Male Infertility Anatomy and Physiology of Male Reproduction SYNDROME
Compared to other species, human males have relatively poor sperm producing capacity and human testicular function is very sensitive to a wide variety of environmental insults. This may be related to the human (upright) posture and hydrostatic pressure on venous testicular outflow, or other unknown factors, but it is necessary for clinicians to be aware of the high incidence of subfertility in men. Perhaps it is a reflection of the incredible ability of humans to adapt the environment to promote their own survival or the expectation that fertility should be nearly spontaneous, but many human couples seek evaluation for infertility.
The human male reproductive system includes the hypothalamic-pituitary-testis axis as well as the epididymis, vas deferens, seminal vesicles, prostate and urethra. Production of spermatozoa requires approximately 3 months from the initial mitotic divisions through the myriad changes readying sperm for ejaculation and fertilization. Highlights of this transformation include (1) the unique environment created within the testis for spermatogenesis to occur; (2) preservation of a set of stem cells relatively resistant to external injury and able to produce rapidly proliferating germ cells destined to become spermatozoa; (3) meiosis, that results in formation of the haploid gamete; and (4) the dramatic differentiation of the prospective gamete in a form that is specialized to transport chromosomal material in a structure ideally suited for transit of the female reproductive tract. The spermatozoon resulting from this complex process assumes its final shape and size in the testis. In the normal state, it also acquires the ability to fertilize as well as a capacity for motility in the epididymis. Unfortunately, the mechanisms by which the epididymis exerts these changes on the traversing spermatozoon and the actions of the human reproductive tract after relief of chronic obstruction remain largely unknown.
1. HORMONAL CONSIDERATIONS
An appropriate hormonal milieu must exist for the reproductive organs to produce, mature and transport the highly specialized male gamete to the ejaculatory duct. The entire system of hormone balance is initiated by the pulsatile hypothalamic release of GnRH ( gonadotropin-releasing hormone). Pituitary LH ( luteinizing hormone) secretion is determined by GnRH pulses from the hypothalamus, that occur approximately every two hours and are carried via a venous portal network to the pituitary. This hypothalamohypophyseal portal connection allows an exact synchrony of GnRH and LH pulse secretion. FSH ( follicle-stimulating hormone) secretion is also stimulated by GnRH, but FSH and LH are differentially regulated by hormonal and other factors that are poorly understood. The factors influencing FSH secretion are produced by Sertoli cells and other components of the testis that probably includes peptides of the inhibin and activin families. Within the testis, LH stimulates Leydig cell synthesis of testosterone. Testosterone production by the Leydig cell provides locally high intratesticular concentrations of this hormone that stimulates spermatogenesis. Testosterone concentrations in peripheral blood of men change dramatically during the life cycle. Testosterone reaches a maximum concentration during the second or third decade of life, then reaches a plateau, and declines thereafter. Additionally, annual and daily rhythms in testosterone concentration occur, typically with a testosterone peak in the early morning. Other, irregular fluctuations in testosterone concentration may also be detectable in peripheral blood. Testosterone is normally aromatized in peripheral tissue to estrogens. Excessive testosterone levels, associated with gonadotropin, clomiphene citrate or flutamide treatment, may paradoxically result in increased feminization from conversion of androgens to estrogens by aromatase. Similarly, increased aromatase activity is associated with alcoholism and chronic liver disease, as well as testis tumors.
Accurate clinical assessment of the pituitary gonadotropins LH and FSH must take into account their pulsatile release. During clinical research studies, three serum samples are obtained, one every 30 minutes, and the sera pooled for accurate determination of mean gonadotropin levels. This process is usually not necessary in clinical practice, but the clinician should be aware of the potential for LH and FSH peaks to be measured in a single gonadotropin determination, and perform repeat evaluation if LH and FSH hormone levels are both elevated. Testosterone levels may be decreased in the late afternoon or evening. Interpretation of serum testosterone levels should take the diurnal secretion of this hormone into account. Prolactin, another pituitary hormone, may affect fertility by decreasing LH production, resulting in a decrease in testosterone and subsequently, decreased libido. The release of prolactin is mediated by dopamine, and the dopamine antagonist bromocriptine will ameliorate the antifertility effects of hyperprolactinemia.
