Clomifene

Ovarian Follicular Development and Steroidogenesis

The increased release of FSH and LH, triggered by this compound's action on the HPO axis, initiates a cascade of events leading to ovarian follicular growth and steroidogenesis. drugbank.compatsnap.comrxlist.com FSH plays a pivotal role in stimulating the growth and maturation of ovarian follicles, which are responsible for producing estrogen as they develop. patsnap.com Following the maturation of follicles, a surge in LH is induced, leading to ovulation—the release of a mature oocyte from the dominant follicle. patsnap.comnih.gov

Endometrial Cellular and Molecular Responses to this compound

This compound interacts with estrogen-receptor-containing tissues, including the endometrium, where it can exert anti-estrogenic effects. drugbank.comrxlist.com This peripheral anti-estrogenic action is believed to contribute to the discrepancy between ovulation rates and pregnancy success rates observed with this compound. scirp.orgoup.com Specifically, this compound can inhibit 17β-estradiol (E2)-induced endometrial cell proliferation and transcriptional activation of the estrogen response element (ERE) gene. oup.comnih.govresearchgate.net This effect is mediated by inhibiting the recruitment of steroid receptor coactivator-1 (SRC-1) to estrogen receptor alpha (ERα). nih.gov

Suboptimal endometrial thickening is a known consequence in some women treated with this compound, which can impair embryo implantation. pacificfertilitycenter.comnih.gov Studies have shown a reduced volume of glandular epithelium in the endometrium of women with suboptimal thickening after this compound treatment. nih.gov

Impact on Cervical and Vaginal Tissues

This compound is capable of interacting with estrogen-receptor-containing tissues in the cervix and vagina. drugbank.comrxlist.com Its anti-estrogenic effects can lead to changes in cervical mucus, potentially decreasing its production and making it more difficult for sperm to pass through the cervix into the uterus. pacificfertilitycenter.comtlcfertility.com This can be a factor contributing to reduced fertility despite successful ovulation. pacificfertilitycenter.com In animal studies, this compound citrate administered during neonatal cervicovaginal epithelial differentiation has been associated with subsequent adenosis, a condition where glandular tissue appears in the vagina. nih.gov

Comparative Analysis of Zuthis compound and Enthis compound Activities

Enthis compound is primarily characterized by its anti-estrogenic activity, whereas zuthis compound is considered to be more estrogenic or mildly estrogenic. wikipedia.orgwikipedia.orgnih.gov

Comparative Isomeric Activities wikipedia.orgmensreproductivehealth.comwikipedia.orgnih.govfda.gov

Enthis compound acts by antagonizing estrogen receptors in the pituitary gland, thereby reducing the negative feedback of estrogen on the hypothalamic-pituitary-gonadal axis and increasing gonadotropin secretion. wikipedia.orgwikipedia.orgprime-sciences.com This leads to increased endogenous testosterone production in men and supports follicular development in women. mensreproductivehealth.comwikipedia.orgprime-sciences.com Conversely, zuthis compound, being more estrogenic, can be antigonadotropic due to estrogen receptor activation. wikipedia.orgwikipedia.org It has been shown to reduce testosterone levels in men. wikipedia.orgwikipedia.org

The differential half-lives of the isomers are also noteworthy; enthis compound has a shorter half-life of approximately 10 hours, while zuthis compound has a significantly longer half-life, ranging from 30 to 50 days, which can lead to its accumulation over time. mensreproductivehealth.comfda.gov This prolonged presence of the estrogenic zuthis compound isomer is thought to contribute to some of the peripheral anti-estrogenic effects and potential side effects associated with this compound, such as those on the endometrium and cervical mucus. mensreproductivehealth.comnih.gov

Absorption Profiles and Bioavailability Studies

This compound is readily absorbed orally in humans drugbank.commims.comnih.gov. Early studies using 14C-labeled this compound demonstrated its efficient oral absorption drugbank.com. The bioavailability of orally administered this compound is reported to be high, exceeding 90% youtube.comwikipedia.org. Following oral administration, the time to peak plasma concentration is approximately 6 hours medscape.com.

Hepatic Metabolism Pathways

This compound undergoes extensive metabolism primarily in the liver drugbank.comyoutube.commims.com. This hepatic biotransformation involves various pathways, including hydroxylation, N-de-ethylation, and glucuronidation semanticscholar.org. The drug also undergoes enterohepatic recirculation, contributing to its prolonged presence in the body youtube.comwikipedia.orgmims.commedscape.com.

Role of Cytochrome P450 Enzymes in this compound Biotransformation

Cytochrome P450 (CYP) enzymes play a crucial role in the metabolism of this compound and its metabolites semanticscholar.orgresearchgate.netmdpi.com. While multiple CYP enzymes are involved, the primary enzymes responsible for this compound's metabolic pathways include CYP2D6, CYP3A4, and CYP2B6 semanticscholar.orgmdpi.com. Specifically, (E)-clomifene is mainly metabolized by CYP2D6, while (Z)-clomifene is primarily metabolized by CYP3A4 and CYP3A5 frontiersin.orgnih.gov.

