteal phase support as part of an assisted reproductive technology (ART) treatment Well established safety and tolerability 46
- 35. Thank You 47
Editor's Notes
- The normal menstrual cycle can be divided into two phases: follicular and luteal, which are separated by ovulation and bookended by the first day of menstrual bleeding. The follicular phase is dominated by the development of the preovulatory follicle, resulting in estrogen-stimulated endometrial proliferation, whereas the corpus luteum (CL) of its namesake luteal phase produces progesterone, which inhibits endometrial proliferation and determines endometrial receptivity. Without both phases working in series, natural reproduction is not possible. Progesterone is essential for the implantation and maintenance of early human pregnancy. The follicular phase of the menstrual cycle is estrogen dominated, while the luteal phase of the menstrual cycle is progesterone dominated (10). Secretion of progesterone converts an estrogen primed proliferative endometrium into a secretory one, which is receptive to the blastocyst. Before ovulation, granulosa cells in the follicle biosynthesize and secrete estrogen. After follicle rupture and release of the ovum, these granulosa cells mature to form the CL, which is responsible for secretion of progesterone and estrogen in the latter part of the cycle. In human, if fertilization does not occur within 1 to 2 days, the CL will continue to enlarge for 10–12 days followed by regression of the gland and concomitant cessation of estrogen and progesterone release. If fertilization occurs, the CL will continue to grow and function for the first 2 to 3 months of pregnancy. After this time it will slowly regress as the placenta assumes the role of hormonal biosynthesis for the maintenance of pregnancy
- After implantation in endometrial lining blastocyst begins to secrete human chorionic gonadotropin (hCG) hCG promotes the maintenance of the corpus luteum within the ovary and prevents its degeneration As a consequence of this, the corpus luteum survives and continues to produce both oestrogen and progesterone Progesterone also functions to maintain the endometrium and thicken the cervix The levels of hCG are maintained for roughly 8 – 10 weeks while the placenta is being developed After this time, the placenta becomes responsible for progesterone secretion and nourishing the embryo At this point the corpus luteum is no longer required and begins to degenerate as hCG levels drop
- Progesterone is essential for creating a suitable endometrial environment for embryo implantation, as well as for the maintenance of pregnancy. For that purpose, progesterone is believed to help in mediating an anti-inflammatory immune response to the allogenic fetus and in inducing uterine smooth muscle relaxation [1–3]. Progesterone is produced by the corpus luteum after ovulation and during the early first trimester, until the placental function is established between 7 and 11 weeks of gestation, and thereafter becomes the main source of progesterone production. The lack of adequate progesterone production by the corpus luteum after ovulation has been associated with infertility After implantation, deficiencies in progesterone production or function can lead to pregnancy loss. This has been supported by studies demonstrating that either a lack of progesterone production due to a lutectomy prior to 7 weeks of gestation [6], or disrupted binding to progesterone receptors caused by progesterone agonists, such as mifepristone both result in pregnancy loss. Therefore, progestogens that mimic the activity of progesterone have been used extensively in an attempt to overcome progesterone deficiency associated with infertility and miscarriage
- Primary amenorrhea is the absence of a first period in a young woman by the age of 16. Secondary amenorrhea is when a woman who has had normal menstrual cycles stops getting her monthly period.
- Menopause hormone therapy (MHT) is the most efficient treatment for symptoms of acute climacteric syndrome and for efficient prevention of long-term estrogen deficiency. Vaginal administration of low doses of estrogen is a therapy of choice for treatment and prevention of urogenital atrophy and its consequences. Systemic treatment may include estrogen, but an equally efficient alternative is tibolone. Nonhormonal therapy relies on phytoestrogens, black cohosh extract, and serotonin reuptake inhibitors.
