Role of suppression of endometriosis with progestins before IVF-ET: a non-inferiority randomized controlled trial.

BACKGROUND: Endometriosis affects the responsiveness to ovarian stimulation. This study aimed to assess the role of Dienogest pretreatment for endometriosis suppression as compared to Gonadotropin-releasing hormone agonist (GnRHa) in patients with endometriosis pursuing IVF treatment. METHODS: In this randomized controlled trial, 134 women with endometriosis-related infertility were randomly allocated to group A (n = 67) who had monthly depot GnRHa for 3 months before ovarian stimulation in IVF treatment (Ultra-long protocol), and Group B (n = 67) who had daily oral Dienogest 2 mg/d for 3 months before starting standard long protocol for IVF. The primary outcome measure was the number of oocytes retrieved. The secondary outcome measures included the number of mature oocytes, fertilization rate, quality of life assessed by FertiQoL scores, cost of treatment, and pregnancy outcomes. RESULTS: Although there was no statistically significant difference between both groups regarding ovarian stimulation, response parameters, and pregnancy outcomes, the Dienogest group had a lower cost of treatment (2773 vs. 3664 EGP, P < 0.001), lower side effects (29.9% vs. 59.7%, P < 0.001), higher FertiQoL treatment scores (33.2 vs. 25.1, P < 0.001) and higher tolerability scores (14.1 vs. 9.4, P < 0.001 < 0.001). CONCLUSION: Our study indicates that Dienogest is a suitable and safe substitute for GnRHa pretreatment in endometriosis patients. TRIAL REGISTRATION: NCT04500743 "Retrospectively registered on August 5, 2020".

Dienogest reduces endometrioma volume and endometriosis-related pain symptoms.

This study aimed to evaluate the efficacy and adverse effects of dienogest for the treatment of endometriomas. Dienogest (2 mg/day) was administered to patients with endometrioma continuously through the 6-month study period. The patients were prospectively examined on the efficacy and side effects at baseline, at third months, and sixth months of the treatment. Twenty-four out of 30 patients were able to complete the study. The mean volume of the endometrioma decreased significantly from 112.63 ± 161.31 cm³ at baseline to 65.47 ± 95.69 cm³ at a 6-month follow-up (-41%) (p = .005). The VAS score for pelvic pain decreased significantly from 7.50 to 3.00 (p < .001) at the sixth months of treatment. The most common side effects were menstrual irregularities. Laboratory parameters did not change during the study. Dienogest considered being effective for 6 months of use in decreasing the size of endometrioma, reducing endometriosis-associated pain with a favourable safety and tolerability profile.Impact statementWhat is already known on this subject? Laparoscopic excisional surgery for endometrioma is currently the most valid approach in the treatment of endometriomas. However, there are concerns about ovarian reserve damage during surgery.What do the results of this study add? Dienogest considered being effective in decreasing the size of endometrioma, reducing endometriosis-associated pain with a favourable safety and tolerability profile. Long-term use of dienogest in younger patients with endometriomas who are yet to give birth may reduce the possibility of surgery by reducing the size of the endometriomas and may preserve ovarian reserve.What are the implications of these findings for clinical practice and/or further research? Dienogest may reduce the incidence of infectious complications such as pelvic abscess after oocyte retrieval and the surgical procedures in infertile patients with endometrioma.

Comparison of dienogest versus combined oral contraceptive pills in the treatment of women with adenomyosis: A randomized clinical trial.

