Progesterone Induced Blocking Factor Levels Research Articles

Aberrations in the progesterone pathway and the Th1/Th2 cytokine dichotomy - An evaluation of RPL predisposition in the northeast Indian population.

Recurrent pregnancy loss (RPL) is the spontaneous loss of two or more consecutive pregnancies prior to 20weeks of gestation, occurring in 1% of the reproductive-age population. It is a major cause of infertility in India with a staggering 7.46% prevalence rate. Blood and product of conception (POCs) from RPL cases (n=65) were enrolled for this study, along with cases of medically terminated pregnancy (MTP, n=80) and term delivery cases (n=90) as control. ELISA for progesterone and progesterone induced blocking factor (PIBF) levels was carried out, followed by mRNA expression analysis of progesterone receptor isoform B (PR-B) and its downstream immunomodulatory effectors, namely, PIBF, IL-10 and IL-12. Screening of PROGINS haplotype of PR gene and PIBF polymorphism were also conducted to correlate with their respective gene expression profiles. Serum progesterone level was found to be comparable in the RPL and MTP cases. Although the mRNA expression of PR-B was found to be downregulated in the RPL cases, no significant PROGINS haplotype was observed. Presence of a single nucleotide polymorphism (SNP) in the PIBF gene (rs1372000) was more in healthy controls compared to RPL cases. Serum PIBF levels were found to be lower in the RPL cases with a resultant increase in IL-12 and a decrease in IL-10 mRNA expression in these cases. This study indicates that progesterone, acting through PIBF, modulates the immunological state of pregnancy to be Th1-biased in RPL, indicative of a pro-inflammatory, labour-like state not desired for a healthy pregnancy.

The Effect of Apium graveolens L. in Progesterone-Induced Blocking Factor (PIBF) During Pregnancy

Progesterone-induced blocking factor (PIBF) is crucial to maintain pregnancy and the mother’s progesterone immunomodulation. Herbal medicine is widely used to induce immunity and treat pregnancy-related problems. Apigenin is a flavonoid type from Apium graveolens and could be a potential herbal medicine. The study aimed to evaluate the effective dose of A. graveolens in pregnant mice’s PIBF level on preclinical research and pregnant women on clinical research. Preclinical research used 32 pregnant mice divided into four groups randomly. The first group was the control group (P1), while P2, P3, and P4 groups were the treatment group. Pregnant mice were given 1mg/g (P2), 2mg/g (P3), and 4mg/g (P4) of A. graveolens extract orally for 14 days. Clinical research was completely randomized design. Thirty pregnant women at Mrs. Sri Lumintu Clinic, Surakarta, Indonesia divided into two groups. The treatment group was given A. graveolens capsule 534mg/50 kg BW, Fe, and calcium, while the control group was given Placebo, Fe, and calcium orally for 14 days. PIBF level in both preclinical and clinical was determined using enzyme-linked immunosorbent assay (ELISA). Our study showed that A. graveolens with 2mg/g (P3) was the most effective dose to increase PIBF level in pregnant mice. The PIBF level of pregnant women increased significantly in the treatment group compared to the control group (444.78pg/mL and 171.74pg/mL, p = 0.000). A. graveolens supplementation in pregnant women increased PIBF levels during pregnancy and could prevent inflammation during pregnancy.

Progesterone and progesterone-induced blocking factor (PIBF) levels in non-obese women with polycystic ovary syndrome

Purpose: This study aimed to evaluate the level of progesterone and progesterone-induced blocking factor (PIBF), an immune mediator, in non-obese patients with polycystic ovary syndrome (PCOS).
 Materials and Methods: Totally 72 patients were recruited into study and divided into 2 groups: The first group was patients diagnosed with PCOS (n = 36) and the second was the healthy control group (n=36). The diagnosis of PCOS was made according to Rotterdam diagnostic criteria. All patients were 18–35 years old and non-obese (body mass index (BMI) < 25 kg/m2). Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), thyroid-stimulating hormone (TSH), prolactin (PRL), total testosterone, and dehydroepiandrostenedione sulfate (DHEA-S) levels were measured on the third day of the menstrual cycle. On the 21st day of the same menstrual period, fasting blood glucose, insulin, progesterone, and PIBF levels were measured. 
 Results: Demographic and clinical characteristics of study participants were similar between the two groups. Serum FSH, E2, TSH, PRL, DHEA-S, total testosterone, fasting blood glucose, fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and hemoglobin A1c values were similar between the groups. Differences in LH, LH/FSH ratio, serum progesterone, and serum PIBF were statistically significant.
 Conclusion: Progesterone and PIBF levels decreased in non-obese PCOS patients. We suggest that even in the absence of obesity, which is the origin and enhancer of inflammation in PCOS, low PIBF as the underlying immunomodulator will drive complications.

