Kallmann's Syndrome + Hypogonadotrophic Hypogonadism
Frequently
Asked questions
These questions & answers are meant as a brief introduction for anybody interested in finding out more about Kallmann’s Syndrome and Hypogonadotrophic Hypogonadism and have been written by people who have Kallmann’s syndrome.
It is highly recommended that expert medical advice should be sought from health professionals specialising in developmental endocrinology or reproductive endocrinology.
What is Kallmann's syndrome?
Kallmann's syndrome is a congenital hormonal condition characterised by the failure of an individual to enter puberty. It is a form of hypogonadotrophic hypogonadism. The underlying cause is a failure in the communication pathways within the body that should operate in order to initiate puberty at the correct time. In particular it is a failure of communication between two structures inside the brain called the hypothalamus and the anterior pituitary gland. This failure of communication results in the sex organs or gonads (testes or ovaries) not maturing in the usual manner during puberty.
Why is it called Kallmann’s
syndrome?
Franz Kallmann was an American scientist who published a paper in 1944 about the cases of 3 families who all had members who failed to enter puberty and had no sense of smell. He was the first person to propose that this was a genetic condition and it was named after him.
The first mention of the condition came in 1856 when a paper was published by Aureliano Maestre de San Juan highlighted an autopsy report on a patient with undeveloped sex organs and absent olfactory lobes (the part of the brain concerned with sense of smell). In Spanish speaking parts of the world the condition is still called after him.
In 1954 de Morsier published a paper on 14 cases of anosmia (lack of sense of smell) and absent puberty and proved the neuro-pathological basis of the condition.
This has led to a number of different names being given to the same syndrome, depending on what part of the world you are in:
de Morsier’s
Syndrome II;
Morsier-Gauthier
Syndrome;
Kallmann-de
Morsier Syndrome;
Maestre-Kallmann-de
Morsier Syndrome;
Maestre de San Juan-Kallmann Syndrome;
Maestre de San Juan-Kallmann-de Morsier Syndrome;
When does puberty become ‘delayed’?
The age of onset of puberty can vary. It starts earlier in girls than in boys. Some specialists think it that if by the age of 13 for girls and 15 for boys no signs of starting puberty then they should be referred to a specialist doctor, usually an endocrinologist.
There is an article on the normal stages of puberty elsewhere on this site. In general any girl who has not had their first period or a boy showing any testicular development by the age of 15 should be investigated for a delay of puberty.
In boys the testes should have descended in the scrotum before or just after birth. Un-descended testes (cryptorchidism) is a not an uncommon event in boys and can be easily rectified with drugs or surgery. A history of bilateral cryptorchidism (both testes undescended) should alert doctors to the possibility of a problem with puberty later, but this does not necessarily mean that a boy with cryptorchadism will develop Kallmann’s.
What does congenital mean?
Congenital means the condition is present from birth. It arises from the genetic make up you are born with. It means Kallmann's cannot be caught or contracted during life.
What does hypogonadal mean?
'hypo' means below or under (as in hypodermic – below the skin). 'gonadal' means relating to the sex organs, i.e. the ovaries or testes. In this context the term implies that the sex organs have not developed into their normal state they would have achieved if puberty had occurred and are not responding in the usual post-pubertal manner in producing the normal sex hormones – oestrogen and testosterone.
The term hypogonadism covers a wide range of conditions and is not unique to Kallmann’s syndrome. There are more common genetic disorders that can result in hypogonadism such as Kleinfelters syndrome and Turner’s syndrome. Hypogonadal conditions can be classed as either primary or secondary.
Primary hypogonadism is due to the sex organs themselves not functionally correctly or being unable to respond to the correct hormone signals. Kleinfelters and Turners are primary hypogonadism conditions. There are other primary hypogonadal conditions that can occur during life where previously normally functional gonads stop producing their specific hormones. Certain types of drugs, mumps and physical injury can all cause primary hypogonadism during life.
Secondary hypogonadism is due a failure in the communication pathways between the endocrine and nervous system with the sex organs resulting in them not developing correctly during puberty. Usually this means some sort of malfunction in two endocrine glands located within the brain called the hypothalamus and the pituitary. Kallmann’s and its related conditions are secondary hypogonadism conditions.
There can be a wide number of reasons for hypogonadism so it is important to seek expert medical help. All the different conditions have different forms of treatment available.
What does hypogonadotrophic mean?
