Progesterone Preparations Research Articles

The role of progesterone preparations in the prevention of premature birth: a modern view of the problem

Despite significant progress achieved in healthcare, preterm birth is an urgent problem in modern obstetrics. The preterm birth can be caused by various risk factors: for example, an ascending infection can trigger the onset of uterine contractions, cervical shortening followed by infection of the fetal membranes, amniotic fluid, and, in rare cases, the fetus itself. In most cases, the infectious and inflammatory process is the etiopathogenetic factor of isthmic-cervical insufficiency (ICI), one of the common causes of late miscarriages and preterm births. The period between 14 and 20 weeks of gestation is the most critical time for the development of ICI. The dynamic ultrasound cervicometry once every 7–14 days from week 16 through week 24 of pregnancy is recommended to the patients with ICI, as well as pregnant women in the high-risk group. Most professional societies guidelines addressing this issue recommend all pregnant women to perform routine transvaginal cervicometry during the second ultrasound screening for the timely formation of risk groups and optimization of approaches to the patient management. The following groups of drugs are used to prevent preterm birth: micronized progesterone, slow calcium channel blockers, β-adrenergic agonists, and non-steroidal anti-inflammatory drugs. The use of progesterone drugs to prevent preterm birth has generated much debate. Thus, the availability of several forms of progesterone and various routes of administration determine the complexity of the drug therapy. Micronized progesterone is the only progesterone drug that was approved for use after 20 weeks of gestation. The vaginal micronized progesterone has been found to be highly effective in the prevention of preterm birth, significantly reduce neonatal mortality and improve infant morbidity outcomes.

Availability, Usage, and Preferences of Estradiol and Progestogen Preparations for Puberty Induction from a Multicentral Perspective

Introduction: Natural oestrogen administration as oral or transdermal 17β-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of oestrogen and progesterone preparations worldwide. Methods: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17β-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022. Results: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17β-estradiol in adult dosage was highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 μg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17β-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 μg/day of 17β-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents. Conclusion: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries, the lowest dose of the estradiol is 50 µg for patches and 2 mg for tablets. Appropriate low-dose 17β-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.

Real-world utilization pattern of dydrogesterone in 7287 Indian women with obstetric and gynecological conditions: data from multicentric, retrospective study.

Despite the literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. This was a multi-center, retrospective, observational, cross-sectional, and descriptive study across 817 centers in India. Data of patients who received dydrogesterone in past and provided consent for future use of their medical record for research purpose was were retrieved and analyzed. Data of 7287 subjects (aged 29.55±4.84 years) was analyzed. Threatened abortion was the most common indication for which the subjects received dydrogesterone (46.9%) followed by recurrent pregnancy loss. Polycystic ovary syndrome (PCOS), thyroid disorders and anemia were the most common comorbid conditions and prior pregnancy loss, advanced maternal age and obesity were the most common risk factors seen in subjects who received dydrogesterone. Total 27.5% of subjects received a loading dose of dydrogesterone, and majority (64%) received 40 mg as loading dose. 10 mg dose was used as maintenance or regular dose in 81.4% of the subjects. Twice daily (BID) was the most common dosing frequency (66.6%). The most common concomitant medications being taken by the subjects on dydrogesterone included folic acid (45.1%), iron supplements (30.3%) and calcium and vitamin D3 supplements (25.5%). Another progesterone preparation (oral, injection, vaginal, tubal) other than dydrogesterone was used concurrently in 7.8% of subjects. The study helped to identify the patient population that is benefitted by dydrogesterone and the preferred indications, risk factors, comorbid conditions and concomitant medication used in this patient population at real-life scenario.

Deteksi Perubahan Berat Badan Akseptor KB Hormonal dengan Menggunakan Model Regresi Linear Berganda

Hormonal contraception, which uses estrogen and progesterone preparations, is a contemporary method of contraception that is popular among active birth control participants. Apart from stopping population growth, it also has negative effects on its users. The side effect of increasing body weight can occur due to the nature of the acceptor and the use of hormonal contraceptives for a long period of time. The aim of the study was to detect changes in body weight of hormonal birth control acceptors based on age, parity and length of use of contraception using a multiple linear regression model. Non-experimental quantitative analytical research method with a cross sectional design. The research was conducted at several PMBs in Palembang City in July-September 2023 with samples consisting of hormonal birth control acceptors taken using a purposive sampling technique. Data were collected using questionnaires and body weight measurements and analyzed by multiple linear regression. The results of the research show that the prediction model for weight change = 5.789 - 0.098 Age + 1.4 Parity - 0.008 Length of birth control. Weight gain will definitely affect the health of the recipient and can increase the risk of obesity if it continues. To maintain a stable weight, birth control acceptors must pay attention to their daily diet and exercise regularly. It is very important to obtain information about the effects caused by the use of hormonal birth control with a high number of parities and ages at risk.

