The impact of medroxyprogesterone acetate on lipid profiles in Women: A time and dose-response meta-analysis of randomized controlled trials.

BACKGROUND: The effect of MPA on the lipid profile and CVD risk is still controversial; hence, this comprehensive dose-response meta-analysis of randomized controlled trials was conducted to assess the effect of MPA on lipid profiles in women. METHODS: A comprehensive search was conducted in the following databases: Web of Science, Scopus, PubMed/Medline, and Embase, up to October 20, 2023. A random-effects meta-analysis approach based on the DerSimonian and Laird method was used to compute the combined estimates of the intervention's impact on the lipid profile. RESULTS: 35 eligible studies with 58 arms were included in our meta-analyses analysis. Combined effect sizes suggested a significant effect of MPA on total cholesterol (TC) levels (WMD: -3.43 mg/dL, 95 % CI: -5.38 to -1.48, p < 0.001), HDL-C levels (WMD: -3.34 mg/dL, 95 % CI: -3.77 to -2.91, p < 0.001), and triglyceride (TG) levels (WMD: -9.13 mg/dL, 95 % CI: -10.92 to -7.33, p < 0.001). The subgroup meta-analysis revealed a more substantial reduction in TC in studies with dosages > 2.5 mg/day (WMD: -4.10 mg/dL), mean participant age lower than 60 years (WMD: -3.80 mg/dL), mean BMI lower than 25 kg/m2 (WMD: -5.61 mg/dL), duration of intervention of 12 months or more (WMD: -3.98 mg/dL), and when the baseline TC value was equal to or greater than 200 mg/dL (WMD: -4.13 mg/dL). CONCLUSIONS: The current meta-analysis showed a statistically significant decrease in TC, TG, and HDL-C levels and a non-significant increase in LDL-C levels after MPA administration in women.

Green Tea Extract has a Protective Effect on Leptin and Lipid Profile Levels Due to the Induction of Depot Medroxyprogesterone Acetate.

Background: Depot medroxyprogesterone acetate (DMPA) is a progesterone derivative synthesized in the laboratory. This substance has the ability to suppress ovulation, induce endometrial shrinkage, and even affect the hypothalamic-pituitary-gonadal axis in the reproductive system. Objective: The purpose of this study was to investigate the effects of administration of green tea extract on reducing visceral fat, increasing leptin levels, and improving the lipid profile in female rats injected with depot medroxyprogesterone acetate (DMPA). Results: This study was to look into the effects of green tea extract administration on visceral fat reduction, leptin levels, and lipid profile improvement as a result of DMPA administration. Analysis of HDL and LDL levels was performed by spectrophotometry. DMPA induced a significant increase in leptin levels compared with the control group (p 0.05). All doses of green tea extract can reduce this increase, with the highest doses reaching levels comparable to the control group (p > 0.05). DMPA significantly increased LDL levels compared to the control group (p < 0.05), and the highest green tea extract dose restored levels similar to the control group. DMPA triggered a decrease in HDL level that was significantly different from the control group (p < 0.05). The first dose of green tea extract can achieve HDL levels comparable to the control group (p > 0.05). Conclusion: It was concluded that green tea extract can protect the metabolic status through decreased leptin and an improvement of the lipid profile induced by DMPA.

MET Inhibits the Proliferation of EC Cells by Increasing MPA Sensitivity.

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.

Combinatory effects of current regimens and Guizhi Fuling Wan on the development of endometriosis.

OBJECTIVE: Endometriosis, defined as the growth of endometrial glands and stromal cells in a heterotopic location under the cyclic influence of ovarian hormones, is a common gynecological disorder manifested by chronic pelvic pain and infertility. In traditional Chinese medicine, endometriosis is characterized by stagnation of vital energy (qi) and blood stasis. Guizhi Fuling Wan (GFW) was first described in Chinese canonical medicine to treat disorders associated with stagnation of qi and blood stasis, including endometriosis. Therefore, the current study aimed to test the effects of combining GFW with western medicine on the suppression of endometriosis. MATERIALS AND METHODS: Endometriosis was generated by suturing endometrial tissue on the peritoneal wall of C57BL/6JNarl mice. The mice were subsequently treated with either GFW or current hormonal therapies or in combination for 28 days. RESULTS: Endometriosis development was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone or GFW + medroxyprogesterone acetate (MPA). The expression of intercellular adhesion molecule 1 (ICAM-1) was inhibited by GFW, Gestrinone, MPA, Visanne, GFW + Gestrinone, GFW + MPA and GFW + Visanne. Vascular endothelial growth factor (VEGF) expression was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone and GFW + MPA. Both ICAM-1- and VEGF-reducing effects of GFW were attenuated by western medicines. Administration of GFW, MPA, Visanne, GFW + MPA and GFW + Visanne also correspondingly reduced macrophage population in peritoneal fluid. GFW, MPA, Visanne, GFW + MPA and GFW + Visanne enhanced B-cell population in peritoneal fluid. CONCLUSION: The current study reveals the therapeutic effects of GFW on endometriosis. However, the combination of GFW and current hormonal therapies potentially impedes the efficacy of each individual agent in treating endometriosis.

