High-dose Progesterone Research Articles

High Dose Progesterone Loaded PCL‐Polysorbate 80 Transdermal Fibers for Potential Application in Gynecological Oncology

AbstractProgesterone (P4), commonly administered in high doses for endometrial cancer palliative management, has limitations in current delivery systems. This preliminary in vitro drug release study introduces electrospun patches to offer a new perspective on P4 delivery. The study aimed to assess the influence of the surfactant polysorbate 80 (PS80) on the release of P4 from polycaprolactone (PCL) fibers. The PS80 effects are examined to inform the fine‐tuning of the fibre generation process. Patches developed, PCL wet (with PS80) and PCL dry (without PS80), showed encapsulation efficiencies of 76% and 42%, respectively. The dose levels studied are 6.1 mg for PCL wet and 4.4 mg for PCL dry samples. Molecular studies show that higher surfactant levels improved P4‐polymer mixing, enhancing dissolution and release rates. Patches with PS80 released 66% of the drug in 17 h, while those without released only 51%. Release data best fit the Weibull model, showcasing promise for these patches in transdermal P4 delivery. This study offers a non‐invasive option compared to traditional methods and underscores the need for further research to confirm the patches' clinical effectiveness for potential use in gynecological oncology.

Progesterone-Induced Hyperphagia is Attenuated by <i>Myrica nagi</i> through Dopaminergic and Serotonergic Modulation in Female Mice

Regulation of feeding behavior to control obesity is an alternative line of research for the treatment of obesity and diabetes. Compared to other models of obesity, the progesterone-induced obesity model is more specific to the female population; it focuses on the eating behavior and behavioral and emotional changes associated with progesterone. We aimed to study the changes in feeding behavior upon progesterone administration and the effects of Myrica nagi Thunb (Myricaceae) extracts on these changes. Further, this study aimed to provide insights into the progesterone-induced hyperphagia modulated by serotonergic and dopaminergic systems. In this study, experimental obesity was induced in female mice by treating with a high dose of progesterone for 28 days (sub-chronic study) followed by the assessment of parameters such as food consumption behavior, behavioral parameters including ambulatory movements, rearing, and grooming, and biochemical parameters such as lipid profile (total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein), liver parameters (alkaline phosphatase and serum glutamic pyruvic transaminase), serotonin and dopamine levels, and liver histopathology. The sub-chronic administration of progesterone, via the subcutaneous route, induced significant hyperphagia and promoted fat accumulation. Even though we did not find significant differences in food intake between mice in the control group and progesterone-treated groups, the final weight in the progesterone-administered groups increased, signifying the impact of this progesterone-induced obesity model. Treatment with MEMN extract reversed the progesterone-induced effects suggesting that herbal extracts can be exploited as serotonergic and dopaminergic agents for the treatment of progesterone-induced eating disorders, especially in the female population.

The effects of gonadal hormones on heroin Self-Administration in male gonadectomized rats.

Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement.Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75mg, sc), estradiol (0.0005 or 0.005mg, sc), progesterone, (0.0125 or 0.125mg, sc), or their vehicles. After 14days of chronic treatment, a dose-effect curve was determined for heroin (0.0003-0.03mg/kg/infusion) over the course of one week. Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder.

Abstract CT044: KGOG2031 A phase II trial of repeated high dose luteal hormone therapy for intrauterine recurrence following fertility preserving therapy for atypical endometrial hyperplasia or endometrial cancer

