GH is produced by the Pituitary gland which is controlled by the Hypothalamus. It controls growth in children and is involved in the maintenance of normal body weight, muscle and bone strength and well-being in adults. GH deficiency in adults can result in loss of energy, fatigue and depression which can lead to a decreased quality of life. If you have not been diagnosed with GH deficiency and feel extremely tired for no apparent reason, you should talk to your doctor or nurse. You can read the Pituitary Foundation booklet for more details on causes and diagnosis of GH deficiency. The aim of GH treatment is to improve your quality of life and well-being, although there are additional health-related benefits from this treatment. The GH used is known as recombinant human Growth hormone (rhGH), which is a synthetic preparation.

One of the most remarkable achievements was the approval of GH treatment in adults by NICE (National Institute for Clinical Excellence) in 2003. This gives equal access to treatment funding for all patients with severe GH deficiency across the country; you no longer have to live in the ‘right area’ to be entitled to GH treatment. NICE recommends that GH should be used to treat adults older than 25 years when they suffer from GH deficiency and a severely affected quality of life. The criteria are:

• You should have a peak GH level of less than 9 mU/litre in an insulin tolerance test or another reliable dynamic test.
• Your quality of life is severely affected (impaired) by GH deficiency. This is measured using a questionnaire called ‘Quality of Life Assessment of Growth Hormone Deficiency in Adults’ (AGHDA-QoL) and you should answer YES to 11 or more of the 25 questions. (see below)
• You should already be receiving replacement for any other deficiencies of pituitary hormones if you have one or more other deficiencies, and these should be optimal before GH is started.

After starting GH, your quality of life is assessed nine months later and you are expected to have a 7-point improvement on the AGHDA-QoL questionnaire compared to the pre-GH score. Should this be the case, you will be advised to continue on lifelong GH treatment, unless your individual circumstances change and/or GH is contraindicated. If your quality of life has not improved at all within 9 months (taking into account that you had no other major negative events in your life during this time), you will be asked to stop your GH treatment. Adult patients younger than 25 years, who are diagnosed with GH deficiency, should be given GH treatment until peak bone mass is achieved (this is at around 25 years old and is measured with a bone mineral density scan).

Red Listed Drug

Because replacement growth hormone (GH) is a ‘high cost drug’, a lot of Primary Care Trusts (PCTs) (and GPs) prefer that this is prescribed and monitored by the Endocrine Centres (Hospital Teams). A drug is ‘red listed’ when PCTs advise GPs not to prescribe it and responsibility for prescribing and monitoring a patient's response to treatment remains solely with the Hospital Team. PCTs often require written confirmation that patients satisfy NICE GH criteria, which should be provided by the Endocrine Clinician.

Shared Care
 
Shared Care is a formal agreement between the Endocrine Team and GP to share responsibility for a patient's GH treatment. In a lot of the cases, monitoring is done in hospital and GPs issue the prescriptions. As this is quite a specialist treatment, a lot of GPs often feel uneasy about prescribing it and prefer this to be undertaken by Endocrine Teams.
 
As GH is a NICE approved drug, PCTs cannot decline treatment for patients. Where NICE guidelines are valid, it does not matter at which hospital the patient is treated; the invoice will be sent to the PCT their GP is listed under.
 
If you require GH and have been told by your GP that GH is ‘red listed’, you should discuss the matter with your Endocrinologist and ask him/her to work closely with their Trust Contracts/Finance and Pharmacy Department so that GH is prescribed and supplied by the Hospital. GPs cannot really be ‘blamed’ for not being able to provide a GH prescription and it is the responsibility of the Endocrine Team to do this.

Quality of Life Assessment of Growth Hormone Deficiency in Adults (AGHDA-QoL) Questionnaire

The AGHDA Questionnaire asks you to answer 'yes' or ‘no’ to 25 statements. Each 'yes' scores 1 point; the higher the score, the worse the quality of life.