Evaluation of maternal serum progesterone-induced blocking factor levels in pregnancies complicated with early- and late-onset preeclampsia

The aim of present study was to evaluate maternal serum progesterone-induced blocking factor (PIBF) levels in pregnancies complicated with early-onset (EO-PE) and late-onset (LO-PE) preeclampsia. Patients with preeclampsia were divided in two groups according to preeclampsia onset and compared to healthy control group: EO-PE and LO-PE defined as being diagnosed before 340/7 and ≥340/7 weeks, respectively. Maternal age, nulliparity, BMI at blood sampling, smoking, history of caesarean section and ethnicity were statistically similar among the groups. Statistically significant differences were found between the eo-PE and lo-PE preeclampsia groups in terms of gestational age at delivery, mean birth-weight percentile and foetal growth restriction rates. The mean serum PIBF level was 528.6 ± 220 ng/mL in the eo-PE and 615.3 ± 269.1 ng/mL in the lo-PE preeclampsia and 782.3 ± 292.4 ng/mL in the control groups; the difference among groups was statistically significant. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset. IMPACT STATEMENT What is already known on this subject? Maternal lymphocytes secrete PIBF that provides the immunological effects of progesterone during pregnancy by activating T-helper type 2 (Th2) cells and inhibiting any activated uterine natural killer (uNK) cells. The recent studies results have shown that there is disproportion in the Th1/Th2 rate in women with preeclampsia. This purports that Th1-mediated immunity is promoted through Th2-mediated immunity, which can be involved in the pathogenesis of preeclampsia. What do the results of this study add? In this study we found that PIBF levels in maternal serum were significantly lower in the EO-PE group than in LO-PE and control group. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset. What are the implications of these findings for clinical practice and/or further research? We can speculate that first trimester maternal serum PIBF levels may be a useful biomarker for prediction of EO-PE. Using serum PIBF levels within the first trimester combined with Doppler values for the uterine artery, and some biochemical markers to predict onset and severity of preeclampsia appear to be a new screening method.

Progesterone-induced blocking factor-mediated Th1/Th2 balance correlates with fetal arrest in women who underwent in vitro fertilization and embryo transfer

The role of progesterone-induced blocking factor (PIBF)-mediated Th1/Th2 balance in delivery outcomes of in vitro fertilization and embryo transfer (IVF-ET) has not been fully elucidated. In this study, 73 infertile women with successful IVF-ET were enrolled (16 fetal arrests and 57 live births). PIBF and IL-4 levels were significantly lower in the fetal arrest group than in the live birth group (p < 0.05). TNF-α level and Th1/Th2 ratios were significantly higher in the fetal arrest group than in the live birth group (p < 0.05). High TNF-α level and Th1/Th2 ratios were risk factors for fetal arrest, whereas increased PIBF and IL-4 levels were protective factors (P < 0.05). Increased TNF-α/IL-4 exhibited relatively strong predictive value for fetal arrest (AUC, 0.855; sensitivity, 93.8%; specificity, 71.9%). In summary, the PIBF-mediated Th1/Th2 balance is closely correlated with delivery outcomes of IVF-ET. TNF-α/IL-4 may be a predictive marker of fetal arrest.

The role of serum progesterone induced blocking factor on unexplained infertility

