Clomiphene citrate, an SERM, is a nonsteroidal antiestrogen drug that has empirically been used in the management of idiopathic oligospermia. The drug competes with estradiol for estrogen receptors in the hypothalamus and blocks the normal negative feedback of circulating estradiol on the hypothalamus [3, 4]. Under clomiphene therapy, the amplitude of GnRH pulses increases, stimulating the pituitary gland to produce more FSH and LH. As a result, testicular testosterone also increases [5, 6, 7, 8]. When used to treat male infertility, clomiphene is well tolerated with no identified serious adverse effects [9, 10, 11].
Few studies have investigated the relationship between clomiphene citrate use and the T/E ratio. Shabsigh  recruited 36 Caucasian men with hypogonadism, defined as having a serum testosterone level of < 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate. The serum levels of testosterone and estradiol were recorded at baseline and follow-up visits. By the first follow-up visit (at 4–6 weeks), the mean testosterone level had increased significantly (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). Thus, the T/E2 ratio of patients with hypogonadism increased after clomiphene use. No further research on clomiphene use and the testosterone ratio in eugonadal patients has been conducted, prompting the current study.
In our study, we observed a significant increase in the mean testosterone level, with an increase of 99.2% (P < 0.001). The mean estradiol level also increased significantly, with a rise of 80.8% (P < 0.001). These results are similar to those of patients with hypogonadism in the aforementioned study  who took clomiphene citrate. As for other hormone levels, the mean FSH and LH levels increased significantly after clomiphene treatment, with a rise of 101.3% (P = 0.002) and 123.1% (P < 0.001), respectively. Because clomiphene citrate competes with estradiol for estrogen receptors in the hypothalamus, it blocks the normal negative feedback of circulating estradiol in the hypothalamus. As a result, LH and FSH levels would increase, which is consistent with our results.
Regarding the T/E2 ratio, compared with the T/E2 ratio in the general male population, that of patients enrolled in our study was relatively low. Gong  enrolled 337 patients in a single center as the control group to study the correlation between the T/E2 ratio and cardiovascular events, revealing the normal range of the T/E2 ratio to be 0.19 ± 0.06. In our study, the mean baseline T/E2 ratio was 0.16 ± 0.09. When including all patients, we noted an increase of 6.25% in the ratio, but the difference was not significant. We obtained different results when setting an upper limit of the T/E2 ratio. The mean T/E2 ratio increased significantly (57.1%) after clomiphene use if only patients with a T/E2 ratio of < 0.10 were included. A significant increase in the T/E2 ratio after clomiphene use was also noted in those with a T/E2 ratio of < 0.20. After slightly increasing the upper limit to a T/E2 ratio of < 0.25, we still noted an increase of 33.3% in the T/E2 ratio; however, the difference was not significant. Therefore, we suggest ceiling effects for increasing the T/E2 ratio; in the current study, the ceiling effect was set at a T/E2 ratio of < 0.20. This result suggests that using clomiphene in infertile men with eugonadism whose T/E ratio is > 0.20 is not advisable.
This study has some limitations. Only 24 patients were included; thus, the sample was relatively small. Moreover, because this was a retrospective study, the exposure method could not be controlled, potentially resulting in variable clomiphene citrate dosage and frequency. Further investigation is required to confirm the T/E2 ratio change and sperm quality improvement after clomiphene citrate use in infertile men with eugonadism.