The use of semiconductor quantum dots (QDs) as fluorescent labels to develop a competitive immunoassay for sensitive detection and quantification of progesterone in cow's milk is described. Colloidal ...water-soluble CdSe/ZnS QDs are conjugated to an antigen derivative (progesterone-BSA conjugate) and a simple methodology is optimised to determine the antigen concentration in the final bioconjugate. The obtained QD-linked antigens were then employed together with unlabelled anti-progesterone monoclonal antibodies, as the biological recognition elements, in the development of the quantitative QDs-based fluorescent immunoassay for progesterone in bovine milk.
After optimization, the developed immunoassay proved to cover a progesterone concentration range from 0.3 to 14.5
ng/mL in cow milk. Milk samples were just diluted 10-fold with deionised water and directly analysed with the proposed immunoassay, without additional sample pre-treatment or analyte extraction. The minimum detectable level (IC
10) of the developed immunoassay turned out to be 0.1
ng/mL of progesterone in bovine milk. The sensitivity (IC
50) achieved was 2.2
ng/mL with a reproducibility of 3.5% RSD as obtained from the results of the analysis of the triplicate of same samples but in three different days. Applicability of the proposed methodology was evaluated by analyzing cow's milk samples enriched with known concentrations of progesterone and recoveries better than 90% were achieved.
The enormous challenge in unraveling the etiology of preterm birth (PTB) is to understand the complex interactions between gestational hormones, the immune system and reproductive tissues. PTB can be ...divided into spontaneous PTB (sPTB) and medically-indicated PTB, e.g. due to preeclampsia (PE) or HELLP syndrome. Progesterone (P4), important for establishment and maintenance of pregnancy, exerts anti-inflammatory effects. The impact of P4 on B cells and its support of maintaining maternal-fetal tolerance is widely unexplored. Therefore, we aimed to determine whether B cells express the progesterone receptor (PR) and to dissect a possible role of PR+ B cells in PTB.
We found enhanced IL-6, IL-21 and TNF-α concentrations in maternal plasma in patients with sPTB and PE/HELLP compared to term delivery (TD), accompanied by enhanced PR-A expression by CD19+ B cells. In a second phase of the study, we recruited patients with imminent PTB (iPTB) and controls. Samples were collected at hospital admission and to a later time point, then divided into iPTB patients who delivered preterm and patients whose PTB was prevented. Within the group of iPTB patients, we observed very clear differences: enhanced levels of pro-inflammatory cytokines and increased percentages of PR-A+CD19+ B cells were found in iPTB patients that delivered preterm compared to patients who did not deliver preterm.
We conclude that PTB is associated with the activation of an inflammatory pathway leading to the induction of PR-A by B cells. This might further trigger inflammation, result in the break of maternal-fetal tolerance and induce delivery.
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•B cells from pregnant women express the progesterone receptor A (PR-A).•Upon admission, PTB patients did not differ from non-delivering iPTB women in cytokine or P4 levels or PR-A+ B cells.•Enhanced inflammation and increased PR-A+CD19 + B cells in patients immediate before PTB delivery.
•Progesterone receptor (PR) localizes in the prostate stroma.•PR suppresses stromal cell proliferation with implications in BPH.•PR suppresses tumor-favoring microenvironment in the prostate.•PR ...regulates stromal differentiation and potentially prevents reactive stroma.•The impact of PR on prostate diseases warrants further investigations.
Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management.
Progesterone and the immunology of pregnancy Druckmann, René; Druckmann, Marc-Alexandre
Journal of steroid biochemistry and molecular biology,
12/2005, Letnik:
97, Številka:
5
Journal Article, Conference Proceeding
Recenzirano
The foetal–placental unit is a semi-allograft and the immunological recognition of pregnancy, together with the subsequent response of the maternal immune system, is necessary for a successful ...pregnancy. This recognition of pregnancy results in an upregulation of progesterone receptors on activated lymphocytes amongst placental cells and decidual CD56+ cells. In the presence of sufficient progesterone, these cells synthesise progesterone induced blocking factor (PIBF), a mediator that exerts substantial anti-abortive activities. PIBF affects B cells and induces an increased production of asymmetric, non-cytotoxic antibodies. It also alters the profile of cytokine secretion by activated lymphocytes resulting in an increase in the production of non-inflammatory, non-cytotoxic interleukins (IL) (e.g. IL-3, IL-4 and IL-10) and a reduction in the production of inflammatory, cytotoxic cytokines (e.g. interferon (IFN)-δ, tumour necrosis factor (TNF)-α and IL-2). PIBF also inhibits the cytotoxity of natural killer (NK) cells by blocking their degranulation and perforin release, as well as inhibiting IFN-δ, TNF-α and IL-2-mediated transformation of NK cells into detrimental lymphokine activated killer (LAK) cells.
