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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 -
Ovariectomized mice and postmenopausal women exhibit analogous loss of genital epithelial integrity.Tissue Barriers Apr 2021Roughly half of all postmenopausal women are affected by the genitourinary syndrome of menopause (GSM). Symptoms of GSM, including vaginal irritation and dyspareunia,...
Roughly half of all postmenopausal women are affected by the genitourinary syndrome of menopause (GSM). Symptoms of GSM, including vaginal irritation and dyspareunia, occur as reduced estrogen (E) production elicits loss of elasticity and other changes in genital tract tissue. While the use of the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) likewise lowers serum E concentrations in reproductive age women and is associated with decreased genital levels of the cell-cell adhesion molecules desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and impaired genital epithelial barrier function, the relevance of these findings to women in menopause is uncertain. Exploring the impact of menopause on genital epithelial integrity herein, we detected significantly lower levels of DSG1 and DSC1 in ectocervical tissue from menopausal and postmenopausal vs premenopausal women. Using ovariectomized (OVX) mice as a menopause model, we comparably saw significantly lower vaginal tissue levels of DSG1 and DSC1 in OVX mice vs. mice in estrus. Compared to estrus-stage mice and E-treated OVX mice, DMPA-treated ovary-intact mice and OVX mice also exhibited significantly reduced genital epithelial barrier function, greater susceptibility to genital herpes simplex virus type 2 infection, and delayed clearance of genital infection. Current studies thus identify analogous loss of genital epithelial integrity in OVX mice and menopausal and postmenopausal women. By showing that loss of genital epithelial integrity is associated with increased mouse susceptibility to bacterial and viral pathogens, our findings also prioritize the need to resolve if reduced genital epithelial integrity in postmenopausal women is a significant risk factor for genital infection.
Topics: Animals; Epithelium; Female; Genitalia, Female; Humans; Mice; Ovary
PubMed: 33427560
DOI: 10.1080/21688370.2020.1865760 -
The Linacre Quarterly May 2021Hormonal contraceptives have been on the market for over fifty years and, while their formulations have changed, the basic mechanism of action has remained the same....
UNLABELLED
Hormonal contraceptives have been on the market for over fifty years and, while their formulations have changed, the basic mechanism of action has remained the same. During this time, numerous studies have been performed documenting side effects, some of which appear over time, some within weeks or months, but all can have a serious impact on health and quality of life. An effort was made to perform a series of comprehensive literature surveys to better understand immediate and long-term side effects of these agents. The results of this literature review uncovered a number of potential side effects, some of which are acknowledged and many of which are not noted in the prescribing information for these agents. Among the unacknowledged side effects are: an increased risk of HIV transmission for depot medroxyprogesterone acetate (DMPA), and for combination contraceptives breast cancer, cervical cancer, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, depression, mood disorders and suicides (especially among women twenty-five years of age and younger, in the first six months of use), multiple sclerosis, interstitial cystitis, female sexual dysfunction, osteoporotic bone fractures (especially for progesterone-only contraceptives), and fatty weight gain. Misleading prescribing information regarding cardiovascular and thrombotic risks are also noted. Women seeking birth control have a right to be informed and educated about risk avoidance through the use of effective nonhormonal methods like fertility awareness methods. In one case-that of DMPA-the increased risk of HIV acquisition has been conclusively demonstrated to be both real and unique to this drug. Considering the availability of numerous alternatives, there is no justification for the continued marketing of DMPA to the public.
SUMMARY
We reviewed the effect of hormonal contraceptives on women's health. A number of potential side effects were noted including increased risks of breast cancer, cervical cancer, inflammatory bowel disease, lupus, multiple sclerosis, cystitis, bone fractures, depression, mood disorders and suicides, fatty weight gain, and female sexual dysfunction. With the long-acting injectable contraceptives there is an increased risk of getting HIV. Misleading prescribing information regarding the risks of heart attacks, strokes and blood clotting problems were also noted. Women seeking birth control have a right to know about how to avoid these risks by using effective hormone-free Fertility Awareness Methods.
PubMed: 33897046
DOI: 10.1177/0024363920982709 -
Frontiers in Cell and Developmental... 2021Human endometrium derived mesenchymal stem cells (hEndSCs) offer a great promise for regenerative medicine and reproductive system disorders treatment methods based on...
