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Objective: This study aims to compare treatment outcomes of a levonorgestrel-releasing intrauterine system (LNGIUS) or oral progestogens in women with non-atypical endometrial hyperplasia (EH). Additionally, the predictors for EH non-regression were determined. Methods: Medical records of women diagnosed with non-atypical EH between April 2016 and March 2022 at Tuen Mun Hospital were retrieved. These patients were offered LNG-IUS as the first-line option or oral progestogens if they refused or had LNG-IUS contraindications such as submucosal fibroid distorting endometrial cavity. The rate of EH non-regression at 12 months and the rate of EH relapse at 24 and 36 months between groups were compared. Univariate and multivariate analyses were conducted to identify predictors for EH non-regression. Results: The median follow-up duration was 24 months for the LNG-IUS group and 19 months for the oral progestogens group. The rate of EH regression at 12 months was higher in the LNG-IUS group (93.9% vs 71.2%, p<0.001). The rate of EH relapse was higher in the oral progestogens group at 24 months (21.1% vs 1.1%, p=0.003) and 36 months (33.3% vs 2.3%, p=0.014). The incidence of hysterectomy for treatment failure was higher in the oral progestogens group (13.7% vs 4.2%, p=0.005). No EH relapse occurred in either group after 36 months posttreatment. Predictors for EH non-regression were postmenopausal status (odds ratio=5.80, p=0.022) and oral progestogens treatment (odds ratio=7.51, p<0.001). Conclusion: In women with non-atypical EH, treatment with LNG-IUS leads to a higher regression rate at 12 months, a lower relapse rate within 36 months, and a lower rate of hysterectomy due to treatment failure, compared with treatment with oral progestogens. Postmenopausal status and treatment with oral progestogens are risk factors for treatment failure. Regular endometrial surveillance should be provided to women at risk. Hysterectomy is recommended for postmenopausal women. [ABSTRACT FROM AUTHOR]

We report a case of probable norethisterone‐related liver injury, manifesting as a significant rise in liver transaminases in a 62‐year‐old woman. Upon discontinuation of norethisterone, liver transaminases decreased to normal level within two weeks. Knowledge of rare adverse effects of drugs such as norethisterone is necessary for rapid identification and management, especially in patients with risk factors such as non‐alcoholic liver disease and obesity. [ABSTRACT FROM AUTHOR]

Case presentation: This case report concerns a 49‐year‐old woman who developed cholestasis (build‐up of bile in the liver) two months and a half after initiating norethisterone, progestin‐only pills, which resolved after the withdrawal of these pills. [ABSTRACT FROM AUTHOR]

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 to aquatic organisms. Marine medaka (Oryzias melastigma) is a brackish fish, often used in ecotoxicology studies. In this study, the effect of norethisterone exposure on the transcriptome of marine medaka larvae was analyzed. Larvae were exposed to 10 ng/L NET for 24 h, then RNA-Seq was performed. Exposure to 10 ng/L NET resulted in 306 up-regulated and 516 down-regulated genes. An enrichment analysis revealed that differentially expressed genes (DEGs) were significantly enriched in metabolic and biosynthetic pathways, including DNA replication, proteasome, steroid biosynthesis, and other amino acid metabolism pathways. In the DNA replication pathway, all the DEGs were down-regulated, while in the steroid biosynthesis pathway, sqle, hmgcr, dhcr7, and dhcr24 were down-regulated. Quantitative real-time PCR (qPCR) was used to verify 12 DEGs, confirming that the validity of the RNA-Seq analysis. These results show that even low environmental concentrations of NET can lead to transcription level changes of genes related to fish growth and development, which may have adverse effects on the early development and growth of aquatic organisms. Highlights Transcriptomes from norethisterone-exposed marine medaka larvae were obtained A total of 822 differentially expressed genes were identified Norethisterone affected 155 pathways, including DNA replication. [ABSTRACT FROM AUTHOR]

