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Norethisterone (NET) is one of the earliest synthetic progestins. Its widespread and long-term use means that NET is often detected on the surface and in groundwater samples, which may cause harm t...

Background: Abnormal uterine bleeding is defined as irregularities in the menstrual cycle involving frequency, regularity, duration, and volume of flow outside of pregnancy. Up to 1/3rd of women experience abnormal uterine bleeding in their life, with irregularities most commonly occurs at menarche and perimenopause due to disruption of the hypothalamic-pituitary-ovarian axis. Aim: To compare the effectiveness of Norethisterone and Dydrogesterone for the treatment of irregular menstrual cycles due to abnormal uterine bleeding of ovulatory or endometrial dysfunction and to check for patient satisfaction after the use of prescribed hormones by taking their feedback. Methods: This observational, comparative, cohort-prospective study was conducted on 100 nonpregnant women between the ages of 15-45 years who presented with complaints of irregular menstruation in gynae outdoor of AMTH for 6 months from April 2021 to September 2021. After excluding pelvic pathology, known thyroid disease, coagulation disorder, or use of the contraceptive method, the participants were divided into Group A and Group B, each having 50 participants. Results: The mean age±SD of the participants in Group A was 29±3.4 while Group B had mean age±SD was 29.5±3.6. In Group A, 38(76%) patients reported a regular menstrual cycle after 3 months of use while 12(24%) patients complained of persistent irregular menstrual cycle despite 3 months use of Norethisterone with compliance in Group B using Dydrogesterone, 22(44%) patients had regular menstrual cycles while 28(56%) patients had persistent irregular menstrual cycles after three months of use. Conclusion: So we concluded from our study that Norethisterone had a better cycle control than Dydrogesterone. Keywords: Abnormal uterine bleeding of ovulatory and/or endometrial dysfunction, Norethisterone, Dydrogesterone

The role of the CTC1-STN1-TEN1 (CST) complex in Coats plus syndrome (CP), as well as other telomeropathy-phenotypes and disorders of genome instability is well documented. We report an Indian child with a clinical diagnosis of CP who presented to us with retinal exudates, extensive cerebral calcification, developmental delay and severe anemia consequent upon chronic gastrointestinal (GI) bleeding. Whole exome sequencing revealed compound heterozygous variants in STN1 as the probable genetic cause leading to CP in the present case. Of the two variants, the nonsense variant c.397C>T (p.Arg133*) was a truncating variant leading to loss of full protein length whereas the second variant c.985G>C (p.Ala329Pro) was novel and neither reported in ExAC, 1KGP or gnomAD. The deleteriousness of the novel variant was explored through molecular dynamics simulation analysis where p.Ala329Pro mutation affected C-terminal domain interaction between STN1 and TEN1 complex. Hormonal therapy using ethinyl estradiol and norethisterone was apparently associated with a clinically useful, although poorly sustained, decrease in blood transfusion requirement in the proband.

Objective The aim of the study was to evaluate whether combined oral contraceptives (COCs) can be used as hormone therapy (HT) to preserve bone mineral density (BMD) in women with premature ovarian insufficiency (POI). Methods An observational study of women with POI comparing the use of COC (ethinylestradiol 30 μg + levonorgestrel, continuously) with: low-dose HT (continuous conjugated estrogen 0.625 mg plus medroxyprogesterone or continuous estradiol [E2] 1 mg + norethisterone), high-dose HT (continuous conjugated estrogen 1.25 mg + medroxyprogesterone or continuous E2 2 mg + norethisterone), tibolone 2.5 mg, or no treatment. Bone density scans were performed every 2 ± 1 years. The difference between final and initial (delta) BMD values was calculated for the lumbar spine, total femur, and femoral neck. Generalized estimating equations were used to analyze the effect of treatment over time. Variables without normal distribution were transformed into ranks. Results Overall, 420 scans (210 deltas) of 119 women were analyzed. The women were 30.3 ± 9.2 years old (mean ± SD). BMD deltas at the lumbar spine and total femur were grater in the COC and high-dose HT groups. At the lumbar spine, the differences between two scans were greater in the COC group when compared to low-dose HT group: -0.043 (95% CI -0.062 to -0.024), untreated: -0.056 (-0.080 to -0.032), and tibolone: -0.050 (-0.094 to -0.006) groups. Total femur BMD decreases and the delta were lower in the low-dose HT group -0.038 (-0.052 to -0.024) when compared to COC. Conclusion Continuous COC was associated with increased BMD in women with POI compared to low-dose HT, with similar improvement in the COC and high-dose HT groups. : Video Summary:http://links.lww.com/MENO/A620.

Infrequent, irregularly irregular delayed menstrual period accompanied by heavy bleeding prolonged for weeks to months was treated with oral norethisterone 5mg tablet in 5mg – 30mg daily divided dose resulted in painful vaginal extrusion of huge fleshy mass (10 x7 x 5 cm) retaining the shape uterus histopathologically confirmed as decidual cast, a rare, as well as incomparable case, is described in an unmarried nulligravida in late twenty’s to alert the association of progesterone to membranous dysmenorrhea. Everyone under the hormonal treatment for menstrual disorders must be educated and made aware of the underlying dreadful possibility of painful vaginal expulsion of decidual cast ascribed to membranous dysmenorrhea to cope or overcome the fright.

Objective-To determine the efficacy and safety of ormeloxifene versus progesterone in controlling Ovulatory Abnormal Uterine Bleeding(AUB-O) Methods-A Prospective Randomized comparative study of total 100 females of reproductive age group 25 to 45 years with AUB-O.Patients were randomly divided in two groups of 50 each. Results-The study showed ormeloxifene was found to be more effective and safe than Norethisterone in AUB-O. Ormeloxifine as compared to norethisterone is more effective in improving Hb and reducing endometrial thickness. Hence, ORM is more superior than Norethisterone Conclusion-In this study ormeloxifene was found to be more effective in reducing blood loss,that leads to improvement in mean haemoglobin and also it had more ability to reduce endometrial thickness.As both ormeloxifene and norethisterone are very effectivebut ormeloxifene is safe , cost effective ,nonsteroidal, non hormonal drug with convenient dosage and better compliance for medical management of AUB-O.Hence, ormeloxifene canbe considered as first drugs in the management of AUB-O.

