Progesterone Preparations Research Articles

Research Progress of Progesterone Preparations: A Mini Review.

Progesterone is a sex steroid hormone. Since it has been discovered, it is widely used in the prevention of spontaneous preterm birth, hormone replacement therapy and other gynecological conditions. We will review the progesterone preparations based on a comprehensive study of papers and patents from the traditional preparations up through the very recent literatures. This review mainly concentrates on oral, vaginal and micro delivery systems, involving different ways to prepare progesterone preparations. Although progesterone has first-pass effects, with these methods, the bioavailability and compliance can be greatly increased.

PATHOGENETIC SUBSTANTIATION OF PERSONAL PRECONCEPTIONAL PREPARATION

Preconceptional preparation is aimed at timely prevention of gestational complications, perinatal pathology.The aim of the study was to assess the effectiveness of personal and preconceptional training using folates, vitamins, macro-, microelements, amino acids, progesterone preparations, correction of the microbiocenosis of the urogenital, gastrointestinal tract.Materials and methods of research. A total of 50 women and 50 of their men who underwent preconception training and 50 pregnant comparison groups were examined.Results of the study and their discussion. The effectiveness of pre-conception training was studied on the basis of the comparative characteristics of the clinical course of pregnancy, the results of laboratory studies on the trimester of gestation. The use of vitamin, macro, microelement, amino acid complexes that contain folates, up to pregnancy by future parents, a complex of vitamin, macro, microelement, amino acid complexes that contain folates, during pregnancy, balanced nutrient complexes, correction of progesterone content, microbiocenosis of the urogenital tract, gastrointestinal tract promoted a decrease in the frequency of gestational complications, perinatal pathology, congenital malformations.Conclusions. Pre-conception training is shown 100% of women and men for 3 - 4 months before fertilization. The algorithm of pre-conceptual preparation should be person-specific according to the results of hereditary predisposition to folate cycle violation, by determining the alleles of folate cycle genes, the content of vitamins of group B, D and ferritin in the blood of women and men, indicators of bacteriological and bacterioscopic examination of the material of the urogenital tract. Taking into account the high frequency (more than 60%) of the occurrence of the polymorphism of the folate cycle enzymes in the population, the pre-conceptual preparation should include the use of vitamin, macro, microelement, amino acid complexes that contain folates, before pregnancy by a man and a woman, during pregnancy, vitamin, macro, microelement, amino acid complexes that contain folates. The high frequency of infectious processes of the urogenital tract in women and men is an indication for etiotropic therapy, restoration of the genital, urinary, gastrointestinal tract before and during pregnancy. Therapy of anemia of pregnant women through the use of iron preparations is expedient to be carried out against the background of accept preparations of vitamin, macro, microelement, amino acid complexes that contain folates, taking into account the high frequency of polymorphism of the genes of folate cycle enzymes.

Administration of Sex Hormone Preparations as a Risk Factor in the Development of Intrahepatic Cholestasis of Pregnancy and Biliary Sludge in Pregnant Women

