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The Journal of Steroid Biochemistry and... Sep 2023Progestins (synthetic progestogens) are progesterone receptor (PR) ligands used globally by women in both hormonal contraception and menopausal hormone therapy. Although...
Progestins (synthetic progestogens) are progesterone receptor (PR) ligands used globally by women in both hormonal contraception and menopausal hormone therapy. Although four generations of unique progestins have been developed, studies seldom distinguish between the activities of progestins via the two functionally distinct PR isoforms, PR-A and PR-B. Moreover, not much is known about the action of progestins in breast cancer tumors where PR-A is mostly overexpressed relative to PR-B. Understanding progestin action in breast cancer is crucial since the clinical use of some progestins has been associated with an increased risk of developing breast cancer. This study directly compared the agonist activities of selected progestins from all four generations for transactivation and transrepression via either PR-A or PR-B, and when PR-A and PR-B were co-expressed at ratios comparable to those detected in breast cancer tumors. Comparative dose-response analysis showed that earlier generation progestins mostly displayed similar efficacies for transactivation on a minimal progesterone response element via the PR isoforms, while most of the 4th generation progestins, similar to the natural progestogen, progesterone (P), were more efficacious via PR-B. Most of the progestogens were however more potent via PR-A. We are the first to show that the efficacies of the selected progestogens via the individual PR isoforms were generally decreased when PR-A and PR-B were co-expressed, irrespective of the ratio of PR-A:PR-B. While the potencies of most progestogens via PR-B were enhanced when the ratio of PR-A relative to PR-B was increased, those via PR-A were minimally influenced. This study is also the first to report that all progestogens evaluated, except 1st generation medroxyprogesterone acetate and 4th generation drospirenone, displayed similar agonist activity for transrepression via PR-A and PR-B on a minimal nuclear factor kappa B containing promoter. Moreover, we showed that the progestogen activity for transrepression was significantly increased when PR-A and PR-B were co-expressed. Taken together, our results highlight that PR agonists (progestogens) do not always display the same activity via PR-A and PR-B, or when PR-A and PR-B are co-expressed at ratios mimicking those found in breast cancer tumors. These results suggest that biological responses are progestogen- and PR isoform-dependent and may differ in target tissues expressing varying PR-A:PR-B ratios.
Topics: Female; Humans; Progestins; Progesterone; Receptors, Progesterone; Medroxyprogesterone Acetate; Breast Neoplasms
PubMed: 37315868
DOI: 10.1016/j.jsbmb.2023.106348 -
Archives of Gynecology and Obstetrics Nov 2023Although many patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) achieve complete remission (CR) after high-dose medroxyprogesterone acetate...
PURPOSE
Although many patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) achieve complete remission (CR) after high-dose medroxyprogesterone acetate (MPA) treatment, no consensus has been reached on management after CR. Currently, patients receive estrogen-progestin maintenance therapy, but no recommendations exist regarding the duration of maintenance therapy or whether hysterectomy should be considered. This study aimed to provide insights into the management of EC/AEH after achieving CR.
METHODS
We retrospectively investigated the prognosis of 50 patients with EC or AEH who achieved CR after MPA therapy. We assessed the association between disease recurrence and clinicopathological features and the pre- and post-operative histological diagnoses of patients who underwent hysterectomy.
RESULTS
The median follow-up duration was 34 months (range: 1-179 months). Recurrence was observed in 17 patients. Among the clinical characteristics investigated, only the primary disease was significantly associated with disease recurrence; patients with EC had a higher risk of recurrence than those with AEH (p = 0.037). During the observation period, 27 patients attempted pregnancy, and 14 pregnancies resulted in delivery. Patients who gave birth had significantly longer relapse-free survivals than those who did not (p = 0.031). Further, 16 patients underwent hysterectomies, and AEH was detected postoperatively in 4 of 11 patients (36.4%) with no preoperative abnormalities.
CONCLUSIONS
We identified several clinical features of patients with EC and AEH after CR. Given the high probability of endometrial abnormalities detected postoperatively, hysterectomy may be considered for patients who no longer want children.
Topics: Pregnancy; Female; Child; Humans; Endometrial Hyperplasia; Retrospective Studies; Fertility Preservation; Treatment Outcome; Neoplasm Recurrence, Local; Endometrial Neoplasms; Medroxyprogesterone Acetate; Prognosis
PubMed: 37310452
DOI: 10.1007/s00404-023-07077-7 -
Research Square May 2023There has been no previous systematic, epidemiological study of the reproductive risk factors for uterine fibroids (UF) in African populations despite African women...
