1. MALE REPRODUCTIVE SYSTEM
testis-03

2. MALE REPRODUCTIVE SYSTEM
 TO REVIEW THE COMPONENTS OF THE MALE REPRODUCTIVE SYSTEM
 TO CHARACTERIZE THE GENERAL ORGANIZATION OF THE TESTIS
 TO UNDERSTAND THE HORMONAL REGULATION AND PROCESS OF SPERMATOGENESIS
epididymus-04

3. MALE REPRODUCTIVE SYSTEM
 TESTES
 EPIDIDYMIS
 VAS DEFERENS
 SEMINAL VESICLES
 PROSTATE
testes within scrotum; temperature 2-3 degrees C below body temperature which is essential for sperm production
descent of testes during development (tunica vaginalis)
 BULBOURETHRAL GLANDS
 URETHRA

4. Male Reproductive System
Pathway of spermatozoa
Epididymis
Ductus deferens (Vas deferens)
Ejaculatory duct
Accessory organs
Seminal vesicles
Prostate gland
Bulbourethral glands
Scrotal sac encloses testes
Penis

5. The Male Reproductive System in Midsagital View
Figure 28.1

6. The Male Reproductive System in Anterior View
Figure 28.3

7. The Structure of the Testes
Figure 28.4

8. The Epididymus
Figure 28.9

9. Epididymis and Ductus Deferens
Epididymis: connection between the testis and ductus deferens
Three parts: head (cauda), body, and tail
Ductus deferens (vas deferens): connects tail of epididymis to ejaculatory duct
Ascends within scrotum in the spermatic cord, into the pelvic region.

10. The Ductus Deferens and Accessory Glands
Figure 28.10a-e

11. Seminal Vesicles and Prostate
Seminal vesicles: enlarged, sac-like structures which open into ejaculatory ducts.
Prostate: lobular structure at base of bladder.

12. Male External Genitalia
Penis: male copulatory organ (also excretion: elimination of urine)
Composed of three columns of erectile tissue, each enclosed by connective tissue
Scrotum: two separate compartments, each containing a testis.
Wall of scrotum: skin, superficial loose connective tissue, smooth muscle (dartos).

13. Male Accessory Sex Organs: the Penis
3 columns of erectile tissue:
- corpus spongiosum: 1 column, includes glans penis, and contains the spongy (penile) urethra
- 2 corpora cavernosa: lateral columns, forming the dorsum and sides of the penis

14. The Penis
Figure 28.11

15. Hormones and Male Reproductive Function
FSH (Follicle stimulating hormone)
Targets sustentacular cells to promote spermatogenesis
LH (leutinizing hormone)
Causes secretion of testosterone and other androgens
GnRH (Gonadotropin releasing hormone)
Testosterone
Most important androgen

16. MALE REPRODUCTIVE SYSTEM
 TESTIS
TUNICA ALBUGINEA
- thick connective tissue capsule
- connective tissue septa divide testis into 250 lobules
- each lobule contains 1-4 seminiferous tubules and interstitial connective tissue
(1) SEMINIFEROUS TUBULES
- produce sperm
INTERSTITIAL TISSUE
- contains Leydig cells which produce testosterone
(2) RECTUS TUBULES
(3) RETE TESTIS
(4) EFFERENT DUCTULES
(5) EPIDIDYMIS

17. MALE REPRODUCTIVE SYSTEM
TUNICA ALBUGINEA
 TESTIS
Mediastinum containing RETE TESTIS
EPIDIDYMIS
testis-06
LOBULES

18. TESTIS H&E
SEMINIFEROUS TUBULES
testis-01

19. INTERSTITIAL CONN. TISSUE
TESTIS H&E
SEMINIFEROUS TUBULES
SEMINIFEROUS TUBULES
INTERSTITIAL CONN. TISSUE
testis-02

20. INTERSTITIAL CONN. TISSUE
TESTIS H&E
SEMINIFEROUS TUBULES
SEMINIFEROUS TUBULES
testis-03
INTERSTITIAL CONN. TISSUE

21. MALE REPRODUCTIVE SYSTEM
 TESTIS
TUNICA VAGINALIS
TUNICA ALBUGINEA
SEMINIFEROUS TUBULES
SEMINIFEROUS EPITHELIUM
- complex stratified epithelium containing two basic cell populations:
(1) SPERMATOGENIC CELLS 3
(2) SERTOLI CELLS