1. I have to struggle to finish jobs
2. I feel a strong need to sleep during the day
3. I often feel lonely even when I am with other people
4. I have to read things several times before they sink in 
5.  It is difficult for me to make friends
6.  It takes a lot of effort for me to do simple tasks
7. I have difficulty controlling my emotions
8. I often lose track of what I want to say
9. I lack confidence
10. I have to push myself to do things
11. I often feel very tense
12. I feel as if I let people down
13. I find it hard to mix with people
14. I feel worn out even when I've not done anything
15. There are times when I feel very low
16. I avoid responsibilities if possible
17. I avoid mixing with people I don't know welI
18. I feel as if I'm a burden to people
19. I often forget what people have said to me
20. I find it difficult to plan ahead
21. I am easily irritated by other people
22. I often feel too tired to do the things I ought to do
23. I have to force myself to do all the things that need doing
24. I often have to force myself to stay awake
25. My memory lets me down

A copy of the AGHDA-QoL questionnaire can be downloaded by clicking here: 

 AGHDA questionnaire.pdf (841KB)

We strongly recommend that you discuss your symptoms with your Endocrinologist or Specialist Nurse, as a high score on this questionnaire does not necessarily mean that you have growth hormone deficiency (although it will prompt your Endocrine Team to investigate this further for you).

Pituitary Foundation Position Statement on Growth Hormone Replacement

History of the 2001 - 03 NICE Appraisal of Human Growth Hormone for Adults

Article from Pituitary Life:

New developments in the use of Human Growth Hormone: ten years on
Sofia Llahana, Consultant Nurse - Endocrinology, University College London Hospitals

In 2000, the Pituitary Foundation published an article by Sister Oscar-Hazel Donaldson which described the developments in Growth Hormone (GH) treatment at the turn of the century; she noted that until then “...there was little choice in available products…”. Pat McBride asked me to provide an update of the developments in GH in the last ten years. There is one thing for certain: due to the hard work and determination of the Foundation and our patients, clinicians and Pharmaceutical industry, we have indeed seen exciting changes which have improved patient care and treatment choice. In 2003, the National Institute for Clinical Excellence (NICE) approved GH treatment in adults, which gave an end to the post-code lottery funding for GH. We have also seen the development and improvement of GH injection devices. Support services and an abundance of information on GH treatment are now available for our patients. Although I have tried to provide as much information as possible, this article is by no means a comprehensive resource and you should read the Pituitary Foundation leaflets for more information. Similarly, some of the services and treatment options described here may not be available across the country and I would urge you to consult your Endocrine Team to explore services offered in your area.

GH treatment in adults and NICE guidelines
GH is produced by the pituitary gland which is controlled by the hypothalamus. It controls growth in children and is involved in the maintenance of normal body weight, muscle and bone strength and well being in adults. GH deficiency in adults can result in loss of energy, fatigue and depression which can lead to a decreased quality of life. If you have not been diagnosed with GH deficiency and feel extremely tired for no apparent reason, you should talk to your doctor or nurse. You can read the Pituitary Foundation leaflets for more details on causes and diagnosis of GH deficiency. The aim of GH treatment is to improve your quality of life and well being, although there are additional health-related benefits from this treatment. The GH used is known as recombinant human growth hormone (rhGH) which is a synthetic preparation.

One of the most remarkable achievements was the approval of GH treatment in adults by NICE in 2003. This gives equal access to treatment funding for all patients with severe GH deficiency across the country; you no longer have to live in the “right area” to be entitled to GH treatment. NICE recommends that GH should be used to treat adults older than 25 years when they suffer from GH deficiency and a severely affected quality of life. The criteria are:

• You should have a peak GH level of less than 9 mU/litre in an insulin tolerance test or another reliable dynamic test.
• Your quality of life is severely affected (impaired) by GH deficiency. This is measured using a questionnaire called “'Quality of Life Assessment of Growth Hormone Deficiency in Adults” or “AGHDA-QoL” and you should answer YES to 11 or more of the 25 questions.
• You should already be receiving replacement for any other deficiencies of pituitary hormones if you have one or more other deficiencies, and these should be optimal before GH is started.

After starting GH, your quality of life is assessed nine months later and you are expected to have a 7-point improvement on the AGHDA-QoL questionnaire compared to the pre-GH score. Should this be the case, you will be advised to continue on lifelong GH treatment, unless your individual circumstances change and/or GH is contraindicated. If your quality of life has not improved at all within 9 months (taking into account that you had no other major negative events in your life during this time), you will be asked to stop your GH treatment. Adult patients younger than 25 years, who are diagnosed with GH deficiency, should be given GH treatment until peak bone mass is achieved (this is at around 25 years old and is measured with a Bone Mineral Density scan). Continuation of GH past peak bone mass is based on the assessment of the quality of life as per above points. For more information, you can ask your clinician or visit the NICE website on http://www.nice.org.uk.