HIGHLIGHTS Endometriosis treatment is still a challenge for modern medicine Therapy with combined oral contraceptives (COCs) may be reconsidered at least for some patients Progestogens may be an effective alternative to COCs when it comes to endometriosis-related pelvic pain Aim The aim of this review article was to analyze and summarize the current treatment options of endometriosis-associated pain to provide additional information about treatment personalization for clinicians. Background Despite numerous studies being published, endometriosis is still one of the main challenges in gynecology. The etiology of endometriosis is unclear while its mechanism is believed to be connected to the peritoneal endometriotic lesions via retrograde menstruation, immunity abnormalities, and genetic, environmental, and lifestyle factors. Patients with endometriosis generally have to cope with chronic pelvic pain which definitely affects the quality of life. The disease is often characterized by a persistent recurrent course; therefore, when choosing a treatment, special attention should be paid not only to its efficacy, but also to long-term safety, tolerability, and compliance. Review results Actual and relevant publications in PubMed and eLibrary databases were studied. The authors highlight the pathogenic mechanisms of endometriosis and the current state of pharmacological management options. The available evidence on the use of combined oral contraceptives (COCs) for pelvic pain is critically assessed and the authors propose their opinion on the alternative treatment options with progestogens which seem to be an effective alternative to COCs with a more favorable safety profile. Conclusion Progestogens are an effective alternative to COCs in the treatment of endometriosis-associated pain; however, further well-conducted trials are needed in both types of therapy. Clinical significance The results of this literature review provide additional information to enable clinicians to personalize the treatment of endometriosis-associated pain. How to cite this article Dubrovina SO, Berlim YD, Bezhenar VF, et al. Pharmacological Management of Endometriosis-related Pain: The Expert Opinion. J South Asian Feder Obst Gynae 2020;12(6):415–420.

Study Objective The purpose of this prospective study was to assess the effectiveness of norethisterone (NET) in the management of abnormal uterine bleeding (AUB) in adolescents in a tertiary care center. Design This was a prospective audit focused on administering high doses of NET in female adolescents with complaints of AUB. Setting We included female adolescents who presented to our Emergency Gynecological Department or Adolescent Gynecological Outpatient Department from October 2016 to January 2019. Participants The study included 29 female adolescents aged 11-17 (mean, 13.14) years. Interventions Patients were administered a daily dose of 10-30 mg, depending on the severity of the condition, bleeding duration, and patient weight. Main Outcome Measures Cessation of vaginal bleeding. Results Mean age at menarche of our patient sample was 11.4 years (range, 10.7-14 years). AUB presented at a mean time of 24.6 months after menarche (range, 0-79 months). Blood transfusion was deemed necessary in 9 patients. Bleeding stopped at a mean of 46.1 (range, 8-120) hours after onset of treatment with NET. No serious adverse events were reported with NET administration, with only 3 cases of minor side effects. Conclusion The use of NET is an effective and reliable treatment option among adolescents for whom control of AUB is desired in the acute setting.

In this short communication, the editorial board publishes the information on safety of the combined hormonal contraceptive (CHC) Jeanine®, containing the fixed dose combination of dienogest and ethinyl estradiol. This information has been received from the Russian regulatory authority (Roszdravnadzor) and the manufacturer. According to a metaanalysis of four observational studies, women using the dienogest/ethinyl estradiol fixed dose combination had a higher risk of developing venous thromboembolism (VTE) as compared with women taking the CHCs containing the levonorgestrel/ ethinyl estradiol combination. The estimated risk of developing VTE in women taking the dienogest/ethinyl estradiol combination is 8-11 cases of VTE per 10,000 women per year, while in women taking the CHCs containing levonorgestrel, norethisterone or norgestimate the risk is 5-7 cases of VTE per 10,000 women per year. A patient information leaflet amendment is under consideration by the regulatory authorities. For now, however, hormonal contraceptives containing the dienogest/ethinyl estradiol combination accompanied with the previous version of the instruction are still available in pharmacies. Therefore, when prescribing the combined hormonal contraceptives with dienogest and ethinyl estradiol, the obstetrician-gynecologist should discuss these risks with the woman.

Objectives A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. Methods (1) In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. Methods (2) Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45–50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. Results (1) In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. Results (2) Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. Conclusion PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.