22. MALE REPRODUCTIVE SYSTEM
 TESTIS
SEMINIFEROUS TUBULES
SEMINIFEROUS EPITHELIUM
- complex stratified epithelium containing two basic cell populations:
(1) SPERMATOGENIC CELLS
stem cells which regularly replicate and differentiate into mature sperm as they migrate toward the lumen 4
(2) SERTOLI CELLS
nonreplicating physical support cells
INTERSTITIAL CONNECTIVE TISSUE
(1) LEYDIG CELLS
produce and release testosterone

23. MALE REPRODUCTIVE SYSTEM
 SPERMATOGENESIS
SPERMATOGONIA
1º SPERMATOCYTE
2º SPERMATOCYTE
SPERMATIDS
SPERMATIDS
2º SPERMATOCYTE
tight junctions of lateral processes may temporarily open to permit the passage of spermatogenic cells toward the lumen
1º SPERMATOCYTE
SERTOLI CELLS:
- columnar with adjoining lateral processes
- extend from basal lamina to lumen
- Sertoli-Sertoli junctions divide seminiferous tubules into basal and adluminal compartments
SERTOLI CELLS
SPERMATOGONIA

24. MALE REPRODUCTIVE SYSTEM
SEMINIFEROUS TUBULES
 SPERMATOGENESIS
THREE PHASES:
(1) Spermatogonial Phase (Mitosis)
- spermatogonia proliferate by mitotic divisions to provide stem cells and cells which will proceed through spermatogenesis (1º spermatocytes)
(2) Spermatocyte Phase (Meiosis)
- diploid cells (2n) created in spermatogonial phase give rise to haploid cells (1n)
- Meiosis I (reduction division) and Meiosis II (equatorial division)
- 1º spermatocytes enter Meiosis I to form 2º spermatocytes which then enter Meiosis II and result in spermatids 5
exchange of genetic material in MI via crossing over
(3) Spermatid Phase (Spermiogenesis)
- spermatid differentiation into spermatazoa

25. Basal Lamina 2n 2n 2n n n n n n n n n n n n
Daughter cell Type A spermatogonium remain at basal lamina as a precursor cell 2n 2n
Spermatogonia (stem cells) 2n
mitosis
Daughter cell Type B Spermatagonium
Moves to adluminal compartment n
1° spermatocyte
Meiosis I completed n
2° spermatocyte n
Meiosis II n n n n
Early spermatids
n n n n
Late spermatids

26. MALE REPRODUCTIVE SYSTEM
 SPERMATOGENESIS
THREE PHASES:
(1) Spermatogonial Phase (Mitosis)
(2) Spermatocyte Phase (Meiosis)
(3) Spermatid Phase (Spermiogenesis)
- acrosome formation; golgi granules fuse to form acrosome that contains hydrolytic enzymes which will enable the spermatozoa to move through the investing layers of the oocyte
- flagellum formation; centrioles and associate axoneme (arrangement of microtubules in cilia)
- changes in size and shape of nucleus; chromatin condenses and shedding of residual body (cytoplasm)

27. MALE REPRODUCTIVE SYSTEM
 SPERMIOGENESIS
Mature sperm 60µm long and acquire full motility in epididymis
(1) HEAD
- nucleus and acrosome
(2) NECK
- centriole and connecting piece
(3) TAIL
- middle piece 2
(axoneme, outer dense fibers, mitochondial sheath)
- principal piece
(axoneme, outer dense fibers, fibrous sheath)
- end piece
(axoneme)

28. MALE REPRODUCTIVE SYSTEM
 SPERMIOGENESIS

29. Maturation of Sperm
Sperm leaving the testis and entering the epididymis are nonmotile and not capable of fertilization.
Sperm acquire motility and final maturation as they travel through the epididymis.

30. Time Span of Sperm Development
It takes about 70 days to develop from spermatogonia to spermatozoa.
It takes another 14 days to travel through epididymis to the ejaculatory duct.
Illness and exposure to toxic agents can have a delayed effect on quality of sperm produced.

