Medroxyprogesterone as the Initial Systemic Treatment of Recurrent Endometrial Cancer: A Single Institutional Study.

BACKGROUND/AIM: Hormonal treatment is the preferred initial systemic therapy for patients with advanced or recurrent G1 or G2 endometrial cancer (EC) in terms of efficacy, toxicity, and economy. Few reports are available on the topic and we, therefore, conducted a retrospective study. PATIENTS AND METHODS: Patients with EC who received high-dose medroxyprogesterone (MPA) at our Hospital between January 2010 and December 2022 were reviewed. Patients who were treated for fertility preservation or had a history of systemic chemotherapy other than adjuvant therapy were excluded. RESULTS: Sixteen patients who were eligible for study inclusion had recurrent G1 or G2 EC. Their median age was 65 years (range=51-82 years), median body mass index was 22.6 kg/m2 (range=15.3-43.2 kg/m2), and all patients had an ECOG Performance Status of 0. All patients received 200 mg/day of MPA, and eight patients concomitantly received 100 mg/day of aspirin. None of the patients experienced severe adverse events. One patient had grade 2 deep vein thrombosis. Two patients discontinued MPA treatment because of adverse events. The response rate was 44% [95% confidence interval (CI)=20-68%] and median progression-free survival (PFS) was 6.9 months (95% CI=7.5-26 months). Four of 16 patients had PFS longer than 12 months, all of whom had positive tissue estrogen receptor (ER) and progesterone receptor (PR), and PFS at 2 years was 35% (95% CI=10.2-59.8%). CONCLUSION: Hormone therapy is effective long-term in ER- and PR-positive EC and can be recommended as initial systemic therapy. Toxicity is mild and manageable.

The Role of Autophagy and Apoptosis in the Combined Action of Plasma-Treated Saline, Doxorubicin, and Medroxyprogesterone Acetate on K562 Myeloid Leukaemia Cells.

The anti-cancer properties of plasma-treated solutions (PTS) and their interaction with drugs are one of the most popular topics in modern plasma medicine. Our research involved comparing the effects of four physiological saline solutions (0.9% NaCl, Ringer's solution, Hank's Balanced Salt Solution, Hank's Balanced Salt Solution with amino acids added in concentrations observed in the human blood) treated with cold atmospheric plasma and studying the combined cytotoxic effect of PTS with doxorubicin and medroxyprogesterone acetate (MPA). Analysis of the effect of the studied agents on the formation of radicals in the incubation medium, the vitality of K562 myeloid leukaemia cells, and the processes of autophagy and apoptosis in them revealed two key findings. The first is that when using PTS and doxorubicin-containing PTS, autophagy is the predominant process in cancer cells. The second is that combining PTS with MPA enhances apoptotic processes. It was hypothesised that while autophagy is stimulated by the accumulation of reactive oxygen species in the cell, apoptosis is stimulated through specific cell progesterone receptors.

Retrospective study on the effectiveness of medroxyprogesterone acetate in the treatment of ER-positive/HER2-negative post-menopausal advanced breast cancer: an additional analysis of the JBCRG-C06 Safari study.

BACKGROUND: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment. METHODS: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate. RESULTS: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer. CONCLUSION: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

Effects of Isoflavone Supplementation on the Response to Medroxyprogesterone in Premenopausal Women with Nonatypical Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The purpose of this study was to evaluate the impact of isoflavone supplementation compared with placebo on endometrial histology and serum estradiol levels in premenopausal women with nonatypical endometrial hyperplasia. Materials and Methods: The present double-blindplacebo-controlled clinical trial was conducted on 100 women with nonatypical endometrial hyperplasia in the age range of 30 to 45 years. Participants were randomly assigned to receive 50 mg of isoflavone (n = 50) or placebos (n = 50) daily for three months. Both groups received the standard treatment of nonatypical endometrial hyperplasia. Endometrial biopsy and blood samples were taken at the baseline and three months after the intervention. The incidence of drug side effects was assessed as well. Results: After three months, 88.4% of isoflavone-administered subjects had a significant histological improvement compared to 68.9% subjects in the placebo group (P=0.02). There were no significant differences between the two groups in the changes of serum estradiol levels and the incidence of drug side effects. Conclusion: The findings of the present study demonstrated that the coadministration of 50 mg of isoflavones and medroxyprogesterone acetate increases the treatment efficacy in women with nonatypical endometrial hyperplasia. Clinical Trial Registration. This trial was registered on the Iranian website for clinical trial registration (https://www.irct.ir/trial/53553).