Sex hormone preparations are widely used in obstetrics for the treatment of infertility and miscarriage. Possible adverse effect of sex hormone preparations during pregnancy is their potential adverse impact on the hepatobiliary system. The most common pathology of the liver and gallbladder associated with pregnancy are intrahepatic cholestasis of pregnancy (ICP) and biliary sludge (BS).Aim. The aim of the study is to evaluate the effect of female sex hormones on the course and effectiveness of treatment of ICP and BS during pregnancy. Materials and methods. The study included 158 pregnant women (97 patients with ICP and 61 patients with BS). Exogenous hormonal effects were the use of assisted reproductive technologies (ARTs) and in vitro fertilization (IVF) for the onset of conception and/or the use of estrogen and progesterone preparations during pregnancy. ICP was diagnosed on the basis of detection of an elevated level of bile acids (above 8 μmol/L) in the blood serum. Patients underwent clinical, laboratory and instrumental studies (abdominal ultrasound, including the assessment of gallbladder motor-evacuator function initially and after 2 months of treatment, and pelvic ultrasound). Pruritus intensity associated with ICP was assessed using a 0–3 score scale. Patients with BS received treatment with ursodeoxycholic acid (UDCA) in a dose of 250–750 mg and choleretic herbal preparation (artichoke extract) for 2 months. Patients with ICP were treated with UDCA in a dose of 500–2000 mg until delivery. Biochemical laboratory parameters in the ICP group were evaluated after 1 and 2 weeks of treatment.Results. More than half of patients with BS and ICP were taking sex hormone preparations or had a pregnancy that occurred after the application of ART programs. In patients who became pregnant after ART, the ICP developed at a significantly earlier time than in patients with a naturally occurring pregnancy (p < 0.001). The use of sex hormones proved to be interrelated with a high frequency of cholestasis recurrence after its regression in the course of the treatment (p < 0.001). Patients with pregnancy after ART programs, as well as taking sex hormones, had an increased risk of BS developement. The intake of sex hormones (p = 0.005) in patients with ICP was associated with a more frequent development of preeclampsia and the need for caesarean section (p = 0.003). The use of ART programs and hormonal therapy, as well as the presence of BS in patients with ICP, were interrelated with oxidative stress. BS on the ICP background was associated with the development of intrauterine fetal hypoxia. In pregnant women with BS, the reception of progestins was significantly (p = 0.004) correlated with functional impairment of the motor function of the biliary tract (BT). In the presence of BS, ICP occurs with more severe liver damage, and the patients are inferior to respond to UDCA treatment. Prognostic factors in the insufficient effectiveness of BS treatment: the use of sex hormone preparations during pregnancy, the presence of the polycystic ovary syndrome (PCOS) in the anamnesis, an older age at the time of pregnancy and conception after ART.Conclusion.The use of sex hormone preparations and ART programs are shown to be additional factors contributing to the emergence of ICP and BS during pregnancy. For the pregnant women taking sex hormone preparations and/or becoming pregnant after ART programs, it is important to conduct laboratory and ultrasound screening for early detection and timely treatment of ICP and BS. BC patients of older ages who have become pregnant after ART programs and take sex hormones preparations and/or have a PCOS in an anamnesis may need longer or repeated courses of BS treatment.

The association of different progesterone preparations with preterm birth prevention

Objective: We aimed to compare the efficacy of commonly available progesterone preparations for preterm birth prevention.Methods: A retrospective cohort study of all women treated with progesterone to prevent preterm birth and delivered in a single university-affiliated tertiary medical-center. Four progesterone preparations were compared: vaginal Endometrin 100 mg twice daily, vaginal Crinone 8% gel 90 mg daily, vaginal Utrogestan 200 mg daily, and intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) 250 mg weekly. All women were considered at risk for preterm birth according to: prior preterm birth or cervical length below 25 mm measured during the second trimester. Significant maternal morbidity, pregnancy achieved by artificial reproductive technique and cerclage placement were excluded. Primary outcome was the rate of preterm birth prior to 37 weeks of gestation.Results: Overall, 422 women were allocated to four study groups according to progesterone preparation: Endometrin 175 (41.5%), Crinone 73 (17.3%), Utrogestan 154 (36.5%), and 17-OHPC 20 (4.7%). Rates of preterm birth prior to 37 gestational weeks were lowest on the Endometrin treatment group (12.6 versus 20.5, 17.5, and 35% in the rest, p = .05). Multivariate analysis revealed that the progesterone preparation was associated with preterm birth prior to 37 gestational weeks (LR = 8.3, p = .004). The need for maternal red blood cells transfusion was significantly higher in the Endometrin subgroup (4% versus 0 in all others, p = .018). This finding remained significant after adjustment to potential confounders (LR 16.44, p < .001). Neonatal outcomes did not differ between groups.Conclusions: Different progesterone preparations prescribed to women at risk, may possess different efficacy in preventing preterm delivery prior to 37 weeks of gestation.

The effect of progesterone use in the first trimester on fetal nuchal translucency.