HUBUNGAN PEMAKAIAN KB SUNTIK 3 BULAN DENGAN PERUBAHAN SIKLUS MENSTRUASI DI BPM ANIK DESA SIDODADI

Injectable contraception is a type of hormonal birth control that contains estrogen and progesterone preparations which have several impacts that are most complained about by injecting birth control acceptors, namely changes in the menstrual cycle. The purpose of this study was to analyze the correlation between acceptors of 3-month family planning injections who experienced changes in the menstrual cycle at Anik independent midwife practice in Sidodadi. The research design was an analytic survey with a cross sectional approach. The population of this study were all women of childbearing age who used the 3-month injection at Anik independent midwife practice in Sidodadi totaling 50 people. The data used are primary and secondary data. The instrument used is a questionnaire. Univariate and bivariate data analysis techniques. Data were analyzed by conducting Chi-square test analysis. The results of the study from 50 respondents who experienced regular menstrual cycles were 13 people (26%), who experienced irregular menstrual cycles were 37 people (74%). The result of the chi-square test is p-value = 0.000. The conclusion in this study is that there is a relationship between the use of 3-month injections and the menstrual cycle at Anik independent midwife practice. It is recommended that midwives provide counseling and counseling to new acceptors regarding the side effects and risks that occur with the use of 3-month injectable birth control.

P-550 Comparison of progesterone levels according to the type of vaginal micronized progesterone used for luteal phase support in artificial-cycles for endometrial preparation in embryo transfer.

Abstract Study question Are there differences in the ongoing pregnancy rate (OPR) using Cyclogest® versus Progeffik® at a dose of 800 mg daily as luteal phase support? Summary answer The administration of Cyclogest® as luteal phase support shows higher ongoing pregnancy rates (OPR) in a cycle of hormone replacement therapy (HRT) with own oocytes What is known already The importance of serum progesterone levels around the time of embryo transfer in patients undergoing FET under artificial endometrial preparation has been well established; some studies have shown that optimizing serum progesterone levels on the day before, leads to an improvement in live birth rates (LBR). However, to date, no study has examined which vaginal preparation reports better serum progesterone levels and its impact on OPR. Study design, size, duration This prospective randomized clinical trial was performed between September 2019 and June 2022 and enrolled 490 patients scheduled for cryopreserved ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal progesterone. They were divided into two groups, those who used Progeffik® and others with Cyclogest® total dose of 800mg. SPLs were measured the day before (P + 4), the day of the transfer (P + 5) and the day of BHCG (P + 19) and compared the OPR. Participants/materials, setting, methods Patients between 18-40 years of age with BMI <30 and triple-layer endometrium > 7,5mm underwent transfer of one blastocysts with own oocytes. The study was carried out in the assisted human reproduction unit of the Virgen de Valme University Hospital (Seville). Ethical approval was granted and formed consent was obtained. The primary endpoint is to assess which vaginal progesterone preparation gives better ongoing pregnancy rates. Main results and the role of chance The 484 patients were randomized (1:1) into two groups. Progeffik was administered to 149 patient and Cuyclogest to 335 patient. The characteristics of the patients were comparable between groups with similar causes of fertility and type of IVF. Regarding the results of serum progesterone levels measured according to the type of micronized vaginal progesterone used to support the luteal phase, we obtained for day P + 4 (13,69 for Progeffik® vs 15.89 for Cyclogest®), while for day P + 5 (11.95 vs 17.69) and on day P + 19 (13.69 vs 15.41), the results obtained after the administration of Cyclogest® being significantly higher with a p-value of 0,01. When assessing the ongoing pregnancy rate, they were also significantly higher with the administration of Cyclogest® versus Progeffik® (59.7% vs 48.3%) with a p value of 0,024. Limitations, reasons for caution The newborm rate needs to be validated as it has not exceeded 9 months since the study. Wider implications of the findings This study demonstrates the statistically significant superiority of Cyclogest-type vaginal micronized progesterone administration over its competitor Progeffik used for luteal phase support, being a more convenient way of administration for women since it's simplicity. Trial registration number 0388-N-22

Comparison of the Pharmacokinetics, Bioequivalence and Safety of Aqueous Progesterone Formulation Administered as either Intramuscular or Subcutaneous Injection versus Oil-based Progesterone Formulation Administered as Intramuscular Injection: A Randomised Study

