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Clomid (Clomiphene citrate) is a selective estrogen receptor modulator that was first developed in 1956 and introduced into clinical practice in 1967 for the treatment of female infertility. Over time, its use has expanded beyond its original indication, and clomid has been widely studied as an off-label option for male infertility and symptoms associated with male hypogonadism. This review examines the existing medical literature on clomid and its role in the management of male hypogonadism.
A comprehensive literature search was conducted using PubMed, including studies published through April 2020. A total of 52 relevant articles were identified and included in this review, while abstracts and individual case reports were excluded. The available evidence suggests that clomid, whether used as monotherapy or in combination with vitamins and other non–FDA-approved agents, produces variable outcomes in the treatment of male factor infertility. Several validated questionnaires have been used to assess changes in hypogonadal symptoms during clomid therapy, though study results regarding symptomatic improvement remain inconsistent.
Overall, clomid is considered a well-tolerated medication, with most studies reporting no serious adverse effects. When side effects are observed, they most commonly include headache, gynecomastia, visual disturbances, dizziness, and mood changes. Despite mixed findings, clomid is regarded as a potentially effective therapeutic option for selected men with infertility and clinical features of hypogonadism. Further high-quality studies are needed to more clearly define its efficacy and long-term role in the treatment of male infertility and hypogonadism.
Background and clinical use
Clomid was originally synthesized by Frank Palopoli and colleagues at the William S. Merrell Company in 1956 as a potential contraceptive agent. Subsequent research revealed its ability to enhance fertility in women, leading to its introduction into clinical practice around 1967. The U.S. Food and Drug Administration initially approved clomid for the induction of ovulation in women with anovulatory disorders, including polycystic ovary syndrome. It was also observed to increase ovarian responsiveness to pituitary hormones.
Advances in the treatment of female infertility contributed to a better understanding of clomid’s effects on the hypothalamic-pituitary-gonadal (HPG) axis. This understanding ultimately led to investigations of clomid as an off-label therapy for male factor infertility. Since its introduction into male reproductive medicine, clomid has also been used to address symptoms related to male hypogonadism.
Mechanism of action
In men, the HPG axis consists of the hypothalamus, anterior pituitary gland, and testes. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins promote testosterone production and spermatogenesis. Testosterone is partially converted to estradiol via the aromatase enzyme, and estradiol plays a key role in negative feedback regulation of the reproductive axis by suppressing GnRH secretion.
Clomid acts by competitively inhibiting estradiol binding at estrogen receptors in the hypothalamus and pituitary gland, thereby disrupting this negative feedback mechanism. As a result, GnRH secretion increases, leading to elevated LH and FSH levels. Clomid has an approximate half-life of five days and consists of two stereoisomers: about 38% zuclomiphene and 62% enclomiphene, both of which are primarily excreted through the gastrointestinal tract. Zuclomiphene exhibits mixed estrogen agonist and antagonist activity, whereas enclomiphene functions as a purely anti-estrogenic compound.
Unlike exogenous testosterone therapy, clomid does not suppress the HPG axis. Instead, it stimulates endogenous gonadotropin release, resulting in increased intratesticular testosterone production by Leydig cells and preservation of spermatogenesis.
Enclomiphene as an alternative therapy
Enclomiphene, the anti-estrogenic isomer of clomid, has also been investigated as a standalone treatment for male hypogonadism. Wiehle and colleagues demonstrated that hypogonadal men treated with enclomiphene at a dose of 25 mg daily maintained normal sperm concentrations throughout the treatment period. In contrast, a randomized controlled trial by Kim et al. found no statistically significant differences in sperm parameters between enclomiphene and placebo groups over a five-month treatment period in hypogonadal men.
Effects on the Testosterone-to-Estrogen Ratio
Clomid (Clomiphene citrate) is also recognized for its ability to influence the testosterone-to-estrogen (T:E) ratio. An increase in this ratio is believed to enhance male fertility potential by mitigating the suppressive effects of estrogen on the hypothalamus. Elevated estrogen levels and increased aromatase activity within the testes are thought to reduce sperm production and increase the risk of embryonic loss both before and after implantation.