Depo Medroxyprogesterone (DMPA) Promotes Papillomavirus Infections but Does Not Accelerate Disease Progression in the Anogenital Tract of a Mouse Model.

Contraceptives such as Depo-medroxyprogesterone (DMPA) are used by an estimated 34 million women worldwide. DMPA has been associated with increased risk of several viral infections including Herpes simplex virus-2 (HSV-2) and Human immunodeficiency virus (HIV). In the current study, we used the mouse papillomavirus (MmuPV1) anogenital infection model to test two hypotheses: (1) contraceptives such as DMPA increase the susceptibility of the anogenital tract to viral infection and (2) long-term contraceptive administration induces more advanced disease at the anogenital tract. DMPA treatments of both athymic nude mice and heterozygous NU/J (Foxn1nu/+) but ovariectomized mice led to a significantly increased viral load at the anogenital tract, suggesting that endogenous sex hormones were involved in increased viral susceptibility by DMPA treatment. Consistent with previous reports, DMPA treatment suppressed host anti-viral activities at the lower genital tract. To test the impact of long-term contraceptive treatment on the MmuPV1-infected lower genital tract, we included two other treatments in addition to DMPA: 17ß-estradiol and a non-hormone based contraceptive Cilostazol (CLZ, Pletal). Viral infections were monitored monthly up to nine months post infection by qPCR. The infected vaginal and anal tissues were harvested and further examined by histological, virological, and immunological analyses. Surprisingly, we did not detect a significantly higher grade of histology in animals in the long-term DMPA and 17ß-estradiol treated groups when compared to the control groups in the athymic mice we tested. Therefore, although DMPA promotes initial papillomavirus infections in the lower genital tract, the chronic administration of DMPA does not promote cancer development in the infected tissues in our mouse model.

Depot Medroxyprogesterone Acetate Use and the Development and Progression of Uterine Leiomyoma.

OBJECTIVE: Investigate the association between use of depot medroxyprogesterone acetate (DMPA) (an injectable progestin-only contraceptive) and leiomyoma development. METHODS: We conducted a cohort study in the Detroit, Michigan, area that involved four clinic visits at 20-month intervals over 5 years (2010-2018) and used a standardized ultrasonography protocol to prospectively measure leiomyomas 0.5 cm or more in diameter. Participants were 1,693 self-identified Black women aged 23-35 years with no prior leiomyoma diagnosis and no hysterectomy. For this substudy, years since last use of DMPA was ascertained from questionnaire data at every visit. Leiomyoma incidence was defined as the first visit with an observed leiomyoma among women who were leiomyoma-free at enrollment. Depot medroxyprogesterone acetate associations were examined with Cox models. Leiomyoma growth was calculated as the change in log-volume for leiomyomas matched at successive visits and was modeled using linear mixed models accounting for clustered data. Leiomyoma loss, defined as a reduction in leiomyoma number in successive visits, was modeled using Poisson regression. All models used time-varying exposure and covariates. RESULTS: Of participants with at least one follow-up visit (N=1,610), 42.9% had ever used DMPA. Participants exposed to DMPA within the previous 2 years experienced reduced leiomyoma development during the subsequent observation interval compared with never users, including lower leiomyoma incidence (5.2% vs 10.7%), adjusted hazard ratio 0.6 (95% CI 0.4-1.0), 42.0% lower leiomyoma growth (95% CI -51.4 to -30.7) and 60% greater leiomyoma loss (adjusted risk ratio 1.6, 95% CI 1.1-2.2). Excess leiomyoma loss was also seen for those who used DMPA 2-4 years before the visit compared with never users, 2.1-fold increase (95% CI 1.4-3.1). CONCLUSION: Recent use of DMPA was associated with reduced leiomyoma development and increased leiomyoma loss. Such changes in early leiomyoma development in young women could delay symptom onset and reduce the need for invasive treatment.