- First‐trimester bleeding is a common complication which affects 16–25% of all pregnancies.1 Threatened miscarriage is diagnosed on the basis of documented fetal cardiac activity on ultrasound with a history of vaginal bleeding in the presence of a closed cervix. Bleeding during pregnancy can cause maternal anxiety and emerging evidence suggests that it may be associated with poor fetal and maternal outcomes.2-9 It is hypothesised that first‐trimester bleeding may indicate an underlying placental dysfunction, which may manifest later in pregnancy causing adverse outcomes such as increased risk of pre‐eclampsia, preterm delivery, preterm prelabour rupture of membranes (PPROM), placental abruption and intrauterine growth restriction (IUGR).8 Knowledge about the outcome of ongoing pregnancies following first‐trimester bleeding is relevant to both women and their obstetricians in order to plan antenatal care and consider clinical interventions in pregnancy. Although general practitioners and gynaecologists often see this condition, management of threatened miscarriage is mostly empirical. Bed rest is routinely recommended, and about a third of women presenting with threatened miscarriage are prescribed drugs.w2 However, two thirds of the general practitioners recommending this do not believe it affects outcome Summary points One in five pregnancies is complicated by vaginal bleeding before 20 weeks' gestation A large empty gestational sac, discrepancy between gestational age and crown to rump length, fetal bradycardia or absence of fetal heart activity at presentation, advanced maternal age, history of recurrent pregnancy loss, a maternal serum progesterone < 45 nmol/l or low maternal serum hCG or inhibin A are adverse prognostic factors Fetal heart activity and lack of adverse prognostic factors conveys a favourable prognosis Although bed rest and progesterone supplements are often advised, little evidence supports their effectiveness Give anti-Rh D immune globulin to non-sensitised women with symptoms near, at, or after 12 gestational weeks
- First‐trimester bleeding is a common complication which affects 16–25% of all pregnancies.1 Threatened miscarriage is diagnosed on the basis of documented fetal cardiac activity on ultrasound with a history of vaginal bleeding in the presence of a closed cervix. Bleeding during pregnancy can cause maternal anxiety and emerging evidence suggests that it may be associated with poor fetal and maternal outcomes.2-9 It is hypothesised that first‐trimester bleeding may indicate an underlying placental dysfunction, which may manifest later in pregnancy causing adverse outcomes such as increased risk of pre‐eclampsia, preterm delivery, preterm prelabour rupture of membranes (PPROM), placental abruption and intrauterine growth restriction (IUGR).8 Knowledge about the outcome of ongoing pregnancies following first‐trimester bleeding is relevant to both women and their obstetricians in order to plan antenatal care and consider clinical interventions in pregnancy. Although general practitioners and gynaecologists often see this condition, management of threatened miscarriage is mostly empirical. Bed rest is routinely recommended, and about a third of women presenting with threatened miscarriage are prescribed drugs.w2 However, two thirds of the general practitioners recommending this do not believe it affects outcome Summary points One in five pregnancies is complicated by vaginal bleeding before 20 weeks' gestation A large empty gestational sac, discrepancy between gestational age and crown to rump length, fetal bradycardia or absence of fetal heart activity at presentation, advanced maternal age, history of recurrent pregnancy loss, a maternal serum progesterone < 45 nmol/l or low maternal serum hCG or inhibin A are adverse prognostic factors Fetal heart activity and lack of adverse prognostic factors conveys a favourable prognosis Although bed rest and progesterone supplements are often advised, little evidence supports their effectiveness Give anti-Rh D immune globulin to non-sensitised women with symptoms near, at, or after 12 gestational weeks
- LPD has been diagnosed in 3-20% of patients who are infertile and in 5-60% of patients experiencing recurrent pregnancy loss. However, data show that 6-10% of women who are fertile demonstrate an inadequate luteal phase, which confirms the need for a better understanding of normal variations in the menstrual cycle and in variations that could be pathologic. Epidemiology Frequency United States No consensus has been achieved regarding frequency; however, a 1991 symposium hypothesized that luteal phase deficiency (LPD) occurs in 3-10% of infertile patients, and healthy women have deficient luteal phase production of progesterone on a sporadic basis. Pathophysiology The following mechanisms can cause an inadequate endometrial response to hormonal stimulation during the luteal phase. [4] Abnormal follicular development Abnormal follicular development results from inadequate follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary gland. FSH stimulates the granulosa cells of the developing follicle to produce estradiol from the conversion of its substrate androstenedione. A decrease in FSH release results in reduced granulosa cell growth and lower estradiol levels. Because the corpus luteum is not a de novo structure but is a direct result of the follicle, it shows the effects of abnormal folliculogenesis with decreased progesterone production. Abnormal luteinization An inadequate LH release can cause a decrease in androstenedione from the theca cells. Less substrate results in a decrease in estradiol and, subsequently, lower progesterone levels. Additionally, a suboptimal LH surge at ovulation causes deficient progesterone because of inadequate luteinization of the granulosa cells. Uterine abnormalities Uterine abnormalities cause changes in vascularization of the endometrium despite normal progesterone levels. Myomas, uterine septa, and endometritis are responsible for poor secretory changes in the endometrium. Hypocholesterolemia Hypocholesterolemia is the substrate responsible for initiation of the steroid