Introduction: Progesterone is the treatment of choice for support of the luteal phase of controlled ovarian stimulation cycles in women undergoing an Assisted Reproductive Technology (ART) treatment. Available progesterone preparations include oral, vaginal and oil-based Intramuscular (i.m.) formulations. Oral formulation has poor bioavailability whereas vaginal formulations cause side-effects such as vaginal discharge and/ or local irritation. Oil-based progesterone formulations for i.m. use are associated with discomfort and pain at the injection site. Hence, a novel aqueous-based progesterone formulation for i.m./Subcutaneous (s.c.) was developed to avoid the local tolerability issues of the existing parenteral formulations. Aim: To assess single-dose Pharmacokinetics (PK) and relative bioavailability of i.m. (test-1; T1) or s.c. (test-2; T2) administration of novel aqueous progesterone formulation with i.m. (reference; R) administration of oil-based progesterone formulation. Materials and Methods: In this open-label, three-sequence, three-period, single-dose, cross-over study, 51 healthy human postmenopausal female subjects between 45 to 65 years of age were included. The study was conducted at Lambda Therapeutic Research Limited, Ahmedabad, Gujarat, India, between 21 May 2018 to 06 July 2018. Subjects were randomised to a single 25 mg dose of T1, T2 or R in three-periods (Period-I: T1, R, T2; Period-II: T2, T1, R; Period-III: R, T2, T1) with ≥18 days washout period. Blood samples were collected at prespecified time points in each period and analysed using validated liquid chromatography with tandem mass spectrometry. PK parameters {maximum plasma concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration vs. time curve (AUC0-t), AUC from time 0 to ∞ (AUC0-∞), plasma half-life (t1/2)} were calculated from the plasma concentration vs. time profile by non compartmental model. The total study duration was about 47 days (11 hours prior to the drug administration in Period-I until the last ambulatory sample in Period-III). All patients provided written informed consent form and an approval from the Conscience-Independent Ethics Committee (CIEC) was taken. Descriptive statistics were calculated and reported for PK parameters for baseline corrected and uncorrected data. Results: Of 72 screened patients, 51 patients were included for the PK and statistical analysis. The mean±SD age of the patients was 55.1±4.67 years. The baseline corrected PK data shows that in T1, T2 and R arms, mean (range) Tmax were 1.00 (0.50– 1.75), 1.00 (0.75–1.75) and 8.00 hours (1.00–12.00), mean±SD t ½ (h) were 15.43±5.81, 15.27±6.68 and 19.80±6.35; mean±SD Cmax (ng/mL) were 101.91±73.07, 51.67±14.81 and 18.89±7.89, and mean±SD AUC0-t (ng/mL) were 385.10±89.29, 349.63±64.41 and 371.50±56.25, respectively. Similarly, the AUC0-∞ was also comparable in all three arms. The baseline uncorrected data were also in line with baseline corrected data. For AUC0-t and AUC0-∞, 90% CIs were 98.44-107.06% and 97.96-106.15%, respectively, for T1/R ratio, and 90.01-97.90 and 89.90-97.42, respectively, for T2/R ratio. Six Adverse Events (AEs) in four subjects were reported. All AEs were mild in nature and there were no deaths, significant or serious AEs reported. Overall, all the treatments were well-tolerated without any new safety concerns. Conclusion: Novel aqueous progesterone formulation i.m./s.c was bioequivalent with oil-based progesterone formulation i.m. with respect to AUC. The s.c. administration of aqueous progesterone formulation could offer a convenient alternative to the i.m. oil-based progesterone formulation for luteal phase support to patients undergoing ART treatments

Real-world prescription patterns for reproductive assistance patients in China: A trend analysis from 2016 to 2020

Background: Pharmacotherapy is one of the primary treatments for patients with Assisted reproductive technology (ART). Despite the publication of various research on ART treatment, there is no clear conclusion regarding the choice of drug treatment in China. Our research intends to examine the trend of widely prescribed medications for ART patients in China. For instance, the study examines the logic of drug indications, usage, and dose in patient prescriptions. Methods: We did a cross-sectional study of the data from the hospital prescription analysis cooperation project supervised by the China Medical Association. The information is extracted from the prescriptions of reproductive assistance outpatients from January 2016 to December 2020. We used the U.S. Food and Drug Administration (FDA) classification to quantify the frequency of drug use and the categories of drugs. We manually extract the information of patients who require ART treatment, divide the patients into various age groups and geographies, followed by study the indications, utilization, and rationale of the most important therapeutic medications. Results: Among the 225225 patients included in this study, Guangzhou (47.83%), Shanghai (19.84%), and Zhengzhou (9.36%) were the top three cities. In the past 5years, the average age was 32.99, and 60.38% of women were between the age of 25 and 34. The main therapeutic medicines taken by each patient, primarily hormone therapies, were tallied. Eleven types of primary therapeutic medicines were employed. Different progesterone preparations (47472, 21.08%), chorionic gonadotrophin gondotrophin for injection (38932, 17.29%), dydrogesterone tables (33591, 14.91%), and triptorelin for injection (26959, 11.97%) rounded out the top five. According to the data on outpatient medications in major cities in China, the variety and proportion of injections are the highest, including the most frequent types of ovulation induction and urotropia, as well as triptorelin and progesterone. Even though the total dosage of urotropin was the highest in 5years, it showed a declining trend. The dosages of progesterone and didroxyprogesterone increased, with progesterone showing the most rapid increase. The top five most expensive prescription medications are triptorelin, urotropin, progesterone, didroxyprogesterone, and leuprorelin, in that order. Goserelin, leuprorelin, triptorelin, growth hormone, and didroxyprogesterone are among the top five most expensive medications per capita. Conclusion: The average age of patients has not increased considerably over the past 5years. However, the opportunity cost of childbirth for women has increased, which has significantly enhanced their willingness for childbearing intentions. The medication selection is reasonable overall. In this study, the recommended dosages of first-line medicines (urotropin and chorionic gonadotropin) are likewise high. In contrast, the dosage of oral first-line treatment for ovarian stimulation in unexplained infertility is modest, and the dosage of progesterone is steadily increasing. In addition, the price of certain medicines is high, which will increase the patients' financial burden. Future research will focus on enhancing the degree of rational drug use among outpatients and realizing the economical, safe, and effective use of pharmaceuticals to lessen the economic burden of patients.

