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Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.

Natural killer cells constitute 50-90% of lymphocytes in human uterine decidua in early pregnancy. Here, CD56(bright) uterine decidual NK (dNK) cells were compared with the CD56(bright) and CD56(dim) peripheral NK cell subsets by microarray analysis, with verification of results by flow cytometry and RT-PCR. Among the approximately 10,000 genes studied, 278 genes showed at least a threefold change with P < or = 0.001 when comparing the dNK and peripheral NK cell subsets, most displaying increased expression in dNK cells. The largest number of these encoded surface proteins, including the unusual lectinlike receptors NKG2E and Ly-49L, several killer cell Ig-like receptors, the integrin subunits alpha(D), alpha(X), beta1, and beta5, and multiple tetraspanins (CD9, CD151, CD53, CD63, and TSPAN-5). Additionally, two secreted proteins, galectin-1 and progestagen-associated protein 14, known to have immunomodulatory functions, were selectively expressed in dNK cells.

CD56 Antigen↗

Human placental protein 14 gene: sequence and characterization of a short duplication.

Differential hybridization of cDNAs corresponding to mRNAs expressed in the human endometrium during the secretory phase or during the first trimester of pregnancy, but not during the proliferative phase, allowed us to isolate and characterize cDNAs encoding human placental protein 14 (PP14). The cDNA was used to isolate the PP14 gene from a human genomic library. The entire gene encompasses 5.05 kb divided into seven exons by six introns. The human PP14 gene shows identical organization with the ovine beta-lactoglobulin gene, as expected from protein homology. Sequencing of 3 kb of the 5'-flanking region of the gene allowed us to characterize a 400-bp duplication of the PP14 gene lying at position -2,660. This duplication was homologous to 100 bp of exon 4 and 300 bp of intron 4, including 180 bp corresponding exactly to the right arm of an Alu element lying on the complementary strand. This homology suggests that this duplication may have arisen through a retroposition event.

Amino Acid Sequence↗

Maternal plasma concentrations of insulin-like growth factor binding protein-1 and placental protein 14 in multifetal pregnancies before and after fetal reduction.

The aim of this study was to investigate the changes in maternal plasma insulin-like growth factor binding protein-1 (IGFBP-1) and placental protein 14 (PP14) in multifetal pregnancies before and after embryo reduction. Maternal plasma IGFBP-1 and PP14 were measured serially in three groups of pregnant women at 8-21 weeks gestation. Groups 1 and 2 were 12 singleton and 12 twin pregnancies achieved after in-vitro fertilization (IVF). Group 3 comprised 26 women with multifetal pregnancies undergoing embryo reduction to twins. In the IVF pregnancies maternal plasma IGFBP-1 and PP14 increased with gestation to reach a peak at 20 and 10 weeks respectively; the mean concentrations in twin pregnancies were significantly higher than in singletons. In multifetal pregnancies the mean plasma concentration of both proteins was similar to that of IVF twin pregnancies before reduction; after reduction, the values fell to less than those of twins. These findings suggest that the maximum secretory capacity of the endometrium is achieved with twin pregnancies. In multifetal pregnancies undergoing iatrogenic reduction to twins, total residual endometrial function was less than in twin conceptions.

Carrier Proteins↗

The production of placental protein 14 by human uterine tubal epithelial cells in culture.

Cells prepared from the mucosal layer obtained from the fimbrial, proximal ampullary and distal ampullary regions of the human uterine (Fallopian) tube have been grown in monolayer culture. Immunocytochemistry with anti-cytokeratin, anti-vimentin or anti-CD 45 antibodies indicated that the overwhelming number of cells were epithelial in nature and were free of fibroblasts and leukocytes. Basal and steroid-stimulated placental protein 14 (PP14) production was investigated in tissue obtained from nine patients undergoing hysterectomy, by addition of oestradiol and/or progesterone to confluent cultures. Basal PP14 production varied considerably between experiments, probably due to differences between individuals from whom the tissue had been obtained. However, there was no difference in basal PP14 production by cells prepared from the fimbrial, proximal ampullary and distal ampullary parts of the tube obtained from the same patient. When total PP14 production by cells obtained from an individual uterine tube was pooled both progesterone and oestradiol significantly (P < 0.05) stimulated the production of PP14 but the effect of progesterone either alone or in the presence of oestradiol was numerically greater than that of oestradiol alone. Considering PP14 production by cells prepared from the different regions of the tube showed that cells from the fimbrial region were more responsive to steroid stimulation than cells prepared from either the proximal or the distal ampullary regions. All combinations of hormonal supplementation stimulated PP14 production by cells from the fimbrial region on all days measured (P < 0.05 - P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗

A role for glycoconjugates in human development: the human feto-embryonic defence system hypothesis.