OBJECTIVE: To compare the efficacy and safety of dienogest with combined oral contraceptives (COCs) for treating adenomyosis-associated symptoms. METHODS: This was a randomized clinical trial including women with symptomatic adenomyosis conducted from March 1, 2019 to August 1, 2020 at Assiut Woman's Health Hospital, Egypt. Participants were randomly assigned to the dienogest group or COCs group. The primary outcome was the level of adenomyosis-associated pain from before to 6 months after treatment measured by a visual analog scale (VAS). Changes in the uterine bleeding pattern, uterine volume, and uterine artery blood flow were also reported. RESULTS: The VAS score of pain was significantly decreased in both groups; however, the decreased rate was more pronounced in the dienogest group (3.21 ± 1.18) in comparison with the COCs group (4.92 ± 1.22). Bleeding pattern was improved greatly; uterine volume and uterine artery blood flow decreased significantly in the dienogest group. However, women in the dienogest group reported a higher rate of side effects. CONCLUSION: Dienogest and COCs are effective in treating adenomyosis-associated symptoms after 6 months of use but dienogest is more effective. The decrease in uterine volume and uterine artery blood flow may be the cause of the treatment effect. Dienogest carries a higher risk of side effects. CLINICAL TRIAL: gov: NCT03890042.

Detecting the abuse of 19-norsteroids in doping controls: A new gas chromatography coupled to isotope ratio mass spectrometry method for the analysis of 19-norandrosterone and 19-noretiocholanolone.

The detection of 19-norsteroids abuse in doping controls currently relies on the determination of 19-norandrosterone (19-NA) by gas chromatography-tandem mass spectrometry (GC-MS/MS). An additional confirmatory analysis by gas chromatography coupled to isotope ratio mass spectrometry (GC-C-IRMS) is performed on samples showing 19-NA concentrations between 2.5 and 15 ng/ml and not originated from pregnant female athletes or female treated with 19-norethisterone. 19-Noretiocholanolone (19-NE) is typically produced to a lesser extent as a secondary metabolite. The aim of this work was to improve the GC-C-IRMS confirmation procedure for the detection of 19-norsteroids misuse. Both 19-NA and 19-NE were analyzed as target compounds (TCs), whereas androsterone (A), pregnanediol (PD), and pregnanetriol (PT) were selected as endogenous reference compounds (ERCs). The method was validated and applied to urine samples collected by three male volunteers after the administration of nandrolone-based formulations. Before the instrumental analysis, urine samples (<25 ml) were hydrolyzed with ß-glucuronidase from Escherichia coli and extracted with n-pentane. Compounds of interest were purified through a single (for PT) or double (for 19-NE, 19-NA, A, and PD) liquid chromatographic step, to reduce the background noise and eliminate interferences that could have affect the accuracy of δ13 C values. The limit of quantification (LOQ) of 2 ng/ml was ensured for both 19-NA and 19-NE. The 19-NE determination could be helpful in case of "unstable" urine samples, in late excretion phases or when coadministration with 5α-reductase inhibitors occur.

Risk factors for non-response and discontinuation of Dienogest in endometriosis patients: A cohort study.

INTRODUCTION: Progestins are commonly prescribed first-line drugs for endometriosis. High rates of non-response and intolerance to these drugs have been previously reported. However, no study to date has investigated the characteristics and comorbidities of patients taking progestins in relation to treatment outcomes, so identifying which patients will respond to or tolerate the treatment is currently impossible. The purpose of this study, therefore, was to identify risk factors for non-response and discontinuation of Dienogest (DNG) in women with endometriosis. MATERIAL AND METHODS: This is a retrospective cohort study including women currently taking, or newly prescribed, DNG for endometriosis-associated pain presenting in the Endometriosis Clinic of the University Hospital of Bern between January 2017 and May 2018. Women with initiation of treatment directly after surgery for endometriosis were excluded. For all participants the symptoms and comorbidities were documented. Effectiveness, tolerability and discontinuation of DNG were the primary end points. Univariate and multivariate binary logistic regression models were carried out to identify risk factors for non-response, intolerance and discontinuation of DNG. RESULTS: A sufficient or excellent treatment response was reported by 85/125 (68%) participants. Genital bleeding during the DNG treatment was negatively (OR 0.185, 95% CI 0.056-0.610, P = .006) and rASRM endometriosis stages III and IV were positively (OR 3.876, 95% CI 1.202-12.498, P = .023) correlated with the DNG response. When accounting for exclusively pretreatment factors, primary dysmenorrhea (OR 0.236, 95% CI 0.090-0.615, P = .003) and suspicion of adenomyosis (OR 0.347, 95% CI 0.135-0.894, P = .028) were inversely correlated with DNG response, and the latter was also correlated with treatment discontinuation (OR 3.189, 95% CI 1.247-8.153, P = .015). CONCLUSIONS: Genital bleeding during the DNG treatment and low rASRM stages are independent risk factors for DNG non-response. Before treatment initiation, primary dysmenorrhea and suspicion of adenomyosis correlate with DNG non-response. The results could assist the clinician first to provide detailed information to women before treatment initiation, second to identify and possibly modify in-therapy factors correlated to treatment effectiveness and lastly to switch treatment on time if needed.

