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Abnormal uterine bleeding (AUB) is an acute/chronic variation in the normal menstrual cycle that affects adolescents, women of reproductive age and perimenopausal women. AUB affects approximately 3–30% of reproductive-aged women worldwide, and reduces their quality of life and productivity whilst increasing the overall healthcare burden. Its management requires thorough medical evaluation and individualized treatment. Depending on the severity and cause of AUB, its treatment ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Although hormonal therapy is the preferred first-line measure in AUB, the available pharmacological options have various adverse effects. There exists a need for safer and more efficient treatment regimens with high patient compliance to effectively treat AUB. Norethisterone, also known as norethindrone, is a widely used synthetic analogue of progestogen. Controlled release formulations of norethisterone/norethisterone acetate help maintain constant drug levels in the blood and exert minimal side-effects; therefore, they are promising therapeutic agents for effective AUB management. The present review summarizes the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of norethisterone/norethisterone acetate in AUB management. We also report a case of AUB in a 40-year-old woman, who was treated with NETA tablets. The treatment resulted in favourable outcomes, and patient satisfaction.

Objective: To assess the clinical characteristics and endocrinological background of women with vascular retained products of conception (RPOC) after miscarriage or abortion and evaluate the effect of estrogen–progestogen therapy (EPT) as an initial treatment on this population based on their endocrinological background. Materials and methods: Women with vascular RPOC after miscarriage or abortion at less than 20 weeks of pregnancy who were given EPT (conjugated estrogen and norethisterone) were retrospectively reviewed. Their clinical characteristics, hormonal parameters, ultrasonographic findings, and outcomes were evaluated. Results: Of 35 women with vascular RPOC, 30 (86%) presented with vaginal bleeding at a visit, and 6 (17%) required inpatient management due to heavy bleeding. Among women who presented with vaginal bleeding, serum progesterone levels were significantly lower (0.25 vs. 6.5 ng/mL, p = 0.004) than those in women who did not present with vaginal bleeding. There were no differences in serum hCG levels (10.5 vs. 3.1 mIU/mL) or serum estradiol levels (65.4 vs. 162.3 pg/mL). After withdrawal bleeding following the first course of EPT, vaginal bleeding was stopped in 27 of the 30 women (90%), and 23 (66%) of all women had a thin and linear endometrium. All women could be treated by up to two courses of EPT and did not require additional interventions. The median duration to hCG normalization after the initial EPT was 24.5 (9–88) days. Conclusion: Women with vascular RPOC who have no bleeding had significantly higher levels of serum progesterone, indicating that administration of progestogen may have an effect on hemostasis. Endometrial bleeding can be prevented or stopped, and retained tissues can be conservatively expelled by oral administration of EPT, including norethisterone, in women with vascular RPOC.

Norethisterone is an effective progestogen with a strong endometrial effect. In this study, the biotransformation of norethisterone was performed using a cultivated human intestinal fungal strain (Rhizopus microsporus PT2906) in vitro. Seven metabolites, including two new metabolites (1 − 2) and five known analogs (3 − 7), were obtained. The determination of their structures relied on comprehensive spectroscopic data, encompassing 1D NMR, 2D NMR, and HRESIMS. Considering the structures of the norethisterone metabolites, the main biotransformation reactions were revealed to be hydroxylation, lactylation, and dehydration. [Display omitted] • The biotransformation of norethisterone was performed by Rhizopus microsporus PT2906. • Seven metabolites were obtained from the biotransformation of norethisterone. • Two new structures were determined for the metabolites of norethisterone. [ABSTRACT FROM AUTHOR]

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]

Cerebral sino-venous thrombosis is a potential life-threatening condition that requires rapid diagnosis and urgent treatment. The association between progestin-only pill used for the treatment of menstrual disorders and cerebral venous thrombosis has rarely been reported in the literature. We report a case of cerebral venous thrombosis following the intake of norethisterone for menorrhagia in a young woman. Although venous thrombosis is usually linked to the ingestion of estrogen, rather than progestogen, this case illustrates that patients who are prescribed progestogen-only pills for gynecological disorders may develop thrombosis.

