[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.

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.

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.

[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.

Treatment of endometriosis by vaginal administration of gestrinone.

The effectiveness and acceptability of gestrinone administered by vaginal route was evaluated in a group of 110 patients with endometriosis. Patients were divided into four groups. The first three groups were treated by vaginal route. Group I (n = 17) received two 2.5-mg tablets weekly; group II (n = 31) received three 2.5-mg tablets weekly; group III (n = 35) received two 5.0-mg tablets weekly. Group IV consisted of 27 patients who received 2.5 mg of gestrinone orally twice weekly. Ninety-eight women completed the 6- to 8-month treatment period. Amenorrhea developed in all treatment groups, including group I (34%). The disappearance of both dyspareunia and dysmenorrhea occurred in most patients in all treatment groups soon after the second month of therapy. Patients treated by vaginal route had significantly less seborrhea and acne than those treated by oral route. Weight gain was also significantly less in vaginally treated women than in those treated orally. Pregnancy rate following discontinuation was not significantly different for the various groups.

A synthetic steroid (R2323) as a once-a-week oral contraceptive.

Five milligrams of the steroid R2323 (13 beta-ethyl-17 alpha-ethynyl-17-hydroxygona-4,9,11-trien-3-one (R2323) were administered orally once weekly to 28 subjects for a total of 138 treatment cycles. No pregnancies occurred. The predominant side effects were irregular vaginal bleeding, headache, weight gain, and acne. Administration of the drug was stopped by the investigator in four patients (14%) because of the onset of headaches. Four patients discontinued the drug for other reasons. In 8 of 26 subjects (31%), endometrial biopsy in the third treatment cycle showed secretory endometrium. This suggests a variable central suppression with the 5-mg dose schedule. Patients were enthusiastic about the once-weekly oral administration. This contraceptive may be useful in a select group of women.

Long-term treatment of leiomyomas with gestrinone.

A prospective randomized study was conducted in 100 women with leiomyomas in order to evaluate the effect of gestrinone, a synthetic derivative of ethynil-nor-testosterone. Patients in group A received capsules containing 2.5 mg of gestrinone three times weekly orally. Those in group B received capsules containing 5.0 mg twice weekly, also orally. In group C, patients used by vaginal route tablets containing 5 mg of gestrinone three times weekly. Reduction in uterine volume occurred in all three groups of patients. Of patients who discontinued treatment at 6 months, uterine volume remained lower than pretreatment values in 89%, 18 months after discontinuation. Of those patients who discontinued at 1 year, uterine volume remained below pretreatment levels in 76% 1 year after discontinuation. In patients treated continuously for 24 months, mean uterine volume decreased from a mean 339 cm3 to 273 cm3, a statistically significant difference. The vaginal route showed statistically more significant volume decreases than the oral route for all treatment intervals.

A randomized comparative study of the metabolic effects of two regimens of gestrinone in the treatment of endometriosis.

OBJECTIVE: To study some of the metabolic effects of oral gestrinone on plasma lipoprotein risk markers for cardiovascular disease and on bone density, a risk marker for osteoporosis. DESIGN: Randomized double-blind study. SETTING: All patients were referred to Gynaecology Clinic of Royal Free Hospital Medical School. PATIENTS: Twenty premenopausal women with laparoscopically confirmed endometriosis. INTERVENTIONS: Subjects were randomized in a double-blind fashion to receive either 1.25 mg or 2.5 mg gestrinone two times per week for 6 months. MAIN OUTCOME MEASURE: Laparoscopy was performed before treatment, and clinical responses were determined by second laparoscopy after 6 months. Plasma lipid and bone density measurements during and after therapy were compared with baseline. RESULT: Median total endometriosis scores decreased from 7.5 to 1.0 in the 1.25-mg group and from 7.0 to 0 in the 2.5-mg group. There were no significant between-group differences in endometriosis scores. At both doses, bone density in the spine and the proximal femur was conserved, but plasma concentrations of low-density lipoproteins rose by 13% and those of high-density lipoproteins fell by 40%. CONCLUSIONS: Reducing the dose of gestrinone to 1.25 mg appeared to maintain the therapeutic effectiveness of this treatment but was still associated with potentially unfavorable effects on lipids and lipoproteins.