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy).

BACKGROUND: Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. OBJECTIVES: To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. SELECTION CRITERIA: All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. AUTHORS' CONCLUSIONS: Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

µ-Opioid receptor-induced synaptic plasticity in dopamine neurons mediates the rewarding properties of anabolic androgenic steroids.

Anabolic androgenic steroids (AAS) have medical utility but are often abused, and the effects of AAS on reward circuits in the brain have been suggested to lead to addiction. We investigated the previously reported correlations between AAS and the endogenous µ-opioid system in the rewarding properties of AAS in mice. We found that a single injection of a supraphysiological dose of natural or synthetic AAS strengthened excitatory synaptic transmission in putative ventral tegmental area (VTA) dopaminergic neurons. This effect was associated with the activation of µ-opioid receptors (MORs) and an increase in ß-endorphins released into the VTA and the plasma. Irreversible blockade of MORs in the VTA counteracted two drug-seeking behaviors, locomotor activity and place preference. These data suggest that AAS indirectly stimulate a dopaminergic reward center of the brain through activation of endogenous opioid signaling and that this mechanism mediates the addictive effects of AAS.

Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial.

CONTEXT: Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood. OBJECTIVE: We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism. DESIGN: Randomized, controlled, open-label clinical trial. SETTING: Two-center study in Helsinki and Oulu University Hospitals. PARTICIPANTS: Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17). INTERVENTIONS: Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control. MAIN OUTCOME MEASURES: Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol). RESULTS: Serum hs-CRP increased after 9-week use of EE + DNG (mean change ± standard deviation 1.10 ± 2.11 mg/L) compared with EV + DNG (-0.06 ± 0.97 mg/L, P = 0.001) or DNG only (0.13 ± 0.68 mg/L, P = 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 ± 0.24 mmol/L vs EV + DNG 0.02 ± 0.20 mmol/L [P = 0.002] vs DNG 0.02 ± 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 ± 0.21 mmol/L vs EV + DNG 0.18 ± 0.36 mmol/L [P = 0.003] vs DNG 0.06 ± 0.18 mmol/L [P < 0.001]). CONCLUSIONS: EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL. TRIAL REGISTRATION: ClinicalTrials.gov NCT02352090.

Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome.

Objectives: The aim of the study was to update the results of a previous study published 10 years ago and compare the effect on hyperandrogenism of a newer progestin, dienogest (DNG), in a combined oral contraceptive (COC) formulation with ethinylestradiol (EE), with that of COCs containing the same dose of EE in combination with drospirenone (DRSP) and chlormadinone acetate (CMA).Methods: Sixty women with polycystic ovary syndrome (PCOS) aged between 16 and 35 and requiring antiandrogenic contraceptive treatment were randomised to one of three treatment groups: EE 30 µg/DRSP 3 mg, EE 30 µg/CMA 2 mg, EE 30 µg/DNG 2 mg. We evaluated the effects of the three COCs on sex hormone-binding globulin (SHBG) and biochemical markers of hyperandrogenism.Results: After 3 months of treatment, serum androgen concentrations were significantly improved in all treatment groups. Serum concentrations of SHBG were significantly increased with all COC treatments (p < 0.0001). Interestingly, DRSP had a greater effect (+218%; p < 0.0001) on serum SHBG concentrations compared with DNG and CMA (p < 0.04 and p < 0.002, respectively). Serum concentrations of total testosterone significantly decreased in all groups (p < 0.0001). DRSP had a significantly greater effect on total testosterone concentrations compared with DNG (p = 0.002) and CMA (p < 0.0001).Conclusion: Our study showed that DNG exerted an important stimulatory effect on SHBG concentrations, which was less than that of DRSP but greater than that of CMA. Similar results were also obtained for dehydroepiandrosterone sulphate and total testosterone.