Primary Contribution of CYP2D6 to Active Metabolite Formation

CYP2D6 is identified as the key enzyme in the conversion of this compound, particularly the (E)-isomer, to its active hydroxylated metabolites researchgate.netmdpi.comoup.comresearchgate.netoup.com. This enzyme is primarily responsible for the formation of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene semanticscholar.orgresearchgate.netmdpi.comoup.comresearchgate.netoup.comnih.gov. The formation rates of these active metabolites are strongly correlated with the amount of microsomal CYP2D6 protein researchgate.net.

Influence of CYP2D6 Genetic Polymorphism on Metabolic Efficiency

CYP2D6 exhibits significant genetic polymorphism, leading to various metabolic profiles among individuals researchgate.netfrontiersin.orgnih.govresearchgate.net. This genetic variability substantially influences the formation of this compound's active metabolites oup.comresearchgate.netoup.comnih.gov. Studies have shown a strong gene-dose effect, where individuals with non-functional CYP2D6 alleles (poor metabolizers, PMs) exhibit significantly lower plasma concentrations of the active metabolites compared to those with normal or extensive metabolizer phenotypes researchgate.netoup.comresearchgate.netoup.comnih.gov. For instance, PM subjects have shown approximately ten-fold lower maximum plasma concentrations (Cmax) of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene compared to normal metabolizers semanticscholar.org. In contrast, carriers of gene duplications demonstrate even higher formation rates of these metabolites researchgate.net.

The impact of CYP2D6 genetic polymorphism on this compound exposure and metabolism has been confirmed in clinical studies involving healthy volunteers researchgate.netoup.comoup.com. This variability in metabolic efficiency provides a biological rationale for the observed differences in response to this compound treatment among patients oup.comoup.comnih.gov.

Identification and Characterization of Active Metabolites

Human liver microsome studies have identified several this compound metabolites oup.comoup.comnih.gov. Among these, (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene have been characterized as the primary active metabolites semanticscholar.orgmdpi.comoup.comresearchgate.netoup.comnih.gov. These metabolites exhibit the strongest inhibitory affinity towards the estrogen receptor semanticscholar.orgoup.comoup.comnih.gov. For example, (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed half-maximal inhibitory concentrations (IC50) of 2.2 nM and 0.9 nM, respectively, against the estrogen receptor semanticscholar.orgmdpi.com. In comparison, the parent drug, (E)-clomifene, and its (Z)-isomer, along with their other metabolites, demonstrate lower inhibitory effects in in vitro assays semanticscholar.orgnih.gov.

Further characterization efforts have also identified other metabolites, including (Z)-3-hydroxyclomiphene and (E)-N-desethylclomiphene, though their activity might be lower or they might serve as precursors to other active forms semanticscholar.orgnih.gov. More than 20 metabolites have been detected in urine after a single dose of this compound, with some newly identified metabolites belonging to a hydrogenation pathway ki-nd.denih.gov.

Table 1: Key Pharmacokinetic Parameters of this compound and its Active Metabolites

Table 2: Influence of CYP2D6 Genotype on Active Metabolite Formation

This compound for Unexplained Infertility and Ovarian Stimulation Protocols

Induction of Spermatogenesis and Androgen Production

This compound operates by blocking the negative feedback of estrogen at the hypothalamus and pituitary glands, which in turn stimulates the secretion of gonadotropin-releasing hormone (GnRH) and subsequently pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) wikipedia.orgmdpi.comnih.govamegroups.orgtandfonline.comresearchgate.netgamedaymenshealth.com. This hormonal cascade is crucial for male reproductive function: LH stimulates Leydig cells in the testes to produce testosterone, while FSH acts on Sertoli cells in the seminiferous tubules to support and promote spermatogenesis mdpi.comresearchgate.netgamedaymenshealth.com.

Research findings consistently demonstrate that this compound administration leads to increased endogenous testosterone production and enhanced spermatogenesis wikipedia.orgmdpi.comnih.govamegroups.orgtandfonline.comresearchgate.netgamedaymenshealth.comnih.govbioscientifica.com. For instance, studies have shown that this compound can increase total testosterone levels by 293 to 362 ng/dL in men with hypogonadism wikipedia.org. A large clinical study reported an increase in testosterone levels from a baseline of 309 ng/dL to 642 ng/dL after three months of this compound therapy (25 mg/day) wikipedia.org. Similarly, another study observed a median total testosterone increase from 256 ng/dL to 630 ng/dL tandfonline.com. These increases are accompanied by significant elevations in free testosterone, LH, FSH, and estradiol levels wikipedia.orgmdpi.comnih.govnih.gov.

