Comparison of safety and efficacy of Ormeloxifene and Norethisterone acetate in the treatment of heavy menstrual bleeding

Background: Menorrhagia (menstrual blood loss more than 80% per cycle) affects 10-33% of women at some stage of their lives. Medical management is the first line of therapy for menorrhagia (heavy menstrual bleeding: HMB). Progestins have been found to be very effective in the management of heavy menstrual bleeding especially during acute episodes, norethisterone acetate being widely used for the same. Ormeloxifene is a new drug with promising results in managing HMB. The study was undertaken to compare the efficacy, safety and acceptability of Ormeloxifene /Norethisterone acetate in the medical management of heavy menstrual bleeding.Methods: This was a retrospective study conducted from January 2016 till December 2018 in which 98 women of reproductive age group presented with abnormal uterine bleeding without any organic, systematic and iatrogenic causes. The patients were divided into 2 groups. Those wanting contraception along with control of HMB were assigned to Group O and given Ormeloxifene and others were given norethisterone (Group N). The primary outcomes measured were menstrual blood loss assessed subjectively by patients and ultrasonography for endometrial thickness. The secondary outcomes measured were acceptability and side effects of Ormeloxifene and norethisterone.Results: There is a significant reduction in menstrual blood loss as evidenced by the history of patients recorded on follow up and there was a significant reduction in the endometrial thickness as evidenced on follow up scan at the end of 3-4 months. no major side effects were observed with both the drugs.Conclusions: Ormeloxifene in comparison to norethisterone acetate with its effectiveness, significant results, convenient dosages schedule and no major side effects is an effective and safe alternative medical management of HMB.

Effect Of Synthetic Progesterone (norethisterone) On Human Chromosomes: A Cytogenetic Study From India

Birth restriction methods dates back to prehistoric times, half a million years ago. Modern contraceptive methodsconstitute most contraceptive use. Nearly 800 million married or in-union women are projected to be usingcontraception in 2030. Norethisterone (synthetic progesterone) is used for many therapeutic purposes, and isbeing used by millions of women in India. The present study was carried out during August 2009 to July 2011 onsixty fertile females within reproductive age group. Chromosomal analysis was carried out to find the effects ofsynthetic progesterone (Norethisterone) on human chromosomes in lymphocyte culture in vitro in three groups at0, 75 µg, 100 µg of drug per ml respectively and observed for chromosomal aberrations like break, gap, dicentricchromosome and chromosomal association. Chromosomal aberrations were significantly increased at higherconcentrations. Mean chromosomal gaps at 0µg/ml, 75µg/ml and 100 µg/ml concentration were 6.90, 7.62 and10.58 respectively and mean chromosomal breaks in that same concentration were 6.63, 7.28 and 10.08respectively. 30 samples of the 60 showed chromosomal associations and 5 showed dicentric chromosomes.There is a direct correlation between increase in concentration of Norethisterone and structural chromosomalaberrations, which may be carried to next generation, and lead to anomalies in progeny of woman taking suchhigh doses of synthetic progesterone

Establishment of the international pharmacopoeia standard for norethisterone tablets / 中国药学杂志

OBJECTIVE: To establish the International Pharmacopoeia standard for norethisterone tablets. METHODS: In accordance with the requirements of the International Pharmacopoeia standard, the existent quality standards of norethisterone tablets and related literatures were referred, appropriate methods were selected, and verification test was carried out to determine the best method. RESULTS: In the system suitability test of thin layer chromatography identification, the spots of norethisterone and ethinylestradiol were separated well. Nine known impurities and other unknown impurities could be separated well by the HPLC method for the examination of related substances, and the impurity with relative retention time of 1.1 was shown to be ethinylestradiol by LC-MS. In 0.1 mol·L-1 hydrochloric acid solution containing 0.09% SDS, norethisterone tablets achieved a dissolution of more than 90% in 30 min and the dissolution curve reached plateau. Under the liquid chromatographic condition for the assay, the linear range was 0.746-29.840 μg·mL-1 (r=0.999 9), and the resolution between norethisterone and ethinylestradiol was over 4.0. CONCLUSION: The established quality standard of norethisterone tablets is simple and accurate, which fully considers the feasibility of the method and accessibility of reagents, thus can effectively control the quality of products.

Quality Evaluation and Study of Dissolution Determination for Compound Norethisterone Tablet / 中国药房

OBJECTIVE:To evaluate the inherent quality differences of different batches of Compound norethisterone tablet from different domestic enterprises by researching its in vitro dissolution,to provide reference for improving relevant standards in pharmacopoeia and optimizing production processes in drug manufacturers. METHODS:Orthogonal test was adopted to screen its dissolving conditions,small glass method was finally confirmed by detecting rotating speed,sampling time and dissolution medi-um,sampling determination was conducted with the dissolution medium of 0.5% sodium dodecyl sulfonate and rotating speed of 50 r/min and 45 min. And HPLC was adopted to simultaneously determine the in vitro dissolution of norethindrone and ethinyl estra-diol,then AV value method was adopted to detect the similarity of dissolution profiles of 8 batches of products from 2 domestic en-terprises. RESULTS:The dissolution profiles and similarity of AV value method showed the cumulative dissolution of 8 batches of Compound norethisterone tablet from 2 domestic enterprises had no significant difference at different time points,overall similarity was relatively high;but the ethinyl estradiol had certain difference,overall similarity was relatively low. CONCLUSIONS:The dif-ference of dissolution profiles of Compound norethisterone tablet may has effect on the drug efficacy,the production process and quality in domestic enterprises should be managed strictly. Meanwhile,the current method of dissolution is weak to distinguish from the quality,which needs to be improved urgently.