'trophism' means acting on or having an affect on. In this context the term hypogonadotrophic hypogonadism means that the sex organs have remained in their pre-pubertal state having not received the correct signals or inducement to under go the normal changes seen during puberty.
Kleinfelter’s syndrome in males and Turner’s syndrome in females are hypergonadotrophic disorders. They both still cause hypogonadism but the levels of circulating pituitary hormones are raised rather than lowered as seen in Kallmann’s and other forms of hypogonadotrophic hypogonadism.
Are there other forms of
hypogonadotrophic hypogonadism?
Yes. Hypogonadotrophic hypogonadism (which we will shorten to HH) covers a range of rare disorders that all result in the failure to enter puberty. Kallmann's syndrome is a specific form of HH in which the individual has no sense of smell. There are other forms of HH where the sense of smell is present but are still very similar to Kallmann's syndrome.
Is this distinction important?
Yes. The different forms of HH and Kallmann's may give similar symptoms but sometimes the causes can be different. An endocrinologist should be able to give you advice on what type of HH you might have, which in turn will affect the types of treatments available.
Does it affect both men and women?
Yes. All forms of HH are seen in both men and women, even though it is more common in men. Current estimates suggest that Kallmann’s and HH is 3 to 5 times more common in men than women. The reason for the difference between the incidence in males and females is not fully understood.
How many people are affected?
Current estimates are that Kallmann’s occurs between1 in 10,000 and 1 in 50,000 men and 1 in 70,000 women. It is a very rare condition that may well go under reported so a more accurate idea of the incidence may be difficult to establish. It is important that in any case of delayed puberty should be properly investigated by an endocrinologist to discover the underlying cause of the delay.
What is an endocrinologist?
An endocrinologist is a doctor who specialises in the
treatment of hormonal disorders. An endocrinologist should be consulted so that
they can fully investigate the causes of delayed puberty. There may be a number
of reasons for the delay and might well be linked to other hormonal problems.
Kallmann's and HH are hormonal disorders and usually need specialist help for the initial diagnosis and treatment. Endocrinology covers a wide field and if a choice were available it might be worth finding a doctor who specialises in reproductive endocrinology.
There is a separate article on this web site outlining the basics of hormones and endocrine glands.
Is it curable?
Not at present. It is very difficult to cure a congenital disorder; most of the genetic research is focused on the fatal congenital disorders such as cystic fibrosis.
Is it treatable?
Yes it is. It does depend on the type of KS or HH but it is treatable. The treatment will depend on the age of diagnosis mainly and a few other factors. The three major areas of treatment are:
Replacing the missing hormones
Fertility treatment
Reducing the risk of osteoporosis
Not all the symptoms are treatable. The lack of smell or anosmia seen in Kallmann’s is on the whole untreatable.
Is KS and HH hereditary?
Yes it can be, but the majority of cases still appear to be ‘sporadic’ or ‘isolated’. There are some types of KS and HH that are passed down from generation to generation. The majority of cases arise with no apparent family history and appear to be sporadic. It must be noted that the terms sporadic and isolated can be a bit misleading as it is quite possible that a seemingly isolated case may just be the first occurrence of a hereditary type. This is why specialist advice is needed to try to determine what form of KS or HH an individual may have.
There are at least 4 different types of inherited KS and HH that are known about at present. The most widely known, and apparently the most common is x-linked Kallmann’s. This means that Kallmann’s is passed down through the generations on the X chromosome. This means that men are for more likely to develop x-linked Kallmann’s than women. Women tend to be carriers of the x-linked type, i.e. they can pass it onto to anther generation without having the condition themselves.
There will be more information on the genetics and inheritance of KS and HH elsewhere on the site.
What causes KS or HH?
KS and HH are classed as congenital disorders because they arise from the genetic code that causes each one of us to be individuals. The genetic code is contained in virtually every living cell and is the blue print or computer programme that is required to produce every part of an individual. Each person’s code is different but only varies very slightly to produce individual characteristics like body shape, eye colour and height. However sometimes an error occurs in the programme that causes a vital part of the body not to be formed or not to function properly. This can lead to a specific disease or disorder. Cystic fibrosis is an example of a very serious congenital disorder.
Kallmann’s in particular and possible a few other forms of HH are thought to arise because the cells of the hypothalamus that should release the correct hormone to initiate puberty are absent. During the development of the brain from a foetus to a baby these cells have to migrate from another area of the brain. In Kallmann’s and some forms of HH this migration is blocked and the hypothalamus is formed without any sex hormone releasing hormone-producing cells. It does however have all its other hormonal functions.
