male infertility

Male InfertilityThis Lecture Collected By Omer Ahmed Al-Samrrai, 5th Grade of T.U.C.O.M

Male reproductive physiology
Hypothalamic & pituitary & testicular axis
The hypothalamus secretes luteinizing hormone-releasing hormone (LHRH), also known as gonadotrophin-releasing hormone (GnRH). This causes pulsatile release of anterior pituitary gonadotrophins, called follicle stimulating hormone (FSH) and luteinizing hormone (LH), which act on the testis. FSH stimulates the seminiferous tubules to secrete inhibin and produce sperm; LH acts on Leydig cells to produce testosterone.

Testosterone

is secreted by the interstitial Leydig cells, which lie adjacent to the seminiferous tubules in the testis. It promotes development of the male reproductive system and secondary sexual characteristics.

Spermatogenesis

Seminiferous tubules are lined with Sertoli cells, which surround developing germ cells (spermatogonium) and provide nutrients and stimulating factors, as well as secreting androgen-binding factor and inhibin . Primordial germ cells divide to form primary spermatocytes. These undergo a first meiotic division to create secondary spermatocytes (46 chromosomes), followed by a second meiotic division to form spermatids (23 chromosomes). Finally, these differentiate into spermatozoa. This process takes about 74 days. The non-motile spermatozoa leave the seminiferous tubules and pass to the epididymis, for storage and maturation (until ejaculation). Spermatozoa that are not released are reabsorbed by phagocytosis.

Mature sperm
have a head, middle piece, and tail. The head is composed of a nucleus covered by an acrosome cap, containing vesicles filled with lytic enzymes. The middle piece contains mitochondria and contractile filaments, which extend into the tail to aid motility. After deposition at the cervix, sperm penetrate cervical mucus and travel through the uterus to the site of fertilization in the fallopian tube.

Aetiology and evaluation of male infertility

Definition of infertility
Failure of conception after at least 12 months of unprotected intercourse. The chance of a normal couple conceiving is estimated at 20-25% per month, 75% by 6 months, and 90% at 1 year.
Epidemiology
Up to 35% of infertility is due to male factors. Up to 25% of couples may be affected at some point in their reproductive years.
Pathophysiology
Failure of fertilization of the normal ovum due to defective sperm development, function, or inadequate numbers. There may be abnormalities of morphology (teratospermia), motility (asthenospermia), low sperm numbers (oligospermia), or absent sperm (azoospermia). Abnormal epididymal function may result in defective spermatozoa maturation or transport, or induce cell death.
Aetiology
Idiopathic (25%)
Varicocele (present in 40%)
Cryptorchidism (undescended testes)
Functional sperm disorders: immunological infertility (sperm antibodies); head or tail defects
Erectile or ejaculatory problems
Testicular injury: orchitis (post-pubertal, bilateral mumps orchitis); testicular torsion; trauma; radiotherapy
Endocrine disorders: Kallmann's syndrome (isolated gonadotrophin deficiency causing hypogonadism); pituitary gland adenoma, radiation, or infection
Hormone excess: excess prolactin (pituitary tumour); excess androgen (congenital adrenal hyperplasia, anabolic steroids); excess oestrogens
Genetic disorders: Kleinfelter's syndrome (47XXY) involves azoospermia,
Male genital tract obstruction: congenital absence of vas deferens; epididymal obstruction or infection; groin or scrotal surgery
Systemic disease: renal failure; liver cirrhosis; cystic fibrosis
Drugs: chemotherapy; alcohol; marijuana; sulphasalazine; smoking
Environmental factors: pesticides; heavy metals; hot baths
History
Sexual: duration of problem; frequency and timing of intercourse; previous successful conceptions; previous birth control; erectile or ejaculatory dysfunction.
Developmental: age at puberty; history of cryptorchidism; gynaecomastia.
Medical and surgical: detailed assessment for risk factors, recent febrile illness; post-pubertal mumps orchitis; varicocele; testicular torsion, trauma, or tumour; sexually transmitted diseases; genitourinary surgery; radiotherapy; respiratory diseases associated with ciliary dysfunction; diabetes.
Drugs and environmental: previous chemotherapy; exposure to substances which impair spermatogenesis or erectile function; alcohol consumption; smoking habits; hot baths.
Family: hypogonadism; cryptorchidism.
Examination
Perform a full assessment of all systems, with attention to general appearance (evidence of secondary sexual development; signs of hypogonadism; gynaecomastia). Urogenital examination should include assessment of the penis (Peyronie's plaque, phimosis, hypospadias); measurement of testicular consistency, tenderness, and volume with a Prader orchidometer (normal >18ml; varies with race); palpate epididymis (tenderness, swelling) and spermatic cord (vas deferens present or absent, varicocele); digital rectal examination of prostate.