The mechanisms underlying the protection of the human embryo/fetus from the maternal immune response are poorly understood. Substantial evidence indicates that carbohydrate recognition plays a primary role in the sequestration of leukocytes during inflammatory processes, lymphocyte homing, and initial gamete binding. Our previous studies suggest a possible convergence in the types of carbohydrate sequences recognized during initial human gamete binding and immune/inflammatory cell interactions. Our more recent findings indicate that oligosaccharides participating in such processes are also associated with soluble glycoconjugates found in the human placenta, amniotic fluid, and decidua. We theorize that such glycoconjugates may abrogate the maternal immune/inflammatory response by blocking the primary adhesive interactions required for the expression of such activities. Foreign embryonic cells may also be protected by surface expression of oligosaccharide sequences that suppress immune effector cell action in a manner not dependent upon classical major histocompatibility (MHC) recognition. Glycoconjugates expressing selectin ligands may also manifest a potent contraceptive effect that may also be beneficial for both the mother and the developing embryo/fetus. This hypothesis provides a preliminary framework for understanding how temporally and spatially restricted immunosuppressive effects could be expressed in utero that protect the human embryo/fetus during this period of human development.

Animals↗

Placental protein 14 production by human Fallopian tube epithelial cells in vitro.

We studied the in-vitro secretory function of non-polarized and polarized cultured Fallopian tube epithelial cells by measurement of the placental protein 14 (PP14) secretion in primary cultures and subcultures from Fallopian tubes obtained from eight premenopausal women in different phases of the ovarian cycle. Primary cultures were established in minimal essential medium in Earle's salts supplemented with fetal bovine serum and the cells were subcultured for six passages, in the polarized cell cultures, the cells being seeded on an extracellular matrix system. Cell freezing was carried out using 10% dimethyl sulphoxide. PP14 secretion into the culture media was measured by a radioimmunoassay using 125I-PP14 as label and rabbit anti-human PP14 serum. There was a large amount of PP14 secretion into the culture media in primary cultures, the secretion decreasing considerably after subculture 1. PP14 secretion after subculture 2 was not different from the control values. Polarized and non-polarized cells secreted similar amounts of PP14 and frozen-thawed cells did not appear to secrete PP14. Epithelial cells from Fallopian tubes obtained at different phases of the ovarian cycle did not appear to show any difference in PP14 secretion rates. Our data suggest that the in-vitro secretion of PP14 by human Fallopian tube epithelial cells is adversely affected by cell ageing and freezing.

Adult↗

Is the measurement of placental protein-14 and CA-125 in plasma and uterine flushings useful in the evaluation of peri-menopausal and post-menopausal bleeding?

In this prospective study, we examined the possible diagnostic value of the measurement of two endometrial proteins, placental protein-14 (PP14) and CA-125, in the evaluation of pre- and post-menopausal bleeding. Concentrations of these two proteins were measured in plasma and uterine flushings obtained from 139 pre- and post-menopausal women with bleeding problems, and 26 normal post-menopausal control women without bleeding. Endometrial biopsy samples were also obtained for histological study. Concentrations of PP14 in both the plasma and uterine flushings in post-menopausal women were significantly lower (P < 0.001) than those of control pre-menopausal women. In post-menopausal women, the concentrations of PP14 (mean +/- SEM) in both plasma and flushing were significantly higher (P < 0.001) in women with endometrial adenocarcinoma (46.9+/-7.5 ng/ml plasma; 3350+/-1711 ng/ml flushing) than in the controls (7.6+/-1.3 ng/ml plasma; 125+/-27 ng/ml flushing) or in women with post-menopausal bleeding and atrophic endometrium (20.4+/-2.1 ng/ml plasma; 453+/-167 ng/ml flushing). In contrast CA-125 concentrations in plasma and flushings were similar in post-menopausal and pre-menopausal women. Plasma concentrations of CA-125 were higher in post-menopausal women with adenocarcinoma (29.1+/-7.4 IU/ml) than in those with post-menopausal bleeding and atrophic endometrium (21.8+/-2 IU/ml) (P < 0.05) or control post-menopausal subjects (16.1+/-2.1 IU/ml) (P < 0.01). CA-125 concentrations in uterine flushings were not significantly different in any group of post-menopausal women. The results show that concentrations of PP14 are correlated more strongly to endometrial histopathology than those of CA-125 in pre- and post-menopausal women. Elevated PP14 concentrations are also associated with the presence of endometrial adenocarcinoma and may have a potential to be used as a marker for this disease.

