scale-female diagnosis of ks/chh normal involves a range of clinical, biochemical and radiological tests to exclude other conditions that can cause similar symptoms. clinical tests comparing height to standard growth charts. determining the tanner stage of sexual development. (males with ks/chh are normally at stage i or ii with genitalia, females at stage i with breast development and both males and females at stage iii with pubic hair development). checking for micropenis and undescended testes (cryptorchidism) in males. measuring testicular volume. checking for breast development and age at menarche in females. checking sense of smell using odorant panel or university of pennsylvania smell identification test (upsit) checking for hearing impairment. checking for missing teeth or presence of cleft lip and/or cleft palate. checking for pigmentation of skin and hair. checking for mirror movements of the hands or signs of neurodevelopmental delay. lab tests early morning hormonal testing including fsh, lh, testosterone, oestrogen and prolactin. gnrh and/or hcg stimulation test to determine activity of hypothalamus and pituitary. sperm test liver function, renal function and inflammation marker testing. karyotype to check for chromosomal abnormalities. medical imaging performing wrist x-ray to determine bone age. brain mri to rule out any structural abnormalities in the hypothalamus or pituitary and to check for presence of olfactory bulbs. ultrasound of kidneys to rule out unilateral renal agenesis. bone density scan (dxa) to check for osteoporosis or osteopenia. treatment testosterone gel sachets, testosterone undecanoate injection (nebido), human chorionic gonadotropin (hcg) injection, menotropin injection (hmg). for both males and females, the initial aim for treatment is the development of the secondary sexual characteristics normally seen at puberty. once this has been achieved, continued hormone replacement therapy is required for both males and females to maintain sexual function, bone health, libido and general wellbeing. in males, testosterone replacement therapy is required for the maintenance of normal muscle mass. early treatment is sometimes required for male infants with suspected ks/chh to correct undescended testes and micropenis if present with the use or surgery or gonadotropin or dht treatment. females with ks/chh normally do not require any treatment before adolescence. currently, no treatments exist for the lack of sense of smell, mirror movement of the hands or the absence of one kidney. treatment for both males and females with ks/chh normally consists of one of three options which can be used for both hormone replacement therapy and/or fertility treatment. sex hormone replacement (testosterone or oestrogen & progesterone). gonadotropin therapy (medications that replicate the activity of fsh and lh). gnrh pulsatile therapy. hormone replacement therapy the method and dose of treatment will vary depending on the individual being treated. initial treatment is normally made with lower doses in younger patients in order to develop the secondary sexual characteristics before adult doses are reached. for males with ks/chh the types of testosterone delivery include daily patches, daily gel use, daily capsules, subcutaneous or intramuscular injections or six-monthly implants. different formulations of testosterone are used to ensure both the anabolic and androgenic effects of testosterone are achieved. nasal testosterone delivery methods have been developed but their use in ks/chh treatment has not been formally evaluated. gonadotropin therapy, in the form of human chorionic gonadotropin (hcg) injections, with or without the use of fsh, can also be used in male patients to induce secondary sexual characteristic development alongside possible fertility induction. for females, hormone replacement involves the use of oestrogen and progesterone. firstly, oestrogen is used in tablet or gel form in order to maximise breast development, then a combination of oestrogen and progesterone is used. cyclical progesterone is normally required to help keep the endometrium (lining of the uterus) healthy. in males, the monitoring of treatment normally requires the measurement of serum testosterone, inhibin b, haematocrit and prostate-specific antigen (psa). if injections are used, trough levels are taken to ensure an adequate level of testosterone is achieved throughout the injection cycle. in females monitoring normally consists of measurement of oestrogen, fsh, lh, inhibin b and anti-müllerian hormone (amh). standard hormone replacement therapy will not normally induce fertility in either males or females, with no testicular growth in males. early treatment as adolescents can help with psychological well-being of people with ks/chh. fertility treatments gonadotropin therapy can be used in both male and female patients in order to achieve fertility for some people. pulsatile gnrh therapy can also be used to induce fertility, especially in females, but its use is limited to a few specialist treatment centres. in males with ks/chh, infertility is primarily due to the lack of sperm production within the testes. sperm production can be achieved through either the use of gnrh administered via a microinfusion pump or through the use of gonadotropin injections (hcg, fsh, hmg). the time taken to achieve adequate sperm production for natural conception will vary from person to person. if the pre-treatment testes are very small and there has been a history of undescended testes it might take longer to achieve sperm production. in these cases, assisted reproductive technology, such as sperm retrieval using testicular sperm extraction (tese) and/or intracytoplasmic sperm injection (icsi), might be required. in females with ks/chh, infertility is primarily due to the lack of maturation of eggs located within the ovaries. ovulation induction can be achieved either with pulsatile gnrh therapy or alternatively with gonadotropin injections (hcg, fsh, hmg) given at set intervals to trigger the maturation and release of the egg for natural conception. prognosis reversal of symptoms has been reported in between 10% to 22% of cases. reversal cases have been seen in both ks and normosmic chh but appear to be less common in cases of ks (where the sense of smell is also affected). reversal is not always permanent and the precise genetic causes are not yet fully understood. epidemiology the epidemiology of kallmann syndrome is not well understood. individual studies include a 1986 report reviewing medical records in the sardinian army which found a prevalence of 1 in 86,000 men and a 2011 report from finland which found a prevalence of 1:30,000 for males and 1:125,000 for females. kallmann syndrome occurs about 4 times more often in males than females, but is only 2.5 times more common among males in familial cases. history franz j. kallmann, circa 1950 kallmann syndrome was first described by name in a paper published in 1944 by franz josef kallmann, a german-american geneticist. the link between anosmia and hypogonadism had already been noted by the spanish doctor aureliano maestre de san juan in 1856. in the 1950s, de morsier and gauthier reported the partial or complete absence of the olfactory bulb in the brains of men with hypogonadism. terminology the terminology used when describing cases of hh vary and can include: gnrh deficiency congenital hypogonadotropic hypogonadism (chh) idiopathic/isolated hypogonadotropic hypogonadism (ihh) normosmic hypogonadotropic hypogonadism (nhh) hypothalamic hypogonadism olfacto-genital syndrome research kisspeptin is a protein that regulates the release of gnrh from the hypothalamus, which in turn regulates the release of lh and, to a lesser extent, fsh from the anterior pituitary gland. kisspeptin and its associated receptor kiss1r are known to be involved in the regulation of puberty. studies have shown there is potential for kisspeptin to be used in the diagnosis and treatment of certain cases of kallmann syndrome and chh.