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Ovid: Oxford Handbook of Urology

Authors: Reynard, John; Brewster, Simon; Biers, Suzanne Title: Oxford Handbook of Urology, 1st Edition Copyright ©2006 Oxford University Press > Table of Contents > Chapter 12 – Infertility Chapter 12 Infertility P.460
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 (Fig. 12.1). 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. Steroidogenesis is stimulated by a cAMP-protein kinase C mechanism, which converts cholesterol to pregnenolone. Further steps in the biosynthesis pathway produce intermediary substances (dehydroepiandrosterone and androstenedione) prior to producing testosterone. In the blood, testosterone is attached to sex hormone binding globulin (SHBG) and albumin. At androgen-responsive target tissues, testosterone is converted into a potent androgen, dihydrotestosterone, by intracellular 5α-reductase (see p.541). 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 (Fig. 12.2). 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 70 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 (Fig. 12.3). 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, during which time they undergo functional maturation (capacitation). Sperm start to penetrate the oocyte, and bind to the zona pellucida. The activation phase is initiated (by ZP3), triggering hyperactivated motility and the acrosomal reaction, leading to enzyme release, penetration into the cytoplasm of the oocyte, fusion, and fertilization.

Fig. 12.1 Hypothalamic–pituitary–testicular axis
Fig. 12.2 Spermatogenesis in the seminiferous tubules of the testis
Fig. 12.3 A spermatozoon

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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 50% 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; Kartagener’s syndrome (immotile cilia); dyskinetic cilia syndrome
  • 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); Prader–Willi syndrome (hypogonadism, short stature, hyperphagia, obesity); pituitary gland adenoma, radiation, or infection
  • Hormone excess: excess prolactin (pituitary tumour); excess androgen (adrenal tumour, congenital adrenal hyperplasia, anabolic steroids); excess oestrogens
  • Genetic disorders: Kleinfelter’s syndrome (47XXY) involves azoospermia, ↑ FSH/LH and ↓ testosterone; XX male; XYY syndrome
  • Male genital tract obstruction: congenital absence of vas deferens; epididymal obstruction or infection; Müllerian prostatic cysts; 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

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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 >20ml; varies with race); palpate epididymis (tenderness, swelling) and spermatic cord (vas deferens present or absent, varicocele); digital rectal examination of prostate. P.466
Investigation of male infertility Basic investigations Semen analysis 2 or 3 specimens over several weeks, collected after 2–7 days of sexual abstinence. Deliver specimens to the laboratory within 1h. Ejaculate volume, liquefaction time, and pH are noted (Table 12.1). Microscopy techniques measure sperm concentration, total numbers, morphology, and motility (Table 12.2). The mixed agglutination reaction (MAR test) is used to detect antisperm antibodies. The presence of leucocytes (>1 × 106/ml of semen) suggests infection, and cultures should be requested. Hormone measurement Serum FSH, LH, and testosterone (Table 12.3). 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 (azoospermia or oligospermia, small atrophic testes with ↑ FSH). Testicular biopsy Performed for azoospermic patients, to differentiate between idiopathic and obstructive causes. May also be used for sperm retrieval. Sperm function tests

  • Post coital test: cervical mucus is taken just before ovulation, and within 8 hours of intercourse, and microscopy performed. Normal results shows >10 sperm per high-powered field, the majority demonstrating progressive motility. Abnormal results indicate inappropriate timing of the test; cervical mucus antisperm antibodies; abnormal semen; inappropriately performed coitus.
  • Sperm penetration test: a sample of semen is placed directly onto pre-ovulatory cervical mucus on a slide and the penetrative ability of spermatozoa observed.
  • Sperm-cervical mucus test: a specimen of semen (control), and one mixed with cervical mucus are placed separately on a slide, and observed for 30 minutes. More than 25% exhibiting jerking movements in the mixed sample (but not the control) is a positive test for antisperm antibodies.

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 (>1.5cm width) or absence and ejaculatory duct obstruction (>2.3mm). 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. Venography used to diagnose and treat varicoceles (embolization).

Table 12.1 Semen analysis: normal parameters *
Semen analysis Normal values
Semen volume >2.0ml
pH 7.2–7.8
Total sperm count >40 × 106/ejaculate
Sperm concentration >20 × 106/ml
Sperm motility >50% with progressive motility (grades >2); or >25% grade 4
Sperm morphology >15% normal forms
Viability >75% viable sperm
Time to liquefy 5–25 min
White blood cells <1 × 106 WBC/ml
MAR test (for antisperm Ab) Negative (<10% with adherent particles)
Zinc >2.4 mol/ejaculate
Semen fructose 120–145 mg/dl
* Adapted from World Health Organization (WHO) reference values for semen analysis.
Table 12.2 Grading of sperm motility
Grade Type of sperm motility
0 No motility
1 Sluggish; no progressive movement
2 Slow, meandering forward progression
3 Moving in a straight line with moderate speed
4 Moving in a straight line at high speed
Table 12.3 Clinical diagnosis on hormone assay
FSH* LH** Testosterone Diagnosis
↑ Normal Normal Seminiferous tubule damage (defective Spermatogenesis)
Normal Normal Normal Normal; or bilateral genital tract obstruction
↑ ↑ Normal/↓ Testicular failure
↓ ↓ ↓ Hypogonadotrophism
* Follicle stimulation hormone.
** Luteinizing hormone.

