Male Infertility

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Stephanya Shear and Jeanne O'Brien Epidemiology

Male infertility is the sole cause of 20% of couple infertility and contributes an additional 30% as a cause for combined couple infertility. Most men seeking infertility counseling and evaluation are referred through gynecologists or primary care physicians caring for the female partner. Thus, specialized knowledge or training about infertility is very important as is the ability to work closely with reproductive endocrinologists and gynecologic physicians. With the advancement of assisted reproductive technologies (ART) and microsurgical techniques, many men previously labeled as sterile are now capable of fathering children.

Physiology

Physiologically, male fertility requires good erectile function; spermatogenesis; normal endocrine function (specifically testosterone and FSH); and ejaculation. In addition, sexual intercourse timed appropriately to ovulation is an important key to conception.

Because of the anxiety and stress that is often associated with couple infertility, male patients often describe difficulty with erections. Obviously, if sexual intercourse is not occurring then conception is impossible! This information must be addressed specifically with the patient as he may not volunteer it. Erectile dysfunction secondary to various disease states including diabetes and atherosclerosis must also be elucidated. Any previous history of genitourinary cancers or pelvic surgeries that may have impaired erectile function should also be addressed.

Spermatogenesis has traditionally been described as requiring a 74 day cycle (recent studies have indicated it may actually be shorter than this time period). Any insult or intervention will usually require at least one spermatogenic cycle prior to seeing its effect.

Follicle stimulating hormone (FSH) and testosterone are imperative for normal spermiogenesis. When FSH is elevated it can be an indication that the testes are not producing sperm in normal amounts related to various causes including: testicular failure; genetic abnormalities, toxic exposures (including radiation, chemotherapy, and heat). The teaching used to be if FSH was elevated by at least twice the upper limit of normal, the probability of finding sperm even on testicular biopsy was almost zero. This has changed with the development of new microsurgical techniques, including microscopic testicular sperm extraction (micro TESE). Nonetheless, FSH levels are useful in counseling patients on potential outcomes of the infertility evaluation. If FSH is elevated (greater than twice normal) in a patient with severe oli-gospermia or azoospermia, the patient must be instructed that advanced reproductive techniques (ART) would most likely be required in order to have a biological child. If the patient is unwilling, financially or psychologically, to undergo ART, other options such as donor sperm insemination or adoption should be discussed. Testosterone, another crucial hormone, contributes to libido, erectile function, and sperm production. Obviously, intercourse must be timed to the periovulatory period. Sperm are able to live in the cervical mucus for an average of approximately 48 hours. Patients should be instructed to have sexual intercourse near the time of anticipated ovulation.

Differential Diagnosis

Differential diagnosis of the causes of male infertility may be broken down into three categories:

Pretesticular (endocrine) causes include:

• Pituitary disease: e.g., hypogonadotropic hypogonadism: low LH, FSH and testosterone levels; Kallman syndrome (associated anosmia); isolated FSH deficiency

• Congenital syndromes: Prader-Willi syndrome

• Elevated exogenous or endogenous androgen levels: anabolic steroid use, metabolic disorders or androgen secreting tumor

• Elevated estrogen levels: hepatic dysfunction (e.g., cirrhosis), estrogen secreting tumors, morbid obesity

• Elevated prolactin: pituitary prolactin secreting tumor, idiopathic hyperprolactinemia

• Elevated glucocorticoids

• Hyperthyroidism Testicular causes include:

• Genetic/karyotypic abnormalities

• Anatomic abnormalities: cryptorchidism (bilateral/unilateral); vanishing testes syndrome (bilateral anorchia—XY males with impalpable testes)

• Gonadotoxins: chemotherapy, radiation; cigarettes, marijuana, alcohol abuse, heavy metal exposure (lead, mercury), sulfa drugs

• Varicocele: Primary laboratory characteristic is combined finding of low mo-tility and low sperm count. Increased abnormal morphology secondary to a stress pattern may be seen as well. Varicoceles can be diagnosed in approximately 35% of infertile men on physical exam only. Varicoceles diagnosed with scrotal ultrasound are defined as subclinical and there is no proven benefit to surgical repair.