Progestogen supplementation during superovulation leads to higher embryo viability and TGFB1 gene expression in sheep.

This study aimed to compare the effect of the administration of either medroxyprogesterone acetate (MPA) or progesterone (P4) in superovulation (SOV) treatments applied during the first follicular wave on follicular development, embryo yield, and the expression of genes related to pluripotency maintenance, differentiation of the trophectoderm, cell growth and differentiation, apoptosis and energy metabolism in sheep embryos. The estrous cycle of 36 multiparous ewes was synchronized with a short protocol, and the animals were randomly allocated to three groups. At the beginning of SOV, 12 ewes per treatment received an intravaginal sponge impregnated with 60 mg of MPA (TMPA), or an intravaginal device containing 0.33 g of P4 (TP4), or received no progestogen treatment (CON). The device was kept until the fifth dose of FSH. Ewes were mated with five fertile rams. Gene expression was performed by RT-qPCR using grade I and II blastocysts. The numbers of corpora lutea, total structures and viable embryos recovered per ewe were similar (P > 0.05) among groups. However, the viability rate was higher in TP4 (71.9 ± 16.3%) compared to CON (24.4 ± 16.8%; P = 0.01) and similar to TMPA (49.9 ± 16.3%; P = 0.2). Similarly, when compared with CON, treatment with P4 or MPA positively regulated the TGFB1 transcript involved in cell proliferation and differentiation (P = 0.01 and P = 0.03, respectively). In conclusion, supplementation with P4 during the first follicular wave of the estrous cycle improves embryo viability and alters the expression of the TGFB1 gene.

Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.

BACKGROUND: We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM). METHODS AND RESULTS: We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing. CONCLUSIONS: Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML.

Melatonin attenuates glucocorticoid effect induced by medroxyprogesterone acetate in rats.

Medroxyprogesterone acetate (MPA) acts on glucocorticoid receptors and, when it is in excess, can cause clinical disorders comparable to hyperadrenocorticism. Melatonin (MEL) is a hormone with potent antioxidant and anti-glucocorticoid activity and it can be beneficial in the excessive activation of glucocorticoid receptors. To evaluate the protective effects of MEL on the glucocorticoid effect of MPA, 34 male Wistar rats were randomized into four groups: CON (control), MEL, MPA, and MPA + MEL. The animals were treated for 28 days, by subcutaneous injection. At the high dose that we used, the MPA caused effects compatible with an excessive activation of glucocorticoid receptors, resulting on a reduction in adrenal size, less weight gain, lower final body weight and feeding efficiency, and fewer lymphocytes compared with the control group. In addition, there was an increase in abdominal fat, cholesterol, very-low-density lipoprotein (VLDL), triglycerides, erythrocytes, hemoglobin, hematocrit, and hepatic vacuolization. We concluded that MEL was effective reducing the mean values of total cholesterol, high-density lipoprotein (HDL), urea, VLDL, triglycerides, hepatic microvacuolization and abdominal fat/weight in rats treated with MPA. These findings indicate that MEL attenuates the harmful effects of MPA.

Ovulation induction with high progesterone levels may be more suitable for elderly patients with low ovarian response.

