15th April 2024

Disorders of Male Reproduction

Hypogonadism

Basic physiology

Activation of hypothalamic GnRH neurons initiates the reproductive hormone axis, this is initiated in response to energy status and peripheral sex hormone levels leading to the onset of puberty.  The onset of puberty leads to pulsatile secretion of GnRH into the hypothalamic-pituitary portal blood supply, GnRH binds to receptors on the cell membrane of pituitary gonadotrophic cells in the anterior pituitary gland.

Stimulation of pituitary gonadotrophic cells leads to the release of follicle stimulating hormone (FSH) and luteinising hormone (LH) in a pulsatile manner.  These travel via the systemic circulation to the testes binding to FSH and LH receptors (G-protein coupled receptor) located on the plasma membrane of Sertoli and Leydig cells, respectively, and the activation of secondary c-AMP protein kinase signalling pathways.

Activation of Leydig cells via activation of the LH receptor leads to the production of testosterone, whereas activation of FSH receptors on Sertoli cells leads to the production of proteins such as inhibin A &B, CYP19A1 and other proteins assisting spermatogenesis. The release of testosterone from the Leydig cells of the testes inhibits the release of GnRH and FSH/LH from the hypothalamus and pituitary gland.

Male hypogonadism

Hypogonadism can be broadly classified into two types; pathological hypogonadism and late-onset hypogonadism.

Primary hypogonadism

There are various causes of primary hypogonadism, the clinical presentation of primary hypogonadism is dependent on when the insulting stimulus occurs.

Congenital causes:

• Klinefelters syndrome
• Cryptorchidism
• Myotonic dystrophy
• LH receptor mutations

Acquired causes:

• Orchitis (mumps, chlamydia)
• Testicular torsion/trauma
• Chemotherapy
• Iatrogenic/Drug induced (Spironolactone, Alcohol, anabolic steroid use, ketoconazole)
• Bilateral orchiectomy

Prenatal hypogonadism

Prenatal hypogonadism occurs due to insufficient testosterone levels during the first three months of foetal development. In a foetus with a normal karyotype, this is associated with disorders of sexual differentiation with the severity dependent on the level of testosterone reduction, ranging from a complete lack of male genital organs to scrotal abnormalities and under masculinisation (ectopic urethral meatus/micropenis).

Prepubertal hypogonadism

If the insult occurs before puberty, the patient will present with characteristic phenotypical features, including a high-pitched voice, ‘eunuchoid proportions’, gynecomastia, increased fat deposition and decreased muscle mass. These patients may also have reduced libido, erections and an inability to ejaculate.

Post pubertal hypogonadism

If the insult occurs after puberty, the clinical presentation depends on the severity and duration of low testosterone levels. These patients may present with a wide range of symptoms, including decreased lean body mass, increased fat deposition, hot flushes, insomnia, low energy levels and decreased bone mineral mass. As puberty has already occurred, the patient’s primary and secondary sexual features do not significantly change.

Central hypogonadism

There are various causes of central hypogonadism. Central hypogonadism can occur secondary to a disease process affecting the hypothalamus or pituitary gland or it may be inherited due to a mutation in particular genes such as those controlling the GnRH pathway (isolated hypogonadotropic hypogonadism /IIH) or genes related to migration of olfactory/GnRH secreting neurones during embryonic development (associated with Kallmann syndrome).

Central hypogonadism can occur in patients with damage to gonadotrophic cells due to compression (pituitary tumours, meningioma, craniopharyngioma), infiltrative disease (sarcoidosis, lymphoma) infections (Tuberculosis, syphilis) or infarction. Furthermore, the use of exogenous androgenous steroids leads to suppression of GnRH cell activity leading to central hypogonadism. Late-onset hypogonadism

Late onset hypogonadism is a biochemical and clinical syndrome which has an association with increasing age, which is characterised by symptoms of low testosterone and low serum testosterone levels. There are 9 key symptoms which have been shown to be related to total or free testosterone levels (3 psychological, 3 physical and 3 sexual).

The sexual symptoms include reduced frequency of morning erections, erectile dysfunction, reduced frequency of sexual thoughts, the physical symptoms include reduced ability to engage in vigorous activity, inability to walk further than 1km and reduced ability to bend knee or stool. The psychological symptoms involve depression, fatigue and loss of energy.

