Structure of the Testes
The male gonads are the testes, which have two functions: spermatogenesis and secretion of testosterone. Normally, the testes occupy the scrotum, which lies outside the body cavity and is maintained at 35° to 36°C, or 1° to 2°C below body temperature. This lower temperature, essential for normal spermatogenesis, is maintained by a countercurrent arrangement of testicular arteries and veins, which facilitates heat exchange.
Eighty percent of the adult testis is composed of seminiferous tubules, which produce the sperm. The seminiferous tubules are convoluted loops, 120 to 300 µm in diameter, which are arranged in lobules and surrounded by connective tissue. The epithelium lining the seminiferous tubules consists of three cell types: spermatogonia, which are the stem cells; spermatocytes, which are cells in the process of becoming sperm; and Sertoli cells, which support the developing sperm.
The Sertoli cells lining the seminiferous tubules have three important functions that support spermatogenesis. (1) The Sertoli cells provide nutrients to the differentiating sperm (which are isolated from the bloodstream). (2) Sertoli cells form tight junctions with each other, creating a barrier between the testes and the bloodstream called the blood-testes barrier. The blood-testes barrier imparts a selective permeability, admitting “allowable” substances such as testosterone to cross but prohibiting noxious substances that might damage the developing sperm. (3) Sertoli cells secrete an aqueous fluid into the lumen of the seminiferous tubules, which helps to transport sperm through the tubules into the epididymis.
The remaining 20% of the adult testis is connective tissue interspersed with Leydig cells. The function of the Leydig cells is synthesis and secretion of testosterone, the male sex steroid hormone. Testosterone has both local (paracrine) effects that support spermatogenesis in the testicular Sertoli cells and endocrine effects on other target organs (e.g., skeletal muscle and the prostate).
Spermatogenesis occurs continuously throughout the reproductive life of the male, from puberty until senescence. Spermatogenesis occurs along the length of the seminiferous tubules, and the process can be divided into three phases: (1) Mitotic divisions of spermatogonia generate the spermatocytes, which are destined to become mature sperm; (2) meiotic divisions of the spermatocytes, which decrease the chromosome number and produce haploid spermatids; and (3) spermiogenesis, in which spermatids are transformed into mature sperm through the loss of cytoplasm and the development of flagella (Fig. 10-4). One full cycle of spermatogenesis requires about 64 days. There is a temporal organization to the spermatogenic cycle, called the spermatogenic wave, which ensures that mature spermatozoa are produced continuously. Two million spermatogonia begin this process daily, and because each spermatogonium gives rise to 64 spermatozoa, 128 million sperm are produced daily.
Figure 10–4 Development and structure of the spermatozoon.
Storage of Sperm, Ejaculation, and Function of Sex Accessory Glands
Sperm leave the testes through ducts that carry them to the epididymis, the primary location for the maturation and storage of sperm. They remain viable in the epididymis for several months.
During sexual arousal, contractions of the smooth muscle around the ducts advance sperm through the epididymis. At ejaculation, sperm are expelled into the vas deferens and then into the urethra. The ampulla of the vas deferens provides another storage area for sperm and secretes a fluid rich in citrate and fructose, which nourishes the ejaculated sperm.
The seminal vesicles secrete a fluid rich in fructose, citrate, prostaglandins, and fibrinogen. As the vas deferens empties its sperm into the ejaculatory duct, each seminal vesicle contributes its secretions, which also will be nutritive for the ejaculated sperm. The prostaglandins present in seminal fluid may assist in fertilization in two ways: (1) Prostaglandins react with cervical mucus to make it more penetrable by sperm; and (2) prostaglandins induce peristaltic contractions in the female reproductive tract (i.e., the uterus and fallopian tubes) to propel the sperm up the tract.
The prostate gland adds its own secretion to the ejaculate, a milky aqueous solution rich in citrate, calcium, and enzymes. The prostatic secretion is slightly alkaline, which increases sperm motility and aids in fertilization by neutralizing acidic secretions from the vas deferens and the vagina. Collectively, the combined secretions of the male sex accessory glands compose 90% of the volume of semen, and sperm compose the remaining 10%.
Ejaculated sperm cannot immediately fertilize an ovum: They must reside in the female reproductive tract for 4 to 6 hours for capacitation to occur. Capacitation is a process in which inhibitory factors in the seminal fluid are washed free, cholesterol is withdrawn from the sperm membrane, and surface proteins are redistributed. Calcium influx into the sperm increases their motility, and the motion of the sperm becomes “whiplike.” Capacitation also results in the acrosomal reaction in which the acrosomal membrane fuses with the outer sperm membrane. This fusion creates pores through which hydrolytic and proteolytic enzymes can escape from the acrosome, creating a path for sperm to penetrate the protective coverings of the ovum.