Testosterone is converted intracellularly within most androgen-sensitive organs to dihydrotestosterone. Function of the prostate, seminal vesicles, vas deferens, and other sex accessory organs are all androgen-dependent. The degree to which partial androgen deprivation in the hypogonadal man affects the function of these organs is unknown. Furthermore, the effects of "low-normal" serum testosterone levels on these organs and a man's fertility potential are unknown. Abnormally elevated serum testosterone levels are peripherally converted by the aromatase enzyme to estrogens. In addition, chromosomal abnormalities such as Klinefelter's syndrome(xxy), and some testicular tumors have elevated aromatase levels. Some obese patients may also have increased aromatase activity, since aromatase levels are high in adipose tissue, as well as fat. Therefore, hormonal evaluation of the infertile man should include determination of serum LH, FSH, testosterone and prolactin. For men with clinical gynecomastia, serum estradiol should be measured.
2. TESTICULAR ANATOMY
The human testis is an ovoid mass that lies within the scrotum. The average testicular volume is 20 cc in healthy young men and decreases in elderly men. In Asian men, testes tend to be smaller. Normal longitudinal length of the testis is approximately 4.5 to 5.1 cm. The testicular parenchyma is surrounded by a capsule containing blood vessels, smooth muscle fibers and nerve fibers sensitive to pressure. The functional role of the testicular capsule is unknown, but may relate to movement of fluid out through the rete testis or control of blood flow to the testis. The testis contains seminiferous tubules and interstitial cells. The tubules are segregated into regions by connective tissue septa. The seminiferous tubules are long V-shaped tubules, both ends of which usually terminate in the rete testis. Measurement of testicular size is critical in the evaluation of the infertile man, since seminiferous tubules (the spermatogenetic region of the testis) occupy approximately 80% of testicular volume. So, a rough estimate of spermatogenic cell capacity is provided by assessment of testicular size. Testicular consistency is also of value in determining fertility capacity. A soft testis is likely to reflect degenerating or shrunken spermatogenic components within the seminiferous tubules. The seminiferous tubules drain toward the central superior and posterior regions of the testis, the rete testis, that has a flat cuboidal epithelium. The rete coalesces in the superior portion of the testis, just anterior to the testicular vessels, to form 5-10 efferent ductules. These efferent ducts leave the testis and travel a short distance to enter the head, or caput region of the epididymis. The efferent ducts coalesce in a somewhat variable pattern within the caput epididymis to form a single epididymal tubule.
The artery to the testis is specialized in that it is highly coiled and intimately associated with a network of anastomotic veins that form the pampiniform plexus. The counterflowing vessels are separated only by the thickness of their vascular wall in some areas. This vascular arrangement facilitates the exchange of heat and small molecules, including testosterone. The transport of testosterone is a concentration-limited, passive diffusion process in men. The counter-current exchange of heat in the spermatic cord provides blood to the testis that is 2 to 4 C lower than rectal temperature in the normal individual. A loss of the temperature differential is associated with testicular dysfunction in humans with idiopathic infertility, as well as men with varicocele or cryptorchidism. Whether elevated testicular temperature causes or is simply a reflection of testicular dysfunction is unknown. Only the association between elevated testicular temperature and seminiferous failure have been demonstrated. In the distal inguinal canal, 50% of men will have a single testicular artery identifiable under l0 x power magnification dissection of the cord, with 30% of men having two arteries and 20% with three arteries.
The venous system is somewhat unique because the spermatic veins are thin-walled, poorly muscularized, and lack effective valves except at the inflow points into the inferior vena cava or the renal vein. The right spermatic vein usually drains into the vena cava. The left spermatic vein drains into the left renal vein. The renal vein on the left side is thought to have a higher intraluminal pressure because the vein is compressed as it passes between the superior mesenteric artery and the aorta. This "nutcracker effect" may impair flow through the left renal and spermatic veins, especially in young men with limited retroperitoneal fat. The differential anatomy of the left and right spermatic veins is thought to explain, at least in part, the higher prevalence of varicoceles on the left side. The exact mechanism by which varicoceles cause infertility is unknown. In animal models, varicoceles are associated with increased blood flow to the testis and increased interstitial fluid in the testis. These two findings may impair regulation of testicular temperature and decrease intratesticular concentrations of testosterone or other local factors important for spermatogenesis.
3. SEMINIFEROUS TUBULES
The seminiferous tubules provide a unique environment for the production of germ cells. The structures involved in this process include germinal elements and supporting cells. The supporting cells include the peritubular cells of the basement membrane and the Sertoli cells. The germinal elements comprise a population of epithelial cells, including a slowly dividing primitive stem cell population, the rapidly proliferating spermatogonia, spermatocytes undergoing meiosis, and the metamorphosing spermatids. The seminiferous tubule also produces an environment known as "the blood-testis barrier". The testis is unique in that the differentiating germ cells are potentially antigenic, and recognizable as foreign; however, little immunological reaction is usually detectable within the testis.