Anastrozole (AZ) has also been shown to be effective in lowering estrogen levels by inhibiting aromatase-mediated conversion of testosterone to estrogen, thereby increasing the T:E ratio. Improvements in sperm concentration and motility have been reported in hypogonadal men who achieved optimized T:E ratios after five months of AZ therapy.
A prospective study demonstrated a 60.9% increase in the T:E ratio after 12 weeks of treatment with clomid at a dose of 25 mg daily. Notably, men aged 40 years and older experienced a more pronounced increase in the T:E ratio compared with younger men. A retrospective cohort study further suggested that patients with baseline estradiol levels ≥18.5 pg/mL and a body mass index (BMI) ≥29 may benefit from combination therapy consisting of anastrozole and clomid 50 mg administered every other day. This regimen was shown to help maintain a T:E ratio greater than 10 while keeping estradiol levels below 50 pg/mL.
Use in Male Infertility
Multiple studies have reported that clomid improves fertility in hypogonadal men by increasing sperm concentration. Several randomized controlled trials have examined its role in the treatment of male infertility. Rönnberg observed, in a randomized double cross-over study, a significant increase in sperm count among patients treated with clomid 50 mg daily.
A World Health Organization trial involving 190 infertile couples treated with clomid at a daily dose of 25 mg reported a statistically significant increase in sperm concentration after four months of therapy. However, this study did not demonstrate a corresponding increase in pregnancy rates or significant changes in other sperm parameters. Additional studies by Wang et al. and Mičić and Dotlić similarly documented improvements in sperm concentration following clomid therapy.
In a retrospective cohort study of hypogonadal infertile men with type 2 diabetes mellitus, treatment with clomid 50 mg every other day in combination with metformin resulted in a significant increase in sperm concentration after three months compared with metformin plus placebo. Hussein and colleagues further reported that severely oligospermic men undergoing clomid therapy for nine months had a higher likelihood of successful microscopic testicular sperm extraction compared with those receiving placebo.
Studies Reporting Limited or No Benefit
Not all studies have demonstrated positive effects of clomid on sperm parameters. Sokol et al. randomly assigned 23 hypogonadal men to receive either clomid 25 mg daily or placebo and found no significant differences in sperm parameters between groups over a 12-month period. Similarly, a double-blind randomized controlled trial failed to show significant improvements in sperm parameters among hypogonadal infertile men treated with clomid. It should be noted, however, that most participants in this study were not oligospermic at baseline, and more than half had concurrent varicoceles.
Another retrospective cross-sectional study involving 47 hypogonadal men treated with clomid 50 mg every other day for three months found no significant changes in sperm parameters. In a separate randomized controlled trial, no significant changes in serum anti-Müllerian hormone or inhibin levels were observed in hypogonadal men with metabolic syndrome treated with clomid 25 mg daily for three months. Importantly, most participants in this study had previously fathered children and exhibited normal baseline sperm parameters.
Combination Therapy With Vitamins and Supplements
Vitamins and other non–FDA-approved nutritional supplements have also been evaluated in combination with clomid for their effects on sperm parameters and pregnancy outcomes. Oxidative stress is known to impair sperm production and quality, and antioxidant supplementation may offer therapeutic benefits in men with infertility.
ElSheikh et al. conducted a prospective cohort study examining the effects of clomid and vitamin E in hypogonadal men with oligoasthenospermia. The study demonstrated a significant increase in sperm concentration with clomid alone, with an even greater improvement observed when clomid was combined with vitamin E.
In a double-blind randomized controlled trial involving 60 infertile men with a mean infertility duration of 4.5 years, the group receiving clomid 25 mg daily in combination with vitamin E 400 mg daily experienced a significantly higher pregnancy rate at 3–6 months compared with the placebo group (36.7% vs. 13.3%). Another randomized controlled trial comparing clomid 50 mg daily with vitamin C 200 mg daily found no overall difference in pregnancy rates between groups. However, a higher pregnancy rate was observed among men treated with clomid who had a duration of infertility of less than 18 months prior to initiating therapy.