Synthesis and Secretion of Testosterone
Testosterone, the major androgenic hormone, is synthesized and secreted by the Leydig cells of the testes. The steroidogenic pathways in the testes, shown in Figure 10-5, are similar to those previously described for the adrenal cortex (see Chapter 9, Fig. 9-23), with two important differences: (1) The testes lack the enzymes 21β-hydroxylase and 11β-hydroxylase and therefore cannot synthesize glucocorticoids or mineralocorticoids; and (2) the testes have an additional enzyme, 17β-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone. Thus, the androgenic end product of the testes is testosterone rather than dehydroepiandrosterone (DHEA) and androstenedione (the androgenic end products of the adrenal cortex).
Figure 10–5 Biosynthetic pathway for testosterone synthesis in the testes. Dihydrotestosterone is synthesized from testosterone in target tissues that contain 5α-reductase. LH, Luteinizing hormone.
Testosterone is not active in all androgenic target tissues. In some tissues, dihydrotestosterone is the active androgen. In those tissues, testosterone is converted to dihydrotestosterone by the enzyme 5α-reductase.
Ninety-eight percent of the circulating testosterone is bound to plasma proteins, such as sex steroid–binding globulin and albumin. Because only free (unbound) testosterone is biologically active, sex steroid–binding globulin essentially functions as a reservoir for the circulating hormone. The synthesis of sex steroid–binding globulin is stimulated by estrogens and inhibited by androgens.
Regulation of the Testes
Both functions of the testes, spermatogenesis and secretion of testosterone, are controlled by the hypothalamic-pituitary axis (Fig. 10-6). The hypothalamic hormone is gonadotropin-releasing hormone (GnRH), and the anterior pituitary hormones are follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Figure 10–6 Control of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) secretion in males.
GnRH is a decapeptide that is secreted by hypothalamic neurons in the arcuate nuclei. GnRH is secreted into hypothalamic-hypophysial portal blood and then delivered in high concentration directly to the anterior lobe of the pituitary. Recall that throughout the reproductive period GnRH secretion is pulsatile and drives a parallel pulsatile secretory pattern of FSH and LH from the anterior lobe. (Note that if GnRH is administered continuously, it inhibits FSH and LH secretion.)
FSH and LH
FSH and LH are the anterior pituitary hormones (gonadotropins) that stimulate the testes to perform their spermatogenic and endocrine functions. FSH and LH are members of the glycoprotein hormone family that includes TSH and HCG; all members of the family have identical α subunits but unique β subunits that confer biologic activity. FSH stimulates spermatogenesis and Sertoli cell function. LHstimulates the Leydig cells to synthesize testosterone by increasing the activity of cholesterol desmolase. Thus, the function of LH in the testes parallels the function of ACTH in the adrenal cortex: It stimulates the first step in the steroidogenic pathway.
Testosterone, secreted by the Leydig cells, has functions both locally within the testes (paracrine effects) and on other target tissues (endocrine effects). Intratesticularly, testosterone diffuses from the Leydig cells to the nearby Sertoli cells, where it reinforces the spermatogenic action of FSH. Extratesticularly, testosterone is secreted into the general circulation and delivered to its target tissues.
The hypothalamic-pituitary axis in the male is controlled by negative feedback, which has two paths. In the first path, testosterone itself feeds back on both the hypothalamus and the anterior lobe, where it inhibits the secretion of GnRH and LH. At the hypothalamic level, testosterone decreases both the frequency and amplitude of the GnRH pulses. In the second path, the Sertoli cells secrete a substance calledinhibin. Inhibin is a glycoprotein that is a feedback inhibitor of FSH secretion by the anterior pituitary. Thus, the Sertoli cells, which produce sperm, synthesize their own feedback inhibitor that serves as an “indicator” of the spermatogenic activity of the testes.
Negative feedback control of the hypothalamic-pituitary axis is illustrated when circulating levels of testosterone are decreased (e.g., testes are removed). Under such conditions, the frequency and amplitude of GnRH, FSH, and LH pulses are increased because of decreased feedback inhibition by testosterone on the hypothalamus and anterior pituitary.
Actions of Androgens
In some target tissues, testosterone is the active androgenic hormone. In other target tissues, testosterone must be activated to dihydrotestosterone by the action of 5α-reductase (Box 10-3). Table 10-1 is a summary of the target tissues for testosterone and dihydrotestosterone and their respective actions.
BOX 10–3 Clinical Physiology: 5α-Reductase Deficiency
DESCRIPTION OF CASE. Jenny was born with what appeared to be an enlarged clitoris, although neither her parents nor the doctor questioned the abnormality. Now, at 13 years old, Jenny’s girlfriends are developing breasts and having menstrual periods, but she is experiencing none of these changes. In fact, her voice is deepening, she is becoming muscular like the boys, and her enlarged clitoris is growing larger. Jenny is diagnosed with a form of male pseudohermaphroditism that is caused by a deficiency of 5α-reductase. On physical examination, she had no ovaries, no uterus, a blind vaginal pouch, a small prostate, a penis, descended testes, and hypospadias (urethral opening low on the underside of the penis). She had a male musculature but no body hair, facial hair, or acne. Her genotype was confirmed as 46, XY, and blood work showed a high-normal level of testosterone and a low level of dihydrotestosterone. Fibroblasts from genital skin had no 5α-reductase activity.