A biotransformation is a key tool for the structural modification of natural and synthetic complex compounds. It is employed to synthesize those compounds, which are arduous to get from chemical synthesis. During the last few decades' research has been focused on the modification of biologically potent compounds. Biotransformation is one of the effective ways in this regard. The current article covers the biotransformation of norethisterone (1) by using various bacteria and fungi as well as metabolism in man and animals i.e. rat, rabbit, monkey and dog, which brought mono-, di-, and tri-hydroxylation, oxidation, reduction, epoxidation and deethynylation of 1. The review covers 26 metabolites (2 to 27) of 1, obtained during 1906 to 2018. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Our objective was to determine the awareness, use of medications to suppress menstruation along with their side effects, and satisfaction level among the pilgrims. Methods: An observational cross-sectional survey was conducted during the pilgrimage (Hajj) period 1437 Hijrah in Makkah, Saudi Arabia. Women pilgrims (n = 594) between menarche and menopause were interviewed. The proportion of females who was aware of menstrual suppression by medication, who used the medication during Hajj period, and who experienced complaints while using drugs to postpone the periods, and after stopping the drugs were sorted. Results: The participants were mean aged 35.3 years (standard deviation = 8.4), with 413 (69.5%) being multiparous, 556 (93.6%) were aware of menstruation postponement by medications, and 313 (56%) got this information from their family doctors. However, 381 (64%) used medications, and 356 (93.3%) successfully achieved menstrual suppression. Out of 381, majority used Norethisterone, i.e., 301 (79%) and 80 (21%) complained of side effects, of which the most common was irregular spotting 31.3% (25/80) followed by abdominal pain. Satisfaction of medications users was 324 (85%). Out of 381 women, 87 (22.8%) reported side effects after discontinuing the hormones; the commonly experienced side effect was heavy prolonged bleeding 47 (54%). Conclusions: The awareness about hormones usage to postpone menstruation was high. Norethisterone was commonly used medication. Overall satisfaction with medications' usage was high. Most women did not know what to do in case of unscheduled bleeding. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Background: Our aim was to compare the therapeutic efficacies of norethisterone acid (NETA), tranexamic acid and levonorgestrel-releasing intrauterine system (LNG-IUS) in treating idiopathic heavy menstrual bleeding (HMB).Methods: Women with heavy uterine bleeding were randomized to receive NETA, tranexamic acid or LNG-IUS for 6 months. The primary outcome was a decrease in menstrual bleeding as assessed by pictorial blood loss assessment charts and hematological parameters analyzed at the 1st, 3rd and 6th months. Health-related quality of life (QOL) variables were also recorded and analyzed.Results: Twenty-eight patients were enrolled in each treatment group, but the results of only 62 were evaluated. NETA, tranexamic acid, and LNG-IUS reduced menstrual blood loss (MBL) by 53.1, 60.8, and 85.8%, respectively, at the 6th month. LNG-IUS was more effective than NETA and tranexamic acid in decreasing MBL. LNG-IUS was also more efficient than tranexamic acid in correcting anemia related to menorrhagia. Satisfaction rates were comparable among the NETA (70%), tranexamic acid (63%) and LNG-IUS (77%) groups. QOL in physical aspects increased significantly in the tranexamic acid and LNG-IUS groups.Conclusion: The positive effect of LNG-IUS on QOL parameters, as well as its high efficacy, makes it a first-line option for HMB. [ABSTRACT FROM AUTHOR]

Background: Menstrual disorders are the second most common gynecological condition resulting in hospital referrals. Dysfunctional Uterine Bleeding is defined as abnormal uterine bleeding in the absence of organic disease. Menorrhagia (menstrual blood loss >80 ml per cycle) affects 10-33% of women at some stage in their lives. Approximately 90% of dysfunctional uterine bleeding result from anovulation and 10% occur with ovulatory cycles. Only half of women complaining of heavy menstrual bleeding fit the clinical criteria of more than 80 ml blood loss per cycle. Among women aged 30-49, one in 20 consults her general practitioner each year with menorrhagia. It can be managed both medically and surgically. Material and methods: Thirty women presenting with DUB were randomly allocated to 2 equal groups, Group-A, which received 60 mg ormeloxifene twice a week for 12 weeks and Group-B, which received 5 mg norethisterone twice daily for 21 days for 3 months. The primary outcome measures were reduction in menstrual blood loss which was measured by fall in PBAC (Pictorial Blood loss Assessment Chart) score, rise in hemoglobin level and reduction in endometrial thickness. Results: The reduction in mean PBAC score with ormeloxifene (277.33 to 70.11) was significantly more than that seen with norethisterone (246 to 108.5) after 3 months of therapy (p<0.05). The increase in hemoglobin level and reduction in endometrial thickness were also found to be significantly more with ormeloxifene than norethisterone (9.68 g% to 11.07 g% vs. 10.17 g% to 10.58 g%, p<0.05, and 7.8 mm to 5.3 mm vs. 6.7 mm to 5.9 mm, p<0.05, respectively). No major side effects were reported in any group. Conclusion: Ormeloxifene was found to be more effective than norethisterone in reducing blood loss and reducing endometrial thickness. [ABSTRACT FROM AUTHOR]

