Male Infertility
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&ot==Male Infertility== Robert D. Oates
Infertility affects approximately 15% of couples trying to conceive.This may be higher or lower depending on the age of the female partner because her fertility potential declines after the age of 35.Male factors contribute to at least 50% of cases of infertility.The traditional definition of infertility is the inability to conceive after 1 year of unprotected intercourse, but this time frame has been substantially shortened over the last several years as couples seek evaluation and treatment sooner and sooner.The fertility evaluation should begin as soon as the couple comes to medical attention.Couples may first seek help from their primary care physician when they become concerned about their inability to conceive.A basic history and physical examination may reveal an obvious cause for either partner, but a referral to a gynecologist or urologist is most appropriate, even at this point.However, the primary care physician may play a critical role in predicting a possible problem with fertility or in preventing future difficulties.
This chapter reviews the most common etiologies of male infertility and provides a list of physical examination findings that may be detected by the primary care physician.Infertility is a “couple” issue, and both partners should be evaluated, even if a dramatic finding (anovulation, azoospermia) is discovered early.
[edit] EPIDEMIOLOGY OF MALE REPRODUCTIVE DYSFUNCTION
Primary infertility is the inability to conceive for the first time within 12 months.However, many couples become concerned after just a few months and initiate conversations with the primary care physician or gynecologist.For many, there are no real limitations to achieving pregnancy.For others, a prior history (e.g., chemotherapy), a present problem (e.g., anovulation), or a female age issue (age >38 years) may be of concern.These types of issues justify an early evaluation because patients are often on target and their chances of natural conception are indeed low.Today, many couples are delaying childbearing, and a woman's fertility potential begins to decline after age 35, with a more precipitous slope after age 38 to 39.
[edit] BASIC ANATOMY AND PHYSIOLOGY OF THE MALE REPRODUCTIVE SYSTEM
The finely tuned interplay of the spermatogenic axis and the androgenic axis is crucial to maximal sperm production.Spermatogenesis occurs in the millions of seminiferous tubules that make up the bulk of the testicular parenchyma.As mature sperm are released into the tubule lumen, they travel to the intratesticular rete testis, a series of widened tubules in the mediastinum of the testis.The rete testis gives rise to six to eight efferent ductules that exit the testis to form the head (caput) of the epididymis.Here the efferent ducts merge to form one continuous epididymal tubule, which is highly coiled and serpentine as it makes up the body (corpus) and the tail (cauda) of the epididymis.The epididymis is not a storage organ for sperm, since the spermatozoa generally make the complete journey in just a few days.[1] The epididymal tubule thickens and develops more of a muscularis as it becomes the convoluted portion of the vas deferens.The vas straightens out in the scrotal portion as it enters the external ring and emerges through the internal ring and then takes a course down, posterior to the base of the bladder.There, it becomes even wider and corkscrew in shape at the ampullary region.The seminal vesicle joins the vas on its lateral aspect to create the ejaculatory duct just outside the capsule of the prostate.The ejaculatory duct pierces the substance of the prostate, traversing the parenchyma obliquely to open into the urethra at the verumontanum.
The process of ejaculation is a complex neurologic eventconsisting of two distinct but integrated phases (Fig.150-1).Emission is a sympathetically mediated contraction of the seminal vesicles, vasal ampullae, and prostate that delivers the various seminal fluid components into the prostatic urethra.Simultaneously, the bladder neck closes, a process controlled by these same sympathetic fibers.This prevents the ejaculate bolus from flowing backward into the bladder.Periurethral musculature contraction is the next phase of the ejaculatory event and propels the fluid contained within the prostatic urethra in an antegrade direction.The rhythmic contraction of this musculature is controlled through somatic efferents emanating from S2-S4 and traveling with the pudendal nerve.The sympathetic outflow originates from spinal segments T10-T12.Within the cord (T12-L1) exists an ejaculation reflex center that coordinates and temporally integrates the ejaculatory event.Any interruption of the sympathetic fibers, as may occur during pelvic surgery, an anterior approach to thoracolumbar disk disease, or a retroperitoneal lymph node dissection, may impair emission, bladder neck closure, or both processes.This may result in complete failure of emission (a dry ejaculate) or retrograde seminal fluid flow.The sensation of orgasm is intact, but no ejaculate is visible to the patient.Spinal cord injury above the sympathetic outflow and reflex center disrupts any augmentation that may arise in the cerebral cortex from visual, auditory, or conceptual stimuli.