Adenocarcinoma↗

Endometrial protein PP14 and CA-125 in recurrent miscarriage patients; correlation with pregnancy outcome.

The concentrations of endometrial proteins PP14 and CA-125 were measured in uterine flushings taken on days LH+10 and LH+12 (10 and 12 days after luteinizing hormone surge) of the menstrual cycle from 15 normal, fertile women and 49 women who suffered recurrent miscarriage. The concentration of PP14 was significantly lower in the flushings from the recurrent miscarriage patients than in those from fertile controls on both day LH+10 (median: 1300, range: 3-10 300 ng/ml versus median: 13 933, range: 2174-40 404 ng/ml; P < 0.01) and LH+12 (median: 1560, range: 820-12 100 ng/ml versus median: 14 047, range 1402-62 108 ng/ml; P < 0.05). Similarly concentrations of CA-125 were significantly lower in flushings from recurrent miscarriage women compared to controls on both day LH + 10 (median: 1555, range: 47-6710 U/ml versus median: 6385.5, range 2884-27 731 U/ml, P < 0.01) and LH+12 (median: 2892, range: 956-9974 U/ml versus median: 7127.5, range: 1591-21 343 U/ml; P < 0.05). In contrast there was no significant difference in the concentration of PP14 in plasma samples taken on the same days as the flushings from recurrent miscarriage patients and fertile controls. The concentrations of PP14 in uterine flushings obtained on day LH + 10 or LH + 12 from recurrent miscarriage women during a pre-pregnancy investigative cycle were significantly lower (P < 0.05) in patients who went on to miscarry (median: 1000, range: 9-2900 ng/ml) than those who went on to have a live birth (median: 1440, range: 4-12 100 ng/ml) during a subsequent pregnancy. In contrast there was no significant difference in uterine CA-125 or plasma PP14 concentrations between these two groups of recurrent miscarriage patients. The results suggest that measurements of uterine PP14 and CA-125 may be useful in the assessment of endometrial development in recurrent miscarriage patients and suggest the importance of PP14 in preparing the endometrium for embryo implantation. In addition pre-pregnancy uterine PP14 measurements may be useful in predicting subsequent pregnancy outcome.

Abortion, Habitual↗

Concentrations of placental protein 14 in uterine flushings from infertile women: validation of the collection technique and method of expression of results.

Concentrations of various proteins in uterine flushings have been described as a direct method for assessment of the secretory activity of the endometrium. We investigated levels of the endometrial protein known as placental protein 14 (PP14) in flushings obtained from 271 infertile women. Under transvaginal ultrasonographic control, 2 ml of 0.154 M sodium chloride solution were injected into the uterine cavity and re-aspirated, five times. In contrast to previous studies the recovered volume of each flushing was not consistent (range: 0.05-2.1 ml); the volume varied significantly between serial samples obtained from an individual (P = 0.02, one-way ANOVA), different cycle days (P < 0.0001, one-way ANOVA) and women with bilaterally blocked versus patent Fallopian tubes (P < 0.05, Student's t-test). Concentrations of PP14 showed a better correlation with protein content (r = 0.506, P < 0.0001) than with the recovered volume (r = 0.087, P = 0.095). We therefore corrected PP14 concentrations for total protein content as an indicator of the efficiency of the flushing process. Corrected PP14 concentrations varied significantly relative to time since the onset of menstruation (P = 0.001, Kruskal Wallis ANOVA) with higher levels on days 1-8, as previously observed in plasma samples. No significant difference in PP14 levels was found with different causes of infertility. This study shows that uterine flushing is not a consistent process in women with differing physical characteristics and at varying times throughout the menstrual cycle.