ObjectiveThe aim of this study was to determine whether the progesterone-induced blocking factor (PIBF) level in women with unexplained infertility differed from that in fertile women. Study designVolunteers between 18 and 35 years old were included in this cross-sectional study and were divided into two groups—the unexplained-infertility group and the control group. Demographic data on all the women were collected using a detailed questionnaire. The infertile participants and their male partners received complete infertility examinations according to the protocol. Blood samples were taken from all participants after the examinations during regular clinic visits. Serum PIBF levels were measured using an enzyme-linked immunosorbent assay. ResultsOf the 46 healthy participants in the study, 22 had unexplained infertility. Age, body mass index, ethnicity, education level, age at first menarche, and length of menstrual cycles, serum follicle stimulating hormone, luteinizing hormone, estradiol, prolactin, thyroid stimulating hormone, and progesterone were similar between two groups. The mean right antral follicle count (AFC) was 6.6 ± 1.8 in the unexplained-infertility group and 6.5 ± 2.0 in the control group. The mean left AFC was 6.6 ± 2.0 in the unexplained-infertility group and 6.9 ± 1.5 in control group. The mean serum PIBF level was 6.92 ± 3.41 ng/mL in the unexplained-infertility group and 12.10 ± 10.47 ng/mL in the control group, which was a significant difference (p = 0.02). ConclusionThe present study showed that serum PIBF levels were significantly lower in unexplained-infertility group than in the fertile control group.

Characterisation of serum progesterone and progesterone-induced blocking factor (PIBF) levels across trimesters in healthy pregnant women

Progesterone-induced blocking factor (PIBF), which plays an important role in maintaining healthy pregnancies, has shown great promise as a prognostic biomarker for threatened miscarriage. To better characterise the physiological trends of progesterone and PIBF, we analysed serum progesterone and PIBF concentrations in healthy non-pregnant and pregnant women across trimesters. We saw increasing concentrations of progesterone and PIBF in pregnant women with advancing trimesters. The serum progesterone and PIBF percentiles across gestational age in healthy pregnancies can be used as a guide for the formulation of reference ranges. We also demonstrated a significant positive correlation between progesterone and PIBF levels. This study demonstrates increasing progesterone and PIBF concentrations in later trimesters and underscores the importance of progesterone and PIBF in healthy pregnancies. Characterisation of progesterone and PIBF across gestational age in healthy pregnant women may help to prognosticate pregnancy viability and support further research into the importance of progesterone and PIBF in the maintenance of healthy pregnancies.

Abstract 586: Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone

Abstract Human leukemia cancer cell line studies have demonstrated the presence of a 34 kDa intracytoplasmic splice variant of the parent 90 kDa nuclear protein associated with the centrosome that has significant immunosuppressive activity, especially, but not limited to natural killer (NK) cells. One mechanism of suppressing NK cell cytotoxicity is by stabilizing perforin granules. The 34 kDa intracytoplasmic isoform has been shown to be present only in rapidly growing cells, e.g., embryonic, mesenchymal, trophoblast, and cancer cells. During the luteal phase in ovulating women, and throughout pregnancy, there is a rise in the serum level of this immunomodulatory protein. Thus, it is called the progesterone induced blocking factor (PIBF). Interestingly, the abortafacient, mifepristone, has been shown to suppress the 34 kDa intracytoplasmic concentration of PIBF in cancer cell lines, but it does not lower serum PIBF. Based on the demonstration of significant increase in quality and length of life in controlled animal studies, and anecdotal experience in compassionate use treatment of human patients with a variety of advanced cancer types, the FDA has granted an investigator initiated salvage study of 40 patients with advanced non-small cell lung cancer (NSCLC) who have failed a minimum of two rounds of chemo or immunotherapy to be treated with single agent oral mifepristone (www.clinicaltrials.gov). The first 2 patients are doing extremely well (2 years and 1 year so far) with a high quality life without significant disease progression. Sera PIBF levels were obtained on these patients every 2 months using an experimental ELISA assay. For patient 1, a man with stage IV NSCLC with brain metastasis, his PIBF levels (ng/ml) were all in the range of normal males and women in the follicular phase (27, 38, 53, 59, 52, 46, 39, 45, 44, and 49). For patient 2, who is a female positive for the PD-L1 marker, and who progressed despite 3 rounds of chemotherapy and 1 round of nivolumab, her levels were 10, 30, 12, 21, 23, 50, 64, and 30. Thus, these results suggest that measuring serum PIBF levels in patients with very advanced NSCLC has little value in determining which patients will respond to the progesterone receptor modulator mifepristone, or be able to monitor their response to progesterone receptor modulator therapy. Citation Format: Jerome H. Check, Diane Check, Maya Srivastava, Ann DiAntonio. Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 586.

High Immune Expression of Progesterone-Induced Blocking Factor in Epithelial Ovarian Cancer.

