Oncologic, fertility, and obstetric outcomes with MPA therapy in women with endometrial cancer and atypical endometrial hyperplasia.

AIM: Medroxyprogesterone acetate (MPA) is one of the treatments of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) to preserve the fertility. Efficacy of MPA therapy and fertility and obstetric outcomes after remission were evaluated in EC or AEH patients. METHODS: Among patients diagnosed with EC or AEH at Tokushima University Hospital between January 2002 and October 2020, we retrospectively analyzed patients, ages range from 26 to 40, who underwent conservative management using MPA (400-600 mg/day). RESULTS: In total, 19 patients underwent MPA therapy. The 18 (94%) patients achieved complete response (CR), and 1 (5%) patient achieved partial response (PR). Relapse occurred in 6 (32%) patients who had achieved CR. Of the patients who relapsed, 4 patients resumed MPA therapy and were in remission. Among 19 patients, 13 patients attempted pregnancy after CR. All of them underwent ovulation induction or assisted reproductive technology. As a result, 20 pregnancies in 10 (77%) patients and 12 live births in 9 (69%) patients were achieved. Rate of spontaneous abortion was 35% (7/20). CONCLUSIONS: MPA therapy can produce a high remission rate, and be considered an effective treatment for patients who wish fertility preservation. Around 70% patients who attempt to pregnancy can have at least one baby by infertility treatments. Because recurrence rate after MPA therapy is high, it may be desirable to aim for early pregnancy by active intervention.

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.

Hormone Therapy in Menopause.

As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).Local vulvovaginal and urinary symptoms, now termed genitourinary syndrome of menopause (GSM), are seen in 50% of postmenopausal women, and it negatively impacts quality of life. Estrogen remains the most effective treatment for both VMS and GSM, for osteoporosis prevention, and for symptom relief as well as chronic disease prevention in women who experience premature menopause whether from primary ovarian insufficiency (POI) or iatrogenic etiologies. For women who have contraindications to estrogen therapy or who personally object, a panoply of nonhormonal modalities can be offered to treat both systemic and local menopausal symptoms. A historical review of estrogen studies reveals why its persona has vacillated from hero to villain (after the WHI) and back to hero. The "timing hypothesis" and its underlying mechanism shed light on the pleiotropic nature of estrogen. Finally reviewed is the compelling argument from notable thought-leaders that estrogen, in those without contraindications, should be considered for primary prevention of cardiovascular disease as well as the prevention of chronic disease.

A Novel Animal Model of Induced Breast Precancerous Lesion in Tree Shrew.

Chinese tree shrew, an animal exhibited closer evolutionary relationship with humans compared to rodents, is getting increasingly attentions as an appealing experimental animal model for human diseases. However, a high-efficiency and stable method to establish tree shrew breast precancerous lesions model has not been clearly elucidated. Thus, the current study aimed to explore the way of establishing breast precancerous model in tree shrew and investigate the pathologic characteristics of induced breast precancerous lesions. The results indicated that 7,12-dimethylbenz(a)anthracene (DMBA) could induce breast lesions in tree shrews. However, comparing to DMBA alone, an addition of medroxyprogesterone acetate (MPA) to DMBA critically increased the rate of induced breast lesion in tree shrews. Half of induced breast lesions were intraductal papilloma and the others were atypical ductal hyperplasia. Induced lesions showed positive expression of estrogen receptor α (ERα), progesterone receptor (PR) and cytokeratin 5/6 (CK5/6), but negative expression of human epidermal growth factor receptor-2 (Her-2). The expression of B cell lymphoma-extra large (Bcl-xl) was significantly higher and the expression of B cell lymphoma 2 associated X protein (Bax) was significantly lower in the precancerous lesions (atypical ductal hyperplasia) compared to benign tumor (intraductal papilloma). These results suggest that DMBA is able to induce breast lesions in tree shrews. Combination of DMBA and MPA may be more effective to establish breast precancerous lesion tree shrew models. Tree shrew might be a promising animal model for studying the tumorogenesis of breast cancer.

Different progestin-primed ovarian stimulation protocols in infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection: an analysis of 1188 cycles.