The objective: decline of frequency of relapses of hyperplastic processes of endometrium for the women of genesial age with surplus mass of body on the basis of improvement and introduction of algorithm of treatment-and-prophylactis and prognostic measures.Materials and methods. The conducted researches carried stage-by-stage character. So, on I stage the analysis of clinical-anamnestic, hormonal and metabolic features of patients of genesial age with surplus mass of body and hyperplastic processes of endometrium is a 1 group (n=90), patients with surplus mass of body, but without the hyperplastic processes of endometrium – 2 group (n=60).On II stage progressive, randomized, opened, comparative research of efficiency of hormonotherapy of hyperplastic processes of endometrium was conducted in 90 women of genesial age with surplus mass of body (1 group) by the agonist of gonadotropin-releasing hormone (sub-group of 1.1, n=30), progestine (sub-group of 1.2, n=30), by estrogen-gestagenic preparation (sub-group of 1.3, n=30) and means that it is powerful enough. On III stage were found out the factors of risk of uneffectiveness of treatment and recurrent flow of hyperplastic processes of endometrium for the women of genesial age with obesity. Method of incremental discriminant analysis (n=90): patients with recurrent motion of hyperplastic processes of endometrium (3 group of, n=40), patients without the relapse of hyperplastic processes of endometrium (4 group of, n=50).Results. At the comparative estimation of efficiency of treatment of hyperplastic processes of endometrium for women it was set with surplus mass of body, that frequency of relapses in 24 months takes place for 6,7% patients after therapy of а-GRG, at 46,7% patients which got norethisterone, and for 63,3% women, treated the combined oral contraceptives. A level of the forced operative treatment (hysterectomia) is 3,3% for women which got а-GRG and 23,3%, – norethisterone and combined oral contraceptives.Conclusion. For the women of genesial age with the hyperplastic processes of endometrium and surplus mass of body for treatment most effective and safe in relation to operating there is application of а-GRG on metabolic processes and hormonal status. The use of norethisterone and combined oral contraceptives is possibly in default of found out the factors of risk., Цель исследования: снижение частоты рецидивов гиперпластических процессов эндометрия у женщин репродуктивного возраста с избыточной массой тела на основе усовершенствования и внедрения алгоритма лечебно-профилактических и прогностических мероприятий.Материалы и методы. Проведенные исследования носили поэтапный характер. Так, на І этапе был проведен анализ клинико-анамнестических, гормональных и метаболических особенностей пациенток репродуктивного возраста с избыточной массой тела и гиперпластическими процессами эндометрия – 1-я группа (n=90), пациентки с избыточной массой тела, но без гиперпластических процессов эндометрия вошли во 2-ю группу (n=60).На ІІ этапе было проведено прогрессивное рандомизированное открытое сравнительное исследование эффективности гормональной терапии гиперпластических процессов эндометрия у 90 женщин репродуктивного возраста с избыточной массой тела (1-я группа) агонистом гонадотропин-рилизинг-гормона (подгруппа 1.1, n=30), прогестином (подгруппа 1.2, n=30), эстроген-гестагенным препаратом (подгруппа 1.3, n=30).На ІІІ этапе были обнаружены факторы риска неэффективности лечения и рецидивного течения гиперпластических процессов эндометрия у женщин репродуктивного возраста с ожирением. Метод пошагового дискриминантного анализа (n=90): пациентки с рецидивирующим ходом гиперпластических процессов эндометрия (3-я группа, n=40), пациентки без рецидива гиперпластических процессов эндометрия (4-я группа, n=50).Результаты. При сравнительной оценке эффективности лечения гиперпластических процессов эндометрия у женщин с избыточной массой тела было установлено, что частота рецидивов через 24 мес отмечается у 6,7% пациенток после терапии а-GRG, у 46,7% больных, которые получали норэтистерон, и у 63,3% женщин, пролеченных комбинированными оральными контрацептивами. Уровень вынужденного оперативного лечения (гистерэктомия) составляет 3,3% у женщин, которые получали а-GRG и 23,3% – у пациенток, которые принимали норэтистерон и комбинированные оральные контрацептивы.Заключение. У женщин репродуктивного возраста с гиперпластическими процессами эндометрия и избыточной массой тела для лечения наиболее эффективным и безопасным относительно действия на метаболические процессы и гормональный статус является применение а-GRG. Использование норэтистерона и комбинированных оральных контрацептивов возможно при отсутствии обнаруженных факторов риска., Мета дослідження: зниження частоти рецидивів гіперпластичних процесів ендометрія у жінок репродуктивного віку з надмірною масою тіла на основі удосконалення та впровадження алгоритму лікувально-профілактичних та прогностичних заходів.Матеріали та методи. Проведені дослідження носили поетапний характер. Так, на І етапі було проведено аналіз клініко-анамнестичних, гормональних і метаболічних особливостей пацієнток репродуктивного віку з надмірною масою тіла та гіперпластичними процесами ендометрія – 1-а група (n=90), пацієнтки з надмірною масою тіла, але без гіперпластичних процесів ендометрія включено до 2-ї групи (n=60).На ІІ етапі було проведено прогресивне рандомізоване відкрите порівняльне дослідження ефективності гормональної терапії гіпер-пластичних процесів ендометрія у 90 жінок репродуктивного віку з надмірною масою тіла (1-а група) агоністом гонадотропін-рилізинг-гормону (підгрупа 1.1, n=30), прогестином (підгрупа 1.2, n=30), естроген-гестагенним препаратом (підгрупа 1.3, n=30).На ІІІ етапі було виявлено фактори ризику неефективності лікування і рецидивного перебігу гіперпластичних процесів ендометрія у жінок репродуктивного віку з ожирінням. Метод покрокового дискримінантного аналізу (n=90): пацієнтки з рецидивуючим перебігом гіперпластичних процесів ендометрія (3-я група, n=40), пацієнтки без рецидиву гіперпластичних процесів ендометрія (4-а група, n=50).Результати. Під час порівняльного оцінювання ефективності лікування гіперпластичних процесів ендометрія у жінок із надмірною масою тіла було встановлено, що частота рецидивів через 24 міс спостерігається у 6,7% пацієнток після терапії a-GRG, у 46,7% хворих, що отримували норетистерон, у 63,3% жінок, що вживала комбіновані оральні контрацептиви. Рівень вимушеного оперативного лікування (гістеректомія) становить 3,3% у жінок, які отримували a-GRG та 23,3% – у жінок, які вживали норетистерон та комбіновані оральні контрацептиви.Заключення. У жінок репродуктивного віку з гіперпластичними процесами ендометрія та надмірною масою тіла для лікування найбільш ефективним і безпечним щодо дії на метаболічні процеси і гормональний статус є застосування a-GRG. Використання норетистерону і комбінованих оральних контрацептивів можливо за відсутності виявлених чинників ризику.

The association between low-dose combined oral contraceptives (COCs) and anticoagulation factors in Japanese women has been rarely studied. A total of 394 Japanese women with a new beginning cycle of COC use were enrolled, of whom 335 women visited the clinic within 4 weeks after starting the first cycle of COC. Visits occurred in the active phase (272 women) and the placebo phase (63 women). Free protein S (PS) antigen and activity levels and antithrombin activity levels decreased significantly in both the active and placebo phase groups. Protein C (PC) activity levels increased significantly in both groups. Larger reductions in free PS antigen and activity levels occurred with COC comprising either 30 µg ethinylestradiol/desogestrel or 20 µg ethinylestradiol/drospirenone than that comprising 35 µg ethinylestradiol/norethisterone. In four women with the Japanese-specific PS K196E mutation, mean PS activity was 65% before COC use and 57% during COC use, indicating further decrease with COC use. In conclusion, decreased antigen and activity levels of PS and antithrombin and increased activity levels of PC were observed even during the first cycle of low-dose COC use. The effects on PS and PC activities were also observed in the hormone-free interval.

