Kallmann's syndrome and hypogonadotropic hypogonadism

The diagnosis of Kallmann's syndrome comprises hypogonadotropic hypogonadism associated with anosmia.

What is the main presenting feature? 

Detailed history, including pubertal development, is mandatory in all patients as this may reduce the differential diagnoses considerably. It is vital to ascertain why the patient has presented now. Determine whether the patient ever went through puberty, or whether they have lost secondary sexual characteristics, libido, erectile function or are seeking fertility.

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.

Has the patient been through the normal sequence of puberty? 

Assess timing of stages of puberty: timing of secondary hair development and rate of change of height in all, breast development and menarche in females, increase in testicular and penile volume, early morning erections and voice breaking in males.

Does the patient have a normal sense of smell?

Patients may not report anosmia unless specifically questioned. Kallmann’s syndrome is typified by either anosmia or severe hyposmia 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 renal system may occur with Kallmann’s and Turner’s syndrome.

Is there any relevant family history?

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

Ask also if any family members have had dental or palatal problems, kidney abnormalities, or anosmia as these may occur without gonadal problems in other family members of a patient with Kallmann's syndrome.

Has the patient developed hot flushes? 

This may indicate sex hormone deficiency.

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

Patients with Kallmann's syndrome or idiopathic hypogonadotropic hypogonadism usually have absent puberty. Secondary amenorrhoea is thus suggestive of alternative pathologies such as polycystic ovarian syndrome, hyperprolactinaemia or thyroid dysfunction.

Has the patient previously sought fertility? Has this resulted in pregnancies?

Previous successful pregnancies are unusual in untreated Kallmann's and suggest late onset or secondary hypogonadotropic hypogonadism rather than a congenital condition. 

Hypogonadotropic hypogonadism may also occur as part of Sheehan's syndrome, where anterior pituitary failure follows a post partum haemorrhage.

Has the patient, if male, ever needed to shave? If so, how often and has the frequency changed? 

Most patients with Kallmann's syndrome or isolated hypogonadotropic hypogonadism have absent puberty and so will not develop secondary hair without treatment. Shaving is thus suggestive of secondary causes.

Does the patient wake with an erection sometimes? Do they describe erectile dysfunction? 

Patients with Kallmann's syndrome or idiopathic hypogonadotropic hypogonadism usually have a low libido and may not be sexually active.

Are there features to suggest elevated prolactin? 

Hyperprolactinaemia of any cause usually causes hypogonadotropic hypogonadism. Ask about visual disturbance, headache, breast swelling and galactorrhoea.

Are there any features of thyroid dysfunction? 

Thyroid dysfunction can be associated with absent puberty, and with gynaecomastia, and secondary amenorrhoea and so should always be excluded in patients describing these symptoms.

Are there any other symptoms of pituitary hormone deficiency? 

Patients with Kallmann's syndrome or idiopathic hypogonadotropic hypogonadism have by definition isolated hypogonadism. Any features suggesting loss of other pitutiary hormones implies an alternative pathology.

What level of exercise does the patient take? 

Excessive exercise may lead to hypothalamic dysfunction.

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 is known to contain large amounts of phytoestrogens which may interfere with the hypothalamo-pituitary-gonadal axis and may be associated with reversible gyncecomastia.

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

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 and fluticasone, interfere with the hypothalamo-pituitary axis.

Exogenous testosterone, for example 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.

Does the patient have any features associated with Turner's syndrome?

Deafness, hypothyroidism, coarctation of the aorta and other vascular abnormalities may all occur with hypogonadotropic hypogonadism in female patients with Turner's syndrome.

Has the patient ever had any psychiatric problems or learning difficulties?

Patients with Klinefelter’s syndrome may also present with absent puberty and hypogonadotropic hypogonadism, and have an increased incidence of psychiatric problems.

Has the patient had any other physical problems in the past?

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