BACKGROUND: The objective of this study was to explore the outcomes of using the progestin-primed ovarian stimulation (PPOS) protocol in aged infertile women. The patients recruited in the study had displayed a poor ovarian response (POR) in the first IVF/ICSI-ET cycles with the ultra-short gonadotropin-releasing hormone agonist (GnRH-a) protocols. MATERIALS AND METHODS: A self-controlled retrospective study was conducted to investigate the clinical outcomes of 117 aged infertile women who met the inclusion criteria. The patients were grouped into two; group B included patients who had displayed a poor ovarian response (POR) in the first IVF/ICSI-ET cycle with the ultra-short GnRH-a protocol. Group A was made up of patients who underwent the PPOS protocol in the second cycle. The study was done between January 2015 to May 2018 in the reproductive and genetic centre of integrated traditional and western medicine, Affiliated hospital of Shandong University of traditional Chinese medicine. Reproduction-related clinical outcomes in the two groups were compared. RESULTS: There were no statistically significant differences in the serum levels of LH, E2, and P on the trigger day between group A and group B (P＞0.05). The number of follicles with a diameter > 14 mm was significantly higher in the PPOS protocol patients than in the ultra-short GnRH-a protocol group (4.83 ± 2.82 vs. 3.25 ± 2.53, P < 0.01). The duration and total dosage of gonadotropin of the PPOS protocol group were less than in the previous ultra-short GnRH-a protocol, although the statistical differences were not significant (P > 0.05). The number of eggs obtained in the PPOS group was significantly higher than that of the previous one (4.29 ± 3.11 vs. 2.76 ± 2.33, P < 0.05). The numbers of MII eggs, cleavage, 2 P N, transplantable embryos, and high quality embryos were higher in the PPOS protocol group than that in the ultra-short protocol group. However, the differences between the two groups in all the above parameters were not statistically significant (P > 0.05). The rate of high-quality embryos was significantly higher in the PPOS protocol group than in the ultra-short protocol group (38.61(100/259) vs. 32.02(65/203), P < 0.05). Although not statistically significant (P > 0.05), the abortion rate of the PPOS protocol group was higher than that of the ultra-short protocol group. The clinical pregnancy and live birth rates were significantly higher in the PPOS protocol group than in the ultra-short protocol group (p < 0.05). The clinical pregnancy rates in the PPOS protocol group and the ultra-short protocol group were 32.35 % and 25.53 % respectively while the live birth rates were 27.45 % and 21.28 % respectively. CONCLUSION: Compared with the ultra-short protocol, the PPOS protocol improves the number of follicles, the number of eggs, clinical pregnancy, and live birth rates in POR patients. The PPOS protocol could, therefore, provide a novel treatment strategy for inducing ovulation in POR patients.

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

Efficacy of a Herbal Formulation Based on Foeniculum Vulgare in Oligo/Amenorrhea: A Randomized Clinical Trial.

BACKGROUND: The aim of this study was to evaluate the efficacy of the herbal tea based on Foeniculum vulgare, on inducing regular bleeding in women with oligomenorrhea and secondary amenorrhea( oligo/amenorrhea). METHODS: Forty women aged 18- 40 with oligo/amenorrhea were enrolled in this randomized controlled clinical trial and were allocated to two groups equally. The women in the first group were treated by Fomentex (Foeniculum vulgare / Mentha longifolia / Vitex agnus-castus) herbal tea 11.2 g/day in 2 divided doses for 2 weeks and the second group were treated by medroxy progesterone acetate (MP)10 mg/day for the last 10 days of their menstrual cycles. The intervention was repeated in three cycles of menstruation in both groups. Bleeding pattern was documented by the patient on diary cards. The occurrence (yes/no) of bleeding, the regularity of bleeding pattern, the interval of cycles, the duration of bleeding, the volume of blood flow, the hormonal parameters (total testosterone, free testosterone luteinizing hormone and follicle-stimulating hormone), and the endometrial thickness in sonography before and after the intervention were evaluated and compared as outcomes. RESULTS: The number of women with bleeding during the first cycle was in the Fomentex group and the MP group 83.3% and 94.1% respectively (p = 0.61). The regularity of bleeding did not significantly differ in patients treated with Fomentex from those given MP (66.7% vs. 94.1%; p = 0.088). Mean interval of cycles decreased in both groups after intervention (P<0.001). Mean duration decreased significantly in MP group after the intervention but it was not different in patients treated with Fomentex. The difference between 2 groups was not significant (P=0.705). Volume of blood flow, with regard to Pictorial Blood Assessment Chart (PBAC), increased significantly in MP group after the intervention (P=0.001) and it was not different in patients treated with Fomentex (P=0.757); however, difference between 2 groups was not significant (P=0.063). The percentage of patients with on time menstruation in the next (drug-free) episode, was higher in the Fomentex group compared with the MP group (50% vs. 23.5%; p = 0.105). Secondary outcomes such as dysmenorrhea, acne and hirsutism reduced in the Fomentex group (P≤0.05), while they increased in the MP group (P=0.007). At the end of the treatment, there was a significant decrease in luteinizing hormone, total testosterone and free testosterone in patients taking Fomentex. The decrease of endometrial thickness, was significant in both groups after the intervention (P=0.001), but the difference between 2 groups was not significant (P=0.58). No notable complication or side effect was reported in relation to Fomentex. CONCLUSION: Fomentex herbal tea is a safe, well-tolerated, and effective choice in inducing bleeding and maintaining regular bleeding in women with oligo/amenorrhea.

