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What is the underlying cause of Kallmann syndrome / HH.

July 29, 2012

Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) are pituitary based conditions. In most cases the root cause is the failure of communication between two endocrine glands located deep inside the brain, the hypothalamus and the pituitary.

The testes and ovaries are normally given the hormonal signals from the pituitary gland (FSH / LH)  to develop correctly at puberty and to function correctly after that.

The pituitary gland acts in response to a hormonal signal from the hypothalamus gland. The signal is in the form of a hormone called gonadotropin releasing hormone (GnRH).

If the hypothalamus fails to release GnRH, the pituitary can not release FSH and LH and so in turn the testes and ovaries remain inactive and no testosterone or oestrogen / progesterone is produced.

In KS / HH the release of GnRH is either totally blocked or vastly reduced. The GnRH is released by the hypothalamus by specialised nerve cells or neurones. During development of the brain in the first 10 weeks of development these GnRH releasing neurones migrate from their original source and end up inside the hypothalamus.

The GnRH neurones originate in an area of the developing brain called the olfactory placode; they then pass through the cribriform plate and into a structure called the olfactory bulb. From there they migrate into what will be become the hypothalamus. The olfactory bulb is where the sense of smell is generated.  Any problems with the development of the olfactory bulb will prevent the progression of the GnRH releasing neurones through it. If the GnRH releasing neurones are prevented from reaching the hypothalamus no GnRH will be released, so in turn no FSH or LH will be released which results in the failure of puberty and the production of testosterone in men and oestrogen and progesterone in women.

In Kallmann syndrome the olfactory bulb is missing or not fully developed which gives rise to the additional symptom of lack of sense of smell (anosmia) or vastly reduced sense of smell (hyposmia). In other forms of HH the olfactory bulb develops correctly, so there is a normal sense of smell but the migration of the GnRH releasing neurones is affected elsewhere and still gives rise to a failure in GnRH being released at the correct time.

In another form of HH the GnRH releasing neurone migrate to the correct position but the hypothalamus does not have the correct receptor present to be able to use them, a bit like not having the correct key to open the door.

Migration of the GnRH releasing neurones from the olfactory placode to the hypothalamus.
Also listed are the genes which have an influence at each stage of the migration.
Prof. N.Pitteloud 2011.

The diagram above (click to enlarge) shows the migration of the GnRH neurones from the olfactory placode and into the hypothalamus which occurs within the first 10 to 12 weeks of life. The diagram also lists the 18 different genes that have so far been identified in being involved in the whole process. Some of the genes like KAL-1 are well-known, others have only recently been identified. Defects in these genes can give rise to a case of KS or HH. These genes have been shown to have an influence either on the production, migration or activity of the GnRH releasing neurones.

It is strongly suspected that is takes defects in two of these genes in combination to give rise to a case of KS / HH. The only notable exception would be KAL-1, where a defect in this gene on its own will cause classic x-linked KS.

The fact that at least 18 genes have already been implicated in causing KS / HH which between them still only account for less than 50% of cases shows there is a long way to go before there is a full understanding of the genetics of KS / HH and any reliable diagnostic genetic test is still a long way off being available.

Additional links from the Healthline.com website showing the position of the hypothalamus and pituitary glands within the brain with some additional information.

http://www.healthline.com/human-body-maps/pituitary-gland

http://www.healthline.com/human-body-maps/hypothalamus

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One Comment
  1. “If the hypothalamus fails to release GnRH, the pituitary can not release FSH and LH and so in turn the testes and ovaries remain inactive and no testosterone or oestrogen / progesterone is produced.”

    That’s a nice and succinct explanation right there. No need to say anything else really.

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