Objective:To evaluate the possible association between progesterone use in the first trimester of pregnancy and fetal nuchal translucency (NT).Material and Methods:This is an observational case-control study, which was conducted with patients who underwent nuchal scans between March 2015 and February 2016 and consequently delivered live and healthy babies. The study group was composed of assisted reproductive technology pregnancies and used intravaginal progesterone 180 mg/day until gestational week 12. The control group comprised pregnant women who became pregnant spontaneously without using any progesterone preparation in the first trimester.Results:One hundred sixty-four (57.5%) of 285 patients were in the control group and 121 (42.5%) were in the progesterone group. Age, bodyweight, gravidity, and parity number of previous births and abortus, gestational week, crown-rump lengths, free β-human chorionic gonadotropin, pregnancy-associated plasma protein A, and NT values of the progesterone and control groups were recorded and we investigated whether there was a statistically significant difference between the two groups in terms of these parameters; maternal weight was found to be higher in the progesterone group than in the control group and the difference between the groups was statistically significant (p=0.019 and p=0.025). Whether the difference in NT was caused by the effect of maternal weight was investigated using the covariance analysis test and maternal weight was not found to be statistically significant in the model (p=0.284).Conclusion:Fetal NT was increased in the progesterone group compared with the untreated group in healthy pregnancies.

Звичне невиношування: що необхідно робити і чого робити не слід (Огляд)

The article presents an overview of domestic and foreign publications on pregravid preparation and early pregnancy in women with a history of habitual miscarriage (HM). Modern terminology is presented, questions about the causes of this pathology are considered and ways of its overcoming are determined. The views of specialists from leading institutions and obstetric and gynecological communities of the world on the issues of pregraved preparation and management of pregnancy in women with HM are presented. Among the main issues considered are the following: optimal timing for the next pregnancy; key recommendations on the management of women with HM (genetic examination, routine administration of progesterone preparations, correction of the «male factor», psychoemotional disorders, anatomical defects of female reproductive organs); the management of women with reproductive losses in the history on the background of antiphospholipid syndrome and congenital thrombophilia. It was noted the need to correct the infectious component of miscarriage. The role of vitamin and micronutrient supplementation in women with HM and their required quantity at the stage of pregravid preparation (folates, iron, iodine, vitamins D, B12) is defined. The evidence base on the use of sublingual and vaginal forms of micronized progesterone (luteina) for correction of the II phase of MC and early pregnancy in women with HM is presented. The emphasis is also on what should be avoided: unreasonable and unjustified prescriptions without special indications (additional examinations, medications, etc.). Key words: habitual miscarriage, pregravid preparation, key recommendations, micronutrient supplementation, micronized progesterone, gestalider, luteina.

Systematic review of the clinical efficacy of vaginal progesterone for luteal phase support in assisted reproductive technology cycles.

Vaginal progesterone via capsule, gel or tablet is the most common route for luteal phase support (LPS) in Europe. Although there is a wealth of data comparing products used at other stages of assisted reproductive technology cycles, there is a lack of systematically identified evidence comparing the wide range of vaginal progesterone products. This systematic review queried the MEDLINE, Embase and Cochrane Library databases on 30 June 2016 to identify head-to-head randomized controlled trials (RCTs) comparing the efficacy or safety of vaginal progesterone preparations (Crinone, Cyclogest, Lutigest or Utrogestan Vaginal) for LPS in assisted reproductive technology cycles. Of 1914 results, 18 RCTs were included. No significant difference in clinical pregnancy rate was identified in comparisons of Utrogestan Vaginal with Crinone. Utrogestan Vaginal and Lutigest were non-inferior to Crinone in ongoing pregnancy rate comparisons. Differences in patient-reported perineal irritation with Crinone and Lutigest were not significantly different to Cyclogest. In studies comparing varying timing or dosage of Utrogestan Vaginal or Crinone, no significant differences were observed. These results suggest Crinone, Cyclogest, Lutigest and Utrogestan Vaginal represent equally safe and effective choices of vaginal progesterone for LPS in assisted reproductive technology cycles. Future quantitative analyses could provide further support for these findings.