PURPOSE: To evaluate the efficacy in suppressing the premature LH surge, embryo quality and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) protocols using medroxyprogesterone acetate versus utrogestan in women of all ages undergoing in vitro fertilization or intracytoplasmic sperm injection. METHODS: 1188 patients were enrolled in the retrospective study, of which 1002 patients were treated with medroxyprogesterone acetate (M group) and recombinant follicle-stimulating hormone (r-FSH)simultaneously from day 3 of the cycle until trigger day, while 186 patients were treated with utrogestan (U group) and r-FSH instead. Viable embryos were cryopreserved for later transfer in both groups. Differences in baseline characteristics, ovarian stimulation characteristics, endocrinological characteristics, embryo development and clinical outcome between two groups were assessed. Statistical analyses were performed stratified by age and number of oocytes retrieved. RESULTS: No significant differences were observed in the baseline characteristics, ovarian stimulation characteristics and clinical outcome of patients between groups. However, blastulation rate in the U group was significantly higher than that in the M group (49.4% vs. 32.9%, P < 0.001). During ovarian stimulation, LH levels remained steady in both groups. Higher percentage of premature LH surge was found in the U group (2.4% vs. 10.2%, P < 0.001), especially for patients aged more than 35 years or who had three oocytes or less retrieved. CONCLUSIONS: Both the administration of medroxyprogesterone acetate and utrogestan in PPOS were sufficient to prevent an untimely LH rise, while for patients with poor ovarian response or aged above 35 years, MPA may result in a more satisfactory LH level. PPOS protocol using medroxyprogesterone acetate or utrogestan was comparable in terms of oocytes and pregnancy outcome, whereas the administration of utrogestan may result in an improved blastulation than medroxyprogesterone acetate, which needs further exploration.

Medroxyprogesterone acetate-resistant endometrial cancer cells are susceptible to ferroptosis inducers.

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.

Quantitative thin layer chromatography for the determination of medroxyprogesterone acetate using a smartphone and open-source image analysis.

Intramuscular medroxyprogesterone acetate (MPA) products are commonly used to treat endometriosis and are the most widely used injectable contraceptives worldwide. Therefore, dependable quality screening of MPA injectables is a crucial measure necessary for ensuring that consumers are provided with safe and effective medications. Here, a thin-layer chromatography (TLC) method for MPA identification is combined with image analysis using a smartphone, 3D-printed light box, and open-source ImageJ software. The method's validation included two brands of MPA injectables, both at 150 mg mL-1 dosage. The TLC procedure used was based on the identity test found in The International Pharmacopoeia's Medroxyprogesterone injection monograph. Spots produced on the TLC plates were then photographed using a smartphone camera and quantified using ImageJ's image analysis software. The pixel data collected from each plate's standard spots were compared to the data generated from its sample spots. Data sets collected across multiple TLC plates and numerous days of method performance were evaluated to assess linearity, accuracy, precision, specificity, and robustness. Across the range of 75-125% of the target concentration, the method was found to have linearity of standard spots (with R2 generally greater than 0.99), overall accuracy of 101.0% (4.1% RSD), repeatability pooled standard deviation of 2.44%, intermediate precision pooled standard deviation of 3.68%, and observed demonstration of specificity and robustness. In low and middle-income countries (LMICs), quality screening of pharmaceutical products like MPA injectables can be challenging when testing resources are expensive, difficult to procure, or complex to utilize. The results of the TLC/ImageJ method validation suggest that this simple procedure that requires minimal resources may serve as a viable option for reliable quality screening of MPA levels in injectable suspensions.

Effectiveness of the flexible progestin primed ovarian stimulation protocol compared to the flexible GnRH antagonist protocol in women with decreased ovarian reserve.

The aim of this retrospective cohort study was to compare the effectiveness of the new flexible progestin primed ovarian stimulation (fPPOS) protocol with the flexible gonadotropin-releasing-hormone antagonist (GnRH-ant) protocol in women with decreased ovarian reserve (DOR). Twenty-seven women who underwent fPPOS and 54 age-matched women who received GnRH-ant for pituitary suppression were included in the study. All women had DOR and underwent oocyte cryopreservation. Three-hundred IU/day FSH was started on cycle day 2-3 and 0.25 mg/day GnRH-ant or 10 mg/day medroxyprogesterone acetate was started when the leading follicle reached 14 mm or serum oestradiol level was ≥200 ng/mL. The median duration of stimulation, day of commencing pituitary suppression and duration of suppression were similar in both groups, with 8, 5, and 5 days, respectively. The median number of cumulus-oophorous complexes (4.0 vs 5.5), metaphase-two oocytes (3 vs 4), the total number of oocytes cryopreserved (3.0 vs 4.5), and oocyte maturation rates (0.67 vs 0.70) were similar between the fPPOS and GnRH-ant groups, respectively. There was one case of premature ovulation in the fPPOS group and none in the GnRH-ant group (p = 0.91). In conclusion, fPPOS may be used in women with DOR without compromising the number of oocytes retrieved and seems a viable alternative to the flexible GnRH-ant protocol.

Impacts of medroxyprogesterone acetate on oocytes and embryos: matched case-control study in women with stage III-IV ovarian endometriosis undergoing controlled ovarian hyperstimulation for in vitro fertilization.

