[Research of gestrinone-related abnormal uterine bleeding and the intervention in the treatment: a multi-center, randomized, controlled clinical trial].

OBJECTIVE: To investigate the incidence, influencing factors and intervention of gestrinone-related abnormal uterine bleeding at different dosage of gestrinone in the clinical treatment. METHODS: This was a multicenter, randomized, control study of 195 Chinese women with endometriosis or adenomyosis from June 2011 to November 2013. The subjects were randomized into three groups with oral administration of gestrinone, 2.5 mg dose at one time; twice a week group: 67 cases with oral administration twice a week last three months; double dose first month group: 67 cases with oral administration triple times a week at first month, then twice a week for two months; three times a week group: 61 cases with oral administration three times a week last three months. The improvement of the abnormal uterine bleeding, the changes in estrogen, liver function and blood coagulation were evaluated. At the same time, B-ultrasound examination evaluation were performed. RESULTS: (1) Three months later, the incidence of abnormal uterine bleeding in twice a week group was 30% (20/67), in double dose first month group and three times a week group were 7%(5/67) and 16% (10/61) respectively, there were significant difference between three groups (P<0.05). The incidence in double dose first month group was the most lower. (2) Univariate analysis showed that the dosage and ovarian size were the significant factors for abnormal uterine bleeding (OR=0.461,P= 0.003;OR=0.303,P=0.016); logistic regression analysis demonstrated that the risk of abnormal uterine bleeding in double dose first month group was the lowest when compared with twice a week group and three times a week group, the risk in twice a week group was 5-fold higher than that in double dose first month group (OR=0.211,P=0.011). The incidence of abnormal uterine bleeding in participants with abnormal ovarian volume results from ovarian cyst or ovarian surgery was significantly lower than those with normal ovarian volume (OR=0.304,P=0.018). (3) After the treatment of three months, there were no significant difference in alanine transaminase level between the groups (P>0.05). The body mass index significantly increased in three group (P<0.05), but there were no significant differences between the groups (P>0.05). As for blood coagulation, there were also no significant differences between the groups (P>0.05). CONCLUSIONS: Double dose of gestrinone in the first month could significantly decrease the incidence of gestrinone-related abnormal uterine bleeding. It is a more optimied dosage of gestrinone and without severe side effects. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, registration number: ChiCTR-TRC-12002327.

Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK.

The study was to investigate the effect of gestrinone on the growth of human uterine leiomyoma cells and on the levels and activity of p38, Src and estrogen receptor alpha (ERα). Human uterine leiomyoma cells were cultured and treated with dimethylsulfoxide (DMSO) or a gestrinone concentration gradient. Morphological changes were observed and apoptosis was evaluated. Levels of p38 and phosphorylated-p38 (pp38) were assayed by enzyme-linked immunosorbent assay (ELISA). Levels of ERα and Src were analyzed using real-time RT-PCR and Western blotting. The result showed that gestrinone significantly inhibited the growth of cultured human uterine leiomyoma cells in a concentration- and time-dependent manner, with a 50% inhibitory concentration (IC(50)) value and corresponding 95% confidence intervals (CI) of 43.67 (23.46∼81.32), 27.78 (12.51∼61.68) and 15.25 (7.17∼32.43) µmol/L at 20, 40 and 60h, respectively. Compared with control-treated leiomyoma cells, gestrinone significantly reduced both the expression of ERα (P<0.05) and the levels of phospho-Ser167-ERα (P<0.05). Gestrinone also markedly suppressed the level of phospho-Tyr416-Src (P<0.05). Moreover, gestrinone significantly increased the ratio of phospho-p38/p38 mitogen-activated protein kinase (MAPK) (P<0.05). However, no significant increase in apoptosis or cell cycle arrest was observed (P>0.05) in response to the tested concentrations of 0.1 to 3.0µmol/L. As a conclusion, gestrinone suppresses the proliferation of uterine leiomyoma cells mainly by regulating the activity of ERα/Src/p38 MAPK in a concentration-dependent manner at a low concentration of 0.1∼3.0µM, but not significantly regulating apoptosis. Gestrinone opposes the growth of uterine leiomyoma through multiple genes.