Diagnosis

The diagnosis of hypogonadism is based on the presence of characteristic signs/symptoms along with reduced blood serum concentration of total testosterone or free testosterone.

Signs and symptoms

According to the 4th international consultation for sexual medicine (ICSM), hypogonadism should be diagnosed based on particular signs and symptoms:

• Sexual dysfunction: This includes reduced sexual desire, decreased morning/nocturnal erections and erectile dysfunction.
• Reduced physical vigour, reduced energy levels, reduced motivation, fatigue, depressed mood and disturbances in sleep
• Hot flushes, changes in cognition and memory
• Visceral obesity with reduced muscle mass/bone density
• Small testis, gynecomastia, reduced body hair

Laboratory diagnosis

Testosterone levels should be investigated in all patients presenting with erectile dysfunction.

Serum levels of testosterone have a diurnal rhythm with testosterone levels highest in the early morning, testosterone levels are recommended to be measured before 11am (7am – 11am) at least twice, 4 weeks apart and preferably not during an acute illness. This includes either total testosterone (TT) or free testosterone (FT).

If FSH and LH levels are low, prolactin levels should also be investigated to differentiate between primary and secondary hypogonadism.

Management

The two most common indications for testosterone replacement in those with low serum testosterone levels

• Treatment of hypogonadism with reduced testosterone levels in men with a significant physiological interruption of the HPG axis, for example, after a hypophysectomy or in those with atrophic or absent testicles
• Patients with low testosterone levels presenting with symptoms of low testosterone regardless of their age

Contraindications to testosterone replacement include:

• Unevaluated prostatic nodule/induration
• Breast cancer
• History of prostatic cancer
• Prostatic-specific antigen above 4ng/ml
• Severe lower urinary tract symptoms (LUTS) along with benign hyperplastic hyperplasia

Furthermore, testosterone therapy can lead to a reduction in spermatogenesis, if a man is planning a pregnancy testosterone therapy should not be given.

Pharmacological management

There are various formulations of testosterone which can be given to patients. These include oral, buccal, transdermal, subcutaneous and IM formulations. Oral formulations are easier to use than others, however, the (17-alpa-alkylated derivates) are associated with a risk of hepatotoxicity.

Adverse effects of testosterone therapy

Side effects of testosterone therapy include:

• Gynaecomastia
• Hepatotoxicity (with oral formulations)
• Impaired sperm production/fertility
• Raised RBC count
• Acne
• Oedema

References

• Marcelli M, Mediwala SN. Male hypogonadism: a review. J Investig Med. 2020;68(2):335-56.
• Ulloa-Aguirre A, Reiter E, Crepieux P. FSH Receptor Signaling: Complexity of Interactions and Signal Diversity. Endocrinology. 2018;159(8):3020-35.
• Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Androl. 2009;32(1):1-10.
• Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-35.
• Lunenfeld B, Mskhalaya G, Zitzmann M, Arver S, Kalinchenko S, Tishova Y, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male. 2015;18(1):5-15.
• Khera M, Adaikan G, Buvat J, Carrier S, El-Meliegy A, Hatzimouratidis K, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med. 2016;13(12):1787-804.
• Hackett G, Kirby M, Edwards D, Jones TH, Wylie K, Ossei-Gerning N, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. J Sex Med. 2017;14(12):1504-23.
• Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med. 2013;10(1):245-84.
• Gooren LJ, Bunck MC. Androgen replacement therapy: present and future. Drugs. 2004;64(17):1861-91.

Cryptorchidism

Cryptorchidism refers to the absence of the testes from the scrotum either unilaterally or bilaterally. It may be bilateral in up to 30% of patients and about 80% of undescended testis can be palpated.

Aetiology

Cryptorchidism can occur as a result of anatomical, hormonal or genetic abnormalities. However, most patients have no identifiable cause for their presentation.

Cryptorchidism can be caused by anatomical abnormalities and hormonal abnormalities, including deficiency of androgens (testosterone), GnRH deficiency, LH/FSH deficiency or insensitivity of the GnRH/LH/testosterone receptors. Mutations in the genes for the androgen receptor, the gene for the 5a-reductase or CAG repeat length may be associated with cryptorchidism.

