J.H. Check

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)

PurposeTo 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.MethodsSerum 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.ResultsProgesterone 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.ConclusionsA 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.

The role of progesterone and the progesterone receptor in human reproduction and cancer

Insufficient progesterone, effect possibly more on immune factors rather than adequate endometrial development, can be an easy remedial cause of infertility by simply supplementing the luteal phase with either vaginal or intramuscular or oral (dydrogesterone) progesterone. Progesterone will also help to reduce miscarriage rates when follicle maturing drugs are used for those with regular menses but follicular maturation defects, or women with recurrent miscarriages. One mechanism of action seems to be related to production of an immunomodulatory protein, the progesterone-induced blocking factor either in the cytoplasm or in the circulation. PIBF inhibits cytotoxicity of natural killer cells. Cancer cells may ‘borrow’ the same mechanism to escape NK cell immunosurveillance.

The role of progesterone and the progesterone receptor in cancer

ABSTRACT Introduction: There is an abundance of accumulating data strongly suggesting there is a key role for the progesterone receptor in the molecular events effecting the growth or containment of a variety of cancers. This knowledge should lead to novel new strategies to combat various cancers, including drugs classified as progesterone receptor modulators or monoclonal antibodies against some of the key proteins needed for cancer proliferation by suppressing immune surveillance. Areas covered: The role of the classic nuclear receptor and molecular events needed for proliferation are reviewed including cancers of the breast, endometrium, prostate, thyroid, and leiomyomas and leiomyosarcoma. The potential role of non-genomic membrane progesterone receptors is reviewed. The prognostic role of the presence of progesterone receptors is also discussed. Over 1000 research publications were read after conducting a PubMed search. Expert commentary: Discussion is made about a unique immunomodulatory protein called the progesterone induced blocking factor (PIBF). The role of this protein, that is unique to rapidly growing cells, may hold a key to how the cancer cells escape immune surveillance. Thus, techniques to suppress the intracytoplasmic isoforms of PIBF may play a significant role in the fight against all cancers, not just the ones with the classic nuclear progesterone receptors.

Abstract 485: Evidence that mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV.

BACKGROUND Mifepristone, a progesterone receptor antagonist, has been found to provide palliative benefits for various types of spontaneous murine cancer in randomized controlled trials and in anecdotal reports from a variety of advanced metastatic human cancer not known to be associated with progesterone receptors. The theory of its mechanism is that it prevents the secretion of a progesterone-induced immunomodulatory protein in the tumor microenvironment, or in the tumor cell itself, called the progesterone-induced blocking factor, which inhibits natural killer cells from attacking the cancer cell. Many anticancer chemotherapeutic agents fail to cross the blood-brain barrier and thus prove ineffective for brain cancer. The objective of the present study was to determine if mifepristone could provide palliative benefits to a patient with end-stage stage IV glioblastoma multiforme. CASE REPORT A 43-year-old male with end-stage stage IV glioblastoma multiforme was exclusively treated with mifepristone 200 mg orally daily. RESULTS The patient showed definite palliative effects for several weeks and his life was significantly extended beyond pre-treatment predictors. CONCLUSION It appears that mifepristone does cross the blood-brain barrier and could be considered for palliative therapy of other patients with chemotherapy-resistant brain cancer.

P-13: The Effect of Endometriosis on Pregnancy Outcome Following In Vitro Fertilization-Embryo Transfer (IVF-ET) in Women With Decreased EGG Reserve

PURPOSE To determine the effect of the presence of endometriosis on the delivered pregnancy rate following in vitro fertilization-embryo transfer. METHODS A retrospective cohort analysis of fresh or frozen embryo transfer in women with diminished egg reserve having IVF-ET and who also had had a laparoscopy. The data was analyzed as to whether endometriosis was present or not. RESULTS The data demonstrated that women with diminished egg reserve can achieve pregnancies following IVF-ET. The presence of endometriosis did not have any negative effects on pregnancy rates. CONCLUSIONS At least in women with diminished egg reserve the presence of endometriosis did not impair outcome following IVF-ET.

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

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.

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

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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) 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

Abstract 490: Clinical improvement of symptomatic advancing chronic lymphocytic leukemia following mifepristone therapy despite normal serum levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF).