A comparative study on the effectiveness of ormeloxifene versus norethisterone in the management of perimenopausal dysfunctional uterine bleeding.

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 norethisteron 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 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

LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial / 부인종양

OBJECTIVE: To compare the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) and oral norethisterone acetate (NET) for treatment of non-atypical endometrial hyperplasia in perimenopausal women. METHODS: One hundred and twenty perimenopausal women with non-atypical endometrial hyperplasia were selected in this randomized controlled trial. Patients received LNG-IUS (n=59) or NET (n=61; 15 mg/day for 3 weeks/cycle) for 3-6 months. Outpatient follow-up with endometrial biopsies were undertaken at 3, 6, and 12 months intervals after treatment. Outcome measures were; the regression rate, the time to regression and hysterectomy rate. RESULTS: A significantly higher regression rate was noted in the LNG-IUS group than in NET group at the 3rd, 6th and 12th month follow-up visits using intention-to-treat analysis (67.8% vs. 47.5%, relative risk [RR], 1.42; 79.7% vs. 60.7%, RR, 1.31; and 88.1% vs. 55.7%, RR, 1.58, respectively). However, no significant difference was found regarding the median time to regression (3 months). The hysterectomy rate during the follow-up period was significantly higher in the NET group (57.4% vs.22%, p<0.001). CONCLUSION: LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women is more effective than NET for achieving disease regression for the majority within 1 year. Moreover, it can reduce the number of hysterectomies performed.

Determination of related substances of compound norethisterone enanthate injection by HPLC / 中国药学杂志

OBJECTIVE: To establish an HPLC method for the determination of related substances of compound norethisterone enanthate injection. METHODS: A Phenomenex Gemini C18 column(4.6 mm × 250 mm, 5 μm) was used with water as mobile phase A and aeetonitrile as mobile phase B. Gradient elution was used for the determination and the flow rate was 1.0 mL · min-1. The detection wavelength was 220 nm. The column temperature was maintained at 35°C. RESULTS: Norethisterone enanthate, estradiol valerate and their related substances were separated well. The calibration curves of the known related substances, namely norethisterone and estradiol, were linear within the concentration ranges of 5.02-45.2 and 0.505-4.55 μg · mL-1 with correlation coefficients of 1.0000 (n = 5) and 0.9992 (n = 5), respectively. The average recoveries of norethisterone and estradiol were 99.4% and 96.2% (n =3), with RSDs of 0.9% and 3.3%, respectively. The self-reference standard solution of norethisterone enanthate and estradiol valerate were linear within the concentration ranges of 2.42-121 and 0.242-12.1 μg · mL-1, and the correlation coefficients were both 1.0000 (n =6). The LODs of norethisterone, estradiol, norethisterone enanthate, and estradiol valerate were 7.3, 2.0, 0.9 and 1.2 ng, respectively. CONCLUSION: The method is accurate, sensitive, and specific. The analsis results of four batches of compound norethisterone enanthate injection showed that there is an evident correlationship between the amount of related substances and storage time of the injection.

Eficácia e tolerabilidade da associação transdérmica matricial de estradiol e noretisterona em regime combinado contínuo na pós-menopausa / Continuous combined transdermal matrix patch delivering estradiol-norethisterone acetate in post menopause: efficacy and tolerability

Objetivos: Avaliar a eficácia e tolerabilidade da associação transdérmica de estradiol e noretisterona, em regime combinado contínuo, em mulheres na pós-menopausa. Casuística e Métodos: Foram estudadas 40 pacientes, com média etária de 56,7 anos em estudo prospectivo, aberto e não comparativo. As pacientes receberam a associação de estradiol e noretisterona em regime combinado contínuo pelo período de seis meses, seguidos de extensão por período de mais um ano. Avaliaram-se os sintomas menopausais por meio do índice de Kupperman, além de parâmetros clínicos e ultra-sonográficos (peso, pressão arterial, espessura endometrial) e aspectos relacionados aos eventos adversos e às manifestações cutâneas, através de exame dermatológico. Resultados: Houve melhora global dos sintomas menopausais avaliados pelo índice de Kupperman. A análise detalhada dos sintomas moderados e graves demonstrou melhora significativa dos fogachos, sudorese, parestesia, fadiga, irritabilidade e psicolabilidade, com início ao terceiro mês de tratamento, mantendo-se até o final do período de avaliação. Eritema e prurido no local da aplicação do adesivo foram os eventos cutâneos mais comuns, ocorrendo em 12,1% e 3,0% das pacientes, respectivamente. Discreta taxa de eventos adversos foi observada. Conclusão: A TH transdérmica, contendo estradiol e noretisterona de uso contínuo, mostrou-se efetiva no alívio sintomático em mulheres climatéricas, associando-se a uma discreta taxa de eventos adversos e boa tolerabilidade.

