David J. Breland and Mark L. Rubinstein
TESTIS
Testicular growth and maturation are largely influenced by testosterone, which is produced by the testicle both before and after birth.1 Testosterone production is regulated centrally by the hypothalamic-pituitary-testicular axis as well as intragonadally. Testosterone effects include embryologic male genital differentiation, neonatal imprinting of androgen-dependent target tissue, maturation of the genitalia at puberty, growth of skeletal muscle, deepening of the voice from laryngeal growth, epiphyseal cartilage growth during puberty, male hair growth and distribution, erythropoiesis, stimulation of sebaceous glands, and male social behavior.1,2
DEVELOPMENTAL ANATOMY AND HISTOLOGY
The adult testicle is ovoid in shape with a volume of 15 to 25 mL, an average length of 4.6 cm (range 3.6–5.5 cm), and an average width of 2.6 cm (range 2.1–3.2 cm). Each testis is surrounded by a capsule made up of 3 layers: the outer visceral layer of the tunica vaginalis, the tunica albuginea, and the inner layer of the tunica vasculosa. Contained by the capsule, each testis is divided into 250 lobules by fibrous septae, with 1 to 4 seminiferous tubules in each lobule. The tubules account for 90% of testicular mass, and the interstitium accounts for the remaining 10%. The interstitium consists of Leydig cells, blood vessels, lymphatic channels, macrophages, and mast cells. Leydig cells are the major source of testosterone and are closely applied to the outer wall of the seminiferous tubule. Each seminiferous tubule is approximately 60 cm in length and 150 to 175 μm in diameter.3 The tubule is the site of spermatogenesis and contains 2 cell types, Sertoli cells and germ cells.4,5
GONADAL DIFFERENTIATION
Although the sex of the embryo is determined at conception, the potential male and female gonads do not differ morphologically until the seventh week of development. Initially, they appear as gonadal ridges, into which the primordial germ cells migrate in the sixth week of growth. Primitive sex cords develop before incorporation of the germ cells and are the progenitors of the seminiferous tubules.1 By the fourth month, the primitive germ cells and Sertoli cells can be identified in the tubules (Fig. 65-1). Leydig cells are abundant during the fourth to sixth month and assist in influencing the sexual differentiation of the genital ducts and external genitalia by means of testosterone production. The fetal testes produce inducer substances, which promote growth of the mesonephric or wolffian duct and inhibit development of the paramesonephric or mÜllerian duct. The mesonephric duct persists (except for the most cranial portion, the appendix epididymis) and gives rise to the epididymis, ductus deferens, and seminal vesicle. The paramesonephric duct completely degenerates except for a small portion at the cranial end, which persists as the appendix testis. Descent of the testes from their abdominal origin to their final location in the scrotal sac begins in the seventh or eighth month.1,5 It is typically complete shortly before birth. However, testicular descent is sometimes completed post-natally. From birth until puberty, the testis remains static, although histologic and ultrastructural changes do occur, as outlined below.4 The prepubertal testis demonstrates tubules of small diameter and is populated by two cell types, progenitors of Sertoli cells and primary spermatogenic cells.4,5 The genetic determinants of sex differentiation is discussed in detail in Chapter 538.
Leydig Cells
Leydig cells are situated between the testicular cords and can first be recognized during the eighth week of gestation.4 They differentiate, multiply, and increase in size from weeks 9 to 14, until they occupy more than 50% of the testicle. Activation of the Leydig cells results in increased testosterone secretion, which peaks at about week 14 of fetal development.4,5 The Leydig cells gradually involute after weeks 17 to 18 of gestation. Involution is complete within a few weeks following birth. Levels of free testosterone are also thought to decline during the first several months after birth. At 4 to 8 years of age, precursors of the Leydig cells reappear and can be found grouped around vessels.1,4,5 At puberty, Leydig cells dramatically increase in number and size. They become well differentiated and are capable of steroid synthesis. In the mature testis, Leydig cells are the main source of testosterone in the pubertal and postpubertal male and thereby are responsible for development of secondary sexual characteristics of puberty.3-5
FIGURE 65-1. Fetal testicular development. A: Transverse section through the lumbar section of a 6-week embryo. Note the primordial germ cells migrating to the primitive sex cords of the indifferent gonad. B: Testis and evolving ductus deferens in the fourth month of development. (Source: Adapted from Langman J: Medical embryology. Baltimore: Williams and Wilkins, 1981.)
Sertoli Cells
Sertoli cells first appear in the fetal testis at approximately the seventh week of gestation and quickly associate with the developing germ cells (gonocytes). They play an important role during spermatogenesis in the postpubertal testis by forming an occlusive barrier representing the blood-testis barrier.3 In addition to their histologic roles, Sertoli cells produce estrogen, androgen-binding protein (see Chapter 538), and inhibin, which are all essential to germ cell maturation and phagocytize-damaged germ cells.3-5
Seminiferous Tubules
As mentioned previously, primordial germ cells invade the primitive sex cords during the sixth week of gestation.3 They continue to divide and are known as gonocytes. The number of germ cells in the cords increases up to the 17th week with marked mitotic activity. By week 20, however, mitoses cease. At birth, the seminiferous tubules appear as solid cords, with cellular debris (degenerated spermatogonia) in the potential lumen. The primary germ cells in the neonatal testis are the gonocytes, which transform to the reserve stem cells and spermatogonia by age 6 months.1,3,5 Spermatogonia evolve into primary spermatocytes at 3 years of age, with no further progression until puberty.1,6Such early transformations involve mitosis only, with meiotic transformation beginning only with puberty.
