Semen Analysis

In a fertility context, the semen analysis forms the primary basis of assessment. It provides the clinician with a snapshot of the male’s fertility and reflects his general health in the preceding 72 to 76 days.

An individual’s semen quality can vary considerably between samples, even in males with normal semen parameters. In interpreting the assessment, it is imperative that the clinician acknowledge the important fact that a diagnosis is not achieved until an abnormality is confirmed by two separate investigations. As a result, at least two and occasionally three semen analyses are needed, each several weeks apart, in order to gain an accurate picture of an individual’s average semen quality. It is well recognized that sperm count can be adversely affected by illness, especially fevers, which may temporarily suppress sperm count in normal males for several months. In this case, the semen analysis should of course be delayed. Additionally, general recommendations such as in-clinic collection (versus at-home collection), careful consideration of laboratory guidelines (abstinence timing, lubricant usage), and the standard of the andrology laboratory facility must be considered in reviewing results. Table 180-2 outlines the World Health Organization’s (WHO’s) guidelines for assessing a semen analysis.

TABLE 180-2 Interpretation of Semen Analysis

SEMEN PARAMETER	LOWEST REFERENCE (REFERENCE RANGE)	INTERPRETATION AND TREATMENT OBJECTIVE
Standard Components of a Semen Analysis
Abstinence	Parameters are defined based on abstinence of 3 days.	It is essential to ensure that males ejaculate and then count the required 3 days’ abstinence.
Collection method	Optimal collection is via masturbation; however, specialized condoms can be provided for males with religious restrictions. Additionally, standard lubricants can interfere with the accuracy of the reading and must be avoided. Andrology laboratories are able to supply alternatives.
Specimen	Semen sample must be complete.	Incomplete samples are frequent and will distort readings. Assessment can be determined only by reviewing a full sample owing to variations in prostatic secretion vs. epididymal involvement.
Analysis time	Sample must be analyzed within 60 min and is best collected in the clinic environment to prevent complications.
Appearance	Nil debris, nil clumping, or viscosity changes, liquefaction complete.	Debris, clumping, viscosity, or liquefaction issues can suggest systemic congestion, poor hydration, poor elimination, or immune reactions (clumping especially). It can also indicate poor ejaculation frequency.
pH	>7.2 (7.2-7.8)	pH control is essential for sperm survival. An abnormally high or low semen pH can kill sperm or affect their ability to move or to penetrate an egg. The pH of the sample will be affected if there was a delay between sample collection and analysis. If the pH is <7.0 and the sample is azoospermic, there may be an obstruction of the ejaculatory ducts or bilateral congenital absence of the vas deferens (CBAVD). pH irregularities can relate to dietary intake and hydration level. Very acidic samples can indicate obstruction and require referral.
Volume	>1.5 mL (1.4-1.7 mL)	Volume can be affected by the period of abstinence (3 days are recommended), incomplete ejaculation, and retrograde ejaculation. It generally indicates dehydration; treatment should consist of hydration calculation based on weight and energy expenditure.
Concentration
Sperm concentration	> 15 million/mL (12-16 million/mL)	Concentration can be affected by a number of factors, including: • Incomplete collection of the sample • Health status of the individual • Obstruction • Genetic condition The finding of no sperm in the ejaculate suggests either an absence of sperm production or obstruction to sperm outflow. It is most important that an azoospermic semen sample be spun down to carefully examine whether the ejaculate contains even a few sperm. The naturopathic approach considers defects in internal processes and hormonal pathways as potential hindrances to an optimal count. Nutritional deficiencies are essential, and interferences with pathways for spermatogenesis require exploration.

Total sperm count >39 million per ejaculate (33-46 million per ejaculate) Motility Total motility 40% (38%-42%)
(>25% rapid, >40% progressive, >50% motile) Sperm must be able to move forward (or “swim”) through cervical mucus to reach an egg. A high percentage of sperm that cannot swim properly may impair a man’s ability to father a child.
There are other important conditions that predominantly affect sperm motility, such as sperm autoimmunity, a condition that accounts for about 6% of male infertility. No movement (immotile sperm) may be due to structural problems in the sperm’s tail or to death of sperm.
The percentage of sperm that are alive (sperm vitality) is noted because this declines in association with genital tract infections and disorders of sperm transport through the genital tract. The proportion of live sperm is assessed if total motility is <50%. Low motility and high vitality could indicate a disturbance of the motility apparatus. If >75% of sperm are dead, immobilizing antisperm antibodies might be present and testing is encouraged.
Poor motility can often indicate autoimmune processes; infection; lack of mitochondrial energy to propel the sperm; or medication, alcohol or other toxins that affect semen quality. Progressive rating >3 Progressive motility >32% (31%-34%) with forward movement Vitality >58% (55%-63%) live Morphology Sperm morphology 4% (3%-4%) normal forms (Tygerberg criteria)
Note: A trial wash can provide specificities of morphologic abnormalities (i.e., head, neck, tail). Sperm shape is an important predictive indicator of the sperm’s fertilizing ability. Morphology is performed on Pap-stained sperm using the Strict Tygerburg criteria of assessment. These criteria have a strong correlation with the presence of abnormalities and clinical pregnancies and accept only sperm that are normal in every way.
Morphology is often a direct reflection of generalized toxicity, because semen is a by-product of the body and is a major eliminatory channel. Detoxification, avoidance of environmental toxins, and immaculate dietary practices are essential. Key nutrients in sperm structure must be considered, including protein, essential fatty acids (DHA), all antioxidants including coenzyme Q10, zinc, vitamins C and E, and selenium. Teratozoospermia index (TZI) <1.64 TZI Specialized Additions to a Semen Analysis Immune factors Peroxidase-positive leukocytes <1.0 million/mL The presence of white blood cells or bacteria indicates the presence of a genitourinary infection.
Ascertaining the type of infection is the primary objective, with subsequent targeted treatment to eradicate it. It is essential to assess the female partner to prevent cross-infection. Semen culture Negative Mixed antiglobulin reaction (MAR) test (motile sperm with bound particles) <50% Antibodies attach to the surface of the sperm and reduce their life span, impairing their motility and ability to penetrate the partner’s cervical mucus. Antibodies located on the sperm head may prevent the sperm from fertilizing the egg.
Abstinence or a barrier method until the immune system is regulated is essential, along with concurrent autoimmune treatment with herbal medicines, dietary modifications, lifestyle modifications, and nutritional supplementation. Immunobead test (motile spermatozoa with bound beads) <50% sperm with adherent particles GAM or isotype >20% positive
>50% pathologically significant (except tail tip binding) Sperm DNA Damage SCIT (sperm chromatin integrity test) DNA Fragmentation Index (DFI):