BACKGROUND: This study investigated the effects of medroxyprogesterone acetate (MPA) on the oocytes and embryos in patients with advanced endometriosis who had a normal ovarian reserve and tubal infertility and received controlled ovarian hyperstimulation (COH) and explored the characteristics and pregnancy outcomes in subsequent frozen-thawed embryo transfer (FET) cycles. METHODS: In this prospective controlled study, 150 advanced endometriosis patients involving 150 in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles and 163 FET cycles and 150 age-matched tubal infertility patients requiring 150 IVF/ICSI cycles and 115 FET cycles were recruited. Patients with endometriosis were sub-grouped into surgery group (n=102) (they were diagnosed with ovarian endometriomas and underwent 102 IVF/ICSI and 115FET cycles) and aspiration group (n=48) [they had ovarian "chocolate" cysts (>3 cm) that were aspirated and underwent 48 IVF/ICSI and 74 FET cycles]. RESULTS: Lower oocyte retrieval rate was noted in the endometriosis group than in the control group. Similar oocyte yield and peak estrogen (E2) level were found in two groups. The rates of mature oocyte, fertilization, cleavage, high-quality embryo, viable embryo, cancellation, implantation, and clinical pregnancy were similar between two groups. A higher oocyte yield was observed in the EMS cyst group than in the surgery group. CONCLUSIONS: The ovary response, oocytes, embryos and pregnancy outcome were not influenced by the advanced endometriosis and the use of MPA and also independent of endometrioma or cyst surgery.

MPA given orally during the first trimester for threatened miscarriage carries no specific risk for foetal abnormalities albeit the rate is higher than non-threatened pregnancies.

This observational study examines the outcomes of pregnancies arising in women referred for infertility, where those who experienced threatened miscarriage were treated with medroxyprogesterone acetate (MPA) tablets. The 14-year study period covers comprehensive real-time data entries into the validated electronic database including details of the infertility management, pregnancy outcomes and any foetal anomalies among the infants, each being tracked and recorded. Of 4057 clinical pregnancies, 1343 received MPA for threatened miscarriage; 934 (69.6 %) of which continued to livebirths. These were compared with the remaining 2714 clinical pregnancies without threatened miscarriage or MPA and which resulted in 2075 (76.5 %) livebirths. There were 134 developmental abnormalities recorded among the 3009 livebirths of which 78 (2.6 %) were categorised appropriate for the Western Australian Developmental Abnormalities Register; WARDA. These comprised 55 in the MPA group, 36 of which were categorised as serious (being 2.7 % of clinical pregnancies and 3.9 % of births). In the group without MPA, there were 79 abnormalities, of which 42 were categorised as serious (being 1.7 % of clinical pregnancies and 2.2 % of births). Specifically, there were no cases of androgenisation noted among the female infants. The abnormality rates were low overall and well within the annual WARDA ranges. We cautiously suggest that oral MPA can be considered for studies throughout pregnancy including the early first trimester to assess a potential role in reducing miscarriage, as well as advanced pregnancies to evaluate a potential role in reducing stillbirths and preterm delivery.

The 11α-hydroxylation of medroxyprogesterone acetate by Absidia griseolla var. igachii and Acremonium chrysogenum.

Medroxyprogesterone acetate (MPA) (1) has been transformed by two filamentous fungi, including Absidia griseolla var. igachii and Acremonium chrysogenum, into 11α-hydroxy-medroxyprogesterone acetate (2) as the major metabolite. The structure of the product was identified by different spectroscopic methods (1D- and 2D-NMR, EI-MS, and elemental analysis). Moreover, a time course study determined by HPLC showed 63% and 48% yields for the metabolite by using the two mentioned fungi, respectively. Finally, the effect of the temperature and concentration of the substrate were investigated, which the optimal fermentation conditions were found to be 25 °C with a substrate concentration of 0.1% (w/v). This study reports for the first time the production of 11α-hydroxy-medroxyprogesterone acetate as a fungal biotransformation product.

Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology.

