Hypogonadism

Loss of gonadal function of any cause. Diagnosis requires testing of sex hormone and gonadotropin levels. This section includes absent or delayed puberty, primary testicular failure, premature ovarian failure, and secondary hypogonadotropic hypogonadism.

What is the main presenting feature: absent or delayed puberty, loss of libido, erectile dysfunction, gynaecomastia, primary or secondary amenorrhoea, or is the patient seeking fertility? 

Detailed history, including pubertal development, is mandatory in all patients as this may reduce the list of differential diagnoses considerably.

Specific lines of questioning are indicated according to the exact problem, as below.

Is this an isolated problem or associated with other physical or developmental problems? 

The list of differential diagnoses will be different in a patient with multiple medical problems or an obvious congenital condition.

Serious systemic illness of any cause is associated with pubertal delay. Specific conditions associated with abnormal pubertal develoment include the intersex disorders, pseudopseudohypoparathyroidism, Cushing's syndrome and congenital hypothyroidism.

Has the patient been through the normal sequence of puberty? 

Pubertal delay is defined by the absence of thelarche by age 13, or menarche by age 16.

Assess the timing of puberty in as much detail as possible: timing of secondary hair development, breast development and menarche in females, increase in testicular and penile volume, early morning erections and voice breaking in males.

Do they complain of loss of body hair, or have difficulty building muscle bulk?

Loss of secondary sexual characteristics such as body hair, and an inability to build new muscle may occur with gonadotropin deficiency of any cause.

Has the patient lost or gained weight, or changed in body shape? 

Weight loss may indicate the development of hypopituitarism or hyperthyroidism. Hypogonadotropic hypogonadism may also occur with Cushing's syndrome and in obesity.

Tall stature and a feminine or 'eunucoid' body shape may be associated with absent puberty in males.

Gynaecomastia may indicate gonadotropin deficiency but in the absence of other symptoms other causes should be considered. Gynaecomastia occurring in conjunction with weight loss should alert to the possibility of malignancy and other systemic diseases.

Does the patient feel their libido is normal or has this changed? 

Absent libido occurs with primary hypogonadism.

New onset loss of libido may be associated with hypogonadism though may be multifactorial.

Has the patient developed hot flushes? 

This may indicate sex hormone deficiency.

Has the patient, if female, started to menstruate, or has their pattern of menstruation changed?

Differential diagnoses differ between primary and secondary amenorrhoea.

For secondary amenorrhoea or oligomenorrhoea, specifically assess for symptoms of polycystic ovarian syndrome as well as hyperprolactinaemia and thyroid dysfunction below.

Has the patient previously sought fertility, or had successful pregnancies?

Previous pregnancies may help define the duration of disease.

Could the patient be pregnant now? 

Amenorrhoea and breast swelling are signs of early pregnancy which may not be noticed in the oligomenorrhoeic patient.

What is the patient's obstetric history? 

Post partum haemorrhage leading to Sheehan’s syndrome as a cause of hypopituitarism is possible if the patient was unable to breast feed and developed secondary amenorrhoea.

Does the patient, if male, shave? If so, how often and has the frequency changed? 

Frequency of shaving varies widely but is usually constant within an individual adult.

Does the patient wake with an erection sometimes, and have they developed erectile dysfunction? 

Loss of early morning erections is usually important though erectile dysfunction is frequently multifactorial. Symptoms of erectile dysfunction may not be forthcoming unless specifically asked about.

Has the patient had mumps, testicular torsion or other testicular trauma? 

These are all causes of gonadal failure, though orchitis is frequently asymptomatic.

Has the patient had any testicular surgery or maldescent of the testes? 

Maldescent may be associated with gonadal dysfunction as well as an increased risk of malignancy.

Are there features to suggest elevated prolactin? 

Hyperprolactinaemia of any cause usually causes hypogonadotropic hypogonadism.

Ask about headache, visual disturbance, breast swelling and galactorrhoea.

Are there any features of thyroid dysfunction? 

