Zuclomiphene Research Articles

Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment.

To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC. Men already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations. A total of 15 men were enrolled in the period from June 2015 to August 2015. The median (range) patient age was 36 (22-70) years, BMI 32.0 (21.1-40.3) kg/m2 and duration of treatment 25.9 (1.7-86.6) months. Baseline median total testosterone, oestradiol and LH levels were 205.0 ng/dL, 17.0 pg/mL and 4.0 mlU/mL, respectively. The post-treatment median total testosterone, oestradiol and LH level increased to 488.0 ng/dL, 34.0 pg/mL and 6.1 mIU/mL, respectively (all P<0.001). The median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least 6 weeks of CC therapy, the median ZUC: ENC serum concentration ratio was 20:1. On linear regression analysis. patient age, BMI, duration of treatment and serum testosterone levels were not predictive of ENC or ZUC concentrations. Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism.

The effect of clomiphene citrate and its Zu or En isomers on the reproductive system of the immature male rat.

The effect of clomiphene citrate (CC) and of its Zuclomiphene (ZuC) and Enclomiphene (EnC) isomers on the reproductive organs of immature male rats under different experimental conditions is reported. CC, ZuC, and EnC were administered daily to groups of either intact or castrated rats between the age of 21-44 d. This led to inhibition of weight increase of testis and accessory glands in the intact group. Spermatogenesis was arrested at the stage of primary spermatocyte following CC and ZuC treatment, and at the stage of young spermatids by EnC treatment. In the castrated group clomiphenes significantly stimulated weight increase of seminal vesicles (SV) compared with castrated control animals, but the former group were unable to achieve organ weight gain comparable to that in normal controls. Administration of human Chorionic Gonadotropin (hCG) together with CC or each of its isomers to intact animals, abolished the drug effect on spermatogenesis and on reproductive organ growth. Administration of CC, ZuC, and EnC together with testosterone to castrated animals, abolished the drug effect on growth inhibition of accessory glands. In intact treated rats LH and testosterone secretion were suppressed by all forms of clomiphenes. In the castrated group ZuC proved to be the most potent inhibitor of LH secretion. Therefore, it is inferred that ZuC and EnC have different potencies as far as their biological activity in the immature male rat is expressed.

Differential responses of estrogen target tissues in rats including bone to clomiphene, enclomiphene, and zuclomiphene.

The substituted triphenylethylene antiestrogen clomiphene (CLO) prevents cancellous bone loss in ovariectomized (OVX'd) rats. However, CLO is a mixture of two stereoisomers, enclomiphene (ENC) and zuclomiphene (ZUC), which have distinctly different activities on reproductive tissues and tumor cells. The purpose of the present dose response study was to determine the effects of ENC and ZUC on nonreproductive estrogen target tissues. These studies were performed in 7-month-old female rats with moderate cancellous osteopenia that was established by ovariectomizing rats 1 month before initiating treatment. OVX resulted in increases in body weight, serum cholesterol, endocortical resorption, and indices of cancellous bone turnover, as well as decreases in uterine weight, uterine epithelial cell height, bone mineral density, bone strength, and cancellous bone area. Estrogen treatment for 3 months restored body weight, uterine histology, dynamic bone measurements, and osteoblast and osteoclast surfaces in OVX'd rats to the levels found in the age-matched sham-operated rats. In contrast, estrogen only partially restored cancellous bone volume and uterine weight, and it reduced serum cholesterol to subnormal values. CLO was a weak estrogen agonist on uterine measurements and a much more potent agonist on body weight, serum cholesterol, and dynamic bone measurements. CLO increased trabecular thickness in osteopenic rats and was the most effective treatment in improving cancellous bone volume and architecture. ZUC was a potent estrogen agonist on all tissues investigated and had dose-dependent effects. In contrast, ENC had dose-dependent effects on most measurements similar to CLO and decreased the uterotrophic effects of ZUC. It is concluded that ENC antagonizes the estrogenic effects of ZUC on the uterus but that the beneficial effects of CLO on nonreproductive tissues in OVX'd rats is conferred by both isomers. Furthermore, the combined actions of the two isomers on bone volume and architecture were more beneficial than either isomer given alone.

A comparison of the effects on follicular development between clomiphene citrate, its two separate isomers and spontaneous cycles

An investigation of the effects on follicular development of clomiphene citrate and its two isomers En clomiphene and Zu clomiphene given separately was carried out on 19 normally cycling women being treated with donor insemination. All women received clomiphene citrate in the first cycle and, following a washout control cycle, were treated with either En clomiphene or Zu clomiphene alone. The number of follicles present, follicular phase oestrogen secretion and luteal phase pregnanediol excretion were not significantly different when Zu clomiphene cycles were compared with control cycles, but were significantly increased in En clomiphene and clomiphene citrate cycles. It is concluded that the En isomer, which has largely antioestrogenic properties, is the isomer active in inducing follicular development. The oestrogenic properties of Zu isomer did not appear to protect it from the possibly detrimental effects on sperm-cervical mucus interaction observed in both isomers and in the combined preparation.