pathway. A deficiency results in low-to-absent progesterone production and a luteal phase defect. Medication Summary The goals of pharmacotherapy in luteal phase deficiency are to restore ovarian function, reduce morbidity, and prevent complications. Class Summary Medical treatment centers on hormonal support of the patient's luteal phase. Bromocriptine (Parlodel) Used if hyperprolactinemia is the underlying pathology causing LPD. Tablets can be used vaginally in patients who cannot tolerate adverse GI effects. Levothyroxine (Levoxyl, Synthroid) If LPD is caused by hypothyroidism, correction of endocrine disease results in normal luteal phase. Clomiphene citrate (Clomid, Serophene) Stimulates release of pituitary gonadotropins. Improves folliculogenesis and, therefore, the luteal phase. Works best in biopsies that are lagging 1 week behind the date of endometrial sampling. Cabergoline (Dostinex) Long-acting dopamine receptor agonist with high affinity for D2 receptors. Prolactin secretion by anterior pituitary predominates under hypothalamic inhibitory control exerted through dopamine. Progesterone intravaginal gel Progesterone supplementation may be administered PO, IM, or vaginally. Oral progesterone is metabolized rapidly in liver, and the metabolites have little effect on endometrial activity. When administered IM, fails to achieve adequate levels of endometrial progesterone compared with vaginal forms. Vaginal progesterone is DOC for LPD; this is because of the proximity of the uterus to where the medication is delivered. Vaginal gel 8%, either qd or bid, is better tolerated compared to suppository form. Gel also provides increased receptor sites in the endometrium compared with suppository. Treatment begins 2 days after ovulation as determined by ovulation predictor kit. Correction of LPD can be confirmed by repeat EB. Follitropins (Follistim, Gonal-F, Fertinex) Improve folliculogenesis, which increases total progesterone. This remains an expensive method associated with increased patient discomfort because medication is administered SC.
- LPD has been diagnosed in 3-20% of patients who are infertile and in 5-60% of patients experiencing recurrent pregnancy loss. However, data show that 6-10% of women who are fertile demonstrate an inadequate luteal phase, which confirms the need for a better understanding of normal variations in the menstrual cycle and in variations that could be pathologic. Epidemiology Frequency United States No consensus has been achieved regarding frequency; however, a 1991 symposium hypothesized that luteal phase deficiency (LPD) occurs in 3-10% of infertile patients, and healthy women have deficient luteal phase production of progesterone on a sporadic basis. Pathophysiology The following mechanisms can cause an inadequate endometrial response to hormonal stimulation during the luteal phase. [4] Abnormal follicular development Abnormal follicular development results from inadequate follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary gland. FSH stimulates the granulosa cells of the developing follicle to produce estradiol from the conversion of its substrate androstenedione. A decrease in FSH release results in reduced granulosa cell growth and lower estradiol levels. Because the corpus luteum is not a de novo structure but is a direct result of the follicle, it shows the effects of abnormal folliculogenesis with decreased progesterone production. Abnormal luteinization An inadequate LH release can cause a decrease in androstenedione from the theca cells. Less substrate results in a decrease in estradiol and, subsequently, lower progesterone levels. Additionally, a suboptimal LH surge at ovulation causes deficient progesterone because of inadequate luteinization of the granulosa cells. Uterine abnormalities Uterine abnormalities cause changes in vascularization of the endometrium despite normal progesterone levels. Myomas, uterine septa, and endometritis are responsible for poor secretory changes in the endometrium. Hypocholesterolemia Hypocholesterolemia is the substrate responsible for initiation of the steroid pathway. A deficiency results in low-to-absent progesterone production and a luteal phase defect. Medication Summary The goals of pharmacotherapy in luteal phase deficiency are to restore ovarian function, reduce morbidity, and prevent complications. Class Summary Medical treatment centers on hormonal support of the patient's luteal phase. Bromocriptine (Parlodel) Used if hyperprolactinemia is the underlying pathology causing LPD. Tablets can be used vaginally in patients who cannot tolerate adverse GI effects. Levothyroxine (Levoxyl, Synthroid) If LPD is caused by hypothyroidism, correction of endocrine disease results in normal luteal phase. Clomiphene citrate (Clomid, Serophene) Stimulates release of pituitary gonadotropins. Improves folliculogenesis and, therefore, the luteal phase. Works best in biopsies that are lagging 1 week behind the date of endometrial sampling. Cabergoline (Dostinex) Long-acting dopamine receptor agonist with high affinity for D2 receptors. Prolactin secretion by anterior pituitary predominates under hypothalamic inhibitory control exerted through dopamine. Progesterone intravaginal gel Progesterone supplementation may be administered PO, IM, or vaginally. Oral progesterone is metabolized rapidly in liver, and the metabolites have little effect on endometrial activity. When administered IM, fails to achieve adequate levels of endometrial progesterone compared with vaginal forms. Vaginal progesterone is DOC for LPD; this is because of the proximity of the uterus to where the medication is delivered. Vaginal gel 8%, either qd or bid, is better tolerated compared to suppository form. Gel also provides increased receptor sites in the endometrium compared with suppository. Treatment begins 2 days after ovulation as determined by ovulation predictor kit. Correction of LPD can be confirmed by repeat EB. Follitropins (Follistim, Gonal-F, Fertinex) Improve folliculogenesis, which increases total progesterone. This remains an expensive method associated with increased patient discomfort because medication is administered SC.
