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.
Typical starting dose in an estrogen naive patient is 1.25mcg ethinylestradiol. Increase dose to 2.5mcg, then by 2.5mcg increments every six months to 10mcg. The dose may then increase to 15mcg.
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, consider adding cyclical progesterone for example norethisterone 5mg for the first five days of the month.
Alternative treatment regimens
The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable in young patients, for example Loestrin 20.
However, these do not provide sufficient bony protection unless used continuously and HRT is more appropriate long term.
Topical, depot and oral preparations should be offered and treatment tailored according to the individual. Topical estrogen gel may also be used to ameliorate vaginal dryness.
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 be useful to guide final dose with monthly testosterone injections. Random levels are sufficient in the monitoring of other forms of testosterone.
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.