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Home , Azoospermia, Oligospermia, Orchitis, Phimosis, Teratospermia, Testicular torsion

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Male

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. 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. is defined as the absence of Interstitial cells Seminiferous tubules (Leydig cells) (Sertoli cells) in the ejaculate and is identified in 10% to 15% of infertile males [2]. is defined as a sperm density of less than 15 million/ml. Unlike the situation with azoospermia, causes 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 (<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 . Sperm abnormalities of oligospermia, converted into a more potent , Microdeletions of region AZFa has asthenospermia and usually , 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 • 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 or symptoms of and formation and development, maturation spermatids and a further differentiation discomfort. of potential at , 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 (). the adult. The HPG axis is illustrated in the seminiferous tubules and pass to the • Functional sperm disorder e.g. Figure 1. for storage and maturation. antisperm ; Karatagener’s The hypothalamus secretes syndrome. gonadotrophin-releasing hormone Aetiology • Testicular e.g. . (GnRH). This causes the release of follicle • e.g. post pubertal stimulating hormone (FSH) and luteinising Pre-testicular causes: . 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 e.g. renal failure; liver • Post surgery e.g. hernia repair. stimulates the seminiferous tubules to cirrhosis; (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 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

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genetic 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. and CF transmembrane • Erectile or ejaculatory problems e.g. • Low androgen levels at the time of conductance regulator (CFTR) gene. retrograde . puberty will lead to disproportionately • Testicular biopsy: In selected cases, • Infection e.g. . 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 . dysfunction, which may induce altered (NOA). Microdissection testicular sperm • Ejaculatory duct obstruction: 1-3% sex metabolism. extraction (TESE) is the technique of choice. may be focal, Assessing Genital examination which means that in about 50% of men • Penis: curvature, Peyronie’s plaque, with NOA, spermatozoa can be found and History , 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 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 • : presence or absence of 3. Sperm-cervical mucus test Duration Orchidopexy vas deference, . Prior conceptions Retroperitoneal / pelvic Current or previous partner surgery Radiological investigations: Outcome Herniorrhaphy Investigations • Ultrasound scan of the : 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 to testicular which should include venous diameter Sexual history 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 ) 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 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 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 levels can be associated with Sexually transmitted disease and may indicate Pre-testicular conditions and idiopathic / prostatitis pituitary disease. Men with testicular Tuberculosis cases may respond to medical therapy: Mumps orchitis deficiency have high levels of FSH and LH, • -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 / radiotherapy hypogonadism. of FSH correlate with the number of • Anti-oestrogens: Anti-oestrogens remain spermatogonia: when spermatogonia the most commonly employed medical Examination are absent or markedly diminished, FSH therapy for idiopathic male infertility General examination values are usually elevated; when the e.g. clomiphene citrate and It is important to perform a comprehensive number of spermatogonia is normal, citrate. A meta-analysis reported general examination with particular but maturation arrest exists at the some improvement in sperm quality attention to: spermatocyte or spermatid level, FSH and spontaneous pregnancy rates [5]. • Evidence of secondary sexual values can be within the normal range. However, these are unlicensed. development. Table 3 tabulates the different endocrine • Oral antioxidants: Vitamins e.g. • Gynaecomastia. profiles in infertile men. (daily 400mg), (1gm twice daily) • Signs of hypogonadism. and co-enzyme Q10 (CoQ10 200mg once