Effects of omega-6/3 and omega-9/6 nutraceuticals on pain and fertility in peritoneal endometriosis in rats.

PURPOSE: To evaluate the effects of the nutraceuticals omega-6/3 and omega-9/6 on endometriosis-associated infertility and pain. METHODS: Controlled experimental study, with each group composed of eight female rats. Fertility groups: sham-operated control (0.9% saline solution); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); and meloxicam (0.8 mg/kg/day). Pain groups: sham-operated control (0.9% saline); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); medroxyprogesterone acetate (5 mg/kg/every 3 days); and meloxicam (0.8 mg/kg/day). Peritoneal endometriosis was surgically induced. Pain was evaluated with the writhing test. Fertility was evaluated by counting the number of embryos in the left hemi-uterus. RESULTS: The mean number of writhings was as follows: sham-operated, 11.1 ± 2.9; control with endometriosis, 49.3 ± 4.4; omega-6/3, 31.5 ± 2.7; omega-9/6, 34.1 ± 4.5; medroxyprogesterone acetate, 2.1 ± 0.8; meloxicam, 1 ± 0.3. There was a significant difference between both controls and all drugs used for treatment. Regarding fertility, the mean values were as follows: sham-operated, 6.8 ± 0.6; control with endometriosis, 4.2 ± 0.7; omega-6/3, 4.7 ± 1; omega-9/6, 3.8 ± 0.9; and meloxicam, 1.8 ± 0.9. CONCLUSIONS: The omega-6/3 and omega-9/6 nutraceuticals decreased pain compared to the controls. There was no improvement in fertility in any of the tested groups.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation.

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and ß-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth.

Comparison Of Cimicifuga foetida extract and different hormone therapies regarding in causing breast pain in early postmenopausal women.

This study aimed to compare the influence between Cimicifuga foetida extract and different hormone therapies on breast pain in early postmenopausal women. A prospective, randomized, controlled clinical trial was conducted among 96 early postmenopausal women. Participants were randomly assigned to three groups: group A received 1 mg/day estradiol valerate plus 4 mg/day medroxyprogesterone acetate on days 19-30; group B received 1 mg/day estradiol valerate plus 100 mg/day micronized progesterone on days 19-30; group C received C. foetida extract, 1talet (contains 33.3 mg extract), t.i.d. Breast pain diary and numerical rating scale was used to access the breast pain. For 6 months' treatment, the total incidence of breast pain in group A and B was significantly higher than that in group C (p < .05). The duration (day) of breast pain in each month decreased over time in group A and B while it was continuously low and without significant change in group C (p > .05). The intensity of breast pain was mild in most participants and did not differ among three groups (p > .05). During treatment of early postmenopausal women with C. foetida extract for 6 months, the incidence and duration of breast pain were lower than upon treatment with E2 plus cyclic MPA or m-P and did not change over time.

Effects of omega-6/3 and omega-9/6 nutraceuticals on pain and fertility in peritoneal endometriosis in rats

Abstract Purpose: To evaluate the effects of the nutraceuticals omega-6/3 and omega-9/6 on endometriosis-associated infertility and pain. Methods: Controlled experimental study, with each group composed of eight female rats. Fertility groups: sham-operated control (0.9% saline solution); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); and meloxicam (0.8 mg/kg/day). Pain groups: sham-operated control (0.9% saline); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); medroxyprogesterone acetate (5 mg/kg/every 3 days); and meloxicam (0.8 mg/kg/day). Peritoneal endometriosis was surgically induced. Pain was evaluated with the writhing test. Fertility was evaluated by counting the number of embryos in the left hemi-uterus. Results: The mean number of writhings was as follows: sham-operated, 11.1 ± 2.9; control with endometriosis, 49.3 ± 4.4; omega-6/3, 31.5 ± 2.7; omega-9/6, 34.1 ± 4.5; medroxyprogesterone acetate, 2.1 ± 0.8; meloxicam, 1 ± 0.3. There was a significant difference between both controls and all drugs used for treatment. Regarding fertility, the mean values were as follows: sham-operated, 6.8 ± 0.6; control with endometriosis, 4.2 ± 0.7; omega-6/3, 4.7 ± 1; omega-9/6, 3.8 ± 0.9; and meloxicam, 1.8 ± 0.9. Conclusions: The omega-6/3 and omega-9/6 nutraceuticals decreased pain compared to the controls. There was no improvement in fertility in any of the tested groups.