Objective: To evaluate the histomorphological effects of Vitamin D on Norethisterone-induced hepatosteatosis in female rats. Study Design: Laboratory-based 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 & 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.

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]

Relugolix+estradiol+norethisterone is a combination therapy used to treat symptomatic uterine fibroids in adult females of reproductive age. It is not available in Australia as a monotherapy. The therapy consists of relugolix, which suppresses the release of certain hormones, estradiol to limit menopausal symptoms, and norethisterone to reduce estrogen-induced endometrial hyperplasia. Clinical trials have shown that the therapy effectively reduces heavy menstrual bleeding and other symptoms associated with uterine fibroids. However, it is important to consider potential drug interactions and contraindications before prescribing this therapy. [Extracted from the article]

Abstract 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.

Fungal transformation of a norethisterone (17a-ethynylestra-4-en-17ß-ol-3-one) (1) by using Macrophomina phaseolina and Paecilomyces variotii was studied. A new metabolite, 17a-hydroxymethyl-androst-4-en-11ß-ol-3-one-17ß-acetate (2) with novel changes and a known metabolite, 17a-ethynylestradiol (3) were obtained from 1 by using M. phaseolina and P. variotii, respectively. Based on various spectroscopic techniques, the structures of both metabolites were characterized. The antimicrobial activities of 1-3 were also evaluated. Compound 1 was found to be moderately active against Salmonella paratyphi while 1-3 were almost inactive against other microorganisms. [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]

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.

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]

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. This was a prospective audit focused on administering high doses of NET in female adolescents with complaints of AUB. We included female adolescents who presented to our Emergency Gynecological Department or Adolescent Gynecological Outpatient Department from October 2016 to January 2019. The study included 29 female adolescents aged 11-17 (mean, 13.14) years. Patients were administered a daily dose of 10-30 mg, depending on the severity of the condition, bleeding duration, and patient weight. Cessation of vaginal bleeding. 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. The use of NET is an effective and reliable treatment option among adolescents for whom control of AUB is desired in the acute setting. [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]

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 0.1–10 nM) and LNG (10 nM) 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 10 nM 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 1 nM and 10 nM, whereas iyd mRNA was reduced by LNG and 10 nM 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 1.0 nM and 10 nM 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. [ABSTRACT FROM AUTHOR]

Purpose: To design a transdermal norethisterone (NE) patch for controlled drug release Methods: Polymers, viz, sodium salt of carboxymethyl cellulose (CMCNa) and hydroxyethyl cellulose (HEC), as well as a plasticizer (propylene glycole, PG) were used at various ratios to prepare NE films. The drug was dispersed in water and mixed with the polymer gel/plasticizer mixture prior to film casting. Weight variation, thickness, tensile strength, and the interaction between drug and film excipient were evaluated. The films were also characterized by Fourier transform infrared spectroscopy (FT-IR). In vitro drug dissolution and release from the transdermal patches (coded C-L, C-T, H-L and H-T) were evaluated. Results: There was significant difference between the batches in terms of in vitro drug release (p > 0.05). Dissolved drug was significantly higher in H-T film when compared to C-L film (p < 0.05). İn addition, drug release was significantly higher from H-T patch than from C-L patch (p < 0.05). Conclusion: NE transdermal patches containing HEC and Transcutol® have been successfully formulated. They can potentially be used to deliver NE via transdermal route to decrease the side effects associated with the oral route of administration of the hormone. [ABSTRACT FROM AUTHOR]

Objectives: 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.Methods: 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.Results: Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p<0.01); 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.Conclusions: 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. [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.

Objective: This study analyzed whether continuous combined oral estradiol and norethisterone had any effect on the pulsatility index (PI) of the internal carotid and uterine arteries in Taiwanese early postmenopausal women. Materials and Methods: A group of 40 healthy postmenopausal women with no history of hormone therapy (HT) participated in this study and were randomly subdivided into two groups: HT treatment group (n = 20) and placebo group (n = 20). PI was evaluated with color Doppler ultrasound at the beginning of the study and after 4 months of HT (2 mg 17 β-estradiol + 1 mg norethisterone acetate) or placebo. Results: There was no significant change in the PI of the internal carotid and the uterine arteries after 4 months of HT. Conclusion: This HT regimen showed no significant negative impact on vascular resistance in Taiwanese early postmenopausal women. Results are compatible with the updated recommendations on HT stating that there is little cardiovascular risk when HT is initiated within a few years of the menopause.