Background:Progesterone-induced blocking factor, which is released from maternal lymphocytes during pregnancy mediates the immune effect of progesterone. According to new reports, it is suggested that proliferating cells, such as human trophoblasts, mesenchymal stem cells, and malignant tumors, can excrete progesterone-induced blocking factor at high ratio to escape from maternal immunity. It is shown in recent studies that progesterone-induced blocking factor is overexpressed in many malignant tumors such as breast, cervical, lymphoma, and leukemia. There are no data about progesterone-induced blocking factor expression in ovarian cancer cells. Hence, it is aimed to determine the progesterone-induced blocking factor expression levels in epithelial ovarian cancer.Methods:The study which was a retrospective cross-sectional study was conducted in a University Hospital. Twenty tissue specimens of patients with epithelial ovarian cancer and 20 tissue specimens of patients with healthy ovary were included in the study. Primary rabbit polyclonal anti- progesterone-induced blocking factor antibody was used to incubate the sections at a ratio of 1:300.Results:When the tissue sections were compared based on immunostaining with progesterone-induced blocking factor, we detected high stromal progesterone-induced blocking factor expression in the epithelial ovarian cancer group as check against to the normal ovarian group (P = .007). Similarly, we found high glandular progesterone-induced blocking factor expression in the epithelial ovarian cancer group as check against to the normal ovarian group (P < .001).Conclusion:Proving the existence of progesterone-induced blocking factor expression in epithelial ovarian cancer cells may lead new visions or new studies for epithelial ovarian cancer immunotherapy. As a result, epithelial ovarian cancer cells have greater levels of expression of progesterone-induced blocking factor protein than normal ovarian tissue according to immunohistochemistry. Further research is needed to understand the clinical importance of this finding, to learn outcomes of high levels of progesterone-induced blocking factor, and to investigate its underlying mechanisms.

Serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF) which is found in high levels during pregnancy is not higher in women with progesterone (P) receptor (R) positive vs. negative breast cancer

To determine if serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF), which is present in high levels during normal pregnancy, is present in higher levels in women with breast cancer positive for progesterone receptors. The study would also determine whether the presence or absence of the estrogen receptor in any way modifies PIBF expression. PIBF using a research ELISA was evaluated in the follicular phase in 21 women with receptor status as follows: seven with estrogen receptor (ER)+ and progesterone receptor (PR)+, seven with ER- and PR+, and seven with ER+ and PR. The results showed no differences in serum PIBF in the three groups. The serum PIBF levels were no different than historical controls in the follicular phase. Measurement of serum PIBF does not seem to be an important marker to use to either detect women with breast cancer or to help determine tumor virulence or potential specific therapies. If PIBF plays a role in helping cancer cells to escape immune surveillance, it seems that the intracytoplasmic PIBF would be the form most likely operative.

Abstract 4876: Long-term high quality survival with single agent mifepristone treatment despite advanced lung cancer and advanced renal cell carcinoma - 2 case reports

Abstract The objective is to report long-term high quality survival in 2 patients with advanced cancer treated by single agent mifepristone. Case 1: An 80 year old woman was admitted to the ICU for respiratory failure. Chest x-ray revealed many lung lesions most consistent with lung cancer with multiple lung metastases. She was subsequently admitted several more times with very low arterial pO2 levels and her serum sodium progressively decreased to 118 mmol/L. The radiologic and clinical diagnosis was probable advanced lung cancer with the syndrome of inappropriate antidiuretic hormone (SIADH) from ectopic tumor production of arginine vasopressin. She refused surgery or chemotherapy. She agreed to experimental use of 200mg daily oral mifepristone. Her pO2 returned to 99-100 mmHg with 1 month and her sodium returned to normal. Six weeks later all her lung lesions were gone by CT scan. Three and a half years after initial treatment, her PO2 remains 96-98 mmHg, she is feeling fine, and her CT-scan continues to show no tumors. Her treatment had been approved by the FDA on a compassionate basis. Case 2 - A 60 year old male with was found to have bilateral renal cell carcinoma with metastases to local lymph nodes. He refused bilateral nephrectomy but agreed to only laparoscopic right hemi nephrectomy to remove the largest lesion, leaving the left kidney intact. He received FDA approval to use 200mg daily mifepristone because at that time there was no chemotherapy that was known to be effective. The left kidney lesions did not recede but stayed stable for 10 years. Furthermore, no new lesions appeared on bi-annual CT scan. After 10 years of therapy, he developed renal failure secondary to diabetes. At this time he underwent bilateral nephrectomy, followed by kidney transplant. 11 years from diagnosis he is doing well. Neither patient has reported any side effects to 200mg mifepristone daily despite a combined 14 years of treatment. The mechanism of action responsible for these phenomena has not been proven thus far. The proposed mechanism is that progesterone inhibits an intracytoplasmic immunomodulatory protein known as the progesterone induced blocking factor (PIBF). By inhibiting PIBF, the cellular immune cells (specifically natural killer (NK) cells) are able to attack the rapidly growing tumor cells. The FDA has approved an investigator initiated study for the use of single agent mifepristone for stage IV human non-small cell lung cancer which has progressed despite either 2 rounds of chemotherapy or 1 round of chemotherapy plus one round of biologic therapy. Mifepristone, a progesterone receptor modulator, has been demonstrated to inhibit the production of a 34-36 kDa intracytoplasmic splice variant of the 90 kDa centrosomally associated parent compound. However, this potent abortifacient failed to suppress serum PIBF levels. Citation Format: Jerome H. Check, Diane Check, Jasmine Aly, Carrie Wilson. Long-term high quality survival with single agent mifepristone treatment despite advanced lung cancer and advanced renal cell carcinoma - 2 case reports. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4876.

