MALE INFERTILITY: CAUSES AND INVESTIGATIONS

Published in Clinical Pathology
Friday, 22 September 2017 00:03
The male reproductive system consists of testes (paired organs located in the scrotal sac that produce spermatozoa and secrete testosterone), a paired system of ducts comprising of epididymis, vasa deferentia, and ejaculatory ducts (collect, store, and conduct spermatozoa), paired seminal vesicles and a single prostate gland (produce nutritive and lubricating seminal fluid), bulbourethral glands of Cowper (secrete lubricating mucus), and penis (organ of copulation).
 
The hypothalamus secretes gonadotropin releasing hormone (GnRH) that regulates the secretion of the two gonadotropins from the anterior pituitary: luteinizing hormone (LH) and follicle stimulating hormone (FSH) (Figure 861.1). Luteinizing hormone primarily stimulates the production and secretion of testosterone from Leydig cells located in the interstitial tissue of the testes. Testosterone stimulates spermatogenesis, and plays a role in the development of secondary sexual characters. Testosterone needs to be converted to an important steroidal metabolite, dihydrotestosterone within cells to perform most of its androgenic functions. Testosterone inhibits LH secretion by negative feedback. Follicle stimulating hormone acts on Sertoli cells of seminiferous tubules to regulate the normal maturation of the sperms. Sertoli cells produce inhibin that controls FSH secretion by negative feedback.
 
Figure 861.1 Hypothalamus-pituitary-testis axis. + indicates stimulation; – indicates negative feedback
Figure 861.1 Hypothalamus-pituitary-testis axis. + indicates stimulation; – indicates negative feedback
 
During sexual intercourse, semen is deposited into the vagina. Liquefaction of semen occurs within 20-30 minutes due to proteolytic enzymes of prostatic fluid. For fertilization to occur in vivo, the sperm must undergo capacitation and acrosome reaction. Capacitation refers to physiologic changes in sperms that occur during their passage through the cervix of the female genital tract. With capacitation, the sperm acquires (i) ability to undergo acrosome reaction, (ii) ability to bind to zona pellucida, and (iii) hypermotility. Sperm then travels through the cervix and uterus up to the fallopian tube. Binding of sperm to zona pellucida induces acrosomal reaction (breakdown of outer plasma membrane by enzymes of acrosome and its fusion with outer acrosomal membrane, i.e. loss of acrosome). This is necessary for fusion of sperm and oocyte membranes. Acrosomal reaction and binding of sperm and ovum surface proteins is followed by penetration of zona pellucida of ovum by the sperm. Following penetration by sperm, hardening of zona pellucida occurs that inhibits penetration by additional sperms. A sperm penetrates and fertilizes the egg in the ampullary portion of the fallopian tube (Figure 861.2).
 
Figure 861.2 Steps before and after fertilization of ovum
Figure 861.2 Steps before and after fertilization of ovum
 
Causes of Male Infertility
 
Causes of male infertility are listed in Table 861.1.
 
Table 861.1 Causes of male infertility 
2. Hypothalamic-pituitary dysfunction (hypogonadotropic hypogonadism)
3. Testicular dysfunction:
  • Radiation, cytotoxic drugs, antihypertensives, antidepressants
  • General factors like stress, emotional factors, drugs like marijuana, anabolic steroids, and cocaine, alcoholism, heavy smoking, undernutrition
  • Mumps orchitis after puberty
  • Varicocele (dilatation of pampiniform plexus of scrotal veins)
  • Undescended testes (cryptorchidism)
  • Endocrine disorders like diabetes mellitus, thyroid dysfunction
  • Genetic disorders: Klinefelter’s syndrome, microdeletions in Y chromosome, autosomal Robertsonian translocation, immotile cilia syndrome (Kartagener’s syndrome), cystic fibrosis, androgen receptor gene defect
4. Dysfunction of passages and accessory sex glands:
 5. Dysfunction of sexual act:
  • Defects in ejaculation: retrograde (semen is pumped backwards in to the bladder), premature, or absent
  • Hypospadias
 
Investigations of Male Infertility
 
  1. History: This includes type of lifestyle (heavy smoking, alcoholism), sexual practice, erectile dysfunction, ejaculation, sexually transmitted diseases, surgery in genital area, drugs, and any systemic illness.
  2. Physical examination: Examination of reproductive system should includes testicular size, undescended testes, hypospadias, scrotal abnormalities (like varicocele), body hair, and facial hair. Varicocele can occur bilaterally and is the most common surgically removable abnormality causing male infertility.
  3. Semen analysis: See article Semen Analysis. Evaluation of azoospermia is shown in Figure 861.3. Evaluation of low semen volume is shown in Figure 861.4.
  4. Chromosomal analysis: This can reveal Klinefelter’s syndrome (e.g. XXY karyotype) (Figure 861.5), deletion in Y chromosome, and autosomal Robertsonian translocation. It is necessary to screen for cystic fibrosis carrier state if bilateral congenital absence of vas deferens is present.
  5. Hormonal studies: This includes measurement of FSH, LH, and testosterone to detect hormonal abnormalities causing testicular failure (Table 861.2).
  6. Testicular biopsy: Testicular biopsy is indicated when differentiation between obstructive and non-obstructive azoospermia is not evident (i.e. normal FSH and normal testicular volume).
 
Table 861.2 Interpretation of hormonal studies in male infertility 
Follicle stimulating hormone Luteinizing hormone Testosterone Interpretation
Low Low Low Hypogonadotropic hypogonadism (Hypothalamic or pituitary disorder)
High High Low Hypergonadotropic hypogonadism (Testicular disorder)
Normal Normal Normal Obstruction of passages, dysfunction of accessory glands
 
Figure 861.3 Evaluation of azoospermia
Figure 861.3 Evaluation of azoospermia. FSH: Follicle stimulating hormone; LH: Luteinizing hormone
 
Figure 861.4 Evaluation of low semen volume
Figure 861.4 Evaluation of low semen volume
 
Figure 861.5 Karyotype in Klinefelter's Syndrome
 Figure 861.5 Karyotype in Klinefelter’s syndrome (47, XXY)
 
Common initial investigations for diagnosis of cause of infertility are listed below.
 

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