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Oligospermia and azoospermia 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. Severe oligospermia is associated with seminiferous tubular failure, small soft testes, and ↑ FSH. Treatment Correct the underlying cause. Idiopathic cases may respond to empirical medical therapy (clomiphene) 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).
  • Chromosomal analysis may be used to exclude Kleinfelter’s syndrome in patients presenting with azoospermia, small soft testes, gynaecomastia, ↑ FSH/LH and ↓ testosterone.
  • 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.

  • Bilateral absence or agenesis of vas deferens Microsurgical epididymal sperm aspiration (MESA), or consider artificial insemination using donor (AID).
  • Primary testicular failure with testicular atrophy Testicular sperm extraction (TESE); in vitro fertilization (IVF); or consider AID.
  • Primary testicular failure with normal testis TESE; IVF; AID.
  • Obstructive cause with normal testis Epididymovasostomy; vasovasostomy.

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Varicocele Definition Dilatation of the veins of the pampiniform plexus of the spermatic cord. Prevalence Found in 15% of men in the general population and 40% of males presenting with infertility. Bilateral or unilateral (left side affected in 90%). Aetiology Incompetent values in the internal spermatic veins lead to retrograde blood flow, vessel dilatation, and tortuosity of the pampiniform plexus. The left internal spermatic vein enters the renal vein at right angles, and is under a higher pressure than the right vein, which enters the vena cava obliquely at a lower level. As a consequence, the left side is more likely to develop a varicocele. Pathophysiology Testicular venous drainage is via the pampiniform plexus, a meshwork of veins encircling the testicular arteries. This arrangement normally provides a counter-current heat exchange mechanism which cools arterial blood as it reaches the testis. Varicoceles adversely affect this mechanism, resulting in elevated scrotal temperatures and consequent deleterious effects on spermatogenesis (± loss of testicular volume). Varicocele grading system

Grade Size Definition
1 Small Palpable only with Valsalva manoeuvre
2 Moderate Palpable in a standing position
3 Large Visible through the scrotal skin

Presentation The majority of varicoceles are asymptomatic, although large varicoceles may cause pain or a heavy feeling in the scrotal area. Examine both lying and standing, and ask patient to perform Valsalva manoeuvre (strain down). A varicocele is identified as a mass of dilated and tortuous veins above the testicle (described as feeling like a ‘bag of worms’), which decompress on lying supine. Examine for testicular atrophy. Investigation

  • Scrotal Doppler ultrasound scan is diagnostic.
  • Semen analysis: varicoceles are associated with low or absent sperm counts, reduced sperm motility, and abnormal morphology, either alone or in combination (oligoasthenoteratospermia (OAT) syndrome).

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Management Embolization Interventional radiological technique where the femoral vein used to access the spermatic vein for venography and embolization (with coils or other sclerosing agents). Surgical ligation

  • Retroperitoneal approach: a muscle-splitting incision is made near the anterior superior iliac spine, and the spermatic vessels are ligated at that level.
  • Inguinal approach: the inguinal canal is incised to access the spermatic cord, and the veins are tied off as they exit the internal ring.
  • Subinguinal approach: veins are accessed and ligated via a small transverse incision below the external ring.
  • Laparoscopic: veins are occluded high in the retroperitoneum.

Surgical complications Varicocele recurrence; hydrocele formation; testicular infarction and atrophy. Surgical outcome 95% success rate; 70% of men have improvement of sperm parameters. P.472
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) 2000IU subcutaneously 3 times a week, 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 25mg OD) 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 (desipramine) or electroejaculation (used in spinal cord injury), where an electrical stimulus is delivered via a rectal probe to the postganglionic sympathetic nerves that innervate the prostate and seminal vesicles. 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. Highest success rates for finding viable sperm occur in the first 8 years post vasectomy (80–90%).
  • Ejaculatory duct obstruction requires transurethral resection of the ducts.

Varicocele Repaired by embolization or open/laparoscopic surgical ligation. Assisted reproductive techniques (ART) Sperm extraction Used for obstructive azoospermia. Sperm are removed directly from the epididymis by microsurgical epididymal sperm aspiration (MESA) or by percutaneous retrieval (PESA). If these methods fail, P.473
testicular sperm extraction (TESE) or aspiration (TESA) may be tried. Sperm undergo cryopreservation until required. Later, they are separated from seminal fluid by dilution and centrifuge methods, with further selection of motile sperm and normal forms using Percoll gradiant techniques. 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.
  • Gamete intrafallopian transfer (GIFT) Oocytes and sperm are mixed and deposited into the fallopian tubes via laparoscopy. Variations include zygote intrafallopian transfer (ZIFT) and tubal embryo transfer (TET).
  • Intracytoplasmic Sperm injection (ICSI) A single spermatozoon is injected directly into the oocyte cytoplasm (through the intact zona pellucida). Pregnancy rates are 15–22% per cycle.

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