Hypothyroidism is a common cause of delayed puberty. 

Also ask whether the patient has developed increased sweating, palpitations, tremor, weight loss or diarrhoea, as thyrotoxicosis may also cause gynaecomastia and oligomenorrhoea.

Are there any other symptoms of pituitary hormone deficiency? 

Patients presenting with infertility can on rare occasion be found to have hypopituitarism.

Are they taking a normal diet? Do they have symptoms suggestive of an eating disorder? Do they take any special supplements or soya products, such as milk? 

Anorexia nervosa and very low BMI of any cause may cause hypothalamic dysfunction.

Soya contains large amounts of phytoestrogens which may interfere with the hypothalamic-pituitary-gonadal axis and may be associated with reversible gyncecomastia.

Steroids also interact with the hypothalamic-pituitary-gonadal axis and may occasionally be found in preparations thought by the patient to be 'natural' or 'herbal'.

What level of exercise does the patient take? 

Excessive exercise may lead to hypothalamic dysfunction.

Are they taking any prescribed or non prescribed medications? 

Various agents associated with hypogonadism are listed below (although it is not exhaustive): 

Opiates and recreational drugs, for example diamorphine, morphine sulphate, heroin, marijuana and alcohol.

Steroids, for example hydrocortisone, beclamethasone, fluticasone interfere with the hypothalamo-pituitary axis.

Exogenous testosterone, for example used for fitness, body building or other sports, will also enhance estrogen synthesis.

Estrogens and drugs with estrogen-like activity, such as diethylstilbestrol and digoxin will also cause gynaecomastia in some cases. 

Phenytoin also enhances estrogen synthesis, as do gonadotropins.

A range of drugs can inhibit testosterone synthesis or action, including ketoconazole, metronidazole, alkylating agents, spironolactone, cimetidine, flutamide, finasteride, and etomidate.

Other agents such as methyldopa, tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors have all been reported as causing gynaecomastia, though the mechanisms underlying this are unclear.

Delayed or absent puberty


Does the patient have a normal sense of smell? 

Patients may not report anosmia unless specifically questioned. Kallmann’s syndrome is typified by anosmia and hypogonadotropic hypogonadism.


Has the patient had any dental problems? 

Dental aplasia, cleft palate and dental malalignment requiring orthodontic treatment may not be obvious and are associated with Kallmann’s syndrome.


Has the patient had any renal problems? 

Congenital abnormalities of the urogenital system may occur with Kallmann’s and Turner’s syndromes.


Is there a relevant family history? 

Specifically ask if any family members, for example cousins, have had late or absent puberty, infertility or simply never had children.

Ask also if any family members have had dental or palatal problems, kidney abnormalities or anosmia which might suggest a family history of Kallmann’s syndrome.


Does the patient have any symptoms suggestive of thyroid dysfunction? 

Congenital hypothyroidism is associated with delayed puberty.

Hypothyroidism is also associated with Turner's syndrome.


Is the patient known to have coarcation of the aorta, or other vascular abnormalities? 

These may be associated with Turner's syndrome.


Has the patient had any hearing problems? 

Deafness may be associated with Turner's syndrome.


Is the patient known to have psychiatric problems or learning difficulties? 

Patients with Klinefelter's syndrome have an increased incidence of psychiatric problems.


Has the patient had other physical or learning difficulties in the past? 

Multiple congenital conditions include abnormalities of sexual development. Examples include pseudopseudohypoparathyroidism, Russell Silver syndrome, congenital hypothyroidism.

Specific disorders of sexual development may also be encountered: congenital adrenal hyperplasia, androgen insensitivity syndrome, 5-alpha reductase deficiency, aromatase deficiency, gonadal dysgenesis, Kallmann's syndrome, Turner's syndrome, Klinefelter's syndrome, and other rarer conditions.

Adult onset hypogonadism


Has the patient noticed any visual symptoms? 

Loss of acuity or failing vision at night are worrying features suggesting optic nerve involvement.