The possibility of prognosis of progesterone preparations interaction

The possibility of prognosis of progesterone preparations interaction

Use of Noninvasive Cerclage in Combination of Micronized Progesterone in Miscarriage Of Multifetal Pregnancy

We represent the results of the combined method of treatment and prevention of miscarriage in women with a multiple pregnancy and a high risk of the threat of termination the pregnancy because of using the obstetric unloading pessaries, combined with micronized progesterone. The efficiency of this method of treatment is evidenced by the rapid elimination of clinical symptoms of threatened abortion, accelerating the regression of ultrasound markers, reducing the number of complications in of pregnant women and reducing the time of their stay in hospital.Goal: To evaluate the effectiveness of the handling the obstetric pessary in combination with micronized progesterone at women with multifetal pregnancy and a high risk of miscarriage.Materials and methods. We analyzed 120 cases of multifetal pregnancies with signs of miscarriage within the terms from 16 to 28 weeks. The first group of the examined women was: 40 pregnant women with twins and signs of miscarriage, who in the scheme of treatment and prophylactic measures were offered to use the unloading obstetric pessaries in combination with continuous therapy by natural micronized progesterone until 36 weeks of pregnancy. The second group included 40 pregnant women with twins, who were laid seam on the cervix because of istmicocervical insufficiency and were applied short-term courses of therapy by gestagens. The control group comprised 40 pregnant women with twins at the age of 16-28 weeks of pregnancy who were conducted the therapy about the threat of miscarriage according to the current clinical protocols (Order of the Ministry of Health of Ukraine No. 624). It was carried out the analysis of the course of pregnancy, childbirth, the postpartum period and the state of neonatal adaptation in the surveyed groups.Results of the research and their discussion. In the first group, urgent childbirth occurred in 34 (85%) cases, in group II in 29 (72.5%) cases, in control group – in 25 (62.5%) cases. Cesarean delivery was performed in 7 (17.5%) patients of group I pregnant women, in 9 (22.5%) of group II patients and in 11 (27.5%) in the pregnant group. When studying the state of neonatal adaptation of newborns in the examined groups, the following results were obtained. The average weight of the newborns in group I was 3245 ±280 g, in group II 2865 ±365 g, in the control group - 2975 ±325 g (p&gt;0.05). The evaluation of the state of newborns on the Apgar scale, respectively at the 1st and 5th minutes, was respectively: in newborns of the I group, 7.5 ± 1.4 and 8.4 ± 1.3 points, in group II - 7.3 ± 1.6 and 8.2 ± 1.1 points, in the control group – 7.2 ± 1.6 and 8.6 ± 1.2 (р 1-р 2&gt; 0.05).Conclusions. Comprehensive prophylaxis of non-pregnancy in multiple pregnancies, combining the use of a traumatic cardiac cervix with the help of unloading obstetric pussies with progesterone preparations, allows prolonging pregnancy, preventing the development of prematurity, contributes to the improvement of perinatal indicators.

Preparation and detection of progesterone by molecularly imprinted film based on reversible addition fragmentation chain transfer polymerization