31. Production of Semen
Semen is composed of spermatozoa and the secretory products of the seminal vesicle (60%) and prostate (30%).
Products of the seminal vesicle and prostate include
- fructose (metabolized for energy by sperm)
- prostaglandins (uterine contractions)
- coagulating and decoagulating factors
- antibacterial agents
- pH adjusters (acids and bases)
The bulbourethral gland secretes an alkaline mucus, neutralizes acidity in the urethra and provides lubrication

32. Capacitation of Sperm
To fertilize an egg, the spermatozoa must undergo capacitation in the female reproductive tract following ejaculation.
Capacitation results in:
- increased velocity of sperm movement
- release of enzymes which allow sperm to reach the oocyte and penetrate it (acrosome reaction)
- requires 2 to 6 hours
(sperm may remain alive in the reproductive tract for days)

33. Male Sexual Response
Three distinct phases have been identified; arousal, emission, and ejaculation.
Arousal: erotic thoughts or physical stimulation result in activation of the parasympathetic system (via pelvic splanchnic nerves).
- increased production of nitric oxide
- nitric oxide activates soluble guanylate cyclase, resulting in increased production of cGMP
- cGMP causes vasodilatation of blood vessels in the penis, resulting in increased blood flow and erection

34. Male Sexual Response
Emission: Sympathetic stimulation causes peristaltic contractions of the ampulla of the ductus deferens, the seminal vesicles, and the prostate. Thus, spermatozoa and seminal fluids enter the prostatic urethra.
At the same time, the internal urethral sphincter closes off the bladder to prevent retrograde ejaculation

35. Male Sexual Response
Ejaculation: Contractions of two skeletal muscles:
- ischiocavernosus: contractions against the erectile tissue of the penis
- bulbocavernosus: contractions push semen from base of penis to urethral opening
(note that these are skeletal muscles under sympathetic control)

36. Role of Testosterone in Male Sexual Response
Testosterone increases libido (sexual thoughts and desires).
However, testosterone plays little role in capacity of men to have sexual intercourse.
Impotence (inability to achieve or maintain erection) can be due to physical causes (circulatory problems, drugs, alcohol, trauma, illness) or psychological state (depression, anxiety, stress).
Viagra: inhibitor of cGMP-specific phosphodiesterase (increases cGMP levels).

37. Mechanism of Action of Viagra
arousal
parasympathetic stimulation
nitric oxide
cyclic GMP
increased penile blood flow
Viagra
PDE5
5’ GMP

38. Hormonal Regulation
of the Male Reproductive
System

39. MALE REPRODUCTIVE SYSTEM
 HORMONAL REGULATION OF MALE REPRODUCTIVE FUNCTION
HYPOTHALAMUS REGULATES ACTIVITY OF ANTERIOR PITUITARY (ADENOHYPOPHYSIS)
ADENOHYPOPHYSIS SYNTHESIZES HORMONES (LH and FSH) THAT MODULATE ACTIVITY OF SERTOLI AND LEYDIG CELLS
Luteinizing Hormone (LH): stimulates testosterone production by Leydig cells
Follicle Stimulating Hormone (FSH): stimulates production of sperm in conjunction with testosterone by regulating activity of Sertoli cells
SERTOLI CELLS STIMULATED BY FSH AND TESTOSTERONE RELEASE ANDROGEN BINDING PROTEIN WHICH BINDS TESTOSTERONE; THEREBY INCREASING TESTOSTERONE CONCENTRATION WITHIN THE SEMINIFEROUS TUBULES AND STIMULATING SPERMATOGENESIS

40. Regulation of LH and FSH Synthesis and Release by GnRH
GnRH stimulates both the synthesis and release of gonadotropins.
GnRH is released from the hypothalamus in a pulsatile manner (once ever minutes in adult men).
Constant, high levels of GnRH will DECREASE gonadotropin release, by down-regulation of GnRH receptors.
GnRH LH LH

41. Mechanism of GnRH Action on Pituitary Gonadotroph Cells
GnRH binds to a G protein-coupled receptor.
Binding of GnRH to receptor results in activation of phospholipase C.
Get increased production of IP3 and DAG.
Increased IP3 leads to release of LH, FSH.
DAG activates PKC, which increases synthesis of LH and FSH.

