FEATURE Male infertility BY ROZH JALIL AND SUKS MINHAS Figure 1: The Hypothalamus-Pitutary-Gonadal axis Definitions Infertility is the inability of a sexually -ve active, non-contracepting couple to HYPOTHALAMUS achieve spontaneous pregnancy in one year [1]. About 15% of couples do not achieve LHRH pregnancy within one year and seek -ve -ve ANTERIOR PITUTARY medical treatment for infertility. Semen GLAND parameters are standardised by the World Health Organization (WHO) and defined LH FSH according to standardised values discussed Testes in the investigation section below. Azoospermia is defined as the absence of Interstitial cells Seminiferous tubules (Leydig cells) (Sertoli cells) sperm in the ejaculate and is identified in 10% to 15% of infertile males [2]. Oligospermia is defined as a sperm density of less than 15 million/ml. Unlike the situation with azoospermia, causes Testosterone Sperm Inhibin of oligospermia can be quite vast and the aetiology is often idiopathic. Figure 1. The hypothalamic-pituitary-gonadal (HPG) axis. Asthenospermia is decreased sperm motility (<32% motile spermatozoa [3]). Teratospermia is abnormal forms of sperm (<4% normal forms [3]). albumin and 2% is free. Testosterone is (AZF) gene on the Y chromosome. Sperm abnormalities of oligospermia, converted into a more potent androgen, Microdeletions of region AZFa has asthenospermia and teratospermia usually dihydrotestosterone, by 5-alpha reductase been associated with Sertoli cell only occur together; this is called oligo-astheno- at the target tissues. syndrome; AZFb with maturation teratozoospermia (OAT) syndrome. Sertoli cells line the seminiferous arrest and AZFc with azoospermia or In 50% of infertile couples, a male tubules, which surround developing severe oligozoospermia. associated factor is found together with germ cells (spermatogonia) and provide abnormal semen parameters [3]. nutrients and stimulating factors as well Testicular causes: as secreting androgen-binding factor • Varicoceles are found in 40% of infertile Physiology and inhibin. Primordial germ cells divide men [4]. Varicoceles may be associated The hypothalamic-pituitary-gonadal (HPG) to form primary spermatocytes. These with failure of testicular growth, axis is responsible for reproductive tract undergo two meiotic divisions to form hypogonadism or symptoms of pain and formation and development, maturation spermatids and a further differentiation discomfort. of fertility potential at puberty, and into spermatozoa. This process takes 72 • Idiopathic 30-40% [1]. the maintenance of sexual function in days. The non-motile spermatozoa leave • Undescended testes (cryptorchidism). the adult. The HPG axis is illustrated in the seminiferous tubules and pass to the • Functional sperm disorder e.g. Figure 1. epididymis for storage and maturation. antisperm antibodies; Karatagener’s The hypothalamus secretes syndrome. gonadotrophin-releasing hormone Aetiology • Testicular injury e.g. testicular torsion. (GnRH). This causes the release of follicle • Infection e.g. post pubertal mumps stimulating hormone (FSH) and luteinising Pre-testicular causes: orchitis. hormone (LH) from the anterior pituitary • Endocrinopathy / hormonal, • Radiation. gland, which act on the testis. LH acts on hypogonadotropic hypogonadism. • Cancer. Leydig cells to produce testosterone. FSH • Systemic disease e.g. renal failure; liver • Post surgery e.g. hernia repair. stimulates the seminiferous tubules to cirrhosis; cystic fibrosis (CF). secrete inhibin and produce sperm. • Environmental factors e.g. hot baths. Post-testicular (obstructive causes): Testosterone is secreted by the • Drugs, alcohol, smoking and cannabis. • Male genital tract obstruction e.g. interstitial Leydig cells. It promotes • Genetic abnormalities e.g. obstruction / absence of vas deferens the development of the male - Klinefelter’s syndrome (47 XXY) (may be associated with CF). CF is an reproductive system and secondary characterised by small firm testes, autosomal recessive disorder that sexual characteristics. Sixty percent of gynaecomastia and high serum affects multiple organs. Most men with testosterone is bound to sex hormone gonadotrophins. azoospermia with congenital bilateral binding globulin (SHBG), 38% bound to - Deletions in the azoospermic factor absence of vas deferens (CBAVD) have urology news | MAY/JUNE 2018 | VOL 22 NO 4 | www.urologynews.uk.com FEATURE genetic mutation in cystic fibrosis • Decreased body hair, absence of temporal Special investigations: transmembrane conductance regulator pattern balding areas – document • Genetic evaluation for Y microdeletion, (CFTR) on chromosome 7p. secondary sexual characteristics. karyotype and CF transmembrane • Erectile or ejaculatory problems e.g. • Low androgen levels