Assessment of placental complex function and miscarriage prevention in pregnant women with uterine fibroid

The objective: to reduce the frequency of the threat of pregnancy interruption and loss in women with uterine fibroid through treatment prediction and improvement.Materials and methods. A complex examination of 70 pregnant women with uterine fibroid at 15-16 weeks of pregnancy (main group) and 50 pregnant women without uterine fibroid at the same gestational term (control group) was carried out at 4 clinical bases of the Department of Obstetrics and Gynecology N1 of the Shupyk National Healthcare University of Ukraine in the time period of 2020-2022. Pregnant women in the main group were divided into 2 subgroups depending on the type of the nodes: Ia – 39 pregnant women with subserous type of fibroid nodes (type 5-6 according to FIGO) and Ib – 31 pregnant women with intramural fibroid (type 3-4 according to FIGO). The pregnant women in the main group received the complex of developed therapy for pregnancy interruption (micronized progesterone, magnesium preparations, vitamin B6, acetylsalicylic acid), in the control one – the common therapy (bed rest, abstinence from sexual life, micronized progesterone preparations, tranexamic acid).The concentrations of estradiol, progesterone, human chorionic gonadotropin (hCG) were determined in the blood plasma of all persons at 15–16 weeks and 24 weeks of pregnancy.Results. In the II trimester the concentration of estradiol in the blood of pregnant women with intramural uterine fibroid, especially with multiple forms, was significantly higher than in the control group (p<0.05). At the same time, in pregnant women with intramural fibroid node(s) the mean concentration of estradiol exceeded the similar indicator in the group with the subserosal type (p<0.05). These changes indicated the stress of the hormonal function of the placenta and were considered by us as one of the signs of the initial stage of placental dysfunction.With an increase in estradiol concentration, a significant decrease in progesterone amount was noted. Progesterone deficiency was significantly more common in the subgroup of pregnant women with multiple intramural uterine fibroid and nodes in contact with the uterine cavity, especially at the place of placenta attachment (type 3) – 165.24±14.71nmol/l compared to the control group – 219.96±16.63 nmol/l, and with pregnant women with subserosal node(s) – 210.61±18.57 nmol/l (р<0.01), which confirms the threat of abortion and indicates the development of placental dysfunction. In the II trimester of pregnancy the concentration of hCG in women with uterine fibroid was significantly lower than in women without uterine fibroid and especially lower in multiple uterine fibroid. In the women of the main group progesterone and hCG concentrations in the blood plasma normalized (p>0.05) after the treatment, but the level of estradiol in the group of pregnant women with multiple intramural uterine leiomyoma remained significantly higher (p<0.05).Conclusions. Pregnant women with uterine fibroid have an increased risk of placental dysfunction with a disbalance of the main placental hormones: an increase in estradiol concentration and a relative decrease in progesterone and human chorionic gonadotropin, a shift in the estrogen-progesterone balance towards relative hyperestrogenia.The use of medical measures with long-term support with progesterone, magnesium and low doses of acetylsalicylic acid for the prevention of miscarriage in persons with the clinical manifestations of the threat of gestation is quite effective.

