10.1 Introduction

• 
  

  A broad range of malignant and benign conditions and their treatments can lead to the loss of future fertility in men and women, and in children of both sexes.

  
  
• 
  

  Advances in cancer treatments have led to increased survival rates and therefore increasing numbers of young people living with the late effects of cancer treatments.

  
  
• 
  

  Compromised fertility is the most common long-term side effect of cancer therapy and affects long-term wellbeing, relationships, and life decisions.

  
  
• 
  

  The average age to have a first child has gradually increased and therefore increasing numbers of men and women have not completed their families when they are given a potentially fertility-damaging diagnosis.

  
  
• 
  

  The endeavour to address this has grown into the new and rapidly developing field termed ‘fertility preservation’, although sperm cryopreservation for men has been available for many years.

  
  
• 
  

  Fertility preservation encompasses a range of techniques to store material which can be used to achieve a pregnancy in the future, as well as techniques to minimise the damage caused by the fertility-damaging treatments.

  
  
• 
  

  As this field involves a range of specialties and disciplines, generally with significant time pressures, effective communication and team-working are key to the success of fertility preservation programmes.

  
  
• 
  

  Elective (often termed social) egg freezing is the freezing of eggs to enable women to delay the opportunity for pregnancy until a later time, for a non-medical indication. This uses the same techniques as used in oocyte cryopreservation for fertility preservation.

10.2 What Are the Indications for Fertility Preservation?

• 
  

  Patients newly diagnosed with cancer, ideally at the pre-treatment stage, where there is a significant risk to later fertility. The most common indications for fertility preservation are breast cancer, testicular cancer and lymphoma. The risk of damage to fertility is mainly related to the treatment and not to the disease itself, although spermatogenesis is often significantly impaired at presentation due to the systemic effects of the cancer. This is less apparent in women. Alkylating chemotherapeutic agents and pelvic radiotherapy are particularly gonadotoxic (see Tables 10.1 and 10.2).

  
  
• 
  

  Patients with benign medical or surgical conditions or undergoing medical or surgical treatment likely to compromise fertility. This includes cytotoxic agents for patients with rheumatological conditions, haematological conditions where treatment involves risk to fertility (e.g. haematopoietic stem cell transplant for haemoglobinopathy), inflammatory bowel disease, Turner syndrome and related chromosomal abnormalities, individuals with FMRP1 mutations and patients with some metabolic diseases. There may also be some women facing treatment for endometriosis for whom consideration of fertility preservation is appropriate.

  
  
• 
  

  The degree of risk to fertility that requires fertility preservation is rather subjective and should take into account the views of the patient, as well as a medical assessment of risk. More invasive and experimental procedures (e.g. ovarian tissue cryopreservation) may require a higher risk to fertility (estimated risk of loss >50%) than less invasive procedures such as semen cryopreservation. The time available, access to appropriate services and financial considerations will all also affect the decision. Criteria have been proposed as a basis for further development and validation (see Table 10.3).

  
  
• 
  

  Transgender men and women. Both transwomen and transmen may want to store gametes prior to endocrine or surgical treatment. Though the effect of transgender endocrine treatment on fertility is considered reversible (for both spermatogenesis and folliculogenesis), once the treatment is initiated individuals may be very reluctant to take the prolonged break from it, with reversion to their dysphoric endocrine state, that would be required to restore fertility.

This list is not exhaustive and future research will define more clearly the indications and where the risk to future fertility is low.

10.3 Why Do Cancer Treatments Damage Fertility?

The primordial follicle pool, or ovarian reserve, is finite and complete before birth. It peaks at 18–22 weeks’ gestation, with an average of 295,000 primordial follicles per ovary at birth, declining to 180,000 at 13 years. These are activated and used up across the reproductive life span. By 30 years of age, around 12% of the ovarian reserve remains, which declines to 3% by age 40 years. Only around 450 follicles will ovulate during a woman’s reproductive lifetime, so the great majority of follicles undergo atresia, until insufficient follicles remain that can develop to later stages, resulting in the menopause at around 50 years. Age contributes to around 80% of the variation in ovarian reserve. Other determinants include genetic and lifestyle factors (stress, parity, basal metabolic index and smoking), the latter being thought to make a 3%–5% contribution to the age at menopause.

Cytotoxic chemotherapy and radiotherapy can cause a reduction in the number of ovarian follicles. Both specifically target DNA and dividing cells; thus growing follicles are important sites of damage, but primordial follicles may also be lost through either a direct effect or indirectly perhaps through increased initiation of growth.

Ovarian damage from chemotherapy and radiotherapy can occur via several mechanisms (Table 10.2) [3]:

1. 
   

   1. Direct DNA damage to growing ovarian follicles causes apoptosis.

   
   
2. 
   

   2. Direct damage to the ovarian stroma can result in fibrosis and hyalinisation of small blood vessels, resulting in indirect follicle damage and probably compromising growth.

   
   
3. 
   

   3. Both direct and indirect damage may alter the development of growing follicles and impair steroidogenesis.

   
   
4. 
   

   4. The destruction of growing follicles causes loss of suppression of growth activation in primordial follicles, resulting in increased growth activation.

Radiation can also impact reproductive function through effects on the uterus, causing microvascular injury, endothelial damage and myometrial fibrosis resulting in poor uterine growth and distensibility resulting in miscarriage, preterm labour, low birth weight, stillbirth and postpartum haemorrhage. In contrast to the impact on ovarian function, the reproductive impact of uterine radiation is greater at a younger age, and pregnancy is of very high risk in those who have been exposed to uterine doses >45 Gy as adults or >25 Gy in childhood.

In males both chemotherapy and radiation therapy can result in germ cell depletion with the development of oligo- or azoospermia. The type of drug (particularly the alkylating agents), duration of treatment, intensity of treatment and drug combination are major variables in determining the extent and duration of testicular injury. Different drugs disrupt spermatogenesis in different ways (see Table 10.2). Spermatogonia proliferate rapidly and so represent the most sensitive target for cytotoxic agents although the less active stem cell pool may also be depleted (see Figure 10.1). Recovery of sperm production after a cytotoxic therapy depends on the survival and ability of mitotically quiescent stem spermatogonia to transform into actively dividing stem and differentiating spermatogonia.

Figure 10.1 Schematic showing cellular site of action and consequences of chemo- and radiotherapy in males.

The likelihood of infertility after radiation of the testes depends on the dose to the testes, shielding and fractionation. The Leydig cells (responsible for testosterone production) are less sensitive to the effects of radiation, with damage occurring at 20 Gy in prepubescent males compared with 30 Gy in mature males.

In both males and females radiotherapy can also adversely affect reproductive function through damage to the hypothalamus and pituitary.

For both men and women, loss of fertility is often temporary, provided a sufficient testicular population of spermatogonial stem cells or ovarian supply of primordial follicles remains.