Additionally, a randomized controlled trial reported improved sperm motility in men treated with either clomid or L-carnitine compared with placebo.
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Use in Men With Hypogonadism
Multiple studies have demonstrated that treatment with clomid (Clomiphene citrate) can lead to improvement in symptoms associated with male hypogonadism, as assessed using a variety of validated questionnaires. Key studies evaluating clomid for hypogonadal symptoms are summarized in Table 2. Guay et al. assessed treatment response using penile rigidity testing and the International Index of Erectile Function/Sexual Health Inventory for Men (SHIM). While no significant improvement in sexual function or rigidity was observed across the entire study population, subgroup analysis revealed that younger men (mean age 53 years), as well as men without diabetes or hypertension, experienced significant improvements in erectile rigidity and sexual function when treated with clomid compared with placebo.
In a separate study by the same investigator, men aged 55 years or younger were found to be 2.3 times more likely to respond positively to clomid therapy than men older than 55 years. A positive response was defined as the ability to successfully complete intercourse in more than 50% of attempts. In contrast, another study failed to demonstrate improvement in SHIM scores after one year of clomid treatment. Additional outcomes observed in hypogonadal men included increases in body mass index (BMI) and reductions in bone mineral density. However, longer-term use of clomid has also been associated with improved bone density and reductions in BMI over a three-year treatment period.
ADAM Questionnaire Outcomes
The Androgen Deficiency in Aging Males (ADAM) questionnaire was the most commonly used tool to assess the impact of clomid on hypogonadal symptoms. The ADAM questionnaire has a reported sensitivity of 97% and specificity of 30%, with a known tendency for false-positive results in patients reporting depressive symptoms.
Taylor and Levine evaluated symptom changes in hypogonadal men treated with either clomid or transdermal testosterone gel using ADAM scores. Both treatment groups achieved mean testosterone levels of approximately 550 ng/dL and reported improvements in libido, reflected by reductions in ADAM scores.
Katz et al. examined a cohort of 86 hypogonadal men treated with clomid 50 mg every other day and observed significant improvements in ADAM scores after six months of therapy. The study also found no difference in symptom response between patients with varicoceles and those without varicoceles. Additional studies have demonstrated significant improvements in ADAM scores after one year of clomid therapy administered at 50 mg daily or every other day.
Conversely, a double-blind randomized controlled trial evaluating obese hypogonadal men found no significant improvement in ADAM scores after three months of clomid therapy compared with placebo. Similarly, another randomized controlled trial comparing clomid with anastrozole did not demonstrate significant improvements in ADAM scores after three months in either treatment group.
Quantitative ADAM (qADAM) and Additional Endpoints
The quantitative ADAM (qADAM) questionnaire was introduced in 2010 to provide numerical scoring for symptom severity. Higher qADAM scores are associated with a lower likelihood of hypogonadal symptoms, although no standardized cutoff values have been established to define positive or negative results. qADAM scores have been shown to correlate positively with total testosterone levels and SHIM scores.
Dadhich et al. evaluated symptom changes after three months of treatment with clomid or testosterone replacement therapy (TRT) and reported significant improvements in qADAM scores in both treatment groups. In another randomized controlled trial, investigators demonstrated that clomid and human chorionic gonadotropin (hCG), whether used independently or in combination, resulted in significant improvements in qADAM scores.
Ramasamy et al. conducted a cross-sectional study showing improvement in qADAM scores with both clomid 25 mg daily and TRT, with a statistically significant difference observed between the two treatment approaches.
Sertoli Cell Function
The effects of clomid on Sertoli cell function in hypogonadal men have also been investigated through measurement of serum inhibin and anti-Müllerian hormone levels. A retrospective cohort study demonstrated a significant increase in serum inhibin levels following three months of treatment with clomid 50 mg administered every other day, suggesting improved Sertoli cell activity.