Abstract Background: Atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) are common disease in menopausal women, however, are gradually increasing in women aged under 40 years. The standard treatment for AEH/EC is hysterectomy, but hormonal therapy is performed for preserving fertility. In general, fertility-preserving treatment is considered for AEH or EEC with well-differentiation and lesions confined to the endometrium without myometrial invasion. According to previous studies, hormonal therapy in these patients responded relatively well. Nevertheless, recurrence was not uncommon, accounting for 26.0% in AEH and 40.6% in EC. The standard treatment for these recurrent patients is hysterectomy, but if there is no myometrial invasion and no extrauterine lesions, repeated hormonal treatment can be considered. However, studies targeting these patients have been very scarce. The purpose of this study was to evaluate the efficacy and safety of high-dose progesterone therapy in recurrence following fertility preserving therapy for AEH or EEC. Methods: KGOG2031 is a multi-center and prospective phase 2 trial. The primary endpoint is a 2-year disease free survival. The secondary endpoints were duration of disease-free survival, overall survival, response rate, adverse events, and infertile rates. Patients with recurrent AEH or EEC without myometrial invasion or extrauterine lesions who underwent high-dose MPA therapy for primary lesions were included. The inclusion criteria are limited to patients with less than two recurrences. The pathologic type for EEC was confined to endometrioid type. The patients should be confirmed histologically at least one complete remission after first treatment. Patients with myometrial invasion, cervical involvement, or extrauterine lesions observed on abdominal/chest computed tomography or pelvic magnetic resonance imaging were excluded. Furthermore, grade 2 or 3 of endometrioid or any grade of other pathologic type of endometrial cancer or non-atypical endometrial hyperplasia were excluded. The enrolled patients should take medroxyprogesterone acetate 500mg every day. D&CB will be performed after anesthesia every 8 weeks to determine the effectiveness, and treatment will be continued for up to 40 weeks until complete remission is achieved. The target number of enrollment is 115 cases, and the recruitment period is 3 years. The follow-up duration is 2 years after the end of treatment, and the total study duration was up to 5 years. Citation Format: Min Kyu Kim, Yung-Taek Ouh. KGOG2031 A phase II trial of repeated high dose luteal hormone therapy for intrauterine recurrence following fertility preserving therapy for atypical endometrial hyperplasia or endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT044.

Direct Effects of Mifepristone on Mice Embryogenesis: An In Vitro Evaluation by Single-Embryo RNA Sequencing Analysis

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Prognosis of direct pregnancy in untreated atypical endometrial hyperplasia: a case report.

An increasing number of atypical endometrial hyperplasia (AEH) or endometrial cancer (EC) patients with fertility requirements choose conservative management, such as oral high-dose progesterone. Most of them use assisted reproductive technology (ART) to become pregnant after experiencing remission. However, the outcome of pregnancy is not ideal, probably because of long-term drug application in large doses or invasive uterine cavity treatment. We presented a case of AEH who underwent direct pregnancy with good results without any treatment for her pathological endometrium. We described her endometrial histological results pre-and post-pregnancy in detail, hitherto absent from reports on this topic. Patients with a strong desire to bear children at the time of an AEH diagnosis could consider taking 1-2 years to try a pregnancy before treating their AEH.

Progesterone Induces Apoptosis and Steroidogenesis in Porcine Placental Trophoblasts.

Simple SummaryThis study investigated the effects of progesterone treatment in vitro on apoptosis and steroidogenesis in porcine placental trophoblasts and the underlying molecular mechanisms. Trophoblasts were treated with different concentrations of progesterone for 48 h. Cell counts, steroidogenesis, and relevant gene and protein expression levels were measured. Progesterone inhibited trophoblast proliferation in a dose-dependent manner. High doses of progesterone significantly altered the expression levels of apoptosis-related and steroidogenesis-related genes and proteins, while low doses had a less pronounced effect. Thus, increased progesterone induces the apoptosis of porcine placental trophoblasts and induces abnormal steroidogenesis in the placenta. We believe that our study makes a significant contribution to the literature because it elucidates the effects of progesterone on porcine placental trophoblast functions.Placentation and placental steroidogenesis are important for pregnancy and maternal–fetal health. As pregnancy progresses, the main site of progesterone (P4) synthesis changes from the corpus luteum to the placenta, in which placental trophoblasts are the main cell type for P4 synthesis. Therefore, this study investigated the effects of P4 on apoptosis and steroidogenesis in porcine placental trophoblasts and the underlying molecular mechanisms. Porcine placental trophoblasts were treated with different concentrations of P4 for 48 h in a serum-free medium in vitro. Cell number, steroidogenesis, and relevant gene and protein expression levels were detected. A high dose of P4 (10.0 μM) significantly increased P4 (p < 0.01), androstenedione (p < 0.05), testosterone (p < 0.05), and estradiol (p < 0.05) production in porcine placental trophoblasts compared with that in control cells, while a low dose of P4 (1 × 10−3 μΜ) had no marked impact on steroid production. The mRNA expression of apoptosis-related genes (CASP3, CASP8, and Bax) (p < 0.05) and steroidogenesis-related genes (CYP11A1, CYP19A1, and StAR) (p < 0.01) was upregulated, and the expression of HSD3B and HSD17B4 was inhibited (p < 0.05) in the porcine placental trophoblasts treated with high doses of P4. Low doses of P4 had a lighter effect on gene expression than high doses. The expression of apoptosis-related proteins CASP3 (p < 0.05), and Bax (p < 0.01) and steroidogenesis-related proteins CYP19A1 (p < 0.05) and StAR (p < 0.01) was raised, but the proliferation-related protein CCND2 (p < 0.01) was downregulated in the pTr cells treated with high dose of P4. In comparison, a low dose of P4 inhibited the expression of Bax, CYP11A1 (all p < 0.01), and CCND2 (p < 0.05), but the expression of CASP3 (p < 0.05) and StAR (p < 0.01) was upregulated. In summary, excessive P4 can induce the apoptosis of porcine placental trophoblasts and lead to abnormal steroidogenesis in the placenta and hormone imbalance.