Treatment start and long term monitoring
Before starting your GH treatment, you will normally have a consultation with an endocrine specialist nurse (or an endocrinologist), who will explain what this treatment involves, its purpose, long-term monitoring, and organise your treatment start. In our Hospital we run a patient-choice clinic for GH and assist our patients to find the most suitable injection device for their needs. The starting GH dose for an adult is 0.2 - 0.3 mg daily. GH is given by injection in the fat tissue just under the skin (subcutaneous) ideally in the evening to mimic your own GH production which happens during sleep. A lot of our patients are very worried at the idea of self-injecting; I often ask patients to try the needle (without actually having an injection) and in most cases their fear is alleviated when they realise that the injection is relatively painless.

You will be seen in the Endocrine clinic at regular intervals, especially during the first 9 months, to assess your response to treatment, any side effects and to make adjustments to your GH dose according to your needs. You will have a blood test to measure Insulin-like Growth Factor 1 (IGF-1) which will guide your GH dose increase. IGF-1 is a protein mainly produced by the liver under GH stimulation; severe GH deficiency is often associated with low IGF-1. You should ensure that IGF-1 is part of your routine endocrine check up as it is the only way to know if you are taking the right dose of GH. As IGF-1 can drop if you have missed a number of GH doses prior to your blood test, it is very important that you do not miss any injections (or if you do, you should report this to your clinician so IGF-1 results can be interpreted accordingly). I have seen a number of patients who had their GH dose increased inappropriately based on low IGF-1 results, when in fact this was low because they had missed several injections prior to their blood test. Overdosing with GH and exceeding normal range for IGF-1 can lead to unpleasant side effects and severe complications.

Support services for GH treatment
As a patient on GH treatment, you should have access to an Endocrinologist and an Endocrine Specialist Nurse who will advise you on and monitor your treatment. The Pituitary Foundation can also provide you with information and support. In addition, most Pharmaceutical companies producing GH sponsor home services (their name can vary depending on the GH brand) which provide a wide range of support services for patients on GH treatment. When starting your treatment, an endocrine nurse can visit you at your home to train you on the injection device and teach you how to do your injections.

Home service will provide you, free of charge, with your treatment starter pack (injecting device, needles, sharps boxes etc), information on GH treatment (on-line, video and in print format), and continuous supply of your needles, sharps boxes etc (also known as “stores”); most of them will also collect clinical waste from your home at the time of stores delivery. Home service can also dispense your GH which will be delivered to your house on a regular basis. A lot of our patients find this a great service as they do not have to attend their Practice and local chemist for repeat prescriptions on a monthly basis. Finally, most home services have a helpline which you can ring if you have any concerns regarding your treatment for example if you need a new supply of needles or your pen is not working.

Injection devices: spoilt for choice

Needle free devices
Some patients, mostly children and adolescents, have needle phobia and are unable to overcome the fear of needles and cope with injections. There are two needle-free devices for GH:

1. Cool.click® (name of the device) for Saizen Click.Easy 8mg (name of GH) by MerckSerono (name of Pharmaceutical Company)
2. Zomajet2Vision® for Zomacton 4 and 10mg by Ferring Pharmaceuticals.

These devices inject GH by creating a fine stream of high-pressure jet liquid which penetrates the skin and deposits medication in the subcutaneous (fat) tissue without the use of a needle. For patients with a genuine fear of needles, these are excellent devices and can improve patient adherence to treatment. The “needle-free” concept can sometimes be misinterpreted for “pain-free” and some patients may chose this option because they think that they can have painless injections. However, this is not the case and injections can be as painful (or even more) as a needle device. It is useful to have an open discussion with your endocrine nurse and explore whether it is indeed needle phobia you are experiencing or you believe that the needle-free device will give you pain-free injections.

The disadvantage to these devices is that they are rather complicated to use; our patients find Zomajet2Vision® to be a more user-friendly device than Cool.click®. In addition, both Saizen and Zomacton need reconstitution, i.e. GH is provided in separate powder and diluents (solvent) vials, which need to be mixed into a liquid form before use.