Impact on Semen Parameters: Concentration, Motility, and Morphology

This compound has been shown to positively influence key semen parameters in men with infertility, particularly sperm concentration and motility mdpi.comresearchgate.netnih.govresearchgate.netcore.ac.uk. A systematic review and meta-analysis of 15 studies (n=566) specifically evaluated the efficacy of this compound citrate on sperm quality in infertile men. The findings indicated a significant improvement in sperm concentration and motility during treatment nih.gov.

Table 1: Impact of this compound on Semen Parameters (Meta-analysis Findings)

While improvements in concentration and motility are observed, the same meta-analysis found no significant difference in sperm morphology before and during this compound treatment nih.gov. It is also important to note that a systematic review including 384 subfertile men from 11 cohorts reported that a subset of this compound-treated subjects experienced a paradoxical decline in semen parameters, with 19% showing a decrease in sperm count, 21% in sperm concentration, and 17% in sperm motility. In some cases (17% of individuals), this deterioration did not recover following discontinuation of therapy researchgate.netmdpi.com.

Hormonal Responses in Male Hypogonadism

This compound effectively increases serum testosterone levels in men with hypogonadism by inhibiting the negative feedback of estrogen, which leads to elevated LH and FSH levels mdpi.comnih.gov. Numerous studies have observed consistent and significant increases in total testosterone, free testosterone, LH, FSH, and estradiol levels in men with hypogonadism treated with this compound wikipedia.orgmdpi.comnih.govnih.gov.

For instance, in young men with hypogonadism (mean age 29 years), this compound treatment resulted in significant increases across these hormonal markers mdpi.com. Similarly, in post-pubertal males (18–21 years) with hypogonadism and obesity, elevations in testosterone, LH, and FSH levels were observed after this compound treatment mdpi.com. A meta-analysis further confirmed a significant increase in testosterone levels in men with obesity-associated secondary hypogonadism (MOSH) following this compound administration mdpi.com. A comprehensive systematic review and meta-analysis of 19 studies involving 1642 patients reported that total testosterone increased with a mean difference of 2.60 (95% CI 1.82-3.38) during this compound citrate treatment, alongside increases in free testosterone, LH, FSH, and sex hormone-binding globulin (SHBG) nih.gov.

Long-Term Efficacy and Safety in Male Endocrine Dysregulation

This compound is considered an effective alternative to traditional testosterone replacement therapy, particularly for hypogonadal men who wish to preserve their fertility mdpi.combioscientifica.comjournalajrimps.commenshealthmelbourne.com.auresearchgate.netnih.gov. Long-term follow-up studies have demonstrated sustained increases in testosterone levels with this compound treatment bioscientifica.commenshealthmelbourne.com.auresearchgate.netnih.gov.

A retrospective study involving 400 patients treated with this compound citrate for a mean duration of 25.5 months (ranging from 0 to 84 months) provided insights into its long-term efficacy. Among patients who received this compound for more than three years, 88% achieved eugonadal testosterone levels researchgate.netauajournals.org. Furthermore, 77% of these patients reported improvements in hypogonadal symptoms researchgate.netauajournals.org. Another study validated the efficacy of this compound over a mean treatment duration of 19 months menshealthmelbourne.com.au. These findings suggest that this compound can serve as a titratable and effective long-term treatment option for male endocrine dysregulation bioscientifica.comnih.gov.

Combination Therapeutic Strategies in Male Fertility

Research has explored the efficacy of this compound in combination with other therapeutic agents to enhance male fertility outcomes. Combination strategies have shown promise in improving hypogonadal symptoms and fertility mdpi.com.

A randomized controlled trial investigated the combination of this compound (25 mg daily) with vitamin E (400 mg daily). This combined therapy led to higher sperm counts, improved progressive sperm motility, and a notably higher pregnancy rate (36.7% in the combination group compared to 13.3% in the placebo group) mdpi.comresearchgate.net. These combination therapies may offer advantages for men undergoing assisted reproductive techniques, particularly due to observed improvements in total motile sperm count (TMSC) journalajrimps.comresearchgate.net. Additionally, combinations involving hCG and letrozole have shown substantial improvements in sperm counts, motility, and morphology in obese men suffering from idiopathic infertility mdpi.com.

Investigations in Specific Neurological Conditions

While this compound is primarily utilized in reproductive medicine, research investigating its direct therapeutic application as a primary treatment for specific neurological conditions is limited. The existing literature largely addresses neurological aspects in the context of potential adverse effects rather than primary therapeutic indications. For example, visual disturbances such as blurred vision, floaters, and scotomata are known ocular side effects associated with this compound, and in rare instances, more severe ocular issues have been reported wikipedia.orgclevelandclinic.orgsfda.gov.sa. There have also been rare reports of convulsions in patients receiving this compound citrate, with some studies mentioning its use in epileptic women with menstrual disorders bmj.com. However, these instances primarily concern the safety profile and potential neurological complications of this compound rather than its investigation as a therapeutic agent for neurological disorders themselves.

