Male factor infertility accounts for approximately 50% of all infertility cases [1]. It is typically identified through abnormal semen analysis, and may also involve identifiable hormonal or anatomical etiologies that can be either reversible or irreversible. The majority of male factor infertility cases feature oligozoospermia (low sperm count), asthenozoospermia (poor sperm motility), and teratozoospermia (abnormal sperm morphology), often without an identifiable cause despite extensive diagnostic efforts [2]. This is known as idiopathic male infertility. The most commonly accepted cause of male infertility is now recognized as idiopathic oligoasthenozoospermia [3]. Affected men usually have no prior history of fertility issues and exhibit normal results in physical examinations and endocrine laboratory evaluations. Although assisted reproductive techniques have expanded the range of therapeutic options for male infertility, significant barriers remain in accessing these technologies. In addition to the high costs, there are concerns about the potential adverse effects of these procedures [4]. These persistent issues underscore the ongoing need to explore other treatment options that are not only less costly and more accessible but also non-invasive and simpler.

A variety of medications have been developed to improve sperm parameters and, consequently, enhance male fertility potential in these cases [5]. Anti-estrogens are the most commonly used treatment for idiopathic infertility. Clomiphene citrate, a racemic mixture comprising two isoforms—enclomiphene and zuclomiphene—is a non-steroidal anti-estrogenic drug and a selective estrogen receptor modulator. It functions by blocking negative feedback at the hypothalamus and pituitary levels [6]. This blockade indirectly promotes the excretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary [6]. Increased levels of LH and FSH promote testosterone production and spermatogenesis, respectively.

According to a survey by the American Urological Association, clomiphene citrate is one of the most commonly prescribed medications for idiopathic male infertility due to its safety and low cost [7]. Previous reviews have indicated that clomiphene therapy increases serum testosterone and gonadotropins; however, its positive effects on sperm parameters and pregnancy rates remain unconfirmed [8]. A Cochrane review conducted in 2000 on clomiphene and tamoxifen for idiopathic oligoasthenozoospermia found that while hormonal parameters improved in men, there was no significant change in pregnancy rates. This review, which included 10 randomized controlled trials (RCTs) with variations in treatment parameters, placebo use, and other factors, faced criticism. Consequently, it has been withdrawn and has not been updated for over a decade [9].

A more recent meta-analysis, which reviewed 11 RCTs, evaluated selective estrogen receptor modulators as empiric medical therapy in idiopathic male infertility characterized by oligo- and/or asthenozoospermia. This analysis reported an increase in pregnancy rates not observed in the previous Cochrane review [10]. The meta-analysis, encompassing 11 high-quality RCTs, provided a pooled estimate showing that estrogen antagonists (clomiphene and tamoxifen) were associated with a significantly increased pregnancy rate compared to controls, along with a significant improvement in sperm concentration and motility [11].

There were improvements in semen volume, sperm count, and sperm motility, but not in sperm morphology, with the clomiphene citrate treatment protocol compared to placebo in a recent prospective RCT involving 200 infertile men with idiopathic oligozoospermia [12]. Additionally, an increased pregnancy rate was observed in the female partners of the treatment group.

Clomiphene citrate is generally well tolerated by most patients. The more common side effects include gastrointestinal distress, dizziness, hair loss, gynecomastia, and minimal weight gain. Additionally, there is a 1.5% risk of visual disturbances, such as blurred vision, photophobia, and diplopia; however, these are reversible upon discontinuation of the medication [13,14].

Although diagnostic and therapeutic guidelines for male factor infertility are well-documented in the literature, consensus treatment pathways for off-label empirical medical therapies remain undefined. Given the limited number of studies conducted, further research is necessary to explore the medical management of male factor infertility. This prospective, randomized, placebo-controlled clinical trial was conducted to evaluate the impact of oral clomiphene citrate on sperm count and motility in infertile men diagnosed with idiopathic oligoasthenozoospermia over a 3-month period.

The RCT was conducted from July 2022 to December 2023 at the Department of Reproductive Endocrinology & Infertility, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. Ethical approval was granted by the Institutional Review Board of the Medical University (No. 4068). The trial has been registered with ClinicalTrials.gov (NCT06564961).