Adult↗

Placental protein 14 in endometrium during menstrual cycle and effect of early luteal phase mifepristone administration on its expression in implantation stage endometrium in the rhesus monkey.

Placental protein 14 (PP14) is a glycoprotein which is secreted by secretory phase endometrium and decidua in women. Despite the suggestion that PP14 is involved in the process of endometrial maturation for blastocyst implantation, our understanding in this regard is poor. In the present study, the concentrations and distribution patterns of immunodetectable PP14 in the endometrium during proliferative and secretory phases of normal ovulatory menstrual cycles, as well as in implantation stage endometrium in naturally mated ovulatory cycles with or without early luteal phase mifepristone treatment, were investigated using the rhesus monkey as a primate model. Immunopositive PP14 was observed mainly in epithelial cells of glands and it was detected in one major immunopositive band at Mr 28 kDa in tissue homogenate and spent medium. The area of immunopositive precipitation of PP14 in glands was minimal in follicular phase endometrium, and was higher (P < 0.01) in early, mid- and late luteal phase endometrium compared with that in pre- and periovulatory phases of the cycle, but there was no change in its area profile in the glandular compartment throughout the luteal phase. Immunopositivity for PP14 in luminal contents of gland displayed an increasing profile from early to late secretory phases. Thus, the concentrations and the distribution of immunodetectable PP14 in luteal phase endometrium of the rhesus monkey showed marked similarity with those of human endometrium during the natural menstrual cycle. Although there was no marked change in the band characterstics for the protein in implantation stage endometrium following early luteal phase mifepristone treatment, it was markedly decreased (P < 0.01) in tissue homogenate and in vitro spent medium along with a lesser (P < 0.02) degree of immunoprecipitation in the glands in implantation stage samples of mifepristone treatment group compared with that in control group samples. Thus, the contragestional effect of early luteal phase mifepristone treatment appears to be associated with a decrease in the concentration of immunodetectable PP14 in implantation stage endometrial glands and its secretion in the rhesus monkey. It remains to be seen whether this decline is caused from direct antiprogesterone action on endometrial glands during progesterone dominance, or secondarily from associated retarded development of endometrium.

Animals↗

The value of biochemical and ultrasound measurements in predicting pregnancy outcome in women with a history of recurrent miscarriage.

In this study, the potential prognostic value of serial ultrasonographic, endocrinological and biochemical measurements in the early pregnancy of women with a history of unexplained recurrent miscarriage was examined. A total of 113 pregnancies among 93 women were studied, of which 77 (68%) resulted in live birth, whereas 36 (32%) ended in a miscarriage. The normal range (5-95th centile) of various measurements was derived from pregnancies which resulted in a live birth. Among the 36 failed pregnancies, 42% had one or more human chorionic gonadotrophin (HCG) measurements, 35% had one or more gestation-sac diameter measurements, 33% had one or more embryonic heart rate measurements, 20% had one or more crown-rump length measurements and 9% had one or more placental protein 14 measurements below the normal range, a week or more prior to the confirmation of miscarriage. Altogether, 22/36 = 61% of the failed pregnancies could have been predicted on the basis of one or more of the measurements below the normal range.

Abortion, Habitual↗

A prospective randomized controlled study comparing the morphological and biochemical responses of the endometrium to two different forms of 'period-free' hormone replacement therapy.