EXPLANATION OF CASE. Jenny is a genotypic male with testes and no ovaries. Her testes secrete testosterone, but she lacks the enzyme 5α-reductase. In normal males, some androgenic target tissues contain 5α-reductase, which converts testosterone to dihydrotestosterone; in those tissues, dihydrotestosterone is the active androgen. Androgenic actions that utilize dihydrotestosterone include differentiation of the external male genitalia, stimulation of hair follicles, male pattern baldness, activity of sebaceous glands, and growth of the prostate. Other androgenic target tissues in normal males do not contain 5α-reductase and do not synthesize dihydrotestosterone; in those tissues, testosterone is active. Androgenic actions that respond directly to testosterone include differentiation of internal male genital tract (epididymis, vas deferens, seminal vesicles), development of muscle mass, pubertal growth spurt, growth of the penis, deepening of the voice, spermatogenesis, and libido.
As a genetic male (46, XY), the presence of the Y chromosome determined that Jenny would have testes. Prenatally, the testes synthesized antimüllerian hormone and testosterone. Antimüllerian hormone suppressed development of the müllerian ducts into the internal female genital tract, so Jenny has no fallopian tubes, uterus, or upper one third of the vagina. Testosterone caused differentiation of the wolffian ducts into the internal male genital tract (epididymis, vas deferens, seminal vesicles), a process that does not require dihydrotestosterone and thus occurred even though she is lacking 5α-reductase. However, differentiation of the external male genitalia (e.g., penis, scrotum) requires dihydrotestosterone. Thus, deficiency of 5α-reductase meant that Jenny’s external genitalia were not normally developed. At puberty, the clitoris grew and became more like a penis because of the high-normal circulating level of testosterone; apparently, with high enough levels, the androgen receptors that mediate growth of the external genitalia can be activated. Her voice deepened and she acquired skeletal muscle mass, actions that are mediated by testosterone and do not require conversion to dihydrotestosterone. Despite acquiring many masculine characteristics, Jenny did not develop body and facial hair because the hair follicles require dihydrotestosterone. Jenny did not develop breasts because she did not have ovaries, which in normal females are the source of the estrogen required for breast development.
TREATMENT. If Jenny chooses to continue life as a woman, it will be necessary to remove her testes, which are producing the testosterone that is causing her to be selectively masculinized (e.g., growth of penis, deepening of voice, muscle mass). In addition, because she lacks ovaries, Jenny has no endogenous source for the estrogen needed for breast development and female fat distribution; thus, she would require treatment with supplemental estrogen. She may elect to have surgical correction of the introitus; however, even with the surgery, she will not be able to bear children because she lacks ovaries and an internal female genital tract. If Jenny chooses to live the rest of her life as a man, she will be treated with androgenic compounds that do not require 5α-reduction for activity. The supplemental androgens will complete the masculinization process including development of male body and facial hair, sebaceous gland activity, growth of the prostate and, in later life, male pattern baldness.
Table 10–1 Actions of Androgens on Target Tissues
Mediated by Testosterone
Mediated by Dihydrotestosterone
Differentiation of epididymis, vas deferens, and seminal vesicles
Increased muscle mass
Pubertal growth spurt
Cessation of pubertal growth spurt (epiphyseal closure)
Growth of penis and seminal vesicles
Deepening of voice
Negative feedback on anterior pituitary
Differentiation of penis, scrotum, and prostate
Male hair pattern
Male pattern baldness
Sebaceous gland activity
Growth of prostate
Testosterone is responsible for the fetal differentiation of the internal male genital tract: the epididymis, vas deferens, and seminal vesicles. At puberty, testosterone is responsible for increased muscle mass, the pubertal growth spurt, closure of the epiphyseal plates, growth of the penis and seminal vesicles, deepening of the voice, spermatogenesis, and libido. Finally, as mentioned previously, testosterone mediates negative feedback effects on the anterior pituitary and the hypothalamus.
Dihydrotestosterone is responsible for fetal differentiation of the external male genitalia (i.e., the penis, scrotum, and prostate); for male hair distribution and male pattern baldness; for sebaceous gland activity; and for growth of the prostate.
5α-Reductase inhibitors such as finasteride block the conversion of testosterone to dihydrotestosterone and, therefore, block the production of active androgens in some target tissues. Because the growth of the prostate gland and male pattern baldness depend on dihydrotestosterone rather than testosterone, 5α-reductase inhibitors can be used as a treatment for benign prostatic hypertrophy and hair loss in males.
The mechanism of action of androgens begins with binding of testosterone or dihydrotestosterone to an androgen-receptor protein in the cells of target tissues. The androgen-receptor complex moves into the nucleus, where it initiates gene transcription. New messenger ribonucleotides (mRNAs) are generated and translated into new proteins that are responsible for the various physiologic actions of androgens.