12 Infertility

The hypothalamus secretes luteinizing hormone-releasing hormone (LHRH), also known as gonadotrophin-releasing hormone (GnRH). This causes the 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 the 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 blood, 60% of testosterone is attached to sex hormone-binding globulin (SHBG), 38% bound to albumin and 2% is free. At androgen-responsive target tissues, testosterone is converted into a potent androgen, dihydrotestosterone (DHT), by intracellular 5A-reductase (see  p. 672; Fig. 16.7).

Spermatogenesis Seminiferous tubules are lined with Sertoli cells, which surround developing germ cells (spermatogonia) 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 72 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 has 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 which leads to enzyme release, penetration into the cytoplasm of the oocyte, fusion, and fertilization.

Failure of conception after at least 12 months of regular unprotected intercourse. The chance of a normal couple conceiving is estimated at 20–25% per month, 75% by 6 months, and 90% at 1y.

Up to 50% of infertility is due to male factors. An estimated 14–25% of couples may be affected at some point in their reproductive years. Twenty-five percent of subfertile couples will have oligozoospermia and 10% azoospermia. Azoospermia exists in 1% of the male population.

Failed fertilization of the normal ovum due to defective sperm development, function, or inadequate numbers. There may be abnormalities of morphology (teratozoospermia, <4% normal forms), motility (asthenozoospermia, <40% motile sperm), low sperm numbers (oligozoospermia, <15 × 10⁶ per mL), or absent sperm (azoospermia). Abnormal epididymal function may result in defective spermatozoa maturation or transport or induce cell death.

Perform a full assessment of all systems, with attention to general appearance (evidence of secondary sexual development; signs of hypogonadism; gynaecomastia). Urogenital examinationshould include assessment of the penis (phimosis, hypospadias, chordee); the presence of testes; 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); DRE of prostate.

Of note, the patient’s partner should also undergo full screening and assessment for infertility by a gynaecologist, in either a separate consultation or in a joint clinic.

Semen analysis: 2–3 specimens over several weeks, collected after 2–7 days of sexual abstinence. Deliver specimens to the laboratory within 1h (ideally keeping the specimen warm in a shirt or trouser pocket). 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 (useful for asthenozoospermia which can be associated with immunological infertility). The presence of leucocytes (>1 × 10⁶/mL in semen) suggests infection and cultures should be requested. Low or absent ejaculate volume may suggest abnormality of seminal vesicles, ejaculatory duct obstruction, hypogonadism, or retrograde ejaculation.

Hormone measurement: serum FSH, LH and testosterone (Table 12.3). In cases of isolated low testosterone level, it is recommended to test early morning and free testosterone levels. Raised prolactin is associated with sexual dysfunction and may indicate pituitary disease.

Karyotype: 5–10% of azoospermic patients have Klinefelter’s syndrome.

Y chromosome microdeletion assay: to assess AZF—regions a, b, and c.

Post-orgasmic urine analysis: the presence of >10–15 sperm per high powered field confirms the diagnosis of retrograde ejaculation.

Scrotal USS: is used to assess for testicular abnormalities and detection of varicocele.

Transrectal USS: is indicated for low ejaculate volumes, to investigate seminal vesicle obstruction (>1.5cm width) or absence and ejaculatory duct obstruction (>2.3mm).

Vasography: the 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 guide embolization treatment of varicocele.

Performed for azoospermic patients to help differentiate between obstructive and non-obstructive causes. Simultaneous sperm retrieval can be carried out (testicular sperm extraction, TESE) for use in intracytoplasmic sperm injection (ICSI) treatment, either at the time or at a later date (following freezing and storage). The degree of spermatogenesis can be histologically scored (this is the Johnsen score; Table 12.4). Only mature spermatozoa (score 8 or above) can be used for fertility treatment.

Defined as a sperm concentration of <15 million per mL of ejaculate.

Aetiology: varicocele; idiopathic; androgen deficiency. It is identified in 760% of patients presenting with testicular cancer or lymphoma.

Associated disorders: Often associated with abnormalities of morphology and motility. The combined disorder is called oligoasthenoteratozoospermia (OAT) syndrome. Common causes of OAT include varicocele, undescended testes, idiopathic; drug and toxin exposure, febrile illness.

Treatment: Lifestyle advice and modification of risk factors. Correct the underlying cause (i.e. varicocele repair or embolization may improve testosterone and sperm production and parameters). Idiopathic cases may respond to empirical medical therapy (clomiphene) or require assisted reproductive techniques (ART) (see  p. 565).

Defined as an absence of sperm in the ejaculate.

Treatment will depend on the underlying aetiology (see also  p. 554).

Dilatation of veins in the pampiniform plexus of the spermatic cord.

Found in 15% of men in the general population, 20–40% of males presenting with primary infertility and 45–80% of men with secondary infertility. Rare prior to puberty; present in 710% of adolescents. Bilateral or unilateral (left side affected in 90%).

Incompetent valves in the internal spermatic veins lead to retrograde blood flow, vessel dilatation, and tortuosity of the pampiniform plexus. The left internal spermatic (testicular) vein enters the left 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.

Testicular venous drainage is via the pampiniform plexus, a meshwork of veins encircling the testicular arteries. This arrangement normally provides a countercurrent 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 (9 loss of testicular volume over time).

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

Adolescents: Pain, bilateral large varicoceles, varicocele in a solitary testis, persistent delayed testicular growth by >20% (as compared with non-affected side).

Adults: Varicocele repair improves semen parameters and is recommended in the United States.^* However, in the UK, the Cochrane review failed to identify any benefit to pregnancy rates and intervention for infertility reasons is not currently recommended by NICE. Patients should be fully counselled on the limitations of varicocele repair for infertility before being booked for treatment.

Embolization: interventional radiological technique where the femoral vein is used to access the spermatic veins for venography and embolization (with coils or other sclerosing agents), with success rates of 83%.

Varicocele recurrence; hydrocele formation; testicular atrophy, ilioinguinal nerve damage.

Ninety-five percent success rate of treating the varicocele; 70% of men have improvement of sperm parameters.

aim to identify and treat reversible causes of subfertility and improve semen quality. Advice on modification of lifestyle factors (i.e. reduce alcohol consumption, avoid hot baths).

Treat any positive semen, urine, or urethral cultures with the appropriate antibiotics.

Vitamin E supplements have been shown to improve sperm function and IVF success rates; zinc and folic acid may increase sperm concentrations.

Erectile dysfunction may be treated conventionally (oral, intraurethral, intracavernosal drugs; vacuum devices or prostheses). Ejaculatory failure may respond to sympathomimetic drugs (desipramine) or electroejaculation or vibro-ejaculation (used in SCI), where an electrical stimulus is used to produce ejaculation. It is delivered via a rectal probe to the post-ganglionic sympathetic nerves that innervate the prostate and seminal vesicles.

Sperm extraction: sperm are removed directly from the epididymis by PESA or MESA. If these methods fail, TESE by conventional biopsy or microsurgical techniques, 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 gradient techniques.