The morning after: novel hormonal approaches to postcoital interception.

PIP: Approaches to postcoital interception are discussed. High dose estrogen only regimens have an overall failure rate of .7%. The mechanism of action is speculated to include luteolysis and disordered endometrial development. Although several preparations have comparable potency if administered within 72 hours, diethylstilbestrol (DES) has received wide attention. As with other estrogen regimens, the main deficiency of DES relates to the need to consume high doses of estrogen, with its attendant potential risks and side effects. Combination regimens, under which women are treated with 2 doses of 2 tablets each containing 1 mg dl-norgestrel and 100 mcg ethinyl estradiol (EE), are being investigated. Experience with 1300 treatment cycles indicated a failure rate of 1.6%. Advantages include a reduction in the duration of therapy, 12 hours versus 5 days; fewer tablets consumed, and a 125-fold reduction in consumed estrogen. Research is continuing on lower doses and nonoral administration. Progesterone receptor antagonists may be ideally suited for luteolytic interception and are being investigated. Administration of 50 mg of R2323 on days 15 to 17 over 2000 treatment cycles has shown a failure rate of 5%. Agonistic analog of gonadotropin-releasing hormone is being studied as a potential luteolytic interceptor. In a recent study, single or double subcutaneous administration between days 5-8 after the luteinizing hormone peak resulted in luteolysis in 96% of the treatment cycles.^ieng

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.

Treatment of fibrocystic disease of the breast with gestrinone, a new trienic synthetic steroid with anti-estrogen, anti-progesterone properties.

Twenty-eight patients with radiologically diagnosed fibrocystic disease were given twice weekly 5 mg tablets of Gestrinone, a synthetic contraceptive steroid with potent anti-estrogen, anti-progesterone properties, for periods ranging from 3 to 9 months. Treatment was discontinued when the nodularity disappeared and the patient became asymptomatic. Twelve patients had palpable nodules or masses in both breasts, while the remaining 16 had a single nodule or lump. In 12 patients, all with small nodules or lumps, complete elimination of nodularity occurred at the end of the first 3 months of treatment. In a further eight patients, five of whom had small nodules and three of whom had large ones, an additional 3 months of therapy were required to achieve complete elimination of nodularity. In two subjects, nodularity was eliminated at the end of 9 months of therapy, and in the remaining six subjects, although a reduction in nodularity greater than 50% occurred, masses remained palpable at the end of 9 months. Pain and tenderness were eliminated during the first 2 weeks of therapy in most cases. The most common complaints were acne and seborrhea (70% of patients) and a weight gain of between 2 and 5 kg in patients treated for 9 months. Main side effects encountered were acne and seborrhea.

[Treatment of endometriosis. Evaluation of preoperative therapy with danazol, gestrinone and buserelin (nasal spray and implant)]. / Traitement de l'endométriose. Evaluation de l'utilisation pré-opératoire du danazol, de la gestrinone et de la buséréline (spray nasal et implant).

In order to adequately assess the effectiveness of danazol, gestrinone, buserelin-nasal spray (IN) and buserelin-implant (SC), a prospective non randomized study was initiated in 178 patients with laparoscopically confirmed ovarian endometriosis. After hormonal therapy, laparotomy with microsurgical resection of endometriotic cysts or laparoscopy laser was carried out. Regression (greater than 25%) of ovarian endometriosis was noted in 30, 34, 73 and 91% of cases after danazol, gestrinone and buserelin IN and buserelin SC respectively. Histological study proves that hormonal treatment leads to an incomplete suppression of ovarian endometriotic implants and this suggests the necessity to remove surgically invasive ovarian endometriosis. The pregnancy rate in moderate endometriosis (55%) differed significantly from the rate obtained in severe endometriosis (44%). The highest percentages were found after buserelin therapy. In conclusion, preoperative use of a potent GnRH agonist, administered subcutaneously, seems to be the best therapeutic approach when associated to surgery (CO2 laser or microsurgery).

[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.

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.