Developmentally, the testis develops from the undifferentiated gonad. These primitive germ cells are referred to as gonocytes after the gonad differentiates into a testis by forming seminiferous cords. At this time, the gonocytes are located in a central position within the seminiferous cords. They are subsequently classified as spermatogonia after the gonocytes have migrated to the periphery of the tubule. From birth to approximately 7 years of life, there appears to be very little morphological change within the human testis. From 7 to 9 years of life, mitotic activity of gonocytes is detectable, with spermatogonia populating the base of the seminiferous tubule in numbers equal to those of the Sertoli cells. There appears to be little further morphological change in spermatogonia until spermatogenesis begins at the time of puberty. Further information regarding the maturation of gonocytes and their migration to the base of the seminiferous tubule, including the factors that may be responsible for these changes, may provide greater insight into the effects of cryptorchidism on fertility and impact on the appropriate timing of intervention for treatment of cryptorchidism.
4. THE EPIDIDYMIS
Spermatozoa in the unobstructed testis are not motile and are incapable of fertilizing ova. Spermatozoa become functional gametes only after they migrate through the epididymis and undergo an additional maturation process, thereby acquiring the capacities for both progressive motility and fertility. The function of the obstructed epididymis and its effects on maturation of spermatozoa may be very different from what is observed in the unobstructed state. Anatomically, the epididymis can be divided into three regions: the caput, the corpus, and the cauda epididymis. However, these anatomical divisions have been defined based on findings in animals, not in humans. The human epididymal epithelium is relatively homogeneous as viewed under the microscope, and grossly, the epididymis does not have the same distinct gross anatomical subdivisions that are easily seen in the rat, rabbit and other animals. Unfortunately, there is little information available regarding the functional diversity of these three regions of the human epididymis. The data that exist on human epididymal function are almost entirely derived from observations of men after relief of chronic epididymal obstruction.
In humans, the epididymis receives its blood supply from two sources: branches of the testicular as well as the deferential vessels that travel along the vas deferens. Clinically, the blood supply becomes important after a vasectomy with interruption of the vasal vessels. At the time of vasectomy reversal, the testicular side of the vas deferens is then supplied by branches off the testicular vessels, which travel either through collaterals, or along the entire length of the epididymis. Similarly, if division of the vasal vessels occurs accidentally during vasography, and a secondary obstruction to the vas deferens (and vasal vessels) is found and addressed in the groin, then the intervening segment of vas deferens can be totally devascularized. The viability of the vas should be considered prior to vaso-vasostomy in this situation.
Observations by Silber regarding the fertility of men who have undergone bilateral vasal anastomosis to the vasa efferentia, indicate that in the obstructed human male reproductive tract, some sperm may acquire motility and fertilizing ability without passing through the epididymis. Although not absolutely required for male fertility, the functional importance of the human epididymis is strongly supported by several other observations regarding men who have undergone intervention for the relief of chronic epididymal obstruction. In 1990, Silber reported fertility results for men who underwent vasoepididymostomy at the level of either the caput or corpus epididymis. For both groups of men, the patency rate was approximately 70%. For men who underwent anastomosis at the corpus level, 72% of men achieved pregnancy with their partners, whereas only 43% of men were able to impregnate their wives after vasoepididymostomy at the caput level. Therefore, the presence of a longer length of epididymis appears to promote fertility after relief of chronic obstruction. Our studies in men with congenital absence of the vas deferens or other surgically unreconstructable obstruction of the vas have indicated that the longer the segment of epididymis present, the greater the likelihood of pregnancy with sperm obtained from these men. Almost all of the information regarding human epididymal function are derived from observations of men who have undergone surgical reversal of long term reproductive tract obstruction. The results of several published observations of men with unobstructed reproductive tracts was compiled by Bedford. As indicated (in NY Acad Sci 541: 284-291, 1988), the fertility potential of sperm from the caput region of the obstructed human epididymis is minimal.
The exact fate of unejaculated epididymal spermatozoa in humans is also unknown. Some sperm have been documented to be phagocytosed by macrophages in the epididymis, and sperm have been detected in urine. However, the mechanisms by which quantitative clearance of sperm occurs from men during periods of sexual abstinence is unknown.
