Medical Therapy: Specific 

Introduction

Medical therapy for the treatment of male factor infertility may be employed when the following specific conditions are present: (1) endocrinopathies, such as hypogonadotropic hypogonadism, (2) leukocytospermia, with or without culture-documented infection, (3) immunologic infertility with antisperm antibodies, and (4) ejaculatory dysfunction. In addition, medical therapy may describe the optimization of lifestyle factors potentially controllable by the patient. While specific, treatable medical conditions comprise only a minority of causes of male subfertility, they represent an important subset because of our ability to potentially overcome their detrimental effects on reproduction.

GENERAL FACTORS

These factors are important to identify because they are under the direct control of the patient. While specific further treatments may not overcome their adverse effects, avoidance of continued exposure may improve sperm production and/or function.

Smoking

While the results of individual reports vary, cumulative evidence suggests that cigarette smoking can be a causal factor in male subfertility. Studies by Vine and Hughes have demonstrated decreased sperm density in smokers as compared with non-smokers. Elevated serum prolactin and estradiol levels have been noted in smokers, and both have been proposed as a contributing cause for the subfertility noted in this population.

Smoking has also been reported to exacerbate the effect of other causes of infertility, such as varicocele. Clearly, cessation of smoking is a simple, specific step that may enhance the fertility potential of the male patient.

Alcohol

The precise effect of alcohol consumption on male fertility is unclear. While chronic alcoholics can demonstrate testicular atrophy, diminished serum testosterone levels, and subfertility, moderate alcohol consumption has not been shown to deleteriously affect semen parameters.

Stress

The biochemical relationship between infertility and emotional stress is somewhat nebulous. Schenker et al. postulated that emotional stress may impair the function of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in gonadotrophic dysfunction. It is important for the urologist treating the subfertile male to realize that the stress of infertility itself may be particularly troublesome. Ragni and Caccamo noted a fivefold increase in the number of men with abnormal semen parameters 3 months after enrollment in an IVF program, suggesting that the emotional stress these men were experiencing had a negative impact on the quality of their semen. It is reasonable, therefore, to reduce emotional stress in the subfertile couple, especially through a team approach employing physicians, social workers, and psychologists.

Exercise

Endurance training at high levels, including running over 100 miles a week or bicycling more than 50 miles per week, has been demonstrated to result in diminished sperm concentration and motility. Moderation of endurance training is therefore a reasonable step in the management of the subfertile male.

Nutrition

Dietary derangements have been loosely linked to male subfertility. This is an untapped research area that needs to be explored thoroughly to identify which dietary factors play a role with the metabolic pathways involved with the development of normally functioning sperm. Suffice it to say, it is always appropriate to recommend a healthy diet to all of our patients, particularly those who may be substantially overweight. Excess fat in the body can act as a storage reservoir for estrogens in the male, thereby throwing off the normal testosterone/estradiol ratio, which may have subtle effects on sperm development and function. Excess fat also enhances the peripheral conversion of testosterone to estrogens by aromatization.

Hyperthermia

Early studies in the 1960s showed that the application of excessive heat to the testicles altered sperm density. Later studies have challenged that view. The boxer shorts versus "jockey shorts" theory is simply theoretical and unproven. There is no scientific evidence that there is a difference. Continuous exposure to high temperature levels, however, may affect the patient who is already borderline-low in some of his semen parameters, so it would seem prudent to discontinue the use of saunas, hot tubs, etc., in the subfertile male.

Occupational Gonadotoxins

A careful history eliciting any exposure to occupational gonadotoxins is mandatory, and minimization of exposure is essential in the treatment of the subfertile male. General categories of harmful toxin exposure include chemicals, radiation, or extreme heat. The U.S. Department of Health and Human Services has a publication available at no charge: Reproductive Hazards in the Workplace: Bibliography.

COITAL FACTORS

Improper timing of intercourse is the most common coital factor responsible for the infertile couple’s failure to conceive. Many couples do not understand the female cycle as to the ideal time for conception. Because sperm are viable for approximately 48 hours, and ovum for 12–24 hours, intercourse should be planned at least every other day for approximately 1-week prior to ovulation and for several days thereafter to maximize the chance of placing viable sperm in contact with the ovum in the fallopian tube during the egg’s period of viability as suggested by Wilcox. Precise prediction of ovulation may be accomplished via commercially available urine assay kits such as Ovuquick and ClearPlan-Easy that measure the preovulatory LH surge.