A multicenter, randomized, placebo-controlled, double-blind, comparative study of dienogest at 1 mg/day in patients with primary and secondary dysmenorrhea.

OBJECTIVE: To evaluate the efficacy and safety of dienogest (DNG), a progestational 19-norsteroid, in patients with primary and secondary dysmenorrhea. DESIGN: Phase III, randomized, double-blind, multicenter, placebo-controlled study. SETTING: Clinical study sites in Japan. PATIENT(S): Ninety-four women with dysmenorrhea. INTERVENTION(S): Random assignment to receive DNG (1 mg/day, orally) or placebo for 12 weeks; patients treated for anemia before randomization in cases of complicated anemia. MAIN OUTCOME MEASURE(S): Change in the dysmenorrhea score from baseline to week 12 of treatment with visual analog scale used for pain assessment. RESULT(S): The DNG group was superior to the placebo group in terms of the change from baseline in the dysmenorrhea score at week 12 of treatment in patients with dysmenorrhea. In both primary and secondary dysmenorrhea, the DNG group was superior to the placebo group for each diagnostic category. The mean serum estradiol concentrations were similar between the DNG and the placebo groups. Although the incidence of irregular uterine bleeding was higher in the DNG group, there were no severe or serious events. Most events of genital bleeding were spotting or breakthrough bleeding, suggesting DNG was well tolerated. CONCLUSION(S): In both primary and secondary dysmenorrhea, DNG at 1 mg/day relieved pain and was well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-173547(en).

Pooled analysis of bleeding profile, efficacy and safety of oral oestradiol valerate/dienogest in women aged 25 and under.

Purpose: To evaluate differences in key outcomes between younger and older women receiving the oral contraceptive oestradiol valerate/dienogest (E2V/DNG).Methods: We conducted a pooled post hoc analysis of primary data from 12 studies of E2V/DNG, stratified by age (≤25 [n = 1309] and >25 [n = 2132] years). Outcomes included safety, efficacy, bleeding profile and hormone-withdrawal-associated symptoms (HWAS). Bleeding and HWAS analyses are also presented for women aged ≤20 years (n = 362). Discontinuations were considered a proxy for patient satisfaction.Results: Results were generally similar for younger and older women. The percentage of women aged ≤25 and >25 years experiencing intracyclic bleeding did not differ between groups (13.4% and 12.8% at cycle 12, respectively), with similar results in women aged ≤20 years (12.7%, cycle 12). Rates of withdrawal bleeding were very similar in women aged ≤25 and >25 years (78.5% and 78.9%, respectively, cycle 12). We also found a similar adjusted Pearl index in the two age groups (0.45 vs 0.57, respectively), similar rates of AEs and HWAS and no difference in discontinuations.Conclusions: Women aged ≤25 and >25 years have a similar experience with an E2V/DNV oral contraceptive, supporting this as an appropriate contraceptive option in younger and older women.

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity.