The study included infertile men diagnosed with idiopathic oligoasthenozoospermia, aged between 25 and 45 years. The diagnosis of idiopathic oligoasthenozoospermia was confirmed when serum FSH and LH levels ranged from 2 to 7 IU/mL and serum testosterone levels were above 300 ng/dL. The exclusion criteria encompassed azoospermia, a body mass index below 18 kg/m² or above 30 kg/m², any abnormalities found during genital examination or scrotal sonography, a history of genital diseases or surgeries, medical and endocrine disorders such as uncontrolled diabetes mellitus, severe kidney disease, and liver insufficiency, psycho-sexual abnormalities, use of antioxidant supplements in the previous 3 months, smoking, drug, alcohol, or substance abuse, a history of chemotherapy or radiotherapy, and the presence of any significant female factor abnormalities. Informed written consent was obtained from all participants after they were fully briefed on the purpose and procedures of the study.

The participants were randomized into two groups: the experimental group, which received 50 mg of clomiphene citrate (Tab. OVULET 50 mg, manufactured by Renata Pharmaceuticals Limited), one tablet daily for 3 months, and the placebo group, which received a placebo for the same duration in place of clomiphene citrate. Treatment commenced following the baseline visit. Participants were instructed to avoid taking any additional medications during the study unless they consulted with their physician. After 12 weeks of treatment, semen analysis and serum testosterone levels were measured. Participants were advised to engage in timed sexual intercourse and to perform a urinary pregnancy test if their partner missed a period.

Semen analysis was conducted using a Makler Counting Chamber. Abnormal semen parameters were identified based on the World Health Organization (WHO) reference values from 2010 [15]. These abnormalities were confirmed through a repeat semen analysis conducted 28 days later. The sperm count was measured in millions per milliliter of semen. The total sperm count represented the entire number of sperm in the ejaculate, calculated as the sperm count in million/mL multiplied by the semen volume in milliliters. Sperm motility was assessed as the percentage of sperm showing progressive and non-progressive movement. The total motile sperm count was determined by multiplying the sperm concentration by the total semen volume and the percentage of progressive motility. Oligozoospermia was defined as a sperm count of less than 15 million/mL, and severe oligozoospermia was defined when the sperm count was less than 5 million/mL.

Random sequence generation was conducted through permuted block randomization using computer-generated random numbers. Eligible men were randomized into either the clomiphene citrate group or the placebo group. Allocation concealment was achieved using serially numbered, closed opaque envelopes. Participants were blinded to the intervention, as a placebo was utilized.

The sample size was calculated to achieve 80% power with an alpha of 0.5, resulting in 21 participants per group, totaling 42. To account for a potential 10% dropout rate, the final sample size was set at 50, with 25 participants in each group. For statistical analysis, we utilized SPSS ver. 23 (IBM Co.). The paired sample t-test was employed to compare measurements before and after treatment, while the independent sample t-test (unpaired t-test) was used to compare the two treatment groups. The Mann-Whitney U test was applied to assess differences between two independent groups when the dependent variable was either ordinal or continuous but not normally distributed. A p-value of less than 0.05 was considered statistically significant.

This study was conducted in the Department of Reproductive Endocrinology and Infertility at BSMMU, spanning from July 2022 to December 2023. It included a total of 50 infertile men diagnosed with idiopathic oligoasthenozoospermia, all of whom met specific inclusion and exclusion criteria. The participants were divided into two groups: 25 received clomiphene citrate, and 25 were given a placebo. At the 12-week follow-up, one patient from the clomiphene citrate group and three from the placebo group had dropped out. Consequently, the final analysis included 46 participants—24 in the experimental group and 22 in the placebo group.