Artificial lubricants may result in a diminished motility and should not be used. One should also ask about the use of common vaginal lubricants, such as K-Y Jelly, petroleum jelly, saliva, skin lotions, and Astroglide, which all may have spermatotoxic effects. If lubricants must be used, light vegetable oils are the least spermatotoxic.

Erectile dysfunction needs to be evaluated and treated according to its etiology. From a psychological perspective, because difficulties with the initiation of a pregnancy are still traditionally considered a "woman’s problem," the diagnosis of a male factor abnormality may have a significant and unexpected impact on a man’s self-esteem and overall sense of manhood. A focus of increasingly more attention, studies of couples with a male factor subfertility disorder have clearly demonstrated higher anxiety levels, an increase in somatic symptomatology, periods of erectile dysfunction, and even feelings of rage by the wife towards the husband. Emotional issues of guilt and depression related to feelings of a loss of self-confidence, security, self-esteem, and health are commonly encountered and often result in erectile dysfunction. Organic erectile dysfunction may also be encountered, albeit less frequently in the reproductive age group. Treatments are focused on counseling and therapy for psychogenic etiologies, and noninvasive treatment options for organic erectile dysfunction.

Premature ejaculation is not uncommon in young men and only rarely is a cause for infertility if ejaculation occurs before vaginal penetration. Treatment is most successful using a combination of methods such as reconditioning, sexual therapy, and oral medications. Medications such as Prozac, Anafranil, Zoloft, fluoxetine, sertraline, paroxetine, and clomipramine have shown clear efficacy.

MEDICATIONS

Prescription drugs can impair fertility and, whenever possible, an equivalent medication should be substituted for one that causes infertility. The pharmaceuticals may be grouped according to the level at which they primarily affect spermatogenesis:

Chemotherapeutic agents are another important cause of infertility. Mechlorethamine, cyclophosphamide, chlorambucil, procarbazine, and nitrogen mustard have a particularly severe effect on the testis with relatively poor recoverability. In contrast, methotrexate has a minimal effect on the testis with excellent recoverability at 6–12 months. Pretreatment semen cryopreservation should be offered to young male cancer patients prior to initiating therapy. Recent animal studies by Meistrich have suggested a possible beneficial effect of LH-RH agonist pre-treatment in preserving spermatogenesis, but their role in humans is still a largely unanswered question.

Illicit drugs, including marijuana, cocaine, and heroin may also impair spermatogenesis or affect sperm motility. Their use must be eliminated in couples trying to establish a pregnancy.

ENDOCRINE DERANGEMENTS

Hypogonadotropic Hypogonadism

Although this condition is present in less than 1% of all infertile males, it represents a treatable form of male factor infertility. Hypogonodotropic hypogonadism may be congenital or acquired. Congenital forms include Prader-Willi syndrome (obesity, hypotonic musculature, mental retardation, small hands, feet, and stature) Laurence-Moon-Bardet-Biedl syndrome (retinitis pigmentosa, polydactyly, hypomentia), or Kallmann’s syndrome (delayed pubertal development, anosmia). Acquired etiologies include radiotherapy, pituitary adenoma, and pituitary infarct. Treatment depends upon the specific goals of therapy and may be summarized as follows:

Although series are small, a recent investigation by Nachtigall has shown that all five men with adult-onset hypogonadotropic hypogonadism had fertility restored with long-term therapy with GnRH alone. Fuse et al. have similarly demonstrated the efficacy of hCG alone or in combination with GnRH therapy in restoring fertility, especially if severe atrophy was not present.

Hyperprolactinemia

Elevated serum prolactin levels impair reproductive function via a negative influence on the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) and by disrupting LH binding to the Leydig cells in the testes. Causes of hyperprolactinemia include pituitary tumors, hypothyroidism, liver disease, and central nervous system acting drugs such as the phenothiazines and the tricyclic anti-depressants. Normally, the release of prolactin is inhibited by the catecholamine dopamine. Thus, the dopamine agonist bromocriptine may be administered to restore normal gonadal function in these patients. The usual dose is between 2.5–10 mg per day, usually given in two to four divided doses. While bromocriptine, introduced in 1971, is the reference preparation against which newer dopamine agonists are compared, up to 12% of patients cannot tolerate the drug at therapeutic dosages.

The newest medication used in the treatment of hyperprolactinemia is the long-acting dopamine agonist cabergoline, which requires administration only once or twice weekly. Ferrari et al. have shown that cabergoline at a median dose of 1 mg weekly is an effective and well-tolerated form of therapy for patients with a prolactin-secreting macroadenoma. Normalization of prolactin levels was achieved in 82% of newly treated patients.