OBJECTIVE: To determine whether a flexible progestin primed ovarian stimulation (fPPOS) protocol is effective for preventing premature ovulation. DESIGN: Retrospective cohort study. SETTING: Private assisted reproduction center. PATIENT(S): Eighty-seven oocyte donors and 191 recipients of fresh oocytes. INTERVENTION(S): Each donor was stimulated with a flexible gonadotropin-releasing hormone (GnRH) antagonist protocol in one cycle and with the new fPPOS protocol in the other, within a period of 6 months. FSH was started on cycle day 2-3, and 0.25 mg/day GnRH antagonist or 10 mg/day medroxyprogesterone acetate (MPA) was started on stimulation day 7 or when the leading follicle reached 14 mm, whichever came first. MAIN OUTCOME MEASURE(S): Duration of stimulation, gonadotropin consumption, duration of GnRH antagonist or MPA administration, number of metaphase II oocytes, and pregnancy rates in fresh oocyte recipients. RESULTS: Duration of stimulation was 11 (10-11) days in both groups. Total gonadotropin consumption was similar. Pituitary suppression was started on day 7 and lasted for 5 days in each group. There were no premature ovulations in any group. The fPPOS yielded a significantly higher number of cumulus oocyte complexes than GnRH antagonist cycles (33 [21-39] vs. 26 [18-36], respectively). Likewise, the fPPOS generated significantly more metaphase II oocytes than GnRH antagonist cycles (24 [17-34] vs. 21 [15-28], respectively). Recipients of fresh oocytes from fPPOS and GnRH antagonist cycles had similar cleavage, blastulation, implantation, and live birth/ongoing pregnancy rates (50% vs. 48.6%). CONCLUSION(S): FPPOS with MPA seems to be an effective choice for preventing premature ovulation in women undergoing ovarian stimulation without compromising oocyte quality.

Discordance between self-reported contraceptive use and detection of exogenous hormones among Malawian women enrolling in a randomized clinical trial.

OBJECTIVE: The objective was to assess the extent of concordance between self-reported contraceptive use and the presence of contraceptive progestins in serum. STUDY DESIGN: We evaluated self-reported contraceptive use by using radioimmunoassay to examine baseline serum levels of medroxyprogesterone acetate (MPA) and levonorgestrel (LNG) among 97 Malawian women enrolling in a contraceptive trial. RESULTS: Twelve percent (12/97) of study participants who reported no hormonal contraceptive use in the previous 6months had either MPA or LNG detected in their serum. CONCLUSIONS: The observed discordance between self-report and detection of exogenous hormones in serum indicates that caution is warranted when drawing conclusions based on self-reported contraceptive use.

Recurrence of cervical cancer and its resistance to progestin therapy in a mouse model.

Studies using K14E6/K14E7 transgenic mice expressing E6 and E7 oncoprotein of human papillomavirus type 16 (HPV16) have demonstrated that estrogen (E2) is required for the genesis and growth of cervical cancer. Our prior study using the same mouse model has showed that progestin drug medroxyprogesterone acetate (MPA) promotes regression of primary cervical cancer. In the present study, we use the same transgenic mouse model to determine whether the cancer recurs after MPA therapy. Cervical cancer recurred even if MPA treatment was continued. Unlike primary cervical cancer, the cancer recurred even in the absence of exogenous E2 when MPA treatment was ceased. Furthermore, recurrent cervical cancer did not fully regress upon MPA treatment. Our results support that MPA fails to completely eliminate primary cervical cancer cells and that remaining cancer cells grow independent of exogenous E2 and are refractory to MPA.

Treatment of endometrial hyperplasia with Medroxyprogesterone acetate(MPA) / 대한산부인과학회잡지

OBJECTIVE: To investigate the response of hyperplastic endometrium to Medroxyprogesterone acetate according to the histologic types such as simple typical, complex typical and atypical hyperplasia. METHODS: A total of 79 patients with histologically proved endometrial hyperplasia were enrolled into this prospective study between March 1996 and May 1998. Patients without atypia were placed on a regimen of cyclic therapy with 10mg MPA orally, each day for 14days per month for 3 months. In the cases in which hyperplasia did not regress , MPA was increased to 20mg. Patients with atypical hyperplasia received continuous MPA therapy, 20mg orally each day for 3 month. All patients were followed up for a minimum of 3 months and a maximum of 1 year(mean 7 months). RESULTS: In patients with simple typical hyperplasia, 45 patients(80.4%) had regression, 11 patients(19.6%) had persistence and none had progression. In patients with complex typical hyperplasia, 10 patients(83.3%) had regression, 2 patients(16.7%) had persistence and none had progression. But, in patients with atypical hyperplasia 5 patients(45.4%) had regression, 4 patients(36.4%) had persistence and 2(18.2%) patients had well differentiated endometrial adenocarcinoma. There was no recurrence during the follow up. CONCLUSION: This data suggest that most women with typical hyperplasia respond to progestin therapy, but there is high failure rate of response to progestin therapy and risk of endometrial cancer in patients with atypical hyperplasia. If the young patient desires to preserve her fertility, then progestin therapy may be considered as primary treatment in patients with atypical hyperplasia. But older patients in whom fertility is not an issue, hysterectomy should be selected as treatment of choice for atypical lesion.