**4. Radiation-induced thyroid nodules and tumours**

The development of thyroid nodules and benign and malignant neoplasms is well described in patients who received neck irradiation for Hodgkin's lymphoma (Oeffinger et al., 2003) or as part of cranio-spinal irradiation for brain tumours (Shalet et al., 1977). There is no literature on this complication following treatment of NPC.

A significantly increased risk is seen in children irradiated before the age of 10 years. Other risk factors include female sex, longer duration of follow up and increased radiation dose above 2 Gy with no reduction in risk with high radiation doses reaching 60 Gy. Most of these thyroid nodules are benign in nature and may regress (Jereczek-Fossa et al., 2004). The risk of nodules being malignant is significantly higher if irradiation was administered before age 16 years and the tumourigenic effects of radiation in this age group can last up to 40 years post treatment (Schneider et al., 1993).

The frequency of diagnosed thyroid nodules after irradiation depends on the diagnostic method used. Clinical examination is usually not robust enough to detect small nodules less than 2cm in size. High-resolution thyroid ultrasound has increased the detection frequency (Mihailescu et al., 2005). Thyroid ultrasonography also helps to identify suspicious nodules that need a diagnostic fine needle aspiration (FNA). Routine surveillance ultrasonography of the thyroid remains a controversial issue, as it may increase anxiety and unnecessary diagnostic interventions. However, patients at high risk of radiation-induced thyroid cancer should undergo regular surveillance ultrasonography. FNA should be performed for suspicious nodules by virtue of size, rapidity of growth and/or ultrasonographic appearance. A diagnostic partial thyroidectomy may also be needed if the FNA was inconclusive.

#### **5. Chemoptherapy-induced gonadal damage**

The gonads are extremely sensitive to chemotherapy. Gonadotoxicity with resulting gonadal failure is a significant complication, which is seen more frequently than before due to increased use of chemotherapy in NPC, in particular Cisplatinum, which is highly gonadotoxic.

#### **5.1 Chemoptherapy-induced ovarian damage**

Chemotherapy-induced ovarian damage depends on the type and the total dose of the drugs used. The chemosensitivity of the ovary is age-dependent with progressively smaller doses being required to produce ovarian failure with increasing age (Rivkees & Crawford, 1988). Chemotherapeutic agents known to be gonadotoxic include alkylating agents, in particular Cyclophosphamide, Vinca-alkaloids, Antimetabolites, Platinum agents (Cisplatinum) and others such as Procarbazine.

Cisplatinum is the most commonly used agent in the treatment of NPC. The pathophysiological mechanisms underlying chemotherapy-induced ovarian damage are not

In contrast to hypothyroidism, the frequency of hyperthyroidism due to Garves' disease is

The development of thyroid nodules and benign and malignant neoplasms is well described in patients who received neck irradiation for Hodgkin's lymphoma (Oeffinger et al., 2003) or as part of cranio-spinal irradiation for brain tumours (Shalet et al., 1977). There is no

A significantly increased risk is seen in children irradiated before the age of 10 years. Other risk factors include female sex, longer duration of follow up and increased radiation dose above 2 Gy with no reduction in risk with high radiation doses reaching 60 Gy. Most of these thyroid nodules are benign in nature and may regress (Jereczek-Fossa et al., 2004). The risk of nodules being malignant is significantly higher if irradiation was administered before age 16 years and the tumourigenic effects of radiation in this age group can last up to 40

The frequency of diagnosed thyroid nodules after irradiation depends on the diagnostic method used. Clinical examination is usually not robust enough to detect small nodules less than 2cm in size. High-resolution thyroid ultrasound has increased the detection frequency (Mihailescu et al., 2005). Thyroid ultrasonography also helps to identify suspicious nodules that need a diagnostic fine needle aspiration (FNA). Routine surveillance ultrasonography of the thyroid remains a controversial issue, as it may increase anxiety and unnecessary diagnostic interventions. However, patients at high risk of radiation-induced thyroid cancer should undergo regular surveillance ultrasonography. FNA should be performed for suspicious nodules by virtue of size, rapidity of growth and/or ultrasonographic appearance. A diagnostic partial thyroidectomy may also be needed if the FNA was

The gonads are extremely sensitive to chemotherapy. Gonadotoxicity with resulting gonadal failure is a significant complication, which is seen more frequently than before due to increased use of chemotherapy in NPC, in particular Cisplatinum, which is highly

Chemotherapy-induced ovarian damage depends on the type and the total dose of the drugs used. The chemosensitivity of the ovary is age-dependent with progressively smaller doses being required to produce ovarian failure with increasing age (Rivkees & Crawford, 1988). Chemotherapeutic agents known to be gonadotoxic include alkylating agents, in particular Cyclophosphamide, Vinca-alkaloids, Antimetabolites, Platinum agents

Cisplatinum is the most commonly used agent in the treatment of NPC. The pathophysiological mechanisms underlying chemotherapy-induced ovarian damage are not

slightly increased post-irradiation (Jereczek-Fossa et al., 2004).