Introduction: Antiphospholipid syndrome is known to be associated with the occurrence of venous and/or arterial thrombosis. There are several factors that might trigger the risk of thrombosis in antiphospholipid syndrome, including drugs, however bleeding is rare. Only a few cases of antiphospholipid syndrome have reported simultaneous bleeding and thrombosis, and only a few of these cases have reported thrombosis induced by norethisterone when used by patients with an underlying risk factor for thromboembolism. Case presentation: We report the case of a 35-year-old Saudi woman diagnosed with antiphospholipid syndrome with a history of several spontaneous miscarriages and two previous lower limb deep vein thromboses. She had used norethisterone to postpone her menstruation and presented to our institution with severe menorrhagia. During admission, she developed thrombocytopenia, and at the same time she was found to have extensive inferior vena cava and bilateral common iliac thrombosis. Conclusions: This case report is of interest to rheumatologists, hematologists and radiologists because we have found that the presence of bleeding and thrombocytopenia do not preclude the concomitant occurrence of thrombotic complications of antiphospholipid syndrome. Norethisterone is normally safe to take, but it is not suitable for patients with an increased risk of deep vein thrombosis. Also, the simultaneous management of thrombosis and heavy vaginal bleeding is a challenge for clinicians since there are no evidence-based guidelines regarding the management of these patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: To evaluate the histomorphological effects of Vitamin D on Norethisteroneinduced hepatosteatosis in female rats. Study Design: Laboratorybased experimental study. Place and Duration of Study: Department of Anatomy, Army Medical College/National University of Medical Sciences Rawalpindi in collaboration with the National Institute of Health (NIH), Pathology Laboratory Pak Emirates Military hospital, and Armed Forces Institute of Pathology, (AFIP) Rawalpindi Pakistan, from Aug to Nov 2021. Methodology: Thirty female Sprague Dawley rats weighing 250-300 gm were randomly divided into three groups (10 for each group). Group-A served as control. For eight weeks, Group-B was given Norethisterone 4.55 mg/kg/day by oral gavage. Group-C was given 1000 IU/kg/day of Vitamin D by intraperitoneal injection for five consecutive days/week, along with Norethisterone for eight weeks. All the animals were sacrificed at the end of the experiment. The colour and consistency of the liver specimen were noted. Liver specimens were processed and staining was done with H and E stains. Histologically steatosis in the specimen was assessed. Results: The results were compared among the groups. Experimental Group-B, when compared with Control Group-A, showed a significant change in the colour (p-value 0.033) and consistency of the liver (p-value 0.033) along with marked steatosis (p-value 0.001). There was a significant improvement in hepatosteatosis (p-value 0.001), which led to improved colour (p-value 0.029) and consistency of the liver (p-value 0.029) in Experimental Group-C when compared with Experimental Group- B. Conclusion: Vitamin D ameliorates hepatosteatosis induced by Norethisterone in the female rat. [ABSTRACT FROM AUTHOR]

Whether hormonal contraceptives increase HIV-1 acquisition, transmission and disease progression are critical questions. Clinical research has been hampered by a lack of understanding that different progestins used in contraception exhibit differential off-target effects via steroid receptors other than the progesterone receptor. Of particular, relevance is the relative effects of medroxyprogesterone acetate ( MPA) and norethisterone enanthate ( NET- EN), widely used as injectable contraceptives in sub-Saharan Africa. While most high-quality clinical studies find no increased risk for HIV-1 acquisition with oral contraception or injectable NET- EN, most do find an increase with MPA, particularly in young women. Furthermore, mounting evidence from animal, ex vivo and biochemical studies are consistent with MPA acting to increase HIV-1 acquisition and pathogenesis, via mechanisms involving glucocorticoid-like effects on gene expression, in particular genes involved in immune function. We report that MPA, unlike NET and progesterone, represses inflammatory genes in human PBMCs in a dose-dependent manner, via the glucocorticoid receptor ( GR), at concentrations within the physiologically relevant range. These and published results collectively suggest that the differential GR activity of MPA versus NET may be a mechanism whereby MPA, unlike NET or progesterone, differentially modulates HIV-1 acquisition and pathogenesis in target cells where the GR is the predominant steroid receptor expressed. [ABSTRACT FROM AUTHOR]

Epilepsy and the medications used in its treatment are known to affect the menstrual cycle, aspects of contraception, and bone health in women. Adolescence is an important time to review the diagnosis of both epilepsy and the epilepsy syndrome because of the implications and decisions, which should be made regarding antiepileptic drug (AED) treatment. In girls, once they are on AED therapy, seizure free, and driving, it becomes difficult to change therapy because of the risk of breakthrough seizures and the fact that the new AED may not be as effective as the first. So a treatment choice made in adolescence is often life-long. Therefore, women need to be started on an AED that currently appears to be the most suitable for their seizure type, has a low teratogenic risk, and hopefully does not interact with contraception. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Nonenzyme-inducing AEDs (valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine, and zonisamide) do not show any interactions with the combined oral contraceptive. There are interactions between the combined oral contraceptive and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages >200 mg/day], oxcarbazepine, eslicarbazepine and perampanel [dosages >12 mg/day]) and lamotrigine. Women taking enzyme inducing AEDs should be encouraged to use a method of contraception that is unaffected by their epilepsy medication. Interactions between AEDs and other hormonal therapies are less well studied. Studies have suggested that women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia. No studies have been undertaken looking at preventative therapies for these comorbidities. This article will concentrate on current contraceptive treatment options in patients taking AEDs. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effects of steady-state concentrations of the selective S1P receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive. Methods: Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis. Results: Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of C and AUC of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of C and AUC of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline. Conclusion: No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration. [ABSTRACT FROM AUTHOR]

