| Drug: | Clomid / Clomiphene |
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What is the mechanism of action of Clomiphene citrate (Clomid) in treating male hypogonadism?
What are the main advantages of Clomid compared to testosterone replacement therapy (TRT)?
What are the most commonly reported side effects of Clomid in male patients?
For which types of hypogonadism is Clomid most effective, and why?
What is the recommended dosage range for Clomid in men, and how is it adjusted?
Clomiphene citrate (Clomid) was initially synthesized in 1956 as a selective estrogen receptor modulator and began clinical use in 1967, primarily to address female infertility. Since then, Clomid has also found off-label applications, particularly in treating male infertility and symptoms related to hypogonadism. This brief review aims to summarize existing research and evaluate the effectiveness of Clomid in managing male hypogonadism.
To conduct this review, we thoroughly examined literature available through the PubMed database, comparing Clomid to testosterone, the FDA-approved treatment for male hypogonadism. After analyzing 29 pertinent research articles, we observed that Clomid effectively increased serum testosterone levels to a degree similar to testosterone gel treatments. Additionally, evidence supports the assertion that Clomid alleviates hypogonadal symptoms. A significant distinction between these two treatments is Clomid’s ability to maintain sperm production, thus preserving fertility—a critical consideration for patients experiencing secondary or tertiary hypogonadism.
In terms of safety, Clomid demonstrated a comparable safety profile to testosterone therapy. Overall, our analysis indicates that Clomid represents a promising therapeutic option for patients suffering from male infertility linked to hypogonadism. Nevertheless, further research is warranted to fully determine the extent and reliability of Clomid’s effectiveness in these contexts.
Keywords: Clomiphene citrate, Clomid, Testosterone, Hypogonadism, Polycythemia, Infertility
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Introduction
Hypogonadism is prevalent among men, especially those older than 45, with approximately 36% affected in this age group who have not received testosterone therapy. Higher prevalence rates have been noted among men with comorbidities, such as hypertension, type 2 diabetes, obesity, or prostate disorders. Conversely, other studies have suggested lower rates of symptomatic hypogonadism, ranging from 2.1% to 13% among men aged 40–79.
According to guidelines by the European Society of Urology, hypogonadism may originate from testicular dysfunction (primary), issues in the hypothalamic-pituitary axis (secondary), mixed causes, or target organ defects. Regardless of cause, low testosterone levels commonly lead to various symptoms such as delayed puberty, reduced testicular size, gynecomastia, infertility, decreased muscle mass, and diminished physical strength.
While testosterone replacement therapy typically does not heighten prostate cancer or cardiovascular risks, common manifestations of hypogonadism include erectile dysfunction, decreased sexual desire, reduced body hair, and fewer morning erections. Hypogonadism frequently occurs alongside conditions such as obesity, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), type 2 diabetes, HIV infection, chronic kidney disease, malignancies, obstructive sleep apnea, liver cirrhosis, and pituitary tumors.
The most common form of hypogonadism is primary hypogonadism, typically diagnosed by identifying low serum testosterone alongside elevated follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) levels. Frequent causes of primary hypogonadism include Klinefelter syndrome, chemotherapy, radiation therapy targeting the testes, mumps infections, and testicular tumors. On the other hand, secondary and tertiary hypogonadism often result from conditions such as hyperprolactinemia, Kallmann’s syndrome, obstructive sleep apnea, hemochromatosis, obesity, and specific medications.
In secondary or tertiary hypogonadism, the testes remain structurally intact but are insufficiently stimulated by FSH or LH, leading to elevated gonadotropins yet impaired testosterone production. Symptoms of testosterone deficiency developing in men over the age of 40 are classified as adult-onset hypogonadism in aging men (ADAM). In these scenarios, the function of the hypothalamic-pituitary-gonadal (HPG) axis remains normal.
Testosterone replacement therapy is a standard treatment for hypogonadism, aiming to restore normal serum testosterone levels. Effective testosterone therapy improves muscle mass, physical strength, libido, bone density, and overall well-being. However, this therapy carries notable risks; polycythemia is prevalent among older patients, and acne frequently affects younger individuals. Moreover, testosterone therapy significantly reduces fertility, making it inappropriate for men who desire to preserve their fertility.