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daily) [6]. Table 2. Lower reference limits (5th centiles and their 95% CIs) for semen characteristics. Testicular conditions (and idiopathic Parameter Lower reference infertility that do not respond to medical limit (range) treatment) can be treated with assisted reproduction techniques (ART). Semen volume (mL) 1.5 (1.4-1.7) Total sperm number (106 per ejaculate) 39 (33-46) Azoospermia Sperm concentration (106 per mL) 15 (12-16) Sperm extraction from the epididymis is Total motility (PR + NP) 40 (38-42) performed by: • Percutaneous epididymal sperm Progressive motility (PR, %) 32 (31-34) aspiration (PESA): This involves Vitality (live spermatozoa, %) 58 (55-63) aspirating fluid from the epididymis Sperm morphology (normal forms, %) 4 (3.0-4.0) through a percutaneous approach. Other consensus threshold values • Microsurgical epididymal sperm aspiration (MESA): This is an open pH > 7.2 surgical sperm retrieval procedure Peroxidase-positive leukocytes (106 per mL) <1.0 from the epididymal tubules under the MAR test (motile spermatozoa with bound particles, %) <50 microscope. Immunobead test (motile spermatozoa with bound beads, %) <50 The above two techniques are useful Seminal zinc (μmol/ejaculate) >2.4 approaches when there is CBAVD or Seminal fructose (μmol/ejaculate) >13 vasectomy reversal is not an option. Seminal neutral glucosidase (mU/ejaculate) >20

Sperm extraction from the testes is Table 3. Endocrine profiles in infertile men. performed by: • Testicular exploration and sperm Condition Testosterone FSH LH Prolactin extraction (TESE / microsurgical TESE Normal Normal Normal Normal Normal or Aspiration TESA). Primary testicular failure Low High Normal Normal • A TESE involves extracting testicular Hypogonadotropic hypogonadism Low Low Low Normal tissue from multiple areas through an open approach or under the microscope Low Low Low High in mTESE. A systematic review showed Androgen resistance High High High Normal that sperm retrieval ranged from 16.7 to 45% in the conventional TESE vs. 42.9 to 63% in the microTESE group [7]. Proximal vas deferens obstruction: Proximal can be used in men with ejaculatory duct • The retrieved sperm is stored by vas deferens obstruction after vasectomy obstruction e.g. intra-prostatic midline cryopreservation or used at the same requires microsurgical vasectomy reversal. cyst. Complications following TURED time as ICSI. The length of time elapsed since vasectomy include retrograde ejaculation due to is the major factor determining success bladder neck injury and urine reflux into Post testicular conditions can be managed rates from surgery. A patency rate of 97% the ejaculatory ducts, , and with either surgery or IVF-ICSI. and a pregnancy rate of 76% was achieved vasa. The alternatives to TURED are MESA, Varicocoeles can be repaired by following reversal in an obstructive interval TESE, ultrasonically guided aspiration of embolisation; open, laparoscopic or of three years, whereas these rates where the seminal vesicle and direct midline cyst microsurgical operations. A meta- lower (patency rate 71%, pregnancy aspiration; although using these latter rate 30%) if this interval was 15 years or analysis has shown that microsurgical techniques, cysts tend to recur. more [14]. The absence of spermatozoa varicocoelectomy technique has a higher In cases of obstruction due to a midline in the intraoperative vas deferens fluid pregnancy rate and is associated with lower intraprostatic cyst, incision or deroofing suggests the presence of a more proximal recurrence rates and formation [8]. of the cyst is required. Intra-operative Varicocoelectomy has been the subject obstruction where a vaso-epididymostomy transrectal ultrasound (TRUS) makes this of much debate. Surgical varicocoelectomy (anastomosis of the vas to the epididymis) procedure safer. of clinical varicoceles has been shown to or a microsurgical tubulovasostomy will be Installation of methylene blue dye into result in a significant improvement of semen required. The presence of spermatozoa is the seminal vesicle can aid confirming parameters [9-11], although subclinical confirmed by examining the fluid from the patency of the ducts. The limited success varicocoeles remain a matter for debate testis end of the vas under the microscope [12]. It has been postulated that there is intraoperatively. rate of surgical treatment of ejaculatory also a significant risk of over treatment of duct obstruction in terms of spontaneous adolescents with varicocoeles [13]. Figure 2 Distal vas deferens obstruction: TESE / MESA pregnancies should be weighed against illustrates the algorithm for evaluation and or proximal vas deferens sperm aspiration sperm aspiration and ICSI. treatment of azoospermia. can be used for cryopreservation for future The management of obstructive ICSI as it is often difficult to correct large azoospermia depends on the level of vas deferens defects e.g. following hernia obstruction: repair.