Nandrolone is a testosterone analogue with anabolic properties commonly abused worldwide, recently utilized also as therapeutic agent in chronic diseases, cancer included. Here we investigated the impact of nandrolone on the metabolic phenotype in HepG2 cell line. The results attained show that pharmacological dosage of nandrolone, slowing cell growth, repressed mitochondrial respiration, inhibited the respiratory chain complexes I and III and enhanced mitochondrial reactive oxygen species (ROS) production. Intriguingly, nandrolone caused a significant increase of stemness-markers in both 2D and 3D cultures, which resulted to be CxIII-ROS dependent. Notably, nandrolone negatively affected differentiation both in healthy hematopoietic and mesenchymal stem cells. Finally, nandrolone administration in mice confirmed the up-regulation of stemness-markers in liver, spleen and kidney. Our observations show, for the first time, that chronic administration of nandrolone, favoring maintenance of stem cells in different tissues would represent a precondition that, in addition to multiple hits, might enhance risk of carcinogenesis raising warnings about its abuse and therapeutic utilization.

Long-term use of dienogest for the treatment of primary and secondary dysmenorrhea.

AIM: To investigate the safety and efficacy of dienogest (DNG), a progestational 19-norsteroid, administered for 52 weeks in patients with primary and secondary dysmenorrhea. METHODS: A total of 147 patients with dysmenorrhea received 1 mg of DNG orally each day for 52 weeks. The dose could be increased to 2 mg/day at or after Week 12 according to the investigator's determination. The primary safety endpoint was evaluation of adverse events, and the secondary safety endpoint was evaluation of adverse drug reactions. The number of days and severity of genital bleeding were assessed according to records in the patients' diary. Lower abdominal pain and/or low back pain because of dysmenorrhea were assessed according to the dysmenorrhea score. RESULTS: The most frequent adverse drug reaction was irregular uterine bleeding (94.6%). Most subjects completed the 52-week administration. Genital bleeding was more likely to occur in subjects with secondary dysmenorrhea than in those with primary dysmenorrhea, and in subjects with "uterine myoma or adenomyosis" than in those with "endometriosis alone." In any of the categorizations, there tended to be fewer days with genital bleeding as the treatment period increased in length, and most of the genital bleeding cases were mild. The change from baseline in the dysmenorrhea score (mean ± standard deviation [SD]) was -3.7 ± 1.6 at Week 24 of treatment and -4.0 ± 1.3 at Week 52. CONCLUSION: This study showed favorable tolerability of the long-term use of DNG to patients with dysmenorrhea and a sustainable pain relief effect.

Expression of Lewis (b) blood group antigen interferes with oral dienogest therapy among women with adenomyosis.

Adenomyosis is frequently observed in premenopausal women, and oral dienogest is the recommended treatment to target the underlying pathology and improve the symptoms. This retrospective study investigated the association of Lewis (b) antigen expression with outcomes of dienogest therapy among women with adenomyosis. Records from a total of 342 adenomyosis patients were analysed, who were prescribed with oral dienogest for a maximum of 16 weeks. Expression levels of Lewis (b) antigen were measured to categorize all patients into either Le (b)- and Le(b)+ groups. Treatment outcomes, in terms of uterine volume, menstrual flow, pain symptoms and quality of life, were compared between the two groups. While oral dienogest therapy showed considerable clinical efficacy in both groups of patients, the extent of improvements in treatment outcomes was significantly more pronounced in Le (b)- group than Le (b)+ group, with respect to treatment time, uterine symptoms, menstrual flow, pain symptoms and quality of life. No difference in adverse effects was observed between the two groups. Expression of Lewis (b) blood group antigen interferes with oral dialogist therapy among women with adenomyosis.

