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Hormonal Regulation in the Treatment of Fibroids
Published in John C. Petrozza, Uterine Fibroids, 2020
Victoria Fitz, Steven L. Young
Virtually all physiological and pathophysiological effects of progesterone are exerted through two nuclear receptors, progesterone receptor alpha (PR-A) and beta (PR-B). The two proteins are transcribed from the same gene and are identical, except PR-B has an extra 165 N-terminal amino acids, significantly complicating separate analysis in human tissues. Thus, most of the published information in leiomyomata includes undifferentiated analysis of PR, without regard to subtype, though both subtypes appear to be upregulated in leiomyomata [10].
Obstetrical Pathophysiology of Cocaine
Published in Richard J. Konkol, George D. Olsen, Prenatal Cocaine Exposure, 2020
J. Christopher Glantz, James R. Woods
Progesterone receptors have been localized to aortic media smooth muscle in the baboon, and to a lesser extent in myocardial and interstitial cells.128 Administration of estrogen increases the progesterone receptor content in these tissues.129 In humans, progesterone receptors have been identified in aortic smooth muscle and myocardium, but not in vessels of the uterus, breast, kidney, or gastrointestinal tract.130 To determine whether the rise in progesterone might explain cocaine’s increased toxicity during pregnancy, Plessinger and Woods catheterized oophorectomized nonpregnant sheep and administered intramuscular progesterone at a dose of 10 mg/kg/day for 3 days.131 During these 3 days, adrenergic receptor sensitivity was monitored using daily challenges with intravenous norepinephrine. Additionally, daily bolus infusions of 1 mg/kg and 2 mg/kg cocaine were administered. Progesterone treatment did not modify alpha adrenergic receptor sensitivity as measured by cardiovascular response to norepinephrine. In contrast, the hypertensive and chronotropic responses to cocaine increased twofold and threefold, respectively, when compared to responses observed before the initial dose of progesterone had been administered (Figure 3.14). Increased cardiovascular toxicity associated with pregnancy appears to be due to an effect of progesterone on the action of cocaine, but does not involve a change in alpha adrenergic receptor sensitivity.
Biology of the endometrium
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
The complete structure of the human progesterone receptor (hPR) gene has been determined’. Progesterone receptor exists in two distinct isoforms, hPR-A and hPR-B, which differ only in that hPR-B contains an additional 164 amino acids at the amino terminus. Both isoforms bind progesterone using the same kinetics, but they exhibit quite different biological functions. The interaction between PR and progesterone induces a series of structural and functional changes in this protein, leading ultimately to an association of the receptor with specific DNA sequences in the regulatory regions of target genes in a cell-specific manner. The PR is down-regulated by its own ligand at the transcriptional level through inhibition of ER-mediated induction and through protein–protein interactions. In addition to estrogen, progesterone, transcription factor AP-1, growth factors such as insulin-like growth factor, and agents that increase intracellular cyclic adenosine monophosphate (cAMP) levels all modulate progesterone receptor or receptor mRNA levels.
Association of Val660Leu, progesterone receptor polymorphic variant, with susceptibility to RRMS disease
Published in Neurological Research, 2023
Mina Salimian, Parisa Mohamadynejad, Mehdi Moghanibashi
In order to determine the genotype of V660L polymorphism in the PGR gene, first, a part of progesterone receptor gene sequence, which contains the desired polymorphic region, was amplified using PCR technique and forward: 5´-TGCTGTTGCTCTCCCACACCCA-3´ and reverse primers 5´-AAGTTGCCTCTCGCCTAGTTG-3´. PCR was performed in a 25 µl reaction containing 1 μl (50–100 ng) genomic DNA, 12.5 µl master mix PCR (Ampliqon), 1 μl of each primer (5 picomoles). PCR program was optimized at 95°C for 5 min for initial denaturation, followed by 28 cycles of denaturation at 95°C for 45 s, annealing at 60°C for 30 s, extension at 72°C for 30 s, and final extension at 72°C for 7 min. In the second step, the PCR products were treated with the restriction enzyme AdeI (Thermo Scientific, Lithuania) according to the protocol specified in the kit. Finally, digested products were electrophoresed on 2.5% agarose gel, followed by safe staining and photographed under gel documentation system. Bands with length of 223bp, 223/204/19 bp, and the 19/204 pb represent TT, TG, and GG genotypes, respectively (Figure 1).
Understanding the killer-cell immunoglobulin like receptor polymorphism in retinoblastoma
Published in Ophthalmic Genetics, 2023
Ritu Aggarwal, Madhulika Sharma, Usha Singh, Kay Poulton, Tanvi Bhatia, Navdeep Mangat, Nandita Kakkar, Deepak Bansal
Among the inhibitory KIRs, we observed KIR2DL5 to be a predisposing gene for retinoblastoma. The role of KIR2DL5 in predisposition to several cancers, including multiple myeloma, Kaposi’s sarcoma, breast cancer, and HNSCC, has been well documented (9,16–18). Their role in the causation of progesterone receptor-positive breast cancer was described by Larki et al (15). The other inhibitory gene which exhibited a significant role was KIR2DL2. Similar to our observation, Larki et al. reported increased susceptibility to estrogen receptor- positive breast cancer (15). Increased susceptibility to breast cancer has been reported in the Brazilian population as well (19). Further, the phase-I clinical trial of IPH2101, a humanized IgG4 monoclonal antibody against common KIRs, in combination with immunomodulating agent lenalidomide, showed promising novel, steroid sapring, dual immune therapy for multiple myeloma (20).
Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids
Published in Expert Opinion on Drug Safety, 2022
Mohamed Ali, Mohamed Raslan, Michał Ciebiera, Kornelia Zaręba, Ayman Al-Hendy
Experimental research showed that the growth of UFs was even more stimulated by progesterone [18,24]. Two isoforms of the progesterone receptor (PR) may be distinguished: PR-A and PR-B. Uterine fibroids are characterized by a larger quantity of both types of those receptors compared to the normal myometrium [28]. A considerable increase in the number of myometrial cell divisions is observed in the second phase of the cycle. The process was also noted in UFs. The phenomenon was associated with the deceleration of apoptosis and the overexpression of a variety of genes determining tumor growth [29]. The luteal phase is also related to the increased amount of progestogen receptors in tissues [24]. Progesterone influences the development and growth of UFs by a number of growth factors that belong to the regulators of growth, differentiation, apoptosis, and tissue remodeling [6]. These factors are secreted and act directly on the fibroid in an autocrine-like fashion. These factors, which may directly influence the pathogenesis of UFs, include transforming growth factors, insulin-like growth factors, vascular growth factors, platelet-rich plasma, interleukins and other proinflammatory factors [6]. Transforming growth factor beta seems to play a particular role [30].