Gestrinone compared with mifepristone for emergency contraception: a randomized controlled trial.

OBJECTIVE: To compare the efficacy of gestrinone with that of mifepristone for emergency contraception. METHODS: A randomized double-blind trial was conducted in five family-planning clinics in China. We randomly assigned 998 healthy women with regular menstrual cycles and negative urine pregnancy tests who were requesting emergency contraception up to 72 hours after unprotected coitus to receive single-dose 10 mg gestrinone (n=499) or 10 mg mifepristone (n=499). We monitored them to 7 days after the expected first day of their next menstrual period. The study was powered to detect a 5% failure rate between the two regimens. RESULTS: The treatment groups did not differ significantly; posttreatment pregnancy rates were 2.4% in the gestrinone group compared with 1.8% in the mifepristone group (P=.51). The majority of women menstruated the first day of expected menses, and groups did not differ regarding side effects. CONCLUSION: The effectiveness of 10 mg gestrinone is not significantly different from 10 mg mifepristone as an emergency contraceptive method. CLINICAL TRIAL REGISTRATION: ISRCTN Register, isrctn.org, ISRCTN87842530. LEVEL OF EVIDENCE: I.

Comparative study on the efficacy of Yiweining and Gestrinone for post-operational treatment of stage III endometriosis.

OBJECTIVE: To observe the clinical efficacy and safety of Yiweining (YWN) and gestrinone (GT) in treating post-operational patients of stage III endometriosis (EM-III). METHODS: Fifty-two patients of EM-III after operation were randomly assigned into three groups, the YWN group (20 patients) was treated through oral intake of YWN 200 ml, twice a day; the GT group (19 patients) treated with gestrinone 2.5 mg, twice every week, with the medication starting from the 7th post-operational day and lasting for 6 months. The control group (13 patients) was untreated. Six months was one therapeutic course, and follow-up study was carried out in the 6 - 30 months after the end of the medication. RESULTS: The recurrence rate in the YWN group and the GT group were 5.0% and 5.3% respectively, showing insignificant difference between the two groups, but they were lower than that in the control group (30.7%, P < 0.05). Besides, the adverse reaction rate in the YWN group was lower than that in the GT group (10.0% vs 31.6%, P < 0.05). CONCLUSION: Application of YWN to prevent the post-operational recurrence of endometriosis is effective and safe, and its efficacy is similar to that of GT.

Dehydroepiandrosterone (DHEA) is an anabolic steroid like dihydrotestosterone (DHT), the most potent natural androgen, and tetrahydrogestrinone (THG).

We have recently taken advantage of the unique power of DNA microarrays to compare the genomic expression profile of tetrahydrogestrinone (THG) with that of dihydrotestosterone (DHT), the most potent natural androgen, thus clearly demonstrating that THG is an anabolic steroid. In 2004, the U.S. Controlled Substances Act has been modified to include androstenedione (4-dione) as an anabolic steroid. However, despite the common knowledge that dehydroepiandrosterone (DHEA) is the precursor of testosterone, DHEA has been excluded from the list of anabolic steroids. We thus used the same DNA microarray technology to analyze the expression profile of practically all the 30,000 genes of the mouse genome modulated by DHEA and DHT in classical androgen-sensitive tissues. Daily subcutaneous injections of DHT (0.1mg) or DHEA (3mg) for 1 month in gonadectomized C57BL6/129 SV mice increased ventral prostate, dorsal prostate, seminal vesicle and preputial gland weight (p<0.01 for all tissues). As early as 24h after single injection of the two steroids, 878, 2681 and 14 probe sets were commonly stimulated or inhibited (p<0.01, change> or =30%), in the prostate (ventral+dorsal), seminal vesicles and preputial glands, respectively, compared to tissues from gonadectomized control animals. After 7 days of daily treatment with DHEA and DHT, 629, 919 and 562 probe sets were commonly modulated in the same tissues while after 27 days of treatment, 1195, 5127 and 2883 probe sets were modulated, respectively. In analogy with the data obtained with THG, the present microarray data provide an extremely precise and unquestionable genomic signature and proof of the androgenic/anabolic activity of DHEA. Such data add to the literature showing that DHEA is transformed into androgens in the human peripheral tissues as well as in laboratory animal species, including the monkey, thus exerting potent androgenic/anabolic activity. The present microarray approach to identify anabolic compounds is applicable to all potential androgenic/anabolic compounds.