**4. Radiation-induced thyroid nodules and tumours** 

literature on this complication following treatment of NPC.

years post treatment (Schneider et al., 1993).

**5. Chemoptherapy-induced gonadal damage** 

**5.1 Chemoptherapy-induced ovarian damage** 

(Cisplatinum) and others such as Procarbazine.

inconclusive.

gonadotoxic.

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 primordial follicles.

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

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 longterm risks of HRT.

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 deficiency coexists.

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 (Howell & Shalet, 2002).

#### **5.2 Chemotherapy-induced testicular damage**

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

Endocrine Complications Following Radiotherapy

of these abnormalities and timely treatment.

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pp: 1131-9.

No. 5, May 1998. pp: 1615-8.

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**7. References** 

and Chemotherapy for Nasopharyngeal Carcinoma 149

anterior pituitary hormone deficiency and hyperprolactinaemia is frequently seen in women. Irradiation of the thyroid is associated with a significant risk of primary hypothyroidism. In the long-term there is increased risk of thyroid nodules and thyroid cancer, especially in children. These abnormalities in the endocrine functions are progressive and irreversible and can result in significant morbidity and impaired quality of life. In addition, chemotherapy may cause transient or permanent direct gonadal damage and hypogonadism. Regular endocrine surveillance is mandatory to achieve early detection

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administered and the total dose, damage to the germinal epithelium and the supporting Sertoli cells, with consequent oligo-or azoo-spermia, occurs in 20-90% of patients following chemotherapy. Recovery of spermatogenesis is not unusual and can be seen several years after chemotherapy (Howell & Shalet, 2005). In patients treated for testicular cancer, for example, variable degrees of recovery of spermatogenesis are seen in 50-80% after 2 to 5 years following completion of cisplatinum-based chemotherapy (Howell & Shalet, 2005). However, patients who have fully preserved or recovered spermatogenesis still have reduced sperm count compared with healthy men. Damage to the germinal epithelium causes gradual atrophy of the testes with reduced volume, reduced inhibin B and increased FSH secretion.

Although less vulnerable to the cytotoxic effects of chemotherapy than the germinal epithelium, Leydig cell dysfunction following chemotherapy is well described. It is often fully compensated with normal testosterone levels and significantly increased LH levels (Howell & Shalet, 2001). The effects of chemotherapy on the production of testosterone from Leydig cells are only seen at much higher doses. The doses required to cause Leydig cell failure will invariably have resulted in damage to the germinal epithelium. However, subtle degrees of Leydig cell dysfunction may be seen in the presence of normal spermatogenesis (Howell & Shalet, 2001). Co-existing radiation-induced gonadotrophin deficiency may impair the extent of compensation and result in combined primary and secondary hypogonadism.

The impact of mild/subclinical Leydig cell insufficiency is unclear (Howell et al., 1999). However, the manifestations of severe degrees of Leydig cell dysfunction depend upon the age of the patient. Loss of Leydig cell function before the onset of, or during puberty will be associated with failure to enter puberty spontaneously or arrest of pubertal development. Leydig cell failure following the development of normal secondary sexual characteristics manifests clinically with reduced libido, erectile dysfunction, fatigue and mood changes. In the long-term, Leydig cell failure may adversely affect skeletal, muscular, cardiovascular, and metabolic health as well as cognitive functions (Bhasin et al., 2010). If not contraindicated, testosterone replacement therapy is recommended for symptomatic men with classical androgen deficiency aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density. Clinical monitoring of testosterone therapy at regular intervals to assess response, compliance and adverse effects is important. Assessment of bone density every 1-2 years in osteoporotic men and annual monitoring of the haematocrit and the PSA (in men 40 yr of age or older) are also important particularly in the long-term (Bhasin et al., 2010).

With regard to fertility preservation, cryopreservation of spermatozoa before sterilizing chemotherapy (sperm banking) in the sexually mature male is currently the only established clinical option. In men with spermatogenic arrest, sperm extraction for intracytoplasmic sperm injection (ICSI) is a potentially successful approach. Other fertility preservation techniques such as cryopresvation of testicular tissues, germ cell transplantation, testis tissue xenografting and hormonal manipulation are largely experimental (Howell & Shalet, 2002).