Background The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A), on host susceptibility to Mycobacterium tuberculosis (Mtb) are unknown. Methods We recruited human immunodeficiency virus–uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, and dexamethasone on Mtb containment in monocyte-derived macrophages co-incubated with purified protein derivative (PPD)–driven peripheral blood–derived effector cells. Results MPA (P < .005) and dexamethasone (P < .01), but not NET-A, significantly attenuated Mtb containment in Mtb-infected macrophages co-cultured with PPD-driven effector cells at physiologically relevant concentrations and in a dose-dependent manner. Antagonizing the glucocorticoid receptor with mifepristone (RU486) abrogated the reduction in Mtb containment. In PPD-stimulated peripheral blood mononuclear cells, MPA and dexamethasone, but not NET-A, upregulated (median [interquartile range]) regulatory T cells (5.3% [3.1%–18.2%]; P < .05), reduced CD4+ T-cell interferon-γ (21% [0.5%–28%]; P < .05) and granzyme B production (12.6% [7%–13.5%]; P < .05), and reduced CD8+ perforin activity (2.2% [0.1%–7%]; P < .05). RU486 reversed regulatory T-cell up-regulation and the inhibitory effect on Th1 and granzyme/perforin-related pathways. Conclusions MPA, but not NET-A, subverts mycobacterial containment in vitro and downregulates pathways associated with protective CD8+- and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in tuberculosis-endemic countries., Injectable contraceptive usage is high in tuberculosis (TB)–endemic countries, and their effect on TB pathogenesis in humans has not been investigated. At physiological concentrations, medroxyprogesterone acetate, but not norethisterone acetate, attenuates Mycobacterium tuberculosis containment and antagonizes pathways associated with protective host immunity through glucocorticoid receptor–mediated mechanisms.

BACKGROUND Dysfunctional Uterine Bleeding is defined as abnormal uterine bleeding in the absence of organic disease. Regarding the medical management of DUB, several drugs have been used, however there is lack of studies suggesting the most appropriate drug. The objective of the study was to compare the two drugs, Norethisterone a progesterone derivative and Ormeloxifene, a selective oestrogen receptor modulator in terms of effectiveness and safety. MATERIALS AND METHODS Women attending Gynaec OPD s with DUB were chosen for the study. Sample size was hundred which was divided in 2 groups. Ormeloxifene 60mg twice weekly for 12 weeks followed by once a week for another 12 weeks was given in group A. Group B women received norethisterone 5mg twice a day from day 5 to day 26 of a cycle for 6 months. Primary outcome parameters noted were reduction in menstrual blood loss as measured by fall in PBAC (Pictorial Blood Loss Assessment Chart) score, increase in haemoglobin, and decrease in endometrial thickness at the end of the study. RESULTS Ormeloxifene showed a better reduction in mean PBAC score (225 to 75) compared to norethisterone (234 to 110) at 6 months (p

Objective The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography–tandem triple quadrupole mass spectrometry (LC–MS/MS) and apply this method to human serum samples. Study design We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC–MS/MS platform. We analyzed serum collected from women self-reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). Results Limits of quantitation were 0.010 ng/mL for E2, EE2 and P4; 0.020 ng/mL for ENG, LNG and MPA; and 0.040 ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%–108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. Conclusions We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. Implications This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing.

Previously, levonorgestrel (LNG) has been shown to be an endocrine disruptor of the amphibian thyroid system. In the present study, we investigated whether anti-thyroidal effects are a common property of progestins other than LNG. Premetamorphic Xenopus laevis tadpoles were exposed to norethisterone (NET) and dienogest DIE (each at 0.1-10nM) and LNG (10nM) until completion of metamorphosis. LNG and NET at all concentrations caused a significant developmental retardation whereas DIE did not impair time to metamorphosis. In LNG and 10nM NET exposed animals, tsh mRNA levels increased considerably later than the developmental delay occurred and thyroid histopathology showed no signs of TSH-hyperstimulation. Instead, thyroid glands from these treatments appeared inactive in producing thyroid hormones. Thyroidal transcript levels of dio2 and dio3 were increased by treatments with LNG and NET at 1nM and 10nM, whereas iyd mRNA was reduced by LNG and 10nM NET. Expression of slc5α5 was not changed by any treatment. Effects of DIE differed from those induced by LNG and NET. No developmental delay was measurable; however, tshβ and dio2 mRNAs were increased in pituitary glands of tadpoles exposed to 1.0nM and 10nM DIE. Thyroid histopathology displayed no abnormalities and thyroidal mRNA expression of the genes analyzed (slc5α5, iyd, dio2, dio3) was not changed by DIE. Overall, our results provide evidence that the anti-thyroidal effects already known from LNG are also present in another progestin, namely NET, even at environmentally relevant concentrations. In conclusion we suggest that progestins do not only pose an environmental risk in terms of their impact on reproductive success of aquatic vertebrates, but also with respect to their anti-thyroidal properties affecting amphibian metamorphosis.

It is known that a small fraction of orally administered norethisterone is metabolically converted to ethinylestradiol. This exploratory, open-label, nonrandomized study was conducted to investigate the systemic exposure to ethinylestradiol after intramuscular administration of norethisterone enantate in comparison with the exposure to ethinylestradiol after administration of a standard combined oral contraceptive. Sixteen healthy premenopausal women received an oral contraceptive (ethinylestradiol 30 μg/levonorgestrel 150 μg) once daily for 21 days and-after a 1-week washout period-a single intramuscular dose of 200 mg norethisterone enantate. Blood samples to determine ethinylestradiol in serum were taken over 24 hours after the last dose of ethinylestradiol/levonorgestrel and over 8 weeks after administration of norethisterone enantate. Oral equivalent doses of ethinylestradiol were estimated based on area under the concentration-time curves. The ethinylestradiol serum concentrations observed after administration of norethisterone enantate were relatively low: The mean maximum concentration was only 32% of the maximum observed after ethinylestradiol/levonorgestrel (90% confidence interval, 22.5%-44.7%). The maximum oral equivalent dose of ethinylestradiol was markedly lower than 30 μg ethinylestradiol per day (20.3 μg/day; 90% confidence interval, 14.8-28.0 μg/day). The same applied to the average oral equivalent dose of ethinylestradiol for the 8-week postdose interval (4.41 μg/day; 90% confidence interval, 3.57-5.46 μg/day). To conclude, the study results indicate that metabolic conversion of norethisterone to ethinylestradiol also occurs after intramuscular administration of 200 mg norethisterone enantate, but is associated with a lower exposure to ethinylestradiol than the use of a combined oral contraceptive containing 30 μg ethinylestradiol (plus 150 μg levonorgestrel).

