The number of smokers has grown to include nearly one-third of the global population above the age of 15 years [2], despite growing evidence of the deleterious impact of smoking on nearly every organ in the human body. Smoking is associated with male subfertility [2]. Although the exact mechanisms through which smoking impacts male fertility are presently unknown, several theories have been proposed, a couple of which include the reduced delivery of oxygen to the testes that compromises the high metabolic requirements of spermatogenesis, and the oxidative stress conferred by several metabolites of cigarette smoke (tar, benzopyrene, carbon monoxide, aromatic hydrocarbons) [2, 4, 5].

In a large meta-analysis of 57 studies, Li et al. [6] reported that smoking is associated with deterioration of multiple semen parameters such as total sperm count, sperm volume, sperm density, sperm morphology, and progressive sperm motility, both in fertile and infertile men. These results were consistent with the results of another meta-analysis that demonstrated an association between smoking and a reduction in sperm density and sperm motility [7].

In addition to semen parameters, the detrimental impact of smoking on male infertility is compounded by its association with a reduction in seminal zinc (a key antioxidant) levels, sperm vitality, and sperm DNA integrity, and an increase in semen reactive oxygen species. A review of 160 fertile men concluded that fertile smokers showed a significantly higher sperm DNA fragmentation percentage and seminal reactive oxygen species levels, as well as a significantly lower progressive sperm motility, hypo-osmotic swelling test percentage, and seminal zinc levels compared to fertile nonsmokers [8]. Moreover, the quantity and duration of smoking were both positively correlated with sperm DNA fragmentation percentage and seminal reactive oxygen species, and negatively correlated with sperm motility, seminal zinc levels, sperm count, and the percentage of morphologically normal sperm. Furthermore, it has been shown that smoking for more than 10 years or greater than 20 cigarettes/day has a deleterious impact on sperm DNA integrity and nuclear maturation [9]. Sperm fertilizing capacity, as assessed by the zona-free hamster oocyte sperm penetration assay, has also been shown to be markedly reduced in smokers as compared to nonsmokers [10].

A clear understanding of the pathophysiologic mechanisms through which smoking negatively effects semen quality and male fertility notwithstanding, the current scientific literature strongly shows that it significantly impairs male reproductive potential.

In light of his long and heavy smoking history as presented in the aforementioned clinical vignette, Mr. PM should be advised to quit smoking, not just as a critical part of improving his fertility potential, but also because of its deleterious impact on other organ systems such as cardiovascular morbidity and tumorigenesis. He should also be counseled that the detrimental effects of smoking on semen quality have been shown to be reversible with smoking cessation. Santos et al. [11] showed that smoking cessation for 3 months led to an increase in sperm count (72 million vs. 29 million/ejaculate), sperm vitality (20% vs. 60% necrotized), sperm motility (79% vs. 33%), and the number of grade A spermatozoa recovered after swim-up (23 million vs. 3 million/ejaculate).

Alcohol has been shown to have a detrimental impact on male fertility at all levels of the male reproductive system [12]. It compromises the regulation of the hypothalamic–pituitary–testicular (HPT) axis, thereby resulting in a reduction of luteinizing hormone (LH) and follicle stimulating hormone (FSH) production [13, 14], and the subsequent impairment of spermatogenesis [15].

A study showed that only 12% of the men that consumed alcohol had normozoospermia, as compared to a control group of nonusers in whom the rate of normozoospermia was 37% [16]. Close et al. [17] analyzed the semen parameters of 164 men and concluded that the seminal fluid leukocyte concentration was significantly higher in chronic alcohol users as compared to nonusers. However, after controlling for a past history of sexually transmitted diseases and exposure to multiple substances of abuse, there was only a trend of higher leukocyte count in alcohol users. Consumption of more than eight alcoholic drinks per week has been shown to be associated with male subfertility, with the most common semen parameter anomaly of teratospermia [4]. Additionally, consuming more than 40 grams of alcohol per day showed an increase in spermatogenic disorders [18]. Not only chronic consumption, but even excessive acute alcoholic binges have been shown to be associated with worse semen parameters and an increase in the free estradiol/free testosterone (E2/T) ratio in a cross-sectional study including 347 men [19].

Despite multiple studies investigating the topic, the threshold of quantity at which alcohol consumption negatively affects semen parameters is not well defined. However, it can be inferred from the current scientific literature that consuming more than eight alcoholic drinks per week is detrimental to semen quality [4].

In our clinical vignette, the current average alcohol consumption of Mr. PM is 17–18 drinks—more than twice the upper limit of consumption that is detrimental to male fertility. He should be strongly counseled to reduce his alcohol intake to help restore his fertility.

There has been a 90% increase in the number of testosterone prescriptions and more than a threefold increase in the use of testosterone replacement therapy (TRT) in men over the past 15 years [20, 21]. In the USA, the rate of TRT has been rising since 2000, but has seen an especially steep increase since 2008 [20]. Furthermore, recent trends suggest that TRT is being prescribed to a significant number of men still in their reproductive years [22].

Exogenous testosterone decreases the levels of FSH, LH, and intratesticular testosterone and impairs spermatogenesis by suppressing the HPT axis [23]. This effect seems to be considerably stronger with intramuscular testosterone as compared to topical formulations [24]. One of the reasons for the high prevalence of testosterone use in infertile men of reproductive age despite its contraceptive effects is the misconception that it enhances fertility—a notion not just limited to patients, but a high percentage of urologists who have indicated that they would use testosterone for the empirical treatment of male infertility [24].

Since it can lead to the atrophy of germinal epithelium, exogenous testosterone may impair spermatogenesis and cause azoospermia within 10 weeks after initiation of TRT [25]. However, most men are able to regain the baseline spermatogenic function after cessation of TRT [26, 27]. The largest study on the topic that involved men receiving intramuscular TRT for a period of 30 months showed that the median time to recovery for baseline spermatogenesis prior to TRT was 6 months, with more than 99% of the men regaining their baseline spermatogenesis by 15 months [26]. Another integrated analysis of 30 studies evaluated the recovery of spermatogenesis after TRT used as hormonal male contraception, and showed that 90, 96, and 100% of men were producing sperm with a concentration ≥20 million/mL by 12 months, 16 months, and 24 months after TRT cessation, respectively [27]. The current scientific evidence clearly shows that most men of reproductive age receiving TRT for treatment of hypogonadism will experience the resolution of their azoospermia or severe oligospermia within 4–12 months after cessation of TRT [28].

Anabolic steroid abuse (without prescription) among men is another significant and underreported issue associated with male infertility, with a lifetime prevalence between 3.0 and 4.2% [1]. Similar to testosterone, anabolic steroids exert a negative feedback effect on the hypothalamus and pituitary glands, thereby suppressing the release of LH and FSH [29] and decreasing the production of endogenous testosterone and spermatogenesis. The deterioration of semen quality after anabolic steroid abuse mainly presents in the form of oligospermia, azoospermia, sperm dysmorphia, and dysmotility [30, 31]. However, most cases of anabolic steroid-induced infertility are also reversible, and usually resolve within 4–12 months after discontinuation of use [32].

Selective estrogen receptor modulators (SERMs) such as clomiphene and tamoxifen were the mainstay of treatment for male infertility before the advent of intracytoplasmic sperm injection (ICSI). The mechanism of action of both drugs relies upon their antagonistic activity that blocks the inhibitory feedback exerted by estrogen on the hypothalamus and anterior pituitary, thereby resulting in increased production of pituitary gonadotropins (FSH and LH) that stimulates spermatogenesis and production of testosterone by testes. Their favorable side effect profile, ease of administration, and low cost makes them viable treatment options.