Research into Endogenous Hormone Modulation for Performance Enhancement

This compound is recognized for its capacity to modulate endogenous hormone levels, particularly in the context of performance enhancement. It is classified as a prohibited substance by the World Anti-Doping Agency (WADA) due to its selective estrogen receptor modulator capabilities and its indirect enhancement of testosterone metabolism wikipedia.orgscielo.br.

The mechanism of action involves this compound binding to estrogen receptors in the hypothalamus, thereby inhibiting the negative feedback effect of endogenous estrogen on the hypothalamus and pituitary gland wikipedia.orgpatsnap.commdpi.comswolverine.com. This disruption prompts the hypothalamus to increase the release of gonadotropin-releasing hormone (GnRH), which in turn stimulates the anterior pituitary gland to secrete higher levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) patsnap.commdpi.comswolverine.com. In males, these elevated levels of LH and FSH stimulate the testes to produce more endogenous testosterone mdpi.comswolverine.com. This endogenous stimulation makes this compound a valuable option for men with suppressed testosterone levels, including those resulting from anabolic steroid use or other hormonal disruptions swolverine.com. This compound has been shown to significantly increase serum testosterone, LH, and FSH levels in men with hypogonadism mdpi.com. It also helps maintain high FSH and LH levels, as well as intratesticular testosterone levels, which can improve spermatogenesis and increase sperm concentration and motility mdpi.com. This compound is also used as an adjuvant to alleviate pituitary suppression nih.gov. Its use for performance enhancement in healthy athletes is considered an off-label application nih.gov.

Table 1: this compound's Mechanism in Endogenous Hormone Modulation

This compound's Historical and Current Role in Breast Cancer Research

This compound has a notable history in breast cancer research. It was investigated for the treatment and prevention of advanced breast cancer between 1964 and 1974 wikipedia.org. While found to be effective, its use for this indication was eventually abandoned wikipedia.org. This abandonment was primarily due to concerns regarding desmosterolosis with extended use, a condition linked to this compound's ability to inhibit the enzyme 24-dehydrocholesterol reductase and consequently increase circulating desmosterol levels wikipedia.org. Such effects raised concerns about potential side effects like irreversible cataracts wikipedia.org. The emergence of Tamoxifen also contributed to the shift away from this compound for breast cancer treatment wikipedia.org.

Effects on Bone Mineral Density

Research has investigated the effects of this compound on bone mineral density (BMD). This compound is considered a weak estrogen agonist and has demonstrated the ability to improve bone density through both direct weak agonist activity and indirect central disinhibition, which increases gonadotrophin release menshealthmelbourne.com.au. In animal models, this compound has largely been shown to be effective in managing bone density menshealthmelbourne.com.au. Some findings suggest that this compound could be clinically equivalent to estrogen in maintaining bone density by disinhibiting central estrogen feedback menshealthmelbourne.com.au.

A 12-week this compound treatment in responsive individuals showed an increase in bone mineral density, which was attributed to a direct agonistic effect of this compound or increased estradiol levels researchgate.net. In a study involving men with hypogonadism, this compound citrate treatment led to significant improvements in mean femoral neck and lumbar spine bone densitometry (BD) scores, with these improvements sustained over a period of up to three years menshealthmelbourne.com.au. Furthermore, a patent was awarded for the use of this compound to predict fertility in women, based on the observation that denser bone mass while on this compound, detectable via CT scanner, could be predictive of fertility .

However, not all research indicates a positive effect on BMD in all populations. A study examining men younger than 50 years with testosterone deficiency found that estrogen modulators, including this compound citrate, or aromatase inhibitors, led to a decrease in lumbar spine bone mineral density nih.gov. This particular study observed no significant change in hip BMD with any of the treatments nih.gov. In ovariectomized rats, this compound was found to prevent cancellous bone loss from the tibia oup.com.

Table 2: Summary of this compound's Effects on Bone Mineral Density

Estrogen Receptor Modulation and Tissue-Specific Anti-Estrogenic Effects

This compound exerts its primary therapeutic effect by acting as an estrogen antagonist in the hypothalamus slideshare.netpicmonic.com. It binds to and depletes hypothalamic estrogen receptors, thereby blocking the negative feedback exerted by circulating endogenous estradiol wikipedia.orgdrugbank.compicmonic.com. This inhibition leads to an increased pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn stimulates the anterior pituitary to release more follicle-stimulating hormone (FSH) and luteinizing hormone (LH) wikipedia.orgdrugbank.comslideshare.netpicmonic.com. This increased gonadotropin secretion ultimately promotes ovarian follicular growth and ovulation wikipedia.orgdrugbank.compicmonic.com.

However, this compound's selective estrogen receptor modulating activity means its effects can vary across different tissues wikipedia.orgdrugbank.com. While it acts as an anti-estrogen in the hypothalamus, it can exhibit estrogenic properties in peripheral tissues patsnap.com. Its anti-estrogenic effects are particularly notable in the uterus, where it can lead to reduced endometrial thickness, which may adversely impact implantation wikipedia.orgnih.govarchivesofmedicalscience.com.