High green stain (HG):

Scrotal Temperature

The scrotal sac normally keeps the testes at a temperature of between 94° F and 96° F. At temperatures above 96° F, sperm production is greatly inhibited or stopped completely. Typically, the mean scrotal temperature of infertile men is significantly higher than that of fertile men. A reduction in the scrotal temperature in infertile men is often enough to make them fertile. This is best achieved by having them avoid tight-fitting underwear, tight jeans, and hot tubs.

In addition, the following exercise or exercise equipment can raise scrotal temperature, especially if a man is wearing synthetic fabrics, exceptionally tight shorts, or tight bikini underwear: rowing machines, simulated cross-country ski machines, treadmills, and jogging. After exercising, a man should allow his testicles to hang free to allow them to recover from heat buildup.

Infertile men should wear boxer-type underwear and periodically apply a cold shower or ice to the scrotum. They can also choose to use a device called a testicular hypothermia device or “testicle cooler” to reduce scrotal temperatures. The testicle cooler looks like a jock strap from which long, thin tubes have been extended. The tubes are attached to a small fluid reservoir filled with cold water that attaches to a belt around the waist. The fluid reservoir is also a pump that causes the water to circulate. When the water reaches the surface of the scrotum, it evaporates and keeps the scrotum cool. Because of evaporation, the reservoir must be filled every 6 hours or so. It is recommended that the testicle cooler be worn daily during waking hours. Most users claim that it is fairly comfortable and easy to conceal.¹⁵

Increased scrotal temperature can be due to the presence of a varicocele. A large varicocele can lead to scrotal temperatures high enough to inhibit sperm production and motility. Surgical repair may be necessary, but scrotal cooling should be tried first.

Estrogen and Xenoestrogen Exposure

According to experts on the impact of the environment and diet on fetal development, we now live in an environment that can be viewed as “a virtual sea of estrogens.”^16,17 Increased exposure to environmental estrogens and other environmental pollutants during fetal development as well as during the reproductive years is suggested to be a major cause of the tremendous rise in the incidence of disorders of development and function of the male sexual system¹⁸ (see Box 180-1).

One can best view the relationship between estrogens and male sexual development by examining the effects of the synthetic estrogen diethylstilbestrol (DES). Between 1945 and 1971, several million women were treated with DES. By 1970, the side effects of DES became better known. DES is now recognized to have led to substantial increases in the number of men suffering from developmental problems of the reproductive tract as well as decreased semen volume and sperm count.¹⁶ Apart from having been used in humans, DES and other synthetic estrogens were used for 20 to 30 years in the livestock industry to fatten the animals and make them grow faster.

Although most synthetic estrogens like DES are now outlawed, many animals, both livestock and poultry, are still hormonally manipulated, especially dairy cows. Cow’s milk contains substantial amounts of estrogen because of modern farming techniques. The rise in dairy consumption since the 1940s inversely parallels the drop in sperm counts. Avoidance of hormone-fed animal products, including milk products, is important for male sexual vitality, especially in men with low sperm counts or low testosterone levels.

There are reports that estrogens have been detected in drinking water.^17,19 Presumably they are recycled from excreted synthetic estrogens (birth control pills) at water treatment plants. These estrogens may be harmful to male sexual vitality because they are more potent—they do not bind to sex hormone–binding globulin (SHBG). Purified or spring water may be a suitable option to prevent exposure. It is also important to ensure that bottled water is avoided owing to the bisphenol A content of plastic bottles.

Other sources of estrogen in the environment (food, water, and air) can weaken male sexual vitality. For example, many of the chemicals with which we have contaminated our environment in the past 50 years are weakly estrogenic. Most of these chemicals, like polychlorinated biphenyls (PCBs), dioxin, and dichlorodiphenyltrichloroethane (DDT), are resistant to biodegradation and are recycled in our environment until they find a safe haven in our bodies. For example, even though DDT has been banned for nearly 30 years, it is still often found in the soil and in root vegetables such as carrots and potatoes. These toxic chemicals are known to interfere with spermatogenesis, but their effects during sexual development may be even more important.