Background: Oral contraceptive therapy (OCT) is associated with an increased risk of deep vein thrombosis, venous thromboembolism and stroke. However, the underlying mechanisms have not yet been elucidated. The objective of this study was to investigate the influence of OCT on blood levels of an oxidative stress maker in pre-menopausal women. Methods: Oxidative stress was determined in 87 pre-menopausal healthy women (24 with and 63 without OCT) using a blood assay for reactive oxygen metabolites (by the d-ROMs test). The subjects with OCT received a triphasic preparation consisting of ethinyl estradiol and norethisterone. Results: Subjects with OCT showed significantly higher d-ROMs levels (median: 380; interquartile range: 328-502 Carr U) than those without OCT (325 [271-369]; P < 0.05). The results remained the same after adjusting for potential confounders. Conclusions: The use of OCT may increase oxidative stress levels, independent of traditional cardiovascular risk factors, in pre-menopausal women, providing new insights to the primary prevention of vascular complications in these subjects. [ABSTRACT FROM AUTHOR]

Background: Biotransformation by using microbial and plant cell cultures has been applied effectively for the production of fine chemicals on large scale. Inspired by the wealth of literature available on the biotransformation of steroids, we decided to investigate the biotransformation of ethynodiol diacetate (1) by using plant andmicrobial cultures. Results: The biotransformation of ethynodiol diacetate (1) with Cunninghamella elegans and plant cell suspension cultures of Ocimum basilicum and Azadirachta indica is being reported here for the first time. Biotransformation of 1 with Cunninghamella elegans yielded three new hydroxylated compounds, characterized as17?-ethynylestr-4-en-3β, 17β-diacetoxy-6β-ol (2), 17β-ethynylestr-4-en-3β,17β-diacetoxy-6β-ol (3), and17β-ethynylestr-4-en-3β, 17β-diacetoxy-10β-ol (4) and a known metabolite, 17?-ethynyl-17?-acetoxyestr-4-en-3-one (5). The biotransformation of 1 with Ocimum basilicum included hydrolysis of the ester group, oxidation of alcohol into ketone, and rearrangement of the hydroxyl group. Thus four major known metabolites were characterized as 17β-ethynyl-17β-acetoxyestr-4-en-3-one (5), 17β-ethynyl-17β-hydroxyestr-4-en-3-one (6), 17β-ethynyl-3 β-hydroxy-17β-acetoxyestr-4-ene (7) and 17β-ethynyl-5β,17β-dihydroxyestr-3-ene (8). Biotransformation of 1 with Azadirachta indica culture yielded compounds 5 and 6. Spectroscopic data of compound 8 is being reported for the first time. Structure of compound 6 was unambiguously deduced through single-crystal x-ray diffraction studies. Conclusion: Biotransformation of an oral contraceptive, ethynodiol diacetate (1), by using microbial and plant cell cultures provides an efficient route to the synthesis of a library of new steroids with potential contraceptive properties. These methods can be employed in the production of such compounds with high stereoselectivity. [ABSTRACT FROM AUTHOR]

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Objectives To evaluate the effect on breast density of two low-dose hormone therapy regimens identical in their estrogen component but different in the progestin. Methods A total of 81 non-hysterectomized postmenopausal women were allocated either to 17β-estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA, n = 43) or to 17β-estradiol 1 mg and drospirenone 2 mg (E2/DRSP, n = 38). Treatment was continuous and lasted 12 months. The main outcomes were the changes in breast density according to the Wolfe classification between baseline and 12-month mammograms. Results Involution of the fibroglandular tissue was not seen in either of the treatment groups. Under E2/NETA, breast density increased in seven women (16.3%). In contrast, only three women (7.9%) exhibited a density increase under E2/DRSP. Conclusions Although hormone therapy appears to suspend breast involution, it does not increase breast density in the majority of treated women. Progestins differing in pharmacological properties may have a variable impact on breast density. [ABSTRACT FROM AUTHOR]