The progesterone receptor antagonist mifepristone does not lower serum progesterone induced blocking factor (PIBF) in the presence of progesterone

Purpose: To determine if mifepristone can lower serum levels of a progesterone (P) induced immunomodulatory protein believed to be needed for the fetus to escape immune surveillance. Materials and Methods: A female volunteer had her serum P induced blocking factor (PIBF) increased by ingestion of oral micronized P. While remaining on P mifepristone, 200 mg/day was given for six days when another serum PIBF level was obtained. Results: The serum PIBF was 273 ng/ml after five days of oral micronized P. It increased further to 737 ng/ml despite taking six days of 200 mg mifepristone. Conclusions: The mechanism for inducing abortion by mifepristone does not seem to be related to decreasing serum levels of PIBF. This does not eliminate the possibility that the mechanism involves reducing the intracytoplasmic PIBF levels.

Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF).

To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion. Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos. Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase. A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient.

Progesterone treatment of threatened abortion, maternal serum levels of progesterone-induced blocking fac-tor and its clinical significance

Objective To investigate the treatment of threatened abortion progesterone maternal serum pro-gesterone-induced blocking factor(PIBF)levels and clinical significance, in order to be able to provide theoretical references of progesterone treatment of threatened abortion. Methods Threatened abortion women(study group)and non-threatened abortion women(control group),50 patients in the observation group given progesterone therapy, enzyme-linked immunosorbent assay(ELISA)was used to detect serum progesterone and PIBF levels of the obser-vation group before treatment and two weeks later, the control group was selected and named after two weeks. Results Observation group after treatment 47 patients progesterone tocolysis successful, success rate was 94.00%, tocolysis bleeding stop time 8.42d, abdominal pain time 11.32d.PIBF of the observation group was(313.52±90.43)mmol／L, which was lower than that of the control group(398.47±104.25)mmol／L, the difference was statistically significant (t＝10.90,P＜0.05). The progesterone of the observation group after 2 weeks of treatment was(92.35±20.85)mmol／L, which was higher than that before treatment(74.49±14.22)mmol／L, compared with progesterone levels of the con-trol group at the same time(83.26±20.14)mmol／L and(78.05±15.38)mmol／L, the difference was statistically significant(t＝7.96,8.11,P＜0.05),PIBF after 2 weeks of treatment in the observation group was(510.73± 87.49)mmol／L, which was higher than that of the control group at the same time(498.26±69.88)mmol／L, the difference was statistically significant(t＝4.35,P＜0.05).Follow-up observation group miscarriage successful term delivery rate 95.74%of pregnant women, childbirth fetal malformations seen in the control group of pregnant women at term birth rate was 94.00%, no delivery fetal malformation, the difference of full-term delivery rate was not statis-tically significant(P＞0.05). Conclusion Reduced PIBF during early pregnancy may be one of the reasons of threatened abortion, the use of progesterone therapy can increase PIBF expression, possibly through this pathway plays a role in tocolysis, so when using progesterone tocolysis monitoring PIBF levels helps evaluate the efficacy of tocolysis. Key words: Abortion, Threatened; Progesterone-induced blocking factor; Progesterone