Thirty postmenopausal women were randomized to receive either continuous combined (cc) 2 mg oestradiol valerate and 0.7 mg norethisterone acetate hormone replacement therapy (HRT) daily (15 women) or tibolone 2.5 mg daily (15 women) and were monitored to determine the relationship between the two biochemical markers placental protein 14 (PP14) and the glycoprotein CA125, endometrial histology and occurrence of irregular bleeding after 12 months of treatment. The concentrations of PP14 and CA125 in plasma and uterine flushings before and after therapy were measured and their concentrations were associated with the histology of endometrial biopsies obtained on the same day as venesection and endometrial flushing. The levels of PP14 in uterine flushings were significantly increased after the administration of both types of HRT (P < 0.05 for tibolone and P < 0.001 for ccHRT). However, the concentrations of PP14 found in flushings after ccHRT were considerably greater than those found in flushings after tibolone; levels were increased about 150-fold by ccHRT and 6-fold by tibolone (P < 0.001). Plasma concentration of PP14 after both types of HRT were also significantly raised to a similar degree (P < 0.01). In contrast, the concentration of plasma and uterine CA125 were unchanged by either treatment. Histological analysis of the endometrium from women after 12 months of HRT treatment showed that 86% (6/7) of women on ccHRT had secretory activity as compared to 44% (4/9) women on tibolone (P < 0.05). Women with higher post-HRT uterine PP14 concentration were more likely to have irregular bleeding (P < 0.05). Our studies have shown that endometrial PP14 but not CA125 concentrations are raised to a significant degree by two different forms of period-free HRT regimens. Increased PP14 concentrations in uterine flushing may suggest endometrial stimulation of some form and predict the predilection to irregular bleeding. Thus uterine PP14 concentrations may be used to monitor endometrial responses in women on HRT.

CA-125 Antigen↗

Circulating concentrations of placenta protein 14 during the natural menstrual cycle in women significantly reflect endometrial receptivity to implantation and pregnancy during successive assisted reproduction cycles.

Placenta protein 14 (PP14), which is the most abundant product of the secretory endometrium, has been proposed as the best biochemical marker of endometrial function in women. In this study, 19 normogonadotrophic women of infertile couples were monitored with serial measurements of concentrations of PP14, gonadotrophins and sex steroids and ultrasound scanning of endometrial thickness throughout three consecutive cycles. The first two of these were natural, unstimulated cycles (cycles 1 and 2), while ovarian stimulation with clomiphene and human menopausal gonadotrophin combined with assisted reproduction (intrauterine insemination in four cases and in-vitro fertilization in 15) was performed in the third cycle (cycle 3). A newly developed enzyme-linked immunosorbent assay was used to measure serum PP14 concentrations. In cycle 3, seven women became pregnant (group A) and 12 did not (group B). Circulating concentrations of PP14 were significantly lower in group A than in group B throughout all three cycles and in all cycle phases with exception of the late luteal phase of cycle 3, during which PP14 concentrations in group A were significantly higher than in group B. Statistical analyses showed no significant correlations between serum concentrations of PP14 and follicle stimulating hormone, luteinizing hormone and progesterone, and endometrial thickness. By contrast, serum oestradiol concentrations during the pre-ovulatory phase were significantly correlated with PP14 concentrations during the mid-luteal phase of the cycle. It is concluded that circulating PP14 is a most reliable biochemical marker of endometrial function in women and that relatively low concentrations in serum during the natural, unstimulated cycle are significantly correlated to implantation and pregnancy during successive assisted reproduction cycles. Measurement of PP14 in serum may thus be useful as a method of screening endometrial function in women, before commencing troublesome and costly treatment for infertility. However, further studies in a much larger number of women are needed to confirm this observation and to elucidate the as yet undefined physiological functions of PP14 in women.

Adult↗

A prospective randomized controlled study comparing two doses of gestodene in cyclic combined HRT preparations on endometrial physiology.

Postmenopausal women taking oestradiol 17-beta 2 mg daily were randomized to receive either 25 or 50 microg gestodene from day 17 to 28 of the cycle in a double-blind study. Placental protein P14 (PP14) and CA 125 concentrations in uterine flushing, endometrial morphology and irregular bleeding after 12 cycles of study were observed. Eleven and 12 women in the 25 and 50 microg groups respectively completed the study. There were no significant differences in pre-treatment biochemical and morphological indices between the groups. The median PP14 concentration increased from 332 to 5800 ng/ml (P < 0.001) and from 145 to 27 160 ng/ml (P < 0.001) in the 25 and 50 microg gestodene groups respectively. No between-group significant rise of PP14 was observed. Similarly, no significant change was seen between the initial and post-treatment concentrations of CA 125 for either group. All biopsies were atrophic at inception of the study, and both regimens produced secretory endometrial transformation in the majority of biopsies. No between-group difference was observed in the morphometric indices measured, or any significant correlation between the concentrations of PP14 or CA 125 and morphology. The mean number of days of withdrawal bleeding (3.8 and 4.2 days for 25 and 50 microg respectively) were similar. In conclusion, both regimens produced a significant rise in uterine flushing concentrations of PP14, but not CA 125. PP14 is a sensitive biochemical marker in the assessment of endometrial response to hormone replacement therapy.