Molecularly imprinted technique is a versatile and straightforward way to produce artificial receptors for a given target molecule. The molecularly imprinted polymers (MIPs) have received widespread attention and application, owing to their high physical stability, remarkable robustness and low cost. Despite the tremendous progress made in this field, many changes still remain to be solved. In general, MIPs are prepared by traditional free radical polymerization. However, this approach causes problems such as low-affinity binding, high diffusion barrier, low-rate mass transfer. In particular, it has been demonstrated that most of the MIPs fail to exhibit specific recognition towards the target molecules in aqueous environments although they can be successfully applied to recognize the target molecules in organic solvent media, which severely limits their potential application in some fields. In this work, a new method to prepare MIPs film for the detection of progesterone based on reversible addition-fragmentation chain transfer (RAFT) polymerization is presented. 2-Methyl-2-[(dodecylsulfanylthiocarbonyl)sulfanyl]propanoic acid (DDMAT) was employed as the sole control agent in the UV polymerization. The SPR sensor chip with 50 nm Au was firstly immersed in an ethanol solution of cysteamine (5 mmol/L) for 24 h. The cysteamine modificated chip was washed by pure ethanol solvent repeatedly and dried under a stream of nitrogen. Then the chip was placed in 40 mL acetonitrile solution with 14.6 mg DDMAT and 16.5 mg N , N ′-dicyclohexylcarbodiimide (DCC) for 24 h. After that, the chip was washed with acetonitrile several times and dried under a stream of nitrogen. The MIPs film was grafted by UV irradiated without adding additional photo initiator or catalyst in the presence of progesterone (31.4 mg), methacrylic acid (33.4 μL), ethylene glycol dimethacrylate (338.5μL) and DDMAT (15 mg) in 4 mL acetonitrile. The growth process of the MIPs film was monitored by surface plasmon resonance (SPR) in situ . A mixture of PBS (pH 7.4) buffer and acetic acid (v:v=9:1) was used as a washing solution to remove the template molecules from the MIPs film. Results indicated that DDMAT acted as both photo initiator and chain transfer agent during the polymerization. The MIPs film was characterized by contact angle measurements, infrared spectroscopy and scanning electron microscope (SEM). Analysis of SPR spectroscopy showed that the MIPs film coated sensor displayed good sensitivity and selectivity to progesterone compared to other analytes with a similar structure. The response of the progesterone ranged from 10−12 to 10−7 mol/L with a limit of detection (LOD) of 3.24×10−13 mol/L ( S / N =3) in PBS buffer (pH 7.4). The MIPs film coated sensor also showed good reusability and stability, and kept about 81% of its original response after 30 d of storage under N2 protection at room temperature. In addition, the SPR sensor was successfully used to determine progesterone in tap water, underground water and artificial urine samples with recoveries from 92.9% to 96.5%, which indicated the SPR sensor can be applied for the real sample detection. This method will expand the surface modification of the MIPs film on the surface of different sensors and is a great candidate for rapid, simple and label-free detection of molecules in aqueous solution. Finally, this study opens a door to re-know the roles of chain transfer agents (DDMAT, in this study) in synthesizing MIPs and we believe that the properties of various chain transfer agents will be excavated and utilized in future study.

The combined use of various forms of micronized progesterone in the treatment of the threat of termination of pregnancy in multiple pregnancies

The article highlights the data on the features of the etiology and pathogenesis of the threat of premature birth in a multiple pregnancy. The results of a clinical study of the effectiveness of combined therapy in the threat of termination of pregnancy in women with multiple pregnancies with sublingual and vaginal forms of micronized progesterone are presented.In the course of the study 120 twins pregnancies with signs of miscarriage in terms of 14–28 weeks were analyzed. The first group consisted of 40 women who were offered a sublingual form of natural micronized progesterone in combination with the vaginal form (drug Luteina) in the scheme of treatment and prophylactic measures. The second group included 40 women, who received a synthetic progesterone preparation (dydrogesterone) for treatment of the threat of termination of pregnancy. The control group consisted of 40 pregnant women, who were treated according to the current clinical protocols.The results of the study showed that the effect of the use of the sublingual form of micronized progesterone in the period of severe clinical symptoms of the threat of premature delivery in multiple pregnancy came out twice as fast compared to the oral form of synthetic dydrogesterone, what contributes the rapid elimination of clinical symptoms, regression of ultrasound markers of the threat of miscarriages and prevents further progression of cervix structural changes. The presence of sublingual and vaginal form of micronized progesterone allows, if necessary, to go from one form to another, and also combine both forms to quickly saturate the body of pregnant woman by progesterone in conditions of gestagen deficiency in order to eliminate the symptoms of the threat of pregnancy termination.Therefore, complex therapy of the threat of premature birth with the use of sublingual and vaginal forms of micronized progesterone has a significant therapeutic effect, contributes to a shorter period of inpatient stay, a reduction in the number of complications compared to other progestins and can be recommended for widespread use. The use of natural micronized progesterone in women with the threat of interruption of pregnancy in multiple pregnancies significantly reduces the risk of preterm labor and improves perinatal outcomes.