Abstract 1282: Comparison of serum progesterone levels of the immunomodulatory protein, the progesterone induced blocking factor, in people with BRCA-2 mutations associated with and not associated with a high risk of cancer

Abstract The BRCA genes normally provide proteins important in degradating the progesterone (P) receptor. BRCA1 and 2 mutations may make mutated protein, leading to prolongation of P receptor activity which may be involved in the mechanism of how these mutations increase the risk of breast and ovarian cancer. The progesterone induced blocking factor (PIBF) is a protein which suppresses natural killer (NK) cell cytotoxicity, and exposure to P increases both serum levels of PIBF and intracytoplasmic levels in rapidly growing cells (both fetus and cancer cells). The objective of this study was to compare serum PIBF levels in a person with a wild type BRCA2 mutation not known to be associated with malignancy versus the familial type of BRCA2 mutation associated with malignancy. Serum levels of PIBF were obtained in the follicular phase x5 in a woman with a benign wild type heterozygote mutation of BRCA2 (NM000059.3 C.1964 (&amp;gt;(P655R) and in two anovulatory women and a man with familial BRCA2 mutations associated with increased risk of malignancy. The PIBF assay was a research ELISA method using a monoclonal antibody to PIBF. All 5 serum samples of the 21 year old woman with the benign BRCA2 mutation were over 700 ng/mL (levels seen only with high levels of serum P) vs. an average of 55.5 in 2 women with breast cancer at an early age and 1 man positive for the familial BRCA2 mutation. The high levels of serum PIBF seen with the wild type heterozygote mutation show that certain types of BRCA mutations can be associated with increased PIBF levels. Perhaps this BRCA2 wild type mutation is more associated with interfering with degradation of the P receptor found in gamma delta T cells, thus increasing serum PIBF levels. Increased virulence of certain cancers, e.g., breast cancer, has been found with increasing P receptor longevity by either phosphorylation or decreased ubiquitination or sumoylation. Blocking P receptor activity by certain P receptor antagonists, e.g., mifepristone, has been shown to decrease tumor virulence irrespective of the presence or not of P receptors in the tumor. The parent compound for PIBF is a 90 kDa nuclear protein found in the centrosome, but it can be converted to 34-36 kDa immunoprotective intracytoplasmic protein which is similar or identical to the circulating PIBF. Conditions associated with consistent high levels of serum PIBF, e.g., grand multiparous women, are not associated with increased risk of malignancy. Thus an attractive hypothesis (that needs to be proven) is that the BRCA2 mutation (and maybe BRCA1 also) leads to prolongation of the nuclear P receptor leading to increased nuclear PIBF, resulting in increased intracellular PIBF, which, in turn, helps protect the cancer cells especially from NK cell immunosurveillance but potentially other immune factors also. Citation Format: Jerome H. Check, Michael P. Dougherty, Gabrielle DiAntonio, Jamie Vaniver, Marie Duroseau, Maya D. Srivastava. Comparison of serum progesterone levels of the immunomodulatory protein, the progesterone induced blocking factor, in people with BRCA-2 mutations associated with and not associated with a high risk of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1282. doi:10.1158/1538-7445.AM2015-1282

Abstract 1281: Serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF) are not higher in women with progesterone (P) receptor (R) positive vs. negative breast cancer