Needle pen devices 
As the name states, these devices resemble a pen (with diameter of about half inch) in which the GH vial is inserted. Injections are relatively painless and the needle is very thin and short (about a third of an inch). The single-use needle is attached to the front of the pen and it should be disposed into the sharps box immediately after each injection. Pen devices are re-usable and can last for 3-4 years. The following pen devices are currently available in the UK  (from left to right):

1. Genotropin Pen® 5.3 and 12 for use with Genotropin 5.3mg and 12mg vials by Pfizer (battery operated pen; dose increments of 0.1 for the 5.3mg vial and 0.2 for 12mg vial; drug reconstitution can be done within the pen and is fairly easy; drug requires refrigeration after reconstitution)
2. NutropinAQ Pen® for use with NutropinAQ 10mg vial by Ipsen Pharmaceuticals (battery operated; dose increments of 0.1; liquid form; should be refrigerated at all times)
3. NordiPen® 5, 10 and 15 for use with Norditropin SimpleXx 5mg, 10mg and 15mg vials by NovoNordisk (manual dose dial, dose increments of 0.05 for the 5mg vial and 0.1 for the 10&15mg vials; liquid form; vials should be stored in the fridge at all times; after the first injection the 5mg and 10mg vials can be stored at room temperature for up to 21 days). The Norditropin PenMate is an accompanying device for the NordiPen and provides an auto-inserting and hidden needle option.
4. Omnitrope Pen5® for use with Omnitrope 5mg vials by Sandoz (manual dose dial; dose increments of 0.05; no need to rewind pen for new vial; liquid form; should be refrigerated at all times). Omnitrope is the first bio-scimilar GH available in the UK and its main advantage is that it is a lot cheaper compared to all other GHs. I do not have a lot of patient feedback to share on this product as it is relatively new, however, Omnitrope has been tested in clinical trials and is licensed for use as an equally effective GH as all the others. An insignificant disadvantage to the device can be its small needle guard and the dialling knob, which can be difficult to handle, especially if you have dexterity problems.
5. HumatroPen3® (not shown in Figure 2) for use with Humatrope 6mg, 12mg and 24mg vials by Elli Lily and Company (battery operated, it requires reconstitution before inserting in the pen, which patients describe as a rather complex process; requires refrigeration once reconstituted; the 24mg vial can be useful for children who require large GH doses, especially girls with Turner’s Syndrome, as vials can last longer).

All pens have similar features and it is not very important which one you use. To dial your dose, you turn the knob at the top of the pen; the dose appears on the window on the side of the pen. All pens have a needle-guard for a hidden needle option; this can also provide better support for the pen on the injection site and guides the needle through the skin. Patients with dexterity or visual difficulties often find the battery operated pens easier to use (Genotropin and NutropinAQ); they have a better dose-dial knob and needle guard. Each pen has a plunger, which when pushing by pressing down the dial knob, it delivers the medication under the skin through the needle. When all liquid in the vial is used, the pen will not allow you to dial your daily dose and tells you that you need to insert a new vial. Most patients find this part the most difficult step to remember and perform correctly. Your should contact your nurse for assistance if you have any doubts; similarly all companies provide DVDs and illustrated leaflets with step-by-step user instruction manual which you can follow.

Depending on your daily dose and the concentration of the vial, one vial can last from 5 to 28 days. All vials should be discarded 28 days after the first injection; if your vial lasts longer ensure you note make a note of the start data or contact your Endocrine nurse to advise you on other options. A simple way to calculate how many days each vial will last is by dividing the concentration of your vial with your daily dose (e.g. a 10mg on a 0.5 mg daily dose will last 20 days). If you need to travel with your GH, you will be supplied with a cool bag which can keep the drug safe for approximately 12 hours.

Non-refrigerated devices
Patients find that one of the main disadvantages of most GH products, is the need for the drug to be refrigerated at all times. For patients who travel a lot and have no access to a refrigerator (for example university students), the non-refrigerated option for GH treatment is Genotropin MiniQuick® by Pfrizer. This can be stored in room temperature for up to three months and has the great advantage of making travelling much easier. You do not have to worry about the inconvenience of carrying a cool bag, whether the flight maybe cancelled or if the hotel room has a refrigerator. Although this device does not require refrigeration, you will have to take extra care and ensure that the drug is kept cool at a temperature below 25 degrees Celsius and away from sun exposure, especially in hot climates.