The estrogenic effects of clomiphene during the neonatal period in the rat

The ability of clomiphene and its isomers to cause estrogenic responses during the neonatal period in the rat was examined. Rats were injected s.c. with clomiphene (CL), zuclomiphene (ZUC) or enclomiphene (ENC) on days 1,3, and 5 of life and the stimulation of the reproductive tract and estrogen receptor binding was observed. Uterine weight and DNA content were increased significantly by day 7 in animals treated with clomiphene or zuclomiphene. Uterine epithelial hypertrophy was present in all groups by day 10 and hyperplasia was present in the animals treated with ZUC and CL. The time of vaginal opening was greatly accelerated in all drug treated groups with the earliest day of opening occurring on day 7. Ovarian hemorrhage and blood in the periovarian sac occurred between days 12–14 and continued to be present through day 25. Drug treatment caused the estrogen receptor to accumulate in the nuclear fraction of the uterus and to be depleted from the cytosol fraction. We conclude that clomiphene administered to neonatal rats causes estrogenic stimulation of the reproductive tract in a fashion similar to other estrogens. This stimulation may account for the reproductive tract abnormalities which develop in rats treated with those drugs during the neonatal period.

Failure of a variety of antiestrogens to mimic estrogen action in the induction of sexual receptivity in a female lizard

The purpose of the present study was to determine whether nonsteroidal antiestrogens could act as estrogens by inducing or facilitating estrogen-induced sexual receptivity in a female lizard ( Anolis carolinensis). Experiments were conducted to (1) test the ability of enclomiphene (ENC) and zuclomiphene (ZUC) to induce sexual receptivity in estrogen-untreated ovariectomized females; (2) to determine the effect of ENC and ZUC pretreatment on E 2B induction of sexual receptivity; and (3) to examine the ability of a variety of antiestrogens to act as estrogens by inducing sexual receptivity in females pretreated with a behaviorally ineffective estrogen treatment regimen.

Inhibitory and facilitatory effects of various anti-estrogens on the induction of female sexual behavior by estradiol benzoate in guinea pigs

The anti-estrogens CI-628 (CI) and enclomiphene (ENC) were used to antagonize the estrogen-induced sexual behavior of female guinea pigs. Full receptivity was activated in 96% of ovariectomized control guinea pigs given 1.6 μg estradiol benzoate (EB) and then injected with 0.5 mg progesterone (P) 39 h later. In experiment 1, the ability of EB to induce lordosis was not blocked when CI (2 mg) or ENC (5 and 20 mg) was administered either concurrently with EB or within 2 h of the EB injection. However, in experiment 2, extensive pretreatment with ENC (5 mg/injection) at 48, 24, 12, and 0 h before the start of the 39 h EB priming period significantly decreased (to 50%) the percentage of animals displaying lordosis. Similar pretreatment with CI (2 mg/injection) had no inhibitory effects on lordosis. Experiments 3 and 4 evaluated the ability of CI, ENC, and zuclomiphene (ZUC) to induce sexual behavior in ovariectomized guinea pigs. In experiment 3, guinea pigs were injected 3 times with CI (2 mg/injection), ENC or ZUC (5 mg/injection) over a 39 h interval and then injected with P. No anti-estrogen was able to induce lordosis in this situation. Experiment 4 assessed the ability of CI, ENC, or ZUC to facilitate the action of EB on sexual behavior. For this study the EB priming period was shortened from 39 h to 11 h. This resulted in a significant decrease in the percentage of animals displaying lordosis (controls= 15%of animals receptive). Administration of ENC (10 mg) 28 h prior to the 11 h of EB priming significantly facilitated the incidence of receptivity (62% of animals receptive). Similar administration of ZUC (10 mg) produced a slight but non-significant facilitation (37% of animals receptive) while CI (4 mg) had no facilitatory effects7 (0% receptive). The results obtained in these experiments using a manual stimulation technique for elicitation of lordosis were replicated by using a male. In all cases tested, treatment that induced lordosis to manual stimulation also facilitated receptivity to a male. These results indicate that CI and ENC do not as readily inhibit the action of EB priming in guinea pigs as they do in rats. Further, it appears that ENC can mimic at least some of the early effects of EB priming. However, the presence of estrogen is necessary in the later portion of the priming period for the expression of lordosis.

Comparative estrogenicity of cis and trans isomers of glomiphene citrate in rats undergoing delayed implantation

The effects of cis or trans isomsrs of clomiphene citrate or estradiol-17β on uterine weight, uterine glycogen and liver glycogen were studied in rats undergoing delayed implantation. Comparative estrogenicity of the cis or trans isomers with estradiol-17β was assessed with reference to changes in uterine glycogen and liver glycogen in response (a) to different doses of the isomer s i.e. 150, 300 or 1SOO gmg/kg and (b) to a small dose (150 gmg/kg) of the compound at different time intervals (6, 18 and 48 hours). High doses of cis clomiphene increased uterine weights more than trans clomiphene. Neither of the two isomers, in small doses, caused any change in uterine weights at any of the time intervals studied. Trans clomiphene caused an increase in glycogen concentration in the uterus and liver 18 hours after the administration of the drug whereas a similar increase was not seen with the highest dose (1800 gmg/kg) of the cis isomer administered. It is concluded that the trans isomer of clomiuhene citrate is more estrogenic than the cis isomer using glycogen as an estrogen sensitive parameter, whereas cis clomiphene is more uterotropic than the trans isomer at higher doses.