Chronic Diseases

Lead: Dr Ratna Chatterjee

Background

With recent improvements in treatment modalities, many children with serious diseases are now surviving into adolescence and adulthood. For example, it is estimated in both Europe and the US that one in thousand young adults in their second and third decade, is a survivor of childhood cancer. Others include patients with haemoglobinopathies, renal, cardiac diseases and cystic fibrosis. Therefore there is an increase in the proportion of long-term adolescent and adult survivors who present to the reproductive physicians with altered body image due to damage to their gonads and reproductive organs, bone and joint pain and other features of osteoporosis, infertility, delayed puberty, sexual and menstrual dysfunction and effects of premature menopause in women and premature andropause in men. Reproductive and sexual damage seldom cause a life threatening disease, but result in severe morbidity and affect the quality of lives of the survivors who often suffer in silence and lead a sequestered life due to stigma and prejudice. These conditions are at best only partially correctable with appropriate hormone supplementation, counselling, education of patients and other therapies. However, there are no clear-cut guidelines regarding the best management protocols. This is hindered due to poor understanding of the reproductive pathophysiology of these serious diseases. Following the initiative of the UCLH trust in 1998 to establish the Adolescent Unit, an emphasis on reproductive and sexual health care is a logical area of expansion. The new speciality of reproductive medicine of survivors of serious disease will become an integral part of management of adolescent patients.

Aims of and endpoints of Reproductive Care

To prevent or treat sexual dysfunction, infertility and premature menopause/andropause consequent on chronic ill health and treatment.
To integrate prevention and treatment of sexual/reproductive dysfunction across primary, secondary and tertiary care in a multidisciplinary setting.
To improve the quality of life of these patients through better service, basic and translational research and long-term follow-up.

Thalassaemia Syndrome

The results have shown that 80-90% thalassaemics have hypogonadotrophic hypogonadism (HH) mainly due to iron overload. Consequent upon this the patients present with sexual infantilism delayed or arrested puberty, infertility, sexual dysfunction or premature menopause. Assessment of pituitary volume by magnetic resonance imaging showed that they have structural damage to the pituitary gland.

Planned developments

We are setting up a multicentric global program with the US group, the Thalassaemia Clinical Research Network (TCRN) to determine the pathophysiology of HH and plan its prevention and intervention strategy. A concept proposal has been submitted to the TCRN in August 2005. If successful, we hope to obtain funding from the TCRN, which is funded by NIH in 2007.
Bone disease in Thalassaemia Syndrome and Renal Disease

70-80% Thalassaemic patients have osteoporosis and osteopenia. Histomorphometry shows that there are two types of bone disese: thalassaemia major have high bone turnover disease and intermedia have a low bone turnover disease. Renal patients have osteodystrophy and osteoporosis.

Planned developments

We hope to apply for funding to undertake clinical trails to determine the efficacy and safety of HRT+ pamidronate Vs HRT alone in the management of osteoporosis in thalassaemia and renal patients. Also, we hope to understand the molecular mechanism of bone dynamics by proteinomics in renal and thalassaemic bone diseases.
Haematological Malignancies: Leukaemia and Lymphoma

We have established that chemotherapy causes early damage and cumulative dose dependent damage to the gonads and high-dose chemotherapy will almost invariably cause premature gonadal failure. Also in vitro studies have shown that cis platinum causes apoptosis of the granulosa cells while taxol damages the organelles.

Planned developments

We aim to dissect the S-1 P pathway by using two models: granulosa cells (Primary culture) and ovarian cells (cell line) respectively to understand the method of damage of chemotherapy induced cytoxicity.
Erectile dysfunction in patients with renal disease haemoglobinopathy and in patients following high-dose chemo-radiotherapy and stem cell transplant

Erectile dysfunction is a common problem in the above-mentioned group of patients. We found hypogonadism and cavernosal arterial insufficiency as evident from the colour Doppler study of the penile blood flow.

Planned developments

Further studies are under way using a live system of 3D imaging with Doppler imaging of the cavernosal arterial system with radiologists (Prof Lees), medical physics, imaging (Prof Pokropek and Dr Jing Deng), cardiologists (Dr D Pellerin) and the department of Obstetrics and Gynaecology (Prof CH Rodeck). We hope to secure substantive MRC funding to understand the physiology of sexual cycle in healthy couple and also to apply this knowledge to the understanding of pathophysiology of erectile dysfunction in patients with chronic and serious diseases (CSD).