The hypothalamus secretes luteinizing hormone-releasing hormone (LHRH), also known asgonadotrophin-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. FS H 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) priorto 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 5α-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.

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.