Background and rationale
Subfertility is a common problem around the globe, affecting one in six couples in Hong Kong. Male infertility is responsible for half of the infertility cases in general. Infertility is defined as failure to conceive after 1 year of regular intercourse [
1,
2]. Regarding semen quality, both sperm motility and concentration play important roles in achieving pregnancy. Among male infertile patients, there are less than 10% with congenital or genetic abnormalities and 20–30% with pathogenic statuses such as anti-sperm antigen, varicocele, or infection. The rest of the patients (30–50%) have idiopathic infertility (infertility for unknown reasons). This latter group of males presents with no adverse history affecting fertility and has normal anatomical and physiological structure and no endocrine or chromosome abnormalities. Among these males, more than 90% of their infertility cases are due to poor sperm motility, low sperm counts, or both [
3].
For those idiopathic infertility males who do not satisfy World Health Organization (WHO) semen parameters, these parameters are categorized with different causes, but the two most important parameters are motility and concentration. Recently, there are reports showing that combining the two parameters as total motile sperm (TMS) count is a better predictive tool for male fertility [
4,
5]. In contrast, there is no effective treatment for patients with idiopathic infertility/poor semen parameters.
In recent years, many new approaches have tried to delineate the etiology of idiopathic infertility, including using specific biomarkers, lifestyle analysis, body weight index, and “-omics” approaches, but the aim of developing a promising treatment remains unfulfilled. Testosterone replacement therapy once showed promise as an effective treatment for suboptimal semen quality even though few new testosterone formulations had been developed; however, the efficacies remain uncertain [
6]. For this untreatable situation, using traditional Chinese medicine (TCM) may serve as an effective strategy to improve sperm quality in men with suboptimal semen parameters.
Wuzi Yanzong (WZYZ) is a traditional Chinese herbal formula with a long history firstly recorded in a Chinese medical book named Standards for Syndromes and Treatments, written by physician Wang Ken-tang of the Ming Dynasty (A.D. 1368–1644). This traditional Chinese herb formula was well documented in ancient Chinese medical books for its effectiveness. The formula consists of at least five herbs, but there are many variations. The original five-herb form included Fructus Lycii, Semen Cuscutae Chinensis, Fructus Schisandrae Chinensis, Semen Plantaginis, and Fructus Rubi, and this herbal formula has the therapeutic function of tonifying the kidney and supplementing the body essence. In Chinese medicine practice, it is commonly used to treat many kidney deficiency-associated medical conditions such as impotence, infertility, seminal emission, premature ejaculation, low back pain, and urinary incontinence. It has been shown that administration of WZYZ pills can significantly elevate the semen volume and sperm density in infertility patients with low semen counts [
7,
8]. However, a large-scale and high-quality randomized placebo-controlled trial on the efficacy of WZYZ pills on semen quality and infertility has never been conducted. It is necessary to conduct a clinical trial to confirm whether WZYZ pills are efficacious in the treatment of patients with poor semen quality.
A recent meta-analysis showed that the WZYZ formula demonstrated a curative effect on male fertility. However, the heterogeneity of the studies did not allow one to draw a definitive conclusion on the therapeutic effect of this formula, mainly due to study problems such as small sample size, unknown randomization methods, bias in the placebo group, and a lack of details on the dosage of the herbal component used. There are no studies using a disclosed WZYZ formula and no double-blinded, randomized trials. An online database search revealed that a well-designed double-blinded, randomized clinical trial with a modest sample size is lacking. The WZYZ TCM formula may provide a good clinical solution for subfertile males for which contemporary western medicine has no cure. The rationale for conducting this randomized controlled trial (RCT) has been further discussed and published in our recent meta-analysis [
9].