All of the estrogenic factors previously discussed are thought to have their greatest impact during fetal development. On the basis of animal studies, these estrogens inhibit multiplication of the Sertoli cells. The number of Sertoli cells is directly proportional to the number of sperm that can be produced, because each Sertoli cell can support only a fixed number of germ cells that will develop into sperm. Sertoli cell multiplication occurs primarily during fetal life and before puberty and is controlled by follicle-stimulating hormone (FSH). In animal studies, estrogens administered early in life have been found to inhibit FSH secretion, resulting in a reduced number of Sertoli cells and, in adult life, diminished sperm counts.

One example of the impairment of male sexual development by environmental estrogens is the ability of vinclozolin, a fungicide used in the wine industry, to disrupt the fertility of male rats.²⁰ Alarmingly, just one exposure of a pregnant female rat to this fungicide was found to disrupt spermatogenesis in more than 90% of the male offspring for at least four generations via an effect exclusively transmitted through the male germ line.

Environmental toxins are also linked to increasing testicular cancer rates, testicular dysgenesis syndrome (TDS), cryptorchidism, and hypospadias.^3,21 Whether the outcome is impaired spermatogenesis, TDS, testicular cancer, or any other disturbance may depend on the timing and nature of the xenobiotic attack and the genetic background on which these factors are acting. As such, a determination of the outcome will have to take into account the patient’s polymorphism profile for proteins involved in detoxification, such as the cytochrome P450s and glutathione-S-transferases. The bottom line is that the environmental impact on spermatogenesis cannot be underestimated. Industrial growth since the end of World War II has introduced many complex chemicals into the environment that are novel to biological detoxification systems. Some of these molecules are reproductive toxicants, capable of impairing fertility and inducing developmental abnormalities in the embryo, including errors in normal sexual differentiation.

The power of reproductive toxicants that target the germ line lies in their capacity to generate damage that can be passed down the generations via genetic or epigenetic means. A prime example is the effect of paternal smoking. Men who smoke heavily generate spermatozoa that may have high levels of DNA damage, largely as a result of oxidative stress. One of the consequences of this DNA damage is that the children of such men exhibit an increased incidence of childhood cancer.²² Although we have traditionally focused on the ability of cigarette smoke to induce lung cancer, a far more sinister effect is its ability to induce DNA damage in the germ line and thereby influence the health and well-being of future generations.

It is therefore advisable to discourage exposure to cigarette smoke in all male fertility patients and, in those with suspected heavy exposure, to initiate further investigations and specialized treatments to chelate and support detoxification.

Exposure Route

Environmental toxins may exert their genetic or epigenetic effects on the germ line via several potential routes of exposure:

For a full discussion of potential environmental effects, see Chapter 35, “Environmental Medicine.”

Assessment

It is advisable to thoroughly assess all presenting patients for exposure to environmental toxins and, depending on the results, to offer appropriate treatment. Specific areas to consider include the following:

It is best to recommend the avoidance of other exposures, such as those from renovation materials, cleaning products, personal toiletries, new furniture, new carpet or cabinets, plastics, gas, chemical gases, and many others. Organic, environmentally sound, sustainable practices are generally the safest.

For men who work in occupations that may affect fertility, it is important to wear protective clothing and follow all occupational health and safety guidelines.

Heavy Metals

Sperm are also particularly susceptible to the damaging effects of heavy metals such as lead, cadmium, arsenic, and mercury.¹⁸A hair mineral analysis for heavy metals should be performed on all men with reduced sperm counts to rule out heavy metals as a cause.

Radiation

Cell phones operate at 400- and 2000-MHz frequency bands and emit radiofrequency electromagnetic waves (EMWs).²³ Cordless phones must be considered in this context as well; these use the 900-MHz, 1.9-GHz, 2.4-GHz, and 5.8-GHz bands. Reports of potential adverse effects of radiofrequency EMWs on the brain, heart, endocrine system, and DNA in humans and animals are commonly found in the literature. Specifically from a fertility context, they have also been implicated in DNA strand breaks.²⁴ The relationship between cell phone use and male infertility remains unclear. Harmful EMWs emitted from cell phones may interfere with normal spermatogenesis and result in a significant decrease in sperm quality. Specific findings pertaining to sperm motility in humans have also been noted.^25,26

In one observational study,²⁷ the use of cell phones decreased semen quality by decreasing the sperm count as well as the sperms’ motility, viability, and normal morphology. This decrease in sperm parameters was dependent on the duration of daily exposure to cell phones and independent of initial semen quality. Of greatest importance was that sperm count, viability, and morphology declined as cell phone use increased. Specifically, use of the cell phone for more than 4 hours a day caused a 25% drop in the number of sperm produced, and only 20% of these looked normal.

It is therefore prudent to discourage cell phone use and recommend that male patients refrain as much as possible from storing cell phones in their pockets, owing to increased genital exposure to the frequency bands.

