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Expert Opinion on Pharmacotherapy Aug 2016Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone... (Review)
Review
INTRODUCTION
Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches.
AREAS COVERED
Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency.
EXPERT OPINION
Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option.
Topics: Administration, Oral; Adult; Animals; Clinical Trials as Topic; Clomiphene; Enclomiphene; Estrogen Antagonists; Eunuchism; Humans; Infertility, Male; Luteinizing Hormone; Male; Testosterone
PubMed: 27337642
DOI: 10.1080/14656566.2016.1204294 -
Cureus Jul 2023Introduction Infertility and hypogonadism in males can greatly affect their reproductive health and overall well-being. Since exogenous testosterone administration for...
Introduction Infertility and hypogonadism in males can greatly affect their reproductive health and overall well-being. Since exogenous testosterone administration for hypogonadism management may disrupt the normal hormonal cascade necessary for spermatogenesis, clomiphene citrate (CC) and enclomiphene citrate (EC) are medications often used to manage hypogonadism and male infertility. This study aims to directly compare the effects of CC and EC on serum testosterone levels and semen parameters in men to determine which medication may have an advantage in managing these conditions. Materials and methods We retrospectively analyzed ≥18-year-old men presenting with primary infertility, abnormal semen parameters, or hypogonadism who received CC or EC monotherapy for at least three months between January 2021 and December 2022. We compared baseline and follow-up hormone levels, semen parameters, and demographics. Variables were compared using paired and unpaired t-tests. Significance was assessed at <0.05. Results A total of 46 men received EC and 32 men received CC. The median age was 42 (IQR: 34-47.75) years in men who received EC and 41 (IQR: 36-44) years in men who received CC (=0.450). The two treatment groups exhibited a significant increase in serum total testosterone, while only EC had a statistically significant increase in FSH and LH. Semen volume and concentration did not significantly change with either treatment. Sperm motility increased in both groups, but total motile sperm count (TMSC) only significantly increased in men who received EC. Conclusions Our study found that EC and CC are effective treatments in increasing total testosterone without negatively affecting spermatogenesis. EC demonstrated to be more effective in raising gonadotropin levels and TMSC.
PubMed: 37546076
DOI: 10.7759/cureus.41476 -
BJU International Jul 2013To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial...
OBJECTIVES
To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism.
PATIENTS AND METHODS
This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids.
RESULTS
After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 25 mg daily) and 500 ± 278 ng in those men treated with transdermal testosterone. These values were higher than Day 1 values but not different from each other (p = 0.23, T-test). All three doses of enclomiphene increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups.
CONCLUSIONS
Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.
PubMed: 23875626
DOI: 10.1111/bju.12363 -
Drug Metabolism and Pharmacokinetics 2008Clomiphene is a first line treatment for anovulation, a common cause of infertility. Response to clomiphene is variable and unpredictable. Tamoxifen is structurally...
Clomiphene is a first line treatment for anovulation, a common cause of infertility. Response to clomiphene is variable and unpredictable. Tamoxifen is structurally related to clomiphene, and also shows considerable variation in response. CYP2D6 and CYP3A4 are major contributors to the metabolism of tamoxifen. The aim of the present work was to define the role of CYP2D6 and CYP3A4 in the in vitro metabolism of enclomiphene, regarded by some as the more active isomer of clomiphene. Enclomiphene (25 microM) was incubated with human liver microsomes (from 4 extensive (EM) and 1 poor metaboliser with respect to CYP2D6) and with microsomes from lymphoblastoid cells expressing CYP2D6. Microsomes from all the EM livers and recombinant CYP2D6 metabolised enclomiphene (the disappearance of drug ranged from 40-60%). No metabolism was detected in microsomes from the PM liver. Quinidine (1 microM) completely inhibited the metabolism of enclomiphene by all the EM livers and by recombinant CYP2D6 (p<0.001, one way ANOVA). Ketoconazole (2 microM) had no significant effect on enclomiphene metabolism in 3 out of the 4 EM livers. The extent of enclomiphene metabolism was correlated with the amount of CYP2D6 present (p<0.001, Pearson correlation test). The findings indicate that CYP2D6 is primarily responsible for the metabolism of enclomiphene.
Topics: Clomiphene; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Enclomiphene; Humans; Ketoconazole; Microsomes, Liver; Quinidine
PubMed: 18445989
DOI: 10.2133/dmpk.23.101 -
Fertility and Sterility Sep 2014To determine the effect of enclomiphene citrate in men with secondary hypogonadism. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine the effect of enclomiphene citrate in men with secondary hypogonadism.
DESIGN
Phase II clinical trial.
SETTING
Community dwelling men making visits to physician offices.
PATIENT(S)
Men with secondary hypogonadism.
INTERVENTION(S)
Oral administration of enclomiphene citrate or 1% topical T gel.
