Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

A Hypothetical Model Suggesting Some Possible Ways That the Progesterone Receptor May Be Involved in Cancer Proliferation.

Cancer and the fetal-placental semi-allograft share certain characteristics, e.g., rapid proliferation, the capacity to invade normal tissue, and, related to the presence of antigens foreign to the host, the need to evade immune surveillance. Many present-day methods to treat cancer use drugs that can block a key molecule that is important for one or more of these characteristics and thus reduce side effects. The ideal molecule would be one that is essential for both the survival of the fetus and malignant tumor, but not needed for normal cells. There is a potential suitable candidate, the progesterone induced blocking factor (PIBF). The parent 90 kilodalton (kDa) form seems to be required for cell-cycle regulation, required by both the fetal-placental unit and malignant tumors. The parent form may be converted to splice variants that help both the fetus and tumors escape immune surveillance, especially in the fetal and tumor microenvironment. Evidence suggests that membrane progesterone receptors are involved in PIBF production, and indeed there has been anecdotal evidence that progesterone receptor antagonists, e.g., mifepristone, can significantly improve longevity and quality of life, with few side effects.

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).

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Significant Palliative Benefits Following Therapy With Mifepristone for Advanced Treatment Resistant Small Cell Lung Cancer.

BACKGROUND/AIM: Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC. CASE REPORT: A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later. CONCLUSION: SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists.

The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years.

INTRODUCTION: Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR). AREAS COVERED: Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells. EXPERT OPINION: The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.

Lung Cancer - Standard Therapy and the Use of a Novel, Highly Effective, Well Tolerated, Treatment With Progesterone Receptor Modulators.

The most recent successful advances in lung cancer therapy have directly and increasingly focused on personalized tumor genetic/epigenetic/immunologic profiling, and the identification and development of novel pharmacologic agents aimed at those mutations [e.g., epidermal growth factor receptor (EGFR), Kristen rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK) and immunotherapy against programmed cell death protein 1 (PD-1) and its ligands] which have extended life and provided palliation for lung cancer-patients positive for these mutations. The objective of this study is to provide a review of the large number of drugs and their efficacy as of 2022, for lung cancer, but also introduce a novel treatment that has the potential, based on one controlled murine lung cancer study and 5 anecdotal human cases, that showed marked palliative and longevity benefits in very advanced lung cancer with no other treatment options, i.e., progesterone receptor (PR) antagonists targeting the immunosuppressive protein, the progesterone induced blocking factor (PIBF). Credibility, however, will only be provided when the efficacy can be demonstrated in a large series of lung cancer cases ideally with certain controls. Thus, the ultimate objective of the review is to interest oncologists with a large population of lung cancer patients to perform a well powered study to corroborate or refute the limited experience to date with PR antagonist therapy.

Live delivery and implantation rates of donor oocyte recipients in their late forties are similar to younger recipients.

OBJECTIVE: To determine if there is a certain age when the uterus is somewhat less receptive to successful pregnancy despite the transfer of embryos from donated oocytes. STUDY DESIGN: We conducted a retrospective evaluation of donor oocyte recipient cycles according to specific ages. The recipients used an oral/vaginal graduated estradiol regimen followed by intramuscular and vaginal progesterone. Only recipients sharing oocytes with either the donor or another recipient were included. RESULTS: Evaluating the pregnancy rate by each year of age from 40-49 following transfer of embryos derived from donor oocytes showed no trend for lower pregnancy rates up to age 49. In fact the highest live delivery pregnancy rates (though not significant) were found at ages 47 (64.3%) and 49 (63.6%). The live delivered pregnancy rates for recipients < or = 39 was 52.5% vs. 55.6% for women > or = age 46. The live delivered pregnancy rate was 34.6% for women > or = age 50. The pregnancy and implantation rates were similar whether the source was infertile women sharing half their oocytes or compensated donors. CONCLUSION: The uterus does not seem to have a diminished capacity for implantation up to the age of 49, but it may be slightly less receptive after age 50.

New Insights as to Why Progesterone Receptor Modulators, such as Mifepristone, Seem to Be More Effective in Treating Cancers that Are Devoid of the Classical Nuclear Progesterone Receptor.