Cigarettes, Alcohol, and Illicit Drugs

Lifestyle exposures including cigarette smoke, alcohol, and caffeine have all been studied in relation to male reproductive health. Over the years the focus has primarily been on semen quality and/or fertility. More recently, the literature evaluating direct adverse effects of lifestyle exposures on sperm, chromosomes, and chromatin has grown owing to concern that induced damage could be transmitted to offspring, causing transgenerational health effects.

Obesity

Obese men are known to have lower sperm counts (up to 50%), reduced sperm motility, reduced spermatogenesis, increased DNA fragmentation in sperm, and increased levels of erectile dysfunction. Additionally, extra-abdominal weight can increase scrotal temperature. Hormonal changes are primarily responsible for such changes in obese men. The levels of total and free testosterone are reduced in obese men in proportion to the level of obesity. Estrogen is increased owing to the peripheral aromatization of androgens in adipose tissue. The estrogens produced have a negative feedback effect on gonadotropin production, thereby reducing FSH. This reduction in FSH further reduces testosterone production and spermatogenesis. Additionally, increased body fat and a sedentary lifestyle are associated with raised testicular temperature, which further adversely affects spermatogenesis.³⁶

Infections and Infertility

Infections in the male genitourinary tract—including infections of the epididymis, seminal vesicles, prostate, bladder, and urethra—are thought to play a major role in many cases of infertility.³⁷ The exact extent of this role is largely unknown because of the lack of suitable diagnostic criteria coupled with the asymptomatic nature of many infections. The presence of antisperm antibodies or high levels of debris in the semen sample are considered to be good indicators of chronic infection in the absence of other clinical findings.

A wide number of bacteria, viruses, and other organisms can infect the male genitourinary system. Table 180-6 offers a list of the more common potential causative agents.

Vitamin C

Vitamin C improves all semen parameters. A marginal deficiency causes oxidative damage to sperm, resulting in reduced sperm motility and viability. Supplementation leads to improvement in both viability and motility, reduced numbers of abnormal sperm, and reduced sperm agglutination.^47,48

The generation of ROS and associated links with infertility has been established and extensively studied. In particular, the effects of increased ROS in the serum, semen, and testicular tissues have been considered. Alterations in the testicular microenvironment and hemodynamics can increase the production of ROS and/or decrease local antioxidant capacity, resulting in the generation of excessive oxygen species.

Vitamin C (ascorbic acid), a major antioxidant present in extracellular fluid, is present at a high concentration in seminal fluid compared with blood plasma (364 vs. 40 mM) and is present in detectable amounts in sperm,⁴⁹ where it prevents sperm agglutination and oxidative damage. In infertile men, vitamin C has been found in reduced quantity in the seminal plasma.^50,51 Males with inadequate seminal vitamin C have also been observed to suffer from sperm DNA damage,⁵⁰ suggesting that a defect or inadequate intake of vitamin C may prompt ROS to cause breakage and oxidation of sperm DNA.

When dietary vitamin C was reduced from 250 to 5 mg/day in healthy human subjects, the ascorbic acid content in seminal fluid decreased by 50% and the number of sperm with damage to their DNA rose by 91%.⁵² These results indicate that dietary vitamin C plays a critical role in protecting against sperm damage and that low dietary vitamin C levels were likely to lead to infertility.

It is now well documented that cigarette smoking greatly reduces vitamin C levels throughout the body, and it is proved that smokers require at least twice as much vitamin C as nonsmokers. In one study, men who smoked one pack of cigarettes a day received either 0, 200, or 1000 mg of vitamin C. After 1 month, sperm quality improved in proportion to the level of vitamin C supplementation.⁵³ Nonsmokers appear to benefit from vitamin C as much as do smokers. In one study, 30 infertile but otherwise healthy men received either 200 or 1000 mg of vitamin C or placebo daily.⁵⁴ Sperm count, viability, motility, agglutination, abnormalities, and immaturity were measured weekly. After 1 week, the 1000-mg group demonstrated a 140% increase in sperm count, the 200-mg group a 112% increase, and the placebo group no change. After 3 weeks, both vitamin C groups continued to improve, with the 200-mg group catching up to the improvement of the 1000-mg group. One of the key improvements was observed in the number of agglutinated sperm. Sperm become agglutinated when antibodies produced by the immune system bind to them. Antibodies to sperm are often associated with chronic genitourinary tract or prostatic infection. When more than 25% of the sperm are agglutinated, fertility is very unlikely. At the beginning of the study all three groups had more than 25% agglutinated sperm. After 3 weeks, the proportion of agglutinated sperm in the vitamin C groups dropped to 11%. Although this result is significant, the most impressive result of the study was that at the end of 60 days, several men in both of the vitamin C groups had impregnated their wives, compared with none in the placebo group. Therefore, vitamin C supplementation can be very effective in treating male infertility, particularly if it is due to antibodies against sperm.

Vitamin E

Vitamin E supplementation appears to be especially warranted because this vitamin is the main antioxidant in various cell membranes, including those surrounding sperm. Free radicals, if left alone, lead to the peroxidation of phospholipids in the mitochondria of the sperm, making the sperm immotile. Vitamin E has been shown to play an essential role in inhibiting free radical damage to the unsaturated fatty acids of the sperm membrane⁵⁵ and in enhancing the ability of sperm to fertilize an egg in an IVF setting. Additionally, it has been shown to protect DNA within the sperm from damage.⁵⁶

In one study, supplementation with vitamin E was found to decrease malondialdehyde concentration in sperm pellet suspensions and to improve sperm motility. Even more important, however, 11 of 52 (21%) treated infertile men impregnated their spouses, whereas none in the placebo group did so. Following completion of the study, 26 of the placebo patients were switched to vitamin E; soon thereafter, 4 were able to successfully impregnate their spouses.⁵⁷ In another study, vitamin E (400 IU) and selenium (225 mcg) significantly improved sperm quality.⁵⁸ Supplementation appears to be indicated on the basis of its physiologic effects alone.