Woman With Dysmenorrhea

A 30-year-old nonpregnant woman presented to the emergency department for a 1-month history of worsening lower abdominal cramping and intermittent vaginal bleeding. She had initiated a high-dose progesterone contraceptive a few months ago. Immediately before presentation, she discharged a mass of blood and tissue (Figure 1). She denied pregnancy, trauma, recent surgery or instrumentation, or the possibility of infection. She was afebrile, and other vital signs were normal; physical examination demonstrated a nontender abdomen; pelvic examination showed no source of vaginal bleeding.

Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer

SummaryProstate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens. In this study, mass-spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients. High doses of progesterone activate canonical and non-canonical androgen receptor (AR) target genes. Physiological levels of progesterone facilitate cell proliferation via GATA2. Inhibitors of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) has been discovered and shown to suppress the generation of progesterone, eliminating its transient and accumulating oncogenic effects. An increase in progesterone is associated with poor clinical outcomes in patients and may be used as a predictive biomarker. Overall, we demonstrate that progesterone acts as an oncogenic hormone in prostate cancer, and strategies to eliminate its oncogenic effects may benefit prostate cancer patients.

The optimal time for the initiation of in vitro fertilization and embryo transfer among women with atypical endometrial hyperplasia and endometrial carcinoma receiving fertility-sparing treatment.

To explore the optimal time for initiating in vitro fertilization and embryo transfer (IVF-ET) in women with complete remission after fertility-sparing treatment for grade I endometrial cancer (EC) or atypical endometrial hyperplasia (AEH). Young women who demonstrated complete remission after fertility-sparing treatment for grade I EC or AEH and underwent IVF-ET treatment were included. A generalized estimating equation (GEE) was used to compare the outcomes of controlled ovarian hyperstimulation (COH) and embryo transfer at different times after discontinuing high-dose progesterone therapy, and patients were divided into three groups: ≤ 3months (time 1), 3-9months (time 2) and > 9months (time 3). Thirty-seven women with complete remission after fertility-sparing treatment for grade I EC or AEH underwent 75 IVF-ET cycles. Regarding initiation of COH, 10 cycles for time 1, 31 cycles for time 2 and 34 cycles for time 3 were included. The odds ratios (95% confidence intervals) for the number of available embryos at time 2 and time 3 were 1.82 (1.08-3.08) and 2.45 (1.39-4.33), and those for the number of high-quality embryos at time 2 and time 3 were, respectively, 3.64 (1.34-9.87) and 3.62 (1.10-11.91), compared with that at time 1. Nineteen (51.4%) women had at least one clinical pregnancy and 13 (35.1%) women had live births. During a median follow-up period of 51months (range 5-168months), 10 (27.0%) women had disease relapse, with a median interval of 15.5months (range 5-104months). Initiating IVF-ET 3months after ceasing high-dose progesterone therapy can lead to better outcomes of controlled ovarian hyperstimulation for women with endometrial cancer or atypical endometrial hyperplasia.

