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Objectives: To characterise contemporary trends in the hormonal management of endometriosis in adolescent and young adult patients with biopsy-proven endometriosis., Methods: Retrospective chart review of women aged 14-25 years who underwent laparoscopy for pelvic pain with biopsy-proven endometriosis between January 2011 and September 2020 at an academic tertiary hospital system. The final sample included 91 patients with biopsy-confirmed endometriosis., Results: Combined oral contraceptives (COCs) were the most common initial treatment (64% of patients). Progestin-only formulations (low- and high-dose norethindrone acetate) were offered to younger patients (age 15.9 ± 2.7 years) than those offered COCs (19.9 ± 3.3 years) and levonorgestrel intrauterine devices (LNG-IUDs) (21.9 ± 1.7 years). Current treatments varied widely and included COCs (32%), LNG-IUDs (18%), oral progestins (low- and high-dose norethindrone, medroxyprogesterone) (14%), elagolix (9%), and leuprolide (8%). Oral adjuncts to LNG-IUD were common: usually low- or high-dose norethindrone (37% of patients with an LNG-IUD), but also included progesterone, COCs, and elagolix., Conclusions: Oral progestins, LNG-IUDs, and COCs were the mainstay of initial treatment. Subsequent treatments varied widely and included COCs, LNG-IUDs, oral progestins, elagolix, leuprolide, and combinations of these agents. We observed that most young women switched between therapies, suggesting that a personalised approach is often used to determine treatment plans among the wide range of options currently available. This study helps define the spectrum of treatment regimens for endometriosis in adolescent females., (Copyright © 2024 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Study Question: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain?, Summary Answer: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months., What Is Known Already?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis., Study Design, Size, Duration: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months., Participants/materials, Setting, Methods: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary., Main Results and the Role of Chance: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy., Limitations, Reasons for Caution: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications., Wider Implications of the Findings: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated., Study Funding/competing Interest(s): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex., Trial Registration Number: NCT03992846., Trial Registration Date: 20 June 2019., Date of First Patient’s Enrollment: 13 June 2019., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree ® (USA); Ryeqo ® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To compare the effectiveness of dienogest (DIE) and norethisterone acetate (NETA) regimens in the treatment of endometrial hyperplasia (EH) without atypia., Methods: Participants were premenopausal women with irregular uterine bleeding, and endometrial hyperplasia without atypia on endometrial biopsy. Enrolled patients were randomly allocated into two groups: group I got DIE 2 mg/day (orally Visanne) for 14 days (10th to the 25th day of cycle) while group II received between the 16th and 25th day of the cycle, norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor) was administered for 10 days. Both groups continued the therapy for six months., Results: The DIE group showed a higher resolution (32.7%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significant regression (p = 0.039). No progression in DIE group while four (6.9%) women in NETA group were recorded a progression to complex type without a significance. Also, NETA group showed a significant persistence rate (22.5%) than DIE group (3.8%) (p = 0.005). Also number in NETA group managed by hysterectomy with significant difference (p = 0.042)., Conclusion: If used as first-line treatment, Dienogest produces a better rate of regression and a lower incidence of hysterectomy than Norethisterone Acetate does when used in EH without atypia., (© 2023. The Author(s).)

Objectives: Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies., Methods: Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration., Results: Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect., Conclusions: Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 μg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected., (© 2022 ViiV Healthcare. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Introduction: Although several studies suggest beneficial effects of low-dose estrogen-progestins (LEPs) and progestins on dysmenorrhea in Japanese women, the difference in efficacy between drugs remains unknown., Methods: We identified studies by searching the MEDLINE, Cochrane Library, and ICHUSHI databases and included randomized controlled trials (RCTs) that used total dysmenorrhea score and visual analogue scale (VAS) as outcome measures to evaluate LEPs and progestins for primary and secondary dysmenorrhea. We analyzed results by meta-analysis and network meta-analysis (NMA)., Results: We identified 10 articles on eight RCTs and included seven drugs (six LEPs and one progestin, i.e., dienogest) and placebo in the analysis. Meta-analysis showed improvements in total dysmenorrhea score and VAS for almost all drugs compared with placebo. In NMA, VAS in secondary dysmenorrhea improved more with dienogest than with norethisterone/ethinylestradiol (mean difference - 25.84 [95% CrI - 44.46 to - 7.15]). In the comparison of administration regimens, VAS improved more with progestin-continuous than LEP-cyclic and the surface under the cumulative ranking (SUCRA) of LEP-extended and progestin-continuous appeared to be higher than that of LEP-cyclic., Conclusions: We confirmed that LEPs and dienogest are effective for primary and secondary dysmenorrhea and suggest that continuous regimens may be more effective than cyclic regimens in improving outcomes., (© 2022. The Author(s).)

Background: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability., Objectives: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding., Search Methods: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers., Selection Criteria: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding., Data Collection and Analysis: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence., Main Results: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis., Authors' Conclusions: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Although surgery and radiotherapy remain the most commonly used treatments for non-melanoma skin cancer, there are a variety of alternatives. Here we discuss the use of electrochemotherapy and ablative treatments and examine the evidence for their effectiveness against a number of non-melanoma skin cancers., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the effects of Dienogest (D) and Norethindrone acetate (N) in symptomatic women with ovarian endometriomas, analyzing the efficacy in reducing endometrioma size and symptom relief and drug tolerability., Study Design: Retrospective study including 135 symptomatic women with ultrasonographic diagnosis of ovarian endometrioma. Women were divided into two groups: 1) women who received D 2 mg/day (group D); 2) women who received N 2.5 mg/day (group N). Women were evaluated at therapy prescription and after 6 and 12 months of treatment: transvaginal ultrasound was performed to assess the mean diameter of endometriomas, a Visual Analogue Scale was used to rank endometriosis related symptoms (dysmenorrhea, dyspareunia, chronic pelvic pain). The main outcome measure was the comparison between the 2 groups in terms of variations in endometrioma size and endometriosis related symptoms during the follow-up. Drug tolerability was also analyzed in terms of side effects., Results: A reduction in ovarian endometrioma size was observed during treatment in both groups, with no significant differences between groups D and N. Endometriosis related symptoms decreased in both groups, but the decrease was significantly higher in group D than in group N for all symptoms, both at 6 and 12 months of treatment. Regarding drug tolerability, uterine bleeding/spotting and weight gain were reported more frequently by women in the group N than women in the group D, both at 6 and 12 months of treatment., Conclusion: Progestin therapy with D or N appears to be effective in reducing the size of endometriomas and related symptoms, with a greater effect on symptoms relief and higher tolerability in women treated with D., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: A systematic review was carried out of studies of women with endometriosis, to examine the evidence for efficacy of the use of hormonal contraception to improve disease-related pain and decrease postoperative risk of disease recurrence., Methods: A search of the Medline/PubMed and Embase databases was performed to identify all published English language studies on hormonal contraceptive therapies (combined hormonal contraceptives [CHCs], combined oral contraceptives [COCs], progestin-only pills [POPs] and progestin-only contraceptives [POCs]) in women with a validated endometriosis diagnosis, in comparison with placebo, comparator therapies or other hormonal therapies. Main outcome measures were endometriosis-related pain (dysmenorrhoea, pelvic pain and dyspareunia), quality of life (QoL) and postoperative rate of disease recurrence during treatment., Results: CHC and POC treatments were associated with clinically significant reductions in dysmenorrhoea, often accompanied by reductions in non-cyclical pelvic pain and dyspareunia and an improvement in QoL. Only two COC preparations (ethinylestradiol [EE]/norethisterone acetate [NETA] and a flexible EE/drospirenone regimen) demonstrated significantly increased efficacy compared with placebo. Only three studies found that the postoperative use of COCs (EE/NETA, EE/desogestrel and EE/gestodene) reduced the risk of disease recurrence. There was no evidence that POCs reduced the risk of disease recurrence., Conclusions: CHCs and POCs are effective for the relief of endometriosis-related dysmenorrhoea, pelvic pain and dyspareunia, and improve QoL. Some COCs decreased the risk of disease recurrence after conservative surgery, but POCs did not. There is insufficient evidence, however, to reach definitive conclusions about the overall superiority of any particular hormonal contraceptive.