Supplementation with vitamin E may also be useful for couples undergoing IVF. Vitamin E (200 mg/day for at least 3 months) was found to improve the in vitro fertilization rate of fertile normospermic males with low fertilization rates after 1 month of treatment, possibly by reducing the lipid peroxidation potential.⁵⁹ Beneficial results have also been observed in patients undergoing ICSI, where vitamin E helps to prevent DNA fragmentation, thus improving ICSI outcomes.⁶⁰

Vitamin A, Beta-Carotene, and Lycopene

Vitamin A is an antioxidant required for cellular growth and differentiation, gene expression and cellular differentiation, immunity, regulatory functions, and epithelial tissue integrity. It is necessary for the health of the testes and for sperm production. Low concentrations of vitamin A are associated with abnormal semen parameters in men,⁶¹ and deprivation of vitamin A in animals has been shown to lead to a loss of spermatogenesis due to degeneration of the germ cells, which is restored once vitamin A is reintroduced.⁶²

Beta-carotene levels are significantly reduced in immune-infertile men. Intake is associated positively with a higher sperm concentration as well as higher quantities of motile sperm.⁶³ Lycopene may be even more useful than beta-carotene. Lycopene is found in high concentrations in the testes and seminal plasma, and reduced levels have been demonstrated in men with infertility. In one clinical trial, 30 men with idiopathic nonobstructive oligo/astheno/teratozoospermia were administered 2 mg of lycopene twice a day for 3 months. Twenty patients (66%) showed an improvement in sperm concentration, 16 (53%) had improved motility, and 14 (46%) showed improvement in sperm morphology. In patients showing an improvement, the median changes were 22 million/mL in concentration, 25% in motility, and 10% in morphology.⁵⁸

Selenium

Selenium is a critical antioxidant that is essential for male fertility because of its role in testosterone synthesis, normal sperm maturation, and motility⁶⁴; moreover, clinical trials reveal that selenium has the ability to increase sperm motility and assist in the production of healthy spermatozoa.⁶⁵ Selenium is also required structurally, because the sperm’s capsular selenoprotein is involved in the stability and motility of the mature sperm and also forms part of the glutathione peroxidase antioxidant system, which is vital for spermatogenesis and protects the sperm against the effects of ROS.⁶⁶ In animal studies, depletion of mitochondrial glutathione peroxidase has been found to cause impaired sperm quality and severe structural abnormalities in the midpiece of spermatozoa, leading to infertility.⁶⁷ The tail of the sperm relies on adequate selenium status to maintain its “whip-like” action. Without sufficient selenium, sperm are unable to swim in the right direction or may display marked immotility, thus preventing oocyte location and fusion.

The effects of selenium on sperm motility are highlighted in a study involving a subgroup of individuals with poorly motile sperm and subsequent subfertility.⁶⁸ Over a 3-month period, the administration of selenium (either on it its own or as a combination of antioxidants, including vitamins A, C, and E) to males led to increased sperm motility when compared with placebo. Five men (11%) achieved paternity in the treatment group, in contrast to none in the placebo group. This small study highlights the efficacy of selenium supplementation in subfertile men and suggests that improved selenium status can, in turn, improve sperm motility and the possibility of successful conception. Although this number may be seen as small, it was highly meaningful to those who were successful in conceiving—and all the more significant in terms of the cost and convenience of supplementation as compared with IVF or ICSI.

More recently selenium (200 mcg/day) in combination with the antioxidant n-acetyl-cysteine (600 mg/day) was found to improve semen parameters in idiopathic oligo-asthenoterato-spermiaplasma males in a double-blind placebo-controlled randomized study undertaken over 6.5 months.⁶⁹ Improvements in sperm count, motility, and morphology were all observed; however, once supplementation stopped, the parameters reverted back to their readings at baseline in two spermatogenesis cycles. This study did not include pregnancy rate.

Zinc

Zinc is perhaps the most important trace mineral for male sexual function and is found in high concentrations within the prostate and testes; particularly high amounts are also found in the semen (approximately 2.5 mg of zinc is lost per ejaculate). It is involved in virtually every aspect of male reproduction, including hormone metabolism, spermatogenesis, and sperm motility.⁷⁰

Zinc plays an important role in all human living cells; it is involved in the transcription of RNA, the replication of DNA, and the synthesis of protein, all of which are crucial for reproduction and fertility. Additionally, it protects against free radical damage and ROS, which can impair sperm.⁷¹ Deficiency of zinc in males can lead to gonadal dysfunction⁷⁰ and has been observed to be associated with idiopathic male infertility⁷¹ and impotence.