Comparison of aqueous subcutaneous vs vaginal progesterone in frozen embryo transfer (FET) cycles

This is the first study evaluating the use of subcutaneous (SC) aqueous progesterone (P4) preparation in FET cycle. The objective of this study was to compare aqueous SC progesterone with vaginal progesterone capsules in GnRH agonist suppressed FET cycle.

A Word About Bioidenticals

A Word About Bioidenticals

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Pharmaceutical and clinical development of a novel progesterone formulation.

Progesterone plays an essential role in reproductive events. Its use for luteal support in patients undergoing infertility treatment is an established practice. The different routes used to administer progesterone impact on its efficacy in luteal support: oral administration has been shown to be ineffective due to an extensive first-pass metabolism in the liver; vaginal application has a good efficacy but has drawbacks such as vaginal leakage, irritation, discomfort and uncertainty about the real dose adsorbed; finally, intramuscular administration ensures a precise dosage but can be extremely painful with, in some cases, formation of sterile abscesses. A new progesterone preparation is now available in several European and extra-European countries that combines the precise dosage of the injectable formulation with the comfort of a well-tolerated subcutaneous self-administration. The pharmacokinetic and pharmacodynamic properties of this new product are reviewed here, together with the clinical evidence obtained in two multicenter randomized clinical trials.

Daily low-dose hCG stimulation during the luteal phase combined with GnRHa triggered IVF cycles without exogenous progesterone: a proof of concept trial.

Can the luteal phase support be improved in terms of efficacy, hormonal profiles and convenience as compared with today's standard care? Daily low-dose rhCG supplementation in GnRHa triggered IVF cycles can replace the traditional used luteal phase support with exogenous progesterone. A bolus of hCG for final maturation of follicles in connection with COS may induce the risk of OHSS and the luteal phase progesterone levels rise very abruptly in the early luteal phase. This is a proof-of-concept study conducted as a three arm RCT with a total of 93 patients. First patient enrolled in January 2012 and the study finished in January 2014. Normal responder women undergoing IVF/ICSI treatment in a university hospital. One arm served as control, where women followed a standard antagonist protocol. Two study arms were included both having 125 IU hCG daily for luteal phase support without exogenous progesterone after using a GnRHa trigger for ovulation induction. In both study arms exogenous FSH was stopped on stimulation day 6 and replaced by exogenous hCG that was initiated on either stimulation day 2 or day 6. Blood samples were obtained on the day of ovulation induction, on the day of oocyte pickup (OPU) and day OPU + 7. The mean serum levels of hCG did not exceeded the normal physiological range of LH activity in any samples. Mid-luteal progesterone levels were significantly higher in the two study groups receiving daily low-dose hCG for luteal phase support as compared with the control group (control group: 177 ± 27 nmol/l; study group 1: 334 ± 42 nmol/l; study group 2: 277 ± 27 nmol/l; (mean ± SEM). No differences in reproductive outcome were seen between groups. The number of patients included is limited and conclusions need to be verified in a larger RCT. Endogenous production of progesterone may become more attractive as the luteal phase support with levels of LH-like activity only in the physiological range and may, from the patients' point of view, replace inconvenient exogenous progesterone preparation. Further hCG may reduce the cost of stimulation and may collectively be used for stimulation of the follicular phase, ovulation induction and for luteal phase support. An unrestricted grant from ARTS Biologics made this study possible. None of the authors has any competing interests to declare. ClinicalTrial.gov number: NCT01504139. 28 December 2011.

Luteal phase support in in vitro fertilization.