Abstract There is evidence that treatment with mifepristone a P receptor antagonist will provide a marked palliative effect for many human and murine spontaneous cancers. One proposed mechanism is that it may work by suppressing the expression of a unique immunomodulatory protein that amongst other things stabilizes perforin granules in natural killer (NK) cells and thus negates their cytolytic activity. In humans exposure to P causes a rapid rise in the serum of this protein called the PIBF. The origin for the circulating PIBF is from gamma/delta T cells and is initiated with P interacting with P receptors on gamma/delta T cells. PIBF exists as a 90 kDa nuclear protein occupying a centrosomal position in near proximity to BRCA-1 and is found in all rapidly growing cells including cancer cells. A 34-36 kDa splice variant is found in the cytoplasm of all cancer cells tested. Mifepristone has been found to provide marked palliation despite the absence of evidence of circulating PIBF in some cancers not known to be positive for P receptors. One possible mechanism is suppression of the formation of the 34-36 kDa intracytoplasmic form from the parent 90 kDa form. The objective of the present study was to determine if tumors known to be P receptor positive may demonstrate circulating PIBF. In a blinded manner, serum PIBF was measured in 21 serum samples of women with breast cancer obtained prior to surgery using a research ELISA assay for PIBF. The PIBF levels were then compared according to estrogen (E) and P receptor status. The mean level of PIBF (ng/mL) for those who were ER positive but P receptor negative in 7 cases was 31.0+49.7 with a range of 2.1 to 142.5. For 7 cases that were ER positive and P receptor positive the mean level +SD was 24.8+37.46 and the range 2.4 to 108.32. For ER negative and P receptor positive for 7 cases, the mean PIBF was 24.6+28.3 and the range 6.0 to 86.9. There were no significant differences by ANOVA. It is not clear as yet if P receptor antagonist therapy will provide better palliative effect for P receptor positive vs. P receptor negative tumors, but if so, the mechanism (if it is immunologic) does not seem to be related to suppressing increased levels of circulating PIBF. Thus, testing serum with this new ELISA assay does not seem to be a helpful method to determine which patients may benefit from P receptor antagonist therapy. Some recent data suggest that the P receptor antagonist may suppress intracellular PIBF but not circulative PIBF. Thus, these data do not exclude the possibility that PIBF may play a vital role in escape of cancer cells from immune surveillance but it is the intracytoplasmic form that provides immune protection. Citation Format: Jerome H. Check, Anne Rosenberg, Ann DiAntonio, Hallgeir Rui, Rachael Cohen, Gabrielle DiAntonio. Serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF) are not higher in women with progesterone (P) receptor (R) positive vs. negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1281. doi:10.1158/1538-7445.AM2015-1281

How can we better predict the risk of spontaneous miscarriage among women experiencing threatened miscarriage?

This study seeks to establish progesterone and progesterone-induced blocking factor (PIBF) levels as predictors of subsequent completed miscarriage among women presenting with threatened miscarriage between 6 and 10 weeks of gestation. Our secondary objective was to assess the known maternal risk factors, toward development of a parsimonious and clinician-friendly risk assessment model for predicting completed miscarriage. In this article, we present a prospective cohort study of 119 patients presenting with threatened miscarriage from gestation weeks 6 to 10 at a tertiary women’s hospital emergency unit in Singapore. Thirty (25.2%) women had a spontaneous miscarriage. Low progesterone and PIBF levels are similarly predictive of subsequent completed miscarriage. Study results (OR, 95% CI) showed that higher levels of progesterone (0.91, 95% CI 0.88–0.94) and PIBF (0.99, 95% CI 0.98–0.99) were associated with lower risk of miscarriage. Low progesterone level was a very strong predictor of miscarriage risk in our study despite previous concerns about its pulsatile secretion. Low serum progesterone and PIBF levels predicted spontaneous miscarriage among women presenting with threatened miscarriage between gestation weeks 6 to 10. Predictive models to calculate probability of spontaneous miscarriage based on serum progesterone, together with maternal BMI and fetal heart are proposed.

The Role of Natural Progesterone Administration on the Levels of Progesterone-induced Blocking Factor, Interleukin-10 and the Prolongation of Gestational Length in Impending Preterm Delivery

ABSTRACTProgesterone plays an important role in maintaining pregnancy. The success of pregnancy depends on the balance of immune response between the mother and the fetus. Progesterone regulates the immunological response through progesteroneinduced blocking factor (PIBF) which is synthesized by lymphocytes. Progesterone-induced blocking factor inhibits the production of arachidonic acid, reduced NK cell activity, and modulates the cytokine balance by increasing interleukin-10 (IL-10) level that is produced by Th2. This study aims to determine the roles of natural progesterone administration on PIBF and IL-10 levels and the increase in gestational length.This is an experimental research with pre- and post-test design. Subjects were pregnant women who met the criteria (n = 22). The treatment was done for 7 days. Progesteroneinduced blocking factor and IL-10 levels were measured before and after the administration of natural progesterone and the length of gestation were noted. The study was conducted at Dr Hasan Sadikin Hospital within July to December 2013.Results showed that after the administration of natural progesterone, there were increases on PIBF (p = 0.039) and IL-10 levels (p = 0.031). A positive correlation was noted between PIBF and IL-10 levels (r = 0.549; Spearman rank correlation test). There was also positive correlation between PIBF serum level (moderate strength correlation) and the length of gestation (r = 0.428; Point biserial correlation test). Progesterone-induced blocking factor serum level had more influence on the prolongation of the pregnancy compared to IL-10 level (OR: 1.016, 95% CI: 1.001 to 1.03; p = 0.033).Increased levels of PIBF and IL-10 after the administration of natural progesterone on the impending preterm delivery may prolong the gestation. Progesterone-induced blocking factor serum level have more dominant role in prolongation of gestation compared to IL-10.How to cite this articleThipasary Y, Effendi JS, Anwar AD. The Role of Natural Progesterone Administration on the Levels of Progesterone-induced Blocking Factor, Interleukin-10 and the Prolongation of Gestational Length in Impending Preterm Delivery. J South Asian Feder Obst Gynae 2015;7(3):118-125.