Study Objective: To explore the potential occurrence of long-term side effects and tolerability of gonadotropin-releasing hormone agonist (GnRHa) plus 2 different add-back regimens in adolescent patients with endometriosis., Design: Follow-up questionnaire sent in 2016 to patients who participated in a drug trial between 2008 and 2012., Setting: Tertiary care center in Boston, Massachusetts., Participants: Female adolescents with surgically confirmed endometriosis (n = 51) who enrolled in a GnRHa plus add-back trial as adolescents., Interventions: Leuprolide depot 11.25 mg intramuscular injection every 3 months, plus oral norethindrone acetate 5 mg daily or oral norethindrone acetate 5 mg daily and oral conjugated equine estrogens 0.625 mg daily., Main Outcome Measures: Side effects during and after treatment, irreversible side effects, changes in pain, overall satisfaction., Results: The response rate was 61% (25 of 41; 10 subjects could not be located). Almost all (24 of 25) reported side effects during treatment; 80% (16 of 21) reported side effects lasting longer than 6 months after stopping treatment. Almost half (9 of 20) reported side effects they considered irreversible, including memory loss, insomnia, and hot flashes. Despite side effects, participants rated GnRHa plus add-back as the most effective hormonal medication for treating endometriosis pain; two-thirds (16 of 25) would recommend it to others. More participants who received a modified 2-drug add-back regimen vs standard 1-drug add-back would recommend GnRHa and believed it was the most effective hormonal medication., Conclusion: Subjects believed that GnRHa used with add-back was effective and would recommend it to others, despite significant side effects. Those who received 2-drug add-back reported more success than those who received standard add-back. A subset of patients reported side effects they consider to be irreversible., (Copyright © 2018 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Introduction: Hormone therapy is widely used in the treatment of patients with ovarian endometriosis after surgery, and progestin and gonadotropin-releasing hormone (GnRH) are two of the most widely used hormones. This study aimed to compare the outcomes of progestin and GnRH in the treatment of ovarian endometriosis after surgery., Methods: A total of 399 patients with ovarian endometriosis were included and divided into four groups to receive different treatments. Group A received no postoperative hormone therapy; patients in group B1 and B2 were treated with different doses of norethindrone (progestin, 1.2 and 5 mg/day, respectively); patients in group C were treated with GnRH (2.0 mg every 2 weeks). Treatment outcomes including menstrual bleeding profiles, cumulative recurrence rate, incidence of complications, and endometrioma diameter in the case of recurrence were recorded and compared between groups., Results: Compared with group A, group B1, B2 and C showed significantly improved menstrual bleeding profiles and reduced cumulative recurrence rate and endometrioma diameter after recurrence. In addition, compared with group C, menstrual bleeding profiles were significantly improved and cumulative recurrence rate and endometrioma diameter were significantly reduced in group B1 and B2. No significant differences in incidence of complications during treatment were found among groups. After treatment, recurrence rate and endometrioma diameter were significantly increased in group B1, B2, and C., Conclusion: Both progestin and GnRH can significantly improve the conditions of patients with ovarian endometriosis after surgery, but progestin may be a better choice. Both therapies are challenged by the increased recurrence rate and endometrioma diameter after treatment.

Background: Data evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent., Objective: We hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis-associated microbes with use compared to women initiating and using hormonal contraceptive methods., Study Design: Vaginal swabs (N = 1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18-35 years in Harare, Zimbabwe, who were confirmed to be free of nonstudy hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate [n = 41], norethisterone enanthate [n = 44], or medroxyprogesterone acetate and ethinyl estradiol [n = 40]), implant (levonorgestrel [n = 45] or etonogestrel [n = 48]), or copper intrauterine device (n = 48) and repeat vaginal swabs were collected after 30, 90, and 180 days of continuous use. Self-reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus, L jensenii, L gasseri/johnsonii group, L vaginalis, L iners, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera-like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use., Results: Bacterial vaginosis prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days, and 49% at 180 days (P = .005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in bacterial vaginosis prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% confidence interval, 0.5-2.0; P = .001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over 6 months, there was an increase in the log concentration of G vaginalis (4.7, 5.2, 5.8, 5.9; P = .046) and A vaginae (3.0, 3.8, 4.6, 5.1; P = .002) between baseline and 30, 90, and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased L iners (mean decrease log concentration = 0.8; 95% confidence interval, 0.3-1.5; P = .004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used., Conclusion: Copper intrauterine device use may increase colonization by bacterial vaginosis-associated microbiota, resulting in increased prevalence of bacterial vaginosis. Use of most hormonal contraception does not alter vaginal microbiota., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to assess the proportion of patients satisfied with their treatment after a change from a low-dose oral contraceptive (OC) to norethisterone acetate (NETA) because of inefficacy of OC on pain symptoms. To this end, prospective, self-controlled study was conducted on 153 women using OC as a treatment for endometriosis and with persistence of one or more moderate or severe pain symptoms. At baseline and during 12 months after a shift from OC to oral NETA, 2.5 mg/d, pelvic pain was measured by means of a 0- to 10-point numerical rating scale and a multidimensional categorical rating scale. Variations in health-related quality of life, psychological status, and sexual function were also evaluated with validated scales. At the end of the study period, participants indicated the degree of satisfaction with their treatment according to a 5-degree scale from very satisfied to very dissatisfied. A total of 28 women dropped out of the study, the main reason was intolerable side effects (n = 15). At 12-month assessment, 70% of participants were very satisfied or satisfied with NETA treatment (intention-to-treat analysis). Statistically significant improvements were observed in health-related quality of life, psychological status, and sexual function. At per-protocol analysis, almost half of the patients (58/125) reported suboptimal drug tolerability. However, complaints were not severe enough to cause dissatisfaction, drug discontinuation, or request for surgery. These encouraging results could be used to counsel women with symptomatic endometriosis not responding to OC and to inform their decisions on modifications of disease management.

