Synthetic Routes and Reaction Conditions: The synthesis of clomifene involves the reaction of 2-chloro-1,2-diphenylethylene with 4-(2-chloro-1,2-diphenylethenyl)phenol in the presence of a base, followed by the reaction with diethylamine . The process can be optimized using acetic acid or trifluoroacetic acid as solvents .

Industrial Production Methods: Industrial production of this compound typically involves the use of acetic acid or trifluoroacetic acid in specific volumes to ensure high yield and purity . The process is designed to produce both the trans and cis isomers of this compound, with trans-clomifene being the more active form .

Types of Reactions: Clomifene undergoes several types of chemical reactions, including:

Oxidation: this compound can be oxidized to form 4-hydroxythis compound and 4-hydroxy-N-desethylthis compound.

Reduction: Reduction reactions are less common but can occur under specific conditions.

Substitution: this compound can undergo substitution reactions, particularly involving the phenoxy group.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

Substitution: Reagents such as sodium hydroxide and potassium carbonate are often used.

Major Products:

Oxidation Products: 4-hydroxythis compound and 4-hydroxy-N-desethylthis compound.

Substitution Products: Various substituted phenoxy derivatives.

Treatment of Female Infertility

Indications : Clomifene is primarily indicated for women experiencing anovulation or oligo-ovulation, particularly those diagnosed with polycystic ovarian syndrome (PCOS). The drug acts by inducing ovulation through its estrogenic and anti-estrogenic effects on the hypothalamus and pituitary gland, leading to increased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) .

Efficacy : Studies have shown that this compound can result in a live birth rate of 20% to 40% over six months of treatment for women seeking to conceive . It is also effective in addressing other conditions such as post-oral-contraceptive amenorrhea and psychogenic amenorrhea .

Applications in Male Infertility

This compound is used off-label to treat male infertility and secondary hypogonadism. It has been shown to increase serum testosterone levels by stimulating the pituitary gland to produce more gonadotropins, which in turn enhances spermatogenesis .

Research Findings : A study highlighted that this compound treatment resulted in significant improvements in sperm motility and viability, suggesting its potential as a therapeutic option for male infertility .

Potential Use in Other Conditions

Recent studies have explored this compound's efficacy beyond infertility treatments. Notably, it has been investigated for its potential to treat short-lasting unilateral neuralgiform headache attacks (SUNCT), although it is not FDA-approved for this indication .

Safety and Side Effects

While this compound is generally well-tolerated, potential side effects include ovarian hyperstimulation syndrome (OHSS), visual disturbances, and risks associated with prolonged use such as endometrial hyperplasia . Regular monitoring during treatment is crucial to mitigate these risks.

Case Studies and Research Insights

Clomifene acts as a selective estrogen receptor modulator. It binds to estrogen receptors in the hypothalamus, blocking the negative feedback of estrogen on gonadotropin release . This leads to an increase in the release of gonadotropins, including follicle-stimulating hormone and luteinizing hormone, which stimulate the ovaries to produce and release eggs . In men, this compound increases testosterone production by stimulating the release of gonadotropins .

Comparison with Structurally Similar Compounds

Tamoxifen

Clomifene and tamoxifen share a triphenylethylene backbone, yielding a structural similarity score of 0.75 (threshold: 0.70) . Both act as SERMs but differ in clinical applications:

• This compound: Ovulation induction (PCOS, anovulation).
• Tamoxifen : Breast cancer treatment (estrogen receptor-positive tumors).

Notably, tamoxifen has been prescribed off-label as an alternative to this compound in PCOS patients unresponsive to standard therapy, demonstrating comparable ovulation induction efficacy .

Toremifene, Ospemifene, and Ormeloxifene

These SERMs exhibit structural and mechanistic overlap with this compound but differ in estrogenic activity profiles:

• Functional divergence :
  • This compound and toremifene are used in fertility and oncology, respectively.
  • Ospemifene and ormeloxifene are approved for vulvovaginal atrophy and contraception, highlighting tissue-specific SERM effects .

Comparison with Functionally Similar Compounds

Letrozole (Aromatase Inhibitor)

Letrozole, a non-steroidal aromatase inhibitor, suppresses estrogen synthesis and is used off-label for ovulation induction. Comparative clinical data from 322 intrauterine insemination (IUI) cycles show:

This compound + HMG significantly outperformed Letrozole + HMG (P < 0.05), though Letrozole is preferred in PCOS patients with hyperinsulinemia due to lower anti-estrogenic endometrial effects .

IDH1 Inhibitors (AGI-5198, Ivosidenib)

Unlike AGI-5198 (a high-potency IDH1 inhibitor with poor metabolic stability) or Ivosidenib (FDA-approved for AML), this compound shows dose-dependent inhibition of mutant IDH1 activity, reducing 2-HG levels and tumorigenic risk . This positions this compound as a repurposing candidate for IDH1-mutant cancers, though clinical validation is pending .

Data Tables

Table 1: Structural and Functional Comparison of this compound and Analogs

Table 2: Clinical Pregnancy Rates in IUI Cycles (n = 322)

Clomifene citrate, commonly referred to as this compound, is a non-steroidal fertility medication primarily used for ovulation induction in women with anovulatory infertility. However, its biological activity extends beyond reproductive applications, demonstrating potential therapeutic effects in various medical conditions, including certain cancers and male infertility. This article explores the biological activity of this compound, supported by research findings, case studies, and data tables.