// Marina Willibald 1 , Giuliano Bayer 1 , Vanessa Stahlhut 1 , Gereon Poschmann 2 , Kai Stuhler 2, 3 , Berthold Gierke 4 , Michael Pawlak 4 , Harald Seeger 5 , Alfred O. Mueck 5 , Dieter Niederacher 1 , Tanja Fehm 1 and Hans Neubauer 1 1 Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Duesseldorf, Germany 2 Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Duesseldorf, Duesseldorf, Germany 4 Institute for Molecular Medicine, University Hospital Duesseldorf, Duesseldorf, Germany 3 NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany 4 Department of Women’s Health, University Hospital and Faculty of Medicine of the Eberhard Karls University Tuebingen, Tuebingen, Germany Correspondence to: Marina Willibald, email: marina.willibald@med.uni-duesseldorf.de Keywords: breast cancer, PGRMC1, progestins, norethisterone, casein Kinase 2 Received: January 24, 2017 Accepted: June 27, 2017 Published: August 02, 2017 ABSTRACT Menopausal hormone therapy, using estrogen and synthetic progestins, is associated with an increased risk of developing breast cancer. The effect of progestins on breast cells is complex and not yet fully understood. In previous in vitro and in vivo studies, we found different progestins to increase the proliferation of Progesterone Receptor Membrane Component-1 (PGRMC1)-overexpressing MCF7 cells (MCF7/PGRMC1), suggesting a possible role of PGRMC1 in transducing membrane-initiated progestin signals. Understanding the activation mechanism of PGRMC1 by progestins will provide deeper insights into the mode of action of progestins on breast cells and the often-reported phenomenon of elevated breast cancer rates upon progestin-based hormone therapy. In the present study, we aimed to further investigate the effect of progestins on receptor activation in MCF7 and T47D breast cancer cell lines. We report that treatment of both breast cancer cell lines with the progestin norethisterone (NET) induces phosphorylation of PGRMC1 at the Casein Kinase 2 (CK2) phosphorylation site Ser181, which can be decreased by treatment with CK2 inhibitor quinalizarin. Point mutation of the Ser181 phosphorylation site in MCF7/PGRMC1 cells impaired proliferation upon NET treatment. This study gives further insights into the mechanism of differential phosphorylation of the receptor and confirms our earlier hypothesis that phosphorylation of the CK2-binding site is essential for activation of PGRMC1. It further suggests an important role of PGRMC1 in the tumorigenesis and progression of breast cancer in progestin-based hormone replacement therapy.

During menopausal hormone therapy (MHT) a possible increase in breast cancer risk is thought to depend mainly on the progestogen component. In vitro studies have shown that the progesterone receptor membrane component 1 (PGRMC1) is important for tumor proliferation induced by progestogens. The primary aim of this study was to compare for the first time the natural progestogen, progesterone (P), with a synthetic progestogen, norethisterone (NET), using a xenograft model.MCF7 cells, transfected with PGRMC1 plasmid or empty vector, were injected into nude mice and estradiol (E2) pellets were implanted. After 12days, NET or P or placebo pellets were implanted. Tumor volumes in all groups (6 mice/group) were monitored for 6-7 weeks. Immunohistochemical expression of PGRMC1 and KI-67 was assessed. These experiments were repeated using T47D cells.Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p0.01); progesterone did not increase growth. Breast cancer cells transfected with empty vectors did not respond to either progestogen. Comparing KI-67 and PGRMC1 expression, the Pearson correlation was r=0.848, p=0.002.E2 plus NET increases tumor growth in human breast cancer cells overexpressing PGRMC1, but there is no change with progesterone. To our knowledge, this is the first comparison of both progestogens in vivo using nude mice, which are frequently used in xenograft models. Clinical trials are needed to determine whether women with overexpression of PGRMC1 are at increased risk of breast cancer if NET instead of progesterone is used in MHT.

Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vi...

IntroductionProgestogens (progestins) are widely used for contraception, in postmenopausal hormone therapy, and in treatment of abnormal uterine bleeding and endometriosis. Norethisterone (NET) and its acetate (NETA) differ from other progestogens by their partial conversion to ethinylestradiol (EE). We review their special characteristics and focus on the clinically relevant risk factors associated with estrogen action, such as migraine with aura and risk of thrombosis.MethodsNarrative review based on a medical literature (OvidMedline and PubMed) search.ResultsNET converts to significant amounts of EE; 10–20 mg NET corresponds to 20–30 µg EE. The effects of NET on the endometrium are pronounced, making it a good choice for treating abnormal uterine bleeding, endometriosis, and endometrial hyperplasia. NET also has beneficial effects on bone mineral density and positive or neutral effects on cardiovascular health. Conversely, long-term use of NET is associated with a slightly increased breast cancer risk, and the risk of venous thromboembolism is moderately increased. This risk seems to be dose-dependent; contraceptive use carries no risk, but therapeutic doses might be associated with an increased risk. Studies suggest an association between combinations of EE and progestogens and ischaemic stroke, which in particular concerns women with migraine. No studies have, however, assessed this risk related to the therapeutic use of NET.ConclusionsNET is a potent progestogen, especially when considering the endometrium. Its partial conversion to EE, however, is important to remember. Clinical consideration is required with women at high risk for either breast cancer or thromboembolism, or experiencing migraine with aura.

Objectives We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods. Study design We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18–49 years. Results In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence. Conclusion All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE. Implications Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users.