The effectiveness of correction methods for isthmic-cervical insufficiency: cohort study results

AIM: To assess the pregnancy outcomes in patients with isthmic-cervical insufficiency (ICN) and the effectiveness of modern methods of correction, namely cervical cerclage, obstetric discharge pessary, and progesterone preparations.
 MATERIALS AND METHODS: The retrospective analysis included 184 females with ICN, who were divided into three groups based on ICN correction methods: 1st group consisted of 82 (44.6%) females who were corrected by cervical cerclage; 2nd group with 67 (36.4%) females by obstetric pessary; and 3rd group with 35 (19.0%) females by progesterone therapy with ICN sign appearance.
 RESULTS: According to the obtained data, every second patient (53.3%) in our study had risk factors for ICN development due to the mechanical expansion of the cervical canal in cervical anamnesis. In most cases, ICN was diagnosed in 20 weeks and more, and the median period of correction was 21 [2022] weeks in 1st group, 24 [2226] weeks in 2nd group, and 22 [2022] weeks in 3rd group (p 0.001). The overall incidence of preterm birth (PTB) in 1st group was 48.8%, whereas 40.3% in 2nd group and 60% in 3rd group. The share of timely births accounted for 41.5% in 1st group, whereas 53.7% in 2nd group and 11.4% in 3rd group.
 CONCLUSION: Correction of ICN with cervical cerclage and obstetric pessary showed similar effectiveness and allowed prolonged pregnancy to more favorable terms. The correction group with only progesterone preparations noted a high frequency of premature pregnancy termination since this group initially included females with a higher risk of PTB and adverse factors for further prolonged pregnancy.

A Comparative Analysis of Outcomes Between Two Different Intramuscular Progesterone Preparations in Women Undergoing Frozen Embryo Transfer Cycles.

Background:The purpose of the current study was to assess if luteal support with intramuscular (IM) 17 alpha-hydroxyprogesterone caproate (17-OHPC) (Lentogest, IBSA, Italy) improves the pregnancy outcome in comparison to natural intramuscular progesterone (Prontogest, AMSA, Italy) when administered to recipients in a frozen embryo transfer cycle.Methods:A retrospective comparative study was performed to evaluate outcomes between two different intramuscular regimens used for luteal support in frozen embryo transfer cycles in patients underwent autologous in vitro fertilization (IVF) cycles (896 IVF cycles) and intracytoplasmic sperm injection (ICSI) who had a blastocyst transfer from February 2014 to March 2017 at the Centre for Reproductive and Genetic Health (CRGH) in London.Results:The live birth rates were significantly lower for the IM natural progesterone group when compared to 17-OHPC group (41.8% vs. 50.9%, adjusted OR of 0.63 (0.31–0.91)). The miscarriage rates were significantly lower in the 17-OHPC group compared to the IM natural progesterone group (14.5% vs. 19.2%, OR of 1.5, 95% CI of 1.13–2.11). The gestational age at birth and birth weight were similar in both groups (p=0.297 and p=0.966, respectively).Conclusion:It is known that both intramuscular and vaginal progesterone preparations are the standard of care for luteal phase support in women having frozen embryo transfer cycles. However, there is no clear scientific consensus regarding the optimal luteal support. In this study, it was revealed that live birth rates are significantly higher in women who received artificial progesterone compared to women who received natural progesterone in frozen embryo transfer cycles.

COMPARATIVE STUDY BETWEEN DIFFERENT TYPES OF VAGINAL PROGESTERONE IN LUTEAL PHASE SUPPORT IN ICSI CYCLES

Background: Assisted reproductive techniques (ART) include all fertility treatments in which the gametes (egg and sperm) are handled outside the human body with the aim of achieving a healthy conception. Common ART procedures include in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI), fresh or frozen embryo transfer, and IVF with donor oocytes. Luteal phase support through pharmaceutical drugs has been universally agreed. Objective: To compare the effectiveness of different types of vaginal progesterone preparations for luteal support in patients undergoing Intracytoplasmic Sperm Injection. Patients and Methods: The current randomized controlled clinical trial study was conducted on 300 patients who were following at the Assisted Reproductive Technology (ART) unit of the International Islamic Center for Population Studies and Research (IICPSR) of Al-Azhar University over the period from May 2016 to January 2018 after being approved by the ethical committee. The patients were divided into 3 equal groups received Prontogest vaginal suppositories 400 mg once per day, Group B received Crinone 8% (90 mg) vaginal gel once per day and Group C received Endometrin vaginal suppositories once per day. Results: Comparison between studied group A (Prontogest), group B (Crinone) and group C (Endometrin) as regards demographic characteristics revealed no statistically significant differences. As regards the cause of infertility, a statistically significant increase in the number of patients with male and tubal factors in group B (Crinone) than group A (Prontogest). Concerning the laboratory hormonal profile of the studied groups before ICSI, there was a statistically significant increase in FSH and LH levels in group A (Prontogest) than group B (Crinone) and group C (Endometrin). On the other hand, there was a difference between the studied groups as regards prolactin and estrogen levels, but did not reach statistical significance. Comparison between studied groups, as regards Endometrial thickness, number of retrieved oocytes and number of transferred embryos revealed no statistically significant difference. Comparison between the studied groups, as regards pregnancy rates, revealed a statistically significant increase in pregnancy rates in group C than group A. Conclusion: The use of Endometrin vaginal suppositories in patients undergoing ICSI had a statistically significant higher clinical pregnancy rates in comparison to Prontogest vaginal suppositories. On the other hand, Crinone vaginal gel had a higher clinical pregnancy rate than Prontogest.