OBJECTIVE
There has been no previous systematic, epidemiological study of the reproductive risk factors for uterine fibroids (UF) in African populations despite African women having the highest burden of UF in the world. Improved knowledge of the associations between UF and reproductive factors would contribute to better understanding of the etiology of UF and may suggest novel opportunities for prevention and therapeutic interventions.
DESIGN
We used nurse administered questionnaires to survey the demographic and reproductive risk factors of UF among 484 women who are members of the African Collaborative Center for Microbiome and Genomics Research (ACCME) Study Cohort in central Nigeria, and who had transvaginal ultrasound diagnosis (TVUS). We used logistic regression models to the evaluate associations between reproductive risk factors and UF, adjusted for significant covariates.
RESULTS
In our multivariable logistic regression models, we found inverse associations with number of children (OR = 0.83, 95%CI = 0.74-0.93, p-value = 0.002), parity (OR = 0.41, 95%CI = 0.24-0.73, p-value = 0.02), history of any type of abortion (OR = 0.53, 95%CI = 0.35-0.82, p-value = 0.004), duration of use of Depot Medroxyprogesterone Acetate (DMPA) (p-value for trend = 0.02), menopausal status (OR = 0.48, 95%CI = 0.27-0.84, p-value = 0.01), and a non-linear positive association with age (OR = 1.04, 95%CI = 1.01-1.07, p-value = 0.003). Other reproductive risk factors that have been reported in other populations (age at menarche and menopause, and oral contraceptives) were not associated with UF in this study.
CONCLUSION
Our study confirms the reproductive risk factors for UF that have been found in other populations and shows that some of them are stronger in the Nigerian population. The associations we found with DMPA suggest opportunities for further research to understand the mechanisms of action of progesterone and its analogues in the etiology of UF, their potential use for prevention and treatment of UF.
PubMed: 37292609
DOI: 10.21203/rs.3.rs-2917100/v1 -
Stem Cell Research & Therapy Jun 2023Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC)...
BACKGROUND
Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.
METHODS
The effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.
RESULTS
Our results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.
CONCLUSIONS
The eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.
Topics: Humans; Mice; Female; Animals; Wnt Signaling Pathway; beta Catenin; Mice, Nude; Mice, Inbred BALB C; Endometrial Neoplasms; Endometrium; Mesenchymal Stem Cells; Cell Proliferation; Intercellular Signaling Peptides and Proteins
PubMed: 37287079
DOI: 10.1186/s13287-023-03387-4 -
Journal of Diabetes and Metabolic... Jun 2023The current study is aimed to perform structure-based screening of FDA-approved drugs that can act as novel inhibitor of the 11beta- hydroxysteroid dehydrogenase type 1...
PURPOSE
The current study is aimed to perform structure-based screening of FDA-approved drugs that can act as novel inhibitor of the 11beta- hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme.
METHODS
Structural analogs of carbenoxolone (CBX) were selected from DrugBank database and their Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters were investigated by SwissADME. Molecular docking of CBX analogs against 11β-HSD1 was performed by AutoDock tool, their binding patterns were visualized using PyMOL and the interacting amino acids were determined by ProteinPlus tool. Molecular dynamics simulation was performed on the docked structure of 11β-HSD1 (Protein Data Bank (PDB) code: 2ILT) using GROMACS 2018.1.
RESULTS
The binding energies of hydrocortisone succinate, medroxyprogesterone acetate, testolactone, hydrocortisone cypionate, deoxycorticosterone acetate, and hydrocortisone probutate were lower than that of substrate corticosterone. The molecular dynamics simulation of 11β-HSD1 and hydrocortisone cypionate docked structure showed that it formed a stable complex with the inhibitor. The Root mean square deviation (RMSD) of the protein (0.37 ± 0.05 nm) and ligand (0.41 ± 0.06 nm) shows the stability of the ligand-protein interaction.
CONCLUSION
The docking study revealed that hydrocortisone cypionate has a higher binding affinity than carbenoxolone and its other analogs. The molecular dynamics simulation indicated the stability of the docked complex of 11β-HSD1 and hydrocortisone cypionate. These findings indicate the potential use of this FDA approved drug in the treatment of type 2 diabetes. However, validation by in vitro inhibitory studies and clinical trials on type 2 diabetes patients is essential to confirm the current findings.
PubMed: 37255841
DOI: 10.1007/s40200-023-01191-8 -
Gynecological Endocrinology : the... Dec 2023To compare the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in infertility patients with normal ovarian reserve function... (Review)
Review
OBJECTIVE
To compare the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in infertility patients with normal ovarian reserve function undergoing invitro fertilization and embryo transfer.