In terms of its side effect profile, it is better tolerated than bromocriptine, particularly in terms of nausea and vomiting. In hyperprolactinemic men, hyperprolactinemic women not wishing to become pregnant, and for suppression of physiological lactation, cabergoline is recommended as first-line treatment. Lastly, quinagolide is a non-ergot dopamine agonist that is administered once daily. It has similar efficacy to bromocriptine, but is probably less effective than cabergoline in this regard.

Congenital Adrenal Hyperplasia

Although CAH usually presents in childhood, several cases of infertility secondary to CAH have been reported in adult men. The disorder is due to a deficiency in the enzyme 21-hydroxylase, resulting in decreased cortisol secretion and increased production of ACTH. Diagnosis in the normal, sexually mature male can be difficult and depends upon the demonstration of elevated levels of serum 17-hydroxyprogesterone and urinary pregnanetriol as well as a high index of suspicion. Infertility secondary to documented CAH is rare may be treated with corticosteroids.

Anabolic Steroid Abuse

Anabolic steroids act as male contraceptives and are becoming more widely abused by athletes. While little is known about anabolic steroid associated male infertility, this is a treatable form of drug related testicular failure. Turek and Lipshultz have reported on an azoospermic bodybuilder with a 5-year history of steroid use, who underwent successful gonadotropin replacement and conception 3 months after therapy was initiated. This particular patient’s sperm density, despite having markedly atrophic testes, around the time of conception was 26x10⁶ sperm/mL with 60% motility. After discontinuation of all anabolic steroids, a suggested regimen is hCG, 2000 units three times weekly for 4 weeks, followed by hCG, 3000 units three times weekly for 3 months, based on the gonadotropin and testosterone response. Tamoxifen (10 mg p.o. b.i.d.) may be used to minimize hCG-induced gynecomastia.

Hypothyroidism

Dubin and Amelar estimated that 0.6% of male infertility cases are due to hypothyroidism. Thyroxine replacement therapy generally restores fertility. Hyperthyroidism can also alter spermatogenesis and cause infertility. These conditions are usually obvious clinically, and screening of asymptomatic infertile males for thyroid dysfunction is not currently recommended.

PYOSPERMIA

Background

The significance of elevated concentrations of leukocytes within the semen is that their presence indicates infection or inflammation within the male reproductive tract. Based on the seminal leukocyte concentration, 10%–20% of male infertility patients may have leukocytospermia. White blood cells are deleterious because of their ability to stimulate the release of reactive oxygen species (ROS), thereby inhibiting sperm motility and sperm function. The World Health Organization (WHO), in its Laboratory Manual for Examination of Human Semen, states that concentrations greater than 1x10⁶ WBC/cc are considered elevated, and the ejaculate is termed leukocytospermic. However, despite an apparently abnormal threshold level for leukocytes within the semen, a wide range of conflicting evidence exists as to the significance of seminal leukocytes and infertility. Once suspected, appropriate leukocyte-specific testing, preferably with a monoclonal antibody technique, should be undertaken.

Evaluation

Using conventional sperm staining techniques, such as Papanicolaou or Giemsa, and the peroxidase stain, it is not possible to reliably differentiate between immature germ cells and leukocytes. Polynucleated spermatids can be confused with polymorphonuclear granulocytes (PMN) and, similarly, spermatocytes confused with lymphocytes and/or monocytes. At present, immunohistocytology using monoclonal antibodies is the current "gold standard" for the detection of all white blood cell populations in semen. However, drawbacks to the use of immunocytology are labor and cost.

We evaluate leukocytospermia by obtaining a semen culture and a urethral swab for Chlamydia, Ureaplasma, and Mycoplasma. Unfortunately, the yield of these diagnostic modalities is low. Wolff summarized the semen microbiology in 100 consecutive leukocytospermic ejaculates, and almost 80% of these samples were microbiologically negative. Thus, although it is important to exclude genitourinary pathogens by culture, leukocytospermia appears to be infrequently associated with a positive seminal culture. While many patients with pyospermia do not have documented infection, Yoshida et al. suggested that Chlamydia trachomatis, but not Ureaplasma urealyticum, infection as detected with in situ hybridization, in the male genital tract correlated well with evidence of inflammation. Evidence suggests that in the absence of urethritis, most inflammatory cells (granulocytes, lymphocytes, and macrophages) originate from the epididymis, prostate, and seminal vesicles. Clinically silent prostatitis and epididymitis may exist in men without overt symptoms. Certainly, if either of these conditions are suspected, a bacterial origin must be excluded.