Genotropin MiniQuick is a fixed dose, preservative free, single-use injection device with two compartments, powder and diluent, which you need to mix prior to each injection. They are packaged in a 7-day supply and needles are included; there is an optional needle guard which hides needle from view and makes injections easier. Dose strength varies from 0.2 mg to 2.0 mg, with increments of 0.2 mg, which may present slight restrictions when you are on an odd-number daily GH dose. We advise patients to use the nearest dose for the duration of travel, for example if your dose is 0.7 mg daily, you can use 0.6 or 0.8 mg depending on your IGF-1 result; your Endocrine nurse or doctor can advise you accordingly. You should carry medication with you at all times and it is useful to carry a travel letter for airport security.
Norditropin SimpleXx® 5mg and 10mg vials (described earlier) is another option, especially for short trips; after the first injection, the vial can be kept in room temperature for up to three weeks.

Non-refrigerated device - Genotropin MiniQuick® with needle guard

Electronic injection device
EasyPod® for Saizen Click.Easy 8.0 mg vials by MerckSerono is an electronic fully automated injection device and is an excellent choice for patients who want to be very precise about their GH treatment. There is a removable back cover if you would like to personalise your EasyPod. It is popular with young adults and patients who like technology. The sensors at the base of the device activate only at contact with human skin and allow delivery of the injection, so you can be assured that you have injected your GH. It has a hidden needle and comfort settings can be individualised, for example how fast and deep you want the needle to go into your skin. Similarly, it has a preset dose and for your daily injections, all you need to do is turn on the device, insert a new needle and inject by pressing the button on top of the device. If you cannot remember whether you had your injection or not, the device records the date of your last injection and will alert you if you try to have a second injection on the same day. The very attractive feature of this device is its calendar recording; if you have missed an injection, the date on the calendar will be red, whilst your injection dates will be in green (so you will know exactly how many injections you have missed, if any).

Although, the device menu can be rather daunting, you will receive full training on its use and the nurse will preset all settings to match your individual preferences and needs. Compared to the pen devices, it is quite large in size, although patients with dexterity problems find it easier to hold during an injection. The main disadvantage is that the GH vials (Saizen Click.Easy) need reconstitution (mixing) before used in the EasyPod and many patients find this quite a complex and time consuming process. Patients can opt for home delivery of the premixed drug on a monthly basis. Once reconstituted, the drug should be refrigerated at all times.

Electronic injection device - EasyPod®

Future developments in GH treatment
GH treatment has come a long way in the last decade. With access to the right clinical support and information, patients receive appropriate treatment and do not suffer the long term consequences of GH deficiency which can often be detrimental to their well being and psychosocial life. Despite the great developments in GH treatment, by no means one can say that perfection has been achieved and there is a lot more we have to learn. A lot of our patients find daily injections inconvenient and painful; others find having to reconstitute GH or change the vial in a re-usable device regularly quite a chore. Similarly, patients would like to have more choice for non-refrigerated GHs.

Pre-filled pens have been released this year and are available in the USA (Norditropin NordiFlex® or FlexPro® by NovoNordisk and NutropinAQ Nuspin® by Genentech). These multi-dose disposable pens are pre-filled and preloaded with the medication. Quick setup and administration make the use of these pens easy to teach; ability to preset the dose is an additional feature of the FlexPro®. At the time of writing this article, pre-filled pens for GH are not licensed for use in the UK but I am certain it will not be too long before they are marketed in this country. We will hopefully see more liquid GH products which will vial reconstitution obsolete. Similarly, we have seen with other drugs and hormone treatments that long acting and slow release preparations have been developed; maybe it will not be too long before GH products which are injected only once a week or even once a month will be developed and licensed for use. I hope that by the time we have the next article describing the new developments in GH treatment, science will have progressed enough and these GH products will no longer be a ‘maybe’ but available for use in clinical daily practice.

It is unlikely that we will see the development of a tablet form for GH treatment any time soon (probably not during my career, which makes my job slightly more secure), but we have seen that science develops remarkably fast so we can never predict what tomorrow may bring…

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