METHODS
A retrospective cohort study was conducted to analyze the clinical data of 2013 cycles of patients with normal ovarian reserve function who underwent invitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in the Department of Human Reproductive Center, Renmin Hospital, Hubei University of Medicine from January 2018 and June 2020. The PPOS protocol group included 679 cycles and GnRH-along protocol group included 1334 cycles, the pregnancy outcomes were compared between the two groups.
RESULTS
The duration of Gn used and total Gn used dosage in the PPOS protocol group were less than those in the GnRH-along protocol group (Duration of Gn used: 10.05 ± 1.48 vs 11.90 ± 1.85 d, < 0.001; Total Gn used dosage: 1944.49 ± 533.61 vs 2661.34 ± 987.97 IU, < 0.001); The LH levels were significantly higher on HCG trigger day in PPOS protocol compared to GnRH-a long protocol (2.8 ± 1 ± 1.07 vs 1.01 ± 0.62 IU/L, < 0.001), the E2 levels on HCG trigger day in PPOS protocol group was lower than that in the GnRH-a long protocol group (2135.92 ± 1387.00 vs 2417.01 ± 1010.70 pg/mL, < 0. 001). The number of oocytes retrieved in the PPOS protocol group was lower than that in the GnRH-along protocol group (8.03 ± 2.86 vs 9.47 ± 2.64, < 0.001). No significant differences were found in pregnancy outcome including clinical pregnancy rate, early miscarriage rate and ectopic pregnancy rate between the two group ( > 0.05); In addition, no severe OHSS occurred in the PPOS protocol group during ovulation induction, while 11 patients of severe ovarian hyperstimulation syndrome (OHSS) occurred in GnRH-a long protocol group ( < 0.001).
CONCLUSION
The clinical efficacy of PPOS protocol combining embryo cryopreservation is comparable to that of GnRH-a long protocol in patients with normal ovarian reserve function, and the PPOS protocol is able to reduce the incidence of severe OHSS significantly.
Topics: Female; Pregnancy; Humans; Male; Progestins; Gonadotropin-Releasing Hormone; Fertilization in Vitro; Retrospective Studies; Ovarian Reserve; Semen; Ovulation Induction; Ovarian Hyperstimulation Syndrome; Pregnancy Rate; Steroids
PubMed: 37236243
DOI: 10.1080/09513590.2023.2217263 -
AIDS and Behavior Nov 2023New pre-exposure prophylaxis (PrEP) strategies tailored to the needs and expectations of individuals at risk of HIV acquisition are needed. In the CAPRISA 082...
New pre-exposure prophylaxis (PrEP) strategies tailored to the needs and expectations of individuals at risk of HIV acquisition are needed. In the CAPRISA 082 prospective cohort study in KwaZulu-Natal, South Africa, sexually active women aged 18 to 30 reported, through interviewer-administered questionnaires, on their prior contraceptive experience and interest in both approved and potential future PrEP dosage forms (oral PrEP, long-acting injectable PrEP, and PrEP implants) between March 2016 and February 2018. Univariable and multivariable Poisson regression models with robust standard errors were used to detect associations between women's prior and current contraceptive use and interest in PrEP options. Of 425 women enrolled, 381 (89.6%) had used at least one modern female contraceptive method previously, with injectable depot medroxyprogesterone acetate (DMPA) being used by 79.8% (n = 339). Women were more likely to show interest in a future PrEP implant if they were currently using (aRR 2.1, CI 1.43-3.07, p = 0.0001) or had ever used (aRR 1.65, CI 1.14-2.40, p = 0.0087) a contraceptive implant, and were more likely to choose an implant as their first choice method than the implant-naïve (current users aRR 3.2, CI 1.79-5.73, p < 0.0001; "ever" users aRR 2.12, CI 1.16-3.86, p = 0.0142). Women were more interested in injectable PrEP if they had used injectable contraceptives (current users aRR 1.24, CI 1.06-1.46, p = 0.0088; "ever" users aRR 1.72, CI 1.20-2.48, p = 0.0033); and were more interested in oral PrEP if they had ever used oral contraceptives (aRR 1.3, CI 1.06-1.59, p = 0.0114). This apparent relationship between women's contraceptive experience and their interest in novel forms of PrEP in an equivalent dosage form may play a future role in strengthening HIV prevention efforts in women at high risk of HIV acquisition.
PubMed: 37221330
DOI: 10.1007/s10461-023-04072-6 -
Alternative Therapies in Health and... Jul 2023The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may...
CONTEXT
The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear.
OBJECTIVE
The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression.
DESIGN
The research team performed a controlled animal study.