Background: Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs, which are designed to reduce bleeding by inhibiting clot-dissolving enzymes in the endometrium.Historically, there has been some concern that using the antifibrinolytic tranexamic acid (TXA) for HMB may increase the risk of venous thromboembolic disease. This is an umbrella term for deep venous thrombosis (blood clots in the blood vessels in the legs) and pulmonary emboli (blood clots in the blood vessels in the lungs)., Objectives: To determine the effectiveness and safety of antifibrinolytic medications as a treatment for heavy menstrual bleeding., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and two trials registers in November 2017, together with reference checking and contact with study authors and experts in the field., Selection Criteria: We included randomized controlled trials (RCTs) comparing antifibrinolytic agents versus placebo, no treatment or other medical treatment in women of reproductive age with HMB. Twelve studies utilised TXA and one utilised a prodrug of TXA (Kabi)., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. The primary review outcomes were menstrual blood loss (MBL), improvement in HMB, and thromboembolic events., Main Results: We included 13 RCTs (1312 participants analysed). The evidence was very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding, and poor reporting of study methods), imprecision and inconsistency.Antifibrinolytics (TXA or Kabi) versus no treatment or placeboWhen compared with a placebo, antifibrinolytics were associated with reduced mean blood loss (MD -53.20 mL per cycle, 95% CI -62.70 to -43.70; I² = 8%; 4 RCTs, participants = 565; moderate-quality evidence) and higher rates of improvement (RR 3.34, 95% CI 1.84 to 6.09; 3 RCTS, participants = 271; moderate-quality evidence). This suggests that if 11% of women improve without treatment, 43% to 63% of women taking antifibrinolytics will do so. There was no clear evidence of a difference between the groups in adverse events (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, participants = 297; low-quality evidence). Only one thromboembolic event occurred in the two studies that reported this outcome.TXA versus progestogensThere was no clear evidence of a difference between the groups in mean blood loss measured using the Pictorial Blood Assessment Chart (PBAC) (MD -12.22 points per cycle, 95% CI -30.8 to 6.36; I² = 0%; 3 RCTs, participants = 312; very low quality evidence), but TXA was associated with a higher likelihood of improvement (RR 1.54, 95% CI 1.31 to 1.80; I² = 32%; 5 RCTs, participants = 422; low-quality evidence). This suggests that if 46% of women improve with progestogens, 61% to 83% of women will do so with TXA.Adverse events were less common in the TXA group (RR 0.66, 95% CI 0.46 to 0.94; I² = 28%; 4 RCTs, participants = 349; low-quality evidence). No thromboembolic events were reported in any group.TXA versus non-steroidal anti-inflammatory drugs (NSAIDs)TXA was associated with reduced mean blood loss (MD -73.00 mL per cycle, 95% CI -123.35 to -22.65; 1 RCT, participants = 49; low-quality evidence) and higher likelihood of improvement (RR 1.43, 95% CI 1.18 to 1.74; 1 2 = 0%; 2 RCTs, participants = 161; low-quality evidence). This suggests that if 61% of women improve with NSAIDs, 71% to 100% of women will do so with TXA. Adverse events were uncommon and no comparative data were available. No thromboembolic events were reported.TXA versus ethamsylateTXA was associated with reduced mean blood loss (MD 100 mL per cycle, 95% CI -141.82 to -58.18; 1 RCT, participants = 53; low-quality evidence), but there was insufficient evidence to determine whether the groups differed in rates of improvement (RR 1.56, 95% CI 0.95 to 2.55; 1 RCT, participants = 53; very low quality evidence) or withdrawal due to adverse events (RR 0.78, 95% CI 0.19 to 3.15; 1 RCT, participants = 53; very low quality evidence).TXA versus herbal medicines (Safoof Habis and Punica granatum)TXA was associated with a reduced mean PBAC score after three months' treatment (MD -23.90 pts per cycle, 95% CI -31.92 to -15.88; I² = 0%; 2 RCTs, participants = 121; low-quality evidence). No data were available for rates of improvement. TXA was associated with a reduced mean PBAC score three months after the end of the treatment phase (MD -10.40 points per cycle, 95% CI -19.20 to -1.60; I² not applicable; 1 RCT, participants = 84; very low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 2.25, 95% CI 0.74 to 6.80; 1 RCT, participants = 94; very low quality evidence). No thromboembolic events were reported.TXA versus levonorgestrel intrauterine system (LIUS)TXA was associated with a higher median PBAC score than TXA (median difference 125.5 points; 1 RCT, participants = 42; very low quality evidence) and a lower likelihood of improvement (RR 0.43, 95% CI 0.24 to 0.77; 1 RCT, participants = 42; very low quality evidence). This suggests that if 85% of women improve with LIUS, 20% to 65% of women will do so with TXA. There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 0.83, 95% CI 0.25 to 2.80; 1 RCT, participants = 42; very low quality evidence). No thromboembolic events were reported., Authors' Conclusions: Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies, but may be less effective than LIUS. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.

Introduction: Endometriosis is a chronic estrogen and progestogen responsive inflammatory disease associated with pain symptoms and infertility. The medical therapy of endometriosis aims to induce decidualization within the hormonally dependent ectopic endometrium, and it is often administered to ameliorate women' pain symptoms or to prevent post-surgical disease recurrence. A variety of progestins have been used in monotherapy for the medical management of women with endometriosis. Areas covered: This review aims to offer the reader a complete overview of pharmacokinetic (PK) and clinical efficacy of progestins for the treatment of endometriosis. Expert opinion: Each progestin has a distinct PK parameters and pharmacodynamics affinity not only for progesterone receptor, but also for other steroid receptors, such as estrogen, androgen, and glucocorticoid. Moreover, progestins can also be delivered in different formulations. All these characteristics influence their final biological effect. Randomized, controlled, non-blinded studies support the use of oral progestin-only treatment for pelvic pain associated with endometriosis. Currently, the only two progestins approved by Food and Drug Administration (FDA) for the treatment of endometriosis are norethindrone acetate (NETA) and depot medroxyprogesterone acetate (DMPA).

Introduction: This patient preference prospective study was designed to compare patients' satisfaction in women with endometriosis treated either by an extended-cycle oral contraception (OC) or by norethindrone acetate (NETA)., Methods: This patient preference prospective study included women of reproductive age with endometriosis. Patients were submitted to one of the following 12 months' treatments: Group A, continuous oral treatment with NETA (2.5 mg/day) and Group B, a 91-day extended-cycle OC (LNG/EE 150/30 mcg for 84 days and EE 10 mcg for 7 days). Patient satisfaction was the primary endpoint., Results: There was no statistically significant difference in the rate of satisfied patients at 12-month follow up between the two study groups, 82.2% and 68.4% in Group A and Group B respectively (p = 0.143). At 6 and 12-months, there was a significant amelioration in the intensity of all pain in both groups. The median number of days of unscheduled bleeding during the first cycle was significantly higher in Group B compared to Group A., Conclusion: Both NETA and extended-cycle OC are effective in treating pain symptoms related to endometriosis. Extended-cycle OC may cause more unscheduled bleeding, but the rate of satisfaction for those who completed the treatment was similar in the two groups., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To compare the clinical efficacy of levonorgestrel intrauterine system with oral norethisterone for the treatment of idiopathic chronic abnormal uterine bleeding., Methods: This cross-sectional study was conducted at Bahawal Victoria Hospital, Jubilee Female Hospital, Civil Hospital and private clinics of consultant gynaecologists in Bahawalpur, Pakistan, from March to August 2014, and comprised patients presenting with abnormal uterine bleeding. The patients were equally and randomly divided into two groups, i.e. intrauterine levonorgestrel administered (group A) and norethisterone administered (group B). Mean age, duration of the disease and parity were determined using a predesigned questionnaire. The primary outcomes of the treatments, i.e. reduction in menstrual blood loss assessed by the pictorial blood assessment chart score, were recorded before the initiation of therapy, at 3 months and at 6months of the study. SPSS 16 was used for data analysis., Results: There were 76 subjects; 38(50%) in each group. In group A, the mean age and mean duration of the disease was 34.16±6.327 years and 6.18±2.415 years compared to 34.21±3.595 years and 6.21±2.418 years in group B. The reduction in menstrual blood loss did not differ significantly between the groups after 3 months (p= 0.321). However, levonorgestrel intrauterine system was found more effective in reducing menstrual blood loss in 36(94.73%) patients, compared to norethisterone-treated patients 28(73.68%) after 6 months of the treatment (p=0.041). The response of both the treatments was found independent of patient's age, parity and chronicity of the disease., Conclusions: The levonorgestrel intrauterine system was better than norethisterone with marked clinical benefit of profound reduction in menstrual blood loss.

Background: Endometriosis-ectopic implantation of endometrial-like tissue-affects 10% of female adolescents and adults. First-line treatment includes progesterone only (such as norethindrone acetate [NET-A]) or combined estrogen/progestin oral contraceptive pills. Estrogen-containing contraceptives confer increased risk of hepatic adenomas, whereas the association with NET-A is very rarely reported., Case: Three adolescents with stage I to II endometriosis managed with NET-A (up to 15 mg/d for 28-78 months) were diagnosed with hepatic adenomas at ages 17-22 years. They previously received estrogen-containing medications, which were stopped 24 months or longer before diagnosis of hepatic adenoma., Summary and Conclusion: NET-A in a dose greater than 10 mg/d might be associated with increased risk for hepatic adenomas, likely due to peripheral conversion to ethinyl estradiol. Use of NET-A might not be advisable in patients with known hepatic adenomas., (Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Objective: To study the efficacy of long-term treatment with norethindrone acetate (NETA) in patients with rectovaginal endometriosis., Study Design: This retrospective cohort study included 103 women with pain symptoms caused by rectovaginal endometriosis. Patients received NETA alone (2.5mg/day up to 5mg/day) for 5 years. Primary outcome was the degree of satisfaction with treatment after 5 years of progestin therapy. Secondary outcomes were the assessment of any variation in pain symptoms and the volumetric assessment of the disease by magnetic resonance imaging (MRI)., Results: Sixty-one women completed the 5-year follow-up (61/103, 59.2%) with 16 women withdrawing because of adverse effects (38.1%). Overall, 68.8% (42/61) of the women who completed the study were satisfied or very satisfied of this long term NETA treatment. This represents a 40.8% (42/103) of the patients enrolled. Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment (p<0.001 versus baseline at 1 and 5year). Dyschezia improved after 1-year respect to baseline (p=0.008) but remained stable between first and second year (p=0.409). At the end of 5 years treatment, a radiological partial response was observed in 33 patients (55.9%, n 33/59); a stable disease in 19 patients (32.2%, n 19/59). Seven women (7/59, 11.9%) displayed a volumetric increase of rectovaginal endometriosis under NETA treatment., Conclusion: Five-year therapy with NETA is safe and well tolerated by women with rectovaginal endometriosis. Due to its low cost and good pharmacological profile, it represents a good candidate for long-term treatment in this setting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up., Patients and Methods: A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up., Results: Sixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467)., Conclusion: To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma., (© 2016 by American Society of Clinical Oncology.)