High-performance liquid chromatography coupled with tandem mass spectrometry has been used for sensitive and specific quantitative analysis of norethisterone (NE) in human serum. NE and the internal standard fentanil were isolated by solid-phase extraction. Chromatographic separation was achieved on a 4.6 mm × 50 mm, 5-μm particle, C18 column. The mobile phase was 70:30 ( v/ v) methanol–0.5% aqueous formic acid. NE and the internal standard were detected by multiple-reaction monitoring of precursor/product ion combinations at m/ z 299.4/231.2 and 377.1/188.1, respectively; an atmospheric-pressure-photoionization source was used in positive-ion mode. Linearity was established in the concentration range 0.2–49.24 ng mL−1 and the lowest limit of quantification was 0.2 ng mL−1. Recovery of NE ranged from 92.54 to 102.74% and relative standard deviations were <15%. The method was used for a pharmacokinetic study of NE in healthy postmenopausal Chinese female volunteers. [ABSTRACT FROM AUTHOR]

Objective To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE). Design Nested case–control study. Setting Database study using the General Practice Research Database for the years 1992–1998. Population Women aged 15–49 years with a diagnosis of menorrhagia. Methods Multivariate conditional logistic regression was used to estimate the risk for VTE associated with different drug treatments for menorrhagia, adjusting for confounders. Main outcome measures Adjusted odds ratios with 95% CI. Results A total of 134 cases of VTE and 552 matched controls were identified. Recent use of tranexamic acid was scarce, yielding an adjusted odds ratio for VTE of 3.20 (95% CI 0.65–15.78). The use of mefenamic acid (ORadj 5.54 [95% CI 2.13–14.40]) or norethisterone (ORadj 2.41 [95% CI 1.00–5.78]) was associated with an increased risk of VTE, as was a recent—in relation to menorrhagia—diagnosis of anaemia or a haemoglobin value <11.5 g/dl (ORadj 2.23 [95% CI 1.02–4.86]). Conclusions We found that tranexamic acid was associated with an increased risk of VTE, although the risk estimate did not reach statistical significance. Increased risks of VTE associated with other treatments for menorrhagia were observed. The increased risk of VTE observed with a diagnosis of anaemia—a proxy for more severe menorrhagia—suggests that menorrhagia could be a prothrombotic condition. The observed association between VTE, tranexamic acid and other treatments for menorrhagia may thus partly be explained by confounding by indication. The possibility that menorrhagia is itself a risk factor for VTE merits further investigation. [ABSTRACT FROM AUTHOR]

Objective To study the influence of smoking on uterine bleeding patterns during continuous and interrupted oral hormone therapy (HT). Methods Using a post-hoc strategy, we included five oral HT groups from three studies. The therapies consisted of continuous estrogen (estradiol, estradiol valerate or piperazine estrone sulfate) in combination with continuous progestogen (cyproterone acetate, gestodene or norethisterone acetate) or in combination with interrupted progestogen (norethisterone) given on days 4-6, 10-12, 16-18, 22-24 and 28-30. A total of 145 healthy postmenopausal women (54 smokers and 91 non-smokers), who had been followed for 2 years, were included in the analyses. Uterine bleeding data were collected from bleeding calendars. Results In general, smoking women experienced significantly less days with uterine bleeding per cycle than non-smoking women during continuous and interrupted HT (0.53 ± 0.1 vs. 1.6 ± 0.1; p < 0.001). Smoking women were also more likely than non-smoking women to be amenorrheic during these therapies (48.2% vs. 29.7%; p < 0.05). Finally, more smoking than non-smoking women attained amenorrhea during HT (94.4% vs. 76.9%p < 0.01). Conclusions In healthy postmenopausal women, smoking may reduce uterine bleeding during interrupted and continuous HT regimens containing a broad selection of estrogens and progestogens. Further study with appropriate stratification for smoking status is warranted. [ABSTRACT FROM AUTHOR]

Objectives: To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks.Methods: This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 microg/day and norethisterone acetate (NETA) 140 microg/day (Estalis; patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest; one tablet containing E2 2 mg/NETA 1 mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44-69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3 : 1 to transdermal or oral E2/NETA treatment.Results: No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (>90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments.Conclusions: Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period. [ABSTRACT FROM AUTHOR]

Objective: Bosentan has been shown in vitro and in vivo to induce the cytochrome P450 enzymes CYP2C9 and CYP3-A4. The present study was conducted to investigate the effect of bosentan on the pharmacokinetics of a combined oral contraceptive. Subjects and methods: In a randomized, 2-way cross over study, 20 healthy fe male subjects received Treatments A and B. Treatment A consisted of a single dose of Ortho-Novum containing 1 mg norethisterone (norethindrone) and 35 mg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration. Results: In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by C max and AUC0-∞ values (95% CI) of 9.8 (8.1, 11.9) ng/ml and 72.9 (57.0, 93.1) ng × h/ml, and 53.0 (47.0, 59.9) pg/ml and 758 (655, 878) pg × h/ml, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (-23.5, -2.6) and 31.0% (-40.5, -20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively. Conclusions: Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered. [ABSTRACT FROM AUTHOR]

