Effect of Oral versus Vaginal Administration of Estradiol and Dydrogesterone on the Proliferative and Secretory Transformation of Endometrium in Patients with Premature Ovarian Failure and Preparing for Assisted Reproductive Technology.

PURPOSE: This study aimed to assess the efficacy of vaginally versus orally administered estradiol (E2) and dydrogesterone (DG) on the proliferative and secretory transformation of endometrium in patients with premature ovarian failure (POF) and preparing for assisted reproductive technology. METHODS: Twenty patients with POF who were awaiting oocyte donation were included in the study; they were randomly assigned to two groups to receive E2 and DG either orally or vaginally. Treatment efficacy was compared between the two groups regarding blood E2 concentrations, endometrial thickness, histology using hematoxylin and eosin staining, immunohistochemical analysis of ER expression, and PR and pinopodes morphology using scanning electron microscopy. RESULTS: E2 concentrations differed significantly between oral and vaginal E2 and DG administration for 14 days (82.3 vs 1015.6 pg/mL; P < 0.001) and 21 days (85.0 vs 809.8 pg/mL; P < 0.001). Endometrial thickening was more pronounced in the vaginal treatment group, and also ER staining was stronger on days 14 and 21 in the vaginal treatment group. PR staining in the endometrium appeared more intense in the oral treatment group, which was, however, not significant. The abundance of developing pinopodes was higher in the vaginal treatment group (P = 0.04). CONCLUSION: Vaginal administration of E2 and DG is more effective than oral administration regarding proliferative and secretory transformation of the endometrium in POF patients and preparing for assisted reproductive technology.

Biotransformation of progestonic hormone dydrogesterone with Macrophomina phaseolina, and study of the effect of biotransformed products on phagocytes oxidative burst.

Biotransformation of a synthetic progestonic hormone dydrogesterone (1), C21H28O2, with a plant pathogenic fungus Macrophomina phaseolina yielded two new 2 and 3, and a known 4 metabolites. These analogues were identified as, 3ß,11α-dihydroxy-5ß,9ß,10α-pregna-7-ene-6,20-dione (2), 15ß-hydroxy-9ß,10α-pregna-4,6-diene-3,20-dione (3), and 8α-hydroxy-9ß,10α-pregna-4,6-diene-3,20-dione (4). Major structural changes were observed in metabolite 2. New metabolite 3 showed anti-inflammatory potential, and was found to be the potent inhibitor of intracellular reactive oxygen species (ROS) from whole blood phagocytes (IC50 = 4.2 ±â€¯0.3 µg/mL), as compared to standard drug Ibuprofen (IC50 = 11.2 ±â€¯1.9 µg/mL). The metabolites 2, 3, and 4 were found to be non-toxic to NIH-3T3 (CRL-1658) normal cell line. This indicated anti-inflammatory potential of resulting metabolites.

[Study of the effects of three luteal phase supporting strategies on clinical outcomes of intrauterine insemination].

OBJECTIVE: To explore the effects of three luteal phase supporting strategies on clinical outcomes of intrauterine insemination (IUI). METHODS: 1 779 subjects who underwent IUI at the Center of Reproductive Medicine, Peking University Third Hospital from November 2014 to June 2015 were enrolled in this retrospectively study.According to the luteal phase supporting strategies, all the subjects were divided into three groups: subjects receiving Dydrogesterone were group A; subjects receiving oral micronized progesterone were group B; subjects receiving vaginal micronized progesterone were group C. The pregnancy outcomes, including clinical pregnancy rate, early miscarriage rate, biochemical pregnancy rate and ectopic pregnancy rate were compared in the three groups. RESULTS: There was no significant difference in the three groups in constituent ratio, average IUI times, rate of the natural cycle, rate ofovulation cycle and dropout rate(P>0.05). Similarly, there was also no significant difference in pregnancy outcomes in all groups.Subsequent stratified analysis demonstrated that pregnancy outcomes in subjects of natural cycle and ovulation cycle still showed no significant difference(P>0.05). CONCLUSION: Our study suggested that the effects of three luteal phase supporting strategies on clinical outcomes of IUI were similar.The medication in clinic should be individualized.

Effect of Progesterone, Its Hydroxylated and Methylated Derivatives, and Dydrogesterone on Lipid Bilayer Membranes.

