How is GnRH deficiency diagnosed?

Are there any early signs to look for?

For many people with GnRH deficient conditions there are no signs before the failure of puberty that they have the condition. Since in the majority of cases the other functions of the hypothalamus and pituitary gland remain unaffected there are no other obvious symptoms that can be seen during childhood.

Anosmia or the lack of sense of smell will be apparent in people with Kallmann syndrome.

In boys, the testes should have descended into the scrotum before or just after birth. Undescended testes (cryptorchidism) is a not an uncommon event in boys and can be easily rectified with medications or surgery. A history of cryptorchidism, either one testis or both together could alert doctors to the possibility of a problem with puberty later, but this does not necessarily mean that a boy with cryptorchidism will have a GnRH deficient condition.

A small percentage of boys with GnRH deficient conditions will be born with ‘micro-penis’; this can normally be corrected at birth with hormonal treatment.

There are a number of other symptoms that can be associated with some forms of GnRH deficient conditions:

  • Deafness caused by nerve deficiency
  • ‘Mirror movements’ of the hands (also called synkinesia)
  • Dental abnormalities (such as.missing teeth, crowded teeth)
  • Facial abnormalities such as cleft palate and/or cleft lip
  • Absence of one of the kidneys

These symptoms can occur in isolation or combined. Having one or more of these symptoms is not always associated with GnRH deficiency but they could be an indication of a GnRH deficient condition if accompanied by a failure to start puberty.

Which hormones are produced in normal puberty?

In normal puberty the pathway is:

  • GnRH being released by the hypothalamus gland
  • This causes the pituitary gland to produce LH and FSH
  • This in turn causes the production of testosterone and sperm by the testes or the production of oestrogen and progesterone in addition to egg maturation by the ovaries.

Oestrogen and to a lesser extent testosterone has a negative feedback on the hypothalamus to regulate the amount of LH and FSH produced at different times throughout the month. In males, the levels of LH and FSH remain fairly constant. However, in females the levels of LH and FSH produced will vary depending on the menstrual cycle.

Testosterone and oestrogen have a number of different functions in the body apart from their function in maintaining fertility. The most important of these is for bone strength and density. Oestrogen and testosterone are also required for the secondary sexual characteristics which are associated with being either male or female.

How is an initial diagnosis made?

Without any previous family history, is not always easy to diagnose a case of GnRH deficiency. Often it is a case of eliminating other causes of the failure to start puberty. Sometimes a case of GnRH deficiency is dismissed as a normal delay of puberty and the correct diagnosis can be delayed for years.

Apart from the standard tests of general overall health, the tests a doctor might order can be separated into two areas:

Pubertal events:

  • Menstruation in girls
  • Testicular development in boys
  • Pubic and axillary hair development
  • Breast development in girls

Hormonal levels:

  • Levels of androgens: testosterone, oestrogen and progesterone
  • Levels of gonadotropins: LH and FSH
  • Levels of other pituitary hormones: prolactin, thyroid stimulating hormone

These are standard tests any primary care physician might do in a case of delayed puberty. If, as a result of these tests, GnRH deficiency is suspected then a referral to an endocrinologist, preferably a reproductive endocrinologist, would required for a more extensive series of tests.

When does puberty become delayed?

The start of puberty can be defined at the point at which a female starts menstruating and the testes start to grow from their childhood size in males. The age at which this happens will vary from person to person.

Medical opinions may vary from country to country but it is generally accepted that puberty is delayed if a girl of 14 has not begun menstruating or a boy of 15 has not had some testicular growth.

Most cases of delayed puberty will resolve themselves naturally, these people used to be called "late developers" or "late bloomers". This is sometimes described as constitutional delay of growth. For these patients puberty will start eventually. However for people with GnRH deficient conditions such as idiopathic hypogonadotropic hypogonadism or Kallmann syndrome, puberty will not start.

Does GnRH deficiency affect my growth?

During puberty the bones, especially the long bones in the arms and legs, grow to their required length. In normal puberty growth hormone causes the bones to lengthen. Subsequently testosterone or oestrogen causes the bone growth plates to fuse to prevent further growth and causes the bones to harden.

In GnRH deficient conditions, the levels of oestrogen or testosterone produced are too low to cause the bones to stop growing at the correct time. This can lead to people with GnRH being taller than average. This lack of oestrogen and testosterone can also lead to the bones being weak. This is a very important consideration for people with GnRH deficient conditions who can be very prone to a condition called osteoporosis or low bone density.

Why do I lack a sense of smell?

Anosmia or a lack of sense of smell is a unique symptom seen in Kallmann syndrome but not in other forms of GnRH deficiency.

At first glance the sense of smell would appear to have little to do with a failure to enter puberty. The sense of smell is created by specialised nerve cells called olfactory neurons. These neurons are responsible to sending signals from the nose to the brain whey they are recognised as smells or odours. The part of the brain where these olfactory neurons connect to the brain is called the olfactory bulb.

Patients with anosmia will STILL be able to sense air-born irritants, such as acids (eg. vinegar), alkali (eg. ammonia) and smoke particles, because this aspect of chemosensation is mediated by the trigeminal nerve, not the olfactory nerve. The most important thing that anosmic patients will miss out on is a decent sense of taste, because much of what we consider as taste sensation actually derives from what is wafted up into out the nose when we eat. Pure taste receptors on the tongue can only sense very basic aspects of taste (salt, sour, sweet, bitter).

GnRH deficiency is caused by the failure of the GnRH releasing neurons to migrate to the correct location. The path of the migration is directly through the olfactory bulb. If the olfactory bulb is missing or not fully formed the GnRH releasing neurons are prevented from reaching their correct location and are left stranded in the wrong place.

One form of Kallmann syndrome is caused by the failure of the production of a protein called anosmin. Anosmin is responsible for making sure the olfactory neurons create the olfactory bulb. If anosmin is missing, the olfactory bulb is not correctly formed so there is no sense of smell. The lack of the olfactory bulb means that the GnRH releasing neurons are also trapped in the wrong place and puberty will fail to start as the hypothalamus cannot release GnRH.

In other forms of GnRH deficiency the olfactory bulb is correctly formed so there is a sense of smell but the migration of GnRH releasing neurons is blocked at another stage of their progress towards the hypothalamus.

 Last updated on 19/06/2018 at 11:45