**3. Radiation-induced primary thyroid dysfunction**

Primary hypothyroidism is the most common clinical consequence of radiotherapy to the cervical area. It is well described in patients treated for Hodgkin's disease with a cumulative incidence of 44% after 25 years of radiotherapy (Hancock et al., 1991). The intensity of the damage, and hence, the degree of thyroid dysfunction is both dose- and time-dependent (Sklar et al., 2000). Primary hypothyroidism has been reported with fractionated radiotherapy with doses exceeding 25 Gy (Shalet et al., 1977). The probability of developing primary thyroid failure is significantly increased beyond 45 Gy (Bhandare et al., 2007). Chemotherapy has not been shown to influence the development of thyroid dysfunction following standard radiation therapy for head and neck cancers (Miller & Agrawal, 2009).

The pathophysiological mechanisms underlying radiation-induced thyroid dysfunction remain controversial. Various mechanisms have been proposed including radiation-induced autoimmune thyroiditis, direct radiation-induced damage to the follicular epithelium, direct

seen in about 20% of euthyroid adult cancer survivors did not reflect a genuine loss of diurnal rhythm, but simply occurred as a result of a physiological shift in the timing of the peak TSH (acrophase) and/or the nadir TSH levels potentially leading to an erroneous diagnosis of "hidden" central hypothyroidism. Therefore, serial thyroid testing to demonstrate a decline in T4 levels provides the only means for diagnosing "hidden" central

Radiation-induced hyperprolactinaemia is mostly seen following intensive irradiation due to hypothalamic damage leading to a reduction in the inhibitory neurotransmitter dopamine. It has been described in both sexes and all age groups but is most frequently encountered in the adult female with radiation doses in excess of 40 Gy. In these patients, a mild to modest elevation in prolactin level is noticed in 20-50% (Agha et al., 2005; Constine et al., 1993; Lam et al., 1991; Littley et al., 1989a; Samaan et al., 1987) compared with less than 5% in children (Rappaportet al., 1982) and after low radiation doses (Littley et al., 1991). A much higher incidence is seen following intensive irradiation; Chen et al (Chen et al., 1989) reported hyperpractinaemia in 21% and 36% in the first 4 years and after 15 years of

Radiation-induced hyperprolactinaemia is not clinically significant in the vast majority of patients. Occasionally, it may be of sufficient severity to impair gonadotrophin secretion and cause pubertal delay or arrest in children, decreased libido and impotence in adult males and galactorrhoea and/or ovarian dysfunction in women (Samaan et al., 1982). A gradual decline in the elevated prolactin level may occur with time and can normalize in some patients. This may reflect time-dependent slowly evolving direct radiation-induced damage

Radiation-induced hyperprolactinaemia responds very well to treatment with dopamine agonists. Galactorrhoea resolves soon after normalising prolactin levels. However, treatment with dopamine agonists will only restore gonadal function and fertility if there is no coexisting gonadotrophin deficiency or primary chemotherapy-induced gonadal damage.

Primary hypothyroidism is the most common clinical consequence of radiotherapy to the cervical area. It is well described in patients treated for Hodgkin's disease with a cumulative incidence of 44% after 25 years of radiotherapy (Hancock et al., 1991). The intensity of the damage, and hence, the degree of thyroid dysfunction is both dose- and time-dependent (Sklar et al., 2000). Primary hypothyroidism has been reported with fractionated radiotherapy with doses exceeding 25 Gy (Shalet et al., 1977). The probability of developing primary thyroid failure is significantly increased beyond 45 Gy (Bhandare et al., 2007). Chemotherapy has not been shown to influence the development of thyroid dysfunction following standard radiation therapy for head and neck cancers (Miller & Agrawal, 2009).

The pathophysiological mechanisms underlying radiation-induced thyroid dysfunction remain controversial. Various mechanisms have been proposed including radiation-induced autoimmune thyroiditis, direct radiation-induced damage to the follicular epithelium, direct

hypothyroidism.

**2.6 Hyperprolactinaemia** 

radiotherapy in NCP, respectively.

to the pituitary lactotroph (Littley et al., 1989b).

**3. Radiation-induced primary thyroid dysfunction** 

microvascular and macrovasular damage resulting in thyroid tissue hypoxemia and nutrient-poor environment leading to reduced synthetic and secretory capacity, and radiation-induced fibrosis that may prevent compensatory hypertrophy of the gland (Miller & Agrawal, 2009). The development of thyroid antibodies after radiotherapy may predict a higher chance of thyroid dysfunction in the long-term.

Subtle thyroid dysfunction occurs soon after radiotherapy for NPC; Chen et al (Chen et al., 1989) have demonstrated increased peak TSH responses to TRH stimulation a month after radiotherapy and more so after 15-18 months of radiotherapy. More severe degrees of thyroid dysfunction with increased TSH and reduced free T4 tend to occur in the long term. However, hypothyroidism may occasionally develop as early as 6 weeks after completion of high dose radiotherapy to the neck.