at the time of conductance regulator (CFTR) gene. retrograde ejaculation. puberty will lead to disproportionately • Testicular biopsy: In selected cases, • Infection e.g. prostatitis. long extremities due to delayed closure of testicular biopsy may be indicated to the epiphyseal plates. exclude spermatogenic failure (non- Furthermore, the level of obstruction in • Examination of thyroid gland obstructive causes). Testicular biopsy obstructive azoospermia (OA) varies: may exclude nodules suggesting should be performed at the time of • Intratesticular obstruction 15%. hyperfunction or hypofunction, which can testicular sperm extraction and be part • Epididymal obstruction 30-67%. affect fertility. of intracytoplasmic sperm injection • Vas deferens obstruction: most common • Hepatomegaly on abdominal (ICSI) treatment in patients with clinical cause of acquired obstruction following examination raises suspicion for hepatic evidence of non obstructive azoospermia vasectomy. dysfunction, which may induce altered (NOA). Microdissection testicular sperm • Ejaculatory duct obstruction: 1-3% sex steroid metabolism. extraction (TESE) is the technique of choice. Spermatogenesis may be focal, Assessing male infertility Genital examination which means that in about 50% of men • Penis: curvature, Peyronie’s plaque, with NOA, spermatozoa can be found and History phimosis, hypospadias. used for ICSI. A thorough history is key in successful • Testes: assessment of testicular • Post-orgasmic urine analysis to confirm diagnosis of male infertility. Many specific consistency, tenderness and volume retrograde ejaculation in men with low factors can affect subsequent fertility or (using an orchidometer or by sonographic ejaculatory volume. sexual function (Table 1). measurement; normally >20ml) and • Sperm function tests, which are not to exclude the presence of testicular commonly performed, include: Table 1. Factors can affect subsequent fertility or sexual masses. 1. Post coital test function. • Epididymis: tenderness and fullness. 2. Sperm penetration test Infertility history Surgical • Spermatic cord: presence or absence of 3. Sperm-cervical mucus test Duration Orchidopexy vas deference, varicocele. Prior conceptions Retroperitoneal / pelvic Current or previous partner surgery Radiological investigations: Outcome Herniorrhaphy Investigations • Ultrasound scan of the scrotum: assess Previous fertility evaluation Vasectomy There are a number of available tools to testicular abnormality (e.g. mass) and the and treatment Bladder neck / prostatic surgery further evaluate the infertile male, ranging presence of varicocele, information on from the basic semen analysis to testicular which should include venous diameter Sexual history Medications Erectile function Gonadotoxins biopsy, as well as imaging studies. and evidence of venous reflux. Lubricants Environmental exposures Basic investigations: Appropriate • Transrectal ultrasound if seminal volume Frequency / timing of (pesticides, heavy metals) laboratory testing of semen plays a key is low to exclude obstructive causes e.g. intercourse Radiation Habits (tobacco, recreational role in evaluation of men presenting with Müllerian duct cyst. Past history drugs, anabolic steroids) Cryptorchidism infertility. • Vasography: This is to diagnose Onset of puberty • Semen analysis: specimens should be and evaluate level of obstruction if Testicular pathology collected over a period of a few weeks obstructive azoospermia is suspected Torsion after two to five days of sexual abstinence. to confirm distal patency prior to Trauma Midline defects (cleft palate) The specimen should be delivered within reconstruction e.g. vaso-epididymostomy. Medical Family history one hour to the laboratory. The normal Diabetes mellitus Infertility values for semen parameters are shown Management Neurologic disease Cystic fibrosis in Table 2. Treatments vary according to the underlying Spinal cord injury Androgen receptor deficiency • Hormonal assessment: these include cause and the degree of the impairment of Multiple sclerosis Infection LH, FSH and testosterone. Increased the male fertility. Urinary infections prolactin levels can be associated with Sexually transmitted disease sexual dysfunction and may indicate Pre-testicular conditions and idiopathic Epididymitis / prostatitis pituitary disease. Men with testicular Tuberculosis cases may respond to medical therapy: Mumps orchitis deficiency have high levels of FSH and LH, • Gonadotropin-releasing hormone Recent viral / febrile illness and sometimes low levels of testosterone agonists: These agents are effective Renal disease secondary to hypergonadotropic for treatment of hypogonadotropic Cancer hypogonadism. Generally, the levels Chemotherapy / radiotherapy