The hypothalamus releases gonadotropin-releasing hormone (GnRH), which stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary (Fig.150-2).LH stimulates intratesticular Leydig cells to produce testosterone that feeds back negatively on the hypothalamus and pituitary to regulate the secretion of LH.Exogenous androgenic compounds (e.g., anabolic steroids) suppress LH secretion and consequently shut down intratesticular testosterone production, which is necessary for spermatogenesis to occur.This is why most men taking illegal anabolic steroids are azoospermic.FSH acts directly on Sertoli cells to stimulate spermatogenesis.Inhibin is released from Sertoli cells to negatively regulate FSH secretion.As spermatogenic ability declines, inhibin levels drop, and FSH output increases.There is no defined cut-off for FSH values below which spermatogenesis is normal and above which it is abnormal.It is a gradual rise, correlated with spermatogenic capability.The “normal” range of FSH, as documented by the manufacturer of the assay machine being used, is really not relevant in clinical practice because the FSH concentration rises steadily as spermatogenesis declines.However, there is no strict correlation.In an azoospermic patient with primary spermatogenic failure, the FSH value is higher than that seen in men with completely adequate sperm production but does not need to be two to three times the upper limit of the assay range.Measurement of FSH, LH, and testosterone levels needs to be performed only in the azoospermic or severely oligospermic patient and has no influence on the diagnostic impressions or therapeutic decisions in a patient with aslightly low count or somewhat impaired motility (mild to moderate oligoasthenospermia).
Spermatogenesis is a complex, highly ordered process with three goals (Fig.150-3).The first is the reduction in the number of chromosomes from a diploid (2n) complement to a haploid (1n) state.When fertilization occurs, the haploid sperm pronucleus joins with the female pronucleus, recreating a diploid chromosomal constitution.The second purpose of spermatogenesis is to allow recombination events to occur between homologous chromosomes, which leads to diversification of the genome, an evolutionary advantage.These first two processes are inherent features of the meiotic process that drives the alteration of spermatogonia to spermatids.The final goal of the spermatogenic cell cycle is accomplished in spermiogenesis, in which profound morphologic changes create a functional spermatozoan, the vehicle that delivers the genetic material to and breaks through the barriers of the waiting oocyte.
[edit] MALE REPRODUCTIVE HISTORY
It is important to review with the couple the elements of the menstrual cycle, proper coital timing, and the necessity of a concomitant female evaluation.Many men and women have poor knowledge of reproductive anatomy and physiology.Education may be all that is required to help them achieve pregnancy.There is no optimal frequency of intercourse; it may occur every day or every other day.Ideally, sperm should be in the female reproductive tract at the time of ovulation because the oocyte is viable for only a short time.Couples who wait until they believe ovulation has occurred may be missing their “window” of opportunity.Ovulation-predictor kits may be used to more precisely pinpoint when ovulation will occur.
[edit] Pediatric Issues (Box 150-1)
Cryptorchidism may be found in up to 9% of men seeking care for infertility.A history of bilateral cryptorchidism puts men at significant risk of severe oligospermia or azoospermia.Most men with unilateral cryptorchidism have sperm in the ejaculate, but their natural fertility rate may be reduced compared to those without such a history.
| Box 150-1 - Etiology of Male Reproductive Dysfunction: Pediatric |
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Hernias and hydroceles in infancy may be associated with testicular maldescent.Therefore hernia and hydrocele repairs, along with orchidopexy, may have been performed, even though the patient is not aware of it.Vasal injury at the level of the internal ring may be a consequence of infant hernia repair and may be the cause of unilateral or bilateral vasal occlusion.
Male patients with cystic fibrosis (CF) are born without vasa deferentia and are azoospermic.Congenital bilateral absence of the vas deferens (CBAVD) is a milder phenotype of CF.