Objective . To compare the efficacy of two sequential 17β-estradiol (17β-E2)/trimegestone (TMG) combinations with the sequential estradiol valerate (E2V)/norethisterone (NET) regimen in relieving climacteric symptoms. Study design . This was a double-blind, randomized, multicenter study conducted among 1218 Caucasian (99%) postmenopausal women with an intact uterus in seven European countries and Israel, over 13 cycles (each of 28 days). Study duration was extended further for 13 cycles, with 531 women receiving treatment for up to 26 cycles. Treatments consisted of 1&ThickSpace;mg 17β-E2 on days 1–14 and 1&ThickSpace;mg 17β-E2/0.125&ThickSpace;mg TMG or 0.25&ThickSpace;mg TMG on days 15–28, and 1&ThickSpace;mg E2V on days 1–16 and 1&ThickSpace;mg E2V/1&ThickSpace;mg NET on days 17–28. Results . Rapid and significant reductions in the mean daily number and severity of hot flushes and in the mean daily number of nocturnal sweats were established in most women with 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG and E2V/NET. These treatments also induced a significant improvement in the quality-of-life assessments. Conclusion . The 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG regimen provides rapid and effective relief of menopausal symptoms, with a reduction in the number of hot flushes ‘at least as good as’ that of the E2V/NET comparator. [ABSTRACT FROM AUTHOR]

Objective . To compare the bleeding profiles and endometrial protection of two sequential regimens of 17β-estradiol (17β-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. Study design . This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1&ThickSpace;mg 17β-E2 on days 1–14 and 1&ThickSpace;mg 17β-E2/0.125&ThickSpace;mg TMG or 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG on days 15–28, and 1&ThickSpace;mg E2V on days 1–16 and 1&ThickSpace;mg E2V/1&ThickSpace;mg NET on days 17–28. Results . Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25&ThickSpace;mg TMG dose showing a lower incidence of proliferative endometrium. Conclusion . The 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile. [ABSTRACT FROM AUTHOR]

Background: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases.Methods: This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database.Results: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden.Conclusion: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs. [ABSTRACT FROM AUTHOR]

FERNANDES, E.O.,et al.: Hormone Replacement Therapy Does Not Affect the 24-hour Heart Rate Variability in Postmenopausal Women: Results of a Randomized, Placebo-controlled Trial with Two Regimens. Postmenopausal women are at greater risk of coronary heart disease. The results of previous studies of the effects of hormone replacement therapy (HRT) on cardiac autonomic modulation in postmenopausal women have been contradictory. This study examined whether continuous treatment for 3 months with estradiol alone (ERT) or with estradiol plus norethisterone (HRT), increases 24-hour heart rate variability (HRV) in postmenopausal women. In this double-blind, placebo-controlled trial, 40 healthy postmenopausal women, 46–63 years of age, were randomly assigned to (1) continuous 2 mg of estradiol plus 1 mg of norethisterone acetate daily (HRT, n= 13), or (2) 2 mg of estradiol daily (ERT, n= 14), or (3) placebo (n= 13). Before and after 3 months of therapy, blood estradiol concentrations were measured and 24-hour electrocardiograms recorded for evaluation of 24-hour time-domain indices of HRV, and indices derived from the three-dimensional return map. Both hormone replacement regimens significantly increased blood estradiol concentrations, while no change occurred in the placebo group. In the three treatment groups, multiple 24-hour time-domain indices of HRV and indices derived from the three-dimensional return map remained unchanged. In healthy postmenopausal women, HRT with estradiol or estradiol and norethisterone for 3 months did not modify cardiac autonomic activity evaluated by 24-hour indices of HRV. These findings are consistent with a lack of protective cardiovascular effect of HRT described in recent large randomized trials.(PACE 2005; 28:S172–S177) [ABSTRACT FROM AUTHOR]