Exogenous progestins are an effective tool for hormonal contraception and family planning. Progestins may be delivered as oral pills, intramuscular or subcutaneous injections, vaginal rings, or intrauterine devices. Drug concentrations may vary based on the route and duration of delivery. Measurement of synthetic steroids in blood plasma can aid in determination of product adherence, evaluation of drug-drug interactions, and investigation of unintended pregnancies. Drug-free K 2 EDTA plasma was spiked with the synthetic steroids etonogestrel (ETO), levonorgestrel (LNG), medroxyprogesterone acetate (MPA), and norethisterone (NET). Plasma was combined with isotopically labeled internal standards, and drugs were extracted via liquid-liquid extraction. Samples were then subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. The method was validated in accordance with regulatory recommendations. The assay was evaluated in a cohort of remnant plasma samples in individuals using one of the aforementioned progestins. The analytical measuring range for ETO, MPA, and NET was 20–10,000 pg/mL; the primary linearity for LNG was 20–20,000 pg/mL. The method showed acceptable precision and accuracy for all progestins. Stability was established for 72 h with room temperature storage and through 3 freeze-thaw cycles. All analytes were stable in whole blood incubated at room temperature for 25 h, and at 40°C and 100% humidity for 2 h. Ion suppression was observed for all analytes spiked in plasma; average ion suppression was 31.6%, 66.6%, 32.1% and 41.2% for ETO, LNG, MPA, and NET, respectively. However, internal standards showed comparable ion suppression, and relative matrix effects were minimal. ETO, LNG, MPA, and NET could also be quantified accurately in K 3 EDTA plasma and serum. Progestins were successfully measured in remnant samples from individuals using hormonal contraceptives. A multiplexed LC-MS/MS assay for the quantification of ETO, LNG, MPA, and NET has been developed and validated. The assay met acceptable performance characteristics and may be used in downstream studies to evaluate progestin pharmacology. • Development of an LC-MS/MS method for the multiplexed measurement of progestins in plasma. • Validation of an LC-MS/MS method for quantification of ETO, LNG, MPA, and NET in plasma. • Characterization of hormonal progestin stability and application of assay to clinical samples. [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]

The pro-inflammatory cytokine, chemokine (C-C motif) ligand 20 (CCL20), is emerging as a therapeutic target for immune-based therapies. Cooperative regulation of CCL20 by glucocorticoids and progestins used in endocrine therapy and pro-inflammatory mediators could modulate immune function and affect disease outcomes. We show that glucocorticoids as well as medroxyprogesterone acetate (MPA), the progestin widely used in injectable contraception in sub-Saharan Africa, cooperate with pro-inflammatory mediators to upregulate CCL20 protein and/or mRNA in human peripheral blood mononuclear cells (PBMCs) and human cervical cell lines. Changes in CCL20 mRNA levels were shown to be synergistic, as assessed by Chou analysis, cell- and gene-specific and to involve transcriptional regulation, with a requirement for a nuclear factor kappa B (NF-κB) site and glucocorticoid receptor (GR) involvement. The novel results suggest a mechanism whereby MPA, like glucocorticoids, may impact inflammation both systemically and in the genital tract in patients using MPA and/or glucocorticoid therapy. • Synergism between glucocorticoids (GCs) and TNFα may amplify inflammation. • MPA like GCs but not NET synergizes with TNFα to upregulate CCL20 expression. • The synergy is cell- and gene-specific, and requires both the GR and NFκB. • MPA and NET may differentially affect HIV-1 pathogenesis and cancer prognosis. [ABSTRACT FROM AUTHOR]