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.

LC-MS/MS quantification of progesterone in ovariectomized miniature swine and its application for preliminary pharmacokinetic study of a novel vaginal sustained release system

Objective We here established a simple, fast, robust and sensitive LC-MS/MS method and validated as well for the quantitative analysis of progesterone (PGT) in ovariectomized (OVX) miniature swine plasma. The method was successfully applied to characterize the pharmacokinetics of a progesterone vaginal drug delivery system. Methods Megestrol acetate was utilized as an internal standard (IS). The separation and detection of PGT from endogenous interference was performed successfully by liquid chromatography with gradient elution and mass spectrometry equipped with positive ESI source using MRM mode. The EVA intravaginal rings (IVRs) were manufactured by hot-melt extrusion (HME), afterward were administrated vaginally to OVX minipigs to evaluate PK study. Results The calibration curve for swine plasma samples across the concentration ranged between 0.25 ng/mL and 100 ng/mL. The intra- and inter-assay accuracy and precision were lower than ±5% and 5.88%, respectively. Recoveries of PGT and IS were ranging from 114–119% and 96.5–112%, respectively. In vitro study showed that the EVA IVRs release 18 mg/day of PGT continuously over 7 days, and corresponding mean PGT plasma concentration in OVX minipigs (CAVG) was 4.892 ng/mL. Conclusion All the study produced reliable results for the measurement of PGT concentration in miniature swine plasma and the method was successfully applied to a PK study for PGT vaginal ring in miniature pigs, which may lay the foundation for further research on the progesterone preparations intended for in assisted reproductive technology.

Do South Asian women with menopausal symptoms have access to optimal therapy?

Background Menopausal symptoms can have a significant impact on a woman's quality of life. Information on availability of menopausal hormone therapy (MHT) in National Essential Medicines Lists (NEMLs) of South Asian (SA) countries has not been widely studied. Objective To review the availability of non-injectable MHT included in NEMLs of SA countries and to assess differences in availability compared to the recommended MHT preparations in the World Health Organization (WHO) model essential medicines list and the list of MHT available to women of a developed country in the Asia Pacific Region, while comparing with the healthcare expenditure and country's economic status. Methods Most recent NEMLs were obtained from all eight SA counties by visiting the Ministry of health/regulatory website of the respective country. Latest WHO model essential medicines list and Pharmaceuticals Benefits Scheme (PBS) schedule from Australia were obtained from the WHO and PBS websites respectively. Per capita health expenditure was obtained from The WHO Global Health Expenditure Database. Two investigators extracted the non-injectable MHT preparations independently from NEMLs and conducted the comparison. Results Except in two countries, in all other SA coun­tries NEMLs were updated within the preceding five years. According to available data, seven SA countries had at least one separate preparation of oestrogen suitable for MHT while all countries had a separate progesterone preparation suitable for MHT. The oestrogen preparations available in the SA NEMLs were limited to either ethinyl estradiol or conjugated oestrogen tablets whilst in the WHO model, oestrogen preparations were not specified. In Australia, estradiol tablets were the only available oral oestrogen while there were four more different dosage forms of oestrogens available through the PBS Scheme. Progesterone preparations found in SA countries, WHO list and PBS schedule were similar, but oestrogen progesterone combination MHT preparations were only available in the PBS schedule. Per capita health expenditure was much higher in Australia compared to SA countries where a wide variation was observed. Conclusions The available evidence suggests that a larger population of SA women have access only to a very limited number of options if in need of MHT. In contrast, importance of MHT is highlighted in PBS Schedule. Although per capita health expenditure was low in SA countries, given that MHT products are relatively low cost and that there is a large proportion of women in menopausal age in this region, it would be imperative to update the WHO model list and NEMLs of SA countries to address the growing need of safe MHT and to improve the quality of life of postlnenopausal women in our region.