Low-grade endometrial stromal sarcoma with intracaval or intracardiac extension: a retrospective study of eight cases.

PURPOSE: This study aimed to improve the knowledge of low-grade endometrial stromal sarcoma (LG-ESS) with intracaval or intracardiac extension and tried to identify the potential risk factors and optimal treatment method influencing prognosis. METHODS: We performed a retrospective review of eight LG-ESS patients with intracaval or intracardiac extension who underwent treatment at Peking Union Medical College Hospital between 2012 and 2020. RESULTS: The median age at diagnosis was 44 years, ranging from 28 to 56 years. Abnormal uterine bleeding was the most common intimal symptom (3/8), followed by low back discomfort (2/8), edema of the lower limbs (2/8), abdominal pain (1/8), and dyspnea (1/8). All patients underwent resection of the intravascular and extravascular portions of the tumor. Two patients were in stage IIIC, and six were in stage IVB. After surgery, four patients received adjuvant radiotherapy, of whom three also received letrozole. One patient was treated with letrozole alone, and one patient received medroxyprogesterone. The average follow-up time was 34.5 months, ranging from 6 to 98 months. No patients died or relapsed during the follow-up period. CONCLUSIONS: LG-ESS with intracaval or intracardiac extension is an uncommon type of tumor which is easily misdiagnosed and can only be diagnosed by histological evaluation after surgery. Complete tumoral excision followed by adjuvant therapy may benefit patient survival time. Long-term follow-up is essential due to the high rate of late recurrence.

Intrauterine device, subdermal contraceptive, and depot medroxyprogesterone use among transmasculine and cisgender patients over a 10-year period.

OBJECTIVE: To describe use of three types of longer-acting contraception-intrauterine devices, subdermal contraceptives, and depot medroxyprogesterone-among transmasculine and cisgender women patients. STUDY DESIGN: A repeated cross-sectional study using electronic medical records of patients, age 18 to 45, receiving care within Kaiser Permanente Northern California between 2009 and 2019. Variations in demographics, clinical characteristics and contraception method uptake were assessed using t tests for continuous variables and chi-square tests for categorical variables for patients enrolled in 2019. A linear trend test for each group was used to assess the age-adjusted uptake of contraception methods by study year. RESULTS: The transmasculine group was younger, with a mean age of 27.3 years (±7.2) vs 32.5 years (±7.8) years, respectively p < 0.001. The transmasculine group used more tobacco, alcohol, and illicit drugs. The uptake of these contraception methods increased from 2009 to 2019 for both groups (transmasculine: 0.7% to 4.1%; cisgender: 5.6% to 6.7%) with a positive linear trend for both groups (p = 0.003 and p < 0.001, respectively). The change in uptake of any intrauterine device from 2009 to 2019 was greater for the transmasculine group (0.3% to 2.3% vs 3.3% to 3.5%). Etonogestrel implant uptake had a positive linear trend from 2009 to 2019 for both groups (transmasculine: 0% to 0.5%, p = 0.02, and cisgender 0.1% to 1.2%, p < 0.001). CONCLUSION: Annual uptake of these contraception methods increased significantly for both transmasculine and cisgender groups, and this increase was greater for the transmasculine patients. Uptake of these contraception methods was higher in the cisgender population. IMPLICATIONS: These findings suggest an improvement in use of long-term contraception and menstrual suppression medications for the transmasculine population. Further research is needed to understand these differences and identify a possible unmet need for intrauterine and subdermal contraceptives and depot medroxyprogesterone use among this often-marginalized population.