Hypospadias of significant degree may impair the delivery of semen.After the repair of hypospadias, male patients may have strictured areas that impede the force of seminal fluid release, again potentially inhibiting seminal fluid and thus sperm contact with the cervical mucus.Testicular torsion that is not surgically corrected in time leads to loss of that testis and functional compromise of the remaining testis as a result of unexplained immunologic effects.Other rare conditions of development can interrupt the ejaculatory process or cause spermatogenic compromise (e.g., bladder exstrophy, prune-belly syndrome).Any malignancy that is treated with chemotherapy may lead to permanent spermatogenic damage.
[edit] Adult Issues
Any neurologic disturbance may impair ejaculatory function (Box 150-2).This may be at the level of the spinal cord (traumatic injury, transverse myelitis, myelodysplasia) or the peripheral neuroanatomy (retroperitoneal surgery disrupting the afferent sympathetic fibers or the autonomic dystrophy consequent to diabetes mellitus).With a malignancy that involves the testis (germ cell tumor) or the prostate or bladder, posttreatment functional and anatomic problems can interfere with ejaculation or sperm production.Chemotherapy acutely suppresses spermatogenesis and may also have significant long-term effects, even to the point of producing permanent azoospermia.The final outcome depends not only on the inherent spermatogenic ability of the individual but also on the exact chemotherapeutic regimen used.Radiotherapy to the pelvic area also has an immediate effect, although long-term consequences are typically not as severe.
| Box 150-2 - Etiology of Male Reproductive Dysfunction: Ejaculatory Disrupters |
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Toxin exposure may lead to the suppression of spermatogenesis (Box 150-3).Cigarette smoking should be discontinued to reduce any possible detrimental effects on the sperm count, motility, and fertilizing ability.Excessive alcohol should be avoided.Marijuana use may lead to alterations in the hormonal axis as well as impaired fertilization.The possible consequences on human spermatogenesis of most medications have not been well explored or investigated.Drugs such as azulfidine and colchicine are known spermatotoxins, and with other pharmaceuticals, there may be ill effects that have not yet been fully realized.If a patient can safely be taken off a medication, then it makes sense to discontinue that medication in case it is having a subtle effect on sperm production or function.
| Box 150-3 - Etiology of Male Reproductive Dysfunction: Adult Toxin Exposure |
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Anabolic steroid use is becoming an epidemic among high school and college athletes.Any exogenous testosterone or derivative feeds back on the hypothalamus and pituitary and suppresses the secretion of LH and FSH, thereby inhibiting the intratesticular testosterone production required for spermatogenesis.These men are severely oligospermic or azoospermic.An occupational history may elicit exposure to chemicals that can impair sperm production.The patient should be counseled to take all precautions recommended by the Occupational Safety and Health Administration (OSHA).Other problems such as epididymitis (possible epididymal tubule occlusion) or prostatitis (possible ejaculatory duct cyst) may be revealed in the genitourinary history.All of the information must be integrated with the semen analysis, physical examination, and simultaneous female evaluation.
Genetic syndromes can have male factor infertility as a part of their phenotypic spectrum (Box 150-4).For example, males with myotonic dystrophy often have reduced spermatogenesis for an unknown reason.Males with CF have bilateral vasal agenesis.Men with Klinefelter's syndrome typically possess markedly impaired spermatogenesis and a compromised androgenic axis.The immotile cilia syndrome may be first recognized because of the respiratory illness often associated with this diagnosis; as the ciliated cells of the lower and upper airway system are paralyzed, so are the sper matozoa, and infertility is the rule.These and other genetic disorders are discussed in later sections.
