APC resistance during the normal menstrual cycle

2007 ◽  
Vol 98 (12) ◽  
pp. 1246-1251 ◽  
Author(s):  
Angela Silveira ◽  
Stella Thomassen ◽  
Jacob Odeberg ◽  
Anders Hamsten ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Protein C ◽  
Activated Protein C ◽  
Serum Levels ◽  
Serum Estradiol ◽  
Menstrual Cycles ◽  
Apc Resistance ◽  
Exogenous Estrogen ◽  
Normal Menstrual Cycle ◽  
Estradiol Concentration

SummaryIncreased serum levels of endogenous as well as exogenous estrogen are regarded to be responsible for acquired activated protein C (APC) resistance. It was the objective of this study to evaluate whether the physiological increase in serum estradiol concentration during the normal menstrual cycle affects the individual’s sensitivity to APC. Seventy-two women with normal menstrual cycles were included in the study. Blood samples for analysis of estradiol (E2), progesterone (P4) and APC resistance were drawn at two time points of the menstrual cycle (day 3–5 and day 22–25). Two methods of measuring APC resistance were used: the activated partial thromboplastin time (aPTT)-based assay and the endogenous thrombin potential (ETP)-based APC resistance test. Independent of the method used, no changes in APC resistance were found, even though the E2 concentration increased significantly between the two menstrual phases. No correlations between E2 levels and APC resistance, P4 levels and APC resistance or changes in E2 concentrations and changes in APC resistance were detected. Ten women were carriers of the factor VLeiden mutation. Their baseline APC resistance was increased, but their response to elevated E2 during the menstrual cycle did not differ from that of non-carriers. In conclusion, our observations suggest that physiological differences in serum levels of estradiol and progesterone between the early follicular and the luteal phase in a normal menstrual cycle do not have any significant impact on the individual’s sensitivity to APC.

Estradiol and progesterone levels in the endometrium and the reproductive tract luminal washing during the pre-implantation stages of gestation in the rhesus monkey

1989 ◽  
Vol 120 (5) ◽  
pp. 649-654 ◽  
Author(s):  
D. Ghosh ◽  
Jayasree Sengupta
Keyword(s):  
Menstrual Cycle ◽  
Rhesus Monkey ◽  
Reproductive Tract ◽  
Sex Steroid ◽  
Menstrual Cycles ◽  
Normal Menstrual Cycle ◽  
Ovulatory Period ◽  
Hormonal Milieu ◽  
Estradiol 17Β ◽  
Estradiol Concentration

Abstract. To obtain an understanding of the sex steroid hormonal milieu during early gestation, the concentrations of estradiol-17β and progesterone were measured in endometria and reproductive tract luminal fluids collected during the post-ovulatory period (days 2 to 6) of conception, and of non-mated menstrual cycles of the rhesus monkey (Macaca mulatta). Estradiol content was found to be higher (P< 0.05) in endometria obtained from conception cycles; day-wise analysis revealed higher (P< 0.05) level of tissue estradiol concentration on day 6 of post-ovulation as compared with the normal menstrual cycle. Endometrial progesterone content remained, however, unaltered in both groups of monkeys and thus relatively lower (P< 0.05) endometrial progesterone to estradiol ratios were seen on days 4, 5 and 6 of gestation compared with normal menstrual cycle. There were no significant changes in the profiles and concentrations of estradiol and progesterone in luminal washings. The typical sex steroid hormonal milieu observed in the endometrium during the peri-implantation stage of gestation in conception cycle may be related to the endometrial differentiation towards implantation in the rhesus monkey.

“Pseudo Homozygous” Activated Protein C Resistance due to Double Heterozygous Factor V Defects (Factor V Leiden Mutation and Type I Quantitative Factor V Defect) Associated with Thrombosis: Report of Two Cases Belonging to Two Unrelated Kindreds

1996 ◽  
Vol 75 (03) ◽  
pp. 422-426 ◽  
Author(s):  
Paolo Simioni ◽  
Alberta Scudeller ◽  
Paolo Radossi ◽  
Sabrina Gavasso ◽  
Bruno Girolami ◽  
...  
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Type I ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance ◽  
Quantitative Factor

SummaryTwo unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F. V defect and F. V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F. V Leiden mutation, the measurement of the responsiveness of patients plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F. V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F. V, instead of protecting from thrombotic risk due to heterozygous F. V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F. V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F. V Leiden mutation based on the APC-resi-stance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.