Prenatal exposure to exogenous progesterone adversely affects fetal development in Albino rats

BackgroundThe current study was carried out to investigate the effects of exogenous progesterone on fetal development in rats.ResultsPlacental weights did not vary in control and treated groups. Fetal weights were significantly reduced in the low- and high-dose progesterone groups. Fetal CVL was significantly reduced in both treatment groups compared to control group. In fetuses that received maternal treatment with low- and high-dose progesterone, several parts of the fetal skeleton showed incomplete ossification. Alkaline phosphatase was decreased in the bones of fetuses born to progesterone-treated dams. The testes and ovaries of the fetuses of the dams treated with low and high doses of progesterone showed degenerative seminiferous tubules and failed sex cord development into primordial follicles, respectively.ConclusionsThe administration of exogenous progesterone during pregnancy adversely influences fetal growth, skeletal construction, and sex organ development.

The inadequate corpus luteum.

SummaryThe corpus luteum is the source of progesterone in the luteal phase of the cycle and the initial two-thirds of the first trimester of pregnancy. Normal luteal function is required for fertility and the maintenance of pregnancy. Progesterone administration is increasingly used during fertility treatments and in early pregnancy to mitigate potentially inadequate corpus luteum function. This commentary considers the concept of the inadequate corpus luteum and the role and effects of exogenous progesterone. Progesterone supplementation does have important beneficial effects but we should be wary of therapeutic administration beyond or outside the evidence base.Lay summaryAfter an egg is released a structure is formed on the ovary called a corpus luteum (CL). This produces a huge amount of a hormone called progesterone. Progesterone makes the womb ready for pregnancy but if a pregnancy does not happen the CL disappears after 12–14 days and this causes a period. If a pregnancy occurs, then the pregnancy hormone (hCG) keeps the CL alive and its progesterone supports the pregnancy for the next 6–8 weeks until the placenta takes over and the corpus luteum disappears. That means that if the CL is not working correctly there could be problems getting pregnant or staying pregnant. If a CL is not producing enough progesterone it usually means there is a problem with the growing or releasing of the egg and treatment should focus on these areas. In IVF cycles, where normal hormones are switched off, the CL does not produce quite enough progesterone before the pregnancy test and extra progesterone is needed at this time. In recurrent or threatened miscarriage, however, there is not any evidence that the CL is not working well or progesterone is low. However, there is benefit in taking extra progesterone if there is bleeding in early pregnancy in women with previous miscarriages. This might be because of the effects of high-dose progesterone on the womb or immune system. As changes to the hormone environment in pregnancy may have some life-long consequences for the offspring we have to be careful only to give extra progesterone when we are sure it is needed.

Differential regulatory effect of progesterone on the proliferation and apoptosis of uterine leiomyoma tissue explants and primary leiomyoma cell cultures.

ObjectiveThe growth of uterine leiomyomas is regulated by progesterone, although the underlying molecular mechanisms are not fully understood.MethodsPrimary leiomyoma cells were isolated by standard method from 16 samples of uterine leiomyoma tissue. Uterine leiomyoma explants and primary leiomyoma cell cultures were exposed to progesterone in concentrations of 0.01 µg/ml, 0.1 µg/ml and 1 µg/ml for 24 h. Cell apoptosis was assessed with Annexin V assays performed in cell cultures by flow cytometry. The expression of PR-A, PR-B, Ki67, Akt, ERK, PTEN and PPARγ mRNAs was estimated in cultured leiomyoma cells and tissue explants by real time RT-PCR.ResultsTreatment with progesterone promoted viability and proliferation of cultured leiomyoma cells in a dose-dependent manner. Low and high doses of progesterone decreased early apoptosis of leiomyoma cells. High concentrations of progesterone increased the number of living cells in Annexin V assays. High doses of progesterone increased the expression of Ki67 mRNA, while low doses increased the expression of PR-A mRNA in cultured leiomyoma cells and tissue explants. In cell cultures, low doses of progesterone increased the expression of PR-B mRNA and the expression of PTEN and PPARγ mRNAs in a dose-dependent manner. Exposure of leiomyoma tissue explants to progesterone led to increased expression of PR-B and ERK mRNAs in a dose-dependent manner.ConclusionsThe effects of progesterone on the apoptosis and proliferation of leiomyoma cells was dose-dependent and different in cell cultures and leiomyoma explants, possibly as a result of impacts derived from the tumor microenvironment.