Evaluation of the efficacy, safety, and clinically recommended dose of dienogest in the treatment of primary dysmenorrhea: a randomized, double-blind, multicenter, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy, safety, and clinically recommended dose of dienogest (DNG; 0.5 mg/d, 1 mg/d, and 2 mg/d) in the treatment of primary dysmenorrhea. DESIGN: A phase II, randomized, double-blind, multicenter, placebo-controlled study. SETTING: Twenty study sites. PATIENTS: A total of 235 patients with primary dysmenorrhea. INTERVENTION(S): Patients were randomized to receive orally a placebo, DNG (0.5 mg/d, 1 mg/d, or 2 mg/d) or ethinylestradiol 0.02 mg/drospirenone 3 mg (an open-label reference drug) for 12 weeks. MAIN OUTCOME MEASURE(S): The primary endpoint was the change from baseline in the dysmenorrhea score at week 12 of treatment. The secondary endpoint was the change from baseline in the visual analogue scale at week 12 of treatment. Subjects were assessed for lower abdominal pain and/or low back pain. RESULTS: All DNG arms were superior to the placebo arm in terms of the change from baseline in the dysmenorrhea score. The results suggest an equal or greater effect of DNG 1 and 2 mg/d in relieving pain, when compared to the reference drug. In the safety profile of DNG, including irregular uterine bleeding, there was no obvious difference among the doses of DNG. A significant decrease in the serum estradiol concentration compared to that in the placebo arm was not observed in the DNG 1 mg/d arm but was observed in the DNG 2 mg/d arm. CONCLUSION(S): The results suggest that DNG at a dose of 1 mg/d is an effective and well-tolerated treatment for primary dysmenorrhea. TRIAL REGISTRATION: JapicCTI-152977 (en).

Modification of endometrioma size during hormone therapy containing dienogest.

The aim of the present study was to evaluate whether hormone therapy containing dienogest is effective in reducing endometrioma size. A retrospective observational study was conducted on 116 women with endometrioma which was evaluated after 6 and 12 months of either no treatment (n = 46), or hormonal therapy containing dienogest (n = 70), without (DNG; n = 34) or with ethinylestradiol (DNG/EE; n = 36). Median (interquartile range) cyst diameter (23.0 mm (21.0 mm)) and volume (9941.2 mm3 (14240.1 mm3)) of untreated were similar to cyst diameter (25.0 mm (14.5 mm) and volume (7587.7 mm3 (13806.2 mm3)) of treated women. After 12 months, endometrioma volume did not vary in untreated women (-34.0 mm3 (55595.0 mm3); -0.77% (93.9%)) while it significantly decreased (-5400 mm3 (15378.7 mm3); -100.0% (27.7%); p<.0001) during hormone therapy. Volume decrease was linearly related to endometrioma volume ([Formula: see text] R2 = 0.899, p<.0001). The effect tended to be greater during DNG alone than DNG/EE (-100.0% (0.0%) vs. -87.9% (47.7%); p<.0004). Cyst disappearance was observed in 4.4% of untreated cases and in 57.1% of cases on hormone therapy (p<.0001) (38.9% with DNG/EE and 76.5% with DNG; p<.03). The early diagnosis and treatment of endometrioma with dienogest-based hormone therapy may be effective in controlling cyst growth and in reducing the need for surgery.

Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis.

We aimed to retrospectively analyze the risk factors of a continuous dienogest (DNG) therapy for serious unpredictable bleeding in patients with symptomatic adenomyosis. This is a retrospective study based on data extracted from medical records of 84 women treated with 2 mg of DNG orally each day between 2008 and 2017. 47 subjects were excluded from the original analyses due to an inadequate subcategorization into subtype I and subtype II and a lack of hemoglobin levels. The influence of various independent variables on serious unpredictable bleeding was assessed. Of the 37 eligible patients who received the continuous DNG therapy, 14 patients experienced serious unpredictable bleeding. Univariate analysis revealed that the serious bleeding group had subtype I adenomyosis (P = 0.027). There was no correlation between age, parity, minimum hemoglobin level before treatment, previous endometrial curettage, and duration of DNG administration, or uterine or adenomyosis size and the serious bleeding. A DNG-related serious unpredictable bleeding is associated with the structural type of adenomyosis (subtype I) in patients with symptomatic adenomyosis.

Nandrolone administration with or without strenuous exercise increases cardiac fatal genes overexpression, calcium/calmodulin-dependent protein kinaseiiδ, and monoamine oxidase activities and enhances blood pressure in adult wistar rats.