Investigation of male infertility
Basic investigations
Semen analysis 2 or 3 specimens over several weeks, collected after 2-3 days of sexual abstinence. Deliver specimens to the laboratory within 1h. Ejaculate volume, liquefaction time, and pH are noted. Microscopy techniques measure sperm concentration, total numbers, morphology, and motility .
The World Health Organization defines the following reference values
Volume: 2.0 mL or morepH: 7.2 or moreSperm concentration: 20 106 or more spermatozoa/mLTotal sperm number: 40 106 or more spermatozoa per ejaculateMotility: 50% or more with grade a + b motility or 25% or more with grade a motilityMorphology: 15% or more by strict criteriaViability: 75% or more of sperm viableWBCs: Less than 1 million/mL
Hormone measurement Serum FSH, LH, and testosterone . In cases of isolated low testosterone level, it is recommended to test morning and free testosterone levels. Raised prolactin is associated with sexual dysfunction, and may indicate pituitary disease.

Special investigations

Chromosome analysis: Indicated for clinical suspicion of an abnormality.
Testicular biopsy: Performed for azoospermic patients, to differentiate between idiopathic and obstructive causes. May also be used for sperm retrieval.

Imaging

Scrotal ultrasound scan is used to confirm a varicocele and assess testicular abnormalities.
Transrectal ultrasound scan is indicated for low ejaculate volumes, to investigate seminal vesicle obstruction or absence and ejaculatory duct obstruction.
Vasography Vas deferens is punctured at the level of the scrotum and injected with contrast. A normal test shows the passage of contrast along the vas deferens, seminal vesicles, ejaculatory duct, and into the bladder, which rules out obstruction.

Oligospermia

Defined as a sperm concentration of less than 20 million/ml of ejaculate.
Aetiology
Varicoceles; idiopathic; androgen deficiency. It is identified in ~60% of patients presenting with testicular cancer or lymphoma.
Associated disorders
It is often associated with abnormalities of morphology and motility. The combined disorder is called oligoasthenoteratospermia (OAT) syndrome. Common causes include varicoceles; cryptorchidism; idiopathic; drug and toxin exposure; febrile illness.


Investigations
Semen analysis: sperm counts <5-10 million/ml (severe form) require hormone investigation, including FSH and testosterone.
Treatment
Correct the underlying cause. Idiopathic cases may respond to empirical medical therapy or require assisted reproductive techniques.

Azoospermia

Defined as an absence of sperm in the ejaculate fluid.
Aetiology
Obstructive Absent or obstructed vas deferens; epididymal or ejaculatory duct obstruction (related to infection, cystic fibrosis).
Non-obstructive Hypogonadotrophism (Kallmann's syndrome, pituitary tumour); abnormalities of spermatogenesis (chromosomal anomalies, toxins, idiopathic, varicocele, orchitis, testicular torsion).
Investigations
Hormone assay (raised FSH indicates non-obstructive cause; normal FSH with normal testes indicates increased likelihood of obstruction).
Testicular biopsy is performed to assess if normal sperm maturation is occurring, and for sperm retrieval (for later therapeutic use).
Transrectal ultrasound scan assesses absence or blockage of vas deferens, and ejaculatory duct obstruction. Exclude cystic fibrosis in patients with vas deferens defects.
Management
Treatment will depend on underlying aetiology.

Treatment options for male factor infertility

General
Modification of life style factors (reduce alcohol consumption; avoid hot baths).
Medical treatment
Correct any reversible causative factors.
Hormonal
Secondary hypogonadism (pituitary intact) may respond to human chorionic gonadotrophin (hCG) which stimulates an increase in testosterone and testicular size. If the patient remains azoospermic after 6 months of treatment, FSH is added (human recombinant FSH or human menopausal gonadotrophin). Alternatively, pulsatile LHRH can be administered subcutaneously via a minipump.
Testosterone deficiency requires testosterone replacement therapy.
Hyperprolactinaemia is treated with dopamine agonists.
Anti-oestrogens (clomiphene citrate & tamoxifen) are often used empirically to increase LHRH, which stimulates endogenous gonadotrophin secretion.
Erectile and ejaculatory dysfunction
Erectile dysfunction may be treated conventionally (oral, intraurethral, intracavernosal drugs; vacuum devices or prostheses). Ejaculatory failure may respond to sympathomimetic drugs or electroejaculation (used in spinal cord injury)


Antisperm antibodies
Corticosteroids have been used, but assisted conception methods are usually required.

Surgical treatment

Genital tract obstruction
Epididymal obstruction can be overcome by microsurgical anastomosis between the epididymal tubule and vas (epididymovasovasostomy).
Vas deferen obstruction is treated by microsurgical reanastomosis of ends of the vas, and is used for vasectomy reversal. Ejaculatory duct obstruction requires transurethral resection of the ducts.
Varicocele
Repaired by embolization or open/laparoscopic surgical ligation.

Assisted reproductive techniques (ART)

Assisted conception
Intrauterine insemination (IUI) Following ovarian stimulation, sperm are placed directly into the uterus.
In vitro fertilization (IVF) Controlled ovarian stimulation produces oocytes which are then retrieved under transvaginal USS-guidance. Oocytes and sperm are placed in a Petri dish for fertilization to occur. Embryos are transferred to the uterine cavity. Pregnancy rates are 20-30% per cycle.
Intracytoplasmic Sperm injection (ICSI) A single spermatozoon is injected directly into the oocyte cytoplasm. Pregnancy rates are 15-22% per cycle.










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Tikrit Medical College

Urology
Fifth year, Oct. 2008.