Male Hypogonadism

Male hypogonadism is a state of Testosterone deficiency which may result from either testicular or pituitary/ hypothalamic diseases.  Males can be affected at any age and present with clinical features which differ according to the timing of disease onset in relation to puberty.

Presenting Symptoms

In pre-pubertal onset of testosterone deficiency, sexual development will be absent or incomplete e.g., lack of genital enlargement, lack of pubic/ axillary hair and beard growth, lack of muscle development, lack of sexual interest and failure of the voice to break.  Spermatogenesis will not be initiated and infertility is the general rule.

In post-pubertal onset of testosterone deficiency, the established secondary sexual characteristics are poorly maintained. Symptoms include tiredness, reduced libido and sexual functioning, reduced body and facial hair and muscle mass, infertility and a lack of general well-being including depression. 

Common to both presentations, testosterone deficiency is associated with reduced bone mass, increased risks for osteoporotic fractures and mild anaemia. 

Classification of Hypogonadism

Primary hypogonadism:  When androgen deficiency is the result of testicular diseases, the condition is described as primary hypogonadism or hypergonadotrophic hypogonadism. The latter is so-called because of high LH and FSH levels from the pituitary which makes a vain attempt to stimulate the failing or absent Gonads to secrete more testosterone. 

Causes of primary hypogonadism:

• Klinefelters syndrome (47 XXY)
• Bilateral cryptorchidism (un-descended testes) 
• Bilateral anorchia (no testicular tissue present)
• Testicular torsion and orchitis Testicular tumour
• Orchidectomy
• Chemotherapy or Radiotherapy (affects fertility more than testosterone production)

Secondary hypogonadism: When androgen deficiency is the result of diseases of the pituitary/ Hypothalamus, the condition is described as secondary hypogonadism or hypogonadotrophic hypogonadism due to the low levels of LH and FSH. When there is no other concurrent pituitary hormone deficit, the condition is usually called isolated hypogonadotrophic hypogonadism. This is due to a congenital deficiency in hypothalamic Gonadotrophin releasing hormone (GnRH)

Causes of secondary hypogonadism:

• Pituitary tumour (factsheet 2)
• Suprasellar tumour i.e., Craniopharyngioma (factsheet 7)
• Isolated hypogonadotrophic hypogonadism
• Kallmann's syndrome (isolated hypogonadotrophic hypogonadism associated with an absent or impaired sense of smell)
• Iron overload (haemochromatosis or frequent blood transfusions)
• Systemic diseases - acute and chronic
• Glucocorticoid treatment
• AIDS 
• Gross obesity

Overall, pituitary tumours are the commonest causes of hypogonadism followed by Klinefelter's syndrome.

Clinical Examination

Physical examination is important to confirm the clinical diagnosis of hypogonadism and to elucidate the underlying cause. Important points include:

• assess pubertal progress and stature in late adolescent patients
• body, facial and pubic hair growth  
• body habitus (i.e., eunuchoidal, muscle bulk, feminine fat distribution, Gynaecomastia) 
• testicular examination (assess size, position, consistency i.e., firm in Klinefelter's)
• visual field assessment which may highlight a pituitary lesion (classically a bitemporal hemianopia resulting from chiasmal compression)
• sense of smell (absent in Kallmann's syndrome)

Investigations

To confirm testosterone concentration is subnormal
A single 9am measurement of total testosterone usually suffices.  In men over 50, SHBG-corrected free testosterone may be useful

To differentiate primary from secondary hypogonadism
A single measurement of LH and FSH will support the biochemical diagnosis of either primary or secondary hypogonadism. 

To identify the underlying cause and assess severity of testosterone deficiency

• Prolactin and thyroid function to further assess pituitary function 
• MRI scanning of the pituitary should be arranged if hypogonadotrophic hypogonadism is confirmed 
• karyotyping (Klinefelters syndrome - 47XXY (80% of cases), mosaics, 48XXXY etc.) 
• haemoglobin 
• bone mineral density
• ultrasound of the testes 

Treatment

Any potentially reversible underlying cause should be treated prior to commencing replacement therapy.
 
Referral to a specialist Endocrinology centre for investigation and subsequent management is recommended. Please see "Who and When to Refer" (factsheet 14).

