Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
The Testis and Male Hypogonadism, Infertility, and Sexual Dysfunction
Male Reproductive Physiology
The testis is a bifunctional organ that serves as the site for synthesis of sex steroids (mainly testosterone) and the production of sperm. Androgens and their metabolites (including estrogens) also act on nonreproductive organs and serve essential roles in muscle, adipose tissue, bone, hematopoietic cells, liver, and brain.
The male reproductive axis consists of three main components: (1) hypothalamus, where the kisspeptin-neurokinin B-dynorphin neurons are located and gonadotropin-releasing hormone (GnRH) is produced; (2) pituitary, where gonadotrophs secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and (3) testes, which produce sex hormones and spermatozoa (sperm) ( Fig. 216-1 ). The components of this system function in an integrated fashion to control the concentrations of circulating gonadal steroids required for normal male sexual development and function, as well as for androgen- and estrogen-mediated effects on critical sex-steroid sensitive end organs. The reproductive axis is also responsible for normal male germ cell development and maturation. Accessory sexual organs, including the epididymides, seminal vesicles, and prostate gland, are important for sperm maturation (epididymis) and seminal fluid production (seminal vesicles and prostate). An anatomically functional sperm transport and ejaculatory system are necessary to ensure male fertility.
Hypothalamic-Pituitary Function
The hypothalamus is responsible for the normal pulsatile secretion of GnRH ( Chapter 205 ) that signals the anterior pituitary to release LH and FSH every 60 to 90 minutes in men. The secretion of GnRH is regulated mainly by kisspeptin, neurokinin B, and dynorphin neurons in the infundibular nucleus in the hypothalamus. Kisspeptin stimulates GnRH secretion directly, whereas neurokinin B stimulates kisspeptin neurons that in turn lead to GnRH secretion. In contrast, dynorphin has inhibitory effects on kisspeptin signaling. Negative feedback from circulating levels of testosterone or its metabolic products (i.e., estradiol and dihydrotestosterone) inhibit the secretion and release of GnRH. Norepinephrine, nitric oxide, and glutamate stimulate this process, whereas gamma-amino butyric acid, prolactin, and glucocorticoid are inhibitory. Caloric restriction is associated with suppressed kisspeptin and leptin, which also are stimulants for GnRH secretion.
Both LH and FSH consist of two subunits (α and β), each of which is required for biologic activity. LH has a shorter half-life than FSH. Feedback regulation of LH and FSH secretion also occurs at the pituitary, with testosterone, dihydrotestosterone, and estradiol inhibiting the synthesis or release of both gonadotropins. The circulating testicular peptide inhibin, produced by Sertoli cells, also selectively inhibits FSH. LH and FSH act through specific cell surface receptors on the Leydig and Sertoli cells, respectively.
Testosterone
The testis is a complex organ consisting of (1) seminiferous tubules containing Sertoli cells and germ cells and (2) the interstitial space, which contains the steroid-secreting (Leydig) cells. Leydig cells synthesize steroid hormones under the regulation of LH. The LH receptors on the cell surface of the Leydig cells signal through G protein–, adenyl cyclase–, and cyclic adenosine monophosphate–mediated activation of steroid biosynthesis.
Testosterone is the principal male hormone secreted by the testes; approximately 5 to 10 mg/day is produced in adult men. Testosterone synthesis occurs in the human testes through either the Δ 4 or the predominant Δ 5 pathway The enzymatic rate-limiting steps in the process are the LH-inducible steroid acute regulatory protein and translocator protein that converts cholesterol to pregnenolone by the cholesterol side-chain cleavage enzyme (P450SCC) ( E-Fig. 216-1 ).