• Structural defects (structural sperm defects which prevent normal motility): immotile cilia syndrome; immotile viable sperm

• Orchitis: Post pubertal mumps, epididymo-orchitis, syphilis, gonorrhea, and leprosy

• Antisperm antibodies (testicular injury, previous vasectomy)

• Testicular cancer

• Idiopathic: occurs in as many as 25% of patients with abnormal semen analysis Post-Testicular causes include:

• Ductal obstruction (CBAVD, vasectomy, scarring from sexually transmitted diseases)

• Retrograde ejaculation (multiple sclerosis, diabetes, retroperitoneal lymph node dissection)

• Anejaculation (spinal cord injury, retroperitoneal lymph node dissection, diabetes)

Evaluation

History and Physical

The comprehensive history should include all past and current medical problems related to reproductive function. Men who have previously fathered children or a pregnancy with the same or different partner are said to have secondary infertility. Men who have never fathered a child are considered to have primary infertility. The length of time the couple has been attempting a pregnancy and the frequency of intercourse should be ascertained. The ideal frequency of intercourse is every day to every other day. Use of artificial lubricants, even water soluble or natural sources, should be discouraged as they may impair sperm motility.

Men should be asked about exposures to pesticides, chemicals, organic solvents, or heat (tanning booths, short order cooks, and foundry workers). Men who smoke tobacco or marijuana are at risk for infertility as these drugs decrease sperm concentration (oligospermia) and effect motility. Illicit drug and copious alcohol use can disrupt the hypothalamic-pituitary axis and adversely affect testicular function. Anabolic steroids can result in testicular atrophy and abnormal or absent spermio-genesis. Many medications can affect sperm concentrations and function including: prescription and over-the-counter medications, vitamin and protein supplements and herbal remedies. A list of pharmacological and environmental causes of infertility is given in Table 18.1.

The surgical history should include questions regarding a history of cryptorchid-ism (undescended testis) and patient's age at the time of repair. Cryptorchidism can cause oligospermia or even azoospermia, if bilateral. Correction of hypospadias, chordee or hernia should also be ascertained as well as any surgery on the bladder neck, urethra, rectum or pelvis. A history of urethral strictures and/or STDs may result in urethral and ductal obstruction causing reduced sperm counts. Men who have been treated for testicular cancer or Hodgkin's lymphoma may have reduced sperm counts related to their disease as well as treatments such as chemotherapy and radiation. Surgery for testicular cancer may include retroperitoneal lymph node dissections and this can injure the sympathetic nerves involved in ejaculation.

The review of systems should include questions regarding diabetes (partial or retrograde ejaculation), cystic fibrosis (CF)—pertinent positives include: history of pneumonia, recurrent sinusitis or bronchitis—(congenital absence of the vas defer-ens), multiple sclerosis (impaired ejaculation), and spinal cord injuries (erectile dysfunction). There are several rare conditions which impact fertility that can be

Table 18.1. Pharmacological and environmental causes of infertility

Diethylstilbesterol (DES)

Radiation

Testosterone

Chemotherapy

Ketoconazole

Heat

Nitrofurantoin

Pesticides

Calcium channel blockers

Lead

Cigarettes

Alcohol

Cocaine

Marijuana

Sulfa drugs

Solvents

uncovered during the review of systems. Recurrent respiratory infections can be associated with nonmotile sperm and may suggest primary ciliary dyskinesia (Kartagener's syndrome). Congenital anosmia (inability to smell) may be associated with Kallmann's syndrome—hypogonadotropic hypogonadism.

Emphasis is placed on a thorough genitourinary examination. The male patient should be examined in a warm room. Normal virilization should be noted. The presence of gynecomastia should prompt questions regarding marijuana use or an evaluation for a prolactin producing pituitary tumor. Normal testicular size is 20 cm3 and the testicle should be firm but not hard,not unlike the feel of a hard boiled egg. An orchidometer can be used to assess size or it can be approximated by measuring. A normal testicle is at least 2.5 x 3 x 4 cm. The epididymis and vas deferens should be palpated and any thickening should suggest the possibility of obstructive causes of infertility.

