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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
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Developmental Anatomy
and Histology
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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
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Gonadal Differentiation
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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 postnatally. 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.
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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
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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
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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.1,6 Such early transformations involve
mitosis only, with meiotic transformation beginning only with puberty.
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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