Benign leiomyoma with multiple metastases to vertebrae and calvarium: An index case with comprehensive review of endocrine targets

"Benign" metastatic leiomyomas (BML) are indolently growing metastatic tumors which mostly associate with uterine leiomyomas in women in reproductive ages. The reason to define these lesions as "benign" despite metastasis is their pathological features with low mitotic counts, lack of or minimal nuclear atypia, pseudocyst formation, and coagulative necrosis unlike leiomyosarcomas. Despite lack of pathological malignant features, they may cause significant morbidity and even mortality. Here, we describe a BML case with metastases to vertebrae and skull bones. Vertebral and skull metastases of BMLs were very rarely reported. In treatment of these tumors, hysterectomy and GnRH modifier treatments are widely employed. GnRH agonists act by desensitization and downregulation of the GnRH receptors, while GnRH antagonists act via the canonical competitive blockage. These treatments reduce FSH and LH levels, thereby reducing the systemic levels of sex steroids which stimulate leiomyoma growth. However, leiomyomas inherently harbor aromatase activity and synthesize their own estrogen; hence, treatment with systemic estrogen antagonists may provide better tumor control. Another important factor in BML pathogenesis is progesterone, and both progesterone receptor antagonists and high-dose progesterone receptor agonists may reduce BML growth. Following surgical treatment of the calvarial mass and radiotherapy of the vertebral metastatic foci, our BML case was successfully managed with hysterectomy and anastrozole treatment. Higher awareness of BML cases and their molecular endocrinological features in the neurosurgical community may pave to develop better strategies for treatment of these tumors causing high morbidity.

Effect of progesterone on the pathogenesis and development of hemangioma in nude mice

To explore the role of progesterone in the pathogenesis and development of hemangioma in nude mice. Methods: The hemangioma model was established. Progesterone was injected intramuscularly at different doses (0.2, 0.4, and 0.8 mg/d) for one week. Camellia oil (0.4 mL/d) was injected intramuscularly as control. The size of hemangioma was observed dynamically. The subcutaneous implants were harvested on the 14th and 28th days. The expression of vascular endothelial growth factor in the tumor tissues were evaluated using immunohistochemistry and microvessel density (MVD) was counted under the microscope. Results: On the 14th day, the expression of vascular endothelial growth factor (P<0.01 and P<0.05, respectively) was higher, the volume of tumors (All P<0.01) and MVD (All P<0.01) were greater in the high-dose progesterone group than those in the control and low-dose progesterone group. On the 28th day, there was no significant difference in the volume of tumors among 4 groups (P>0.05). The expression of vascular endothelial growth factor (P<0.01) was lower, and MVD (All P<0.05) were less in the middle-dose and high-dose progesterone group than those in the control and low-dose progesterone group. Conclusion: Progesterone promotes angiogenesis via upregulation of vascular endothelial growth factor expression, promotion of hemangiomas proliferation, suggesting that excessive progesterone supplementation may be one of the initial factors for early hemangioma formation.

Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus

Female sex hormone, progesterone, in addition to seizure modifying activity is also known as a potential protective agent against various brain injury conditions. Considering the predisposal role of traumatic brain injury (TBI) on developing post-traumatic epilepsy (PTE), the effect of progesterone on post-traumatic epileptogenesis is not investigated yet. Male Wistar rats were given a moderate focal weight drop injury (500 gr) or sham surgery and then progesterone (16 and 32mg/kg) was given daily for two consecutive weeks. On day 15 of injury, seizures were induced by administration of a GABAA receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale.Traumatized animals that received 32 mg/kg progesterone had reduced score, duration of seizures and almost did not show tonic-clonic seizures during 60 min versus the untreated trauma group. In line with behavioral alterations, 32 mg/kg progesterone enhanced the amount of Nrf2 and HO-1 proteins and decreased the level of NF-kB, BDNF, Caspase 3 and ratio of Bax/Bcl-2 in the ipsilateral hippocampus. Additionally, the number of TUNEL-positive apoptotic cells, as well as injured dark neurons in the parietal cortex and hippocampal CA1 of 32 mg/kg-treated animals showed a significant reduction. Administration of 16 mg/kg progesterone elevated production of BDNF, Bax and Caspase 3 and decreased anti-apoptotic Bcl-2 protein. Taken together, an early administration of 32 mg/kg of progesterone after TBI for two weeks post-injury modified seizure activity.Our findings suggest that post-traumatic anti-epileptogenesis property of a high dose of progesterone partly occurs through the manipulation of BDNF-TrkB axis along with control of cell survival pathways.