Treatment

Specific genital tract infections should be identified and treated to prevent scarring to the seminiferous tubules and/or obstruction of the epididymis. The most common causes of epididymitis in males under the age of 35 are the sexually transmitted pathogens Chlamydia trachomatis and Neisseria gonorrhea. The treatment of choice for is Neisseria gonorrhea is ceftriaxone, 250 mg I.M. once, plus Doxycycline, 100 mg p.o. b.i.d. for 10 days. When Chlamydia trachomatis is present, Doxycycline, 100 mg p.o. b.i.d. for 10 days or Floxin 400 mg p.o. b.i.d. for 10 days should suffice. An alternative regimen for treating Chlamydia trachomatis is tetracycline, 500 mg p.o. q.i.d. for 10 days. Spectinomycin, 2 g I.M., may be used in patients who are allergic to cephalosporins, an erythromycin-based product, 500 mg p.o. q.i.d., may be given to patients who are allergic to or intolerant of tetracyclines.

Culture specific antimicrobial agents should be used if routine bacterial cultures indicate significant bacterial growth. Standard course of a fluoroquinolone or trimethoprim-sulfamethoxazole DS p.o. b.i.d. for 2–12 weeks should be adequate for most infections. Longer treatment courses when a chronic prostatitis is present result in higher eradication rates. Branigan et al. concluded that antibiotics combined with frequent ejaculation helped to provide durable responses at 3 months. Antimicrobial therapy may be used even when cultures are negative, although results are variable.

Sperm processing techniques (such as the swim-up, swim-down, sedimentation, and Sephadex gel filtration) and density gradients (such as Percoll) have been used to separate the seminal plasma from sperm as well as associated cellular contaminants from seminal plasma. In particular, two of these techniques — Percoll density gradients and Sephadex gel columns — are frequently used to recover a highly motile fraction of sperm.

antisperm antibodies

The presence of semen antisperm antibodies is often associated with impairments of sperm function. However, clearly, not all antisperm antibodies interfere with reproduction. The detrimental effect of antisperm antibodies on sperm function is related to impaired penetration of the zona pellucida of the oocyte and to decreased sperm motility, depending on the site of sperm binding. Because of scientific limitations regarding the identification and isolation of distinctly pathogenic sperm antigens, our present-day initial approach has been to treat the male with systemic corticosteroids in an effort to decrease antibody production. Admittedly, this approach remains quite controversial. Our regimen has been to use:

Prednisone: 20 mg p.o. q.d. weeks 1–3

10 mg p.o. q.d. week 4

The risks of mood changes, altered glucose metabolism, aggravation of peptic ulcers, acne, and aseptic necrosis of the hip need to be discussed with the patient. However, with a short course of therapy in typically healthy young men, the risks are small. A second monthly course of prednisone is administered to those who fail to demonstrate a decrease in the quantity of antibodies or an improvement in the semen analysis.

Large, placebo-controlled studies using corticosteroid therapy are lacking. Alexander et al. administered 60 mg of prednisone for 7 days and observed a decrease in antisperm antibodies and a pregnancy rate of 37% (7/19) versus 25% (3/12) in the placebo group. Similarly, Haas et al. found a pregnancy rate of 15% (3/20) with methylprednisolone 96 mg/day for 7 days, versus 7% (1/15) in the control.

Failure of corticosteroid therapy may lead to the recommendation of sperm washing techniques for intrauterine insemination (IUI). However, given only limited success in published series of IUIs in the presence of antisperm antibodies, proceeding directly to intracytoplasmic sperm injection (ICSI) with IVF may be most efficacious.

RETROGRADE EJACULATION

The backward propulsion of seminal fluid from the urethra into the bladder, or retrograde ejaculation, results from failure of the bladder neck to close during ejaculation. Any condition that disrupts the normal sympathetic innervation of the bladder neck, such as retroperitoneal lymph node dissection, diabetes mellitus, previous bladder neck surgery, or spinal cord injury, can cause retrograde ejaculation. Rarely, urethral stricture disease may also be responsible for retrograde ejaculation. Medications used to treat psychoses (e.g., haloperidol) as well as certain antihypertensive medications (e.g., phenoxybenzamine) can also result in retrograde ejaculation. The diagnosis of retrograde ejaculation is suggested by an abnormally low volume ejaculate, and is made by examination of the centrifuged postejaculatory urine specimen.