BACKGROUND: Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their physical, emotional, social and material quality of life. Whilst abnormal menstrual bleeding may be associated with underlying pathology, in the present context, HMB is defined as excessive menstrual bleeding in the absence of other systemic or gynaecological disease. The first‐line therapy is usually medical, avoiding possibly unnecessary surgery. Of the wide variety of medications used to reduce HMB, oral progestogens were originally the most commonly prescribed agents. This review assesses the effectiveness of two different types and regimens of oral progestogens in reducing ovulatory HMB. This is the update of a Cochrane review last updated in 2007, and originally named "Effectiveness of cyclical progestagen therapy in reducing heavy menstrual bleeding" (1998). OBJECTIVES: To determine the effectiveness, safety and tolerability of oral progestogen therapy taken either during the luteal phase (short cycle) or for a longer course of 21 days per cycle (long cycle), in achieving a reduction in menstrual blood loss in women of reproductive age with HMB. SEARCH METHODS: In January 2019 we searched Cochrane Gynaecology and Fertility's specialized register, CENTRAL, MEDLINE, Embase, CINAHL and PsycInfo. We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved trials. We also checked citation lists of review articles to identify trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing different treatments for HMB that included cyclical oral progestogens were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. We contacted trial authors for clarification of methods or additional data when necessary. We only assessed adverse events if they were separately measured in the included trials. We compared cyclical oral progestogen in different regimens and placebo or other treatments. Our primary outcomes were menstrual blood loss and satisfaction with treatment; the secondary outcomes were number of days of bleeding, quality of life, compliance and acceptability of treatment, adverse events and costs. MAIN RESULTS: This review identified 15 randomized controlled trials (RCTs) with 1071 women in total. Most of the women knew which treatment they were receiving, which may have influenced their judgements about menstrual blood loss and satisfaction. Other aspects of trial quality varied among trials. We did not identify any RCTs comparing progestogen treatment with placebo. We assessed comparisons between oral progestogens and other medical therapies separately according to different regimens. Short‐cycle progestogen therapy during the luteal phase (medroxyprogesterone acetate or norethisterone for 7 to 10 days, from day 15 to 19) was inferior to other medical therapy, including tranexamic acid, danazol and the progestogen‐releasing intrauterine system (Pg‐IUS (off the market since 2001)), releasing 60 mcg of progesterone daily, with respect to reduction of menstrual blood loss (mean difference (MD) 37.29, 95% confidence interval (CI) 17.67 to 56.91; I(2) = 50%; 6 trials, 145 women, low‐quality evidence). The rate of satisfaction and the quality of life with treatment was similar in both groups. The number of bleeding days was greater on the short cycle progestogen group compared to other medical treatments. Adverse events (such as gastrointestinal symptoms and weight gain) were more likely with danazol when compared with progestogen treatment. We note that danazol is no longer in general use for treating HMB. Long‐cycle progestogen therapy (medroxyprogesterone acetate or norethisterone), from day 5 to day 26 of the menstrual cycle, is also inferior compared to the levonorgestrel‐releasing intrauterine system (LNG‐IUS), tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss (MD 16.88, 95% CI 10.93 to 22.84; I(2) = 87%; 4 trials, 355 women, very low‐quality evidence). There was no clear evidence of a difference between progestogen therapy long cycle and other medical therapy in terms of headache (OR 1.45, 95% CI 0.40 to 5.31; I(2) = 0%; 2 trials, 189 women; low‐quality evidence). Breakthrough bleeding or spotting was more likely in women with the LNG‐IUS (OR 0.18, 95% CI 0.06 to 0.55; I(2) = 0%; 3 trials, 220 women; low‐quality evidence). No trials reported on days of bleeding or quality of life for this comparison. The evidence supporting these findings was limited by low or very low gradings of quality; thus, we are uncertain about the findings and there is a potential that they may change if we identify other trials. AUTHORS' CONCLUSIONS: Low‐ or very low‐quality evidence suggests that short‐course progestogen was inferior to other medical therapy, including tranexamic acid, danazol and the Pg‐IUS with respect to reduction of menstrual blood loss. Long cycle progestogen therapy (medroxyprogesterone acetate or norethisterone) was also inferior to the LNG‐IUS, tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss.

During menopausal transition, various phenotypical and metabolic changes occur, affecting body weight, adipose tissue distribution and energy expenditure as well as insulin secretion and sensitivity. Taken together, these can predispose women to the development of type 2 diabetes mellitus (T2DM). Many women in midlife experience climacteric symptoms, including hot flashes and night sweats. Menopausal hormone therapy (MHT) is then indicated. MHT has a favourable effect on glucose homeostasis in both women without and with T2DM. T2DM was considered in the past as a cardiovascular disease (CVD) equivalent, which would suggest that women with T2DM should not receive MHT. This notion may still deter many clinicians from prescribing MHT to these patients. However, nowadays there is strong evidence to support an individualised approach after careful evaluation of CVD risk. In older women with T2DM (> 60 years old or > 10 years in menopause), MHT should not be initiated, because it may destabilise mature atherosclerotic plaques, resulting in thrombotic episodes. In obese women with T2DM or in women with moderate CVD risk, transdermal 17β-oestradiol could be used. This route of delivery presents beneficial effects regarding triglyceride concentrations and coagulation factors. In peri- or recently post-menopausal diabetic women with low risk for CVD, oral oestrogens can be used, since they exhibit stronger beneficial effects on glucose and lipid profiles. In any case, a progestogen with neutral effects on glucose metabolism should be used, such as natural progesterone, dydrogesterone or transdermal norethisterone. The goal is to maximise benefits and minimise adverse effects.

Objectives: To evaluate the effect of oral progesterone for the treatment of abnormal uterine bleeding in patients taking warfarin after prosthetic valve replacement. Methods: A total of 85 women of reproductive age, who were on warfarin due to prosthetic valve replacement were enrolled in the study. After detailed evaluation, their menstrual bleeding was quantified using Pictorial Bleeding Evaluation Chart. The patients were then prescribed an oral progesterone (Norethisterone) 5 mg three times daily. The first follow up was done after one-month then at 3-months and at six months. The improvement in PBAC score was recorded at each visit. Data was entered and analyzed using SPSS (version 23.0). The mean ± Standard Deviation were calculated for quantitative variables while qualitative variables were presented in frequency table. The normality of data was checked using Kolmogorov-Smirnov test. Due lack of normal distribution of data in various groups, the Wilcoxon Sign Rank test was used to test the significance before and after treatment. The p-value of

Objective: Experience of Norethisterone Tablets in the treatment of perimenopausal dysfunctional uterine bleeding, which in order to exchange experience with Clinician. Methods: 60 patients who were treated in our hospital during May 2015 to May 2016 have been diagnosed with perimenopausal dysfunctional uterine bleeding as the research object, and performed Diagnostic curettage on all patients. Then, randomly divided all the patients into two groups that every group has 30 cases. The patients in the experimental group were given Norethisterone Tablets after curettage, but the control group was given Medroxyprogesterone Acetate Tablets. Results: In the experimental group, 14 cases were cured, 11 cases were markedly effective, 3 cases were effective, and the total effective rate was 93.33%. While in the control group, 5 cases were cured, 9 cases were markedly effective, 10 cases were effective, the total effective rate was 80%. The comparison showed that the total effective rate of the two groups was different, and the difference was statistically significant (P

Endometriosis is a chronic inflammatory disorder associated with pelvic pain and infertility. Because surgical and medical therapies control symptoms, but it is hard to cure completely endometriosis, long term of pharmacologic management is necessary. Norethisterone (NET), one of progestins, has safety profile and advantage that allow long-term use. In this preliminary report, we showed the efficacy of NET in 6 patients with endometriosis. The size of ovarian endometrioma was decreased after treatment with NET for 6 months, and all patients were relieved from dysmenorrhea pain within 6 months, suggesting that NET would be a suitable medication to treat endometriosis.

