Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.

Effective, safe and rational pharmacotherapy of endogenic progesterone deficiency

Today, the most frequent complication of pharmacotherapy is an allergic reaction, the so-called drug or drug allergy. An allergic reaction can be caused both by the active ingredients and by the excipients included in the composition of the drug to provide a certain dosage form and its physicochemical properties. Vaginal progesterone preparations are characterized by a large variety of dosage forms: gels, tablets and gelatin capsules for intravaginal administration. It is known that the safety and efficacy of pharmacotherapy depend on the active substance, the dosage form, and the base of the intravaginal preparation, as well as the indices of adherence to medication therapy. At the same time, the base - excipients can cause the development of adverse reactions.The authors of the article, based on an analytical review of domestic and foreign literature, analyzed effective, safe and rational pharmacotherapy of endogenous progesterone deficiency.It is shown that micronization is currently used to improve the bioavailability of natural progesterone – a method of increasing solubility by reducing the particle size of the drug substance. Due to the high solubility of the substance, the risk of possible side effects is reduced, which allows increasing the safety of the drug.The peculiarity of the dosage form for vaginal administration is described. On the basis of the analysis of various forms of progesterone, the clinical efficacy of natural progesterone for vaginal administration has been substantiated.The authors found that the use of progesterone in sublingual and vaginal forms is the most rational in terms of convenience, efficacy and safety.

Comparative study between vaginal natural progesterone and oral dydrogesterone in prevention of red degeneration of uterine fibroid in pregnancy

Background: Uterine leiomyomas are highly prevalent benign monoclonal tumors, arising from the smooth muscle of the myometrium; they occur in up to 50-60% of reproductive age women, causing significant morbidity in up to 30% of women. The most serious complication of uterine fibroids; is red degeneration that causes severe pain, and may lead to preterm labour, miscarriage, fetal and maternal morbidity and mortality. Objective of this study was designed to compare between the effect of vaginal natural MP and oral dydrogesterone in prevention of red degeneration of uterine fibroid during pregnancy.Methods: Patients were recruited from El-Shatby Maternity University Hospital. They were 50 pregnant females, diagnosed having a uterine fibroid more than 3 cm in size then there were divided into two groups, Group A: twenty-five treated by vaginal natural progesterone, Group B: twenty-five treated by oral dydrogesterone. All patients at 14-15 weeks of gestational age underwent complete history taking, clinical examination and ultrasound examination for mean gestational age and assessment of the type and uterine fibroid.Results: Results showed that there were no statistically significant differences as regards age, obstetric history (gravidity and parity), number, Site, grade and size of the fibroid. There was a significant difference between the two studied groups, regarding the acute abdominal pain, it occurred to only 3 cases (12%) in Group A, versus to 16 cases (64%) in Group B. Regarding occurrence of red degeneration, it occurred only to 3 cases (12%) in Group A, while in Group B it occurred to 15 cases (60%).Conclusions: Vaginal natural micronized progesterone is more effective than oral dydrogesterone in prevention of red degeneration of uterine fibroid in pregnancy with fewer complications. Vaginal natural progesterone daily dose of 200 mg is recommended to all pregnant females with uterine fibroids.

The effect of early administration of rectal progesterone in IVF/ICSI twin pregnancies on the preterm birth rate: A randomized trial

Background: The rate of multiple pregnancies in IVF/ICSI ranges from 20-30% . The incidence of preterm birth in multiple pregnancies is as high as 60% and is even higher in pregnancies conceived after IVF & ICSI. The effect of progesterone on prevention of preterm birth in twins is controversial . Our group has proven a positive effect in reduction of preterm birth ,by starting progesterone from the mid-trimester ,in exclusively IVF/ICSI singleton pregnancies but not twins. The purpose of our current study was to explore the effect of earlier administration of natural progesterone, in IVF/ICSI twin pregnancies starting at 11-14 weeks for prevention of preterm birth. Methods: This is a double-blind, placebo controlled, single center, randomized clinical trial. Women with dichorionic twin gestations, following an IVF/ICSI trial were randomized to receive natural rectal progesterone (800 mg daily ) vs placebo, starting early from 11-14 weeks. They were randomized regardless of cervical length and had no previous history of preterm birth or known Mullerian anomalies. The primary outcome was, spontaneous preterm birth rate <37 weeks. The secondary Outcome was; spontaneous preterm birth <34,32,28 weeks and neonatal outcome. Results: A total of 203 women were randomized to both groups, final analysis included 199 women as 4 were lost to follow up. The base line characteristics as well as gestational age at delivery were not significantly different between the study and the placebo group (34.7±3.6 vs 34.5±4.5, P=0.626). Progesterone administration was not associated with a significant decrease in the spontaneous preterm birth rates <37 weeks (73.5% vs 68%, P = 0.551), <34 (20.6% vs 21.6%, P = 0.649), <32 (8.8% vs 12.4%, P = 0.46) & <28 (4.9 % vs 3.1 %, P = 0.555). Conclusions: Rectal natural progesterone starting from the first trimester in IVF/ICSI twin pregnancies did not reduce spontaneous preterm birth.The trial was registered on 31 January 2014 at www.ISRCTN.com, 69810120.

