US Kallmann syndrome meeting 2013. Notes taken. Part 3.

USA Patient Meeting 2013. Notes taken. Part 3.

Obtaining medications with health insurance.

There are companies that can provide basic testosterone medication free of charge without insurance in the USA as long as you have a valid prescription. There is a post in the Facebook groups listing these companies.

Gaining hCG and hMG medications on health insurance is possible but it is a time consuming and lengthy process. One key point is emphasise the point that the hCG / hMG medications are required for testosterone production only and not for fertility. Insurance companies are very unlikely to approve medication for fertility use. However in patients with KS / CHH the primary reason is testosterone production and osteoporosis prevention. If you leave a message in the Facebook groups somebody who has had a lot of experience in dealing with insurance companies will be able to help and advice you.

 

Genetics.

The understanding of the genetics of KS / CHH is changing all the time and it is difficult to give many clear cut answers.

So far over 20 different genes have been implicated in causing cases of KS / CHH.

With puberty being such a defining point in human development it is not surprising there are many different genes involved in its control. No one single gene is responsible for the initiation of puberty so a defect in one gene does not always mean puberty is delayed or is absent.

KS / CHH is primarily a two or more gene defect condition, which accounts for its rarity. One gene defect on its own might cause visible symptoms such as hearing loss, dental problems, cleft lip, and delayed puberty. However it is only when this gene defect is combined with another that you get a case of KS / CHH with the full range of symptoms. It is clear by looking at families with KS / CHH that the range and severity of symptoms is not consistent, even within siblings. This makes the prediction of inheritance and the genetic screening for KS / CHH very problematic.

Over 50% of KS / CHH cases still show an unknown genetic origin. You can screen blood for the currently known genes but any negative result just means it is negative for the genes discovered so far. Research centres in Boston & Augusta in the USA or in Switzerland will test blood samples for current gene defects and then store the samples for re-testing once new gene defects are discovered.

The only exception to this is the KAL-1 mutation on the x-chromosome. KAL-1 is termed a high penetrance gene. A mutation in the KAL-1 gene can cause a case of KS on its own with no other gene defect present. Any small defect in the KAL-1 gene gives rise to a high probability of having Kallmann syndrome. The KAL-1 mutation is the one associated with the additional symptoms of anosmia, mirror movements of the hands, absence of one kidney and hearing loss.

KAL-1 causes x-linked KS, so is only found in males (there is a theoretical chance of a female having x-linked KS but has never been proved yet). X-linked KS accounts for less than 10% of all KS / CHH cases but is the one that is most easily tested for.

US Kallmann syndrome meeting 2013. Notes taken. Part 2.

USA Patient Meeting 2013. Notes taken. Part 2.

 

Growth spurt.

The growth spurt seen in late puberty in both males and females is controlled primarily by testosterone and oestrogen levels under the influence of growth hormone. Normally height will increase until the pre-determined height is reached and then the end plates of the long bones fuse & harden preventing any further growth.

In KS / CHH where there is a lack of testosterone & oestrogen no growth spurt occurs but instead there is a linear height increase under the influence of growth hormone. This can lead to patients with KS / CHH being of above average height unless they start hormone treatment at the appropriate time.

The lack of oestrogen or oestrogen in KS / CHH patients can lead to early onset osteoporosis which should be checked for by the use of DEXA / bone density scan.

No puberty v partial puberty.

In patients with KS / CHH it is estimated that 60% of cases will show no pubertal development at all while the remaining 40% will show partial pubertal development.

Use of hCG in males.

hCG is human chorionic gonadotropin, it is normally derived from human placentas and has the same activity as luteinising hormone (LH). In males hCG can be given instead of testosterone preparations in order for the testes to produce their own testosterone. Pregnyl is a common trade name for hCG.

hCG acts on the Leydig cells in the testes in the same way as LH, with the production of testosterone. Normal levels of testosterone can be achieved within two months of starting treatment. Injections are given sub-cutaneously and the dose and frequency given is dependent on the testosterone levels achieved.