Introduction The aim was to compare contraceptive use in the Nordic countries and to assess compliance with recommendations from the European Medicines Agency regarding the use of combined oral contraception containing low-dose estrogen and levonorgestrel, norethisterone or norgestimate. Material and methods Data on hormonal contraceptive prescriptions and sales figures for copper intrauterine devices were obtained from national databases and manufacturers in Denmark, Finland, Iceland, Norway and Sweden in 2010–2013. Results Contraceptive use was highest in Denmark (42%) and Sweden (41%), followed by Finland (40%). Combined oral contraception was the most used method in all countries, with the highest use in Denmark (26%). The second most used method was the levonorgestrel-releasing intrauterine system, with the highest use in Finland (15%) and ≈10% in the other countries. Copper intrauterine devices (7%) and the progestin-only pill (7%) were most often used in Sweden. Combined oral contraception use decreased with increasing age and levonorgestrel-releasing intrauterine system and progestin-only pills use increased. The use of long-acting reversible methods of contraception (=levonorgestrel-releasing intrauterine system, copper intrauterine devices, and implants) increased with time and was highest in Sweden (20%) and Finland (18%). The highest use of European Medicines Agency recommended combined oral contraception was in Denmark, increasing from 13 to 50% between 2010 and 2013. In Finland, recommended combined oral contraception remained below 1%. Conclusions Contraceptive use was highest in Denmark and Sweden, levonorgestrel-releasing intrauterine system use was highest in Finland and all long-acting methods were most common in Sweden. The use of combined oral contraception recommended by the European Medicines Agency was highest in Denmark.

Objective To evaluate the efficacy and safety of an ultra-low-dose oral contraceptive (NPC-01; 0.02 mg ethinyl estradiol and 1 mg norethisterone) in subjects with dysmenorrhea. Design Placebo-controlled, double-blind, randomized trial. Setting Clinical trial sites. Patient(s) Two hundred fifteen subjects with dysmenorrhea. Intervention(s) Subjects were randomly assigned to receive NPC-01, placebo, or IKH-01 (0.035 mg ethinyl estradiol and 1 mg norethisterone) for four cycles. Main Outcome Measure(s) Total dysmenorrhea score (verbal rating scale) assessing pain on the basis of limited ability to work and need for analgesics. Result(s) The reductions of total dysmenorrhea score and visual analog scale score after the treatment were significantly higher in the NPC-01 group than in the placebo group. Furthermore, the efficacy of NPC-01 was comparable to that of IKH-01. The overall incidence of side effects was significantly higher in the NPC-01 group than in the placebo group. All side effects that occurred in the NPC-01 group were previously reported in patients receiving IKH-01. No serious side effects occurred. Conclusion(s) The ultra-low-dose contraceptive NPC-01 relieved dysmenorrhea as effectively as IKH-01. Thus, NPC-01 could represent a new option for long-term treatment of dysmenorrhea. Clinical Trial Identification Number NCT01129102.

Ulipristal acetate was investigated in four phase 3 trials. In PEARL I, ulipristal produced significant normalisation of blood loss within 1 week and decreased fibroid volume. In PEARL II, ulipristal produced faster and more consistent control of bleeding than leuprorelin acetate and had a more favourable side-effect profile. Ulipristal-induced decreases in fibroid volume persisted for 6 months, whereas fibroids regrew after leuprorelin was stopped. PEARL III showed that ulipristal was effective during long-term treatment, with norethisterone further reducing the magnitude of bleeding in the off-treatment period. PEARL IV investigated ulipristal over four cycles, finding little difference between 5 and 10 mg ulipristal, further changes in menstruation and fibroid volume with repeat courses, and no increase in side effects.

Drug induced liver injury (DILI) is uncommon and severe forms are associated with significant morbidity and mortality. Female sex hormones (estrogens and progestogens) related DILI generally occur with estrogen component. Progesterone component related DILI are infrequently reported. Norethisterone is commonly used drug in gynecologic practice to prevent excess per vaginal bleeding. We report 3 cases of Norethisterone related DILI manifesting as significant rise of transaminases. All of these patients took Norethisterone for prolonged periods and improved completely after withdrawal of drug.

Steroid hormones regulate a variety of physiological processes, including reproductive function, and are widely used in hormonal therapy. Synthetic progestogens, or progestins, were designed to mimic progesterone (P4) for use in contraception and hormonal replacement therapy in women. Medroxyprogesterone acetate (MPA) and norethisterone (NET) are the most widely used injectable contraceptives in the developing world, while other progestins such as levonorgestrel (LNG), etonogestrel (ETG) and nestorone (NES) are used in or being developed for other forms of contraception. As concerns remain about the most appropriate choice of progestin and dosage, and the associated side-effects, the mechanisms and biological effects of progestins are frequently investigated in various in vitro mammalian cell line and tissue models. However, whether progestogens are differentially metabolised in different cell types in vivo or in vitro is unknown. For nine mammalian cell lines commonly used to investigate progestogen mechanisms of action, we developed and validated an ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) protocol for simultaneously quantifying the metabolism of the above-mentioned steroids. We show for the first time that, while 50–100% of P4 was metabolised within 24 h in all cell lines, the metabolism of the progestins is progestin- and cell line-specific. We also show that MPA and NET are significantly metabolised in human cervical tissue, but to a lesser extent than P4. Taken together, our findings suggest that differential progestogen metabolism may play a role in cell-specific therapeutic and side-effects. Relative affinities for binding to steroid receptors as well as potencies, efficacies and biocharacters for transcriptional activity of progestins, relative to P4, are most frequently determined using some of the cell lines investigated. Our results, however, suggest that differential metabolism of progestins and P4 may confound these results. In particular, metabolism may under-estimate the receptor-mediated intrinsic in vitro binding and dose-response values and predicted endogenous physiological effects of P4.