Effects of Natural Progesterone and Synthetic Progestin on Germ Layer Gene Expression in a Human Embryoid Body Model

Natural progesterone and synthetic progestin are widely used for the treatment of threatened abortion or in in vitro fertilization (IVF) cycles. This in vitro study aimed to assess whether the treatment with natural progesterone or synthetic progestin influences the germ layer gene expression on the early human embryonic development using human embryonic stem cells (hESCs)-derived embryoid bodies (hEBs) as a surrogate of early stage human embryonic development. Human EBs derived from hESCs were cultured for nine days, and were treated with natural progesterone (P4) or synthetic progestin, medroxyprogesterone acetate (MPA) at 10–7 M for five days. To reverse the effects of treatment, mifepristone (RU486) as progesterone antagonist was added to the hEBs for four days starting one day after the initiation of treatment. Mouse blastocysts (mBLs) were cultured in vitro for 24 h, and P4 or MPA at 10−7 M was treated for an additional 24 h. The treated embryos were further transferred onto in vitro cultured endometrial cells to evaluate chorionic gonadotropin (CG) expression. To analyze the effects of P4 or MPA, the expression of differentiation genes representing the three germ layers was investigated, GATA-binding factor 4 (GATA4), α-fetoprotein (AFP), hepatocyte nuclear factor (HNF)-3β, hepatocyte nuclear factor (HNF)-4α (endoderm), Brachyury, cardiac actin (cACT) (mesoderm), and Nestin (ectoderm), using quantitative reverse transcription PCR (qRT-PCR) and immunostaining. Significantly lower expressions of HNF-3β, HNF-4α, Brachyury, and Nestin were observed in MPA-treated hEBs (all p < 0.05), which was negated by RU486 treatment. This inhibitory effect of MPA was also observed in mouse embryos. Conclusively, the effects of natural progesterone and synthetic progestin may differ in the germ layer gene expression in the hEB model, which suggests that caution is necessary in the use of progestogen.

The effect of early administration of rectal progesterone in IVF/ICSI twin pregnancies on the preterm birth rate: A randomized trial

Background: The rate of multiple pregnancies in IVF/ICSI ranges from 20-30% . The incidence of preterm birth in multiple pregnancies is as high as 60% and is even higher in pregnancies conceived after IVF & ICSI. The effect of progesterone on prevention of preterm birth in twins is controversial . Our group has proven a positive effect in reduction of preterm birth ,by starting progesterone from the mid-trimester ,in exclusively IVF/ICSI singleton pregnancies but not twins. The purpose of our current study was to explore the effect of earlier administration of natural progesterone, in IVF/ICSI twin pregnancies starting at 11-14 weeks for prevention of preterm birth. Methods: This is a double-blind, placebo controlled, single center, randomized clinical trial. Women with dichorionic twin gestations, following an IVF/ICSI trial were randomized to receive natural rectal progesterone (800 mg daily ) vs placebo, starting early from 11-14 weeks. They were randomized regardless of cervical length and had no previous history of preterm birth or known Mullerian anomalies. The primary outcome was, preterm birth rate <37 weeks. The secondary Outcome was; preterm birth <34,32,28 weeks and neonatal outcome. Results: A total of 203 women were randomized to both groups, final analysis included 199 women as 4 were lost to follow up. The base line characteristics as well as gestational age at delivery were not significantly different between the study and the placebo group (34.7±3.6 vs 34.5±4.5, P=0.626). Progesterone administration was not associated with a significant decrease in the preterm birth rates <37 weeks (73.5% vs 68%, P = 0.551), <34 (20.6% vs 21.6%, P = 0.649), <32 (8.8% vs 12.4%, P = 0.46) & <28 (4.9 % vs 3.1 %, P = 0.555). Conclusions: Rectal natural progesterone starting from the first trimester in IVF/ICSI twin pregnancies did not reduce preterm birth. The trial was registered on 31 January 2014 at www.ISRCTN.com, 69810120.