Background: Greater trochanteric pain syndrome (GTPS) is pathology in the gluteus medius and minimus tendons and trochanteric bursa that causes debilitating tendon pain and dysfunction, particularly in post-menopausal women. Limited evidence in clinical studies suggests hormone changes after menopause may have a negative effect on tendon. This protocol describes a randomised controlled trial comparing the effectiveness of menopausal hormone therapy (MHT) and exercise therapy in reducing pain and dysfunction associated with GTPS in post-menopausal women., Method: One hundred and sixteen post-menopausal women will be recruited and randomised to receive one of two exercise programs (sham or targeted intervention exercise) and transdermal creams (MHT cream containing oestradiol 50mcg and norethisterone acetate 140mcg or placebo cream). Interventions will be 12-weeks in duration and outcomes will be examined at baseline, 12-weeks and 52-weeks. The primary outcome measure will be the VISA-G questionnaire and secondary outcomes measures will include three hip pain and function questionnaires (Hip dysfunction and Osteoarthritis Outcome Score, Oxford Hip Score, Lateral Hip Pain questionnaire), a global change in symptom questionnaire (using a 15-point Likert scale) and a quality of life measure (AQoL-8D questionnaire). Data will be analysed using the intention to treat principle., Discussion: This study is the first randomised controlled trial to compare the effectiveness of menopausal hormone therapy therapy alone, and with the combination of exercise therapy, to treat pain and dysfunction associated with GTPS. This study has been pragmatically designed to ensure that the interventions in this study can be integrated into policy and clinical practice if found to be effective in the treatment of GTPS in post-menopausal women. If successful, there is potential for this treatment regimen to be explored in future studies of other persistent tendon conditions in the post-menopausal population., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12614001157662 Registered 31 October 2014.

Background: Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects., Objective: To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only., Methods: This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics., Results: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92)., Conclusions: For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA., Disclosures: This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript.

Women with benign heavy menstrual bleeding have the choice of a number of medical treatment options to reduce their blood loss and improve quality of life. The role of the clinician is to provide information to facilitate women in making an appropriate choice. Unfortunately, many options can be associated with hormonal side effects, prevention of fertility and lack of efficacy, leading to discontinuation and progression to surgical interventions. Herein, we discuss the various options currently available to women, including antifibrinolytics, nonsteroidal anti-inflammatory preparations, oral contraceptive pills and oral, injectable and intrauterine progestogens. In addition, we describe the more novel option of selective progesterone receptor modulators and their current benefits and limitations., Competing Interests: Financial & competing interests disclosure HOD Critchley has received collaborative Research Grant Support for research staff and consumables in context of AUB treatment from TAP Pharmaceuticals and Bayer Pharma AG; and provided Consultancy/Advisory Board contributions on AUB Treatment (Bayer Pharma AG, Preglem/Gedeon-Richter, Vifor Pharma). HOD Critchley and JA Maybin have received research grant support from the Medical Research Council (G1002033 (HODC, JAM), MR/J003611/1 (HODC) and The Wellcome Trust (100646/Z/12/Z [JAM]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

The study was performed to compare the clinical effect of a hormone replacement therapy (HRT) with two different progestins. Postmenopausal women (PMW) with climacteric symptoms (CS) randomly received for 12 months orally, either placebo (n = 20), 1 mg estradiol (E) plus 0.5 mg noretisterone acetate (NETA; n = 40), or 2 mg drospirenone (DRSP; n = 40), a testosterone- and spironolactone-derived molecule, respectively. Weight (W) declined only during E/DRSP (p < 0.04 versus placebo). Fat mass (FM) decreased, similarly, during E/NETA and E/DRSP. Intracellular water (ICW) did not change, while extracellular water (ECW) decreased during E/DRSP (p < 0.0001) (p < 0.002 versus E/NETA). During E/NETA and E/DRSP, similar decreases were observed for insulin resistance (IR) by the homeostatic model assessment for IR (HOMA-IR) (p < 0.0001 versus placebo for both), systolic (p < 0.04 versus placebo for both) and diastolic (p < 0.002) blood pressure (BP). Lipids did not change. In comparison to placebo CS, by the Kupperman Index (KI), significantly declined (p < 0.0001) during E/NETA or E/DRSP. Menopause-specific Quality of Life (MENQoL) significantly declined versus placebo (p < 0.04) during both E/NETA and E/DRSP. In conclusion, differences between the two progestins are mainly limited to body composition (BC), where the addition of DRSP decreases ECW and body W (BW).

Background: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 mL. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative.The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and improvements in dysmenorrhoea (pain or cramps during menstruation). Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months after commencing treatment., Objectives: To determine the effectiveness, acceptability and safety of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding., Search Methods: All randomised controlled trials of progesterone or progestogen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, the specialised register of MDSG, MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), CINAHL (inception to December 2014) and PsycINFO (inception to January 2015). Additional searches were undertaken for grey literature and for unpublished trials in trial registers. Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials., Selection Criteria: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded., Data Collection and Analysis: Potential trials were independently assessed by at least two review authors. The review authors extracted the data independently and data were pooled where appropriate. Risk ratios (RRs) were estimated from the data for dichotomous outcomes and mean differences (MD) for continuous outcomes. The primary outcomes were reduction in menstrual blood loss and satisfaction; in addition, rate of adverse effects, changes in quality of life, failure of treatment and withdrawal from treatment were also assessed., Main Results: We included 21 RCTs (2082 women). The included trials mostly assessed the levonorgestrel-releasing intrauterine device (LNG IUS) (no conclusions could be reached from one small study assessing Progestasert which was discontinued in 2001) and so conclusions are based only on LNG IUS. Comparisons were made with placebo, oral medical treatment, endometrial destruction techniques and hysterectomy. Ratings for the overall quality of the evidence for each comparison ranged from very low to high. Limitations in the evidence included inadequate reporting of study methods and inconsistency.Seven studies compared the LNG IUS with oral medical therapy: either norethisterone acetate (NET) administered over most of the menstrual cycle, medroxyprogesterone acetate (MPA) (administered for 10 days), the oral contraceptive pill, mefenamic acid or usual medical treatment where participants could choose the oral treatment that was most suitable. The LNG IUS was more effective at reducing HMB as measured by the alkaline haematin method (MD 66.91 mL, 95% CI 42.61 to 91.20; two studies, 170 women; I(2) = 81%, low quality evidence) or by Pictorial Bleeding Assessment Chart (PBAC) scores (MD 55.05, 95% CI 27.83 to 82.28; three studies, 335 women; I(2) = 79%, low quality evidence), improving quality of life and a greater number of women continued with their treatment at two years when compared with oral treatment. Although substantial heterogeneity was identified for the bleeding outcomes, the direction of effect consistently favoured the LNG IUS. There was insufficient evidence to reach conclusions on satisfaction. Minor adverse effects (such as pelvic pain, breast tenderness and ovarian cysts) were more common with the LNG IUS.Ten studies compared the LNG IUS with endometrial destruction techniques: three with transcervical resection, one with rollerball ablation and six with thermal balloon ablation. Evidence was inconsistent and very low quality with respect to reduction in bleeding outcomes and satisfaction was comparable between treatments (low and moderate quality evidence). Improvements in quality of life were experienced with both types of treatment. Minor adverse events were more common with the LNG IUS overall, but it appeared more cost effective compared to thermal ablation within a two-year time frame in one study.Three studies compared the LNG IUS with hysterectomy. The LNG IUS was not as successful at reducing HMB as hysterectomy (high quality evidence). The women in these studies reported improved quality of life, regardless of treatment. In spite of the high rate of surgical treatment in those having LNG IUS within 10 years, the LNG IUS was more cost effective than hysterectomy., Authors' Conclusions: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy.When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques.The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment.