| Box 150-4 - Etiology of Male Reproductive Dysfunction: Genetic Disorders |
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[edit] MALE REPRODUCTIVE PHYSICAL EXAMINATION
As in all disease processes, the physical examination may reveal the reason for infertility or may predict male reproductive dysfunction (Box 150-5).The general appearance ofthe individual is important, since profound obesity may affect spermatogenesis.The patient may be undervirilized with poor beard growth and minimal muscular development, potentially indicating conditions such as Kallmann's or Klinefelter's syndrome.Gynecomastia may be seen when the testosterone/estradiol ratio deviates from the norm.The penis should be examined carefully for hypospadias or phimosis.The testes should be oblong and measure approximately 3.5 by 2.5 cm.Their consistency should be slightly firm.Decreased testis size and consistency are signs of depressed spermatogenic ability because most of the bulk of the testis consists of the spermatogenic epithelium within the seminiferous tubules.The vasa deferentia are easily palpable in most men.Their presence must be documented, especially in the azoospermic man in whom congenital vasal aplasia is a distinct possibility.Only the caput and cauda epididymis are typically palpable, since the corpus is generally flat in the unobstructed system.When the entire epididymis can be appreciated and it is firm, distal obstruction may be present, as occurs in the patient who has had a vasectomy.A distended pampiniform plexus is easily felt, usually in the left hemiscrotum, and defines a varicocele.Approximately 15% of men have a clinically palpable left varicocele, and it is one of the most frequent causes of male infertility.Another finding to note is the presence of any inguinal or scrotal incisions, which may implicate infant genitourinary surgery of which the patient was unaware.
| Box 150-5 - Physical Examination Findings that May Predict Infertility |
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[edit] BASIC PARAMETERS OF THE SEMEN ANALYSIS(Table 150-1)
The sperm count is the most important sperm parameter but is not very predictive of pregnancy achievement.Even though the lower limit of normal is considered to be 20×106sperm/ml, this does not mean that patients are necessarily sterile with counts below this level or fertile with counts above it.[2] The “normal” limit is just a number that allows classification of patients in terms of sperm count.The lower the count, the less likely pregnancy will occur, but the couple's entire situation must be taken into account.The same holds true for motility (the percentage of sperm that are moving), forward progression (how well the motile sperm are moving), and morphology (the percentage of “normally” shaped sperm as defined by a number of criteria).[3] The semen volume is especially relevant when creating a differential diagnosis for the azoospermic patient.In patients with a volume greater than 2 ml and a pH higher than 7.0, seminal vesicle fluid is present in the ejaculate, since it makes up 70% of the total ejaculate volume and is alkaline.This overwhelms the small amount of acidic contribution from the prostate (20% of the total) and creates an alkaline milieu for the spermatozoa.If there is less than 1.5 ml of fluid and it is acidic (pH, 6.5), then seminal vesicle fluid will not be in that ejaculate.(See the later section for a discussion of the differential diagnosis of azoospermia.)Oligospermia is defined as a count below 20×106sperm/ml.Asthenospermia occurs when the motility is below the limits of normal and teratospermia when the morphology is so categorized.Therefore a sample with a low count, motility, and morphology is considered to be oligoasthenoteratospermic and have the so-called OAT syndrome.
Table 150-1 Semen Analysis: Normal Ranges
| Parameter | Value |
|---|---|
| Ejaculate volume | 1.5-5.0 ml |
| Sperm density | >20 million/ml |
| Sperm motility | >60% |
| Forward progression | >2 (scale of 1-4) |
| Morphology | >30% (WHO criteria) |
| >14% (Strict criteria) | |
[edit] DIFFERENTIAL DIAGNOSIS OF OLIGOASTHENOTERATOSPERMIA
No one specific etiology gives rise to the OAT syndrome or to a lowering of only the sperm count, motility, or morphology.All of the factors listed in the sections on history and physical examination need to be considered.That is, a varicocele might be present, drug use might be harming sperm production, or cryptorchidism might be in the history and indicate less of a potential for normal spermatogenic capability.
[edit] DIFFERENTIAL DIAGNOSIS OF AZOOSPERMIA
In the case of azoospermia, the differential diagnosis is greatly dependent on the semen volume and pH as well as on the findings of the physical examination.If the volume and pH are low, indicating the absence of seminal vesicle fluid, then either the patient has complete ejaculatory duct obstruction bilaterally or he has CBAVD.In ejaculatory duct obstruction, the seminal vesicles and vasal ampullae areunable to empty their contents into the posterior urethra during emission because the ejaculatory ducts are occluded.However, the prostate is able to contribute to the ejaculate, so the antegrade fluid is acidic and of low volume, generally 0.5 ml.Obviously, the patient has the sense of orgasm.In CBAVD, the seminal vesicles are most often aplastic or completely dysfunctional.If the vasa are not palpable in the scrotum, the diagnosis is secure.