There is normally no increase in size in the testes when on hCG injections.

There was a bit of debate at the meeting about the possibility of achieving sperm production while on hCG alone. It is certainly possible for some patients with KS / CHH to achieve a low level of sperm production while on hCG injections alone but normally this tends to be the patients who have had some form of gonadotropin treatment in the past or who have partial testicular development already.

Patients with KS / CHH can sometimes achieving fertility with sperm counts a lot lower than those seen in other men. The theory is that fertility is based on the quality of sperm produced and not just the number produced.

There is no evidence of any long term adverse risk in males using hCG injections.

Use of FSH injections in fertility treatments in males.

Follicle stimulation hormone (FSH) acts on the Sertoli cells in the testes in order to induce sperm production. It is the increase in the Sertoli cells that gives the testes their size. Normally testes need to be 4ml or bigger in order to produce enough sperm for natural conception.

In most males, but not all, with KS / CHH FSH type medication is required to induce fertility. It is thought that giving FSH on its own for a few months before the addition of hCG increases the chances of sperm production and can speed up production.

In the past hCG has been given on its own first but new evidence suggests that pre-treatment with FSH can be more effective.

FSH can be given in its pure form or combined with LH in the form of human menopausal gonadotropin (hMG or menotropin).

FSH and hMG injections are expensive and not always easy to get hold of but can provide an effective form of fertility treatment for me along with the psychological benefit of testicular development.

 

 

 

 

 

US Kallmann syndrome meeting 2013. Notes taken. Part 1.

USA Patient Meeting 2013. Notes taken. Part 1.

Gender difference between males & females.

It used to be thought that there were about five times more cases of KS / CHH in males than in females. This has never been fully explained by genetics.

One school of thought is that there is actually no gender imbalance in reality. The disproportion in diagnosed cases might well be due to the lack of correct diagnosis of KS / CHH in females. It is not easy to correctly diagnose KS in females, especially if the oral contraceptive pill is used in treatment.

Un-published work done in Boston took the numbers of 600 patients in known KS / CHH families and came out with a ratio of 1 : 1.3 male to female cases.

Definition of a “rare disease”.

A rare disease is defined as one that is found in 1 in 2,000 of the general population. With KS / CHH being at around the 1 in 20,000 mark roughly it falls neatly in this category. About 8% of the general population of the USA could be classified as having a rare disease.

Start of puberty.

The age of onset of puberty has a range of 10 to 15 years in females with a mean of 12 years old. In males the range is 12 to 16 with a mean of 13 years old. Typically puberty takes 5 years to fully complete.

The age puberty starts in males is not easy to distinguish in boys whereas in girls it is marked by the first menstrual bleed.

2% of the population will show a constitutional delay of puberty. This group will start puberty naturally at some stage but early hormonal treatment might be given in appropriate cases.

Any delay of puberty by the age of 15 in females and 16 in males should be investigated by a reproductive endocrinologist or a paediatric endocrinologist.

Un-descended testes at birth.

Occurs in 2% of the male population but in up to 40% of boys with Kallmann syndrome.

GnRH and sexual differentiation.

Sexual differentiation into the male and female physical forms occurs in the first few weeks of life and is controlled by the hCG derived from the placenta. This is normally unaffected in people with KS / CHH so they are born physically male or female.

Normally there is a GnRH surge from the hypothalamus in the developing baby in the final trimester and into the first 6 months of life. This is a “mini-puberty” and can give rise to detectable levels of LH / FSH / testosterone or oestrogen. This mini-puberty is missing in patients with KS / CHH. This can be used as a diagnostic tool for babies where there is a likelihood of KS / CHH being passed on. This test is more sensitive in male infants than female infants.

The presence of micro-penis and un-descended testes at birth seen in some boys with KS / CHH is related to the lack of testosterone in boys in this mini-puberty.