Alternatives for treating secondary or tertiary hypogonadism include human chorionic gonadotropin (hCG), follicle-stimulating hormone, and selective estrogen receptor modulators (SERMs) or selective androgen receptor modulators (SARMs). Clomiphene citrate (Clomid), a SERM, functions by binding to estrogen receptors in the hypothalamus and pituitary gland, thereby enhancing gonadotropin release. Increased gonadotropins subsequently stimulate testicular testosterone production. Initially approved in 1960 for ovulation induction in women, Clomid’s use in males remains off-label due to incomplete evidence of efficacy. Nevertheless, it is commonly used in clinical practice for hypogonadal men who wish to maintain fertility.
Mechanism of Action of Clomiphene Citrate
Clomid acts predominantly as a competitive estrogen receptor modulator at hypothalamic and pituitary receptors, competing with estradiol. This competition increases the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, leading to higher LH and FSH secretion from the anterior pituitary. LH and FSH then stimulate testicular testosterone production and sperm formation. The two primary components of Clomid, zuclomiphene (cis-isomer) and enclomiphene (68%), differ significantly from testosterone by not suppressing the HPG axis; rather, they elevate LH and FSH levels, supporting natural testosterone production and fertility.
Adverse effects
Clomid is considered safe and is an inexpensive treatment for male hypogonadism [21]. The most commonly reported side effects are fatigue, breast tenderness, headache, flushing, and abdominal/pelvic pain. These side effects occurred in approximately 4–11% of male patients [6]. Wheeler et al. [22] observed a lower incidence of secondary polycythemia (1.7%) with Clomid compared to testosterone therapy (11.2%). Furthermore, studies have indicated that Clomid does not significantly affect cholesterol, prostate-specific antigen (PSA), or hemoglobin levels [19].
Literature includes two notable cases where patients transitioned from testosterone replacement therapy to Clomid due to secondary polycythemia [23, 24]. After switching to Clomid, these patients experienced resolution of polycythemia. Remarkably, one patient with both polycythemia and transient ischemic attack (TIA) saw normalization of hematocrit (HCT) levels and resolution of TIA symptoms following Clomid initiation [22]. Kavoussi et al. [25] reported treating 694 hypogonadal male patients with testosterone and 486 with Clomid for a duration of 22 months. Their findings indicated a lower incidence of deep-vein thrombosis (DVT) among patients treated with Clomid, and notably, no occurrences of polycythemia in either treatment group [25].
When Clomiphene Citrate is used and its effective dose:
Clomiphene citrate is primarily used off-label in the United States for male patients experiencing secondary hypogonadism with an intact hypothalamic-pituitary-gonadal (HPG) axis who desire to maintain fertility. Despite its common usage, Clomid is not FDA-approved for these indications due to inconsistencies in available data [26, 27, 28]. Clomid administration results in increases in total and free testosterone levels, along with elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol. Typically, patients experience an improved testosterone-to-estradiol ratio during treatment [29], highlighting Clomid’s efficacy in enhancing endogenous testosterone secretion through stimulation of the hypothalamic-pituitary-gonadal axis.
Clomid has demonstrated efficacy comparable to testosterone gels, achieving optimal male testosterone levels between 400–700 ng/dL [10, 14, 17]. Although testosterone injections may yield higher testosterone levels, this elevation is generally unnecessary for most clinical purposes [17]. Clomid offers distinct advantages over testosterone therapy, including lower cost, non-invasive administration, and fertility preservation.
Clinically administered doses of Clomid range from 25 mg every other day up to 100 mg daily [10]. It is advisable to initiate treatment at the lowest dose of 25 mg every other day, adjusting based on clinical responses and biochemical markers.
Research indicates improvement in Adult-onset Hypogonadism (ADAM) scores with Clomid treatment; however, approximately 10% of patients do not experience symptomatic relief [30]. These results should be interpreted cautiously due to the limitations of study designs and the absence of standardized questionnaires for assessing hypogonadal symptoms. Developing such standardized questionnaires would enhance the accuracy and reliability of symptom evaluations [31, 32].
Studies suggest Clomid treatment does not significantly alter PSA, lipid profiles, plasma glucose, or prolactin levels, and it has a markedly lower association with deep-vein thrombosis compared to testosterone therapy [21].
Conclusion
Clomiphene citrate effectively improves both clinical symptoms and serum testosterone levels in men with hypogonadism who possess an intact hypothalamic-pituitary-gonadal axis. Its favorable safety profile and ability to maintain fertility present significant advantages over testosterone replacement therapy. Lifelong administration of clomiphene citrate may be required to sustain clinical and biochemical benefits. Thus, Clomid represents a viable and potentially superior treatment option for symptomatic male hypogonadism, especially in fertility-focused cases.