Objective: To compare cervical mucus score (CMS) with and without protease inhibitors (PI) before and after taking norethindrone (NET)., Study Design: This two-arm, researcher blinded, non-randomised, prospective study was conducted to evaluate cervical mucus quality in HIV-positive women taking progestin only pills. The study group was taking a PI, and compared to women taking ARV regimens that have demonstrated no significant interaction with NET in prior pharmacokinetic trials with combined oral contraceptives. The women had a cervical mucus score prior to NET administration. Mucus Scoring was repeated after 21 days of steady state exposure to oral NET 0.35 milligrams. Cervical mucus quality was quantified according to the World Health Organisation criteria, which include: volume, consistency, cellularity, spinnbarkeit, and ferning., Results: Sixteen women took PI and 17 were controls. Baseline CMS were similar (p ≥ 0.1). After 21 days CMS were similar among the two groups (p = 1)., Conclusions: HIV-positive women taking PI demonstrated thickened cervical mucus with oral norethindrone 0.35 mg and are similar to HIV-positive women taking no PI therapy. This may suggest no difference in contraceptive efficacy of progestin only pills in HIV-positive women taking PI.

Objective: To evaluate patient satisfaction at 6-months dienogest (DNG) treatment in women with symptomatic rectovaginal endometriosis who had pain persistence and were unsatisfied after 6-months of norethisterone acetate (NETA) therapy., Study Design: This 24-weeks pilot open-label prospective study enrolled 25 women. The main outcome was the degree of patient satisfaction measured by using a Likert scale. Secondary outcomes were to evaluate differences in endometriosis-related pain, quality of life, sexual function changes and volumetric nodules changes during DNG compared to NETA treatment., Results: Patient satisfaction improved at 3- and 6-months (p<0.001, respectively) treatment with DNG compared with baseline treatment with NETA. Six months DNG treatment decreased the intensity of all the endometriosis-associated pain (chronic pelvic pain, dyspareunia, dyschezia) compared to baseline (p<0.001 for all comparisons). Quality of life and quality of sexual life evaluated with the EHP-30 and FSFI, respectively, increased after 6 months treatment. The volume of the endometriotic nodules did not significantly change during treatment., Conclusions: This study confirms the efficacy of DNG in treating symptomatic women with rectovaginal endometriosis even in a particular endometriotic subpopulation of NETA "resistant" patients. Further randomized clinical trials comparing these two progestins both in first than second line are warranted., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the efficacy of preoperative treatment with aromatase inhibitors (AIs) in premenopausal women undergoing laparoscopic myomectomy of large uterine myomas., Study Design: Prospective non-randomized assessor-blind comparative trial., Results: This study included 80 patients undergoing laparoscopic myomectomy of large uterine myomas (≥8cm). Forty patients were treated with a combination of oral letrozole (2.5mg/day) and norethindrone acetate (2.5mg/day) continuously in the three months prior to surgery (group A) and 40 patients received no treatment before surgery (group B). The total operative time (mean±SD, range) was significantly lower in group A (121.5±19.9min; 89-181min) than in group B (134.4±16.8min; 111-185min; p<0.001). The time required to close the hysterotomies (mean±SD, range) was lower in group A (27.1±5.1min; 16-39min) than in group B (37.1±9.6min; 17-57min; p<0.001). The intraoperative blood loss (mean±SD, range) was lower in group A (271.0±125.6ml; 95-625ml) than in group B (460.4±205.7ml; 180-1115ml; p<0.001). No major complication occurred in any case. The cleavage plane was better defined in group B compared with group A (p<0.001). The quality of the myometrial scar, defined by ultrasound evaluation, was similar in the two study groups both at one-week (p=0.356) and at 3-month follow-up (p=0.201)., Conclusions: The total operative time, the time required to close the hysterotomies and the intraoperative blood loss significantly decrease after preoperative treatment with letrozole. Future randomized studies should compare the efficacy of preoperative administration of AIs and GnRHa prior to laparoscopic myomectomy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Recurrence of deep endometriosis remains a major issue in the management of endometriosis. The main cause for recurrence appears to be an incomplete excisional surgery. Therefore, the goal of the primary surgery should be the complete resection of all endometriotic lesions. If surgical skills cannot meet this objective it seems preferable to refer the patient to a center with a recognized expertise in this field rather than performing an incomplete surgery. It seems also possible to tailor the indications according to the symptoms, especially when endometriosis affects the bladder in association with an asymptomatic vaginal and/or rectal involvement. This strategy does not increase the rate of recurrence. Postoperative medical treatment based on ovarian function suppression is attractive as it diminishes the recurrence rate. Facing the recurrence, appropriate assessment of the benefit risk balance must be performed. Medical treatment is an option. When surgery is chosen, it seems interesting to discuss carefully the indication of hysterectomy with bilateral oophorectomy, especially for women over 40 years old with no desire for pregnancy and/or symptomatic adenomyosis. Risks of induced ovarian castration must be taken into account., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: The standard treatment for complex atypical hyperplasia is hysterectomy and bilateral salpingo-oophorectomy. Although radical surgery offers high survival prospects, it also eliminates any chance of further fertility, thus in young nulliparous women who wish to preserve their childbearing potential, a conservative progestin therapy is preferable., Case Report: The authors report a case of complex atypical hyperplasia in a 29-year-old nulliparous woman with polycystic ovary syndrome treated with norethisterone acetate in order to preserve her childbearing potential. The specimens sampled during the follow-up demonstrated inactive endometrium with pseudodecidual changes and no ultrasonographic images exhibited abnormal endometrial thickness., Conclusion: According to literature and to the authors' experience, they can affirm that progestin treatment is the most reasonable option for young nulliparous women affected by complex atypical hyperplasia who desire to maintain their fertility potential, showing its efficacy also in patients with an associated polycystic ovary syndrome.

Objective: Clinical trials have demonstrated an increased risk of breast cancer during estrogen/norethisterone (NET) therapy. With this in mind, the effects of estrogen/NET combination on the proliferation of breast cancer cells overexpressing the progesterone receptor membrane component 1 (PGRMC1) were examined. The same combination was used for the first time in a mouse xenograft model to determine its effects on tumor development., Methods: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells) or empty vector control (pcDNA-3HA). NET, medroxyprogesterone acetate (MPA), and progesterone were tested alone and sequentially and continuously combined with estradiol (E2). Six-week-old nude mice were inoculated with E2 pellets 24 hours before the injection of tumor cells into both flanks (n = 5-6 mice per group). After 8 days, animals were inoculated with a NET pellet or with placebo pellets, and tumor volumes were recorded twice a week., Results: NET alone significantly increased the proliferation of WT-12 cells, MPA was effective only at the two highest concentrations, and progesterone had no effect. The twofold to threefold E2-induced increase (10 M) was not significantly influenced by the addition of the various progestogens. In contrast, 10 M E2 had no effect; however, addition of MPA and NET triggered a significant proliferative response. In vivo, a sequential combination of NET and E2 also significantly increased the tumor growth of WT-12 cells; empty vector cells did not respond to NET., Conclusions: We have demonstrated for the first time that an E2/NET combination increases the proliferation of PGRMC1-overexpressing breast cancer cells, both in vivo and in vitro. Our results suggest that undetected tumor cells overexpressing PGRMC1 may be more likely to develop into frank tumor cells in women undergoing E2/NET hormone therapy.