A cumulative incidence of increased TSH of 18% and 45% was reported in 166 patients treated for NPC in the first 4 years and after 15 years of follow up, respectively (Samaan et al., 1987). In a prospective study of 408 patients who had received radiation therapy for NPC; the estimated incidences for clinical hypothyroidism were 5.3%, 9.0%, and 19.1% and for sub-clinical hypothyroidism were 9.7%, 15.7%, and 20.5% at 3, 5 and 10 years after radiotherapy, respectively (Wu et al., 2010). This study has also showed that clinical hypothyroidism occurred more frequently in younger patients, female sex and following conformal radiotherapy. Some reports have also suggested a higher incidence of radiationinduced hypothyroidism in the younger age group treated for Hodgkin's disease (Shalet et al., 1977) or for NPC (Zubizarreta et al., 2000), while other reports did not (Daoud et al., 2003; Kupeli et al., 2006). These rates of radiation-induced hypothyroidism are significantly higher than the reported rates of 0.3-1.3% in the general population (Wu et al., 2010). Much higher rated of hypothyroidism are seen in other head and neck tumours that involved thyroid surgery in addition to radiotherapy (Wu et al., 2010).

The diagnosis of primary hypothyroidism is straight forward. Frank (clinical) hypothyroidism is associated with increased TSH and subnormal free T4. Sub-clinical cases are characterised by increased TSH but apparently normal free T4. The presence of radiation-induced hypothalamic-pituitary damage with TSH deficiency may compound the biochemical picture and interpretation of the thyroid functions tests. Significant reduction in free T4 levels, albeit in the normal range, may be seen in the presence of normal or slightly elevated TSH levels. Under these circumstances a trend showing a progressive decline in free T4 levels despite a stable/mild increase in TSH levels following radiotherapy supports the diagnosis of central hypothyroidism or a combined primary and secondary hypothyroidism that may warrant a trial of thyroxine replacement therapy.

It is recommended that all patients have a thyroid function test at baseline and every 6-12 months after radiotherapy. Symptoms and signs of hypothyroidism should be explored during any consultation. The symptoms of overt hypothyroidism include weight gain or difficulty loosing weight, intolerance to cold, dry skin, hair loss, constipation, menorrhagia or intermenstrual spotting, decrease physical activity, lethargy, easy fatigability, muscle cramps, and slow mentation. The signs include periorbital oedema, loss of eyebrows, cool and dry skin, a prolonged relaxation phase of deep tendon reflexes, and pleural or pericardial effusions. If the biochemical diagnosis is uncertain, a trial of thyroxine replacement therapy in those with "sub-clinical" hypothyroidism with "normal" free T4 levels is worth considering with a proper assessment of the response.

Endocrine Complications Following Radiotherapy

primordial follicles.

term risks of HRT.

deficiency coexists.

(Howell & Shalet, 2002).

**5.2 Chemotherapy-induced testicular damage** 

and Chemotherapy for Nasopharyngeal Carcinoma 147

fully understood. They are thought to be related to the cytotoxic effects of the drugs on ovarian follicles leading to impairment of follicular maturation and/or depletion of

Chemotherapy-induced ovarian damage is unlikely to occur in the pre-pubertal patients. However, it is quite frequent in women with a frequency reaching 50% in those who received Alkylating agents. Acute ovarian failure may occur shortly after completion of chemotherapy. Recovery of acute ovarian failure is variable and can occur after many months or even years of amenorrhoea. Patients who retain their ovarian function after completion of chemotherapy and those who recover from acute ovarian failure are still at

Depending on severity, chemotherapy-induced ovarian damage can lead to delayed, arrested or absent pubertal development (in children), oligomenorrhoea, amenorrhoea, infertility, or sub-fertility. Oestrogen deficiency symptoms such as hot flushes, sweating, sexual dysfunction, and psychosomatic complaints are common especially with acute ovarian failure. These symptoms can have very negative impact on quality of life and physical well-being. In the long-term early ovarian failure may lead to accelerated decline in bone density and osteoporosis, increased cholesterol levels and possible increased risk of cardiovascular disease. Adequate oestrogen replacement therapy is recommended to relieve symptoms and preserve bone density, especially in younger people providing there are no contra-indications for their use. The decision to use HRT and its duration should be individualised and agreed with the patient taking into account the benefits and the long-

Biochemically, ovarian damage is characterised by reduced oestrogen levels and increased gonadotrophin levels and/or impaired ovulation tests. The compensatory increase in FSH/LH levels may be attenuated or completely absent if radiation-induced gonadotrophin

Fertility preservation in young women, if resources allow, should be considered and offered to certain patients depending on their age, presence of a partner, desire for fertility, psychosocial issues, and the extent of the disease and prognosis. Methods to preserve fertility in women include freezing (embryo crypreservation, oocyte cryopreservation, and ovarian tissue cryopreservation) and ovarian suppression with GnRH analogues or antagonists. Unfortunately, fertility preservation techniques are not widely available and each method has its own advantages and disadvantages with no guaranteed outcome

Temporary or permanent chemotherapy-induced testicular damage occurs at all ages of life (Howell & Shalet, 2001, 2005). Unlike in females, children seem to be more susceptible to the damaging effects of cytotoxic agents. Although all chemotherapeutic drugs may have some effects on fertility, some are known to be more gonadotoxic than others. Alkylating agents are the most gonadotoxic; others include Cisplatinum, Cytarabine, Dacarbazine and Procarbazine. The germinal epithelium in the seminiferous tubules is more chemo-sensitive than Leydig cells. Germinal epithelium damage following chemotherapy can be seen in the presence of normal Leydig cell function. Depending on the type and number of agents

risk of early or premature ovarian failure later in life (Howell & Shalet, 1998).

In contrast to hypothyroidism, the frequency of hyperthyroidism due to Garves' disease is slightly increased post-irradiation (Jereczek-Fossa et al., 2004).