During childhood, the tubules become long and sinuous, with no increase in diameter. At puberty, the tubules begin to increase in diameter, doubling from an average of 72 μm in the prepubertal child to 150 μm in the adult, resulting in the development of a lumen. In addition, cellular differentiation of the spermatogonia can be seen, and meiotic processes begin to yield true spermatogenesis. In the mature testis, the tubules are distinguished by their large cell diameter, a thin but identifiable basement membrane, a tubular wall 2 to 3 cell layers thick, and complete spermatogenic activity from basal spermatogonium, primary spermatocyte, secondary spermatocyte, and spermatid to terminal spermatozoa.5
HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS
Male reproduction is controlled by the hypothalamic-pituitary-testicular axis, which has 3 levels of organization: the hypothalamus, the pituitary gland, and the testis.3 Spermatogenesis is also influenced by local hormonal control within the testicle itself. Luteinizing hormone stimulates the Leydig cells to secrete testosterone.1,3,6 Three paths of testosterone have been described: absorption by venous channels in the testicle and subsequent systemic distribution; diffusion locally in the interstitial tissue of the testicle and into the seminiferous tubule; or binding to Sertoli cells, resulting in stimulation of the cell to produce androgen-binding protein and other proteins vital to spermatogenesis.1,3,6 Testosterone then binds to androgen-binding protein and is transported in the seminal tubule and duct system.1,3,6 This bound testosterone maintains the androgen milieu of the seminiferous tubule.
FIGURE 65-2. The hypothalamic-pituitary-testicular axis. ABP, androgen binding protein; FSH, follicle stimulating hormone; GnRH, gonadotrophin releasing hormone; LH, luteinizing hormone. (Source: Adapted from Fitzgerald PA, ed. Handbook of Clinical Endocrinology, 2nd ed. Norwalk, CT: Appleton & Lange, 1992, p. 354.)
The rates of testosterone secretion and sperm production are regulated by the hypothalamic-pituitary-testicular axis and are fined tuned by a network of negative feedback relationships between the testis and the upper level of the hypothalamic-pituitary-testicular axis. This control mechanism results in a rather constant level of testosterone, although there are oscillations in levels and a circadian rhythm exists with higher levels in the morning. Testosterone and estradiol suppress secretory activity by gonadotropin-releasing hormone neurons in the hypothalamus and gonadotropes in the pituitary. Follicle-stimulating hormone stimulates Leydig cells to increase the number of luteinizing hormone receptors.3 It also stimulates the Sertoli cells to produce androgen-binding protein as well as inhibin. Inhibin in turn exerts a negative feedback effect on the anterior pituitary.1 An outline of the hormonal control of the hypothalamic-pituitary-testicular axis is presented in Figure 65-2.
SPERMATOGENESIS
The process of spermatogenesis can be histo-logically identified between ages 11 and 15 years with a mean age of spermaturia of 13.3 years.1 As noted previously, mature seminiferous tubules are lined by spermatogonia, which undergo mitotic division to give rise to primary spermatocytes. Subsequently, these cells mature and undergo meiosis so that the resultant secondary spermatocyte contains 23 chromosomes.5 These haploid cells then evolve into spermatids and spermatozoa. The cells are arranged in an orderly sequence in the tubule, according to their developmental stage. The complete 64-day cycle includes 6 stages that occur one after the other in a predictable and constant fashion.3 Roughly 45 to 205 million sperm are produced by the testes each day.
Testosterone initiates and maintains the process of spermatogenesis in humans. The onset of spermatogenesis (“spermarche”) corresponds with a time of rapid increases in testicular weight as well as in tubular diameter, length, and relative volume. It occurs early in puberty and corresponds to a mean pubic hair stage of Tanner and Marshall SMR 2.5. The mean age of first reported ejaculation is 13.5 years.1
EPIDIDYMIS AND VAS DEFERENS
The epididymis and the ductus vas deferens are derived from the mesonephric (wolffian) duct. The epididymis is divided into 3 sections: caput, corpus, and cauda. The mature epididymis consists of an epididymal tubule that is roughly 3 to 4 meters in length and functions in sperm transport, storage, and maturation. Sperm are stored in the cauda epididymis for variable amounts of time depending on the frequency of sexual activity. The vas deferens is about 30 to 35 cm in length and begins in the cauda epididymis and ends in the ejaculatory duct. Prior to emission, the spermatozoa are transported to the ejaculatory ducts from the distal epididymis through the ductus vas deferens.3