In normal, unobstructed systems, the majority of spermatozoa taken from the vasa efferentia and diluted in a physiologic solution are immotile or exhibit only weak tail movements. These observations in the unobstructed human epididymis are very different from what is seen after relief of chronic epididymal obstruction. Our observations confirm those of several investigators, that, although the motility of ejaculated spermatozoa is initially poor following vaso-epididymostomy at the level of the caput epididymis, sperm motility may improve greatly up to 1 1/2 years after vasoepididymostomy. These findings suggest that following vasoepididymostomy the caput epididymis or vas deferens may undergo compensatory adaption over time and support sperm motility maturation despite exposure of sperm to a shortened length of epididymis. In animal models, vasal obstruction causes changes in the intrinsic motility of fluid through the epididymal lumen. These changes are not completely reversed by technically successful vasovasostomy. It is not known what effect the apparent change in epididymal contractility may have on epididymal function.
Studies on laboratory animals describe many changes that occur to sperm during epididymal transit. These include a change in net sperm surface charge, addition and alteration of membrane proteins, alterations in sperm lectin-binding properties, changes in immunoreactivity and iodination characteristics, acquisition of an increased capacity for glycolysis, modification of adenylate cyclase activity, alterations in cellular phospholipid and phospholipid-like fatty acid content and an increased ability to adhere to the zona pellucida of the egg. Whether similar modifications occur in human spermatozoa during epididymal migration is unknown. Biochemical changes observed in human spermatozoa during epididymal transit involve the formation of disulfide bonds within the sperm nucleus and tail and the oxidation of sperm membrane sulfhydryl groups. These changes are thought to provide improved structural integrity to the sperm membrane. The changes in structural integrity of sperm may be necessary for the development of progressive motility and successful penetration of eggs.
Protein secretion and the storage capacity of the epididymis has been shown to be profoundly affected by changes in epididymal temperature in animals. Some have even postulated that the driving force for evolution of the scrotal location of testes is to have the epididymis maintained at a temperature below that of body core temperature, in the scrotum. Whether the functions of the human epididymis are similarly affected by body temperature is unknown. The potential influence of temperature on epididymal function in man may be an important consideration in explaining the relationship between varicocele and male infertility. If temperature significantly affects human epididymal function, then it could explain improvements in semen parameters that may occur less than three months (one full cycle of spermatogenesis) after varicoceletomy.
The human spermatozoon is approximately 60 µm in length. Normal forms have an oval sperm head, 4.5 µm long and 3 µm wide, consisting principally of a nucleus, which contains the highly compacted chromatin material, and the acrosome, a membrane-bound organelle that covers 40-70% of the surface of the sperm head and contains the enzymes required for penetration of the outer vestments of the egg prior to fertilization. The middle piece of the spermatozoon is a highly organized segment consisting of helically arranged mitochondria surrounding a set of outer dense fibers and the characteristic 9 + 2 microtubular structure of the sperm axoneme. The mitochondria contain the enzymes required for oxidative metabolism and the production of adenosine triphosphate (ATP), the primary energy source for the cell. Absence of some components of the microtubules is associated with immotile cilia in the sinus and pulmonary tracts, with resultant pulmonary and sinus infections. The association of sperm immotility with upper respiratory infections (Young's syndrome) due to ciliary dysfunction or absent dynein cross-arms between the microtubules (Kartagener's syndrome) resulting in bronchiectasis and nonmotile sperm have been well documented. Other syndromes of ciliary dysfunction have recently been described in children with recurrent sinusitis (ciliary dyskinesia). It is yet to be demonstrated whether the boys affected with the childhood manifestations of ciliary dyskinesia will suffer from infertility problems after puberty. The highly specialized structure and physiology of the spermatozoon is marvelously suited for its single purpose: to carry genetic material to the egg during reproduction.
The rate of transport of fluid through the vas deferens is not known in the human. Just prior to ejaculation, the testes are brought up close to the abdomen and fluid is rapidly transported through the vas deferens toward the region of the ejaculatory ducts and subsequently into the prostatic urethra. After ejaculation, intravasal fluid is transported back toward the epididymis and occasionally into the seminal vesicles as well. The retrograde transport of sperm to the seminal vesicles has been documented by videoradiography during ejaculation after vasography. The return of sperm to the seminal vesicles after ejaculation may help explain the prolonged presence of sperm in the ejaculate for some men after vasectomy.
The ejaculatory ducts enter the prostatic urethra just lateral to the verumontanum. In the case of obstruction of the ejaculatory ducts, resection of the floor of the prostate should be performed just lateral to the midline and superior to the verumontanum. Vasography can be performed prior to transurethral resection (TUR) of the ejaculatory ducts with placement of methylene blue in the vasography fluid. This allows the surgeon to cystoscopically identify the lack of flow of dye and confirm relief of obstruction of the ejaculatory ducts during TUR.
The ejaculate consists of components from different accessory organs. Each of these organs and the characteristics of the fluid that they produce is listed below. These characteristics can be used clinically to evaluate ejaculatory dysfunction.