Testosterone circulates mainly bound to two plasma proteins: sex hormone–binding globulin and albumin. In young adult men, approximately 54% of testosterone is bound to albumin, 44% is bound to sex hormone–binding globulin, and 2 to 3% is unbound (free). Bioavailable testosterone refers to the sum of albumin-bound and free testosterone and is measured by separating sex hormone–binding globulin–bound testosterone from total testosterone. Serum sex hormone–binding globulin levels are increased in hyperestrogenic states, hyperthyroidism, aging, phenytoin treatment, anorexia nervosa, and prolonged stress. In contrast, the levels are lowered in hyperandrogenic states (endogenous and exogenous as in androgen treatment), obesity, acromegaly, and hypothyroidism. In most instances, measurement of serum total testosterone provides biochemical support for the diagnosis of testosterone deficiency. In conditions with abnormal sex hormone–binding globulin levels, however, the total testosterone measurement may be misleading, and measurement of non–sex hormone–binding globulin–bound testosterone may allow better interpretation of the bioactive testosterone levels.
Testosterone exerts its effects either through direct action or after conversion to dihydrotestosterone by two separate 5α-reductase isozymes or to estradiol by the aromatase enzyme. Both testosterone and dihydrotestosterone bind efficiently to the androgen receptor. Testosterone also can serve as a precursor for estradiol, notably in bone and adipose tissues. After conversion, estradiol binds to the estrogen receptors (α or β) to induce its effects. Various end organs differ in their 5α-reductase isoenzyme and aromatase concentrations or activity. Congenital and acquired defects in these two enzymes, as well as in the estrogen and androgen receptors, result in distinct syndromes with characteristic phenotypes ( Chapter 214 ).
Spermatogenesis
The spermatogenic compartment of the testis consists of the Sertoli and germ cells that are intimately interactive with the interstitial compartment. The Sertoli cells bridge the entire space between the basement membrane and the lumen of the tubules. They are the target of androgen and FSH action to regulate spermatogenesis. Sertoli cells secrete a multitude of paracrine regulators of spermatogenesis (e.g., inhibin, activin, growth factors, and cytokines).
The development and maturation of germ cells depend on the proper hormonal (FSH) and paracrine (testosterone) milieu. Both testosterone and FSH stimulate progression of spermatogonia to mature spermatozoa, limit the amount of germ cell death (apoptosis), and regulate sperm release from the germinal epithelium.
After spermatogenesis is completed, mature spermatozoa are released into the lumen of the seminiferous tubule and travel through the rete testes and epididymis, where they become functionally mature, before traversing the vas deferens. The seminal fluid from the testes gains constituents from the seminal vesicles, prostate, and bulbourethral glands before ejaculation.
Sexual Function and Erectile Physiology
Sexual function in men requires normal sexual desire (libido) as well as erectile, ejaculatory, and orgasmic capacity. This complex process involves cognitive, sensory, hormonal, autonomic neuronal, and penile vascular integrative actions for normal function. Defects can occur at multiple levels.
The brain is the integrative center of the sexual response system. It processes sensory input and hormonal signals to create the hypothalamic neuronal message that traverses the spinal cord to the T9-12 sympathetic and sacral parasympathetic outflow tracts. The nonadrenergic, noncholinergic autonomic plexus nerves initiate vasodilation of the cavernosal arterial and corpora cavernosal sinusoids of the penis by the release of local vasodilators (e.g., nitric oxide and vasoactive intestinal peptide) from the vascular endothelium and the sinusoidal smooth muscle cells of the sinusoids ( E-Fig. 216-2 ). Nitric oxide produces smooth muscle dilation by the generation of cyclic guanosine monophosphate (cGMP) and the modification of calcium flux. The neurogenic mechanisms leading to vasodilation of the cavernosal arterioles and sinusoids result in a rapid increase in penile blood flow and expansion of the vascular channels; these effects inhibit venous return by compressing the venous channels against the tunica albuginea to limit venous drainage.
Testosterone’s primary effect on erectile function is to enhance libido. Testosterone also increases penile nitric oxide synthase activity and enhances smooth muscle cell growth. Sexual desire and fantasy are highly sensitive to testosterone, thereby explaining the preservation of erectile capacity in many men with partial androgen deficiency.