Zinc levels are typically much lower in infertile men with low sperm counts, indicating that a low zinc status may be the contributing factor to infertility.^72,73 It has also been shown that zinc status directly correlates with an increase in sperm count as well as improvements in morphology and motility.⁷⁴ In considering sperm structure, zinc has been shown to influence motility and the head-neck connection of the sperm⁷⁵; it is also important in the stabilization of cell membranes and sperm chromatin.⁷⁶ Finally, it has been shown to exert an antimicrobial effect on the seminal plasma, which is helpful if sperm antibodies or underlying genitourinary infection is present.⁷⁷

Several studies have evaluated the effect of zinc supplementation on sperm counts and motility.^78–81 The results of all of the studies support the use of zinc supplementation in the treatment of oligospermia, especially in the presence of low testosterone levels. The effectiveness of zinc is best illustrated by a study in 37 men with infertility of greater than 5 years’ duration whose sperm counts were less than 25 million/mL.²⁷ Blood testosterone levels were also measured. The men received a supplement of zinc sulfate (60 mg elemental zinc daily) for 45 to 50 days. In the 22 patients with initially low testosterone levels, the mean sperm count rose significantly from 8 to 20 million/mL. Testosterone levels also increased, and 9 of the 22 wives became pregnant during the study. This result is quite impressive, given the long-term nature of the infertility and the rapidity of the results. In contrast, in the 15 men who had normal testosterone levels before the study, sperm counts increased slightly, but there was no change in testosterone levels and no pregnancies occurred.

Optimal zinc levels must be attained if optimal male sexual vitality is desired. Zinc deficiency is increasing throughout the world and is dependent on the country’s soil content and on environmental legislation that prevents harmful farming practices. Additionally, owing to the negative effects of excess copper, it is advisable to check serum zinc and copper status. Where a deficiency state is diagnosed, it is important to ensure that a 1:1 ratio (or better) is achieved.

B Vitamins (Especially Folic Acid and vitamin B₁₂)

Folic acid and vitamin B₁₂ are concentrated within the head of the sperm and provide vital nutritional potential in sperm generation and survival. Folic acid and B₁₂ are required for healthy DNA and RNA synthesis, normal protein synthesis, and the regulation of gene expression.⁸⁰ These nutrients are required to ensure that the DNA within the head of the sperm is structured appropriately and that each sperm (and the DNA within it) replicates identically.

Both folic acid and B₁₂ facilitate spermatogenesis,⁸² which is reliant on DNA synthesis⁸⁰ for germ cell growth and the rapid division of cells. Multiple studies have found that low levels of folic acid in seminal plasma are associated with increased sperm DNA damage,⁸³ whereas B₁₂ deficiency is strongly associated with reduced sperm motility and count.⁸⁴ Because the human body has a high turnover of B₁₂ and requires a continuous supply on a daily basis, supplementation is advisable for all men experiencing infertility regardless of proved deficiency state and especially for men who have sperm counts below 20 million/mL or a motility rate of less than 50%. In one study, 27% of men with sperm counts less than 20 million/mL who were given 1000 mcg/day of B₁₂ were able to achieve a total sperm count in excess of 100 million/mL.⁸¹ In another study, 57% of men with low sperm counts who took 6000 mcg/day demonstrated improvements.⁸⁵

It is important to remember that it is advisable to refrain from prescribing one nutrient without the other owing to the possibility of inducing a rebound anemia. Where this occurs, disorders of homocysteine metabolism such as methylenetetrahydrofolate reductase (MTHFR) polymorphisms may present with count or morphologic issues.

Carnitine

Carnitine is derived from the amino acids lysine and/or methionine and plays a vital role in fatty acid metabolism. It works synergistically with coenzyme Q₁₀ (CoQ₁₀), highlighting the importance of coprescription for optimal benefit. It is essential in the transport of fatty acids into the mitochondria, and deficiency results in a decrease in fatty acid concentrations in the mitochondria and reduced energy production. It is believed to have protective antioxidant effects and provides energy to the testicles and spermatozoa specifically. Several studies comparing fertile with infertile men found that fertile men had a statistically significant larger amount of carnitine in their seminal sample than the infertile men, and that low levels of L-carnitine in the seminal plasma may be a potent marker for infertility.⁸⁶

Carnitine concentrations are extremely high in the epididymis and sperm, suggesting a role in male reproductive function. The epididymis derives the majority of its energy requirements from fatty acids, as do the sperm, during transport through the epididymis. After ejaculation, the motility of sperm correlates directly with carnitine content; the higher the carnitine content, the more motile the sperm. Conversely, when carnitine levels are low, sperm development, function, and motility are drastically reduced.⁴⁴

Several clinical studies have shown that carnitine supplementation can produce dramatic improvements in sperm counts and sperm motility. In the Italian Study Group on Carnitine and Male Infertility, 100 subjects were given 3000 mg of L-carnitine daily for 4 months.⁸⁷ Carnitine was able to increase sperm counts and sperm motility in both a qualitative and a quantitative manner, as follows:

These results are even more impressive if results for only the patients with the poorest sperm motility are examined. This subgroup saw even more significant gains on all parameters. For example, the percentage of motile sperm increased from 19.3% to 40.9%, and the percentage of sperm with rapid linear progression increased from 3.1% to 20.3%. These results have been confirmed in several double-blind studies.^88–92