Visual disturbances are a well-documented adverse effect, occurring in 1% to 10% of individuals, and are thought to be related to this compound's anti-estrogenic actions on the eye wikipedia.orgnih.govmedscape.comnih.govmedicinenet.com. These can include blurred vision, double vision, scotomata (spots or flashes), light sensitivity, and pupil constriction wikipedia.orgmedscape.commedicinenet.com. While often reversible, vision changes can, in rare cases, be permanent medscape.com. Hot flashes, or vasomotor flushes, are another very common side effect, affecting more than 10% of patients, and are also linked to the anti-estrogenic effects of this compound wikipedia.orgpatsnap.comnih.govmedscape.comprogyny.comrxlist.com.

Hemodynamic and Coagulation Alterations

Although rare, this compound has been associated with cardiovascular adverse events. Post-marketing reports have identified various cardiovascular issues, including arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, and thrombophlebitis medscape.commedicinenet.comfda.govrxlist.com. There are documented case reports of venous thromboembolism (VTE) in patients receiving this compound, including deep vein thrombosis and pulmonary embolism clevelandclinic.orgresearchgate.net. Specifically, intracranial venous thrombosis has been reported in rare instances, with this compound being considered a likely contributing factor in some cases researchgate.net. Animal studies have also indicated that this compound can affect blood coagulation parameters nih.gov.

Inflammatory Responses in Reproductive Tissues

Research suggests that this compound administration can induce a dysregulated inflammatory response, particularly in the endometrium nih.gov. In mice, periconception this compound citrate administration was observed to cause a dysregulated inflammatory response in the endometrium, potentially contributing to implantation failure and adverse perinatal outcomes nih.gov. While inflammation is a natural and necessary process for successful reproduction, including implantation, excessive or dysregulated inflammatory responses can lead to complications such as infertility and miscarriage tandfonline.com. Ovarian Hyperstimulation Syndrome (OHSS), a serious complication of ovulation induction, involves the release of vasoactive cytokines from the ovaries, suggesting an inflammatory component in its pathophysiology tandfonline.comuwmedicine.orgreumatologiaclinica.orgasrm.org.

Ovarian Hyperstimulation Syndrome (OHSS) Etiology and Severity

Ovarian Hyperstimulation Syndrome (OHSS) is a potentially serious complication of ovulation induction, characterized by ovarian enlargement, fluid accumulation in the abdomen (ascites), and electrolyte imbalances uwmedicine.orgreumatologiaclinica.orgwikipedia.org. While OHSS is more commonly associated with gonadotropin therapy, it can occur with this compound, though the incidence is generally low, reported to be less than 1% in clomiphene-treated women wikipedia.orgdrugbank.comarchivesofmedicalscience.comrxlist.comuwmedicine.orgwikipedia.orgnih.gov.

The exact etiology of OHSS is not fully understood, but it is believed to involve high hormone levels, particularly human chorionic gonadotropin (hCG), which can lead to increased vascular permeability and fluid leakage from blood vessels into the abdominal and chest cavities uwmedicine.orgasrm.orgwikipedia.org. Women who develop many small follicles are more susceptible to OHSS uwmedicine.org. This compound can cause reversible ovarian enlargement, which is a common adverse drug reaction (occurring in >10% of people) and can present with abdominal or pelvic pain, weight gain, or bloating wikipedia.orgslideshare.netmedscape.comprogyny.comfda.govrxlist.comnih.gov. This ovarian enlargement is distinct from OHSS but can precede or be a component of the syndrome rxlist.com.

Research indicates that interventions to reduce OHSS risk, such as individualized gonadotropin dosing and supplementing with oral ovulation-inducing medications like clomiphene citrate, may be considered asrm.org.

Table 1: Reported Incidence of Ovarian Hyperstimulation Syndrome (OHSS) with this compound

Research into Multiple Gestation Rates and Mechanisms

One of the most significant and well-researched adverse consequences of this compound use is the increased risk of multiple pregnancies, predominantly twin gestations drugbank.compicmonic.comprogyny.comtheluckyegg.comoup.comresearchgate.netuq.edu.ausunderland.ac.ukpinkwomenscenter.com. This elevated risk is directly linked to this compound's mechanism of action, which stimulates the growth of multiple ovarian follicles capable of releasing eggs theluckyegg.com.

Studies indicate that the incidence of twin pregnancies with this compound ranges from approximately 5% to 12%, which is substantially higher than the natural twinning rate of about 1-2% progyny.comtheluckyegg.comoup.comsunderland.ac.uk. While twins are the most common outcome, triplet and higher-order multiple pregnancies can also occur, though they are rare oup.com.

The mechanisms contributing to multiple gestations include the increased FSH levels induced by this compound, which leads to the development of more ovarian follicles than would typically occur in a natural cycle wikipedia.orgpicmonic.comsunderland.ac.uk. Factors such as dosing variation, the use of adjuvant therapies, pretreatment weight loss, and the cumulative effect of multiple this compound cycles may also influence the risk of multiple pregnancies researchgate.netuq.edu.au. Ultrasound monitoring of follicular development has been suggested as a method to potentially reduce the risk of higher-order multiple pregnancies by allowing for intervention if too many follicles are developing, although evidence supporting routine use with this compound is limited oup.comresearchgate.net.