Human endometrium derived mesenchymal stem cells (hEndSCs) offer a great promise for regenerative medicine and reproductive system disorders treatment methods based on cell therapy due to their broad differentiation potential and highly efficient proliferation. In our study, we investigated the characteristics of hEndSCs that were isolated from two sources: endometrium and menstrual blood, which both contain endometrial origin stem cells. Changes in gene and protein expression levels during long-term cultivation and decidualization potential were examined in endometrial stem cells (EndSCs) and menstrual blood stem cells (MenSCs). The decidualization process was induced on early and late passages of hEndSCs using dibutyryl cyclic-AMP (db-cAMP) and medroxyprogesterone acetate (MPA) agents. We demonstrated that after long-term cultivation of hEndSCs the expression of typical mesenchymal stromal cell surface markers such as CD44, CD73, CD90, CD105 and perivascular marker CD146 remains at a similar level throughout long-term cultivation. Additionally, hematopoietic and endothelial markers CD34, CD45 were also tested, they were negative in all cases. Analyzed stem cells gene markers, such as OCT4, SOX2, NANOG, KLF4, showed similar expression in all passages of hEndSCs. RT-qPCR results demonstrated that the expression of cell cycle control associated genes - CDK2, CCNA2, CCNE2, p21, p53 and Rb, among all groups was very similar. Expression of genes associated with senescence (ATM, JUND, TOP2A, MYC) was maintained at a similar level throughout passaging. In addition, Western blot analysis was used to assess changes in proteins' levels associated to epigenetics (EZH2, SUZ12, H3K27me3) and cell cycle control (cyclinE1, p53) during long-term cultivation. The levels of proteins associated with epigenetic changes were fluctuated slightly depending on the patient. Also, we demonstrated that in all induced hEndSCs the expression of decidualization markers Prolactin (PRL), IGFBP1 and WNT4 was upregulated. In conclusion, we demonstrated successful decidualization of stem cells derived from two reproductive system resources: endometrium and menstrual blood by using db-cAMP and MPA regardless of the length of the stem cell passaging. According these findings, we suppose that endometrium derived stem cells and menstrual blood derived stem cells could have a potency not only for endometrium tissue regeneration, but could also become a successful therapy for reproductive system disorders, including infertility or recurrent pregnancy loss.
PubMed: 34869358
DOI: 10.3389/fcell.2021.765265 -
Current Issues in Molecular Biology Nov 2021Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as...
Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as estradiol (E), and progesterone (P). Matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) control the invasion of extravillous trophoblast cells after implantation. Several MMPs and TIMPs function in the decidua and endometrial stromal cells (ESCs). Here, we aimed to systematically investigate the changes in MMPs and TIMPs associated with ESC decidualization. We evaluated the expression of 23 MMPs, four TIMPs, and four anti-sense non-coding RNAs from MMP loci. Primary ESC cultures treated with E + medroxyprogesterone acetate (MPA), a potent P receptor agonist, showed significant down-regulation of , , , , , and in decidualized ESCs, as assessed by quantitative reverse transcription PCR. Further, and were significantly upregulated in decidualized ESCs. siRNA-mediated silencing of Heart and Neural Crest Derivatives Expressed 2 (HAND2), a master transcriptional regulator in ESC decidualization, significantly increased expression in untreated human ESCs. These results collectively indicate the importance of and in ESC decidualization and highlight the role of HAND2 in repressing transcription, thereby regulating decidualization.
Topics: Adult; Biomarkers; Cells, Cultured; Decidua; Endometrium; Female; Gene Expression Regulation; Humans; Matrix Metalloproteinases; Middle Aged; Steroids; Stromal Cells; Tissue Inhibitor of Metalloproteinases; Young Adult
PubMed: 34940120
DOI: 10.3390/cimb43030146 -
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 -
Environmental Research Jan 2022Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in commercial and consumer goods. Black women are underrepresented in studies of PFAS exposure.
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in commercial and consumer goods. Black women are underrepresented in studies of PFAS exposure.