Study Question: Does surgical and low-dose progestin treatment differentially affect endometriosis-associated severe deep dyspareunia in terms of sexual functioning, psychological status and health-related quality of life?, Summary Answer: Surgery and progestin treatment achieved essentially similar benefits at 12-month follow-up, but with different temporal trends., What Is Already Known: Conservative surgery and hormonal therapies have been used independently for endometriosis-associated deep dyspareunia with inconsistent results., Study Design, Size, Duration: Patient preference, parallel cohort study with 12-month follow-up. The effect of conservative surgery at laparoscopy versus treatment with a low dose of norethisterone acetate per os (2.5 mg/day) in women with persistent/recurrent severe deep dyspareunia after first-line surgery was compared., Participants/materials and Setting, Methods: A total of 51 patients chose repeat surgery and 103 progestin treatment. Variations in sexual function, psychological well-being and quality of life were measured by means of the Female Sexual Function Index (FSFI), the Hospital Anxiety and Depression Scale (HADS) and the Endometriosis Health Profile-30 (EHP-30)., Main Results and the Role of Chance: Four women in the surgery group and 21 women in the progestin group withdrew from the study for various reasons. Total FSFI scores, anxiety and depression scores and EHP-30 scores improved immediately after surgery, but worsened with time, whereas the effect during progestin use increased more gradually, but progressively, without overall significant between-group differences at 12-month follow-up. A tendency was observed towards a slightly better total FSFI score after surgery at the end of the study period., Limitations, Reasons for Caution: Treatments were not randomly allocated, and distribution of participants as well as of dropouts between study arms was unbalanced. However, the possibility of choosing the treatment allowed assessment of the maximum potential effect size of the interventions., Wider Implications of the Findings: Both surgery and medical treatment with progestins are valuable options for improving the detrimental impact of endometriosis-associated dyspareunia on sexual functioning and quality of life. Women should be aware of the pros and cons of both options to decide which one best suits their needs., Study Funding/competing Interest(s): This study was supported by a research grant from the University of Milan School of Medicine (PUR number 2009-ATE-0570). None of the authors have a conflict of interest.

Purpose: To evaluate the changes in the volume of rectovaginal endometriotic nodules infiltrating the rectum during 12-month treatment with hormonal therapies., Materials and Methods: This prospective, non-randomized, self-controlled clinical trial included patients with rectovaginal endometriotic nodules infiltrating at least the muscularis propria of the rectum, who received one of the following therapies: norethisterone acetate, triptorelin and tibolone, norethisterone acetate and letrozole, desogestrel, sequential oral contraceptive pill. The volume of the nodules was determined by virtual organ computer-aided analysis (VOCAL, GE Healthcare, USA) at baseline and after 6 and 12 months of treatment., Results: Eighty-three women (90.2 %) completed the 12-month treatment. When compared with baseline values, the volume of the nodules decreased at 6-month (p < 0.001) and 12-month treatment (p < 0.001). After 12-month treatment, the volume of the nodules decreased in all study groups. The volume of the nodules decreased during therapy in 68 women (73.9 %) and increased in 11 women (12.0 %)., Conclusion: 12-month administration of hormonal therapies reduces the volume of rectovaginal endometriotic nodules infiltrating the rectum in the majority of cases.

Purpose: To assess the efficacy of gonadotropin-releasing hormone agonist (GnRHa) in preventing chemotherapy-induced ovarian failure in patients treated for Hodgkin or non-Hodgkin lymphoma within the setting of a multicenter, randomized, prospective trial., Patients and Methods: Patients age 18 to 45 years were randomly assigned to receive either the GnRHa triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) concomitantly with alkylating agents containing chemotherapy. The primary end point was the premature ovarian failure (POF) rate (follicle-stimulating hormone [FSH] ≥ 40 IU/L) after 1 year of follow-up., Results: Eighty-four of 129 randomly assigned patients completed the 1-year follow-up. The mean FSH values were higher in the control group than in the GnRHa group during chemotherapy; however, this difference was no longer observed after 6 months of follow-up. After 1 year, 20% and 19% of patients in the GnRHa and control groups, respectively, exhibited POF (P = 1.00). More than half of patients in each group completely restored their ovarian function (FSH < 10 IU/L), but the anti-Müllerian hormone values were higher in the GnRHa group than in the control group (1.4 ± 0.35 v 0.5 ± 0.15 ng/mL, respectively; P = .040). The occurrence of adverse events was similar in both groups with the exception of metrorrhagia, which was more frequently observed in the control group than the GnRHa group (38.4% v 15.6%, respectively; P = .024)., Conclusion: Approximately 20% of patients in both groups exhibited POF after 1 year of follow-up. Triptorelin was not associated with a significant decreased risk of POF in young patients treated for lymphoma but may provide protection of the ovarian reserve.

Objective: This study compared the effects of a continuous-combined regimen of low-dose hormone therapy (LD-HT) versus tibolone and supplemental calcium/vitamin D3 (control) on quality of life (QoL) in symptomatic postmenopausal women., Design: This study was a prospective, randomised, double-blind, comparative trial with a control group., Setting: The study was conducted in a climacteric outpatient clinic in the University Hospital of Federal University of Juiz de Fora, Brazil., Population: A total of 174 postmenopausal women under 60 years of age who attended the climacteric outpatient clinic between June 2009 and June 2011 were recruited. These women complained of moderate or intense vasomotor symptoms and exhibited no contraindications for the use of hormone therapy., Interventions: The patients were randomised into three groups: (1) daily treatment with 2.5mg tibolone (n=64), (2) 50mg calcium carbonate+200 IU vitamin D3 (Ca/Vit D3, n=54) or (3) 1mg oestradiol+0.5mg norethindrone acetate (E2/NETA, n=56) for 12 weeks., Primary Outcome Measures: The primary outcome was the evaluation of QoL using the Women's Health Questionnaire (WHQ) in all subjects at baseline and after 4, 8 and 12 weeks of treatment., Results: A total of 130 women in the following groups completed the study: tibolone (n=42), Ca/Vit D3 (n=44) and E2/NETA (n=44). An improved QoL based on the WHQ was observed at T0 (80.12±14.04, 77.73±15.3, 77.45±15.4) and T12 (57.0±15.5, 55.7±16.7, 58.4±12.6) for the tibolone, E2+NETA and Ca/Vit D3 groups, respectively (p values <0.05). The three groups exhibited significantly different scores at T12 for sexual behaviour and vasomotor symptoms. The tibolone group exhibited better sexual function compared with the E2/NETA and Ca/Vit D3 groups (4.2±26, 5.6±2.8, 5.4±2.8, respectively, p values <0.05). LD-HT was superior to tibolone and Ca/Vit D3 treatment for improvements in vasomotor symptoms (3.2±1.5, 4.0±1.8, 4.3±2.0, respectively, p values <0.05). Adverse effects were few and mild., Conclusions: An improved QoL was observed in the three study groups. Tibolone primarily improved sexual function, and E2/NETA exhibited a superior response for vasomotor symptoms., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

It is established that hormone therapy (HT) is related with significant increased prothrombotic risk factor. The aim of our study was to assess the effects of oral hormone therapy (o-HT) and transdermal hormone therapy (t-HT) on hemostasis parameters: fibrinogen (Fg) concentration, the maximum velocity of polymerization of clot formation, fibrin half-time lysis, plasma level of thrombin inhibitor of fibrinolysis (TAFI) and activity of generated thrombin and plasmin amidolytic activity. We observed that values of initial velocity of polymerization in o-HT group were increased (94.64 mOD/min vs. 131.50 mOD/min, p < 0.001) compared to control group. Fibrin lysis half-time increased in both groups with HT (controls - 18.26 min vs. 32.43 min (o-HT); 23.34 min transdermal hormone therapy (t-HT) p < 0.001) compared to controls. The activity of thrombin was statistically higher in plasma of women after o-HT (72.6 ± 8.5 mOD/min) than in patients with t-HT (53.7 ± 10.1 mOD/min) and controls (51.2 ± 10 mOD/min. Plasmin activity was the highest in controls (84.5 ± 10.2 mOD/min). The highest level of TAFI we observed in patients after oral hormones (80.38 ± 8.23%); women on transdermal HT had 61.58 ± 9.81% and the lowest concentration of TAFI we noted in controls 44.70 ± 10.16). The results of our study show that HT may partly explain the increase in venous thrombosis (VTE) and cardiovascular events reported after the use of it, especially the oral form of treatment.