The intramuscular progestin-only injectable contraceptive, depo-medroxyprogesterone acetate (DMPA-IM), is more widely used in Sub-Saharan Africa than another injectable contraceptive, norethisterone enanthate (NET-EN). Epidemiological data show a significant 1.4-fold increased risk of HIV-1 acquisition for DMPA-IM usage, while no such association is shown from limited data for NET-EN. We show that MPA, unlike NET, significantly increases R5-tropic but not X4-tropic HIV-1 replication ex vivo in human endocervical and ectocervical explant tissue from pre-menopausal donors, at physiologically relevant doses. Results support a mechanism whereby MPA, unlike NET, acts via the glucocorticoid receptor (GR) to increase HIV-1 replication in cervical tissue by increasing the relative frequency of CD4+ T cells and activated monocytes. We show that MPA, unlike NET, increases mRNA expression of the CD4 HIV-1 receptor and CCR5 but not CXCR4 chemokine receptors, via the GR. However, increased density of CD4 on CD3+ cells was not observed with MPA by flow cytometry of digested tissue. Results suggest that DMPA-IM may increase HIV-1 acquisition in vivo at least in part via direct effects on cervical tissue to increase founder R5-tropic HIV-1 replication. Our findings support differential biological mechanisms and disaggregation of DMPA-IM and NET-EN regarding HIV-1 acquisition risk category for use in high risk areas.

Aim To study the feasibility of conservative management with progesterone as a treatment option for postabortal patients with uterine arterio-venous malformations (AVMs). Methods This prospective observational study was conducted in the tertiary care teaching hospital over a period of 2 years. Postabortal patients with abnormal uterine bleeding were enrolled. Diagnosis was made by history, clinical and radiological examinations. Oral norethisterone was used (10 mg twice daily for 3 weeks, maximum of three cycles). Descriptive statistics was used to present the data. Results A total of 30 patients were included. Majority (n = 17) had complete resolution of symptoms after a single 3-week course of progesterone therapy. Rest (n = 13) remained symptomatic and required second course. Of the later, only three remained symptomatic after 2 months, and underwent CT angiography followed by embolization. There was no report of any serious adverse events. Conclusion Oral norethisterone is a safe, effective and novel oral drug as an alternative to embolization or surgical therapy for patients with postabortal AVM bleed. Larger studies are required to confirm the findings of the present study.

Thirteen steroidal derivatives were synthesized through a Sonogashira cross-coupling reaction which has been found to be an excellent synthetic strategy to introduce halo-aromatic groups into C-17-ethynyl substituted steroidal frameworks. The structural modification was performed on ethynylestradiol, mestranol, norethisterone, ethisterone and 3-ethynyl-3-epi-sarsasapogenin. The solid state study by X-ray diffraction showed that most of them belong to the orthorhombic P212121 space group and the whole family has an “L” conformation, regardless of the nature of the steroid A-ring (3-hydroxy-aromatic or 3-oxo). Due to the presence of several moieties which are susceptible to forming secondary interactions, the crystalline packing is governed by O–H⋯O, C–H⋯O, and C–H⋯π interactions, and only 17α-(4′-iodophenylethynyl)-3-methoxy-estra-1,3,5(10)-trien-17-β-ol (mestranol derivative 3) showed an iodine–iodine interaction (dI⋯I = 4.116 A). The crystalline packing for ethynylestradiol derivatives 1, 2 and 4 showed the formation of holes with diameters greater than 5.2 A suggesting their potential application in host guest chemistry or as porous materials.

In the present study, the whole-cell biotransformation using strains expressing CYP BM3 mutants has been evaluated for the stereoselective hydroxylation of the steroid norethisterone (NET), a widely used contraceptive. First, an in vitro CYP BM3 mutant library screen was performed to identify mutants with high activity, as well asstereoselectivity. Subsequently, two different whole-cell setups (resting and growing cells) were tested in two different host organisms ( Escherichia coli and Saccharomyces cerevisiae ) expressing CYP BM3. It was found that resting E. coli whole cells produced the highest amounts of products and therefore this biocatalytic setup was further optimized for application in a laboratory-scale fermentor. In the optimized fermentor setup, high product yields (0.3 g/L 15β-OH-NET and 0.16 g/L 16β-OH-NET) were achieved while it was also shown that the regio- and stereoselectivities of the steroid hydroxylations, as determined during the in vitro library screen, were preserved in the whole-cell system. The combination of a mutant CYP BM3 library and the optimized whole-cell oxidation system represents a promising and cost-effective alternative to a wide range of in vitro biosynthetic routes.

OBJECTIVE This study aims to compare the effects of a soy-based dietary supplement, low-dose hormone therapy (HT), and placebo on the urogenital system in postmenopausal women. METHODS In this double-blind, randomized, placebo-controlled trial, 60 healthy postmenopausal women aged 40 to 60 years (mean time since menopause, 4.1 y) were randomized into three groups: a soy dietary supplement group (90 mg of isoflavone), a low-dose HT group (1 mg of estradiol plus 0.5 mg of norethisterone), and a placebo group. Urinary, vaginal, and sexual complaints were evaluated using the urogenital subscale of the Menopause Rating Scale. Vaginal maturation value was calculated. Transvaginal sonography was performed to evaluate endometrial thickness. Genital bleeding pattern was assessed. Statistical analysis was performed using χ(2) test, Fisher's exact test, paired Student's t test, Kruskal-Wallis test, Kruskal-Wallis nonparametric test, and analysis of variance. For intergroup comparisons, Kruskal-Wallis nonparametric test (followed by Mann-Whitney U test) was used. RESULTS Vaginal dryness improved significantly in the soy and HT groups (P = 0.04). Urinary and sexual symptoms did not change with treatment in the three groups. After 16 weeks of treatment, there was a significant increase in maturation value only in the HT group (P < 0.01). Vaginal pH decreased only in this group (P < 0.01). There were no statistically significant differences in endometrial thickness between the three groups, and the adverse effects evaluated were similar. CONCLUSIONS This study shows that a soy-based dietary supplement used for 16 weeks fails to exert estrogenic action on the urogenital tract but improves vaginal dryness.

Objectives Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV. Study design We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography–mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use. Results Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had ≥1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status. Conclusion Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health outcomes. Implications Research studies investigating associations between hormonal contraceptive use and HIV should consider validating self-reported use by objective measures; because both overreporting and underreporting of use occur, potential misclassification based on self-report could lead to biased results in directions that cannot be easily predicted.