There are other situations where all the other hormones produced by the hypothalamus and pituitary is affected, along with the sex hormones. This will cause a wide range of symptoms not just the developmental symptoms as seen in KS or HH. This is why it is important to consult an endocrinologist in order to determine how well the hypothalamus and pituitary glands are functioning.
These errors occur in very small sections of the genetic code called genes, which is where the term genetic disease comes from. There are tens of thousands of genes within the genetic code, more correctly called the genome. There are 4 genes in which errors have been found that can cause the inherited form of KS or HH. Some errors appear at random and are termed ‘isolated’.
The issue of the genetics of Kallmann’s and HH will be gone into in greater detail elsewhere on the site.
How is KS or HH diagnosed?
Unless there is a family history the peak age of diagnosis still appears to be in the early 20’s. KS and HH are usually picked up because of absent puberty and all other possible causes have been eliminated. There are some physical features, other than absent pubertal growth of that occurs in KS and HH cases. Not all the features will occur; it does depend on the type of HH.
Possible physical features:
Failure to enter puberty by the age of 15
Failure to begin periods in females
Lack of breast development in females
Lack of testicular growth in males
Lack of muscle bulk
Young appearance
Tall stature –above average arm span and height.
Lack of pubic hair.
Lack of smell (Kallmann’s only)
Cryptorchidism (un-descended testes at birth)
Nerve deafness
Unilateral renal agenesis (absence of one of the kidneys)
‘Mirror’ movements of the hands or feet
Cleft palette / hare lip or other facial deformities
This is not an exhaustive list. The failure to go through puberty and the lack of smell are definitive characteristics. The other features may or may not occur depending on each individual case, and may or may not be connected to Kallmann’s or HH.
Hormonal features:
Low levels of circulating testosterone / oestrogen / progesterone
Low levels of serum LH and FSH.
No sperm production.
Hormonal tolerance tests, to asses the functioning of the
pituitary and hypothalamus glands.
Medical imaging (MRI or CT scan):
MRI (magnetic resonance imaging) can produce a picture of the pituitary and hypothalamus glands and related structures. It can theoretically be used to detect Kallmann’s very early life, well before the age of puberty.
A GP or local doctor can do some of these tests in the first instance. However specialist medical advice is need for a definite diagnosis and to rule out any other possible cause of delay of puberty.
Why do I appear to be so tall?
During puberty the bones, especially the long bones in the arms and legs grow to their maximum length and are then hardened by the deposition of calcium. The sex hormones, testosterone and oestrogen are required at puberty to ensure the ends of the bones get fused and harden to prevent further growth. If the hormones are not present or are at very low levels this hardening gets delayed and bone growth continues past its usual stage. The bones will stop growing eventually but the level of calcium deposition will be less than normal and may make the bones weaker than normal. This important feature is discussed in more depth later in the section on osteoporosis.
Why do I lack a sense of smell?
In KS but not other forms of HH a person will not have a sense of smell. A first glance puberty and sense of smell may not go together. The part of the brain that is involved in the sense of smell is called the olfactory bulb. It just so happens that the olfactory bulb lies very close to the pituitary and hypothalamus glands within the brain.
The olfactory bulb is linked to the brain via a small bridge of tissue called the olfactory tract. For the hypothalamus to be fully functional this tract must be present. In Kallmann’s this tract is missing or not fully formed. This means that there is no connection between the olfactory bulb and the brain so there is no sense of smell. In addition vital parts of the hypothalamus are not present so it cannot produce the hormone to initiate puberty. In other forms of HH there are other reasons why the hypothalamus cannot produce the correct hormone but the olfactory tract is present so the sense of smell is present.
What are these hormones?
In a general sense hormones are the body’s messenger service. There are over 40 known hormones that act on the body. They are each released by a specific endocrine gland in response to a specific stimulus, possibly another hormone. A hormone is released to generate a specific result. In normal circumstances the hormonal system works on a negative feedback mechanism.
A stimulus-----ŕhormone released by endocrine gland to reduce the effect of the stimulus-----ŕstimulus gets reduced / stopped-------ŕhormone production is stopped.
The classic case is the role of insulin in the role of maintaining the blood sugar levels. Insulin is only released in response to an increase in sugar levels, as soon as blood sugar levels falls; the production of insulin is stopped. The breakdown in this regulation causes one of the most common hormonal diseases – diabetes mellitus.