It has been well demonstrated that luteal phase physiology is disrupted in in vitro fertilization (IVF) cycles conducted with either gonadotropin-releasing hormone (GnRH) agonists or antagonists, and that supplementation of the luteal phase with either exogenous progesterone or human chorionic gonadotropin (hCG) is necessary to optimize IVF cycle outcomes. Though both progesterone and hCG supplementation resulted in comparable pregnancy rates, hCG supplementation was associated with increased risk for ovarian hyperstimulation syndrome (OHSS). For that reason progesterone has been used for luteal support by most IVF programs around the world. Vaginal progesterone preparations have been shown definitively to be equally efficacious and better tolerated by patients than intramuscular progesterone injections, but new data on the subcutaneous and oral progesterone are also emerging. New evidence has been accumulating on the benefits of low-dose luteal hCG supplementation in GnRH-antagonist cycles where GnRH agonists are used for the final maturation trigger. New approaches to luteal phase support as well as new formulations of progesterone have been developed since the last comprehensive review was published in 2011. In this article, we examine current evidence for efficacy, dosing, and timing of progesterone preparations as well as the role of hCG for luteal support in IVF cycles triggered with GnRH agonists. We also discuss the data on the role of estrogen supplementation in the luteal phase, optimal duration of progesterone support in early pregnancy, and progesterone replacement in frozen embryo transfer cycles and donor egg recipient cycles.

A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization.

STUDY QUESTIONIs the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex®) non-inferior to vaginal progesterone (Endometrin®) when used for luteal phase support of in vitro fertilization?SUMMARY ANSWERIn the per-protocol (PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of −2.8% (95% confidence interval (CI) −9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support.WHAT IS KNOWN ALREADYLuteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support.STUDY DESIGN, SIZE, DURATIONThis prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18–42 years, with a BMI of ≤30 kg/m2, with <3 prior completed assisted reproductive technology (ART) cycles, exhibiting baseline (Days 2–3) FSH of ≤15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011.PARTICIPANTS/MATERIALS, SETTING, METHODSIn total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mg daily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS®). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation.MAIN RESULTS AND THE ROLE OF CHANCEUsing a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of −2.8% (95% CI −9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive β-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI −9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI −10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI −7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI −8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI −8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups.LIMITATIONS, REASONS FOR CAUTIONThe conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study.WIDER IMPLICATIONS OF THE FINDINGSSubcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration.STUDY FUNDING/COMPETING INTERESTSThe study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA.TRIAL REGISTRATION NUMBERNCT00828191.

Embryo Transfer Catheter Contamination With Intravaginal Progesterone Preparations in a Simulated Embryo Transfer Model Impairs Mouse Embryo Development: Are There Implications for Human Embryo Transfer Technique?

To study the effect of embryo transfer (ET) catheter contact with intravaginal progesterone preparations on mouse embryo development. In a simulated ET model, ET catheters were loaded with culture medium, placed in contact with intravaginal progesterone gel (Crinone 8%) or micronized progesterone intravaginal inserts (Endometrin 100 mg), and the intracatheter culture medium flushed. Embryos were cultured in the flushed culture medium at variable dilutions for variable lengths of time. Proportion of embryos progressing to blastocyst, embryo cell number, and apoptotic index was analyzed. None of the embryos cultured in undiluted progesterone-exposed medium progressed to blastocyst. The likelihood of achieving blastocyst status and the average embryo cell number increased significantly as culture media exposed to intravaginal progesterone was diluted. A significant decrease in cell number became apparent between 1 and 2 hours of exposure. Interestingly, the apoptotic index was significantly higher in progesterone-exposed embryos as compared to unexposed embryos. The contamination of ET catheter with intravaginal progesterone significantly impairs mouse embryo development, likely due in part to increased programmed cell death.

Compound interest: Petersen shares expertise on women’s health, leads APhA–APPM Compounding SIG

When Carol Petersen, BSPharm, fi rst joined Women's International Pharmacy in 1993, it was just a small Madison, WI–based compounding practice concentrating on the newly developed use of oral progesterone and estradiol preparations to treat symptoms of premenstrual syndrome (PMS) and menopause.