Adult↗

Endometrial proteins: a reappraisal.

Uterine factors influence reproduction at the macro-anatomy level, and the effects of hormonal steroids on endometrial morphology are well recognized in the histopathological diagnosis of dysfunctional bleeding and infertility. During the past decade, attention has been paid to endometrial protein synthesis and secretion with respect to endocrine stimuli and implantation, and to the paracrine/autocrine effects of endometrial peptide growth factors, their binding proteins and other factors. The emphasis of this presentation is on protein secretion of the secretory endometrium, in which progesterone plays a pivotal role. Insulin-like growth factors have receptors on the endometrium, and IGF-binding proteins, stimulated by progesterone, modulate the effects of IGFs locally. Also other protein products of the secretory endometrium have been reviewed in this communication, with special emphasis on studies of a progesterone-associated endometrial protein which has many names in the literature, such as PEP, PP14, alpha 2-PEG and AUP. Extensive studies are ongoing in many laboratories to elucidate the regulation, function, interplay at tissue and cellular levels, and clinical significance of these proteins.

Carrier Proteins↗

Concentrations of endometrial protein PP 14 and CA-125 in uterine flushings performed in natural and stimulated cycles.

BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum estradiol (E(2)) concentrations may be attributed to abnormal endometrial development. This study compared concentrations of endometrial proteins in uterine flushings of infertile patients between natural and stimulated cycles. METHODS: Patients received a standard regimen of ovarian stimulation. Seven days after the LH surge in natural cycles or the hCG injection in stimulated cycles, uterine flushings were performed by slowly injecting and aspirating normal saline through a paediatric Foley catheter. Natural cycles were considered as group A whereas stimulated cycles with serum E(2) <20 000 pmol/l and serum E(2) >20 000 pmol/l were classified as groups B and C respectively. PP 14 and CA-125 in uterine flushings were measured and expressed per total protein content. RESULTS: Concentrations of the total protein, PP 14 and CA-125 in the uterine flushings were similar among the three groups. PP 14 per total protein in the uterine flushings was significantly correlated with serum E(2) on the day of hCG (r = 0.459; P = 0.009) in natural cycles only but not in stimulated cycles. CONCLUSION: There was no significant difference between natural and stimulated cycles in concentrations of PP 14 and CA-125 in uterine flushings performed in the mid-luteal phase.

Adult↗

The effects of post-ovulatory administration of onapristone on the developmnent of a secretory endometrium.

The purpose of this study was to assess the ability of the anti-progestin onapristone administered in the immediate post-ovulatory period to disrupt endometrial differentiation as a potential method of fertility control. In all, 10 healthy female volunteers were given 400 mg onapristone 2 days after the mid-cycle luteinizing hormone (LH) surge in urine (LH+2). An endometrial biopsy was taken 4 or 6 days after the LH surge (i.e. LH+4 or LH+6) in a control cycle and on the corresponding day of the treatment cycle. Biopsies were assessed for histological dating and immunolocalization of oestrogen receptors, progesterone receptors and 15-hydroxyprostaglandin dehydrogenase (PGDH). On day LH+12, blood was taken for the measurement of insulin-like growth factor binding protein-1 (IGFBP-1) and placental protein 14 (PP14). Hormonal measurements in blood and urine were used to monitor the effects on the menstrual cycle. In addition, the concentration of cortisol in plasma was measured to determine if this dose of onapristone exerted significant anti-glucocorticoid activity. Treatment with onapristone retarded the development of secretory changes within the endometrium without affecting the length of the luteal phase. Intense nuclear immunostaining of oestrogen and progesterone receptors was evident in glands and stroma after treatment, suggesting that the progesterone-dependent down-regulation of steroid receptors was inhibited by the anti-progestin. Onapristone also affected the production of luteal phase endometrial proteins, as judged by the pronounced reduction in immunostaining of PGDH within the glands and the significant reduction in plasma concentrations of PP14. However, plasma concentrations of IGFBP-1 did not differ between cycles. Onapristone did not appear to exert significant anti-glucocorticoid activity because concentrations of cortisol were unaffected. These findings suggest that onapristone could potentially be used as a method of postovulatory fertility control.

Adult↗