42. Mechanism of GnRH Action on Pituitary Gonadotroph Cells
Calcium release
GnRH R
synthesis
Protein Kinase C
LHb mRNA

43. Feedback Regulation of LH and FSH by Gonadal Steroids
Testosterone (and estradiol, from peripheral conversion) exerts negative feedback effects on LH and FSH synthesis and release in the male.
- decreased pulsatile release of GnRH
- decreased pituitary response to GnRH stimulation
Males do NOT show positive feedback responses of LH to high levels of estradiol.

44. Regulation of LH and FSH by GnRH Alone?
To date, only one hypothalamic releasing factor controlling release of LH and FSH has been found (GnRH).
There are cases when LH release is different from FSH release. How can this happen?
Two possibilities:
- influence of GnRH pulse frequency on LH versus FSH levels
- other factors which control FSH levels exist

45. Influence of GnRH Pulse Frequency on LH versus FSH Release
GnRH is released from the hypothalamus as discrete pulses.
High frequency pulses (once every 30 minutes) result in stimulation of LH release, with less release of FSH.
Low frequency pulses (once every 60 minutes) result in stimulation of FSH release, with less release of LH.
Thus, regulating the pulse frequency of GnRH release can give preferential release of LH or FSH.
GnRH
LH FSH
LH FSH

46. Influence of Gonadal Peptides on Synthesis and Release of FSH
The testis and ovary produce two hormones which influence FSH, but not LH release.
Inhibin: preferentially inhibits the synthesis and release of FSH from the anterior pituitary (no effect on LH).
Activin: preferentially stimulates the synthesis and release of FSH from the pituitary (no effect on LH).
Both act at the level of the pituitary (do not influence GnRH release).

47. Regulation of Inhibin Production
Inhibin production from Sertoli cells is stimulated by FSH.
However, a real role of inhibin and activin from the testis on FSH release is not clear in adult males (blocking inhibin action doesn’t increase FSH).
There is evidence that inhibin and activin are also produced locally from the pituitary (and possibly hypothalamus), providing local control of FSH release.

48. Mechanism of Action of LH and FSH on Testicular Cells
Leydig cells have receptors for LH, but not for FSH.
Sertoli cells have receptors for FSH, but not for LH.
Both the LH and FSH receptor are G protein-coupled receptors, with a fairly high degree of homology.
Specificity of hormone binding is determined by the amino terminus extracellular domains.

49. The Structure of LH and FSH
LH and FSH are composed of two subunits.
The  subunit is shared by FSH, LH, TSH, and hCG
Distinct ß subunits confer specific receptor binding and biological activity of these glycoproteins
Each subunit is glycosylated, folded, and joined to its corresponding subunit

50. Binding Specificity Due To Extracellular Domains of the LH and FSH Receptors
cyclic AMP
cyclic AMP

51. Mutant LH/FSH Receptor
LHR Extracellular
Domain
FSHR Transmembrane and
Intracellular Domains + LH
cyclic AMP

52. Mechanism of Action of Gonadotropins
Gonadotropin receptors are coupled to Gs
- increased cAMP
- leads to activation of protein kinase A
- phosphorylation of cAMP response element binding protein (CREB), a transcription factor

53. Actions of FSH on the Testis
FSH acts on Sertoli cells
- stimulate spermatogenesis
- increase production of inhibin
- increase production of androgen-binding protein, which binds to testosterone to increase local levels in the testis and epididymis
FSH also augments effects of LH on testosterone production (possibly through peritubular cells?)

54. Actions of LH on the Testis
Primary action: stimulate testosterone production
- binds to LH receptors on Leydig cells
- increases conversion of cholesterol esters to free cholesterol
- increases expression of steroidogenic acute regulatory protein (cholesterol transfer)
- increases expression of P450 side chain cleavage to stimulate steroidogenesis
- increases expression of 17a-hydroxylase

55. Transport and Metabolism of Testosterone
Testosterone is bound to binding proteins in the plasma
- 45% bound to TeBG (not biologically available)
- 35% bound to albumin, 16% to other proteins
- only 4% free in blood
T can be metabolized to other hormones, or conjugates
- peripheral conversion to E2 or DHT
- conjugation in liver, excretion via kidney

56. Actions of Testosterone
Testosterone acts on a wide variety of tissues during sexual differentiation and puberty, and in the adult (see previous lecture).
In the testis, a major action of testosterone is the maintenance of spermatogenesis, via stimulation of Sertoli cells.
The actions of T are mediated through an intracellular androgen receptor, which acts as a transcription factor.