Intratesticular obstruction: Only TESE Ejaculatory duct obstruction: Transurethral provides a means of obtaining sperm. resection of the ejaculatory ducts (TURED)

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Figure 2. Algorithm for evaluation and treatment of azoospermia.

References 6. Imamovic Kumalic S, Pinter B. Review of clinical trials on 11. Esteves SC, Miyaoka R, Roque M, Agarwal A. Outcome 1. World Health Organization. WHO Manual for the effects of oral antioxidants on basic semen and other of varicocele repair in men with nonobstructive Standardised Investigation and Diagnosis of the Infertile parameters in idiopathic oligoasthenoteratozoospermia. azoospermia: systematic review and meta-analysis. Couple. Cambridge, UK: Cambridge University Press; Biomed Res Int 2014;2014:426951. Asian J Androl 2016;18(2):246-53. 2000. 7. Deruyver Y, Vanderschueren D, Van der Aa F. Outcome of 12. Yamamoto M, Hibi H, Hirata Y, et al. Effect of 2. Jarow JP, Espeland MA, Lipshultz LI. Evaluation of microdissection TESE compared with conventional TESE varicocelectomy on sperm parameters and pregnancy the azoospermic patient. The Journal of Urology in non-obstructive azoospermia: a systematic review. rate in patients with subclinical varicocele: a randomized 1989;142(1):62-5. 2014;2(1):20-4. prospective controlled study. The Journal of Urology 3. Jungwirth A, Giwercman A, Tournaye H, et al.European 8. Cayan S, Shavakhabov S, Kadioglu A. Treatment of 1996;155(5):1636-8. Association of Urology Working Group on Male palpable varicocele in infertile men: a meta-analysis to 13. Ding H, Tian J, Du W, et al. Open non-microsurgical, Infertility. European Association of Urology guidelines define the best technique.J Androl 2009;30(1):33-40. laparoscopic or open microsurgical varicocelectomy on Male Infertility: the 2012 update. European Urology 9. Agarwal A, Deepinder F, Cocuzza M, et al. Efficacy of for male infertility: a meta-analysis of randomized 2012;62(2):324-32. varicocelectomy in improving semen parameters: new controlled trials. BJU International 2012;110(10):1536-42. 4. Wein A, Kavoussi L, Novick A, et al. Campbell-Walsh meta-analytical approach. Urology 2007;70(3):532-8. 14. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of Urology, 10th Edition Philadelphia, USA: Elsevier 10. Baazeem A, Belzile E, Ciampi A, et al. Varicocele and male 1,469 microsurgical vasectomy reversals by the Saunders; 2012. factor infertility treatment: a new meta-analysis and Vasovasostomy Study Group. The Journal of Urology 5. Chua ME, Escusa KG, Luna S, et al. Revisiting oestrogen review of the role of varicocele repair. European Urology 1991;145(3):505-11. antagonists (clomiphene or tamoxifen) as medical 2011;60(4):796-808. empiric therapy for idiopathic male infertility: a meta- analysis. Andrology 2013;1(5):749-57.

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TAKE HOME MESSAGE

• History, examination and the semen are the key aspects of diagnosing male factor AUTHORS infertility. These, in addition to hormonal profile, would likely determine the diagnosis of oligospermia or azoospermia (non-obstructed vs. obstructed). • Available algorithms provide a pivotal tool for diagnosis and management. • In treating male factor infertility, the female partner’s age has an influence on the choice of intervention. • Eligibility for NHS funding should be considered and discussed with the patient. • In obstructive azoospermia, the choice of intervention depends on the level of obstruction. • Surgical sperm retrieval techniques vary in success rates and the use of microscopy is Suks Minhas, MD FRCS (Urol), a valuable adjunct. Consultant Urologist and Andrologist, Imperial College Healthcare, NHS Trust, London. E: [email protected]

Rozh Jalil, MBChB, MRCS, MD(Res), Andrology Specialist Registrar, University College London Hospital.

Declaration of competing interests: None declared.

urology news | MAY/JUNE 2018 | VOL 22 NO 4 | www.urologynews.uk.com