Objectives: To assess sexual function in a clinical sample of Lithuanian postmenopausal women and identify the most important determinants of sexual function, including the use of hormone replacement therapy (HT), emotional status and menopausal symptoms., Methods: Three hundred postmenopausal women who were referred to a gynecologist for a routine yearly check-up were enrolled for the study. Data for 246 women were appropriate for statistical analysis. Participants filled the Female Sexual Function Index for evaluation of sexual function, the Greene Climacteric Scale for the assessment of menopause symptoms and the Hospital Anxiety and Depression Scale for the evaluation of depression and anxiety symptoms., Results: Sexual function was better in younger women and in HT users compared with non-users. Thus, to analyze the other variables, an adjustment for age was applied. HT significantly increased the likelihood of higher desire, lubrication, satisfaction, and lower pain when adjusting results for age. HT reduced the likelihood of psychological and depression symptoms and increased the likelihood of vasomotor symptoms of menopause when results adjusted for age were analyzed. HT did not appear to affect anxiety symptoms after the results were adjusted for age., Conclusions: HT increased chances for better sexual desire, lubrication, satisfaction, less pain and lower depression symptoms in postmenopausal women, even when the results were adjusted by age. HT did not improve sexual arousal, orgasm, menopausal and anxiety symptoms. Depression, anxiety, menopausal symptoms and age were the main risk factors for the possible development of sexual dysfunction.

Objectives: Low-dose estrogen-progestin (LEP) agents are often used for relieving endometriosis-associated chronic pelvic pain, but a direct effect of LEP on endometriotic lesions remains to be demonstrated. The objective of this study is to investigate the antiproliferative and apoptotic effects of the synthetic progestin norethisterone (NET) against human endometriotic stromal cells (ESCs)., Study Design: Ovarian endometrioma specimens were obtained at laparoscopy from 19 patients with endometriosis, and ESCs were isolated. The antiproliferative effect of compounds against cultured ESCs was evaluated by measuring the inhibition of [(3)H]thymidine incorporation. The ability of compounds to induce apoptosis in the cultured cells was evaluated by the measurement of caspase 3/7 activity and by nuclear staining. The cytotoxicity of compounds was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the supernatant of the cell culture., Results: NET and progesterone (P4) at concentrations of greater than 10nM significantly inhibited [(3)H]thymidine incorporation in a dose-dependent manner. Co-treatment with 17β-estradiol at 0.1 ng/mL did not affect the inhibition of [(3)H]thymidine incorporation by NET. At concentrations greater than 100 nM, NET significantly increased caspase 3/7 activity and the numbers of apoptotic cells, whereas P4 did not. Treatment of ESCs for 24h with NET or P4 at concentrations of up to 1000 nM did not cause LDH leakage., Conclusions: NET inhibits the proliferation of ESCs and induces their apoptosis. These results suggest a possible direct effect of NET on endometriotic lesions in patients with endometriosis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Study Question: Does surgical or medical treatment for endometriosis-associated severe deep dyspareunia achieve better results in terms of patients' satisfaction (main study outcome), variation of coital pain and frequency of intercourse?, Summary Answer: Surgery and progestin therapy were equally effective in the treatment of deep dyspareunia in women with rectovaginal endometriosis, whereas medical therapy performed significantly better than excisional treatment in those without deeply infiltrating lesions., What Is Known and What This Paper Adds: Conservative surgery and hormonal therapies have been used independently for endometriosis-associated deep dyspareunia with inconsistent results. This study reports a direct comparison between the two treatment options in women with severe pain during intercourse., Design: Patient preference, parallel cohort study with a 12-month follow-up. The effect of conservative surgery at laparoscopy was compared with treatment with a low-dose of norethisterone acetate per os (2.5 mg/day) in women with persistent/recurrent severe deep dyspareunia after first-line surgery., Participants and Setting: A total of 51 patients chose repeat surgery and 103 progestin treatment. Patient satisfaction was graded according to a five-category scale. Variations in pain during intercourse were measured by means of a 100-mm visual analogue scale., Main Results and the Role of Chance: In the surgery group, a marked and rapid short-term dyspareunia score reduction was observed, followed by partial recurrence of pain. The pain relief effect of the progestin was more gradual, but progressive throughout the study period. At a 12-month follow-up, the frequency of intercourse per month (mean ± SD) was 4.6 ± 1.8 in the surgery group and 5.3 ± 1.5 in the norethisterone acetate group (P = 0.02). A total of 22/51 (43%) women were satisfied in the surgery group compared with 61/103 (59%) in the progestin group [adjusted odds ratios (OR), 0.36; 95% confidence interval (CI), 0.16-0.82; P = 0.015]. Corresponding figures in women with and without rectovaginal endometriotic lesions were, respectively, 13/24 (54%) versus 18/35 (51%; adjusted OR, 0.77; 95% CI, 0.22-2.67; P = 0.68), and 9/27 (33%) versus 43/68 (63%; adjusted OR, 0.23; 95% CI, 0.07-0.76, P = 0.02). BIAS, CONFOUNDING, AND OTHER REASONS FOR CAUTION: Treatments were not randomly assigned, and distribution of participants as well as of dropouts between study arms was unbalanced. However, the possibility of choosing the treatment allowed assessment of the maximum potential effect size of the interventions., Generalizability to Other Populations: Caucasian patients able to choose their treatment., Study Funding/competing Interest(s): This study was supported by a research grant from the University of Milan School of Medicine (PUR number 2009-ATE-0570). None of the authors have a conflict of interest.

Objective: To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women., Design: Open label, randomised controlled trial., Setting: Denmark, 1990-93., Participants: 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone., Interventions: In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years., Main Outcome Measure: The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction., Results: At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer., Conclusions: After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke., Trial Registration: ClinicalTrials.gov NCT00252408.

Objectives: This article is aimed to review the novel actions of progesterone, which otherwise is considered as a female reproductive hormone. The article focuses on its important physiological actions in males too and gives an overview of its novel perspectives in disorders of central and peripheral nervous system., Key Findings: Progesterone may have a potential benefit in treatment of traumatic brain injury, various neurological disorders and male related diseases like benign prostatic hypertrophy (BPH), prostate cancer and osteoporosis. Norethisterone (NETA), a progesterone derivative, decreases bone mineral loss in male castrated mice suggesting its role in osteoporosis. In the future, progesterone may find use as a male contraceptive too, but still needs confirmatory trials for safety, tolerability and acceptability. Megestrol acetate, a progesterone derivative is preferred in prostatic cancer. Further, it may find utility in nicotine addiction, traumatic brain injury (recently entered Phase III trial) and Alzheimer's disease, diabetic neuropathy and crush injuries. Studies also suggest role of progesterone in stroke, for which further clinical trials are needed. The non genomic actions of progesterone may be in part responsible for these novel actions., Summary: Although progesterone has shown promising role in various non-hormonal benefits, further clinical studies are needed to prove its usefulness in conditions like stroke, traumatic brain injury, neuropathy and crush injury. In male related illnesses like BPH and prostatic Ca, it may prove a boon in near future. New era of hormonal male contraception may be initiated by use of progesterone along with testosterone., (© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)