Table 2: Multiple Gestation Rates Associated with this compound Treatment

Endometrial Adverse Effects and Implantation Compromise

This compound exerts anti-estrogenic effects on the uterus, which can lead to structural and functional alterations of the endometrium, potentially compromising embryo implantation drugbank.comacaciofertility.com. A significant concern is the thinning of the uterine lining, which can seriously hinder implantation acaciofertility.com. Research indicates that suboptimal endometrial thickening (e.g., less than 6 mm) following this compound treatment is associated with a reduced volume of glandular epithelium, decreased markers of proliferation (PCNA, Ki67) and angiogenesis (PECAM-1), and an increase in inflammatory markers (CD45) researchgate.net. Furthermore, altered estrogen receptor expression patterns, specifically decreased estrogen receptor alpha (ERα) and increased estrogen receptor beta (ERβ) immunostaining, are observed in cases of suboptimal endometrial thickness researchgate.net.

Studies in animal models have provided insights into the mechanisms of implantation compromise. In mice, periconception administration of this compound citrate resulted in a dysregulated inflammatory response within the endometrium, leading to impaired embryo implantation and a reduction in viable pregnancy rates researchgate.netoup.comnih.gov. A dose-dependent adverse effect was observed, with a moderate dose sufficient to cause altered reproductive outcomes, including a 30% reduction in viable pregnancy and a 16% decrease in late gestation fetal weight oup.comnih.gov. Prolonged use of this compound, specifically for three or more consecutive months, can exacerbate these anti-estrogenic properties, leading to a progressive decline in pregnancy potential and an increased risk of early spontaneous abortion acaciofertility.com. Additionally, this compound can negatively impact the quality of cervical mucus, further impeding sperm capacitation and transport acaciofertility.com.

Ovarian Enlargement Characterization

Ovarian enlargement is a frequently reported adverse effect associated with this compound therapy, observed in approximately 13.6% of patients exphar.com. This enlargement can manifest with symptoms such as pelvic or abdominal pain mims.comnih.gov. The maximal extent of ovarian enlargement may not be apparent until several days after the discontinuation of this compound treatment exphar.comhres.ca.

While small residual follicular cysts are a common occurrence during consecutive treatment cycles, these typically regress spontaneously without requiring treatment postponement . However, in certain patient populations, particularly those with polycystic ovary syndrome (PCOS) who exhibit heightened sensitivity to gonadotropins, an exaggerated ovarian response to standard this compound doses can lead to significant ovarian enlargement and cyst formation exphar.comhres.ca.

In severe cases, ovarian enlargement can progress to Ovarian Hyperstimulation Syndrome (OHSS), a potentially serious medical condition hres.canih.govfda.gov. OHSS is characterized by gross ovarian enlargement, accompanied by gastrointestinal symptoms, ascites (fluid accumulation in the abdomen), dyspnea (shortness of breath), and pleural effusion (fluid around the lungs) hres.canih.govfda.gov. These severe manifestations underscore the importance of careful monitoring during this compound therapy.

Vasomotor Symptoms and Their Endocrine Link

Vasomotor symptoms, commonly known as hot flashes or flushes, are a prevalent systemic adverse effect, reported in approximately 10.4% of patients treated with this compound exphar.comhres.camedscape.com. These symptoms are endocrinologically linked to the anti-estrogenic action of this compound, particularly at the hypothalamic level acaciofertility.combiospace.commenopause.org.au. By blocking estrogen receptors in the hypothalamus, this compound mimics a state of estrogen withdrawal, similar to that experienced during menopause acaciofertility.combiospace.commenopause.org.au. This estrogen deprivation can disrupt the brain's thermoregulatory center, leading to the characteristic sensations of heat and flushing biospace.commenopause.org.au.

Neuropsychiatric Manifestations: Mood Alterations and Psychological Impact

This compound therapy has been associated with a notable incidence of neuropsychiatric manifestations, impacting mood and psychological well-being. Common psychological side effects include mood instability, mood swings, irritability, anxiety, and feelings of sadness tandfonline.comwomensmentalhealth.orgresearchgate.netfrontiersin.orgbiomedres.usnih.gov. A 2005 study indicated that 40% of women receiving this compound experienced psychological side effects womensmentalhealth.org. Mood instability, specifically, has been reported in 60-70% of cases biomedres.us.

In rare instances, more severe psychiatric symptoms such as psychosis or manic delirium have been documented biomedres.uspsychiatrictimes.com. The biological basis for these neuropsychiatric effects is thought to involve this compound's anti-estrogen activity and its influence on the hypothalamic-pituitary-gonadal axis biomedres.uspsychiatrictimes.com. Rapid decreases in estrogen activity or increases in circulating testosterone levels, driven by this compound's mechanism, may lead to alterations in neurotransmission and subsequent changes in emotional states biomedres.uspsychiatrictimes.com.

