Kallmann's syndrome and hypogonadotropic hypogonadism

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

Discuss diagnosis, offer counselling, and discuss fertility issues

Many of these diagnoses will come as a shock to patients and their families. Psychological as well as genetic counselling may therefore be helpful. Fertility should also be discussed early with the patient and their family where appropriate.

Patients need to understand that pubertal induction alone with not affect or restore fertility, although appropriate uterine development is essential prior to possible future pregnancies. Fertility can frequently be acheived with pulsatile gonadotropin therapy or further assisted fertility techniques.

Pubertal induction and sex hormone replacement therapy


Discuss treatment aims, timescales and outcomes

Treatment aims to replicate the natural process of puberty and should occur over approximately the same timescale - approximately two to three years.

Patients need to understand that accelerating the treatment may have adverse psychological and physical consequences, for example poor breast development.


Initiate treatment: females

Initiate very low dose estrogen replacement therapy.

An alternative is to use topical estrogen therapy. This may give a better eventual breast shape, and is well tolerated, with the patches often easier to source in the community than low dose ethinylestradiol. A typical start dose is with one quarter of a 25mcg Estradiol patch given either overnight every day, or left on and replaced every 72 hours. The dose should then increase every 3-4 months to half a patch, then a whole 25mcg patch, then a 50mcg patch, then a 75mcg, then a 100mcg patch.  


Dose titration

Consider pelvic ultrasound scan to assess uterine size at this stage.

Once the patient experiences vaginal bleeding or if the patient has tolerated 15mcg orally, or 100mcg transdermally, consider adding cyclical progesterone. Measurement of LH and FSH levels may also be used to help judge whether the final dose of topic estradiol is sufficient, as some girls will require higher doses.


Alternative treatment regimens

Cyclical estrogen and progesterone replacement therapy should be considered in all patients.

The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable at diagnosis and in young patients. However, there has been some doubt as to whether this offers sufficient bony protection unless taken continuously, with some authorities advising taking this 3 packs at a time. Combined oral contraceptive pills are also contraindicated in patients with a history of migraines with aura. Low dose HRT is more suitable in these cases.

Hormone replacement therapy is more appropriate in the long term, and should be tailored to suit the individual, for example by offering topical, depot or oral preparations. Choice will also depend on the age of the patient, presence or absence of a uterus, and history or family history of breast or endometrial cancer. A history of, or strong risk factors for cardiovascular or thromboembolic disease will also need to be considered.

Topical estrogen is particularly useful in patients at high cardiovascular risk, or with abnormalities of liver function. Combined patches are available, or if estrogen gel is used, low dose continuous progesterone will also be required to prevent endometrial hyperplasia eg 1x350mcg progesterone only pill daily.

Estrogen replacement therapy should be continued until the time of the natural menopause - typically to age 50. Vaginal dryness may be ameliorated by topical estrogen gels.


Duration of treatment

Continue sex hormone replacement therapy until the time of the natural menopause - typically to age 50.


Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner’s syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.


Initiate treatment: male patients

Initiate very low dose testosterone therapy, and warn patient of expected psychological and physical effects.

Typical starting dose in a testosterone naive patient is approximately 20% of an adult dose. This has traditionally been given as an intramuscular injection of 50mg testosterone esters, monthly.


Dose titration

Monthly testosterone treatment is then typically increased by a further 50mg every six months according to clinical response.

Alternatives include low dose depot testosterone, or topical gel using the same dosing schedule.


Treatment monitoring

Routine monitoring of serum testosterone levels is not necessary until the expected adult dose is reached.

Peak and trough levels may then be useful to confirm the appropriateness of the final dose in patients taking monthly testosterone undecanoate. Peak 7 days post injection should typically be 25-30nmol/l, with a predose trough level of 8-12nmol/l. Subsequently, the dose should not be altered unless the clinical response is suboptimal, or in the light of changes in serum monitoring of prostate specific antigen, full blood count, liver function, or pre dose testosterone levels.

In patients taking depot preparations, a random or pre dose level of 15-20nmol/l, and for patients taking daily topical preparations, a level of 15-20nmol/l 4-6 hours post application of the gel is usually sufficient.


Warn patients that testicular volume is not likely to change

Testicular volume may be enhanced during gonadotropin treatment used in the induction of spermatogenesis, however, this tends to reverse on treatment cessation, and is not expected with testosterone replacement therapy.

Synthetic implants can be considered to restore testicular volume where required.


Alternative treatments

Once patient is virilised appropriately and established on full adult dose, offer switching to alternative preparation, for example daily gel or depot preparation.

Optimise final dose according to symptoms and serum levels.


Annual monitoring

Annual random testosterone levels are generally sufficient after the dose has been optimised, although trough levels are also assessed in patients on monthly or more frequent testosterone injections.

Digital rectal examination, prostate specific antigen, full blood count and liver function tests should also be performed annually with dose reduction and/or onward referral if abnormalities arise.


Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner’s syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.

Osteoporosis

Osteoporosis is common in patients with hypogonadism of any cause. It is worth ensuring that patients are vitamin D replete and, if not, prescribing vitamin D supplementation where necessary. General life style advice should also be given to patients with confirmed osteoporosis.

Osteoporosis should respond well to standard sex hormone replacement therapy. However, it may be worth repeating a bone densitometry scan after five years of treatment to determine whether other agents should be considered.

Kallmann's syndrome

Offer genetic counselling.

Ensure that an MRI scan of the pituitary and olfactory bulbs has been performed, and that pituitary function, karyotype and where necessary pelvic ultrasound scan have all been reviewed to exclude other diagnoses.

Arrange a renal ultrasound scan, as abnormalities of the urogenital tract may be associated with this condition. 

Arrange an echocardiogram and cardiology review where indicated, as multiple congenital heart defects including ventricular and atrial septal defects and rhythm disturbances have been decribed in a small subset of patients with Kallmann's syndrome.

Arrange neurology review in those patients with other neurological sequellae such as epilepsy.

Treat with standard pubertal induction and long term testosterone or estrogen replacement therapy.

Offer life long follow up.

Klinefelter's syndrome

Offer genetic counselling to all patients diagnosed with this condition. Psychological counselling may also be beneficial in some cases, and other psychological, psychiatric, or learning difficulties should be treated on their own merits.

Medical treatment is the same as for any other patient presenting with hypogonadism.

Follow up should be life long.

Androgen insensitivity

The diagnosis of androgen insensitivity or 'testicular feminisation' is difficult for many patients and families to understand, and counselling should be offered to all women with this condition.

Medical treatment is with standard pubertal induction, long term estrogen replacement therapy as with any other form of hypogonadism.

Offer life long follow up.

Turner's syndrome

Offer genetic counselling.

Medical treatment is the same as for other women with hypogonadism or absent puberty, although specific follow up for patients with Turner's syndrome is necessary to detect and treat other complications.