Molecular Characterization of a Type I Quantitative Factor V Deficiency in a Thrombosis Patient that Is “Pseudo Homozygous” for Activated Protein C Resistance

1997 ◽  
Vol 77 (02) ◽  
pp. 252-257 ◽  
Author(s):  
Joan F Guasch ◽  
Ruud P M Lensen ◽  
Rogier M Bertina
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Type I ◽  
Factor V ◽  
Sequencing Analysis ◽  
Apc Resistance ◽  
Quantitative Factor ◽  
Factor V Deficiency ◽  
Fv Leiden

SummaryResistance to activated protein C (APC), which is associated with the FV Leiden mutation in the large majority of the cases, is the most common genetic risk factor for thrombosis. Several laboratory tests have been developed to detect the APC-resistance phenotype. The result of the APC-resistance test (APC-sensitivity ratio, APC-SR) usually correlates well with the FV Leiden genotype, but recently some discrepancies have been reported. Some thrombosis patients that are heterozygous for FV Leiden show an APC-SR usually found only in homozygotes for the defect. Some of those patients proved to be compound heterozygotes for the FV Leiden mutation and for a type I quantitative factor V deficiency. We have investigated a thrombosis patient characterized by an APC-SR that would predict homozygosity for FV Leiden. DNA analysis showed that he was heterozygous for the mutation. Sequencing analysis of genomic DNA revealed that the patient also is heterozygous for a G5509→A substitution in exon 16 of the factor V gene. This mutation interferes with the correct splicing of intron 16 and leads to the presence of a null allele, which corresponds to the “non-FV Leiden” allele. The conjunction of these two defects in the patient apparently leads to the same phenotype as observed in homozygotes for the FV Leiden mutation.

Effectiveness of zona pellucida protein ZPB as an immunocontraceptive antigen

Reproduction ◽  
2000 ◽  
pp. 19-32 ◽  
Author(s):  
ML Martinez ◽  
JD Harris
Keyword(s):  
Menstrual Cycle ◽  
Recombinant Protein ◽  
Antibody Titre ◽  
Zona Pellucida ◽  
Protein A ◽  
Papio Cynocephalus ◽  
Cynomolgus Monkeys ◽  
Menstrual Cycles ◽  
Normal Menstrual Cycle

Immunization of female mammals with native zona pellucida (ZP) proteins is known to cause infertility. Since each human ZP protein is now available as a purified recombinant protein, is it possible to compare the immunocontraceptive potential of each ZP protein. A breeding study was conducted in cynomolgus monkeys (Macaca fasicularis) after immunization with recombinant human ZP (rhZP) proteins (ZPA, ZPB, ZPC) separately and in combinations. This study demonstrated that immunization with recombinant human ZPB (rhZPB) protein caused cynomolgus monkeys to become infertile for 9-35 months. A second study was conducted in baboons (Papio cynocephalus), which yielded a similar result. The baboons immunized with rhZPB became infertile for 9 to > 20 months. During the time of maximum antibody titre, some animals experienced disruption of the menstrual cycle, but eventually all of the animals resumed normal menstrual cycles. Control animals and animals immunized with other rhZP proteins all became pregnant before any of the rhZPB-treated animals. This is the first study in which a recombinant ZP protein has consistently induced infertility in a primate without permanent disruption of the normal menstrual cycle.

Does the menstrual cycle influence the sensitivity of vagally mediated baroreflexes?