In normal puberty the pathway is:
Hypothalamus gland produces GnRH
(gonadotrophin releasing hormone)
Which causes the
Pituitary gland to produce LH / FSH
(luteinsing hormone / follicle stimulating hormone)
Which cause the
Testes to produce testosterone &
sperm
Or
Ovaries to produce progesterone and
oestrogen & ovulate
Which causes puberty to occur. The sex hormones also have other affects around the body, not just linked to puberty and fertility.
In KS or HH either the pituitary gland either does not receive the GnRH, or it is unable to respond to the GnRH. Without the first signal the pituitary will not produce its hormones (LH and FSH) that in turn will prevent the testes or ovaries producing their own hormones at the required time to cause puberty.
There is a more detailed article on puberty and the effects each hormone causes elsewhere on this site.
Will a person with KS or HH go
through puberty?
It is possible if diagnosed early enough that a person with KS or HH can go through puberty normally with the appropriate treatment. The situation gets a little more complicated if diagnosis is made after pubertal age but there are treatments available that in some cases can induce some of the features of puberty and possibly induce a low level of fertility. It must be emphasised that all cases are different and specialist advice is required.
Can a person with KS or HH become
fertile?
Yes, possibly, but only with specialist treatment and if other circumstances are favourable. There have been many cases of people with Kallmann’s having children, usually through a form of IVF or other assisted fertilisation programmes. As with any type of fertility treatment there are many other factors to consider and it can take many months of treatment and there is no guarantee as with any form of fertility treatment. It has been noted that fertility can be achieved with Kallmann’s women more quickly than with other patients.
Is there any affect on expected
lifespan?
There is no reliable evidence that KS or HH has any affect on the life span on an individual. It is worth point bearing in mind though that there are some rare symptoms that can occur with KS and HH that may have an affect on life span. These other symptoms may be connected to KS or HH or may have arisen regardless.
There is also evidence, but not conclusive that long term HRT has a positive effect on life expectancy, especially in females.
Are there any risks if KS or HH is
left untreated?
Yes there can be. The major problem with a person with untreated KS or HH is the increased risk of osteoporosis or ‘brittle bone disease’. The greatly reduced levels of sex hormones seen with KS and HH have a detrimental effect on the strength of the bones. This can be easily treated with the appropriate drugs that will reduce the risk of osteoporosis to that seen in the rest of the population. It is advised that a person with KS or HH should have a bone scan at least every 5 years to assess their bone age and to assess the risk of osteoporosis. This important subject is dealt with in greater detail elsewhere on this site.
What types of treatment are available?
This will be covered in more detail elsewhere on the site.
On first presentation the usual form of treatment is with the use of the sex hormones that should have been produced during and after puberty.
For males this will be testosterone or one of its derivatives.
For females it will be oestrogen in the first case and then later a combination of oestrogen and progesterone.
It is possible that if puberty is just delayed that these drugs will initiate, or ‘kick-start’ puberty and the whole process will progress as normal.
However if you have KS or HH these sex hormones will not induce puberty. They are designed to cause the other affects seen during puberty such as muscle and bone growth, sex drive (libido), control of mood swings and general metabolism.
The use of testosterone and oestrogen will not cause fertility and no growth in the sex organs will occur.
Hormone replacement therapy for men:
Testosterone can be administered to men in a number of ways. Each method has its own advantages and disadvantages and it might be down to a matter of personal choice or even cost as to which one to go for.
Self-administered injections every 2 to 3 weeks into the thigh muscle.
6 monthly implants inserted deep into the thigh / hip under local anaesthetic.
Tablets taken 2 to 3 times a day
Skin patches worn on the skin, releasing a small amount of testosterone throughout the day.
Gel preparation, similar to the patch by applied directly onto the skin.
Buccal patches placed on the gum.
All these are designed to release a set amount of testosterone into the blood stream, raising the circulating testosterone levels back up to normal levels.
Hormone replacement therapy for females:
A slightly different approach is taken with female HRT to take into account the fact that two hormones are involved, progesterone and oestrogen.
The steps taken will vary between individuals depending on the desired outcome.
One common method for pre-menopausal women is to start with a step-by-step increase in oestrogen dosage.
A bone scan is taken at the start of treatment so bone age can be determined. Without the presence of oestrogen it is likely that the bone age will be behind that normally seen at that chronological age. The aim is to match the oestrogen dose to the bone age so that bone development can be enhanced so it matches the chronological age. This stage of the treatment is usually monitored closely by the doctor to ensure the correct oestrogen dose is given.