The relation of estradiol conditions and usage length to sexual dysfunction in progesterone acetate medroxepo acceptories at Bara-Baraya public health center of Makassar.

OBJECTIVE: This study aims to determine the relationship between estradiol hormone levels and duration of the usage on sexual dysfunction in Depo Medroxy Progesterone Acetate acceptors. METHOD: Family Planning (KB/Keluarga Berencana) Depo Medroxy Progesterone Acetate as many as 43 respondents who meet the sample criteria. The sampling technique used was accidental sampling. Data analysis was performed by using chi square. RESULTS: The results showed that there was a significant relation between levels of the hormone estradiol and the incidence of sexual dysfunction (p=0.000), as well as the length of time using Depo Medroxy Progesterone Acetate on sexual dysfunction (p=0.000). CONCLUSION: The result of data analysis is that the duration of Depo Medroxy Progesterone Acetate injection usage significantly reduces the level of the hormone estradiol which can cause sexual dysfunction in Depo Medroxy Progesterone Acetate acceptors.

Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review).

This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered.

Treatments with intravaginal sponges for estrous synchronization in ewes: length of the treatment, amount of medroxyprogesterone, and administration of a long-acting progesterone.

We evaluated if alternative treatments achieve at least similar results as traditional long treatments with intravaginal sponges (IVS) in three experiments considering (1) the use of 6-day treatments associated or not with the administration of PGF2alpha at IVS insertion; (2) a reduction of 50% MAP content in short-term or traditional treatments, with or without change of the IVS 6 days after its insertion; and (3) the substitution of IVS for long-time acting injected progesterone associated with the administration of a PGF2alpha. More ewes came into estrus with long than short IVS treatments, independently of the MAP IVS content. Fewer ewes came into estrus if the IVS containing 30 mg was replaced 6 days after its insertion. The length of the treatment did not affect the conception rate, but the pregnancy rate was greater in 12 than 6 days treatments. The administration of long-acting progesterone did not prevent the lower conception rate associated with the use of PGF2alpha and was less effective to synchronize estrus, but the conception rate did not differ from that of 12d IVS treatments. Overall, MAP content could be decreased without affecting the estrous rate; thereafter, the MAP IVS content should be decreased in the commercial devices. Although pregnancy rate was lower using long-acting injected progesterone than with IVS, as the conception rate did not differ, it is interesting to study deeper the use of this treatment, especially if preparations of progesterone with a longer half-life are developed. However considering all the results, the traditional long IVS treatment still provided the best result.

Does a single application of contraceptive cause pathological changes in bitches? / [Uma única aplicação de anticoncepcional causa alterações patológicas em cadelas?]

O presente trabalho objetivou avaliar os efeitos da administração em dose única de progestágenos em fêmeas caninas hígidas, as quais nunca haviam recebido tais fármacos. Foram selecionadas 20 cadelas, que foram examinadas clinicamente e por meio de exames complementares. Nessas cadelas, foi aplicado medroxiprogesterona por via subcutânea. Noventa dias após, as fêmeas foram esterilizadas cirurgicamente, sendo os tecidos reprodutivos encaminhados para histopatologia. Foi possível verificar que, aos 30 dias, 12 animais (60%) apresentaram hiperplasia mamária. Aos 90 dias, 18 animais (90%) apresentavam sinais de hiperplasia endometrial cística, tendo cinco (27,77%) destes animais apresentado conteúdo purulento no lúmen uterino. No exame microscópico, apenas uma fêmea não demonstrou alterações patológicas, sendo a única que recebeu o contraceptivo na fase correta (anestro). As demais fêmeas apresentaram alterações que variaram entre alterações circulatórias a hiperplasia endometrial cística grave. Assim, foi possível concluir que uma única aplicação de anticoncepcional em fêmeas hígidas pode causar complicações leves a graves.(AU)

CNR1 may reverse progesterone-resistance of endometrial cancer through the ERK pathway.

Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo. The above datas suggest that targeting CNR1 may reverse the progesterone resistance in endometrial cancer and may coordinate the role of ERK pathway activation.

Bilateral Boston keratoprosthesis type 1 in a case of severe Mooren's ulcer.

INTRODUCTION: Mooren's ulcer is a painful, inflammatory chronic keratitis that affects corneal periphery, progressing centripetally, ultimately ending in perforation. The first line of treatment includes systemic immunomodulators, with surgery being the last option. We present a case of bilateral Boston keratoprosthesis implantation for severe Mooren's ulcer that responded differently in each eye. CLINICAL CASE: A 32-year-old male with corneal opacification, anterior staphylomas, vision of hand movement, was started on systemic immunosuppression with cyclosporine. After two failed penetrating keratoplasties in each eye, high intraocular pressure despite diode cyclophotocoagulation, and cystic macular edema, we performed Boston keratoprosthesis type 1 in both eyes. The right eye responded initially well, with a best-corrected visual acuity of 20/80 and normal intraocular pressure. The left eye presented high intraocular pressure, which required cyclophotocoagulation, ultimately resulting in hypotony. Boston keratoprosthesis was performed but had peripheral corneal necrosis that progressed despite amniotic membrane transplantation and aggressive intensive treatment with medroxyprogesterone, autologous platelet-rich-in-growth-factors eye drops, and oral doxycycline. Thus, replacement of the semi-exposed Boston keratoprosthesis with tectonic penetrating keratoplasty was necessary. However, both eyes developed phthisis bulbi with final visual acuity of perception of light with poor localization. CONCLUSION: Mainstay treatment of Mooren's ulcer is systemic immunomodulation. Surgical treatment must be considered only when risk of perforation, preferably with inflammation under control. Penetrating keratoplasty frequently fails, and Boston keratoprosthesis may be a viable option. However, postoperative complications, especially uncontrolled high intraocular pressure, corneal necrosis, and recurrence of Mooren's ulcer may jeopardize the outcomes and need to be addressed promptly with intensive topical and systemic treatment.

Efficacy and safety of pharmacological cachexia interventions: systematic review and network meta-analysis.

AIMS: Randomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia. METHODS: PubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI. RESULTS: 80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo. CONCLUSIONS: Our findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.

Luteotropic effects of human chorionic gonadotropin administered 7.5 days after synchronous estrous induction in Morada Nova ewes.

This study was conducted in ewes to assess effects of human chorionic gonadotropin (hCG) administration after imposing an estrous induction treatment regimen. Ewes (n = 115) were treated with a 60 mg medroxyprogesterone-intravaginal-sponge for 6 d plus 200 IU of equine chorionic gonadotropin (eCG) im and 37.5 µg d-cloprostenol im 36 h before sponge removal (Day 0). After natural mating, ewes having at least one corpus luteum (CL; n = 108) were administered either 1 mL of saline (G-Control; n = 53) or 300 IU of hCG (G-hCG; n = 55) on Day 7.5 after sponge removal (Day 0). Ovarian ultrasonography and blood collection were performed on Days 7.5, 13.5, 17.5, 21.5, and 30.5. Accessory CL (aCL) were observed in 81.5 % (G-hCG) and 0.0 % (G-Control) of ewes (P = 0.0001). Diameter, area, and volume of luteal tissue were greater (P < 0.05) in G-hCG from Day 13.5 to 30.5. Progesterone (P4) concentrations were greater (P < 0.05) on Days 13.5, 17.5, 21.5 and 30.5 for ewes of the G-hCG group. Pregnancy percentage was similar (P = 0.25) between groups [47.1 % (G-control) compared with 60.0 % (G-hCG)], although total number of lambs produced by estrous synchronized ewes was greater (P = 0.005) in ewes of the G-hCG group (90.9 % compared with 66.0 %). In conclusion, hCG administration 7.5 days after sponge removal from Morada Nova ewes during the non-breeding season is an effective treatment to induce aCL formation, improve luteal tissue biometry and P4 concentrations, and to enhance the total number of lambs born.

Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma.

More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

Medroxyprogesterone opposes estradiol-induced renal damage in midlife ovariectomized Long Evans rats.

OBJECTIVE: Our laboratory previously published that long-term administration of estradiol (E2) was detrimental to the kidneys of midlife ovariectomized Long Evans rats, contrasting clinical studies in showing that menopausal hormone therapy is associated with decreased albuminuria. However, it is unknown whether this renal benefit was due to estrogen and/or the combination with progestogen. Therefore, the objective of the current study was to determine the impact of medroxyprogesterone (MPA) on E2-mediated renal damage using a rodent model. METHODS: Female Long Evans retired breeders underwent ovariectomy at 11 months of age and were treated for 40 days with subcutaneous E2, E2+MPA or vehicle at doses mimicking that of menopausal hormone therapy (N = 5-7 per group). Systolic blood pressure was measured along with indices of renal damage and function to investigate the impact of MPA on E2-mediated renal outcomes. Renal estrogen receptor alpha and G protein-coupled estrogen receptor transcript copy numbers were measured in all treatment groups through droplet digital PCR. RESULTS: Middle-aged female Long Evans rats displayed spontaneous hypertension with similar systolic blood pressures and heart weights between groups. Even though blood pressure was comparable, E2 reduced glomerular filtration rate and increased proteinuria indicating pressure-independent renal damage. Coadministration with MPA prevented E2-induced glomerular filtration rate impairment and proteinuria by promoting renal hypertrophy and preventing renal interstitial fibrosis. Both E2 and E2+MPA reduced renal estrogen receptor alpha (ERα) and increased renal G protein-coupled estrogen receptor mRNA, but neither ERα nor ERß protein was different between groups. CONCLUSION: MPA was protective against E2-induced renal damage and dysfunction in middle-aged female Long Evans rats. Assessing the impact of hormone therapy on renal outcomes may be an important clinical factor when considering treatment options for postmenopausal women.

Medroxyprogesterone derivatives from microbial transformation as anti-proliferative agents and acetylcholineterase inhibitors (combined in vitro and in silico approaches).

The fungal transformations of medroxyrogesterone (1) were investigated for the first time using Cunninghamella elegans, Trichothecium roseum, and Mucor plumbeus. The metabolites obtained are as following: 6ß, 20-dihydroxymedroxyprogesterone (2), 12ß-hydroxymedroxyprogesterone (3), 6ß, 11ß-dihydroxymedroxyprogesterone (4), 16ß-hydroxymedroxyprogesterone (5), 11α, 17-dihydroxy-6α-methylpregn-4-ene-3, 20-dione (6), 11-oxo-medroxyprogesterone (7), 6α-methyl-17α-hydroxypregn-1,4-diene-3,20-dione (8), and 6ß-hydroxymedroxyprogesterone (9), 15ß-hydroxymedroxyprogesterone (10), 6α-methyl-17α, 11ß-dihydroxy-5α-pregnan-3, 20-dione (11), 11ß-hydroxymedroxyprogesterone (12), and 11α, 20-dihydroxymedroxyprogesterone (13). Among all the microbial transformed products, the newly isolated biotransformed product 13 showed the most potent activity against proliferation of SH-SY5Y cells. Compounds 12, 5, 6, 9, 11, and 3 (in descending order of activity) also showed some extent of activity against SH-SY5Y tumour cell line. The never been reported biotransformed product, 2, showed the most potent inhibitory activity against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.