Gestrinone versus danazol as preoperative treatment for hysteroscopic surgery: a prospective, randomized evaluation.

OBJECTIVE: To compare danazol and gestrinone treatment as preoperative endometrial preparation for operative hysteroscopy. DESIGN: Prospective, randomized clinical study. SETTING: University department of gynecological, obstetrical sciences and reproductive medicine. PATIENT(S): One hundred thirty-five patients with endouterine pathologies (endometrial polyps, submucous myoma, septate uterus). INTERVENTION(S): Patients pretreated with gestrinone (n = 68) and with danazol (n = 67) underwent operative hysteroscopy. MAIN OUTCOME MEASURE(S): Endometrial response to the medical pretreatment, side effects, procedure time, intraoperative bleeding, infusion volume, patient satisfaction. RESULT(S): Side effects were infrequent in both groups, though the patients' personal satisfaction was in favor of gestrinone. The rate of endometrial response was higher for the gestrinone group (97.1% vs. 83.6%). Operative time (mean +/- SD) was 12 +/- 1.8 and 15.2 +/- 1.9 minutes for the gestrinone and danazol groups, respectively. The gestrinone group showed a lower incidence of moderate bleeding (3% vs. 22.4%) and a lower infusion volume (2,100 +/- 200 mL vs. 2,400 +/- 250 mL). Regarding cervical dilatation time, no significant difference was found between the two groups (1.6 +/- 0.3 minutes vs. 1.5 +/- 0.4 minutes). CONCLUSION(S): Both treatments are good ways to prepare the endometrium for operative hysteroscopy. However, the data suggest that gestrinone pretreatment is preferable to danazol.

[Effect of gestrinone on the lipid metabolic parameters and bone mineral density in patients with endometriosis].

OBJECTIVE: To observe the change of lipid metabolic parameters, sex hormone and bone mineral density (BMD) in patients with endometriosis before and after oral administration of gestrinone. METHODS: Fifty-six patients with endometriosis, aged from 20 to 45, were treated with gestrinone 2.5 mg two times a week for 6 months one week after operation. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), ApoA(1), ApoB, follicle stimulating hormone (FSH), luteinizing hormone (LH), E(2) and BMD were determined before taking gestrinone, after taking for 6 months and withdrawal for 6 months. RESULTS: After administration of gestrinone for 6 months, serum HDL-C and ApoA(1) decreased significantly (P < 0.05). Serum LDL-C and ApoB increased significantly (P < 0.05). Serum E(2) and BMD decreased evidently. Serum TG, TC, FSH and LH were not changed evidently. After withdrawal of gestrinone for 6 months, serum parameters restored to levels before taking gestrinone except BMD. CONCLUSIONS: Gestrinone can decrease serum E(2) and BMD in patients with endometriosis, which may not be good for lipid metabolism. It is not advisable to take gestrinone for long term.

Tetrahydrogestrinone is a potent androgen and progestin.

Tetrahydrogestrinone (THG) was recently identified as a novel steroid used illicitly to improve athletic performance. Although its structure is closely related to gestrinone, a 19-nor progestin, and resembles that of trenbolone, THG was never marketed, so information on its hormonal properties is not known. In this study, we demonstrate that THG is a highly potent androgen and progestin in a yeast-based in vitro bioassay system expressing human androgen and progesterone receptors. It has no estrogenic activity and no antagonism for any of the three steroid receptor classes.