Misuse of anabolic androgenic steroids (AAS) increases prevalence of cardiovascular abnormalities in athletes, and the underlying molecular mechanism involved in those abnormalities continues to be investigated. The aim of this study was to investigate the effect of chronic nandrolone exposure on alpha and beta-myosin heavy chain (MHC) isoforms gene expression transition, blood pressure related parameters, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ), and monoamine oxidase (MAO) activities in rats' hearts. It was also planned to evaluate the effect of strenuous exercise on cardiac abnormalities induced by nandrolone. Thirty-two male wistar rats were assigned into four groups, namely control, nandrolone, nandrolone with strenuous exercise, and strenuous exercise groups. Nandrolone consumption significantly increased systolic, diastolic, pulse and dicrotic pressure, mean arterial pressure, as well as the amplitude of first peak (H1). Moreover, exercise combined with nandrolone completely masked this effect. The mRNA expression of ß-MHC and the ratio of ß -MHC/α -MHC showed a significant increase in the nandrolone and nandrolone with strenuous exercise groups compared to those in the control group. The values of heart tissue calcium/calmoldulin-dependent protein kinase IIδ (CaMKIIδ), and monoamine oxidase (MAO) in the nandrolone, nandrolone with strenuous exercise and exercise groups were significantly higher than those values in the control group. These findings indicate that nandrolone-induced heart and hemodynamic abnormalities may in part be associated with MHC isoform changes and Ca2+ homeostasis changes mediated by increased CaMKIIδ and MAO activities and that these effects can be provoked via strenuous exercise.

Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11ß-Methyl-19-Nortestosterone-17ß-Dodecylcarbonate in Men.

Context: 11ß-Methyl-19-nortestosterone-17ß-dodecylcarbonate (11ß-MNTDC) is an orally bioavailable prodrug of 11ß-methyl-19-nortestosterone (11ß-MNT) with androgenic and progestational activity. Objectives: (i) Quantify 11ß-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11ß-MNTDC in men. Design and Setting: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Participants and Intervention: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11ß-MNTDC or placebo given with or without food. Main Outcome Measures: (i) In vitro 11ß-MNT/11ß-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. Results: 11ß-MNT avidly binds and activates human androgen and progesterone receptors, but 11ß-MNTDC has minimal activity. Single oral doses of 11ß-MNTDC were well tolerated without serious adverse events. Administration of 11ß-MNTDC with food markedly increased average 11ß-MNTDC and 11ß-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). Conclusions: A single, oral dose of 11ß-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11ß-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill.

Context: Dimethandrolone (DMA) has androgenic and progestational activity. Single oral doses of DMA undecanoate (DMAU) were well tolerated and reversibly suppressed serum LH and testosterone (T) in men. Objective: Assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of oral DMAU. Design: Double-blind, randomized, placebo-controlled study. Setting: Two academic medical centers. Participants: Healthy men (18 to 50 years). Interventions: One hundred men received DMAU [0, 100, 200, or 400 mg, formulated in castor oil/benzyl benzoate (C) or powder (P)] for 28 days. Subjects underwent 24-hour PK sampling on days 1 and 28 and twice weekly ambulatory visits throughout treatment. Main Outcome Measures: Primary outcomes were safety and tolerability parameters (vitals, laboratory data, mood, and sexual function scores) and adverse events. Secondary outcomes were drug PK profiles and PD effects (serum LH, FSH, and sex hormones). Results: Eighty-two subjects completed the study and were included in the analysis. There were no serious adverse events. No clinically significant changes developed in safety laboratory parameters. A significant dose effect was seen for weight, hematocrit, high-density lipoprotein cholesterol, corrected QT interval, and sexual desire. Serum 24-hour average concentrations of DMAU and DMA showed dose-related increases (P < 0.001). All six subjects in the P400 group and 12 of 13 subjects in the C400 group achieved marked suppression of LH and FSH (<1.0 IU/L) and serum T (<50 ng/dL). Conclusions: Daily oral administration of DMAU for 28 days in healthy men is well tolerated. Doses of ≥200 mg markedly suppress serum T, LH, and FSH. These results support further testing of DMAU as a male contraceptive.