Influence of hormone therapy or C. foetida extract on breast tenderness in postmenopausal women.

OBJECTIVE: To evaluate the prevalence of breast tenderness in a population treated with menopausal hormone therapy (MHT) or Cimicifuga foetida extract. METHODS: A prospective, randomized, controlled trial was conducted. Ninety-six postmenopausal women were randomly assigned to three groups: group A, 1 mg estradiol valerate daily plus 4 mg medroxyprogesterone acetate (MPA), days 19-30; group B, 1 mg estradiol valerate daily plus 100 mg micronized progesterone (MP), days 19-30; group C, 100 mg C. foetida extract daily. Breast tenderness was evaluated daily for 12 months. RESULTS: Seventy-three patients completed the study. Group A had the highest prevalence of breast tenderness, while group C had the lowest. More than 50% of all participants reported no symptoms throughout the period. The participants in group A experienced a sharp increase in breast tenderness after treatment, but decreased after 1 month. No significant decline was found in the duration of pain in group B. The patients in group C reported no remarkable changes after 1 month. Compared to estrogen only, estrogen plus MPA/MP led to a higher incidence of prolonged breast symptoms. CONCLUSIONS: Compared to MHT groups, C. foetida extract had the lowest prevalence of breast tenderness. Most participants experienced mild or no symptoms.

Hypercalcemia after the Discontinuation of Medroxyprogesterone Acetate.

A 39-year-old woman was admitted to our hospital with symptoms of general fatigue, nausea, and vomiting that appeared three months after she stopped seven years of medroxyprogesterone acetate (MPA) medication for endometrial stromal sarcoma. Laboratory tests demonstrated moderate hypercalcemia. Several tests demonstrated that she was suffering from adrenal insufficiency. Glucocorticoid supplementation decreased her calcium level to a normal range, indicating that hypercalcemia was induced by adrenal insufficiency. It was suggested that she was suffering from MPA-induced adrenal insufficiency, but hypocortisolemia was being compensated by a high dose of MPA; hypocortisolemia and hypercalcemia then became evident after MPA treatment was discontinued.

Efficacy and safety evaluation of Cimicifuga foetida extract in menopausal women.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of long-term treatment with Cimicifuga foetida extract in menopausal women. METHODS: A prospective, randomized, controlled clinical trial was conducted. A total of 96 early postmenopausal women were randomly assigned to three groups: group A received 1 mg estradiol valerate daily plus 4 mg medroxyprogesterone acetate on days 19-30; group B received 1 mg estradiol valerate daily plus 100 mg micronized progesterone on days 19-30; group C received 100 mg C. foetida extract daily. The efficacy was evaluated. Safety parameters were recorded. RESULTS: A total of 81 patients completed the treatment and follow-up visit. The modified Kupperman Menopausal Index scores decreased after 3 months in all groups. No significant changes were observed in the liver, renal function and components of metabolic syndrome in group C (p > 0.05). There were no significant differences in the incidences of metabolic syndrome among the three groups (p > 0.05). After 24 months, the endometrial thickness increased significantly in group B (p = 0.014), but not in the C. foetida extract group (p > 0.05). CONCLUSIONS: C. foetida extract is safe and effective for the treatment of menopausal symptoms in postmenopausal women.

Contraception, pregnancy, and peripartum experiences among women with epilepsy in Bhutan.