Influence of preoperative preparation on the vaginal architectonics of postmenopausal women with severe genital prolapse

Patients with severe postmenopausal genital prolapse (GP) are the most clinically difficult group of women, in which surgical treatment with mesh implants presents significant difficulties due to the duration of lesions amid pronounced structural changes in the tissues of the urogenital tract under conditions of hormone deficiency. That is why it is of particular importance to study the histological characteristics of the vaginal mucosa in women with GP, who must conduct surgical treatment of vaginal access.
 Aim. To study the histological features of the vaginal mucosa in postmenopausal women with severe GP in preparation for surgical treatment with vaginal access.
 Materials and methods. The study involved 70 postmenopausal women suffering from GP of stage III, IV in combination with genitourinary menopausal syndrome. Patients were randomized blindly into two groups. The therapy was carried out using vaginal forms of estrogen and progesterone preparations in combination with lactobacilli. In the comparison group, preoperative preparation was not performed. All patients underwent clinical and laboratory examination: general examination and gynecological examination, morphological examination of biopsy samples of the mucous membrane of the anterior vaginal wall, which were obtained during subsequent surgical treatment of GP. Methods of parametric statistics were used.
 Results. It was established that focal dystrophy, acanthotic severity, keratinization of the vaginal epithelium, moderate inflammation are characteristic morphological changes in the vaginal mucosa in women with postmenopausal GP. Application at the stage of preparation for surgical treatment using vaginal forms, as a result of which estrogen and progesterone enhance the inflammatory process in the ulcerative vagina, reduce dystrophic changes and their severity in relation to complex changes and differentiation of the vaginal epithelium and activation of regeneration processes in tissues.
 Conclusion. Reducing inflammation and the severity of dystrophic processes in vaginal enemas at the stage of preoperative preparation of women with postmenopausal GP favorably affects the regeneration processes, which in the first place can improve the outcome of surgical treatment.

Vaginal progesterone treatment for the prevention of preterm birth and intrahepatic cholestasis of pregnancy: A case-control study

IntroductionIntrahepatic cholestasis of pregnancy (ICP) is associated with a distinctive maternal pruritus, abnormal liver function tests, raised serum total bile acids, and increased rates of adverse fetal outcomes, including intrauterine fetal death. Progesterone has been implicated in the pathogenesis of ICP. We aimed to evaluate whether the incidence of ICP is altered in women receiving long-term daily vaginal progesterone, indicated for a short cervical length. Study designA matched 1:3 case-control study of pregnant women between January 2014 and January 2019. Study cases included pregnant women with the diagnosis of ICP. Control cases were women without ICP. The primary outcome was the rate of vaginal progesterone treatment among the groups. ResultsThe use of vaginal progesterone throughout pregnancy was higher in the ICP group compared with the control group (8/174 [4.6 %] versus 6/522 [1.1 %], respectively, P = 0.03, odds ratio 4 [95 % confidence interval 1.4–11.7]). ConclusionsPregnant women treated with long-term vaginal progesterone preparations for the prevention of preterm birth are at increased risk of developing ICP. In the presence of pruritus during pregnancy, we recommend an early consultation and diagnostic test to confirm or rule-out ICP.

The INTRACELLULAR PRODUCTION OF CYTOKINES IL-1 AND IL-10 IN PATIENTS WITH THIN ENDOMETRIUM SYNDROME WITH RECURRENT IMPLANTATION FAILURE

Abstract. Evaluation of endometrial cytotoxic lymphocytes using flow cytometry for “thin endome- trium” syndrome in 24 patients with recurrent implantation failure (RIF). The revealed changes in the level of immunocompetent cells indicate that the pathogenesis of recurrent unsuccessful implantation lies in a pronounced decrease in the level of CD8+ cytotoxic / suppressor lymphocytes and CD56 + lymphocytes, as well as a sharp decrease in the intracellular production of cytokines IL-1 and IL-10 by endometrial lymphocytes. Deficiency of signaling molecules and their synthesis of proteins, which oc- curs in the syndrome of “thin endometrium”, is accompanied by disruption of peri-implantation mecha- nisms, including the regulatory action of sex steroid hormones. Prospects for the treatment of failed implantation attempts lie in the selective effect on the endometrium with impaired receptivity. The treatment strategy is to eliminate the microbial-infectious agent with the use of rational antibacterial and immunomodulatory therapy at the first stage, induction of intracellular regeneration: biphasic hor- mone therapy (low doses of estrogen and progesterone). Preference is given to micronized progesterone preparations with bioidentity to endogenous progesterone, higher bioavailability and efficiency in the intravaginal route of administration. Key words: thin endometrial syndrome, recurrent implantation failure, endometrium, endometrial cytotoxic lymphocytes, intracellular cytokines IL1, IL10.