Abstract 4096: A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer

Abstract PIBF is a unique protein that is secreted by gamma/delta T cells and precipitously rises in the sera following progesterone (P) exposure. The 34 kDa protein protects the fetal semi-allograft from immune surveillance by reducing cytoxicity of natural killer (NK) cells by stabilizing perforin granules. The parent 90 kDa form occupies a centrosomal position close to BRCA-1. PIBF can be found in most rapidly dividing cells. One study found an over-expression of the mRNA for the PIBF protein in all 29 leukemia cell lines tested. The P receptor antagonist mifepristone was found to down-regulate PIBF protein. Mifepristone provided significant palliative benefit to a large variety of spontaneous murine and human cancers. P could also be responsible for converting the 90 kDa parent form to a 34-36 kDa split variant in the cytoplasm which may be the immunosuppressive form in cancer cells. Alternatively, some P-like secretion by the tumor could influence gamma/delta T cells in the tumor microenvironment to secrete PIBF and possibly spill over to the sera. The aim of this study was to determine if there is any increase in serum PIBF in women with gynecologic cancer as opposed to controls. Serum was obtained from women about to have surgery for gynecologic problems including malignant and benign disorders. The samples would then be measured for PIBF using a new non-commercial enzyme linked immunoabsorbent assay (ELISA) for PIBF and serum progesterone. The PIBF levels (ng/mL) from lowest to highest in women with various gynecologic cancers (in all cases serum progesterone (P) &amp;lt;2ng/mL) were 10.06, 17.35, 32.59, 35.62, 54,7, and 57.17. The average serum PIBF was 34.6 ng/mL. There were 3 women with benign gynecologic tumors and the serum PIBF was 14.76, 15.7, and 36.64 their average serum PIBF was 22.5 ng/mL). There were 2 women with no tumors having gynecologic surgery and their serum PIBF levels (ng/mL) were 9.56 and 35.27 (with an average of 22.4 ng/mL). At least for gynecologic cancers if PIBF is conferring immune protection it is more likely operating through its intracytoplasmic presence rather than working through sera levels. In women or men exposed to exogenous or endogenous P for just 6 days it is not unusual to see sera PIBF rise to 300 to &amp;gt;800ng/mL. Citation Format: Jerome H. Check, Mojirayo Sarumi, Ann DiAntonio, Krystal Hunter, Gunda Simpkins, Marie Duroseau. A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2014-4096

Maternal Serum Progesterone-Induced Blocking Factor at 11–13 Weeks’ Gestation in Spontaneous Early Preterm Delivery

Objective: Progesterone-induced blocking factor (PIBF) may be the mediator of the pregnancy maintenance effects of progesterone. The aim of this study is to investigate the potential value of measuring the maternal serum concentration of PIBF at 11–13 weeks’ gestation in the prediction of spontaneous early preterm delivery. Method: The maternal serum concentration of PIBF at 11–13 weeks was measured by enzyme-linked immunosorbent assay in 25 singleton pregnancies which subsequently delivered spontaneously before 34 weeks, and 75 controls who delivered at or after 37 weeks. The values in the 2 groups were compared by the Mann-Whitney U test. Results: The median maternal serum concentration of PIBF in women who subsequently delivered before 34 weeks (157.5, interquartile range 99.5–208.8 ng/ml) was not significantly different from the control group delivering at term (167.5, interquartile range 105.0–212.0 ng/ml; p = 0.519). Conclusions: In women who have a spontaneous early preterm delivery, the maternal serum levels of PIBF are not altered at 11–13 weeks of gestation.