The spermatic cords should be examined in the upright position to evaluate the man for a varicocele-dilation of the spermatic pampiniform plexus. It is thought that varicoceles may impact sperm quality by increasing testicular temperature or perhaps by causing reflux of adrenal metabolites via incompetent veins. However, 15% of the general male population has a varicocele, and up to 45% of men with infertility present with a varicocele. Grading of varicoceles is based on physical exam alone though occasionally ultrasound may be used as a confirmatory study or if body habitus makes examination difficult. Absence of the vas deferens is found in 1-2% of all infertile men and 10% of men with low sperm counts. It can be unilateral or bilateral. It is often associated with other genitourinary abnormalities such as absence of the ipsilateral kidney or incomplete epididymis formation. Importantly, 80% of men with bilateral congenital absence of the vas (CBAVD) have at least one cystic fibrosis mutation. Men with CBAVD and their partners should undergo genetic testing and counseling regarding possible CF gene carrier status.

Laboratory Studies

All men undergoing infertility evaluation and counseling should have a semen analysis. Two samples should be given one week apart with two or three days of abstinence prior to the sample for optimal analysis. Masturbation without use of lubricants is preferred. Normal semen parameters, based on World Health Organization criteria, are given in Table 18.2. More than one abnormal parameter is common. If ejaculate volume is low, the man should give a urine sample within minutes of ejaculation to look for sperm in the urine after ejaculate collection errors are ruled out (spilled specimen, incomplete collection). If sperm are found in the urine and his history is not indicative of obstruction, the man is considered to have retrograde

Table 18.2. Classification of semen abnormalities*

Oligospermia

Azoospermia

Teratospermia

Asthenospermia

Leukocyto(Pyo)spermia

<20 million sperm/ml Absence of sperm in the ejaculate <30 % normal morphology <50% sperm motile >1 million/ml WBCs

*Based on WHO criteria.

ejaculation. Low sperm volume with no sperm in the post ejaculatory urine sample may be secondary to ejaculatory duct obstruction or ejaculatory duct absence. Both can be further evaluated by transrectal ultrasound.

A reduced sperm count, or oligospermia, is defined as an ejaculate with <20 million sperm per milliliter. Azoospermia is defined as the absence of sperm in the ejaculate. Men with either should undergo hormonal analysis to determine if the source of low sperm count is pretesticular—the hypothalamic-pituitary axis, testicular—primary testicular failure, or post testicular—obstruction or absence of the vasa. Treatment ultimately depends on the source: medical intervention for hypothalamic abnormalities, sperm cryopreservation for severe oligospermia with primary testicular failure versus surgical correction for post testicular obstruction.

Sperm should have tail movement regardless of motility. Asthenospermia or poor motility is most often seen in the setting of other semen abnormalities. Movement of the tails without progression may be secondary to presence of sperm antibodies or agglutination (clumping) of the sperm. If antibodies are present, couples have successfully had pregnancies after in vitro fertilization and intracytoplasmic sperm injection (ICSI).

Teratozospermia is the presence of a disproportionate concentration of morphologically abnormal sperm. According to the World Health Organization (WHO), 30% of the sperm should be classified as structurally normal. Others who advocate for more stringent histologic grading use strict criteria to examine the sperm head. Using the so-called strict criteria, only four percent of sperm are typically defined as normal. Morphologically abnormal sperm are less likely to fertilize an egg.

Pyospermia--white blood cells in the ejaculate is often treated with antibiotics though often without a documented source of infection. Patients are instructed to ejaculate frequently and a repeat semen analysis is completed after antibiotic treatment. There are various tests to analyze sperm function (such as electron microscopy for 0% motility) if the semen analysis appears normal. As a practical matter, these tests are not frequently performed as couples usually proceed to in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) if a functional problem is suspected.

Depending on the history, physical exam and semen analysis, a patient may require hormone analysis. Useful serum tests include FSH, LH, testosterone, and prolactin. Endocrine evaluation will often assist in distinguishing between pretesticular and testicular causes of infertility though endocrine causes of male infertility are fairly rare.

In clinical practice, the initial consult is sometimes performed without the required two semen analyses. Laboratory tests and sperm testing can be performed at a future date with follow up scheduled to review all results and formulate a possible treatment plan.

Radiologic Studies

If an abnormality is noted on the testicular exam, an ultrasound should be performed immediately to look for testicular masses consistent with cancer. Men with testicular cancer can have reduced sperm counts and will often present seeking consultation for infertility. Men with a low ejaculate volume and a negative post-ejaculatory urinalysis, normal testosterone and palpable vasa should undergo

transrectal ultrasound. Findings of dilated seminal vesicles (>1.5 cm in AP diameter) are suggestive of partial or complete obstruction. Patients with CBAVD may also have dilation of the seminal vesicles, but diagnosis of vasal agenesis is made by clinical examination alone and does not require ultrasound. Scrotal ultrasound is not indicated for nonpalpable varicocele as these are of little clinical significance.