Progesterone Treatment Attenuates Glycolytic Metabolism and Induces Senescence in Glioblastoma

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which control glycolytic metabolism through upstream PI3K/Akt/mTOR signaling in GBM. In addition, progesterone administration attenuated EGFR/PI3K/Akt/mTOR signaling, which is highly activated in grade IV GBM. High-dose progesterone also induced senescence in GBM as evidenced by changes in cell morphology and β-galactocidase accumulation. In conclusion, progesterone inhibits the modulators of glycolytic metabolism and induces premature senescence in GBM cells and this can help to reduce/slow tumor progression.

Do High Dose Progesterone Levels Affect Clinical Pregnancy Rates in Freeze-All Cycles?

Do High Dose Progesterone Levels Affect Clinical Pregnancy Rates in Freeze-All Cycles?

Fertility-preserving treatment of stage IA, well-differentiated endometrial carcinoma in young women with hysteroscopic resection and high-dose progesterone therapy

ObjectiveThe standard treatment for endometrial cancer is surgery with hysterectomy. However, this procedure will cause infertility in young women who desire to preserve pregnant ability. Conservative management with hormone therapy has been shown to be satisfactory in both tumor control and fertility preservation. Recently, hysteroscopic tumor resection followed by progestin therapy has been reported to be an alternative strategy. In this study we present our experience with this approach. Materials and methodsSix young patients (30–36 years old) diagnosed with grade 1 stage IA endometrial cancer who wished to preserve fertility were enrolled for this treatment procedure. The patients underwent hysteroscopic tumor resection followed by oral progestin therapy with either megestrol acetate or medroxyprogesterone acetate for at least 6 months. Interval hysteroscopy with biopsy was performed during the treatment course to evaluate disease response. ResultsAll of the six patients had complete tumor remission after hysteroscopic resection and progestin therapy (five in 6 months, one in 9 months). In a median follow-up of 32 months (range 4–49months), one patient became pregnant spontaneously and delivered a full-term healthy baby via cesarean section. She received a definite surgery 3 months later, and the pathology confirmed no tumor existence. The other five patients were also free of disease at the last follow-up. ConclusionHysteroscopic tumor resection followed by progestin therapy for early-stage and well-differentiated endometrial cancer is a safe conservative treatment strategy. It could be an option for young patients who wish to preserve fertility.

Solid state behavior of progesterone and its release from Neusilin US2 based liquisolid compacts

The aim of present work was to investigate the role of liquisolid technique in improving dissolution of high dose Progesterone. Progesterone-PEG 400 dispersions were prepared and evaluated for technological properties, and further formulated into liquisolid tablets using Neusilin US2 and Syloid 244 FP as a carrier and coat respectively. Due to polymorphic behavior of Progesterone, liquisolid tablets were investigated by XRPD, DSC and SEM, whereas, improvement in dissolution was studied by in vitro technique. Results of liquid load factor and liquid retention potential demonstrated a role of Neusilin US2 and Syloid 244 FP as a superior carrier and coat material respectively. Both excipients enabled incorporation of higher amount of liquid medication and high Progesterone loading (50 mg). Acceptable flowability and compressibility of liquisolids were noted, uncompromising tablettability and tablet size. Noteworthy findings of XRPD and DSC suggested polymorphic transition of Progesterone from stable α to metastable β form in liquisolid formulation having high liquid medication. Consequently, superior dissolution profiles for liquisolid tablets, compared to conventional tablet were noted. Hence, it can be concluded that, liquisolid tablets of high dose progesterone were successfully formulated using Neusilin US2 and Syloid 244 FP. Besides improved dissolution, polymorphic transition was also revealed for Progesterone.