MAIN OUTCOME MEASURE(S)
Luteinizing hormone, FSH, T, and semen analysis.
RESULT(S)
Treatment with enclomiphene citrate resulted in increased morning serum T, E2, and LH levels similar to those obtained with a topical T gel in men with secondary hypogonadism. Follicle-stimulating hormone and LH were increased with enclomiphene, and sperm counts were conserved.
CONCLUSION(S)
Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production.
CLINICAL TRIAL REGISTRATION NUMBER
NCT01270841 (ClinicalTrials.gov Identifier NCT01270841).
Topics: Administration, Oral; Administration, Topical; Adult; Enclomiphene; Estradiol; Humans; Hypogonadism; Luteinizing Hormone; Male; Middle Aged; Oligospermia; Sex Hormone-Binding Globulin; Testosterone; Up-Regulation
PubMed: 25044085
DOI: 10.1016/j.fertnstert.2014.06.004 -
Plastic Surgery (Oakville, Ont.) Nov 2023The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may...
The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may be responsible. This study examined effects of the fertility drug clomiphene citrate (CC) on calvarial development in an established model for craniofacial development, the zebrafish Danio rerio. Zebrafish larvae were exposed to clomiphene citrate or its isomer enclomiphene for five days at key points during calvarial development. Larvae were then raised to adulthood in normal rearing water. Zebrafish were analyzed using whole-mount skeletal staining. We observed differential effects on survivability, growth and suture formation depending on the treatment. Treatments with CC or enclomiphene at 5.5 mm SL led to increased fusion of the interfrontal suture (p < .01) compared to controls. Exposure to fertility drugs appears to affect development of the cranial vault, specifically the interfrontal suture, in zebrafish. Further research is required to identify the signaling mechanisms at play. This work suggests that fertility drug treatment may contribute to the increased incidence of metopic craniosynostosis observed globally.
PubMed: 37915340
DOI: 10.1177/22925503211057526 -
Fertility and Sterility Apr 1999To determine the serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate treatment in anovulatory infertile women.
OBJECTIVE
To determine the serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate treatment in anovulatory infertile women.
DESIGN
Prospective cohort.
SETTING
Tertiary institutional infertility clinic.
PATIENT(S)
Fourteen consenting anovulatory infertile women receiving standardized, cyclic, incremental treatment with clomiphene citrate for ovulation induction.
INTERVENTION(S)
Clomiphene citrate treatment (50-150 mg/d, cycle days 5-9), titrated to the minimum effective ovulation-inducing dose, was administered for three to six total cycles. Blood samples were obtained on cycle days 3 and 10 in each treatment cycle.
MAIN OUTCOME MEASURE(S)
Serum concentrations of enclomiphene and zuclomiphene.
RESULT(S)
Cycle day 3 zuclomiphene levels were below assay limits in all initial cycles, increased progressively across three consecutive cycles, and thereafter plateaued. Cycle day 3 enclomiphene concentrations were uniformly undetectable. Cycle day 10 enclomiphene levels increased with dose administered, but these observations were not statistically significant.
CONCLUSION(S)
Clomiphene citrate induction of ovulation results in an isomer-specific systemic accumulation of zuclomiphene across consecutive cycles of treatment. The combined maximum concentration of enclomiphene and zuclomiphene attained in practice approximates 100 nmol/L and is generally well below levels previously demonstrated to have adverse effects in vitro.
Topics: Adult; Anovulation; Clomiphene; Cohort Studies; Enclomiphene; Female; Fertility Agents, Female; Humans; Infertility, Female; Ovulation Induction; Prospective Studies
PubMed: 10202872
DOI: 10.1016/s0015-0282(98)00537-8 -
Viruses Aug 2016The 2014 outbreak of Ebola virus (EBOV) in Western Africa highlighted the need for anti-EBOV therapeutics. Clomiphene is a U.S. Food and Drug Administration...
The 2014 outbreak of Ebola virus (EBOV) in Western Africa highlighted the need for anti-EBOV therapeutics. Clomiphene is a U.S. Food and Drug Administration (FDA)-approved drug that blocks EBOV entry and infection in cells and significantly protects EBOV-challenged mice. As provided, clomiphene is, approximately, a 60:40 mixture of two stereoisomers, enclomiphene and zuclomiphene. The pharmacokinetic properties of the two isomers vary, but both accumulate in the eye and male reproductive tract, tissues in which EBOV can persist. Here we compared the ability of clomiphene and its isomers to inhibit EBOV using viral-like particle (VLP) entry and transcription/replication-competent VLP (trVLP) assays. Clomiphene and its isomers inhibited the entry and infection of VLPs and trVLPs with similar potencies. This was demonstrated with VLPs bearing the glycoproteins from three filoviruses (EBOV Mayinga, EBOV Makona, and Marburg virus) and in two cell lines (293T/17 and Vero E6). Visual problems have been noted in EBOV survivors, and viral RNA has been isolated from semen up to nine months post-infection. Since the clomiphene isomers accumulate in these affected tissues, clomiphene or one of its isomers warrants consideration as an anti-EBOV agent, for example, to potentially help ameliorate symptoms in EBOV survivors.