Drug therapy may become difficult when a significant amount of the small intestine is resected, as happens in patients with a short small bowel. Drug absorption from the gastrointestinal tract is altered in these patients; however, this effect is variable in patients and differs with each drug. Literature regarding clinical outcomes of normal or alternative administration routes in patients with a short small bowel is limited. We explored what is written about the normal absorption of commonly used drugs and what difference the resection of different but substantial parts of the small intestine makes. Changes in the gastrointestinal tract after resection of >50% of the small intestine causes malabsorption of macronutrients and micronutrients, and may alter the drug absorption process. The metabolic activity of the abundantly present intestinal lactobacilli can also affect the enteral drug absorption in patients with short small bowel as this results in the production of lactic acid, gaseous CO(2), ethanol and an increased bile acid deconjugation. Accelerated intestinal luminal transit time causes a reduction in absorption of certain antimicrobial agents, digoxin, hydrochlorothiazide, ciclosporin, cimetidine, mesalazine (5-aminosalicylic acid), oral contraceptives and levothyroxine. Gastric hypersecretion and lack of sufficient contact time with the intestinal mucosa in patients with short small bowel leads to insufficient absorption of drugs such as omeprazole. Successful treatment with warfarin, tricyclic antidepressants, metronidazole, fluconazole, procainamide, sotalol and pindolol are reported in several studies. Many different factors cause this variability in drug absorption in such patients. Monitoring the serum drug concentration in these patients may ease dealing with the management problems. [ABSTRACT FROM AUTHOR]

Objective: Two randomized comparative multicenter studies were conducted to establish the endometrial safety and tolerability of a triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate (E2V/MPA) therapy regimen.Methods: Study 1 was a randomized, double-blind, clinical phase III study in 399 postmenopausal women, following parallel-group design with two groups. The duration of study treatment was 12 or 13 cycles of 28 days. A double-dummy technique was used to ensure blinding in the study. The investigational drugs were E2V/MPA triphasic and E2V/MPA biphasic (Diviseq and Divina, respectively; Orion Pharma). In study 2, a total of 341 subjects were randomly allocated by computer into two parallel groups receiving either E2V/MPA or estradiol/norethisterone acetate triphasic (E2/NETA, Trisequens; Novo Nordisk A/S) for 12-13 cycles. The study was an open, clinical phase III trial with a randomized, parallel-group design. Endometrial biopsies combined with transvaginal ultrasound were undertaken before and at the end of treatment during the progestogen phase. Bleeding patterns and symptom control were assessed throughout both studies.Results: E2V/MPA triphasic was found to have similar endometrial effects and bleeding patterns to those with E2V/MPA biphasic and E2/NETA triphasic. Climacteric symptoms were relieved as quickly and effectively as with the two comparator treatments. No adverse drug reactions specific to E2V/MPA triphasic were observed. At the end of the study, the proportions of secretory samples were 67.1% for the combined E2V/MPA triphasic groups, 65.6% for the E2V/MPA biphasic group and 71.6% for the E2/NETA triphasic group. One case of hyperplasia occurred in the E2V/MPA triphasic group. Thus the incidence of hyperplasia for the combined groups was 0.33%.Conclusions: The triphasic E2V/MPA regimen was well tolerated and produced endometrial effects similar to those of the two comparators. Extending estrogen during the so-called treatment-free week with a lower dose of estradiol was effective in controlling vasomotor symptoms. [ABSTRACT FROM AUTHOR]

New and more potent progestins and antiprogestins suitable for reproductive therapy and contraception are currently the target of intensive research. The design of such drugs has been hampered by the complex technology required for screening these compounds at the molecular level. To solve this problem, we developed an in vitro cell system that allows detection of the progestagenic effects of a given compound using a PRE-TATA-CAT reporter vector transiently introduced in a cell line stably transfected with the rabbit progesterone receptor (PR). The African Green Monkey Kidney CV1 (AGMK-CV1) cell line was chosen because these cells do not express endogenous steroid receptors; the selected clone stably expressing the rabbit PR has been maintained in our laboratory for more than 2 yr without detectable losses in PR content and progestagenic response. The presence and function of the PR were assessed by immunohistochemical and saturation analyses as well as by monitoring transactivation of the PRE-TATA-CAT reporter gene. In this cell line, the PR is expressed at a concentration of 0.170 fmol/mg of protein, and the receptor is localized within the cell nucleus in either the presence or absence of the potent synthetic progestin R5020. This PR-expressing cell system allowed study of the in vitro progestational activity of several 19-nor progestins. The anti-progestin RU486 inhibited CAT activity induced by R5020; norethisterone (NET), levonorgestrel (LNG), and gestodene (GSD) induced PRE-TATA-CAT activity at concentrations similar to those of R5020, whereas NET A-ring-reduced metabolites induced CAT activity at an extent lower than (5α-NET) or similar (3β,5α-NET) to that of the precursor compound. The PRE-TATA-CAT induction by 17β-estradiol was also analyzed and no crossreactivity was detected. However, when the ERE-VitA2-TK-CAT (estrogen-responsive element-vitellogenin A2-thymidine kinase promoter-CAT) reporter vector and the estradiol receptor α or β were cotransfected, CAT activity was induced in the presence of 17β-estradiol, and NET tetrahydro-reduced derivatives. The results indicate that this AGMK-CV1-PR cell assay system appears to be suitable for measuring the effects of different synthetic progestins at the transcriptional level. In this assay system, NET, LNG, and GSD exhibit potent progestational effects at the transcriptional level. In the particular case of NET, the assay system allowed us to determine that the single or multiple hormonal transcriptional effects of this compound are partially mediated by its A-ring-reduced derivatives. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450-600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of 1 mg norethisterone from 37.8±13.1 to 21.9±5.9 ng/ml X h (p<0.01). The plasma norethisterone half life (β-phase) was also reduced from 6.2±1.7 to 3.2±1.0 h (p<0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6β-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A. U. C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin. [ABSTRACT FROM AUTHOR]