Once this has been done the other sex hormone, progesterone is introduced in combination with oestrogen. Progesterone is essential for building up the lining of the uterus.
As with the combined contraceptive pill progesterone is removed for 10 to 14 days per month. This allows for the uterine wall lining to be shed to mimic a menstrual bleed.
In women approaching menopausal age it is sometimes common to remain on progesterone to stop the ‘menstrual’ bleeds, once again trying to mimic the usual conditions seen in menopausal women.
In both males and females the use of the sex hormones is a form of hormone replacement therapy and is designed to produce the other affects caused by the sex hormones but not any growth in the sex organs.
Fertility treatments:
There are specialist treatments available that can in certain cases that can induce a certain level of fertility. This involves the use of the hormones that should have been produced by the pituitary and hypothalamus glands. Their aim is to try to induce a natural production of the sex hormones. Results can vary and it can take 6 to 18 months for effects to be seen but it is possible to induce fertility in some cases. This sort of treatment can only be achieved with specialist help and results will depend on individual circumstances.
One method is with the use of the pituitary hormones LH (luteinsing hormone) and FSH (follicle stimulating hormone). These are given in an attempt to induce the testes or ovaries to start to develop normally and produce sperm / eggs and their relevant hormones.
The hormones are either given in a purified form of human LH / FSH or in a recombinant form of manufactured LH / FSH. Both hormones have different actions on the testes and ovaries but over time it is possible in some cases to induce a low level of fertility and production of sex hormones. There are various drugs available depending on what part of the world you are in but they are usually a form of hCG (human chorionic gonadotrophin and hMG (human menopausal gonadotrophin). The drugs are usually self-injected 2 to 3 times a week over a period of at least 6 months.
There is another approach where the hypothalamic hormone, GnRH (gonadotrophin releasing hormone), is given instead. This is a less common approach and your endocrinologist will give you a test first to see if you can respond to GnRH. There is a form of inherited HH where GnRH is released normally but the pituitary is unable to detect it and respond to it. Instead of injections it is administered via a small credit card sized pump, which releases a small amount of GnRH in s pulsile manner, through a needle inserted into a vein.
Reducing the risk of osteoporosis:
Along with the use of testosterone and oestrogen replacement therapy it might be necessary to take tablets to help reduce the risk of osteoporosis. The tablets help increase the calcium uptake by the bones to help strengthen them. The medication will not eliminate the risk of osteoporosis totally but will reduce the risk down to that of the rest of the general population.
A bone scan may be required at the time of diagnosis and then possibly every 3 to 5 years to ensure the bone age does not fall to far behind the chronological age.
Can KS and HH affect my life in
other ways?
It can do, but to what extent will depend a lot on a lot of other factors. Since Kallmann’s and HH cases are so rare there is very little scientific evidence on the psychological effects of the condition.
Anosmia / Lack of sense of smell:
The sense of smell might be considered the least most important sense but its absence can cause a few problems:
Some points to remember:
Unable to smell strong warning smells such as smoke or gas.
Unable to smell caustic products such as bleach
Unable to smell rotten / spoiled food
Personal hygiene – body odour & clothes
The sense of smell is also linked to the sense of taste, so some foods will not taste the same as with other people.
Absence of puberty:
As might be expected there are a number of psychological problems that have been reported because of the absence of puberty. The teenage years can be traumatic enough for ‘normal’ teenagers but to be left behind by your peer group brings up a number of other potential issues:
Lack of self-esteem
Shyness
Unable to interact with social peer group
Depression
Anxiety
Just how this might affect an individual will vary depending on personal circumstances. Early diagnosis, education, personal outlook and support from family and friends will all help to reduce any possible problems.
It has to be remembered that there are lots of people with Kallmann’s and HH who have got on with their lives, had relationships, got married and do not let it become a major issue.
There is no reason why a person with Kallmann’s or HH cannot have the same sort of physical and emotional relations that anybody else can have.
The feelings of shyness and anxiety of dating and relationships are not unique to people with Kallmann’s or HH.
Web based support groups as well as local support groups can all help to provide a forum for a person to talk through any issues they may have. It may just be a case of talking to somebody else with the condition or more practical help with treatment issues.
There is a list of endocrine and pituitary groups listed on this site including an excellent web based support group on Yahoo.
Neil Smith
November 2004.
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