Luminal breast cancer (L-BCa) comprises the majority of incurable, distally metastatic breast cancer cases. Estrogen supports growth of L-BCa cells but suppresses invasiveness. Estrogen also induces ...the progesterone receptor (PR). Invasiveness and metastasis of L-BCa cells is supported by the short PR isoform (PR-A), in response to the range of pre- and post-menopausal plasma hormone levels, by counteracting the effects of estrogen via micro RNA-mediated cross-talk with the estrogen receptor (ER). PR-B directly supports L-BCa invasion and metastasis and also inhibits tumor growth, both only at high progesterone levels. As public datasets on L-BCa tumors cannot distinguish PR-A, this study was designed to seek clinical evidence for the role of PR-A in metastasis in comparison with PR-B and ER.
Measurement of tumor PR-A, PR-B and ER mRNA expression in 125 treatment-naive primary L-BCa patients with differential node involvement and analysis using linear mixed effects models. Transcriptional activity assays of PR-A and PR-B.
Lymph node involvement was strongly associated with PR-A expression (median, 3-fold higher vs. node-negative), independent of age, pathologic type, tumor grade, HER2 and PR-B. PR-B and ER correlated weakly with PR-A, but whereas PR-B and the PR-A/PR-B ratio were not significantly associated with node involvement, ER weakly negatively correlated with node positivity. PR-A was hypersensitive to mifepristone compared with PR-B.
Taken together with previous mechanistic studies, the findings provide clinical evidence in support of the role of PR-A in L-BCa metastasis. They also suggest the possibility of developing selective PR-A modulators for future interventions in appropriate clinical situations.
In about 35% of cases undergoing ovarian stimulation may occur a rise in serum progesterone in the late follicular phase. This could produce premature luteinization and affect the endometrial ...receptivity. However, some studies suggest that the elevated progesterone could generate damage to the oocyte affecting the embryo quality and therefore increasing the rate of aneuploidy in the generated embryos which contributes decrease the implantation and newborn live rate.
A total of 2509 patients undergoing preimplantation genetic testing for aneuploidy screening (PGT-A) were included in this retrospective study performed between 2016 and 2018. The age of patients ranged from 22 to 49 years. Laser assisted blastocyst biopsies were done in all cases by either pulling or flicking method. Antagonist protocol was used in the majority of the cases and P4 levels were measured the day of hCG administration. Poisson regression model was used as statistical analysis where progesterone was considered as a continuous variable. Other variables such age, body mass index (BMI), estradiol and ovarian sensitivity index were included in the model. P values < 0.05 were considered statistical significant.
The increase of ovarian sensitivity index in one unit predicted the increase of euploid embryos in 1.67 times when controlling for the rest of variables. The increase in age had a negative influence decreasing the mean number of euploid embryos by 10%.
On the other hand the increase of P4 values predicted an increase in the number of euploid embryos by 7%.
The increasing values of progesterone does not decrease the availability of euploid embryos for transfer therefore, based in this initial approach P4 seems a surrogate marker of higher ovarian response which is also positively associated with embryo euploidy.
Progesterone and its metabolites promote the viability of neurons in the brain and spinal cord. Their neuroprotective effects have been documented in different lesion models, including traumatic ...brain injury (TBI), experimentally induced ischemia, spinal cord lesions and a genetic model of motoneuron disease. Progesterone plays an important role in developmental myelination and in myelin repair, and the aging nervous system appears to remain sensitive to some of progesterone's beneficial effects. Thus, the hormone may promote neuroregeneration by several different actions by reducing inflammation, swelling and apoptosis, thereby increasing the survival of neurons, and by promoting the formation of new myelin sheaths. Recognition of the important pleiotropic effects of progesterone opens novel perspectives for the treatment of brain lesions and diseases of the nervous system. Over the last decade, there have been a growing number of studies showing that exogenous administration of progesterone or some of its metabolites can be successfully used to treat traumatic brain and spinal cord injury, as well as ischemic stroke. Progesterone can also be synthesized by neurons and by glial cells within the nervous system. This finding opens the way for a promising therapeutic strategy, the use of pharmacological agents, such as ligands of the translocator protein (18 kDa) (TSPO; the former peripheral benzodiazepine receptor or PBR), to locally increase the synthesis of steroids with neuroprotective and neuroregenerative properties. A concept is emerging that progesterone may exert different actions and use different signaling mechanisms in normal and injured neural tissue.
Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function.
Ovarian cancer human and murine cell lines, ...cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression.
Herein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers.
Our results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer.
This work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Foundation (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW).
Autoimmune progesterone dermatitis represents cyclical, pruritic eruptions of variable morphology of lesions corresponding to upsurge of the levels of progesterone in second half of the menstrual ...cycle. Eczematous, urticarial, target lesions are the most common manifestations, though unrelatable presentations like fixed drug eruption, anaphylactic shock, purpuric lesions, and acute generalized pustules are also reported in the literature. The authors report a case of a 38-year-old woman who first presented to our OPD with gravida 2, para 2, 32 weeks of gestation, being treated for recurrent furunculosis caused by methicillin-resistant Staphylococcus aureus with antibiotics. Biopsy of the lesions for histopathology and direct immunofluorescence was suggestive of furunculosis. The patient was reviewed 1.5-year after delivery and emphasized on history of premenstrual flare-ups and flare-up during third trimester of first pregnancy as well. Based on consolidating history by the patient, intradermal progesterone test conducted with progesterone 50 mg/ml showed a wheal and flare response of 18 mm as opposed to 3 mm of negative control. The patient was advised oral contraceptives containing desogestrel-ethinyl estradiol, after which the patient reported significant long-lasting improvement, preventing relapses premenstrually every month. This case highlights the versatile clinical presentation of autoimmune progesterone dermatitis, but consistent history of premenstrual flare-up with positive intradermal progesterone test helps in confirming the diagnosis and providing targeted treatment by temporary or permanent cessation of ovulation, resulting in cessation of apprehended flare-ups.
The objective was to evaluate the effect of estrus occurrence (based on removal of tail-head marks) on ovarian responses and pregnancy per AI (P/AI; 30 d after AI) in suckled Bos indicus beef cows ...submitted to timed AI (TAI) protocols. Cows received an intravaginal device containing 1.0 g progesterone, and 2.0 mg estradiol benzoate im; 8 d later, the intravaginal device was removed, and they were given PGF₂α (0.25 mg of cloprostenol sodium) and 300 IU of eCG, with TAI 48 to 52 h later. In Experiment 1, cows were assigned to receive one of three treatments: 1 mg of estradiol cypionate (ECP) im at progesterone (P4) device removal (N = 178); 10 μg of GnRH im at TAI (N = 190); or both treatments (N = 172). In cows given estradiol (ECP or ECP + GnRH), more displayed estrus (P = 0.002) and became pregnant (P < 0.0001) compared with those receiving only GnRH. In Experiment 2, the effect of the occurrence of estrus on ovarian responses was evaluated in cows (N = 53) synchronized using ECP at device removal. Cows that displayed estrus had a greater diameter of the largest follicle (LF) at device removal (P < 0.0001), a greater diameter at TAI (P < 0.0001), a greater ovulation rate (P = 0.02), a larger CL (P = 0.02), and a greater P4 concentration (P < 0.0001) than cows that did not display estrus. In Experiment 3, the effect of GnRH treatment on P/AI at TAI was evaluated in cows that received ECP at device removal, and either displayed, or did not display, estrus (N = 726). There was no estrus by GnRH interaction (P = 0.22); the P/AI was greater (P < 0.0001) in cows that displayed estrus (61.9%) than cows that did not display estrus (41.4%). However, GnRH did not improve (P = 0.81) P/AI (GnRH = 53.7% vs. no GnRH = 52.6%). In conclusion, exogenous estradiol at device removal increased both the proportion of suckled Bos indicus cows that displayed estrus and P/AI. Cows that displayed estrus had better ovarian responses (i.e., larger follicles at TAI, a greater ovulation rate, larger CL, and greater P4 concentrations) following an estradiol/P4-based synchronization protocol. Although occurrence of estrus improved pregnancy outcomes, GnRH at TAI did not improve P/AI in suckled Bos indicus cows treated with ECP, regardless of estrus occurrence.
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