Pubertal Development and Aging
Reproductive Axis Development during Childhood and Puberty
Adrenarche and Puberty
Adrenarche occurs at approximately 7 or 8 years of age when the zona reticularis of the adrenal gland undergoes maturation and secretes adrenal androgens, including androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. The process is under the control of adrenocorticotropic hormone, not LH or FSH. Androstenedione and dehydroepiandrosterone are androgenic pre-hormones, and the prepubertal growth spurt and development of pubic and axillary hair are mediated by the conversion of these precursors to testosterone and dihydrotestosterone in peripheral tissues.
Initiation of puberty is determined by an increase in the pulsatile pattern of hypothalamic GnRH secretion. The secretory pulses of GnRH are synchronized by increased kisspeptin secretion from the hypothalamic neurons and nocturnal bursts of LH secretion. As puberty progresses, feedback sensitivity of the hypothalamus and pituitary to circulating steroids lessens, thereby increasing the secretion of gonadotropins. The increasing concentrations of intratesticular testosterone and circulating FSH stimulate the Sertoli cell to produce factors leading to the initiation and maturation of spermatogenesis. As spermatogenesis advances, the first sign of puberty is marked by testes increasing in size from 3 to 5 mL at the outset of puberty to 15 to 35 mL in adulthood. The majority of the extratesticular end-organ events of puberty are secondary to the increased testosterone and its metabolic products (dihydrotestosterone and estradiol) ( Table 216-1 ). The penis and scrotum grow and become pigmented. A progressive increase is seen in facial, axillary, chest, abdominal, thigh, and pubic hair; frontal scalp hair regresses, and the voice deepens. Genital and sexual hair development and temporal scalp hair regression require dihydrotestosterone (DHT). The increased levels of sex steroids result in closure of the epiphysis and achievement of adult height.
TABLE 216-1
PUBERTAL STAGES IN BOYS
Modified from Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch Dis Child . 1970;45:13-23; Daniel WA Jr, Feinstein RA, Howard-Peebles P, et al. Testicular volumes of adolescents. J Pediatrics . 1982:101:1010-1012.
| STAGE/AGE (YEARS) | PUBIC HAIR | GENITAL |
|---|---|---|
| I | Absence of pubic hair | Childlike penis, testes, and scrotum (testis 5.0 ± 3.6 cm 3 ) |
| II 11.7 ± 1.3 | Sparse, lightly pigmented hair mainly at base of penis | Scrotum enlarged with early rugation and pigmentation; testes begin to enlarge (6.7 ± 3.5 cm 3 ) |
| III 13.2 ± 0.8 | Hair becomes coarse, darker, more curled, and more extensive | Penis has grown in length and diameter; testes now 14.7 ± 6.3 cm 3 ; scrotum more rugated |
| IV 14.7 ± 1.1 | Hair adult in quality, but distribution does not include medial aspect of thighs | Penis further enlarged, with development of glans; scrotum and testes (20.1 ± 6.2 cm 3 ) further enlarged |
| V 15.5 ± 0.7 | Hair is adult and extends to thighs | Penis and scrotum fully adult; testes 29.3 ± 9.1 cm 3 |
Aberrations of Timing of Puberty
Delayed Puberty
Delayed puberty, more common in boys than in girls, is usually diagnosed when male sexual development has not begun by age 14 years. The majority of boys with delayed development have a functional hypothalamic–pituitary disorder and a family history of delayed puberty. Most eventually attain full sexual maturation when puberty is completed within 4.5 years. Other causes of delayed puberty include genetic factors (congenital hypogonadotropic hypogonadism), prior chemotherapy or radiation therapy, malnutrition, excessive exercise, chronic illnesses, and diseases of the hypothalamus and pituitary.
Diagnosis
Careful documentation of changing physical findings and measurement of serum LH, FSH, and testosterone concentrations may provide valuable clues to the beginning of puberty. An increase in testicular size to more than 3 mL usually heralds the onset of puberty. Inquiring and testing for hyposmia or anosmia and other midline defects may indicate a common variant of congenital hypogonadotropic hypogonadism (e.g., Kallmann syndrome; Chapter 214 ).