Mifepristone treatment for advanced cancer has demonstrated considerable improvement in both length and quality of life in patients who no longer have any other treatment options. The target is the progesterone induced blocking factor (PIBF), which helps the tumor to invade the normal tissue and proliferate and suppress cellular immunity. Most of the benefit has been observed in cancers not associated with the classical nuclear progesterone receptor (nPR). There are data showing that the presence of a nPR may be associated with a better prognosis. Membrane PRs seem to be responsible for PIBF secretion. Mifepristone, possibly fails to block another P associated protein that enables the tumor to proliferate, e.g., the progesterone receptor membrane component-1 (PGRMC-1) protein. One hypothesis is that the nPR helps to inhibit tumor production of PGRMC-1 protein. Thus, mifepristone may inhibit tumor spread by suppressing PIBF, but this may be negated by blocking the nPR, allowing PGRMC-1 levels to increase.

Palliative Benefits of Oral Mifepristone for the Treatment of Metastatic Fibroblastic Osteosarcoma.

BACKGROUND/AIM: It has been hypothesized that many, or even most cancers, utilize a unique immunomodulatory protein, called the progesterone induced blocking factor (PIBF) to allow spread of the cancer. Support for this concept has been provided by cancer cell line studies showing that PIBF is produced by these cancer cells and mifepristone suppresses this protein and inhibits proliferation of these cells. Furthermore, controlled murine studies with several spontaneous different types of cancer showed a clear beneficial effect of mifepristone over placebo control. Finally, there have been a variety of anecdotal reports showing efficacy of mifepristone in providing increased length and quality of life in patients with different types of advanced cancers. CASE REPORT: Single agent mifepristone was found to provide significant palliative benefit for a 51-year-old male whose metastatic advanced fibroblastic osteosarcoma progressed despite surgery, radiotherapy, multiagent chemotherapy, and targeted therapy. CONCLUSION: Thus, osteosarcoma can be added to the list of cancers, not necessarily associated with the classic nuclear progesterone receptor, that seem to respond to progesterone receptor antagonist therapy.

Treatment With Mifepristone Allows a Patient With End-stage Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life.

BACKGROUND: There is evidence that a unique immunomodulatory protein, known as the progesterone induced blocking factor (PIBF), is utilized by a large variety of cancers to escape immune surveillance. Mifepristone, a progesterone receptor antagonist/modulator, anecdotally, has been found to increase both length and quality of life in many different types of advanced cancers. CASE REPORT: Though there was one previous case of pancreatic cancer that showed a significant reduction in pain for the one month she took mifepristone before changing to an experimental drug, the case presented here provided much greater evidence that this drug can markedly improve both length and quality of life, in at least some patients, with very advanced pancreatic cancer. CONCLUSION: It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients.

Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon - case report.

BACKGROUND: Mifepristone, a progesterone receptor antagonist has been found to improve the length and quality of life in various spontaneous murine cancer models including tumors without progesterone receptors theoretically by inhibiting an immunomodulatory protein that suppresses natural killer cell function in the tumor microenvironment. MATERIALS AND METHODS: Mifepristone 200 mg per day by mouth was given to two patients with stage 4 colon cancer with extensive metastases. RESULTS: Both patients not only survived far longer than expected but had marked improvement in their quality of life similar to mice. Though the metastatic lesions did not disappear, no new ones appeared for a long time and the ones present did not grow. The drug was extremely well tolerated. CONCLUSION: The use of progesterone receptor antagonists may present a novel immunotherapy to help fight cancer. A larger controlled study is needed.

Therapy Aimed to Suppress the Production of the Immunosuppressive Protein Progesterone Induced Blocking Factor (PIBF) May Provide Palliation and/or Increased Longevity for Patients With a Variety of Different Advanced Cancers - A Review.

Progesterone induced blocking factor (PIBF) is a unique protein that is not present in normal cells, but is found predominantly in rapidly growing cells of the fetal placental unit or cancer cells. There is a larger "parent" form that is a nuclear protein involved in cell to cell regulation, allowing tumor cells to proliferate and invade tissues. The parent compound is cleaved into smaller intracytoplasmic isoforms that can suppress cellular immune response, especially, but not limited to natural killer cells. The progesterone receptor antagonist mifepristone can suppress messenger RNA for PIBF, but can also suppress the intracytoplasmic protein. Treating cancer cell lines, intact animals with a variety of spontaneous cancers, and people with various cancers with mifepristone, has been found to inhibit cancer growth, and provide both palliation of symptoms and longevity possibly by suppressing this unique immunomodulatory protein.