If the semen volume is normal and the pH is alkaline, the diagnosis cannot be bilateral complete ejaculatory duct obstruction.If these semen parameters exist coupled with palpation of the vasa, CBAVD cannot be the diagnosis.In the azoospermic patient with a normal semen volume, the differential diagnosis then focuses away from the distal ductal system and turns to the scrotum.Most commonly, the spermatogenic ability of the testes is severely compromised (nonobstructive azoospermia [NOA]), or vasal or epididymal occlusion prevents sperm flow.In the case of NOA, the testes may be small and soft and the FSH elevated.In the situation of epididymal occlusion, the testes are normal in size and consistency, the FSH value is adequate, and the epididymides may feel full and firm.In general, a testis biopsy is not required to distinguish between NOA and obstructive azoospermia.
[edit] Genetic Basis of Azoospermia
CBAVD is a mild phenotypic form of CF.[4] Patients need to be screened for mutations in the CF gene.Most have at least one recognized mutation, but many demonstrate a second known mutation or a polymorphism on the opposite allele that has an impact on the quantity or the quality of the CF gene protein product known as CFTR. Once the patient's CF gene status is known, his immediate family also needs genetic counseling.It is mandatory that the patient's wife be screened also to help define and determine their risk, as a couple, of having an offspring with CF or CBAVD.If the spouse is a carrier of a CF gene mutation, the couple is clearly at risk of generating children that may be affected by CF or CBAVD.
NOA may be caused by a karyotypic anomaly such as 47,XXY Klinefelter's syndrome; 46,XX male syndrome; a translocation; or an anomaly of the Y chromosome.In all patients with NOA, a karyotypic analysis should be performed and the couple should be counseled before therapy is instituted because translocations, depending on their exact nature, may confer a risk of poor reproductive outcome if sperm can be found in the testis tissue (see later section).In certain situations, couples may choose not to pursue therapy based on this information.NOA is most often due to microdeletions of the Y chromosome in areas where important genes regulate sperm production.So far, three such regions have been defined, AZFa, AZFb, and AZFc (Fig.150-4).AZFc contains the DAZ gene cluster and is found to be deleted in 13% of patients with NOA.Any sperm that are found and that bear the Y chromosome will also be missing this critical region.Any male child conceived by the couple will later in life have either severe oligospermia or azoospermia and may be sterile (Fig.150-5).This is a heavy burden for the couple to consider and may lead to a decision not to undertake therapy but to use donor sperm instead.
[edit] TREATMENT OF OLIGOASTHENOSPERMIA
The removal of all spermatotoxins is mandatory in the treatment of any patient with any deficiency in the semen.Surgical correction of varicoceles is certainly indicated because improvement in the semen analysis parameters can be seen in approximately 70% of patients after surgery.As long as the patient is living a healthy lifestyle and all potential suppressive factors have been altered, removed, or corrected, he will be able to realize his full spermatogenic potential.If at that time the couple is still not pregnant or if no change is anticipated or has been seen in sperm quality or function, additional procedures may be instituted.These include intrauterine insemination (sperm are placed into the uterine cavity timed with ovulation), in vitro fertilization (IVF) (sperm are placed next to each oocyte in a Petri dish after multiple oocytes are harvested following ovulation-inductiontherapy), and intracytoplasmic sperm injection (ICSI) (a single sperm is placed into a single oocyte after harvesting as in IVF).[5][6] The number of sperm required for ICSI is extremely low.ICSI is also a tremendous treatment advance for a man with spermatozoa that do not fertilize well, since the fertilization process is almost completely bypassed.