The strategy for treatment of retrograde ejaculation is the use of sympathomimetic agents orally to increase bladder neck tone. If a single agent is not successful, two agents may be combined. The following regimens may be used to treat this condition:

Pseudoephedrine, 60 mg q.i.d.

Phenylpropanolamine, 75 mg b.i.d.

Ephedrine, 25-50 mg q.i.d.

Imipramine, 25 mg t.i.d.

I generally start with ephedrine sulfate or pseudoephedrine to be taken starting 1 week prior to the wife’s expected day of ovulation and for 3 days beyond. Intermittent dosing seems to prevent the tachyphylaxis seen in continuous dosing.

Gilja et al. reported on 17 diabetic men who were treated with ephedrine or Imipramine (for ephedrine failures) during a 4-week period. Positive results were obtained in 5/17 (29.3%) patients, i.e., in 3 (17.6%) and 2 (11.7%) patients on ephedrine and Imipramine, respectively. In the group with retroperitoneal lymphadenectomy, after treatment with ephedrine, only 1 (12.5%) had retrograde ejaculation while the remaining patients (n=7) continued to lack semen emission. These 7 patients were treated with Imipramine, and 3 of them (42.8%) achieved anterograde ejaculation.

If these medications fail to reverse the condition, sperm may be harvested from the bladder for use in intrauterine insemination (IUI). Sperm function may be optimized by alkalinizing the urine with sodium bicarbonate, 650 mg q.i.d., for 1 day before and the day of sperm recovery, and by pre-washing the bladder with an appropriate buffered solution (BWW/Ham’s F-10/HTF or Ringer’s lactate) just prior to ejaculation.

REACTIVE OXYGEN SPECIES

Background

Reactive oxygen species (ROS) are a group of highly reactive oxygen radicals that possess the ability to damage aerobic cellular systems and consist of the superoxide anion (.O₂), the hydroxyl radical (OH), and the hypochlorite radical (OHCl). Because high levels of ROS have been identified in the semen of approximately 40% of infertile patients, they have been implicated as a cause of idiopathic infertility. This association is strengthened by the observation that ROS are not typically detectable in normal volunteers and azoospermic men under physiologic conditions. Elevated ROS levels have been associated with diverse causes of male infertility. In men with oligozoospermia and abnormal oocyte penetration rates, Aitken et al. have determined that 40% have abnormally high levels of ROS. Elevated ROS levels have been correlated with abnormal sperm concentration, motility, and morphology.

ROS are produced by sperm as a normal physiologic process and are important mediators of normal sperm function, capacitation, and the acrosome reaction. However, pathologic states associated with a positive oxidative stress are created when an increased production of ROS occurs, rather than a decreased degradation of the ROS species. It is likely that a significant amount of ROS-scavenging activity is provided by seminal plasma. The principal sources of ROS production are spermatozoa and leukocytes, which are capable of producing massive amounts of ROS. ROS species damage spermatozoa by attacking the sperm membrane and causing lipid peroxidation by a chain reaction mechanism.

Similarly, sperm washing techniques, especially those involving repeated centrifugation, can result in significantly higher ROS levels. When centrifugation speeds of 200-500g are used, ROS-negative specimens may become positive. More importantly, prolonged centrifugation time can increase ROS generation. The most effective techniques to minimize ROS generation appear to be Percoll washes and sperm swim-up methods.

Treatment

The clinical use of antioxidants in men with elevated ROS levels is an area of active investigation in its infancy. During sperm preparation for IUI or IVF, steps such as using an anti-oxidant supplemented culture media and removing contaminating leukocytes appear to be beneficial. The use of oral anti-oxidants such as alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) also have shown promise, but the number of placebo-controlled studies is limited. In a double-blind randomized placebo cross-over controlled trial using oral vitamin E or placebo for 3 months, Kessopoulou et al. determined that although semen analyses were unchanged, the zona binding test, a sperm function assay, was significantly improved with vitamin E administration.

Glutathione also has antioxidant activity by its actions as a free radical scavenger. In a 2 month placebo-controlled double-blind cross-over trial of 20 infertile patients with dysspermia associated with unilateral varicocele or germ-free genital tract inflammation, patients received either glutathione (group 1) or placebo (group 2) for 2 months, then crossed over to the alternative treatment for an additional 2 months. In this investigation, Lenzi et al. found that glutathione therapy demonstrated a statistically significant positive effect on sperm motility and on sperm morphology. The next several years should help determine whether the use of other anti-oxidants such as selenium and vitamin C have sustained and measurable effects on improving sperm function.

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