Testicular Abnormalities LEARNING OBJECTIVES The student will be able to: (MUST KNOW) 1. Name the hormones secreted from testis. 2. Outline the steps of synthesis and metabolism of testosterone. 3. Describe the functions of testosterone. 4. List the secondary sex characteristics in males. 5. Comprehend the feedback regulation of testicular functions. 6. Remember the functions of inhibin, activin, and follistatin. 7. Appreciate the importance of 17-ketosteroids. 8. Learn the causes and treatment of cryptorchidism. 9. Understand the physiological basis of other testicular abnormalities. TESTOSTERONE The principal steroid secreted from testis is testosterone. It is the essential hormone for male reproduction, and its absence or decreased production leads to sterility. Primarily, it allows the development of male reproductive organs during fetal life, controls spermatogenesis, guides development of secondary sex characteristics, and maintains male vigor. Source Testosterone is synthesized by the Leydig cells of testis. Testosterone is also secreted from adrenal cortex, ovaries, and placenta. Thus, a small amount of testosterone is secreted in females. STEPS OF TESTOSTERONE SYNTHESIS METABOLISM About 98% of testosterone binds with plasma proteins and only 2% is free in plasma. • The free testosterone enters the target tissues in which it is converted to its active form dihydrotestosterone (DHT) by 5α-reductase and estradiol (17β-estradiol) by aromatase. • Thus, testosterone acts as prohormone and DHT is the biologically active hormone. • Dihydrotestosterone has 2–3 times more affinity than testosterone for binding with androgen receptors. • Dihydrotestosterone causes hypertrophy of prostate. MECHANISM OF ACTION FATE OF TESTOSTERONE SECRETED FROM LEYDIG CELLS PHYSIOLOGICAL ACTIONS Development of Secondary Sex Characteristics 1. Changes in external genitalia: Penis enlarges in length and width. The scrotum becomes more rugose and pigmented. 2. Changes in internal genitalia: Seminal vesicles increase in size and start secreting fructose. Prostate gland enlarges and secretion increases from prostate and bulbourethral gland. 3. Growth and distribution of body hairs. 4. Skin changes: In general, skin becomes tough. Secretion of sebaceous gland increases and becomes thick. 5. Mental changes: The individual becomes more active and aggressive. He takes more interest in opposite sex. 6. Voice change: Enlargement of larynx and thickening of vocal cord occur. Therefore, voice becomes thick and deep. 7. Body configuration: General increase in body height and girth occurs (growth spurt). 8. Musculoskeletal changes: Growth of long bones, pectoral girdle, and vertebral bones occurs at puberty. Effects on Spermatogenesis Testosterone stimulates spermatogenesis, the exact mechanism of which is not known. It is essential for sperm production and maturation. 1. It mainly facilitates the process of spermiogenesis. 2. It initiates spermatogenesis at puberty, and then maintains it throughout adulthood and also in old age. Effects during Embryonic Life In male fetus, between 8th week and 18th week, testosterone causes the differentiation of male genitalia. 1. The development of Wolffian duct into epididymis, vas deferens, and seminal vesicles depends directly on the effects of androgen. 2. Also, the differentiation of urogenital sinus and genital tubercle into penis, scrotum, and testis is mediated by testosterone and DHT. 3. Further, descent of testis into scrotum is promoted by testosterone. Anabolic Effects Testosterone increases the synthesis of proteins and decreases its catabolism. This results in increased growth and development of bones and muscles. 1. It causes sodium, potassium, calcium, phosphate, and water retention from kidney. 2. It is used as an anabolic drug in patients suffering from wasting diseases. Athletes use it as anabolic steroids. Effects on Brain Many areas in the brain have androgen receptors. However, the receptors are densely located in limbic areas, especially in amygdala and septum, and in hypothalamus, pituitary, and preoptic area. 1. In these areas, testosterone is aromatized to estrogen. 2. Sexual dimorphism of neurons in the brain with respect to their distribution, size, number, and activity has been reported in preoptic area and amygdala. OTHER TESTICULAR HORMONES Inhibin Source Inhibin is secreted from Sertoli cells of testes in males and granulosa cells of ovaries in females. Functions The main function of inhibin is to provide feedback signal to inhibit FSH secretion from anterior pituitary. Inhibin B mainly inhibits FSH secretion. Activin It is a polypeptide hormone with molecular weight of 30,000. Activin is produced by Sertoli cells. 1. It stimulates secretion of FSH. 2. Activin results from various combinations of βA and βB subunits of inhibin that forms βAβB, βBβB, and βAβA. 3. They stimulate WBC development in the bone marrow, formation of mesoderm during embryonic life, and also gonadal development. Follistatin Follistatin is a single-chain protein having molecular weight of about 40,000. It has various isoforms that bind and inactivate activin. 1. When activins bind with follistatin, they lose their functions. 2. Thus, FSH secretion is reduced from pituitary cells. 3. Follistatin influences developing spermatogenic cells by a paracrine mechanism. REGULATION OF TESTICULAR FUNCTIONS TESTICULAR ABNORMALITIES Cryptorchidism The failure of migration of testis from abdominal cavity into the scrotum during fetal development is called undescended testis or cryptorchidism. The usual site of undescended testis is inguinal rings. 1. From posterior wall of the abdomen testis first descends into the inguinal region, and then from there into the scrotum. 2. The descent from abdomen into the inguinal region depends on MIS. 3. The descent from inguinal region to scrotum depends on testosterone and other factors. 4. Descent of testis normally completes in few days before the birth. Treatment Treatment with gonadotropin hormones facilitates the descent of testis. Surgical correction is required when the hormonal treatment fails. Complications Undescended testis decreases sperm production, as temperature is high in the abdomen. The incidence of malignant tumors is significantly more in undescended testis. MALE HYPOGONADISM Hypergonadotropic Hypogonadism If this occurs due to testicular dysfunctions, plasma level of gonadotropin is increased. Hypogonadotropic Hypogonadism This occurs mainly due to tumor of hypothalamus or pituitary. Gonadotropin level in plasma is depressed. 1. If hypogonadism occurs after puberty, the secondary sex characteristics regress slowly as androgenic maintenance of these features is less essential. However, loss of libido is common. 2. If loss of Leydig cells occurs from childhood, eunuchoidism results. • Eunuchoids are usually tall, with narrow shoulders and less muscular development. • The genitalia are small. • Though pubic hairs are present, they are usually sparse and exhibit female pattern, i.e. triangle with base-up.