Alpha Lipoic Acid

Alpha lipoic acid is a powerful antioxidant indicated for its lipid and water solubility and because it assists in the chelation of heavy metals regardless of their storage site in the body. It is especially useful owing to its ability to regenerate other antioxidants, including vitamins C and E, CoQ₁₀, and glutathione.⁹³

Alpha lipoic acid exhibits marked antioxidant activity to sperm in animal studies.^94–96 On review of research, it appears to act as a shield for the sperm, forming a protective barrier around the midpiece (aqueous layer) and within the structure itself (lipid layer). This protection is crucial, because it has been identified as one of the first places at which free radicals attack.⁹⁶ It is therefore useful to consider in patients with high DNA fragmentation levels. Additionally, animal studies reveal that alpha lipoic acid improves sperm motility and viability, minimizes DNA damage,⁹⁶ and protects against bacterial lipopolysaccharides, which can induce acute inflammation⁹⁷; it and may also assist with energy supply to the sperm.⁹⁶

Coenzyme Q₁₀

CoQ₁₀ is concentrated in the head and midpiece (neck) of the sperm. It is considered to be the most crucial and powerful antioxidant in sperm structure because of its role in mitochondrial energy release. It is believed to promote motility, foster sperm survival, and provide optimal energy to assist the sperm’s travel on its journey to the oocyte.

As a fat-soluble antioxidant and free radical scavenger, CoQ₁₀ is required for the maintenance of cell membrane integrity and cell functioning. It is also specific for the health of all new cells, especially spermatozoa. CoQ₁₀ in the seminal fluid and sperm⁹⁸ helps to maintain optimal sperm motility.^99,100 Decreased levels have been found in the seminal plasma and spermatozoa of males with idiopathic and varicocele-associated asthenospermia.¹⁰¹

L-Arginine

The amino acid arginine is required for the replication of cells, making it essential in sperm formation. Nitric oxide synthase uses L-arginine to synthesize nitric oxide, which can protect spermatozoa from lipid peroxidase damage. Via its role as a precursor to nitric oxide synthesis, arginine is required for angiogenesis, spermatogenesis, and hormone secretion.¹⁰²

Some studies have shown that L-arginine can improve sperm count and motility.^84,103 Stress, in particular, has been found to decrease the levels of arginine in sperm production pathways. Arginine supplementation is often but not always an effective treatment for male infertility. The critical determinant appears to be the level of oligospermia. If sperm counts are less than 20 million/mL, arginine supplementation is less likely to be of benefit. In order to be effective, the dose of L-arginine must be at least 4 g/day for 3 months. In perhaps the most favorable study, 74% of 178 men with low sperm counts had significant improvements in sperm counts and motility after arginine therapy.¹⁰⁴

One double-blind randomized placebo-controlled crossover clinical trial examined the effects of Prelox, a combination of 80 mg/day of pycnogenol and 3 g/day of L-arginine aspartate.¹⁰⁵ The results showed an improvement in semen parameters in 50 males with idiopathic infertility over a treatment period of 4 weeks. Also observed were significant increases in ejaculate volume, concentration, and number of spermatozoa as well as the percentage of vital spermatozoa as compared wih placebo. The percentage of spermatozoa with good progressing motility also increased significantly, whereas the percentage of immotile spermatozoa decreased. These results appear to be due to a combination of the antioxidant activity of Pycnogenol and/or the activity of L-arginine in stimulating the activity of endothelial NOS, leading to enhanced motility of spermatozoa. In a small pilot study, Pycnogenol (200 mg daily for 90 days) alone was shown to improve sperm morphology by 38% and the mannose receptor binding assay scores by 19%.¹⁰⁶

Panax ginseng (Korean ginseng)

Current scientific investigation suggests that Panax ginseng (Chinese or Korean ginseng) may be supportive in the treatment of male infertility. Both botanicals have a long history of use as male “tonics.” In studies with animals, Panax ginseng has been shown to improve the growth of the testes, raise sperm formation and testosterone levels, and increase sexual activity and mating behavior. It is classed as an energy tonic, indicated when there is lowered vitality and therefore impaired physical performance and sexual function. The active constituents (ginsenosides) have been shown to enhance nitric oxide production, which is useful in regulating the capacitating process of spermatozoa and the acrosome reaction, thus improving fertilization sperm motility.^107,108 Additionally, ginsenosodes have been shown to affect different levels of the hypothalamic-pituitary-testicular axis,¹⁰⁹ which can assist in modulating stress-induced infertility or lowered testosterone from insufficient DHEA synthesis. In clinical trials, Panax ginseng has been shown to increase testosterone levels as well as, sperm counts and motility in patients with oligospermia, some of whom had varicocele,¹⁰⁹ and to improve erection and libido.¹¹⁰ For additional information and references, see Chapter 110.

Pygeum africanum (Pygeum)

Pygeum africanum may be effective in improving fertility in cases where diminished prostatic secretion plays a significant role. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal fluid.^111–113 Specifically, Pygeum administration to men with decreased prostatic secretion has led to increased levels of total seminal fluid plus increases in alkaline phosphatase and protein content.

Pygeum appears to be most effective in men in whom alkaline phosphatase activity is reduced (i.e., <400 IU/cm³) and there is no evidence of inflammation or infection (i.e., absence of white blood cells and immunoglobulin A[IgA]). The lack of IgA in the semen is a good indicator of clinical success. In one study, the patients with no IgA in their semen demonstrated an increase in alkaline phosphatase from 265 to 485 IU/cm³.¹¹³ In contrast, those with IgA showed only a modest increase, from 213 to 281 IU/cm³.