Management

The results of the diagnostic evaluation will guide treatment. Pretesticular etiologies are differentiated by endocrine analysis, and the specific findings will determine the treatment. High testosterone, low FSH and LH are indicative of anabolic steroid use. Low FSH, LH, T and high prolactin are suggestive of a prolactin pituitary tumor and warrant MRI evaluation. These etiologies are generally treated with medications or patient counseling.

The most common cause of infertility is a varicocele. Clinically significant varicoceles are diagnosed by physical examination alone. Semen analysis and endocrine profile supplement the physical examination and aid the physician and the patient in determining whether surgical repair would be beneficial. Surgical management of varicocele includes microsurgical subinguinal varicocelectomy, laparoscopic ligation of the varicocele and radiologic embolization. Recent studies have indicated that varicoceles when repaired surgically may result in sperm in the ejaculate in 55% of azoospermic men though many of these men will require ART for successful pregnancy. Postoperative varicocele pregnancy rates can be as high as 40% for all grades of varicocele.

Intervention for obstruction of the vas deferens or the epididymis is reconstruction: either vasovasostomy or vasoepididymostomy. As noted above, transrectal ultrasound can support a diagnosis of seminal vesicle or ejaculatory duct obstruction if dilated seminal vesicles (>1.5 mL), ejaculatory duct cysts or prostatic utricular cysts are present. Obstruction from a prostatic utricular cyst or ejaculatory duct obstruction is treated with transurethral resection of the cyst or transurethral resection of the ejaculatory ducts, respectively.

Treatment of male infertility depends on the classification. Final treatment relies on diagnosis; however testicular causes, with the exception of a varicocele, are challenging to treat as they are often irreversible. Testicular biopsy is indicated when diagnosis cannot be made by physical exam, semen analysis, and endocrine profile. For example, azoospermic men with ductal obstruction will have normal hormone parameters and a normal testicular exam. Testicular causes of infertility are varied and may include cryptorchidism, viral orchitis, trauma, infections, obstruction, toxins and idiopathic etiologies. Men can attempt ART with sperm taken from the ejaculate, testicular extraction /biopsy or sperm aspiration from the epididymis even if the etiology of the infertility is idiopathic or is not amenable to surgical or medical correction.

Post Evaluation—Follow Up Care

All patients should have a follow up semen analysis three months after any treatment, whether it is a medical or surgical. If there is no change in seminal parameters within a designated period of time (usually one year for surgery, and 1-2 spermio-genesis cycles for medical therapy) the couple should be counseled regarding ART, donor sperm, and adoption.

Other Surgical and Medical Treatments for Infertility

Retrograde ejaculation—sympathomimetic medications (ephedrine, pseudoephe-drine). Urine can be alkalinized with oral sodium bicarbonate and the sperm separated and used for ART anejaculation in the spinal cord patient—electrostimulation to the glans penis or prostate/seminal vesicle. With the latter two, the patient must be pretreated with nifedipine and closely monitored for autonomic hypertensive dysreflexia. Urethral strictures—stricture ablation or reconstructive repair.

Key Points/Summary

• Male factor infertility can be caused by pretesticular, testicular and post testicular abnormalities. History, physical exam, endocrine analysis and radio-logic studies will guide diagnosis and treatment.

• A full examination for male infertility should include a complete medical and reproductive history, a physical exam by a urologist or male reproductive specialist and at least two semen analyses.

• An endocrine evaluation should be performed if there is an abnormal semen analysis, combined with impaired sexual function, and/ or physical exam findings suggestive of hormonal dysfunction.

• Men with an abnormal testicular exam should have an immediate scrotal ultrasound to look for testicular masses consistent with cancer.

Suggested Reading

1. Goldstein M. Surgical management of male infertility and other scrotal disorders. In: Walsh PC et al, eds. Campbell's Urology. Philadelphia: WB Saunders, 2002.

2. Sigman M, Jarow J. Male Infertility. In: Walsh PC et al, eds. Campbell's Urology. Philadelphia: WB Saunders, 2002.

3. Lipshultz LI et al. Infertility in the Male. Baltimore: Mosby, 1997.

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