Clinical analysis on the treatment of hysteroscopic resection and norethisterone in abnormal uterine bleeding / 中国基层医药

Objective To analyse the efficacy of hysteroscopic resection and norethisterone in abnormal uterine bleeding.Methods 38 cases of submucos myoma of uterine body,26 cases of endometrium polyps and 16 cases of complex hyperplasis of endometrium were treated with hysteroscopic resection,and all the cases take norethisterone for one month before hysteroscopic resection and go on taking norethisterone for three months after operation.All the cases were followed up with the improvement of symptoms and the chang of uterine cavity.Results All the cases were followed up for 3～18 months after operation.The efficacy of submucous myoma of uterine body was 92.10%(36/38) and that of endometrium polyps was 84.61%(22/26) and that of complex hyperplasis of endometrium was 93.75%(15/16).Conclusion The treatment of hysteroscopic resection and norethisterone in submucous myoma,endometrium polyps and complex hyperplasis has advantages of satisfied results,slight trauma,fast recovery and fewer recurrence relapse.

Combination of norethisterone with ethinylestradiol showed synergetic effect on ovariectomy induced osteopeniain rats / 中国药理学通报

AIM To determine whether norethisterone in combination with ethinylestradiol can completely prevent bone loss in ovariectomized rats. METHODS Twenty-four Sprague-Dawley female rats at the age of 4.5 months were sham-operated and treated orally with vehicle, or ovariectomized (OVX) and treated orally with either vehicle or combined norethisterone (norethisterone at 60 ?g?kg -1?d -1 and ethinylestradiol at 3.5 ?g?kg -1?d -1) for 90 days. Double in vivo fluorochrome labeling was administrated. The undecalcified longitudinal proximal tibial metaphyseal sections were used for the bone histomorphometric analysis. The humerus and urine calcium contents were assayed by the method of atomic absorption spectrometry. The humerus and urine hydroxyproline contents were assayed by colorimetry. Blood serum alkaline phosphatase (ALP) were tested by BECKMAN auto bio-chemistry analyzer. RESULTS After 90 days post OVX the cancellous bone mass and showed high bone turnover indices. Bone hydroxyproline contents were lost markedly. The ALP activity increased. The urine hydroxyproline contents increased significantly. The combined norethisterone treated group prevented bone lost when compared with OVX. The combined norethisterone were shown to inhibit osteoclasts surface and decrese bone turnover rate. The combined norethisterone can increase hydroxyproline contents and reduce urine hydroxyproline contents significantly from OVX group. CONCLUSION Combining norethisterone can prevent OVX-induced cancellous bone loss in rats.

Analysis of the Uncertainty of the Content and the Content Uniformity in HPLC Determination of Norethisterone Tablets / 中国药房

OBJECTIVE:To establish a method for uncertainty analysis about the content of norethisterone and its content uniformity in HPLC determination of norethisterone tablets. METHODS: The mathematic model of uncertainty measurement was deduced in the procedure of determining the content and content uniformity in norethisterone tablets by HPLC, and the factors influencing the uncertainty were determined and the factors were evaluated. RESULTS: The combined uncertainty of both content and content uniformity were 1.2%; the extended uncertainty of both were 2.4%, and the determined content were (101.8?2.4)% and (102.3?2.4)% respectively. CONCLUSIONS: This method is applicable for the uncertainty analysis about the content and content uniformity of norethisterone tablets.

NET LEVELS IN SALIVA AND SERUM AFTER MULTIPLE INJECTIONS OF NET-OEN PLUS EV AND THEIR RELATION / 中国药理学通报

Since saliva has been widely used as a fluid for monitoring drug concentrations, both saliva and serum samples were collected after multiple injections of Norethisterone Enanthate ( NET-OEN ) 50mg and Estradiol Valerate ( EV ) 5mg from 10 women. The concentration of NET in saliva was measured by RIA using diluted antisera working solution and serum NET level was measured by RIA according to our lab. regular method. The assay was running very well. The phar- macokinetics of NET in saliva were observed from the data obtained. The time to reach peak levels in saliva was 5d after injection, which was similar to the Tmax of NET in blood. Mean peak values of NET in saliva were about 220, 218, and 158 ng/L which were almost 1/30 to 1/40 of the Cmax of NET in serum (8506, 6888, and 5619 ng/L) for 1st, 6th, and 12th injections. The concentration of NET in saliva showed to be very closely related to the serum NET concentration in the same subject, and the correlation coefficients were 0.86, 0.83, and 0.80 ( P