Pygeum extract has also shown an ability, in a double-blind clinical trial, to improve the capacity of patients with benign prostatic hypertrophy (BPH) or prostatitis to achieve an erection, as determined by nocturnal penile tumescence.¹¹⁴ BPH and prostatitis are often associated with erectile dysfunction and other sexual disturbances. Presumably by alleviating the underlying condition, Pygeum can improve sexual function.

Tribulus terrestris

Tribulus terrestris has been used traditionally in Ayurvedic medicine as a tonic and aphrodisiac and in European folk medicine to increase sexual potency. Protodioscin, one of the steroidal saponins, is considered the chief constituent responsible for the herb’s effects on libido and sexual functioning. Of prime importance is correct sourcing of Tribulus to ensure its effectiveness. All of the data and clinical outcomes have been based on a leaf extract from Bulgaria, which has been shown to be highest in protodioscin. Therefore, if a Tribulus product is made from the root or fruit of the plant or is obtained from anywhere other than eastern Europe, it will probably contain low levels of protodioscin and therefore not be effective.

In animal studies, Tribulus has been shown to increase the levels of certain sex hormones including testosterone and also to improve nitric oxide synthesis¹¹⁵; however, these same results have not been observed in some human studies.¹¹⁶ One possible explanation is that there were differences in the extract and plant parts of the Tribulus used as well as the fact that many of the studies have comprised healthy males with normal testosterone levels rather than males with testosterone deficiency.

Tribulus appears to enhance male fertility through its ability to increase sperm count, viability, and libido; however, the published material is unclear, reporting studies that were poorly designed and and results that are not sufficiently definitive. A number of papers to support the extract product Tribestan highlight significant efficacy; however, owing to poor study design and lack of reliability, it is difficult to rely on these findings, which include increased ejaculate volume, sperm concentration, and motile sperm¹¹⁷ and improved conception rates.¹¹⁸

Astragalus membranaceous

In experimental studies, Astragalus membranaceus has been observed to increase the motility of sperm in semen.¹¹⁹ Studies show that Astragalus increases the motility of sperm in semen, but it also increases the motility of washed sperm, which is of special relevance to those seeking ART treatment.¹²⁰ Additionally, it has been shown to increase sperm motility and progression.¹²¹

Turnera diffusa (Damiana)

The traditional application of damiana was for “its positive aphrodisiac effects, acting energetically on the genito urinary organs of both genders where it was highly indicated for sexual weakness and debility,”¹²² and “its ability to act as a stimulant tonic of the sexual apparatus especially if there is enfeeblement of the central nervous system.”¹²³ Modern clinicians continue to prescribe damiana in this context and find it is especially beneficial when there is sexual debility, erectile difficulty, and depression. Human studies are lacking; however, a number of animal studies show promising supportive research. Turnera diffusa has been shown to facilitate the sexual behavior of male rats with sexual dysfunction, to reduce ejaculation latency,¹²⁴ to produce a restorative effect in sexually exhausted male rats, and to hasten their recovery.¹²⁵ It has also been observed to suppress aromatase activity, leading to the hypothesis that it may increase levels of testosterone.¹²⁶

Mucuna pruriens (Velvet Bean)

Velvet bean has been used in Ayurvedic medicine for endurance against stress, general resistance against infection, retardation of the aging process, and eventual improvement of male sexual function; it has been known to alleviate disorders including psychogenic impotence and unexplained infertility.¹²⁷ One paper showed that M. puriens seed powder produced dramatic improvements in 70% of study participants and helped fight stress-mediated poor semen quality; it has also acted as a restorative and invigorating tonic/aphrodisiac in infertile subjects.¹²⁸ The same researchers reporting these positive effects determined that they were achieved through the regulation of steroidogenesis and a resulting improvements in semen quality.¹²⁹ Specifically, this herbal treatment significantly improved testosterone, luteinizing hormone (LH), dopamine, adrenaline, and noradrenaline levels in infertile men and reduced levels of follicle stimulating hormone (FSH) and prolactin. Sperm count and motility were also significantly improved in infertile men.

Withania somnifera (Withania)

Withania has shown considerable antistress and adaptogenic effects. To investigate the effects of Withania on male fertility, 75 normal healthy fertile men (control subjects) and 75 men undergoing infertility screening participated in a 3-month clinical trial. The men in the Withania group received 5 g of the powdered root daily. Before and after the treatment, semen analysis, antioxidant vitamins, and serum sex hormone levels were determined. Results showed that Withania inhibited lipid peroxidation and improved sperm count and motility. Treatment also significantly increased serum testosterone and luteinizing hormone (LH) and reduced the levels of follicle stimulating hormone (FSH) and prolactin (PRL), all beneficial effects in infertile men.¹³⁰

Panax ginseng (Korean ginseng)

Pygeum africanum (Pygeum)

Tribulus terrestris (Tribulus)

Astragalus membranaceous (Astragalus)

Dosages to be administered one to three times a day are as follows:

Turnera diffusa (Damiana)

Mucuna pruriens (Velvet bean)

Withania somnifera (Withania)