SETTING
The study took place at Xuzhou Medical University in Xuzhou, China.
ANIMALS
The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight.
INTERVENTIONS
The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET.
OUTCOME MEASURES
The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein.
RESULTS
The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups.
CONCLUSIONS
MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.
Topics: Humans; Female; Animals; Mice; Medroxyprogesterone Acetate; Metformin; Mice, Nude; Proto-Oncogene Proteins c-akt; Receptors, Progesterone; Mice, Inbred NOD; Mice, SCID; Endometrial Neoplasms; Cell Proliferation; TOR Serine-Threonine Kinases; Apoptosis; Cell Line, Tumor
PubMed: 37171945
DOI: No ID Found -
Life Sciences Jul 2023Medroxyprogesterone acetate (MPA) is the most common fertility-sparing treatment in patients with early-stage endometrial cancer. If MPA treatment fails, hysterectomy is...
AIMS
Medroxyprogesterone acetate (MPA) is the most common fertility-sparing treatment in patients with early-stage endometrial cancer. If MPA treatment fails, hysterectomy is recommended. Thus, there is an urgent need for novel treatment approaches for MPA-resistant endometrial cancer patients who wish to preserve their fertility. Ferroptosis is a recently discovered type of regulated cell death caused by the excessive accumulation of reactive oxygen species (ROS), followed by aberrant lipid peroxidation. Recent studies have shown that inducing ferroptosis is a potential therapeutic strategy for cancer. However, the role of ferroptosis in endometrial cancer treatment remains to be discussed. We therefore investigated the effects of ferroptosis inducers on MPA-resistant endometrial cancer cells.
MAIN METHODS
The levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), the main mediators of ferroptosis, were examined. Cell viability was evaluated after treatment with the ferroptosis inducers sulfasalazine, erastin, or RSL3. The degree of intracellular oxidative stress after treatment with these drugs was evaluated by the glutathione level, ROS level, ferrous iron level, lipid peroxidation and changes in mitochondrial morphology. The effect of ferroptosis inducers in vivo was also examined.
KEY FINDINGS
The expression of SLC7A11 and GPX4 in MPA-resistant ECC-1 cells decreased in comparison to parental ECC-1 cells. Sulfasalazine, erastin, and RSL3 significantly reduced cell viability and increased intracellular oxidative stress in MPA-resistant ECC-1 cells. Ferroptosis inducers also suppressed in vivo tumor growth more effectively in MPA-resistant ECC-1.
SIGNIFICANCE
Treatment with ferroptosis inducers could be a novel therapeutic approach for MPA-resistant endometrial cancer.
Topics: Female; Humans; Ferroptosis; Medroxyprogesterone Acetate; Reactive Oxygen Species; Sulfasalazine; Endometrial Neoplasms
PubMed: 37160245
DOI: 10.1016/j.lfs.2023.121753 -
Journal of Advanced Veterinary and... Mar 2023The percentage of infertility cases in this world is about 50%. Seahorses ( spp.) are widely used in traditional medicine. Several studies suggest that seahorses have...
OBJECTIVE
The percentage of infertility cases in this world is about 50%. Seahorses ( spp.) are widely used in traditional medicine. Several studies suggest that seahorses have ethnopharmacological characteristics, such as fertility, antioxidants, and antifatigue. The purpose of this study was to determine whether seahorse extract (SE) ( L.) has an effect on fertility and serum biochemistry in rats induced by depo medroxyprogesterone acetate (DMPA).
MATERIALS AND METHODS
All animals were induced with 1.25 mg/kg BW of DMPA. Animals were grouped into five groups: namely aquadest, 1% CMC, and SE doses of 150, 225, and 300 mg/kg BW. The rats were gavage every morning from week 7 until 18. At the end of our study, semen from the vas deferens and blood from the heart were analyzed. We analyzed with a one-way analysis of variance and Bonferroni's post hoc tests (α 95%).
RESULTS
The concentration of spermatozoa had a significant difference in dose of 150 mg/kg BW compared to other groups ( 0.04). In contrast, the motility ( = 0.012) and viability of spermatozoa ( 0.007) were highly significant differences ( 0.05 and 0.01) at 300 mg/kg BW. Testosterone levels were not significantly ( = 0.162; > 0.05), but tended to increase at 300 mg/kg BW (11.01%). Nevertheless, serum biochemistry was insignificant ( 0.05) in all groups.
CONCLUSION
SE ( L.) ameliorates fertility and serum biochemistry in rats induced by DMPA.
PubMed: 37155542
DOI: 10.5455/javar.2023.j661