The interaction of progesterone (PG), 17-hydroxyprogesterone (17-OHPG), 21-hydroxyprogesterone (21-OHPG), medroxyprogesterone (MP), medroxyprogesterone acetate (MPA), and dydrogesterone (DYG), with zwitterionic dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposome, was investigated as a function of drug concentration using Fourier transform infrared spectroscopy and differential scanning calorimetry. The results reveal that progesterone and its derivatives changed the physical properties of the DPPC bilayers by decreasing the main phase-transition temperature (T m) and enthalpy (ΔH m), abolishing the pre-transition and disordering the membrane. From the thermodynamic parameters analysis, we concluded that PG, 21-OHPG, and MPA are localized inside the membrane. Whereas, the insertion of 17-OHPG in the lipid bilayers cannot be excluded in view of the significant decrease in the transition enthalpy at two molar ratios. MP and DYG are rather localized near the polar heads of phospholipids at the interface water-lipid bilayer. PG derivatives increase the membrane fluidity in the order: PG ≈ 21-OHPG ≈ MPA > 17-OHPG > MP ≈ DYG. The distinct effects produced by steroids are discussed in terms of hydrophobicity and chemical structure.

Fungal transformation of dydrogesterone and inhibitory effect of its metabolites on the respiratory burst in human neutrophils.

The biotransformation of the synthetic hormone dydrogesterone (1) by a number of fungal strains - including Cephalosporium aphidicola, Rhizopus stolonifer, Cunninghamella elegans, and Fusarium lini - afforded ten different metabolites, compounds 2-11. From a structural point of view, these transformations involved a combination of hydroxylation, oxidation, reduction, and/or epoxidation. The pregnane-based metabolites 10 and 11 are new compounds. All the known compounds were obtained for the first time from 1 by fungal transformation. The metabolites 3, 5, and 8 showed more-potent respiratory-burst inhibitory activity than the substrate 1 in a neutrophil-based cellular assay (Table 3).

A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.

6-Dehydroretroprogesterone (dydrogesterone) and three other natural or synthetic progestins (progesterone, retroprogesterone, and 6-dehydroprogesterone) were submitted to a conformational study through theoretical calculations at the B3LYP/6-31G(*) level and high field NMR spectroscopy. The study allows to define the role of the two structural features which differentiate these steroids, i.e., the C9 and C10 configuration and the C6-C7 unsaturation. The combined effects of the conformational preference of A ring, determined by the configuration at C9 and C10, and the enhanced rigidity due to the C6-C7 double bond, could account both for the higher activity and selectivity of dydrogesterone with respect to the other three steroids.

DNA fragmentation, DNA repair and apoptosis induced in primary rat hepatocytes by dienogest, dydrogesterone and 1,4,6-androstatriene-17beta-ol-3-one acetate.

Four steroids that share the 17-hydroxy-3-oxopregna-4,6-diene structure - cyproterone acetate, chlormadinone acetate, megestrol acetate, and potassium canrenoate - have been shown previously to behave with different potency as liver-specific genotoxic agents, the response being markedly higher in female than in male rats, but similar in humans of both genders. In this study, performed to better define the relationship between chemical structure and genotoxicity, dydrogesterone (DGT) with double bonds C4=C5 and C6=C7, dienogest (DNG) with double bonds C4=C5 and C9=C10, and 1,4,6-androstatriene-17beta-ol-3-one acetate (ADT) with double bonds C1=C2, C4=C5 and C6=C7, were compared with cyproterone acetate (CPA) for their ability to induce DNA fragmentation and DNA repair synthesis in primary cultures of hepatocytes from three rats of each sex. At subtoxic concentrations, ranging from 10 to 90 microM, all four steroids consistently induced a dose-dependent increase of DNA fragmentation, which in all cases was higher in females than in males; their DNA damaging potency decreased in the order CPA > DNG > ADT > DGT. Under the same experimental conditions, the responses provided by the DNA repair-synthesis assay were positive or inconclusive in hepatocytes from female rats and consistently negative in hepatocytes from male rats. In the induction of apoptotic cells, examined in primary hepatocytes from female rats, CPA was more active than ADT and DGT, and DNG was inactive. Considered as a whole these findings suggest that a liver-specific genotoxic effect more marked in female than in male rats might be a common property of steroids with two or three double bonds.

Induction of micronuclei and of enzyme-altered foci in the liver of female rats exposed to progesterone and three synthetic progestins.

Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg kg-1 3 days before partial hepatectomy and sacrificed for cell sampling 2 days later, the frequency of micronucleated hepatocytes was 3.5-fold higher than in controls with PG, 2.8-fold with DG, 2.2-fold with NE and 2.1-fold with AE, but the increase was statistically significant only for PG. In the liver foci assay, performed to evaluate the tumor initiating activity of p. o. dosing with 100 mg kg-1 once a week for 6 successive weeks, the values of the number and area of gamma-glutamyltranspeptidase-positive foci were, as compared to controls, 15.9- and 100-fold higher with NE, and 13.9- and 52-fold higher with AE, but only the increase of area produced by NE was statistically significant; PG and DG did not display in this test any activities. Considered together with previous findings, these results suggest that NE might be biotransformed in the liver into reactive species and thus behave as a weak genotoxic agent.