Treatment
The decision to institute early treatment with testosterone (e.g., testosterone enanthate 10 mg subcutaneous injections every week or 20 mg intramuscular injections every 2 weeks, with the dose increased very slowly every 3 months) depends on the perceived degree of psychological stress associated with the maturational delay. The major concern is early fusion of the epiphyses induced by treatment with testosterone, which compromises optimal height; however, with judicious dosing and monitoring of bone age, this adverse effect is unusual. In adolescent boys with delayed puberty and low levels of gonadotropins, periodic withdrawal of treatment can determine whether spontaneous puberty has occurred. Many adult men diagnosed with and treated as adolescents for a presumed diagnosis of hypogonadotropic hypogonadism achieve normal reproductive function when they discontinue therapy.
Precocious Puberty
Precocious puberty in boys is defined as the onset of pubertal (secondary sexual characteristics) development before 9 years of age. Sexual precocity can be subcategorized as either true (central) isosexual precocious puberty or pseudo–precocious (peripheral) puberty.
Central or true precocious puberty is associated with increases in GnRH-stimulated LH and FSH secretion (hypothalamic–pituitary origin), whereas pseudo–precocious puberty (peripheral precocious puberty) is independent of GnRH stimulation of LH and FSH secretion. Central precocious puberty in boys is often associated with central nervous system (CNS) disease (two thirds of boys), including hypothalamic tumors, cysts, inflammatory conditions, and seizure disorders.
Diagnosis
Diagnostic findings include sexual precocity, inappropriately elevated serum LH levels, and associated elevations of testosterone. Magnetic resonance imaging can localize most lesions. Another cause of central precocious puberty is human chorionic gonadotropin secretory germinomas (hypothalamic or pineal tumors). Pseudo–precocious puberty is characterized by increased testosterone with suppressed LH.
Causes of pseudo–precocious puberty include congenital virilizing adrenal hyperplasia, and testicular testosterone-secreting neoplasms. Constitutively active LH receptor mutations result in uncontrolled testosterone secretion (testotoxicosis).
Treatment
Treatment of true precocious puberty is removal or correction (with surgery or radiation therapy) of the CNS lesion, if possible, and treatment with GnRH analogues (e.g., leuprolide acetate 3-month depot 11.25 or 30 mg; or triptorelin, 6 month depot 22.5 mg every 6 months) to suppress LH and FSH secretion temporarily. There is no consensus on optimal age to withdraw treatment, but between 11 and 11.5 years of chronologic age has been recommended. Treatment of peripheral precocious puberty depends on the cause but includes glucocorticoids (e.g., hydrocortisone 15 mg/m 2 ) for congenital virilizing adrenal hyperplasia and ketoconazole (10 to 20 mg/kg/day) to suppress steroidogenesis, with or without an antiandrogen (e.g., spironolactone 5 to 7 mg/kg/day or bicalutamide 2 mg/kg/day).
Male Senescence: Decreased Testosterone and Other Anabolic Hormones
Testosterone Deficiency in the Elderly
Blood concentrations of androgen pre-hormones (e.g., dehydroepiandrosterone, dehydroepiandrosterone sulfate) peak at approximately the third decade of life and then decline at about 2% per year, thereby resulting in levels that are 10 to 20% of baseline by 80 years of age. As a result, both total and free serum testosterone levels also progressively decrease ( E-Fig. 216-3 ) by as much as 1 to 2% per year. Serum sex hormone–binding globulin levels also rise with age in men, thereby resulting in a higher percentage of circulating testosterone that is tightly bound and causing a greater decline of free testosterone with aging. Older men have increased body fat, particularly visceral fat, and low testosterone levels are associated with comorbid conditions such as obesity and the metabolic syndrome.
In men between ages 40 and 70 years, the crude prevalence rate of symptomatic testosterone deficiency is estimated to be approximately 2 to 6%. Many of the effects of low testosterone levels in aging men are similar to those observed in younger hypogonadal men: decreases in libido, erectile function, muscle mass, muscle strength, bone mass, as well as impaired mood and sense of well-being.