- J Reprod Med. 1995 Jul;40(7):521-4.
- Dydrogesterone has a methyl group at carbon 10 in the alpha-orientation rather than the beta-orientation and a hydrogen at carbon 9 in the alpha-orientation rather than the b-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
- Hum Reprod . 2017 May 1;32(5):1019-1027. doi: 10.1093/humrep/dex023. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization Herman Tournaye 1, Gennady T Sukhikh 2, Elke Kahler 3, Georg Griesinger 4 Affiliations expand PMID: 28333318 PMCID: PMC5400051 DOI: 10.1093/humrep/dex023 Free PMC article Erratum in A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization.Tournaye H, Sukhikh GT, Kahler E, Griesinger G.Hum Reprod. 2017 Oct 1;32(10):2152. doi: 10.1093/humrep/dex266.PMID: 28938733 Free PMC article. No abstract available. Abstract Study question: Is oral dydrogesterone 30 mg daily (10 mg three times daily [TID]) non-inferior to micronized vaginal progesterone (MVP) 600 mg daily (200 mg TID) for luteal support in in vitro fertilization (IVF), assessed by the presence of fetal heartbeats determined by transvaginal ultrasound at 12 weeks of gestation? Summary answer: Non-inferiority of oral dydrogesterone versus MVP was demonstrated at 12 weeks of gestation, with a difference in pregnancy rate and an associated confidence interval (CI) that were both within the non-inferiority margin. What is known already: MVP is routinely used in most clinics for luteal support in IVF, but it is associated with side effects, such as vaginal irritation and discharge, as well as poor patient acceptance. Dydrogesterone may be an alternative treatment due to its patient-friendly oral administration. Study design, size, duration: Lotus I was an international Phase III randomized controlled trial, performed across 38 sites, from August 2013 to March 2016. Subjects were premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF. A centralized electronic system was used for randomization, and the study investigators, sponsor's study team, and subjects remained blinded throughout the study. Participants/materials, setting, methods: In total, 1031 subjects were randomized to receive either oral dydrogesterone (n = 520) or MVP (n = 511). Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer. Main results and the role of chance: In the full analysis set (FAS), 497 and 477 subjects in the oral dydrogesterone and MVP groups, respectively, had an embryo transfer. Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates at 12 weeks of gestation of 37.6% and 33.1% in the oral dydrogesterone and MVP treatment groups, respectively (difference 4.7%; 95% CI: -1.2-10.6%). Live birth rates of 34.6% (172 mothers with 213 newborns) and 29.8% (142 mothers with 158 newborns) were obtained in the dydrogesterone and MVP groups, respectively (difference 4.9%; 95% CI: -0.8-10.7%). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP. Limitations, reasons for caution: The analysis of the results was powered to consider the clinical pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the differences between treatments in live birth rate, observed in this study, should therefore be made with caution. Wider implications of the findings: Oral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment. Study funding/competing interest(s): Sponsored and supported by Abbott Established Pharmaceuticals Division. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring and Mithra (now Allergan) and H.T. has received consultancy fees from Finox, Ferring, Abbott, ObsEva and Ovascience. G.S. has nothing to disclose. E.K. is an employee of Abbott GmbH. G.G. has received investigator fees from Abbott during the conduct of the study; outside of this submitted work, G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, Glycotope, as well as personal fees from VitroLife, NMC Healthcare LLC, ReprodWissen LLC and ZIVA LLC.