Mifepristone Extends Both Length and Quality of Life in a Patient With Advanced Non-small Cell Lung Cancer that Has Progressed Despite Chemotherapy and a Check-point Inhibitor.

CASE REPORT: Case 1 of an investigator-initiated study using oral single agent mifepristone to halt stage IV non-small cell lung cancer whose tumor was devoid of any targeted markers has remained ECOG zero and in good health for over 3 years. Case 2, reported here, is a 68-year-old woman with stage IV non-small cell lung cancer whose tumor was positive for the programmed death ligand-1 (PD-L1) marker. Her cancer progressed despite treatment with a check-point inhibitor (nivolumab), besides 3 rounds of multi-agent chemotherapy. After 1 ½ years of treatment with single agent mifepristone, her cancer remains stable (even some tumor regression) and her quality of life is only impaired by her pre-existing chronic obstructive lung disease, not her cancer. CONCLUSION: Mifepristone therapy may provide a method to halt metastatic lung cancer positive for the PD-L1 marker when check-point inhibitors are no longer effective.

Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone.

Progesterone (P), required for successful pregnancy, influences autoimmune, infectious, and malignant diseases via adaptive and innate immune effects. P induces NK inhibitor progesterone induced blocking factor (PIBF) in CD8+ T cells. PIBF isoforms could permit solid tumor immune escape. Expression and modulation of PIBF and innate immune proteins by P in leukemia cells and leukocyte subpopulations have not been reported. Ten T, seven myeloid, six B, five epithelial, fibroblast BG9, G-CSF mobilized CD34+ stem cells, and peripheral blood mononuclear cells were screened for PIBF mRNA by RT-PCR, and protein by immunohistochemistry in SRIK-NKL, MOT, U937, HL60, R-CLL, MD-E, 729pH6neo, SRIH-B(ATL), SRIK-B(T-PLL), and MeWo. Cell lines expressing PIBF and exemplifying myeloid/monoblast, natural killer/T, and B lineages were cultured with and without 0.5 - 5 microM P or 0.5 - 0.05 microM mifepristone (RU486) for 24 h. Subsequently they were examined for changes in the expression of mRNA by RT-PCR and protein by immunohistochemistry for PIBF and some innate immune factors. All cells expressed PIBF mRNA; protein only in four (SRIK-NKL, U937, SRIK-B(T-PLL) and HL60) out of 10 cell lines tested. P increased and RU486 decreased PIBF in U937, SRIK-B(T-PLL) and SRIK-NKL. P upregulated TLR-4 in U937, and HNP1 - 3, LL-37, IRAK-2, and IRAK-4 in multiple lines and RU486 down regulated these. PIBF may be used by some leukemias to evade immune surveillance and is a potential therapeutic target. P may impact infection and autoimmunity via effects on LPS receptor, TLR signaling, and antimicrobial peptides.

A retrospective comparison of pregnancy outcome following conventional oocyte insemination vs intracytoplasmic sperm injection for isolated abnormalities in sperm morphology using strict criteria.

Initial in vitro fertilization (IVF)-embryo transfer studies found poor fertilization and pregnancy rates following conventional fertilization of oocytes when using sperm with <4% normal morphology using strict criteria. Some consider today that sperm with only < or =5% normal morphology using strict criteria are associated with infertility. However, other studies have disputed the diagnostic potential of low strict morphology in identifying subnormal male fertility. Based on the original studies most IVF centers perform intracytoplasmic sperm injection (ICSI) when the sperm shows low morphology using strict criteria to allow selection of normal sperm. However, ICSI adds extra time for the embryologist and extra expense for the infertile couple. The present study retrospectively compared fertilization, pregnancy, and implantation rates according to the 2 methods of oocyte fertilization with sperm having normal morphology using strict criteria of < or =5% in women < or =39 years. All fresh embryo transfers were performed on day 3. There was a significantly higher fertilization rate with ICSI. However, there were significantly higher clinical and delivered pregnancy and implantation rates following conventional insemination. The rate of canceled transfers due to no available embryo was 1.9% with conventional insemination vs 1.5% for ICSI in women with adequate egg reserve. Hopefully, this retrospective study will generate interest in a prospective study.