This compound functions as a selective estrogen receptor modulator (SERM). It exerts its effects by binding to estrogen receptors in the hypothalamus, blocking the negative feedback of estrogen on gonadotropin release. This action increases the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), promoting ovarian stimulation and ovulation.

Key Mechanisms:

• Estrogen Receptor Modulation: this compound acts as an antagonist in the hypothalamus but can exhibit agonistic properties in other tissues.
• Increased Gonadotropin Secretion: Enhanced release of FSH and LH leads to follicular development and ovulation.

1. Ovulation Induction

This compound is widely used for treating women with ovulatory dysfunction. A meta-analysis involving 616 patients indicated that this compound significantly improves sperm concentration and pregnancy rates compared to placebo or baseline levels (p<0.00001) .

Table 1: Summary of this compound Efficacy in Ovulation Induction

2. Male Infertility

Recent studies have explored this compound's role in treating male infertility, particularly in cases of oligospermia and azoospermia. A multicenter study found that this compound administration resulted in sperm detection in 64.3% of men with nonobstructive azoospermia .

Table 2: this compound Effects on Male Infertility

3. Cancer Treatment Potential

Emerging research suggests that this compound may have applications beyond reproductive health, particularly in oncology. A study demonstrated that this compound inhibits mutant isocitrate dehydrogenase (IDH1), a target in certain cancers such as glioma. The compound showed a dose-dependent inhibition of IDH1 activity with IC50 values indicating significant selectivity against mutant forms .

Table 3: this compound's Inhibition of IDH1 Activity

Case Study 1: Female Infertility

A cohort study involving women with polycystic ovary syndrome (PCOS) treated with this compound showed a marked increase in ovulation rates and subsequent pregnancies compared to control groups.

Case Study 2: Male Infertility

In a clinical trial focusing on men with idiopathic oligospermia, treatment with this compound resulted in significant improvements in sperm concentration and motility, leading to successful pregnancies through assisted reproductive technologies.

Adverse Effects and Considerations

While this compound is generally well-tolerated, it is associated with several adverse effects, particularly when used during the periconception phase. Research indicates potential risks for congenital abnormalities and adverse perinatal outcomes when administered at doses approximating human exposures .

Notable Adverse Effects:

• Increased risk of multiple pregnancies
• Ovarian hyperstimulation syndrome (OHSS)
• Visual disturbances

Basic Research Questions

Q. How should researchers design experiments to investigate Clomifene’s pharmacological effects in vitro or in vivo?

• Methodological Answer : Begin by formulating a hypothesis-driven research question (e.g., "Does this compound modulate estrogen receptor activity in ovarian tissue?"). Use controlled experimental groups (e.g., dose-response assays, positive/negative controls) and standardized protocols for cell culture or animal models. Include statistical power analysis to determine sample size and validate reproducibility through triplicate trials. Report raw data with error margins (e.g., SEM) and use ANOVA for multi-group comparisons .

Q. What are the best practices for synthesizing and characterizing this compound citrate in a laboratory setting?

• Methodological Answer : Follow pharmacopeial guidelines (e.g., The International Pharmacopoeia) for synthesis, ensuring purity via HPLC or NMR. For characterization, use infrared (IR) spectroscopy (1.1 mg this compound citrate in 300 mg potassium bromide, as per ICRS standards) and compare spectra to reference materials . Document synthesis yields, melting points, and spectral data in the main manuscript, with detailed protocols in supplementary materials .

Q. How can researchers ensure reproducibility in this compound studies?

• Methodological Answer : Provide granular experimental details (e.g., solvent purity, incubation times, equipment calibration) in the "Materials and Methods" section. Use international reference standards (e.g., this compound CITRATE ICRS batch 1.0) for analytical comparisons. Share raw datasets, code for statistical analysis, and instrument settings in supplementary files to enable replication .

Advanced Research Questions

Q. How can contradictory findings about this compound’s mechanism of action across studies be resolved?

• Methodological Answer : Conduct a systematic review to identify confounding variables (e.g., dosage variations, model organisms). Perform meta-analysis using PRISMA guidelines to quantify effect sizes and heterogeneity. Validate hypotheses through orthogonal assays (e.g., receptor-binding studies vs. gene expression profiling) . Address biases by re-analyzing raw data from public repositories (e.g., PubChem, ChEMBL) .

Q. What methodologies are optimal for comparative studies of this compound and its structural analogs?

• Methodological Answer : Use molecular docking simulations to predict binding affinities, followed by in vitro competitive inhibition assays. Apply QSAR (Quantitative Structure-Activity Relationship) models to correlate structural modifications (e.g., substituent groups) with pharmacological outcomes. Include enantiomeric purity data, as this compound’s cis/trans isomerism impacts bioactivity .

Q. How can researchers investigate this compound’s long-term metabolic fate in preclinical models?

• Methodological Answer : Employ stable isotope labeling (e.g., ¹⁴C-Clomifene) for pharmacokinetic tracing. Use LC-MS/MS to quantify metabolites in plasma, liver, and adipose tissues over time. Model data using non-compartmental analysis (NCA) to estimate AUC, half-life, and clearance rates. Cross-validate findings with human hepatocyte assays .

Q. What statistical approaches are recommended for analyzing this compound’s variable efficacy in heterogeneous populations?

• Methodological Answer : Apply mixed-effects models to account for inter-individual variability (e.g., age, hormonal status). Stratify data by covariates (e.g., BMI, genetic polymorphisms in CYP enzymes) and use Kaplan-Meier curves for time-to-event analyses. Conduct sensitivity analyses to test robustness against outliers .

Q. Tables: Key Methodological Considerations