You will remember that the root cause of Kallmann's syndrome is the failure of the hypothalamus to release the hormone GnRH. Normally, GnRH encourages the pituitary gland to release LH and FSH which in turn target those areas of the testes or ovaries in which sperm or egg cells are produced. Without GnRH, there is no LH, no FSH, no testosterone or oestrogen and no sperm or egg cells. In this case, the solution is a hormonal one. If either GnRH or a combination of LH and FSH is introduced artificially, the testes or ovaries often respond accordingly. Here we will deal with both GnRH pulsatile therapy and combined hCG and hMG therapy.

The use of GnRH pulsatile therapy as a method of inducing puberty in hypogonadal patients by encouraging the development of their secondary sexual characteristics has already been touched on briefly in the answer to Question 19. In this section, the other use of GnRH pulsatile therapy, that of treating infertility, is explained

Some years ago when the effects of GnRH replacement therapy were being investigated, it was discovered that the continuous administration of GnRH "desensitised" the hypothalamus and pituitary gland. LH and FSH are only released by the pituitary gland if GnRH is released in pulses or short bursts, usually at 90 to 120 minute intervals. If GnRH were released continuously, it would have exactly the opposite effect, actually suppressing the release of LH and FSH. LH and FSH then target the gonads (testes or ovaries), the development and maturation of sperm or egg cells and are almost entirely dependent on these pituitary hormones. In order for the pituitary gland to work properly and before the infertility can be reversed, the missing GnRH needs to be replaced.

GnRH pulsatile therapy is a simple, yet effective way of replacing the missing hormone in sufferers of Kallmann's syndrome. The fertility success rate is relatively high with this form of treatment. What does GnRH pulsatile therapy involve and how does it work ?

A GnRH pump is a battery-powered device no larger than a pack of playing cards, as shown in Figure 19. It is essentially a "high tech" needle and syringe arrangement; an ampoule (item 1) containing a supply of GnRH has a piston consisting of a screw and rubber stopper assembly (items 2 & 3) driven by a small electric motor. A programmable timer allows pulse intervals of between 90 and 120 minutes and enables pulse doses to be set accurately, these settings being clearly displayed on an LCD display (item 4). As the electric motor drives the screw, the pre-set dose of GnRH is forced through a catheter (item 5) (a thin, flexible tube) and then finally through a very fine needle (item 6) which is inserted just under the skin of the abdomen.

The pump itself is attached to a special belt which you can either wear around your waist or thigh, depending on where you find it more comfortable and the least obtrusive. The needle is held in place by a special adhesive dressing or plaster and ideally, both the needle and catheter should be replaced every three to four days in order to minimise the risk of infection. How long each ampoule of GnRH lasts depends on the pulse intervals and doses, but when the GnRH does run out (around 10 days for many Kallmann's syndrome patients), a new ampoule containing a fresh supply of GnRH replaces the old one.

GnRH pulsatile therapy has been shown to work particularly well for women with Kallmann's syndrome and 90% of women are able to become pregnant within six months of starting treatment. Most of these women ovulate normally and they have regular menstrual cycles. The success rate for male sufferers is also relatively high, the best results being observed for those who have never had undescended testes (see the answer to Question 8). If a man has undescended testes and he has never had surgery to bring them down into the scrotum, preferably as a young child, his chances of becoming a father are very low. "Sperm counts" every few months tell the doctor how successful the GnRH pulsatile therapy is in getting the testes to make sperm cells, but in many cases the first sperm cells might only appear after several months, sometimes not until 18 months after treatment was started.

It does not matter if you interrupt the treatment. So if you find that GnRH pulsatile therapy works for you but you are not yet ready to become a parent, you can always resume treatment later and carry on where you left off.

The GnRH pump is not designed to be waterproof and you must therefore take it, the catheter and the needle off before you have a shower, go for a swim or have vigorous physical exercise which involves heavy perspiration. Since there can be up to 120 minutes between pulses of GnRH, you have a certain amount of time during which it doesn't matter if you take the pump off. Alternatively, you can switch the pump off during the interval between pulses. There are virtually no side-effects except that occasionally, a mild local infection occurs at the injection site, but this is easily treated by re-siting the needle and only rarely are antibiotics required to treat the infection.

This second form of fertility treatment works at the pituitary rather than the hypothalamic level. The hormones hCG and hMG ("human menopausal gonadotrophin") are derived naturally and once injected, they behave like the pituitary gonadotrophins, LH and FSH. The LH-like hCG (human chorionic gonadotrophin) is normally produced by the placenta. Large amounts of hCG can be found in the urine of pregnant women and in fact, this is where the hCG used to treat delayed puberty comes from. hMG is extracted from the urine of post-menopausal women and contains not only LH, but also FSH.

Both men and women with Kallmann's syndrome can be treated with hCG and hMG. A man's testosterone gradually increases to near-normal levels due to hCG and hMG helps to stimulate the production of sperm cells. A woman responds by ovulating regularly as her menstrual cycle becomes established.

Although there are no hCG and hMG preparations currently on sale which are 100% pure, they are pure enough to ensure that the body responds well to them. The extracted hCG and hMG are freeze-dried and sealed in small glass ampoules. A typical course of treatment for a patient with Kallmann's syndrome is two injections of hCG and three injections of hMG a week in the buttock or thigh (see the answer to Question 21), but the individual dose can vary from patient to patient.

It is not necessary to continue having testosterone or oestrogen therapy for as long as these kinds of fertility treatment are given. This function is taken care of by the replacement of GnRH and LH and FSH.

Both GnRH pulsatile therapy and hCG and hMG are successful in treating many of those with Kallmann's syndrome for their infertility. Interrupting fertility treatment at any time has no effect on the final outcome and either of the above can be resumed without harm to the body. It is important to remember though, that the induced fertility is not permanent; it only lasts for as long treatment is given.

So which form of fertility treatment is the right one for you ? There are advantages and disadvantages to both, but it is often a matter of personal preference. Wearing a pump around the waist continuously and having to take it off every time you want to have a shower can sometimes be inconvenient, but you do get used to it and it soon becomes a matter of routine. On the other hand, the demand for hCG and hMG has increased dramatically over the last few years as more and more people with Kallmann's syndrome want to become parents. The problem is that the demand currently exceeds availability, because hCG and hMG are derived from human volunteers and there is therefore a limited supply of these hormones. Many doctors believe that GnRH pulsatile therapy is more "elegant", because it targets the pituitary gland as if the GnRH were coming directly from the hypothalamus, the "Achilles heel" or fundamental weakness of Kallmann's syndrome. Other doctors believe that there is no advantage in having GnRH pulsatile therapy. Discuss the subject with your doctor and see which type of treatment he or she recommends.

Fertility treatment can be costly, sometimes running into the thousands of pounds a year. Fortunately however, many GPs are prepared to fund fertility treatment for their patients with Kallmann's syndrome, partially because the success rates are relatively high and the course of treatment is fairly brief (rarely longer than 18 months' duration) but also because testosterone or oestrogen therapy would be necessary anyhow. Kallmann's syndrome is a relatively rare and unusual disease and your GP will probably be keen to help you, especially when the diagnosis has already been made.