Androgen replacement can be administered in the following modalities

• Oral testosterone undecanoate (Restandol) can be given.  Disadvantages include unreliable absorption requiring a twice or three times daily dosage and therefore inconsistent testosterone replacement.  This is not a reliable form of replacement for adult men.
• Testosterone patches are available for use on the body (Andropatch).  The patches require daily application and good skin adhesion is essential for adequate drug transfer.  The commonest side effect is skin irritation at the site of application.
• Testosterone implants are placed subcutaneously in the skin of the lower abdominal wall.  The implants are small cylindrical pellets containing a dose of 200mg.  The usual replacement dose is 600-800mg every 4-6 months and is very effective.  Insertion of the implants requires a minor surgical procedure under local anaesthesia and should be carried out by trained and experienced personnel.
• Testosterone esters (Sustanon 100 and 250) are administered as a deep intra-muscular injection usually every 2-3 weeks.  They provide reliable replacement with a good safety record for over 50 years.  The main side effect is limited to relatively short duration, localised pain at the injection site. Recently a new long acting intramuscular preparation has become available (Nebido). This formulation requires only 3-monthly injections in to the muscles of buttocks, and provides constant testosterone levels for up to 14 weeks. Testosterone levels begin to rise within 24 hours of the injection.
• Testosterone gel (Testogel) is an alcoholic gel, 5g of which applied once daily to the skin surface over the shoulders, upper arms and abdomen will deliver stable physiological blood levels of testosterone. 
• A buccal testosterone preparation has recently been marketed (Striant SR*). This is a twice daily mucoadhesive tablet which adheres to the gum and is placed above the incisors. Psysiological levels of testosterone are achieved in most patients. Side effects are infrequent and are usually local, including gum irritation, gingivitis and a bitter taste.

Infertility resulting from secondary hypogonadism is usually amenable to treatment.  In this situation there is dormant testicular tissue which should respond to gonadotrophin treatment with human chorionic gonadotrophin (hCG) and FSH self-administered subcutaneously twice to thrice weekly over 6-12 months.  Primary hypogonadism including Klinefelter's syndrome are synonymous with irreversible and permanent infertility.

The psychological impact of infertility can be great and counselling may be required. See "Psychological Issues" (factsheet 13) for basic information.

Initiation and monitoring treatment and assessing response

Initial treatment will depend upon the age of the patient and the underlying cause of the hypogonadism.  Younger patients are often androgen-na've and will benefit from lower starting doses and gradual increase over 2-3 years to the full adult replacement dose of testosterone. This is particularly desirable for maximising linear growth potential. Older men should ideally be treated with shorter acting preparations in case of aggravating undetected androgen-responsive diseases e.g., prostate cancer. Adult men may have a preference for longer acting preparations such as testosterone implants.

The aim should be to maintain plasma testosterone within the physiological range. It is good practice to ascertain that this has been achieved in the first 3-6 months of initiating treatment by dose titration. Thereafter, an annual pre-dosing check of testosterone should be more than sufficient.

The clinical response should be apparent within the first few weeks and best judged by the patient's own observations. Physical changes such as genital, hair and muscle growth are generally observed within 3-6 months. Bone mineral density changes may be used as a more long-term parameter of responses and compliance to testosterone.

In older patients, monitoring the haematocrit, prostate size (digital rectal examination) and function (PSA) constitute sensible clinical practice.

Counselling in accepting the invariably life-long testosterone treatment, subfertility or infertility is important.

Side effects may include gynacomastia, exacerbation of prostatic disease, fluid retention in those with pre-existing cardiac or renal disease, exacerbation of pre-existing liver dysfunction, obstructive Sleep apnoea, polycythaemia and exacerbation of premorbid behavioural problems.

Watchpoints

Urgent - refer to hospital

• back pain or urinary obstruction ' may indicate prostate cancer and metastatic disease
• testicular mass
• deterioration of vision (suggesting secondary hypogonadism)

Questions patients may ask

Will my sex life improve?

Testosterone treatment will increase your sex drive.  Sexual functioning is more complicated and is dependent on several factors in addition to testosterone.  Testosterone will not help erectile impotence with normal sex drive

Will I be able to have children?

If the underlying cause is due to a testicular problem then invariably the patient will be infertile.  With secondary causes hCG treatment is successful in up to 70% of cases.

Will it make me more aggressive?

Not in an antisocial sense but it will make you have more self-confidence and be more assertive.

Have I inherited this, will my children get it?

In all but very exceptional circumstances there is no hereditary link.

Resources for patients

Please go to the Resource Library of this website to access resources for patients.  Our library includes literuature, newsletters and articles available from The Pituitary Foundation as well as the contact information for other organisations who provide support and information.  All of our patient leaflets are available to read as well as downloadable in PDF format from this website. 

Patients may also wish to contact:

Klinefelter's Syndrome Association
13 York Rise, Orpington, Kent, BR6 8PR

Resources for GPs

Endotext.org "Your Endocrine Source"
http://www.endotext.org/    (www.endotext.org/neuroendo/index.htm)

Oxford Handbook of Endocrinology OUP (2002) JAH Wass & H Turner (Eds).

More Specialist Resources

Management of Pituitary Tumors: The Clinician's Practical Guide (2003) (Second Edition), Editors and authors Michael P. Powell, Stafford L. Lightman and Edward R. Laws. Humana Press, Totowa, New Jersey

Pituitary Tumours. Recommendations for service provision and guidelines for management of patients. Consensus statement of a working party (1997) RN
Clayton & JAH Wass (Eds) London: Royal College of Physicians

The Diagnosis and Treatment of Pituitary Insufficiency (1997) Lamberts SWJ (Ed) Bristol, UK: BioScientifica

Endocrinology (1997) Levy A & Lightman SL New York: Oxford University Press

The Epidemiology, Pathogenesis and Management of Pituitary Tumours (1998) Webb SM (Ed) Bristol, UK: BioScientifica