Gastrointestinal and General Systemic Effects

Patients undergoing this compound treatment may experience various gastrointestinal and general systemic adverse effects. Nausea and vomiting are reported in approximately 2.2% of cases exphar.commedscape.com. Abdominal discomfort, including distension, bloating, pain, or soreness, is also a common complaint exphar.comhres.camedscape.com.

Other frequently observed systemic effects include headaches (1.3%) exphar.commedscape.comnih.gov, breast discomfort or tenderness (2.1%) exphar.commedscape.com, and visual symptoms (1.5%) exphar.comnih.govmedscape.comnih.gov. Visual disturbances can manifest as blurred vision, scotomata (blind spots), or seeing spots or flashes mims.comnih.govmedscape.com. While these visual changes typically resolve within days or weeks after discontinuing treatment, permanent vision changes have been reported in rare cases medscape.com. Pelvic pain is also a common side effect wikipedia.orgmims.comnih.gov.

Less common, but potentially severe, adverse events include transient elevations in serum aminotransferase levels and, rarely, clinically apparent liver injury, which can be severe and even fatal nih.govnih.gov. Rare systemic effects also encompass high blood levels of triglycerides and reversible baldness wikipedia.org.

Endocrine Effects Beyond Reproductive Axes

This compound's primary mechanism involves modulating the HPO axis by blocking estrogen receptors in the hypothalamus, thereby increasing the release of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) wikipedia.orgpatsnap.comdrugbank.com. While its direct interference with pituitary-adrenal or pituitary-thyroid function is not apparent, some research suggests broader endocrine implications fda.gov.

Specifically, studies have indicated a potential association between this compound use and an increased risk of certain cancers, including thyroid cancer and malignant melanomas wikipedia.orgnih.gov. This risk appears to be elevated with prolonged use, particularly beyond six treatment cycles, and in nulligravid women wikipedia.orgnih.gov. Further research is needed to fully elucidate these potential long-term endocrine effects. Additionally, in males, this compound administration can lead to significantly elevated testosterone levels by increasing LH and FSH secretion biomedres.usoup.com.

Adverse Event Profile Summary

The following table summarizes the reported frequencies of common adverse events associated with this compound:

Reproductive and Non-Reproductive Long-Term Health Outcomes

Research into the long-term health outcomes associated with this compound use has explored both reproductive and non-reproductive aspects, yielding varied findings.

Reproductive Long-Term Health Outcomes

Ovarian Cancer Risk: Some earlier studies suggested a potential increase in ovarian cancer risk with this compound use exceeding one year, particularly in individuals who did not achieve pregnancy. However, subsequent research has largely failed to corroborate these findings. wikipedia.org

Endometrial Cancer Risk: An increased risk of endometrial cancer has been observed in subfertile women who used this compound citrate when compared to a general population control group (Relative Risk: 1.87, 95% CI: 1.00 to 3.48). nih.gov It remains unclear whether this association is directly attributable to the medication or the underlying infertility conditions. nih.gov The risk has been noted to increase with the number of treatment cycles, particularly after six or more cycles, leading to recommendations that this compound use be restricted to a maximum of six cycles. vrachi.name

Ectopic Pregnancy: Descriptive studies have reported an incidence of ectopic pregnancy ranging from 0.5% to 4.4% following this compound citrate administration, which is higher than the estimated general population incidence of 0.7% to 0.8%. rug.nl However, current data are considered insufficient to definitively establish a causal link between this compound use and an increased risk of ectopic pregnancy. rug.nl

Non-Reproductive Long-Term Health Outcomes

Malignant Melanoma and Thyroid Cancer: this compound has been associated with an increased risk of malignant melanomas and thyroid cancer. wikipedia.org This elevated risk was particularly noted among nulligravid women. vrachi.name

Liver Abnormalities: this compound has been linked to a low incidence of transient elevations in serum aminotransferase levels and, in rare cases, to clinically apparent liver injury, which can be severe or even fatal. wikipedia.orgctdbase.org

Outcomes in Male Hypogonadism Treatment: In the context of long-term treatment for male hypogonadism, this compound citrate has demonstrated efficacy and a favorable safety profile. Studies, including one retrospective review of 400 patients treated for a mean duration of 25.5 months (with some treated for over 3 years), indicated that this compound is safe and effective with few reported side effects. Common side effects reported in long-term male users included mood changes, blurred vision, and breast tenderness. No significant adverse events were reported in patients treated for more than three years, and no clinically significant changes in lipid profiles, bone density, hemoglobin, or prostate-specific antigen were observed.