2002 ◽  
Vol 102 (6) ◽  
pp. 639-644 ◽  
Author(s):  
William H. COOKE ◽  
David A. LUDWIG ◽  
Paul S. HOGG ◽  
Dwain L. ECKBERG ◽  
Victor A. CONVERTINO
Keyword(s):  
Menstrual Cycle ◽  
Young Women ◽  
Regulatory Mechanisms ◽  
Physiological Changes ◽  
Menstrual Cycles ◽  
Time Points ◽  
Normal Menstrual Cycle ◽  
Cardiac Regulation ◽  
Neck Pressure ◽  
Noradrenaline Levels

The menstrual cycle provokes several physiological changes that could influence autonomic regulatory mechanisms. We studied the carotid-cardiac baroreflex in ten healthy young women on four occasions over the course of their menstrual cycles (days 0-8, 9-14, 15-20 and 21-25). We drew blood during each session for analysis of oestrogen, progesterone and noradrenaline (norepinephrine) levels, and assessed carotid-cardiac baroreflex function by analysing R-R interval responses to graded neck pressure sequences. Oestrogen levels followed a classical two-peak (cubic) response, with elevated levels on days 9-14 and 21-25 compared with days 0-8 and 15-20 (P =0.0032), while progesterone levels increased exponentially from days 9-14 to days 21-25 (P = 0.0063). Noradrenaline levels increased from an average of 137pg/ml during the first three measurement periods to 199pg/ml during days 21-25 (P = 0.0456). Carotid-cardiac baroreflex gain and operational point were not statistically different at any of the time points during the menstrual cycle (P⩾0.18). These findings are consistent with the notion that beat-to-beat vagal-cardiac regulation does not change over the course of the normal menstrual cycle.

scholarly journals A Factor V Genetic Component Differing From Factor V R506Q Contributes to the Activated Protein C Resistance Phenotype

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1552-1557 ◽  
Author(s):  
F. Bernardi ◽  
E.M. Faioni ◽  
E. Castoldi ◽  
B. Lunghi ◽  
G. Castaman ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Activated Protein C ◽  
Functional Assay ◽  
Factor V ◽  
Resistance Phenotype ◽  
Apc Resistance ◽  
Genetic Components ◽  
Factor V Gene ◽  
V Gene

AbstractFactor V gene polymorphisms were investigated to detect components that may contribute to the activated protein C (APC) resistance phenotype in patients with venous thromboembolism. A specific factor V gene haplotype (HR2) was defined by six polymorphisms and its frequency was found to be similar in normal subjects coming from Italy (0.08), India (0.1), and Somalia (0.08), indicating that it was originated by ancestral mutational events. The relationship between the distribution of normalized APC ratios obtained with the functional assay and haplotype frequency was analyzed in patients heterozygous for factor V R506Q (factor V Leiden). The HR2 haplotype was significantly more frequent in patients with ratios below the 15th percentile than in those with higher ratios or in normal controls. Moreover, the study of 10 patients with APC resistance in the absence of the factor V R506Q mutation showed a 50-fold higher frequency of HR2 homozygotes. The HR2 haplotype was associated with significantly lower APC ratios both in patients with venous thromboembolism and in age- and sex-matched controls. However, the two groups showed similar HR2 haplotype frequencies. Plasma mixing experiments showed that an artificially created double heterozygote for the factor V R506Q mutation and the HR2 haplotype had an APC ratio lower than that expected for a simple R506Q heterozygote. Time-course experiments evaluating the decay of factor V in plasma showed the normal stability of the molecule encoded by the factor V gene marked by the HR2 haplotype, which ruled out the presence of a pseudo-homozygous APC resistance mechanism. Our results provide new insights into the presence of factor V genetic components other than the factor V R506Q that are able to contribute to the APC resistance phenotype in patients with venous thromboembolism.

scholarly journals Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives

2004 ◽  
Vol 2 (9) ◽  
pp. 1594-1600 ◽  
Author(s):  
M. Alhenc-Gelas ◽  
G. Plu-Bureau ◽  
S. Guillonneau ◽  
J.-M. Kirzin ◽  
M. Aiach ◽  
...  
Keyword(s):  
Oral Contraceptives ◽  
Protein C ◽  
Activated Protein C ◽  
Apc Resistance

Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

2007 ◽  
Vol 97 (06) ◽  
pp. 938-943 ◽  
Author(s):  
Sigurd Liestøl ◽  
Marie-Christine Mowinckel ◽  
H. Coen Hemker ◽  
Per-Morten Sandset ◽  
Anette Eilertsen
Keyword(s):  
Hormone Therapy ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
System Sensitivity ◽  
Conventional Dose ◽  
Apc Resistance ◽  
The Difference ◽  
Progestin Therapy

SummaryRecent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.

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