INTRODUCTION: Reports on the reproductive health of women with epilepsy (WWE) in low- and middle-income countries (LMICs) are limited. Bhutan is a lower income country with a high estimated prevalence of epilepsy and no out-of-pocket payment requirements for health visits or medications. METHODS: We developed a 10-category survey to interview WWE ages 20-59 years in the Kingdom of Bhutan to understand their contraceptive use and peripartum experiences. WWE were recruited from 2016-2017 from an existing epilepsy cohort and their reproductive health data were merged with epilepsy and socioeconomic data obtained from initial clinical evaluations performed between 2014 and 2016. RESULTS: Of the 134 WWE eligible for the study, 94 were reachable and there was 1 refusal to participate (response rate 99% among reachable WWE; 69% of all WWE in the cohort). Of the 93 WWE (median age 27 years, range 20-52), 50 (54%) reported prior pregnancies. Of the entire cohort, 55 women responded on contraception: 26 (47%) WWE had never used contraception in their lifetime. Of the 29 WWE who had ever used contraception, the most commonly reported form was male condoms (14/29, 48%), followed by depot medroxyprogesterone acetate injections (13/29, 45%), and intrauterine devices (5/29, 17%). Sixty-three percent of WWE recalled receiving information on family planning (31 of 49). Of the 50 WWE with prior pregnancies, 37 of 46 (80%) used folic acid; 6 WWE reported commencing it in the first trimester while 29 WWE began supplementation in the second trimester. Primary school education or higher was associated with folic acid supplementation during pregnancy (26/29 vs. 11/17, p=0.040). Epilepsy affected at least one of the pregnancies in 38 of the cases (76%) with an average of 2.3 pregnancies per woman). There was a total of 86 pregnancies and an average inter-pregnancy interval of 3.5 years. Ninety-five percent of women attended prenatal care (36/38), 22% had at least one miscarriage (8/37), 14% had at least one pre-term delivery (5/36), and 21% had Caesarean sections (8/38). Seventeen of 38 (45%) of WWE had seizures during pregnancy. A majority of WWE (97%, 37 of 38) with a prior pregnancy reported breastfeeding their infant. CONCLUSIONS: Nearly half of Bhutanese WWE did not use contraception; among those who used it, male condoms were most common but 11% were at risk of potential drug-drug interactions between oral contraception and enzyme-inducing antiepileptic drugs. Bhutanese WWE had a high rate of prenatal visits. Folic acid was prescribed in most pregnant WWE but the majority began supplementation in the second trimester. The number of pregnancies in WWE in Bhutan (2.3 per woman) was comparable to the number of children per women in Bhutan (2.3). Breastfeeding was practiced almost universally. Points of intervention may include pre-conception initiation of folic acid, optimization of dosing of AEDs with contraceptives, guidelines for peripartum seizure treatment, and establishment of a prospective registry for WWE and their offspring.

Acceptability of the community-level provision of Sayana® Press by medical and nursing students in Kinshasa, Democratic Republic of the Congo.

OBJECTIVES: The objectives were to assess acceptors' attitudes toward Sayana® Press as a method and toward the mechanism of community-based distribution by medical and nursing (M/N) students, known locally as "DBCs," in Kinshasa, Democratic Republic of the Congo, and to evaluate the experience of these DBCs. STUDY DESIGN: In 2015, surveys were conducted among (1) acceptors of Sayana® Press on the day of the initial injection, (2) these same acceptors 3 months later and (3) the DBCs providing community-based services. The analysis was descriptive and involved no significance testing. RESULTS: Acceptors of Sayana® Press expressed high levels of satisfaction with the method, despite some pain experienced at injection and subsequent side effects. Although most were satisfied with the counseling and services received from the DBCs, less than one third realized that the providers were M/N students. The DBCs expressed satisfaction in serving as community-based distributors; more than 95% would recommend it to others. Their primary complaints were lack of remuneration, stockouts and need for greater supervision. CONCLUSIONS: Consistent with results from previous pilot introductions of Sayana® Press in three African countries, clients were highly satisfied with Sayana® Press as a method. The reported preference for resupply at health centers may reflect a lack of client awareness that the DBCs administering methods near the health center were not in fact staff from the health center. The pilot served to gain acceptance for the use of M/N students in community-based distribution, paving the way for additional task-shifting pilots in Kinshasa. IMPLICATIONS: Sayana® Press represents a promising new method for increasing access to modern contraception in low-income countries. The Kinshasa experience is the first to test the use of medical and nursing students as providers at the community level. The study reports high levels of satisfaction on three counts: acceptors of the contraceptive method, acceptors of the mode of service delivery, and DBCs in their role as providers of contraception at the community level. However, many clients were not aware that the DBCs were students. The study represents an important contribution to the literature on task-shifting, especially in a country with chronic shortages of healthcare personnel.

Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial.

OBJECTIVE: To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C). RESULTS: Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03). CONCLUSION: Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.