Table 1 demonstrates that the socio-demographic, clinical, and endocrine characteristics were comparable, showing no significant differences between the two groups. Table 2 indicates that in the clomiphene citrate group, there were significant increases in mean sperm count, progressive motility, and total motile sperm count post-treatment (p<0.05). Additionally, mean serum testosterone significantly increased post-treatment, with a mean difference of 433.97 ng/dL. Table 3 shows that in the placebo group, mean sperm count, progressive motility, and total motile sperm count decreased post-treatment; however, these differences were not statistically significant (p>0.05). Similarly, mean serum testosterone increased post-treatment, but this increase was not statistically significant (p>0.05). There were some changes in a negative direction; specifically, sperm count and motility decreased in some participants, contrary to expectations. This occurred in both groups.

Table 4 indicates that severe oligozoospermia post-treatment was significantly lower in the clomiphene citrate group compared to the placebo group (odds ratio, 0.31). Additionally, the incidence of normozoospermia was higher in the clomiphene citrate group than in the placebo group (odds ratio, 2.06). Table 5 demonstrates that the improvement in WHO sperm concentration was proportionally greater in the clomiphene citrate group than in the placebo group.

The minor side effects of clomiphene citrate, such as nausea and dizziness, subsided over time, and no participant required discontinuation of the drug.

The primary objective of this study was to observe the effect of clomiphene citrate on sperm parameters in infertile men diagnosed with idiopathic oligoasthenozoospermia. Treatment consisting of 50 mg of clomiphene citrate administered daily for 3 months significantly improved both sperm parameters and serum testosterone levels in these men, whereas no significant changes were observed in the placebo group. Clinical studies [12,16,17] and a meta-analysis [11] have examined the effect of clomiphene citrate on sperm parameters in infertile males with idiopathic oligoasthenozoospermia.

Our study observed a significant increase in sperm count after administering 50 mg of clomiphene citrate daily for 3 months. Similarly, Mandal et al. [12] reported a significant increase in sperm count following the administration of clomiphene citrate 25 mg/day for 25 days, followed by a 5-day rest period over 3 months. Thomas et al. [18] administered 50 mg of clomiphene citrate every other day for 3 months and also noted a significant increase in sperm count. Ghanem et al. [16] combined vitamin E (400 mg/day) with clomiphene citrate for 6 months and observed a significant rise in sperm concentration compared to a placebo. Micic and Dotlic [19] administered 50 mg of clomiphene citrate daily for 6 to 9 months and observed a significant change compared to no treatment. Post-treatment sperm counts in our study were 13.88±7.27 million/mL, compared to 25.6±8.89 million/mL [12], 8.2 million/mL [18], 18 million/mL (min-max, 1 to 60 million/mL) [16], and 16±2.14 million/mL [19] in different studies. Zaman et al. [17] administered 100 mg of clomiphene citrate 5 days a week, resulting in a significant increase in sperm count from 13.24 million/mL to 20.24 million/mL by the 74th day of the trial. The differences observed may be attributed to variations in the dosage and duration of clomiphene citrate treatment, or to additional drugs combined with clomiphene citrate. Our participants had idiopathic oligoasthenozoospermia with serum FSH levels ranging from 2 to 7 mIU/mL. Neither Mandal et al. [12] nor Ghanem et al. [16] specified FSH levels in their studies. Zaman et al. [17] reported a mean serum FSH of 5.73±3.09 mIU/L, while Micic and Dotlic [19] reported FSH levels between 5 and 15 mIU/mL. Jiang et al. [20] noted that changes in sperm count were associated with baseline gonadotropin levels, with greater increases in sperm concentration observed when FSH levels were below 7 mIU/mL.

Meta-analyses by Bridges et al. [13], Huijben et al. [21], and Chua et al. [11] reported increases in sperm count, supporting the findings of our study. In our study, the mean increase in sperm concentration was 4.71 million/mL. Bridges et al. [13] analyzed data from two RCTs and one prospective trial, encompassing a total of 197 oligospermic men. Of these, 115 men received 25 mg of clomiphene citrate at least every other day for a minimum of 3 months, while 82 men were in the placebo or no treatment group. There was a highly significant increase in mean sperm concentration of 7.7 million/mL after administering clomiphene citrate. Huijben et al. [21] included 15 studies in their meta-analysis, with a total of 731 participants. The study populations ranged from 11 to 140 participants, with doses of clomiphene citrate varying from 25–50 mg per day to 25–50 mg every other day. Chua et al. [11] included 11 RCTs of good methodological quality with 903 participants. The dosage of clomiphene citrate was 25 and 50 mg daily. Nine trials included a control group receiving a placebo, and the duration of the treatment period ranged from 3 to 12 months, with an average of 3 months of post-treatment follow-up. The mean increase in sperm count was 8.38 million/mL in the study by Huijben et al. [21] and 5.24 million/mL in the study by Chua et al. [11].