- Randomized Controlled Trial Fertil Steril . 2014 Nov;102(5):1357-1363.e3. doi: 10.1016/j.fertnstert.2014.07.1251. Epub 2014 Sep 17. Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial Ashok Kumar 1, Nargis Begum 2, Sudha Prasad 2, Sarita Aggarwal 3, Shashi Sharma 4 Affiliations expand PMID: 25241364 DOI: 10.1016/j.fertnstert.2014.07.1251 Abstract Objective: To study the impact of administration of dydrogesterone in early pregnancy on pregnancy outcome and its correlation with Th1 and Th2 cytokine levels. Design: Double-blind, randomized, placebo-controlled study. Setting: A medical college and its associated hospital. Patient(s): Women with either: [1] a history of idiopathic recurrent pregnancy loss (RPL), in either a dydrogesterone group or a placebo group, or [2] no history of miscarriage. Intervention(s): Dydrogesterone 20 mg/day from confirmation of pregnancy to 20 weeks of gestation. Main outcome measure(s): Occurrence of another pregnancy loss and concentrations of T-helper (Th)1 (interferon-γ and tumor necrosis factor-α) and Th2 (interleukin (IL)-4 and IL-10) cytokines in serum at recruitment (4-8 weeks of gestation) and at abortion or 20 weeks of gestation, using commercially available ELISA kits. Result(s): Occurrence of another abortion after 3 consecutive abortions was significantly higher (29 of 173; 16.76%) in women with RPL compared with healthy pregnant controls (6 of 174; 3.45%). Risk of occurrence of miscarriage after 3 abortions was 2.4 times higher in the placebo group vs. the treatment group (risk ratio=2.4, 95% CI=1.3-5.9). Mean gestational age at delivery (excluding those aborted before 20 weeks of gestation) increased significantly in the dydrogesterone group (38.01±1.96 weeks) compared with the placebo group (37.23±2.41 weeks). Baby weight was significantly lower in the placebo group (2421.4±321.6 g) compared with the healthy pregnant controls (2545.3±554.3 g). At recruitment, serum IL-4 and tumor necrosis factor-α levels were significantly lower in the RPL group compared with the healthy pregnant controls. However, serum interferon-γ level was significantly higher in the RPL group (8.87±0.72 pg/mL) compared with the healthy pregnant controls (8.08±1.27 pg/mL). Conclusion(s): The present study supports the use of dydrogesterone in women with recurrent abortions to improve pregnancy outcome, such as a reduction in abortions and improved gestational age and baby weight at delivery. However, these outcomes were not modulated by Th1 and Th2 cytokine production.
- Randomized Controlled Trial J Steroid Biochem Mol Biol . 2005 Dec;97(5):421-5. doi: 10.1016/j.jsbmb.2005.08.013. Epub 2005 Nov 15. Dydrogesterone in threatened abortion: pregnancy outcome M H Omar 1, M K Mashita, P S Lim, M A Jamil Affiliations expand PMID: 16293412 DOI: 10.1016/j.jsbmb.2005.08.013 Abstract Objective: To determine whether therapy with dydrogesterone in threatened abortion during the first trimester of pregnancy will improve pregnancy outcome. Design: Prospective open study. Subjects: Pregnant women presenting to the obstetric and gynaecology clinic admitting center with vaginal bleeding before 13 weeks gestation were evaluated for entry into the study. Women were excluded if they had a history of recurrent miscarriage. Method: Eligible subjects were randomized to receive either dydrogesterone 40 mg stat dose followed by 10 mg twice a day for one week or conservative therapy. Results: One hundred and 54 women were recruited. There was no statistically significant differences between the two groups with regard to pre-treatment status. The continuing pregnancy success rate was significantly (p=0.037) higher in women treated with dydrogesterone (95.9%) compared with women who received conservative treatment (86.3%). The odds ratio of the success rate between dydrogesterone treatment and non-treatment was 3.773 (95% confidence interval: 1.009-14.108). Conclusion: Corpus luteal support with dydrogesterone has been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion.
- Review Endocr Rev . 2013 Apr;34(2):171-208. doi: 10.1210/er.2012-1008. Epub 2012 Dec 13. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects Frank Z Stanczyk 1, Janet P Hapgood, Sharon Winer, Daniel R Mishell Jr Affiliations expand PMID: 23238854 PMCID: PMC3610676 DOI: 10.1210/er.2012-1008 Free PMC article Abstract The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.