Although empiric medical therapy is generally unsuccessful, specific medical treatment may be beneficial.This may include replacement of FSH and LH for men with hypothalamic or pituitary hypogonadism.α-Agonist, sympathomimetic medications can be used to augment emission, which is often helpful for patients with such failure secondary to diabetes mellitus or retroperitoneal lymph node dissection.Penile vibratory stimulation can be used to help approximately 60% of men with spinal cord injuries to reflexively ejaculate.The semen specimen can be used for home insemination or intrauterine insemination.For those anejaculate men who have not responded to penile vibratory stimulation or in whom this type of stimulation is not successful, rectal probe electroejaculation will allow recovery of a semen specimen for use with whatever adjunctive technique is most appropriate.[7] Discontinuation of anabolic steroid use leads to the renewal of pituitary elaboration of FSH and LH, with consequent resumption of spermatogenesis.This may take several months because the process of spermatogenesis is a long one.
[edit] TREATMENT OF AZOOSPERMIA
If obstruction exists, reconstructive surgery is carried out to restore sperm to the ejaculate, thereby giving the couple an opportunity to achieve conception naturally.For the patient who has had a vasectomy, sperm return to the ejaculate occurs in approximately 90% after reconstruction.The most important determinant is the time that has elapsed since the vasectomy (Fig.150-6).If reconstruction is not possible, as in CBAVD, microsurgical epididymal sperm aspiration may be used to provide sperm (either fresh or cryopreserved) to be used in conjunction with ICSI.For men with NOA, approximately 50% have a tiny amount of spermatogenesis, and individual spermatozoa can be found in pieces of the testis tissue.Even azoospermic men with Klinefelter's syndrome may have sperm in the testis tissue.[8] Surgery is similar to a testis biopsy but may involve extraction of many pieces.The tissue can be frozen and the sperm used at a later date.For men with a midline cystic structure or dilation of the ejaculatory ducts as imaged by transrectal ultrasonography, transurethral resection is carried out to allow the free flow of seminal fluid into the posterior urethra.As previously discussed, testing is carried out before any therapy for patients in whom a genetic basis may exist.Couples may choose not to proceed with the use of the male partner's sperm if there may be major genetic consequences in their children.[9]
[edit] SUMMARY
The primary care physician is often the first person that a male partner in an infertile marriage asks for assistance.An immediate referral to a urologist is most appropriate in these circumstances, but at least some of the information obtained from the history and physical examination can direct these initial conversations.Most important, the primary care physician is in a position to prevent or predict reproductive dysfunction.Large varicoceles, anabolic steroid use, small and soft testes, and a history of childhood chemotherapy should lead to a discussion of either the possible or definite effects of these conditions on fertility potential.The primary care physician can help identify factors that can be altered or corrected and can help preserve or improve a couple's ability to conceive and become parents.
[edit] REFERENCES
- ↑ RC Jones: To store or mature spermatozoa? The primary role of the epididymis. Int J Androl 1999; 22 (2):57.
- ↑ M Ulstein, A Irgens, LM Irgens: Secular trends in sperm variables for groups of men in fertile and infertile couples. Acta Obstet Gynecol Scand 1999; 78 (4):332.
- ↑ M Szczygiel, M Kurpisz: Teratozoospermia and its effect on male fertility potential. Andrologia 1999; 31 (2):63.
- ↑ GR Dohle, HJ Veeze, SE Overbeek,et al.: The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data. Hum Reprod 1999; 14 (2):371.
- ↑ RP Dickey, R Pyrzak, PY Lu,et al.: Comparison of the sperm quality necessary for successful intrauterine insemination with World Health Organization threshold values for normal sperm. Fertil Steril 1999; 71 (4):684.
- ↑ RG Edwards: Widening perspectives of intracytoplasmic sperm injection. Nat Med 1999; 5 (4):377.
- ↑ Z Taylor, D Molloy, V Hill,et al.: Contribution of the assisted reproductive technologies to fertility in males suffering spinal cord injury. Aust N Z J Obstet Gynaecol 1999; 39 (1):84.
- ↑ R Ron-El, S Friedler, D Strassburger,et al.: Birth of a healthy neonate following the intracytoplasmic injection of testicular spermatozoa from a patient with Klinefelter's syndrome. Hum Reprod 1999; 14 (2):368.
- ↑ JC Giltay, PM Kastrop, JH Tuerlings,et al.: Subfertile men with constitutive chromosome abnormalities do not necessarily refrain from intracytoplasmic sperm injection treatment: a follow-up study on 75 Dutch patients. Hum Reprod 1999; 14 (2):318.