The present study demonstrated a significant improvement in progressive sperm motility among individuals treated with clomiphene citrate, with post-treatment progressive motility recorded at 21.42%. In comparison, other studies reported increases in post-treatment sperm motility to 53.8% [12], 42% [18], 34% [16], and 36.53% [19]. The mean difference in progressive motility observed with clomiphene citrate in this study was 6.75%, while meta-analyses reported differences of 8.14% [21] and 4.55% [11].

In our study, administering clomiphene citrate significantly increased serum testosterone levels, with a mean difference of 433.97 ng/dL post-treatment. This finding aligns with previous studies [12,18,20] and meta-analyses [11,21]. Similarly, Surbone et al. [22] observed a significant increase in plasma testosterone levels, from 9.1 to 20.2 nmol/L, after treating patients with low gonadotropin levels with 50 mg of clomiphene citrate daily for 1 month.

The results show that there was a decrease in sperm count and motility among some participants taking clomiphene citrate. A similar decrease was observed in those taking a placebo. Although clomiphene citrate has been used off-label to treat sub-fertile men for over six decades, paradoxical effects have been reported in only a few studies. Possible explanations for these findings include technical errors and intra-individual biological variability in sperm parameters [23]. In nearly 10% of cases with abnormal semen at the initial evaluation, a second analysis, conducted without any treatment, can reveal a normal sperm count. When the first semen analysis was abnormal, we repeated the analysis and included only those with consistently abnormal results in the study. Changes were still observed in the placebo group, which can be attributed to the normal variation in sperm parameters over time. The changes observed in the clomiphene citrate group should be attributed to the effects of clomiphene and its role in increasing serum testosterone [23].

The WHO sperm concentration categories are more clinically relevant. Recent studies have shown a new trend in the distribution and changes in these categories [20,24], which we analyzed in our study. Our findings indicated an upgrade in the WHO sperm concentration category (WHO-SCC) for 50% of patients, a downgrade for 8.3%, and no change for 41.7% of patients in the clomiphene citrate group. The change in WHO-SCC was significantly greater in those receiving clomiphene citrate compared to those given a placebo. Jiang et al. [20] reported improved sperm concentration categorization in 34% of cases, a worsening in 13%, and no change in 53% when administering clomiphene 25/50 mg daily for 3 months to infertile men with oligospermia and azoospermia. An upgrade in WHO-SCC represents a clinically meaningful endpoint that not only broadens the range of infertility treatment options, such as intrauterine insemination, but also potentially allows for trials of natural conception.

Regarding side effects, only two participants taking clomiphene citrate experienced nausea, and three reported dizziness. Mandal et al. [12] noted nausea, hypertension, and blurred vision in patients using clomiphene citrate.

The inability to conceive carries both social and psychological stigma. Often, the blame is placed on the female partner, while the male counterpart is overlooked, leading to delayed and costly treatments. Male factors account for approximately 50% of overall infertility cases. To facilitate fertility treatment for these men, low-cost oral treatment with clomiphene citrate may be considered for idiopathic oligoasthenozoospermia.

There are limitations to the study. It was conducted with a small sample size over a short period and involved participants recruited from a single center in Dhaka city. Consequently, the external validity of the study findings is limited. Estimating baseline gonadotropins (FSH and LH) and monitoring their changes over 3 months could help explore their relationship with changes in testosterone levels and sperm parameters. Additionally, changes in non-progressive motility and sperm morphology could be assessed.

In conclusion, clomiphene citrate, administered to infertile men with idiopathic oligoasthenozoospermia for 3 months, significantly improves sperm count and motility. Additionally, clomiphene citrate enables significant upgrades in the WHO sperm concentration categories when compared to a placebo.