Background: Postmenopausal hormone therapy is associated with many diseases and conditions, e.g., cardiovascular diseases and asthma, but the underlying molecular mechanisms are incompletely understood. The aim of the current study was to investigate the effect of four different postmenopausal hormone therapy regimens on gene transcription., Materials and Methods: Twenty-four healthy postmenopausal women (six women in four groups) were randomly allocated to conventional-dose 17β-estradiol/norethisterone acetate (NETA), low-dose 17β-estradiol/NETA, tibolone, or raloxifene hydrochloride. RNA was isolated from whole blood before and after 6weeks of treatment. The changes in mRNA were assessed with a microarray chip., Results: The genes FKBP5, IL13RA1, TPST1, and TLR2 were up-regulated and among the most significantly changed genes in the groups treated with conventional-dose 17β-estradiol/NETA and tibolone. Up-regulation of TPST1 was associated with reduction of tissue factor pathway inhibitor in plasma. Nine biological pathways were associated with conventional-dose 17β-estradiol/NETA, most significantly the pathways for asthma, toll-like receptor signaling, cell adhesion molecules, and MAPK signaling. Transcriptional changes with false discovery rate below 0.10 were found in 10 genes in the conventional-dose 17β-estradiol/NETA group, 7 genes in the tibolone group, and zero genes in the women on low-dose 17β-estradiol/NETA. No genes or pathways were associated with raloxifene treatment., Conclusions: The difference between low-dose and conventional-dose17β-estradiol/NETA indicates an effect of dose on transcriptional response. Several genes and pathways related to cell adhesion molecules and immunity related cell surface receptors were influenced by conventional-dose 17β-estradiol/NETA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Gonadotropin-releasing hormone agonists (GnRHa) are an effective treatment of endometriosis-associated pelvic pain. The use of hormonal add-back therapy can alleviate the hypoestrogenic symptoms associated with GnRHa therapy, while preserving therapeutic efficacy. Norethindrone acetate (NETA) is a unique progestin that has both estrogenic and androgenic properties and is effective as an add-back regimen without estrogen supplementation. Through its estrogenic activity, NETA exerts beneficial effects on bone mineral density and vasomotor symptoms in women treated with GnRHa. In addition, NETA exhibits strong endometrial antiproliferative effects, which may result in further benefits for the endometriosis patient population. However, NETA add-back may be associated with progestogenic side effects and may lower high-density lipoprotein due to androgenic activity. These effects must be balanced with the overall benefits of NETA add-back therapy.

Study Objective: To evaluate the efficacy and tolerability of norethindrone acetate (NA) as single-agent hormonal therapy for suppression of endometriosis symptoms in adolescents and young adults., Design: Retrospective study., Setting: Two academic medical centers., Participants: A keyword search using the query 'NA' was applied to the electronic medical records of all women treated by one gynecologist (M.R.L.) from 1992 to 2010. IRB-approved chart review was then conducted on the index records., Interventions: Continuous treatment with NA (5-15 mg daily)., Main Outcome Measures: Postoperative bleeding and pain scores; adverse effects., Results: One hundred and ninety-four patients with surgically diagnosed endometriosis initiated NA postoperatively during the study period. Median patient age was 18.9 years. 92.2% of patients had stage 1 or 2 disease, and distribution was similar among those excluded. Median pain scores decreased from 5 at NA initiation to 0 at follow-up (P = .0001) and bleeding scores from 2 to 0, respectively (P = .001) for all stages of endometriosis. Post-NA bleeding scores were improved regardless of prior hormonal regimen, and post-NA pain scores improved in all patients except for those previously prescribed GnRH-agonist plus add-back. Most patients (55.2%) did not report any side effects. The most common adverse effect was weight gain (16.1%), with a mean increase in BMI of 1.2 ± 1.6 kg/m(2) at 12 months., Conclusion: NA alone is a well-tolerated, effective option to manage pain and bleeding for all stages of endometriosis. Among those on prior hormonal therapy, symptoms improved after NA initiation., (Copyright © 2012 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background: Dysfunctional uterine bleeding (DUB) is a common problem with complex management. It can be quite harrowing for the physicians as in most instances they are unable to pinpoint the cause of abnormal bleeding even after a thorough history and physical examination. Aim was to compare patient satisfaction for Levonorgestrel intra uterine system (LNG-IUS) and Norethisterone for the treatment of Dysfunctional Uterine Bleeding (DUB). It is Descriptive case series conducted in Department Obstetrics and Gynaecology, Shifa International Hospital, Islamabad from September, 2011 to September, 2012., Methods: One hundred and nineteen (119) female patients of reproductive age Group with DUB were selected by consecutive sampling. Informed written consent was obtained. A structural patient satisfaction questionnaire (PSQ) was used to collect information regarding age of patients, type of method used for treatment of DUB (Levonorgestrel or Norethisterone), treatment outcome in terms of patient satisfaction scale, and decrease in bleeding after 6 months., Results: The mean age of the patients was 41.03 +/- 4.415 year ranging from 28-60 years. The mean parity of women in the study was 3.22 +/- 1.188 with a range of 1-7. The satisfaction level was significantly (p < 0.05) greater (90% versus 20%) in Group A (levonorgesterol-releasing intrauterine system) as compared with Group B (Norethisterone). The blood loss was significantly (p < 0.05) decreased in Group A (98%) as compared with Group B (80%). The preference of continuing the method as well as recommendation to a friend was significantly greater in Group A as compared to Group B., Conclusion: The levonorgesterol-releasing intrauterine system (LNG-IUS) is a better choice as compared to Norethisterone, for treatment of DUB with 90% patients highly satisfied.

Risk assessment of future breast cancer risk through exposure to sex steroids currently relies on clinical scorings such as mammographic density. Knowledge about the gene expression patterns in existing breast cancer tumors may be used to identify risk factors in the breast tissue of women still free of cancer. The differential effects of estradiol, estradiol together with gestagens, or tibolone on breast cancer-related gene expression in normal breast tissue samples taken from postmenopausal women may be used to identify gene expression profiles associated with a higher breast cancer risk. Breast tissue samples were taken from 33 healthy postmenopausal women both before and after a six month treatment with either 2mg micronized estradiol [E2], 2mg micronized estradiol and 1mg norethisterone acetate [E2+NETA], 2.5mg tibolone [T] or [no HRT]. Except for [E2], which was only given to women after hysterectomy, the allocation to each of the three groups was randomized. The expression of 102 mRNAs and 46 microRNAs putatively involved in breast cancer was prospectively determined in the biopsies of 6 women receiving [no HRT], 5 women receiving [E2], 5 women receiving [E2+NETA], and 6 receiving [T]. Using epithelial and endothelial markers genes, non-representative biopsies from 11 women were eliminated. Treatment of postmenopausal women with [E2+NETA] resulted in the highest number of differentially (p<0.05) regulated genes (16.2%) compared to baseline, followed by [E2] (10.1%) and [T] (4.7%). Among genes that were significantly down-regulated by [E2+NETA] ranked estrogen-receptor-1 (ESR1, p=0.019) and androgen receptor (AR, p=0.019), whereas CYP1B1, a gene encoding an estrogen-metabolizing enzyme, was significantly up-regulated (p=0.016). Mammary cells triggered by [E2+NETA] and [E2] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. In this prospective study, prolonged administration of [E2+NETA] and to a lesser extent of [E2] but not [T] were associated in otherwise healthy breast tissue with a change in the expression of genes putatively involved in breast cancer. Our data suggest that normal mammary cells triggered by [E2+NETA] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. This feasibility study provides the basis for whole genome analyses to identify novel markers involved in increased breast cancer risk., (Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Testosterone administered alone or in combination with progestogens in male contraception induces reversible oligo-azoospermia, but its effects on body composition and metabolism are less known. We analysed anthropometric and metabolic parameters in five groups of 10 males: four receiving testosterone undecanoate (TU: 1000 mg) plus norethisterone enanthate (NETE: 200 mg) at different intervals (every 8 weeks: NETE-8; every 12 weeks: NETE-12; every 6 weeks for 12 weeks and then every 12 weeks: NETE-6/12; every 6 weeks for 12 weeks and then TU plus placebo every 12 weeks: NETE-6/12/0) and one placebo (NETE-0/0) for a total of 48 weeks. Body mass index (BMI) and waist circumference did not change in any groups except for the NETE-8 in which BMI increased significantly (p = 0.02) at the end of the treatment period. Lean body mass (MAMC or AMA) increased significantly in the highest hormonal dose groups (p = 0.04, NETE-6/12; p = 0.004, NETE-8). No differences were observed in glucose levels, insulin sensitivity index and lipid profile as well as in biochemical and cell count parameters in any groups. In conclusion, NETE and TU for 48 weeks were not accompanied by any metabolic changes and any adverse effects. The weight gain of the highest NETE plus TU dosage was mainly because of gain in muscle mass., (© 2010 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)