Presentation

Cryptorchidism is a relatively common presentation in new-borns with a prevalence between 1.8% to 8.4%. It is typically identified by manual palpation during the new born physical examination. The position of the testis can be classified as:

• Cryptorchid – This is a testis that is not located within the scrotum and can’t be manipulated to reposition it into the scrotum
• Ectopic – An ectopic testis is a testis that has not followed the normal developmental route of the testis during descent, it may be femoral, perineal, pubopenile or crossed scrotal
• Gliding – A testis which can be manipulated to be located in the upper scrotum but once the manipulation is stopped, the testis retract to their original position
• Retractile – A testis which can be manipulated to be located in the scrotum and does not immediately return to its original position (15)
• Acquired – In a patient born with scrotal testis, if they later ascend to a higher position, this is known as acquired cryptorchidism

Management

Screening of all new born babies should take place within 72 hours of birth and at 6-8 weeks of birth, which should involve evaluation of the scrotum for the presence of the testis, if not identified, the child should be reviewed at 4-5  months in case of spontaneous descent of the testes, if still undescended these patients should be urgency referred to a surgeon.

A child presenting with bilateral impalpable testis, abnormalities of the penis or ambiguous genitalia requires urgent referral to a tertiary paediatric centre for identification of disorders of sexual differentiation.  

Surgical treatment

If the testis are palpable during examination, they should be treated with orchidopexy (release of the undescended testis and fixation in the scrotum) via either an inguinal or scrotal approach.  If the testis are not palpable examination under anaesthesia (EUA) along with inguinal exploration/diagnostic laparoscopy is needed to identify the site of the testis to facilitate a subsequent orchidopexy/orchidectomy.

References

• Radmayr C. Management of undescended testes: European Association of Urology/European Society for Paediatric Urology guidelines. J Pediatr Urol. 2017;13(5):550.
• Titi-Lartey OA, Khan YS. Embryology, Testicle.  StatPearls. Treasure Island (FL)2022.
• Virtanen HE, Toppari J. Epidemiology and pathogenesis of cryptorchidism. Hum Reprod Update. 2008;14(1):49-58.
• Niedzielski JK, Oszukowska E, Slowikowska-Hilczer J. Undescended testis – current trends and guidelines: a review of the literature. Arch Med Sci. 2016;12(3):667-77.
• Rodprasert W, Virtanen HE, Mäkelä JA, Toppari J. Hypogonadism and Cryptorchidism. Front Endocrinol (Lausanne). 2019;10:906.
• National Institute for Health and Care Excellence: Clinical Guidelines.  Postnatal care. London: National Institute for Health and Care Excellence (NICE) Copyright © NICE 2021.; 2021.
• Cho A, Thomas J, Perera R, Cherian A. Undescended testis. BMJ. 2019;364:l926.

Klinefelter syndrome

Background

Epidemiology

Klinefelter’s is the most common cause of congenital primary hypogonadism associated with chromosomal abnormalities occurring in 1 out of every 500-700 male neonates with a prevalence at adulthood of 1 out of 2500 males the lower prevalence of Klinefelter’s at adulthood is thought to be due to the condition being ignored or underdiagnosed.

Aetiology

Klinefelter’s occurs due to one or more extra X chromosomes as a result of either maternal or paternal meiotic non-disjunction, 90% of Klinefelter’s occurs due to the 47, XXY karyotype with the remaining 10% due to mosaic Klinefelter’s (47, XXY/46, XY) with some patients having more than one extra X chromosome (48, XXXY/49XXXXY).

Presentation

Patients with mosaic Klinefelter’s syndrome tend to have a milder form of the condition and if the karyotype located in the testis is of the 46, XY type spermatogenesis is normal, patients with more than one extra copy of the X chromosome tend to have a more severe presentation.  The characteristic phenotype associated with Klinefelter’s includes:

• Small firm testis
• Above average height
• Erectile issues
• Sparse male-pattern body hair
• Bilateral gynaecomastia
• Infertility

References

• Marcelli M, Mediwala SN. Male hypogonadism: a review. J Investig Med. 2020;68(2):335-56.
• Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88(2):622-6.
• Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet. 2008;16(2):163-70.
• Nieschlag E. Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Dtsch Arztebl Int. 2013;110(20):347-53.