Treatment
The decision of whether to treat low testosterone levels in older men is controversial. Testosterone treatment currently is not recommended to improve energy, vitality, physical function, metabolic syndrome, diabetes, or cognition (see Testosterone treatment).
Male Hypogonadism
Definition and Epidemiology
Hypogonadism (androgen deficiency) is diagnosed in men with consistent symptoms and signs and unequivocally low circulating levels of testosterone. Most men with more severe androgen deficiency have very low intratesticular testosterone concentrations and are infertile.
The true prevalence male hypogonadism is not known except for Klinefelter syndrome, which has a prevalence of about 5 per 10,000 men. Moderate to severe brain injury may also cause low testosterone with a prevalence probably about 5 per 10,000. Classic causes of male hypogonadism (e.g., pituitary tumors, iron overload) are probably rare, seen in less than 1 per 10,000 men. Iatrogenic causes, including systemic chemotherapy and testicular and pituitary radiotherapy, are the most common etiologies of male hypogonadism other than age and obesity.
Pathobiology
Primary hypogonadism, which is characterized by increased serum LH and FSH levels, indicates that the abnormality originates in the testis. Secondary hypogonadism indicates a defect of the hypothalamus ( Chapter 204 ) or anterior pituitary ( Chapter 205 ), thereby resulting in decreased gonadotropins (LH, FSH, or both).
Many conditions can cause primary ( Table 216-2 ) and secondary ( Table 216-3 ) hypogonadism (see also Chapter 214 ). Combined primary and secondary hypogonadism occurs in aging and in a number of systemic diseases, such as alcohol abuse disorder ( Chapter 364 ), liver disease ( Chapter 132 ), type 2 diabetes mellitus ( Chapter 210 ), human immunodeficiency virus (HIV) infection ( Chapter 359 ), hemochromatosis ( Chapter 196 ), and sickle cell disease ( Chapter 149 ). Obesity ( Chapter 201 ) leads to low total and free testosterone levels, with greater decreases in the total testosterone level because obesity not only decreases testosterone secretion but also lowers sex hormone–binding globulin levels. Decreased androgen action with normal or elevated testosterone and LH levels, mimicking androgen deficiency, may occur in patients with androgen receptor defects (androgen resistance), post-receptor signaling abnormalities, and an inability to convert testosterone to the active metabolite dihydrotestosterone (5α-reductase abnormalities).
TABLE 216-2
CAUSES OF PRIMARY TESTICULAR FAILURE AND END-ORGAN RESISTANCE
Congenital disorders
Developmental disorders
Acquired defects
Toxins (e.g., alcohol, fungicides, insecticides, heavy metals, cottonseed oil, DDT, other environmental “endocrine disruptors”)
Autoimmune testicular failure
Systemic diseases ∗ (e.g., cirrhosis, chronic renal failure, sickle cell disease,) |
DDT = dichlorodiphenyltrichloroethane.
∗ Systemic diseases and aging produce a mixed pattern of testicular and hypothalamic-pituitary dysfunction.
TABLE 216-3
CAUSES OF HYPOGONADOTROPIC HYPOGONADISM
| IDIOPATHIC OR CONGENITAL |
Isolated deficiency of gonadotropin-releasing hormone
Partial deficiency of gonadotropin-releasing hormone (fertile eunuch syndrome) |
| ACQUIRED |
| Traumatic brain injury, after surgery or irradiation Neoplastic Pituitary adenoma (prolactinoma, other functional and nonfunctional tumors) Craniopharyngioma, germinoma, glioma, leukemia, lymphoma Pituitary infarction, carotid aneurysm Infiltrative and infectious diseases of hypothalamus and pituitary (sarcoidosis, tuberculosis, coccidioidomycosis, histoplasmosis, syphilis, abscess, histiocytosis X) Hemochromatosis Autoimmune hypophysitis and cancer immunotherapy–induced hypogonadism Aging and systemic diseases ∗ Obesity Malnutrition Anorexia nervosa, starvation, renal failure, liver failure Exogenous hormones and drugs including opiates
|
∗ Aging and systemic diseases produce a mixed pattern of central and testicular dysfunction.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here