Norethisterone (NET), one of the synthetic progestins, is detected with increasing frequency in the water environment and distributed in the ocean, with a potential toxicity risk to marine organisms. However, current studies on the adverse effects of progestins (including NET) in aquatic environments have focused on freshwater organisms, mainly fish. In the present, marine medaka (Oryzias melastigma) larvae were exposed to 91.31 ng/L NET for 10 days, and then the swimming behavior, oxidation-antioxidant-related enzyme activities, sex and thyroid hormone levels, and the gene transcription patterns of the larvae were measured. After NET treatment, medaka larvae were raised in artificial seawater until 5 months of age, and the sex ratio was counted. Ten-day exposure to 91.31 ng/L NET inhibited swimming behavior, of marine medaka larvae, which showed that the time in the resting state was significantly prolonged, while the time in the large motor state was significantly reduced; disrupted oxidative-antioxidant system, significantly up-regulated the enzymatic activities of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px); affected the hormone levels of larvae, lowered 11- keto testosterone (11-KT) and triiodothyronine (T3) concentrations. RNA-seq results showed that 91.31 ng/L NET exposure for 10 days changed the transcript levels of 275 genes, of which 28 were up-regulated and 247 were down-regulated. Differentially expressed genes (DEGs) were mainly significantly enriched in piwi interacting RNA (piRNA), gonadal development, gametogenesis, and steroidogenesis biological processes, etc. After removing NET exposure and returning to breeding for 140 days, a significant increase in male proportions (69.67%) was observed in sexually mature medaka populations in the NET-treated group. These results show that exposure to 91.31 ng/L NET for 10 days can lead to various adverse effects on marine medaka larvae. These findings shed light on the potential ecological risks of synthetic progestins to marine organisms. [Display omitted] • NET exposure inhibited the swimming behavior of marine medaka larvae. • Marine medaka larvae showed an antioxidant response after exposure to NET. • Short-term exposure to NET altered 11-KT and T3 levels in marine medaka larvae. • NET exposure altered the transcriptome of marine medaka larvae. • Larvae exposed to NET resulted in masculinization of adult marine medaka. [ABSTRACT FROM AUTHOR]

Norethisterone, a commonly used oral contraceptive, and treatment for various gynecological disorders such as menorrhagia, abnormal uterine bleeding, and breast cancer, has been associated with multiple liver injuries. These injuries can manifest as hepatitis or cholestatic types of injury, benign neoplasms, peliosis hepatis, sinusoidal obstruction syndrome, and enlargement of existing hemangiomas. This report presents three cases in which liver enzyme levels were elevated due to norethisterone intake. Two of the cases were individuals undergoing evaluation as potential kidney donors in the nephrology department for their spouses, while the third case involved a patient with chronic kidney disease (CKD) stage-5 on maintenance hemodialysis. Regular follow-up of these patients, particularly due to the significance of two being kidney donors and one having advanced CKD, allowed for early detection of asymptomatic liver enzyme elevation and prompt discontinuation of norethisterone. Prescribing norethisterone is common in gynecological settings, including ours. To assess gynecologists' knowledge regarding norethisterone-related side effects, we conducted an online survey, the results of which are discussed in this report., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Rather et al.)

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. [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]

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. [ABSTRACT FROM AUTHOR]

A comparison between the performance of spayed female racing Greyhounds and those suppressed with norethisterone acetate (NTA) was made. Previous work by the author has shown that the racing performance of spayed bitches is the same as that of entire bitches in anoestrus, i.e. spaying is just a permanent anoestrus. The aim was to assess any performance difference between suppression and anoestrus, and thus to determine the effect of norethisterone acetate on race performance. The study was designed as a retrospective case-control. Raceform data was obtained for female racing Greyhounds which had raced, and which were either spayed or suppressed with norethisterone acetate. Analysis showed that suppressed bitches run on average 0.049 to 0.061 s slower over 480 m (centralised models). Since endogenous progesterone (P4) has been linked with reduced race performance, it is logical that progesterone analogues like NTA should have a similar effect. It is likely that the depression in performance is dose-related, but not quantifiable with the current dataset., Competing Interests: Declaration of Competing Interest The author expresses no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)