Clinical, endocrine, and metabolic effects of two doses of gestrinone in treatment of pelvic endometriosis.

OBJECTIVE: Our purpose was to determine and compare the efficacy and hormonal and metabolic effects of 1.25 mg with 2.5 mg of gestrinone given twice a week in the treatment of mild and moderate pelvic endometriosis. STUDY DESIGN: A phase II, prospective, randomized, double-blind study involving 11 patients given gestrinone 1.25 mg (five patients) or 2.5 mg (six patients) orally twice a week for 24 weeks was performed. Revised American Fertility Society scores were determined by laparoscopy before and at the end of treatment. Serum hormone (free thyroxine, free testosterone, estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone), sex hormone binding globulin, and lipid concentrations were measured before, throughout, and for 6 months after treatment. Quantitated computerized tomography of thoracic 12 through lumbar 4 vertebral bodies were determined before, at the end of, and 6 months after treatment. RESULTS: Gestrinone 2.5 mg significantly reduced the endometriosis implant score from 10.3 +/- 2.8 to 3.8 +/- 0.8 (p = 0.05). Both doses significantly reduced serum progesterone and sex hormone binding globulin levels. Estradiol, free testosterone, free thyroxine, follicle-stimulating hormone, and luteinizing hormone levels were not significantly affected. Spinal bone increased significantly by 7.1% with 2.5 mg but lost significantly by 7.1% with 1.25 mg gestrinone; these changes had not reversed completely 6 months after stopping treatment. CONCLUSIONS: In mild to moderate pelvic endometriosis 2.5 mg of gestrinone twice a week was more effective and had a more positive effect on bone mass than did 1.25 mg of gestrinone.

Individual and combined effects of triptoreline and gestrinone on experimental endometriosis in rats.

OBJECTIVES: To evaluate the effects of triptoreline, gestrinone, and both, on experimental endometriosis in rats. STUDY DESIGN: Experimental endometriosis was surgically induced in 225 Wistar rats. Of these, 202 rats showed at least one grown implant, 22 of which composed the control group, while 180 were treated with triptoreline, gestrinone, or both, for 28 days. The implants were evaluated again after 25 days. RESULTS: There were no changes in size in the control group. About 73% of the implants treated with triptoreline showed a high reduction (> 50%), vs. 51% with gestrinone (P < 0.0005) and 65% with both (P < 0.005). Triptoreline caused macroscopic resolution in 40% of the implants vs. 31% for gestrinone (not significant) and 26% for both substances (P < 0.05). In the triptoreline group, the mean size of the implants decreased by 65% between the 25th and 28th days, 58% between the 29th and the 35th, and 39% after the 36th day. This reduction was 51%, 36%, and 33%, respectively, in gestrinone group. CONCLUSIONS: Triptoreline was more effective than gestrinone, but perhaps not in the long run. Their association did not improve the results.

Gestrinona versus danazol resultados del tratamiento de la endometriosis estadios I y II / Gestrinoma versus danazol on the treatment of endometriosis

Objetivo. Comparar los resultados del tratamiento de la endometriosis con gestrinona y danazol. Material y método. 107 pacientes con diagnóstico de endometriosis por laparoscopía fueron divididas en dos grupos en forma aleatoria. En el primer grupo se incluyeron 53 pacientes a las cuales se les administró 600 mg por día de danazol por 6 meses. En el grupo dos se incluyeron 54 pacientes a las cuales se les administró 2.5 mg de gestrinona dos veces a la semana. Un mes después de concluir el tratamiento se efectuó laparoscopía de segunda mirada en las pacientes que estuvieron de acuerdo (43 en las del grupo de gestrinona y 40 en las del grupo de danazol). Resultados. Hubo marcada disminución de dolor en ambos grupos. La laparoscopía de segunda mirada reveló una disminución mayor de la endometriosis en el grupo de danazol. Diez meses posteriores al tratamiento la tasa de embarazo fue del 15 por ciento para gestrinona y del 33 por ciento para danazol. El dolor regresó en 57 por ciento para gestrinona y 50 por ciento para danazol. Los efectos secundarios fueron mas frecuentes y severos con danazol que con gestrinona. Conclusiones. El resultado de este estudio sugiere que gestrinona es menos efectiva en el tratamiento de la esterilidad asocida a endometriosis en comparación a danazol