METHODS
We performed a cross-sectional analysis of correlates of plasma PFAS concentrations among 1499 Black women aged 23-35 participating in the Study of Environment, Lifestyle, and Fibroids (SELF), a Detroit-based cohort study. At baseline (2010-2012), participants provided questionnaire data on socio-demographics; behaviors; diet; and menstrual, contraceptive, and reproductive histories. Using mass spectrometry in non-fasting plasma samples collected at enrollment, we quantified several PFAS, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and 2-N-methyl-perfluorooctane sulfonamido acetate (MeFOSAA). We used linear regression to calculate percentage differences (%D) and 95 % confidence intervals (CIs) for associations between selected correlates and PFAS concentrations, adjusting for all other correlates.
RESULTS
PFHxS, PFOS, PFOA, and PFNA were detected in ≥97 % of women; PFDA in 86 %; MeFOSAA in 70 %; and PFUnDA in 52 %. Age, income, education, and intakes of water, alcohol, and seafood were positively associated with several PFAS. Current smoking was positively associated with MeFOSAA. Body mass index was inversely associated with most PFAS, except PFHxS. Strong inverse associations (%D; 95 % CI) were observed between parity (≥3 vs. 0 births) and PFHxS (-34.7; -43.0, -25.1) and PFOA (-33.1; -39.2, -26.3); breastfeeding duration (≥6 months vs. nulliparous) and PFOA (-31.1; -37.8, -23.7), PFHxS (-24.2; -34.5, -12.3), and PFOS (-18.4; -28.3, -7.1); recent birth (<2 years ago vs. nulliparous) and PFOA (-33.1; -39.6, -25.8), PFHxS (-29.3; -39.0, -18.1), PFNA (-25.2; -32.7, -16.8), and PFOS (-18.3; -28.3, -6.9); and intensity of menstrual bleed (heavy vs. light) and PFHxS (-18.8; -28.3, -8.2), PFOS (-16.4; -24.9, -7.1), PFNA (-10.5; -17.8, -2.6), and PFOA (-10.0; -17.2, -2.1). Current use of depot medroxyprogesterone acetate (DMPA) was positively associated with PFOS (20.2; 1.4, 42.5), PFOA (16.2; 1.5, 33.0), and PFNA (15.3; 0.4, 32.4).
CONCLUSIONS
Reproductive factors that influence PFAS elimination showed strong associations with several PFAS (reduced concentrations with parity, recent birth, lactation, heavy menstrual bleeding; increased concentrations with DMPA use).
Topics: Adult; Alkanesulfonic Acids; Cohort Studies; Cross-Sectional Studies; Diet; Environmental Pollutants; Female; Fluorocarbons; Humans; Pregnancy; Reproduction
PubMed: 34403666
DOI: 10.1016/j.envres.2021.111860 -
Frontiers in Immunology 2020Depot Medroxyprogesterone (DMPA) is one of the most widely used contraceptives in Sub-Saharan Africa where HIV incidence is high. We explored the effect of DMPA on the...
BACKGROUND
Depot Medroxyprogesterone (DMPA) is one of the most widely used contraceptives in Sub-Saharan Africa where HIV incidence is high. We explored the effect of DMPA on the activation of HIV cellular targets and inflammation as a possible mechanism of increased HIV risk with DMPA use. Since sex work is known to affect the immune system, this study aimed to understand the effect of DMPA on the immune system among sex workers and non-sex worker women.
METHODS
Twenty-seven DMPA-using HIV seronegative female sex workers (FSW) and 30 DMPA-using HIV seronegative non-sex worker (SW) women were enrolled in the study. Twenty-four FSWs and 30 non-sex workers who were not using any hormonal contraception (no HC) were recruited as controls. Blood and cervico-vaginal samples were collected from all participants and assayed for T cell activation and proinflammatory cytokines.
RESULTS
Among no HC users, sex workers had lower expression of CD38 and CD69 on blood-derived CD4 T cells along with lower CD4CCR5 cells frequency in the endocervix. Plasma MCP-1, TNFα and IL-17 also had reduced expression in FSW not using HC. Non-sex workers using DMPA had elevated proportions of blood-derived CD4CD38, CD4CD69 and CD4HLA-DR T cells relative to non-sex workers who were not taking any HC. DMPA-using non-sex workers also had an increased level of plasma interferon gamma (IFN-), monokine induced by interferon- (MIG) and sCD40L, alongside higher proportion of CD4CD38 and CD4CD69 T cells at the cervix compared to non-sex workers no-HC controls., Finally, non-sex workers and FSWs using DMPA had similar levels of genital and peripheral CD4 T cell activation and inflammation.