Topics: Animals; Antiviral Agents; Cell Line; Clomiphene; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Selective Estrogen Receptor Modulators; Virus Internalization; Zuclomiphene
PubMed: 27490565
DOI: 10.3390/v8080206 -
The Journal of Biological Chemistry Oct 1982The calf uterine estrogen receptor showed positive cooperativity of [3H]estradiol equilibrium binding; the Scatchard plot was convex and the Hill coefficient was 1.69...
The calf uterine estrogen receptor showed positive cooperativity of [3H]estradiol equilibrium binding; the Scatchard plot was convex and the Hill coefficient was 1.69 +/- 0.021 (n = 14). The effects of the estrogenic antagonists, zuclomiphene (cis-2-(p-[2-chloro-1,2-diphenylvinyl]phenoxy)triethylamine citrate) and enclomiphene (trans-23-(p-[2-chloro-1,2-diphenylvinyl]phenoxy)triethylamine citrate), on the positive cooperativity of [3H]estradiol binding were measured by titrating the receptor with a variable concentration of [3H]estradiol and antagonist while maintaining a constant excess in a specific ratio of the antagonist to the [3H]estradiol. With a 45- to 55-fold molar excess of zuclomiphene or an 820- to 900-fold molar excess of enclomiphene above the [3H]estradiol concentration, the receptor's positive cooperative [3H]estradiol binding was inhibited. A transition from a convex to a linear Scatchard plot and a decrease in the Hill coefficient from 1.69 to 1.10 +/- 0.02 (n = 6) were induced. The specifically bound [3H]estradiol was inhibited 43 to 50% by the zuclomiphene and enclomiphene. The addition of unlabeled estradiol in a 1- or 2.3-fold molar excess above that of the [3H]estradiol concentration produced a 50 to 75% competitive displacement of the specifically bound [3H]estradiol; nevertheless, the Scatchard plot remained convex and the Hill coefficient was 1.74 and 1.80, respectively. Thus, inhibition of the positive cooperativity of [3H]estradiol binding by the clomiphene isomers was not due to dilution of the specifically bound [3H]estradiol by the antagonist. These data demonstrate that there are two molecular mechanisms by which an estrogen antagonist interferes with the function of the receptor: as a competitor, thus blocking the estrogen receptor's binding site to an agonist, and second by inducing conformational changes that inhibit site:site interactions and receptor activation.
Topics: Animals; Binding, Competitive; Cattle; Clomiphene; Enclomiphene; Estradiol; Female; Kinetics; Receptors, Estrogen; Structure-Activity Relationship; Uterus
PubMed: 7118895
DOI: No ID Found -
Fertility and Sterility Apr 2009To investigate the relationship between the plasma concentrations of clomiphene citrate (CC) isomers zu- (Zu) and enclomiphene (En), and ovulation outcome. (Clinical Trial)
Clinical Trial
Evaluation of the relationship between plasma concentrations of en- and zuclomiphene and induction of ovulation in anovulatory women being treated with clomiphene citrate.
OBJECTIVE
To investigate the relationship between the plasma concentrations of clomiphene citrate (CC) isomers zu- (Zu) and enclomiphene (En), and ovulation outcome.
DESIGN
Prospective, cohort study.
SETTING
Reproductive medicine and fertility center in a university teaching hospital, United Kingdom.
PATIENT(S)
Forty-two women with World Health Organization type 2 infertility.
INTERVENTION(S)
The clinical and biochemical features of patients who were about to start CC for induction of ovulation were recorded. Plasma concentration of Zu and En were monitored at three points (days 2, 8, and 21) throughout the treatment cycle(s).
MAIN OUTCOME MEASURE(S)
Ovulation.
RESULT(S)
Thirty-nine patients completed the study. Both En and Zu accumulated throughout treatment. Among the 36 responders, there was no statistically significant relationship between the clinical and biochemical characteristics of the patients, En or Zu concentrations, and the dose required to induce ovulation. Moreover, the Zu and En concentrations were not different in the three patients who failed to respond.
CONCLUSION
The concentrations of En and Zu in plasma, on their own or in combination with other covariates (e.g., weight, body mass index, free androgen index), are not a predictor of the ovulation response to CC or of the dose requirement. Further studies are needed to explore the role of additional covariates, including the presence of active metabolites, and the balance of the effects of En and Zu.
Topics: Adult; Anovulation; Body Mass Index; Clomiphene; Enclomiphene; Female; Fertility Agents, Female; Humans; Ovulation; Ovulation Induction; ROC Curve; Time Factors; Young Adult
PubMed: 18353317
DOI: 10.1016/j.fertnstert.2008.01.058