The role of progesterone and the progesterone receptor in cancer.

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.

Hypofunction of the Sympathetic Nervous System as a Possible Etiologic Cause of Recurrent Aphthous Stomatitis.

Recurrent aphthous stomatitis is a common disorder of the oral mucosa. The symptoms can range from a minor nuisance to severe forms that can be extremely debilitating. Two cases of chronic aphthous stomatitis are described. The patients sought help to ameliorate vasomotor symptoms. A diagnosis of sympathetic nervous system hypofunction was established. Treatment was aimed at restoring normal sympathetic function by the administration of dextroamphetamine sulfate. Since the patients have been on the amphetamine salts, neither their vasomotor symptoms nor their aphthous lesions have returned. Hypofunction of the sympathetic nervous system should be considered as a possible etiologic factor in patients with recurrent oral ulcers when not associated with known systemic diseases.

Long-term High-quality Survival with Single-agent Mifepristone Treatment Despite Advanced Cancer.

CASE REPORT: We show long-term high-quality survival following single-agent treatment with a progesterone receptor antagonist in two cases of advanced metastatic cancer. Because no biopsy was performed (patient refused) the exact type of lung cancer was not determined but the majority of oncologists who evaluated the patient thought that the rapid onset and syndrome of inappropriate anti-diuretic hormone was more consistent with small-cell lung cancer. The US Food and Drug Association granted a compassionate-use investigational new drug approval for use of single-agent 200 mg mifepristone orally/day to a moribund woman with never-treated metastatic lung cancer and a male with bilateral renal cell carcinoma who had undergone only a unilateral hemi-nephrectomy. Both had long-term high-quality survival (5 years for the patient with lung cancer with complete remission of all lung lesions, and 12 years for the male patient with kidney cancer). Neither patient had any side-effects from mifepristone therapy. CONCLUSION: These cases helped influence the US Food and Drug Association in granting an investigator-initiated investigational new drug study on advanced non-small cell lung cancer.

Effect of treating sperm with low hypo-osmotic swelling test scores with chymotrypsin on pregnancy rates after conventional in vitro fertilization-embryo transfer.

The embryos formed from fertilizing oocytes with sperm with subnormal hypo-osmotic swelling tests with conventional insemination rather than intracytoplasmic sperm injection are very unlikely to implant. The toxic factor transferred to the zona pellucida by such sperm can be negated by pretreating the sperm with the protein digestive enzyme chymotrypsin, resulting in markedly improved implantation rates.

Evaluation of a nonhomogeneous endometrial echo pattern in the midluteal phase as a potential factor associated with unexplained infertility.

OBJECTIVE: To determine whether the failure to develop a homogeneous hyperechogenic pattern in the midluteal phase is associated with decreased fecundity in infertile women who are not receiving follicle-maturing drugs. DESIGN: Observational study. SETTING: Outpatient infertility clinic of a University Medical Center. PATIENT(S): Two hundred ninety-six infertile women (> or =6 months) with regular menses, normal fallopian tubes and uterine cavity, and absence of severe male factor on their initial investigation cycle for follicular dynamic studies. INTERVENTION(S): Midluteal phase sonographic endometrial evaluation. MAIN OUTCOME MEASURE(S): Viable pregnancy rates (live fetus at end of first trimester) according to endometrial echo pattern in the midluteal phase. Other variables considered were age of patient, endometrial thickness and serum E(2) levels at midcycle and midluteal phase, midcycle echo pattern, and P levels in the midluteal phase. RESULT(S): The viable pregnancy rate was significantly higher in those women who exhibited a homogeneous hyperechogenic pattern (8.5%) compared to those women whose endometrium was found to be nonhomogenous (2.2%). No other confounding variables were found that could explain this outcome. CONCLUSION(S): A nonhomogeneous hyperechogenic sonographic endometrial echo pattern predicts lower fertility potential in women who are not receiving follicle-maturing drugs.