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Limitations of Symptom Assessment
There remains debate regarding the validity of the Androgen Deficiency in Aging Males (ADAM) questionnaire as a reliable tool for monitoring hypogonadal symptoms during clomid (Clomiphene citrate) therapy. The ADAM questionnaire was originally designed to assess hypogonadal symptoms in the context of bioavailable testosterone rather than total testosterone. However, the majority of studies evaluating clomid have defined testosterone deficiency based on total serum testosterone levels rather than bioavailable testosterone.
Several investigations have demonstrated that the ADAM questionnaire lacks the ability to consistently distinguish between individuals with positive and negative ADAM scores when total testosterone is used as the primary biochemical marker. This limitation may partially explain the variability in reported symptom outcomes across studies assessing clomid therapy.
Clinical Dosing Approach
In our clinical practice, baseline laboratory evaluation is obtained prior to initiating clomid therapy. This assessment includes serum total testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Treatment is initiated at the lowest effective dose, typically 25 mg administered every other day, recognizing the variability in individual patient response. Follow-up laboratory testing is performed after 6 to 8 weeks, and the dosage is titrated based on hormonal response, with gradual escalation to a maximum of 50 mg daily when clinically indicated.
Adverse Effects and Safety Profile
Clomid is generally regarded as a well-tolerated medication in clinical practice. To date, relatively few studies have specifically examined adverse effects of clomid in men, particularly in comparison with testosterone replacement therapy (TRT). Most investigations assessing its efficacy report no major adverse events.
Reported side effects associated with clomid therapy include headache, gynecomastia, visual disturbances, dizziness, and mood instability. In a multi-institutional retrospective study of 363 patients, Wheeler et al. observed a significantly lower prevalence of secondary polycythemia in men treated with clomid compared with those receiving TRT (1.7% vs. 11.2%). Notably, no patients in the clomid group developed hematocrit levels requiring therapeutic phlebotomy.
Taylor and Levine evaluated the long-term safety and efficacy of clomid compared with testosterone gel in a cohort of 104 men and reported no significant increases in cholesterol levels, prostate-specific antigen (PSA), or hemoglobin with clomid therapy. Similarly, Chandrapal et al. found no significant changes in PSA or hematocrit in 77 men treated with clomid.
Case reports have also described successful transition from TRT to clomid in patients who developed secondary polycythemia on testosterone therapy, with resolution of polycythemia following the switch. More recently, Kavoussi et al. assessed the risk of deep vein thrombosis (DVT) in 1,180 hypogonadal men treated with either TRT or clomid. Only one of 486 patients receiving clomid developed DVT, compared with nine of 694 patients treated with TRT.
In a prospective study of 125 hypogonadal men receiving clomid, Da Ros and Averbeck found no statistically significant changes in high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, or prolactin levels when comparing pre- and post-treatment values. Collectively, these findings underscore the favorable safety profile of clomid, particularly in comparison with TRT regarding the risks of secondary polycythemia and thromboembolic events.
Conclusion
Clomid (Clomiphene citrate) is widely regarded as a valuable therapeutic option for men presenting with both infertility and symptoms of hypogonadism. The existing literature generally supports its safety in hypogonadal patients. However, studies evaluating its impact on sperm parameters have produced mixed results. This variability may reflect the off-label status of clomid for male infertility and hypogonadism, as well as the absence of standardized dosing regimens and treatment protocols.
Because clomid is not FDA-approved for the treatment of male hypogonadism, there are currently no consensus guidelines defining optimal dosing strategies or treatment duration. Additionally, heterogeneity in study design, inclusion criteria, and outcome measures further complicates interpretation of results. The inconsistent findings related to symptom improvement may also be influenced by the limited diagnostic accuracy of commonly used assessment tools such as the ADAM questionnaire.
Overall, further well-designed studies incorporating standardized diagnostic criteria and outcome measures accepted by the male sexual health community are needed to more definitively establish the role of clomid in the management of male infertility and hypogonadism.