Kallman syndrome

Background

Kallman syndrome is a congenital hypogonadotropic hypogonadism associated with hypo/anosmia (1). It occurs due to a failure of gonadotrophin releasing neurons to migrate from the olfactory placode to the hypothalamus (2, 3). It is a relatively rare condition thought to affect 1 out of 48,000 people (1).

Aetiology

Kallman syndrome is a clinically and genetically heterogenous condition with ~60% of cases occurring due to sporadic mutations (1), inherited Kallman syndrome has different patterns of inheritance (Autosomal recessive, Autosomal dominant and X-chromosome recessive(1)). There are several different genes associated with Kallman syndrome, with the most common mutations occurring in the ANOS1 and FGFR1 genes (4)

Presentation

Patients with Kallman syndrome will present with symptoms of hypogonadism and pubertal failure in association with hyposmia/anosmia. It may also be associated with other phenotypical features such as cleft lip/palate, poor hearing, dental agenesis, renal agenesis and limb anomalies (1).

References

• Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, et al. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis. 2011;6:41.
• Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res. 1989;6(4):311-26.
• Cariboni A, Maggi R. Kallmann’s syndrome, a neuronal migration defect. Cell Mol Life Sci. 2006;63(21):2512-26.
• Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum Genet. 2021;140(1):77-111.

Male infertility: Oligospermia & Azoospermia

Infertility, by definition, is the inability to conceive after frequent unprotected sexual intercourse for 1 or 2 years.

Aetiology

There are various causes of male infertility

• Primary spermatogenic failure
• Congenital – Anorchia, testicular dysgenesis, Cryptorchidism
  • Acquired – trauma, infection, varicocele, surgery, testicular tumour
• Genetic disorders
  • Klinefelter’s
  • Kallman syndrome
• Obstructive azoospermia
  • Congenital: Prostatic cysts, absence of vas deferens
  • Infection, surgery
• Hypogonadism
• Pharmacological
  • Anabolic steroids, cytotoxic

Investigations

Semen analysis

If the results of a patient’s semen analysis are consistent with the WHO criteria, then only one test is sufficient, however, if the patient has abnormal results in at least two tests, then further investigations are required, the repeat test should be repeated after a period of 3 months to facilitate the completion of a cycle of spermatozoa. The semen sample should be collected after a minimum of 2 days but not more than 7 days of sexual abstinence and delivered to the laboratory within 1 hour.

Oligozoospermia – <15 million spermatozoa/ml

Azoospermia – < 1 million spermatozoa / ml

Asthenozoospermia – <32% progressive motile spermatozoa

Teratozoospermia – < 4% normal forms

Screen for chlamydia

Ideally, both partners should be screened for chlamydia.

Laboratory investigations

In a patient with symptoms of hypogonadism, serum hormone levels should be investigated to differentiate between primary and central hypogonadism. Raised LH and FSH are associated with hypergonadotropic hypogonadism. Typically, FSH levels are related to the levels of spermatogenesis, in patients with significantly reduced spermatogenesis FSH levels tend to be increased, however, if the disorder occurs at the spermatocyte/spermatid level FSH levels may be normal.

Ultrasonography

Ultrasonography may be useful in identifying signs of an obstructive cause for infertility, such as dilatation of the rete testis, enlarged epididymis or absence of the vas deferens; it may further help to identify signs of testicular dysgenesis.

References

• National Institute for Health and Care Excellence: Guidelines.  Fertility problems: assessment and treatment. London: National Institute for Health and Care Excellence (NICE) Copyright © NICE 2020.; 2017.
• Weidner W, Colpi GM, Hargreave TB, Papp GK, Pomerol JM, Ghosh C. EAU guidelines on male infertility. Eur Urol. 2002;42(4):313-22.
• Bjorndahl L, Kirkman Brown J, other Editorial Board Members of the WHOLMftE, Processing of Human S. The sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: ensuring quality and standardization in basic examination of human ejaculates. Fertil Steril. 2022;117(2):246-51.
• Hargreave TB, Mills JA. Investigating and managing infertility in general practice. Bmj. 1998;316(7142):1438-41.