[Gestrinone in pelvic endometriosis. A one-year evaluation]. / Gestrinona en endometriosis pélvica. Evaluación a unaño.

The therapeutical effectiveness of gestrinone in endometriosis treatment, as well as its long term side effects, were evaluated. Prospective, clinical trial. At "Dr. Alejandro Castanedo Kimball" Hospital (PEMEX). Salamanca, Guanajuato. México. Thirty women with laparoscopically confirmed endometriosis, were studied. Subjects received 2.5 mg. of gestrinone two times per week for 6 months. Laparoscopy was performed before treatment, and clinical response was determined by second laparoscopy after 6 months. The pregnancy rate, frequency of side effects and recurrence of symptoms were determined. Median total endometriosis scores and symptoms decreased significantly after treatment. Four pregnancies were observed after treatment. The principal side effects were: ponderal increase, changes in the voice and hirsutism. However, the side effects disappeared after one year of clinical survey. The results indicate that gestrinone is effective in the treatment of pelvic endometriosis. In despite of a clear benefic effect on stage of the disease and symptoms; the use of gestrinone should weigh the risk-benefit (cost versus metabolic side effects) of treatment.

Gestrinona en endometriosis pélvica. Evaluación a un año / Gestrinone on pelvic endometriosis. Evaluation after one year treatment

Se evaluó la eficacia terapéutica de la gestrinona para el tratamiento de la endometriosis; y los efectos secundarios a largo plazo del fármaco. Estudio clínico prospectivo, Hospital "Dr. Alejandro Castanedo Kimball" (PEMEX), Salamanca, Guanajuato. Treinta mujeres con diagnóstico laparoscópico de endometriosis fueron estudiadas. Las pacientes recibieron tratamiento con gestrinona (2.5 mg. dos veces a la semana, durante 6 meses). Se realizó laparoscopia antes del tratamiento con gestrinona; y la respuesta clínica fue evaluada con otra laparoscopia seis meses después. Se determinó la tas de embarazos; la frecuencia de efectos secundarios y la recurrencia de la sintomatología. Después del tratamiento se observó una mejoría significativa en el grado de la endometriosis; así como en los síntomas referidos por las pacientes. Se obtuvieron cuatro gestaciones después de terminado el tratamiento. Los efectos secundarios más frecuentes fueron: incremento ponderal, cambio en el timbre de la voz e hisutismo; los cuales remitieron en la mayoría de las pacientes después de un año de vigilancia clínica. La gestrinona es un fármaco útil para el tratamiento de la endometriosis, no obstante, su uso debe basarse en la selección cuidadosa de las pacientes y en la valoración del beneficio versus el costo y los efectos metabólicos del medicamento

[Antihormones and laparoscopy in the combined treatment of disseminated forms of genital endometriosis externa]. / Antigormony i laparoskopiia v kombinirovannom lechenii rasprostranennykh form naruzhnogo genital'nogo éndometrioza.

A total of 100 patients with disseminated forms of external genital endometriosis were administered multiple-modality treatment including surgery and antihormone therapy. Twenty patients with the same diagnosis were controls and subjected to surgery alone. The results of treatment assessed on the basis of analysis of the clinical course of the disease, status of the menstrual and generative functions, drug effects on the central nervous system, hormonal status, and target organs (mammary glands and osseous tissue) evidence good potentialities of laparoscopy and high efficacy of subsequent therapy with antihormones in the treatment of patients with grave forms of endometriosis.