Actual aspects of vaginal progesterone use to prevent reproductive losses and optimize perinatal outcomes

Miscarriage is a complex socio-medical problem, the relevance of which throughout the world is determined by the stable frequency of spontaneous abortions and premature births for half a century. Premature termination of pregnancy as a typical multifactorial disease regardless of the term has a universal pathogenetic mechanism of realization, which is progesterone deficiency. This justifies the need for subsidies with progesterone drugs for women at the real risk of miscarriage and preterm pregnancy.The aim of the review is to summarize the information of relevant scientific publications with a high level of evidence on the effectiveness of progesterone drugs to prevent early spontaneous termination of pregnancy and an adverse perinatal outcome. To understand the features of micronized progesterone preparations that guarantee maximum effectiveness, to clarify the points of its application in connection with the risk of prematurity and perinatal outcome have been carried out studies in the world: PROMIS, TRISTAN-1, TRISTAN-2, OPPTIMUM, PRISM.It is proved that the target groups for progesterone drugs are women with the threat of miscarriage in the early stages, patients with habitual miscarriage. Progesterone preparations (micronized progesterone) are aimed not only at prolonging pregnancy, but also at preventing late complications. To date, strong evidence has been obtained (PRISM, 2019) that vaginal micronized progesterone provides better results: live birth value in the general population of women with bloody discharge in the early period (4153 observations) is 3% more than placebo, best effect obtained women with a history of three or more miscarriages who have a 28% higher chance of a live baby (up to 34 weeks). A change in the system of views on assessing progestogen effectiveness in the treatment of miscarriage (its criterion is a live birth), the best prospects for viability, which is provided by proven safety and a positive effect on perinatal outcomes was noted.

EFFICIENCY OF DIFFERENT METHODS OF DETERMINATION AND STIMULATION ESTROUS CYCLE OF CATTLE

In the conditions of industrial milk production and productivity growth in cows, the increase in the duration of the inter- calving period is noted. This is due to a somewhat prolonged process of involution of the uterus after calving in high-yielding animals and prolongation of the service-period due to lack of detection of animals in estrous cycle. Depending on the technology of maintenance and qualification of service personnel, the number of such animals may increase. The contributing factors include the year-round stall system of keeping cows, the uncontrolled retention of animals in large groups, short intervals of detection of animals in hunting and others. The paper uses the materials of the first-time animal and veterinary record of a number of husbandries specializing in industrial milk production with different systems of keeping animals and the detection of animals in hunting. Methods of hormonal stimulation of sexual intercourse in cows were studied in the state enterprise "Khrystynivske" (n = 243) for the binding system for the maintenance of cows and auto-mated control of motor activity of cows for unbroken maintenance for the detection of animals in hunting – LLC "Nd. a. Lesia Ukrainka" (n = 74). For hormonal stimulation, methods using estrogens and prostaglandins were used: the protocol Ovsinh (n = 164) and the use of progesterone (preparation Delta® Ceva Santa Animale) (n = 79). The obtained results were sorted by the methods of variation statistics in the software product Statistica 12.5. An analysis of the detection of spontaneous hunting in animals by the traditional method - observing them during the walk allowed us to establish that in the first cows, the indicators of regenerative (VP) and service-periods (SP), under the same conditions of abstinence and feeding, differed from full-age cows in the duration of only one sexual cycle (20–21 days), for almost identical index of insemination (IO). Analysis of the results of determining the sexual cycles of cows using the help of DATA SLOW software and Triolact sensors conducted at the LLC nd. a. Lesia Ukrainka of Kovel region of Volyn oblast (n = 74) showed that even short-term hunting, which takes place within 2–3 hours, can detect and carry out insemination of animals. The obtained results coincide with the duration of the service-period during the systematic visual detection of animals in the stage of sexual hunting, but there is a reduction of the three-fold of the recovery period, the duration of which is associated with certain difficulties of visual detection in animals of the first hunting (irreducible manifestation , short duration and others). Also, the results of the analysis confirm the increase in the service-period in cows-primates for approximately the duration of one sexual cycle. In the following cases, there is a decrease in the variability of reproduction rates. The growth of milk productivity negatively correlated with the indicator of the duration of service-period in cows. The force of influence was almost 96% (P < 0.01). In cases of tied animals maintenance in the first place, methods of hormonal stimulation of sexual hunting in cows are obtained. Indicator of efficiency of detection of animals in hunting during the period of maintenance was 28–35%, and during the summer-camp – grew to 47–62%. Analysis of the duration of the service period and the index of insemination with the synchronization of cows according to the protocol "Ovsinh" has shown a decrease in the effectiveness of insemination of cows for stimulated hunting. Fertility of animals after the first insemination was 20.1%, and after the second procedure the introduction of hormonal drugs increased by 8–12% and was 38%. In the application of progesterone in the form of vaginal applicators "Pride Delta" results were better – the fertility rate from the first insemination was 37%, and from two – 56%. As with the use of prostaglandin, and in the application of the protocol "Ovsinh" there is a tendency to increase the effectiveness of insemination, depending on the duration of the recovery period, that is, the time from calving to the use of the drug.