15th April 2024

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.