Association with Adverse Perinatal Outcomes

This compound citrate use is generally associated with an elevated risk of adverse perinatal outcomes and birth defects. nih.gov

Multiple Pregnancies: A well-documented adverse outcome of this compound use is the increased incidence of multiple pregnancies. A nationwide cohort study found a significantly higher multiple pregnancy rate in women exposed to this compound citrate compared to matched controls, with an odds ratio of 4.1 for twin pregnancies and 5.1 for triple or more pregnancies. Multiple gestations are inherently associated with increased risks of complications such as preeclampsia, premature labor, and growth restriction, which contribute to higher mortality and morbidity rates.

Stillbirth and Neonatal Death: A population-based cohort study in South Australia (2003-2015) investigated the association between this compound citrate use and perinatal death. Among singleton pregnancies conceived with this compound citrate, the prevalence of stillbirth was 10.2 per 1000 births, and neonatal deaths occurred at a rate of 3.1 per 1000 live births. The combined outcome of perinatal death showed an odds ratio of 1.54 (95% CI: 1.15, 2.07) for pregnancies following this compound citrate use, even after adjusting for biological and social risk factors.

Other Adverse Obstetrical and Perinatal Outcomes: Women exposed to this compound citrate have shown significantly more adverse obstetrical and perinatal outcomes. Even in singleton pregnancies, after adjusting for confounders, there was a significantly higher risk of stillbirth, gestational diabetes, placenta previa, pre-eclampsia, preterm delivery, and small for gestational age (SGA). In cases of multiple pregnancies, there was an elevated risk of placenta previa, preterm delivery, and SGA compared to non-exposed women.

Miscarriage Rates: Miscarriage rates in studies involving this compound citrate have been reported between 13% and 25%. rug.nl However, some data suggest that the miscarriage rate is not significantly increased in anovulatory women treated with this compound citrate. rug.nl

Teratogenic Potential and Congenital Anomalies Research

The evidence concerning the teratogenic risk of this compound in human pregnancies remains inconclusive and somewhat controversial.

Reported Associations: Some retrospective studies have reported associations between this compound use and certain birth defects, including neural tube defects (NTDs), hypospadias, congenital heart defects, anencephaly, blindness, limb reduction, cardiac, renal, and anal agenesis, and urogenital defects. More recently, potential teratogenic effects such as conjoined twins and ambiguous external genitalia have been suggested, warranting further investigation.

Minor Malformations: One study on post-conceptional exposure to this compound citrate found no increased risk of major malformations, but an increased risk of minor malformations (crude relative risk = 4.05, 95% CI: 1.70–9.64) was observed, although without a specific clinical pattern.

Confounding Factors: A significant challenge in interpreting human data is differentiating whether observed adverse outcomes are due to the drug itself or the underlying subfertility condition that necessitated treatment.

Animal Model Studies on Fetal Development and Pregnancy Outcomes

Preclinical studies in animal models have provided compelling evidence regarding the teratogenic and embryotoxic effects of this compound citrate. vrachi.name

Mouse Studies:

Periconception administration of this compound citrate in mice, at doses approximating human exposures, resulted in dose-dependent adverse effects on fetal development and pregnancy outcomes. nih.gov

Observed effects included a 30% reduction in viable pregnancy, a 16% reduction in late gestation fetal weight, and approximately 30% of fetuses exhibiting delayed development or congenital abnormalities not seen in control groups. nih.gov

Specific congenital abnormalities identified in mice included defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. nih.gov

this compound citrate also caused an average 30-hour delay in birth time and an elevated rate of pup death in the early postnatal phase. nih.gov

In utero exposure during early pregnancy was shown to compromise implantation and impact fetal growth and development, leading to adverse perinatal outcomes. nih.gov

Preovulatory administration in mice was found to impair uterine function, subsequently reducing embryonic growth and development, and causing neural tube defects (exencephaly).

Morphological observations in developing mice included open eyelids, anophthalmia, fore and hindlimb micromelia, meromelia, amelia, hygroma, hydrocephaly, hemorrhagic spots, kyphosis, and clubbed feet. Reductions in fetal body weight, crown-rump length, head circumference, eye circumference, and limb lengths were also noted.

Rat Studies:

Studies in Wistar rats comparing this compound citrate and letrozole indicated that pups whose mothers received this compound citrate had the lowest heart weights and showed greater necrosis in cardiac tissue.

this compound has been shown to induce hydramnios and fetal cataracts in rats.

Oral administration of this compound to neonatal rats resulted in reproductive tract abnormalities.

Administration to pregnant rats caused reproductive tract abnormalities in both offspring and mothers.

Guinea Pig Studies:

In guinea pigs, this compound citrate administered on the day of mating (2 mg/kg body weight) could block or interrupt pregnancy.

Only 25% of treated females achieved regular pregnancies with healthy fetuses; other females exhibited embryo resorption or no signs of pregnancy.

In affected females, corpus luteum size was reduced, progesterone concentrations were very low, and endometrial glands and epithelium were often altered.

These findings suggest that this compound reduces fertility by altering the uterus and, directly or indirectly, inducing luteolysis, leading to later pregnancy loss.