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Recently a sensitive ELISA assay been created to detect serum levels of the immunomodulatory protein, the PIBF. One of the 34 kDa forms of PIBF increases markedly after exposure to progesterone (P) and inhibits natural killer (NK) cytolytic activity by stabilizing perforin granules and causes of shift from thymic helper (TH)1 to TH2 dominance thus diminishing the activity of the cellular immune system. The 34 kDa form is secreted by gamma/delta T cells and is considered a vital step in preventing immune destruction of the fetal semi-allograft. Evaluation of mRNA for PIBF and PIBF protein found that 29 of 29 human leukemia cell lines over-expressed mRNA for PIBF but only 3 of the lines expressed the PIBF protein. Adding P to the culture up-regulated PIBF protein expression whereas adding the P receptor antagonist mifepristone caused down-regulation of PIBF expression. Mifepristone treatment has been demonstrated to show significant palliative effects on a wide variety of murine and human cancers many of which are not known to be P receptor positive. The hypothesized mechanism is that these tumors either secrete PIBF or direct secretion by gamma/delta T cells in the tumor microenvironment and thus inhibit NK cell cytolytic activity. The inhibition is abrogated by inhibiting P receptors and thus a local form of P secretion by the tumor is hypothesized. The objective of this study was to determine if mifepristone will only help inhibit cancer growth in those individuals who have an increased PIBF level present in their serum. An 81 year old woman with chronic lymphocytic leukemia (CLL) started more rapid advancement and became very symptomatic. She refused chemotherapy when she almost had a lethal complication to oral chlorambucil. She requested mifepristone. Her serum PIBF level of 34.9 ng/mL was in the same range as controls without cancer. However within a month of taking 200mg daily of mifepristone orally she showed a dramatic improvement in her CLL with her white blood cell count dropping from 28,000 to 8,000. Her platelet count increased from 40,000 to 240,000 and 2 lung nodules thought to represent possible primary lung cancer (but possibly nodules from her CLL) completely disappeared on repeat CT scan. Also her energy markedly improved and her persistent cough stopped. The serum PIBF did not decrease with mifepristone therapy - 48.3 ng/mL one month later. These data demonstrated that failure to see a marked increase in serum PIBF in a patient with cancer does not predict failure to respond to mifepristone. Though mifepristone has ameliorated murine leukemia in AKR mice this is the first case report of this drug improving human leukemia. The 34-36 kDa PIBF found in cytoplasm of cancer cells may either not be secreted in the serum or may be immunologically different from serum PIBF found after P exposure. Citation Format: Jerome H. Check, Ann DiAntonio, Diane Check, Alex Jaffe, Rachael Cohen, Mojirayo Sarumi, Maya Srivastava. Clinical improvement of symptomatic advancing chronic lymphocytic leukemia following mifepristone therapy despite normal serum levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 490. doi:10.1158/1538-7445.AM2013-490

AbstractPoster presentationP-14: Relationship of Serum Progesterone (P) Level the Day After Human Chorionic Gonadotropin (hCG) Injection on Outcome Following In Vitro Fertilization-Embryo Transfer (IVF-ET)

PURPOSE To determine if either too little or too much of a rise in serum progesterone (P) on the day after human chorionic gonadotropin (hCG) injection has any negative impact on pregnancy outcome following in vitro fertilization-embryo transfer (IVF-ET). METHODS Retrospective review. Three progesterone groups established--low, normal and high. RESULTS There was a significantly higher clinical pregnancy rate in the normal P group vs low or high. There were no significant differences in ongoing delivered pregnancy rates but a trend for higher implantation rates in the normal P group. CONCLUSIONS These data are consistent with the hypothesis that either too little or too much P can adversely effect implantation. However, the differences are not of sufficient magnitude to warrant a clinical intervention, e.g., deferring fresh transfer and freezing the embryos for future transfer.

Prognosis following in vitro fertilization-embryo transfer (ivf-et) in patients with elevated day 2 or 3 serum-follicle stimulating hormone (fsh) is better in younger vs. older patients

PURPOSE To determine if younger women with increased day 2 or 3 serum follicle stimulating hormone (FSH) levels have a better prognosis than older women with similar FSH elevations. METHODS Retrospective comparison of in vitro fertilization (IVF) outcome from cycles from 1/1/97 to 9/30/99 according to serum FSH < or = 12 vs > 12 and age < or = 38 or > 38. Only cycles where follicular phase leuprolide acetate was used were included. RESULTS Age group < or = 38 - clinical pregnancy rate (PR)/transfer was 32% with lower FSH vs 28.6% with higher FSH. The respective PRs for the older group were 30.3% and 5.5%. CONCLUSIONS Oocyte quality as evidenced by PRs following IVF-ET seems to be better in younger vs older patients despite increased basal serum FSH levels.