57. testis-05

58. testis-09

59. MALE REPRODUCTIVE SYSTEM
 TESTIS
TUNICA ALBUGINEA
- thick connective tissue capsule
- connective tissue septa divide testis into 250 lobules
- each lobule contains 1-4 seminiferous tubules and interstitial connective tissue
(1) SEMINIFEROUS TUBULES
- produce sperm
INTERSTITIAL TISSUE
- contains Leydig cells which produce testosterone
(2) RECTUS TUBULES
(3) RETE TESTIS
(4) EFFERENT DUCTULES
(5) EPIDIDYMIS

60. EPIDIDYMIS
epididymus-01
EFFERENT DUCTULES

61. MALE REPRODUCTIVE SYSTEM
 EFFERENT DUCTULES
CONNECT RETE TESTIS WITH EPIDIDYMIS
IRREGULAR LUMINAL APPEARANCE DUE TO TALL CILIATED CELLS AND SHORT NON-CILIATED CELLS
CILIATED CELLS BEAT TOWARD EPIDIDYMIS; THIN LAYER OF SMOOTH MUSCLE ALSO AIDS MOVEMENT INTO EPIDIDYMIS 6

62. MALE REPRODUCTIVE SYSTEM
 EPIDIDYMIS
RECEIVES EFFERENT DUCTULES
DIVIDED INTO HEAD, BODY, AND TAIL
PSEUDOSTRATIFIED EPITHELIUM CONSISTING OF PRINCIPAL AND BASAL CELLS
SMOOTH MUSCLE IN HEAD AND TAIL CONTRACT SPONTANEOUSLY; SMOOTH MUSCLE IN TAIL REQUIRES SYMPATHETIC INNERVATION FOR CONTRACTION 7

63. EPIDIDYMIS
STEREOCILIA
MATURE SPERM
epididymus-04

64. EFFERENT DUCTULES
EPIDIDYMIS
epididymus-06

65. EFFERENT DUCTULES
EPIDIDYMIS
epididymus-07

66. epididymus-08
EPIDIDYMIS

67. MALE REPRODUCTIVE SYSTEM
 VAS DEFERENS
CONNECTS EPIDIDYMIS WITH SEMINAL VESICLES
PSEUDOSTRATIFIED COLUMNAR EPITHELIUM
SMOOTH MUSCLE ARRANGED IN 3 LAYERS
SMOOTH MUSCLE CONTRACTION VIA SYMPATHETIC STIMULATION DURING EJACULATION 8

68. MALE REPRODUCTIVE SYSTEM
 VAS DEFERENS 9

69. VAS DEFERENS H&E
vas-02

70. MALE REPRODUCTIVE SYSTEM
 SEMINAL VESICLES
MUCOSA HIGHLY FOLDED
EPITHELIUM PSEUDOSTRATIFIED
SECRETIONS ARE HIGH IN FRUCTOSE AND BASIC
REGULAR SMOOTH MUSCLE CONTRACTS DURING EJACULATION 13

71. MALE REPRODUCTIVE SYSTEM
 SEMINAL VESICLES
EPITHELIUM PSEUDOSTRATIFIED 14

72. MALE REPRODUCTIVE SYSTEM
 PROSTATE
SIMPLE OR PSEUDOSTRATIFIED COLUMNAR EPITHELIUM
30-50 TUBULOALVEOLAR GLANDS WHICH EMPTY INTO URETHRA
PROSTATIC SECRETIONS RICH IN CITRIC ACID, ACID PHOSPHATASE, AND PROTEOLYTIC ENZYMES 10

73. MALE REPRODUCTIVE SYSTEM
 PROSTATE
SIMPLE OR PSEUDOSTRATIFIED COLUMNAR EPITHELIUM 12

74. MALE REPRODUCTIVE SYSTEM
 PROSTATE
PROSTATIC CONCRETIONS
- precipitation of secretory product 11

75. MALE REPRODUCTIVE SYSTEM
 URETHRA
PROSTATIC, MEMBRANOUS, SPONGY (PENILE)

76. PENIS CC CC
URETHRA
penis-01 CS

77. PENIS
ERECTILE BODIES
penis-02