Plasma tartrate-resistant acid phosphatase (TR ACP), urinary hydroxyproline excretion (UH), serum osteocalcin, and bone alkaline phosphatase isoenzyme were determined in a prospective study in 31 women who had undergone bilateral ovariectomy (OOX). Nine patients were followed up for 1 year without treatment and for the following 3 years when on mestranol (M) substitution. On the basis of UH, 22 patients were identified as having increased bone resorption (BR) within 3 months of OOX. Subsequently, 11 patients were treated with transdermal estradiol (E) and 11 patients with norethisterone (norethindrone, NE). In untreated patients, the biochemical indices of BR peaked 3-6 months following OOX and biochemical indices of bone formation (BF) continued to increase from 3 until 12 months. The substitution with both E or M resulted in normalization in serum and urinary calcium, serum phosphate, renal threshold phosphate concentration (Tm /GRF), and biochemical indices of BR within 4 months of treatment. Biochemical indices of BF normalized within 6 months of treatment. In the M-treated group, these effects continued for 3 years of the follow-up. The hormonal substitution had a protective effect on cortical and lumbar spine bone mass. A significant decrease, but not to normal values, in biochemical indices of BR and a persistent elevation in indices of BF were found in NE-treated patients. Unlike E, NE does not depress osteoblastic function. There is strong evidence supporting the utility of measurements of TR ACP in plasma in examination of women who had ovariectomies and in assessment of the efficacy of treatment. [ABSTRACT FROM AUTHOR]

UV irradiation of ethisterone ( 1) and norethisterone ( 2) in the solid state yielded one photoproduct each: 17,20-epoxy-17ξ H-pregna-4,20-diene-3-one ( 3) and the dimerization product 17′-hydroxy-(13β H, 17′β H)-13,17- seco-[20, 21]bipregnayl-4,20,4′-trien-20′-in-3,17,3′-trione ( 4), respectively. Compounds 3 and 4 were characterized by their spectral and analytical data and further confirmed by the molecular packing of 1 and 2 in the crystal, as shown by X-ray crystallography. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Toxicology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Peritoneal fluid and blood samples were collected at surgical sterilization from 30 untreated women at various stages of the luteal phase and from 43 women treated with 300 g norethisterone daily. Levels of oestradiol, progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured. The highest peritoneal fluid volume (mean, 23.1 ml) was found in the early luteal phase (LH 0 to +3) and the lowest (mean, 5.9 ml) in the late luteal phase (LH + 12 to menses). The norethisterone treatment diminished the formation of peritoneal fluid and the degree of inhibition was dependent upon the type of ovarian reaction to norethisterone. Progesterone and oestradiol levels were higher in peritoneal fluid compared to plasma throughout the luteal phase and during norethisterone treatment. A comparison of the levels of these steroids between untreated controls (LH +8 to +11) and norethisterone-treated women demonstrated that the progesterone levels in peritoneal fluid were highly reduced by norethisterone treatment, while the oestradiol levels were not affected. The FSH and LH levels were, in contrast to the steroid hormones, significantly lower in peritoneal fluid than in plasma, both in the untreated and the treated women. No differences in the FSH or LH levels between the untreated and treated women were found. The results indicate that the peritoneal fluid volume and the steroid hormone levels In peritoneal fluid vary with the stages of the luteal phase. Norethisterone treatment significantly reduced the peritoneal fluid volume as well as its progesterone concentration, whereas the oestradiol and gonadotrophin levels remained unchanged. [ABSTRACT FROM PUBLISHER]

Copyright of African Journal of Reproductive Health is the property of Women's Health & Action Research Centre and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We report a case of a patient with Glanzmann's thrombasthenia and anti-GPIIb/IIIa alloantibodies who developed life-threatening and intractable bleeding from gastrointestinal telangiectatic lesions. After a period of transfusion-dependent gastrointestinal bleeding despite tranexamic acid, oral iron, omeprazole and platelet transfusions, the use of oral norethisterone produced a significant improvement with a marked reduction in her transfusion requirements. [ABSTRACT FROM AUTHOR]