Visual field loss, for example homonymous hemianopia, is common indicating chiasmal impingement. 

It is worth specifically asking whether patients drive and, if so, whether they have had trouble noticing street signs on either side of the road as this may be the first instance in which field loss is noticed.


Has the patient developed a new headache or neuralgia? 

Assess for red flag symptoms: headaches present on waking, which worsen on coughing or leaning forward, are more suggestive of increased intracranial pressure.

Headaches or lancing pain across one section of the head or face only are more suggestive of cranial nerve involvement particularly with disease in the cavernous sinus.


Does the patient feel well in themselves? Have they noticed loss of energy, fatigue, nausea or dizziness? 

Vague symptoms of tiredness, nausea and dizziness may indicate the development of hypopituitarism with ACTH or TSH deficiency.


Does the patient complain of excessive thirst or polyuria? 

Diabetes insipidus is uncommon with intrinsic pituitary disease and suggests para sellar pathology.


Are there any features to suggest underlying malignancy? 

Pituitary metastases are common and may be the first presentation of malignant disease.

Ask specifically about change of bowel habit, new prostatic symptoms and breast lumps.


Are there any features of prolactin excess? 

Hyperprolactinaemia of any cause is a common cause of hypogonadotropic hypogonadism.


Are there any features of cortisol excess or other pitutiary hyperfunction? 

Ask the patient whether there has been a change in their weight or body shape. New bruising, redness, acne, hirsuitism, oligomenorrhoea, diabetes, hypertension, depression, osteoporosis or muscle weakness are all associated with Cushing's syndrome, which leads to pubertal delay and hypogonadotropic hypogonadism.

Gynaecomastia


How long has the gynaecomastia been present? 

A detailed history of gynaecomastia will help elucidate likely causes.

Peripubertal breast swelling is common and usually requires no treatment. Long standing obesity may be associated with bilateral non-glandular breast swelling. Sudden onset and unilateral gynaecomastia should alert to the possibility of breast cancer.


Is the gynaecomastia bilateral or unilateral? 

Sudden onset and unilateral gynaecomastia should alert to the possibility of breast cancer.


Is there any galactorrhoea, nipple change or other discharge? 

Changes in the skin, nipple or unilateral discharge is highly suspicious for breast cancer.

Bilateral galactorrhoea is suggestive of elevated prolatin.


Are there any other features to suggest underlying malignancy? 

Weight loss and malaise occur with hypopituitarism but may indicate malignancy.


Are there features to suggest elevated prolactin? 

Hyperprolactinaemia of any cause may lead to tender gynaecomastia and galactorrhoea.


Are there any features of thyroid dysfunction? 

Hyperthyroidism may be associated with gynaecomastia: ask about sweating, palpitations, tremor, weight loss or diarrhoea.

Hypothyroidism may be associated with delayed puberty.


Does the patient have any risk factors for, or symptoms of, cardiac or hepatic disease? 

Cirrhosis, haemachromatosis and congestive cardiac failure are frequently associated with gynaecomastia.


Is the patient taking any drugs known or suspected of causing gynaecomastia? 

Various agents associated with hypogonadism are listed below (although it is not exhaustive): 

Opiates and recreational drugs, for example diamorphine, morphine sulphate, heroin, marijuana and alcohol.

Steroids, for example hydrocortisone, beclamethasone, fluticasone interfere with the hypothalamo-pituitary axis.

Exogenous testosterone, for example used for fitness, body building or other sports - will also enhance estrogen synthesis.

Estrogens and drugs with estrogen-like activity, such as diethylstilbestrol and digoxin will also cause gynaecomastia in some cases. 

Phenytoin also enhances estrogen synthesis, as do gonadotropins.

A range of drugs can inhibit testosterone synthesis or action, including ketoconazole, metronidazole, alkylating agents, spironolactone, cimetidine, flutamide, finasteride, and etomidate.

Other agents such as methyldopa, tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors have all been reported as causing gynaecomastia, though the mechanisms underlying this are unclear.