CONCLUSION
DMPA increased inflammation and expression of activation markers on potential HIV target cells in non-sex workers. These data show that DMPA is a strong immune modulator and its use counteracts the decreased immune activation associated with sex work. These findings suggest that inflammation and increased HIV target cells in blood and at the genital tract may be mechanisms by which DMPA increases susceptibility to HIV.
Topics: Adolescent; Adult; Biomarkers; CD4-Positive T-Lymphocytes; Contraceptive Agents; Cytokines; Female; Humans; Immunophenotyping; Inflammation; Kenya; Lymphocyte Activation; Medroxyprogesterone; Mucous Membrane; Public Health Surveillance; Sex Workers; Young Adult
PubMed: 33717049
DOI: 10.3389/fimmu.2020.598307 -
International Journal of Women's... Dec 2020Hidradenitis suppurativa (HS) predominantly affects women of childbearing age, and sex hormones are thought to play a role in HS pathogenesis. However, there is a...
BACKGROUND
Hidradenitis suppurativa (HS) predominantly affects women of childbearing age, and sex hormones are thought to play a role in HS pathogenesis. However, there is a paucity of data regarding the pattern of HS perimenstrual flares, as well as patient responses to hormone-based therapies.
OBJECTIVE
We aimed to characterize the temporal pattern of perimenstrual flares, as well as factors associated with perimenstrual flares. We also sought to investigate responses to hormonal therapies in women with HS.
METHODS
An anonymous web-based questionnaire was distributed to various online HS support groups in May 2020.
RESULTS
A total of 283 participants met the inclusion criteria as adult women who self-reported having HS and menstrual cycles. The majority (176 of 282 women; 62.4%) reported HS worsening with menses, and 86.9% (153 of 176 women) noted that perimenstrual HS flares occurred always or often. Most women (138 of 175 women; 78.9%) reported that their HS flared in the week preceding menses. Perimenstrual HS flares were more likely in women with a family history of HS compared with those without (49.6% vs. 28.2%; = .019). More than a third of respondents who had been treated with spironolactone reported improvement of HS symptoms, but more than a quarter of participants who used medroxyprogesterone acetate or used a hormonal intrauterine device reported worsened HS symptoms.
CONCLUSION
Female patients with HS have high rates of perimenstrual HS flares, specifically during the week preceding the onset of menses. Additional investigations on the role of sex hormones in HS pathogenesis and the efficacy of hormone-based therapies are warranted.
PubMed: 33898701
DOI: 10.1016/j.ijwd.2020.09.002 -
Revista Da Associacao Medica Brasileira... 2022In the beginning of the pandemic, measures, such as social distancing, lockdown strategies, and restrictions on mobility, as well as the fear of transiting through...
OBJECTIVE
In the beginning of the pandemic, measures, such as social distancing, lockdown strategies, and restrictions on mobility, as well as the fear of transiting through health facilities, raised concerns about the impact of COVID-19 on women's ability to continue using contraceptives.
METHODS
This is a retrospective cohort study, which evaluated reports of medication distribution spreadsheets in Bauru - SP, from January 2019 to June 2021.
RESULTS
Our study showed that the municipal dispensation of contraceptives in the SUS was markedly impacted by the COVID-19 pandemic, suffering reductions that can impact on an increase in unplanned pregnancy rates. It is possible to note a significant decrease in the distribution of combined oral contraceptives (44.18%), combined injectable contraceptives (47.58% reduction), and medroxyprogesterone acetate (13.98%). This fact may be associated with the reduction in offers of face-to-face consultations in gynecology, due to the social isolation necessary at the time of the pandemic.
CONCLUSION
Ensuring access to contraceptives during health emergencies should be a public health policy priority. Thus, it is essential to draw up strategic plans to encourage full access to reproductive planning services even in times of health emergency, so that the occurrence of unplanned pregnancies can be adequately prevented.
Topics: Pregnancy; Female; Humans; Pandemics; Retrospective Studies; COVID-19; Brazil; Communicable Disease Control; Contraceptives, Oral, Combined; Prescriptions
PubMed: 36449808
DOI: 10.1590/1806-9282.20220999