Guideline 76: Long term follow up care or survivors of childhood cancer

Long term follow up of survivors of childhood cancer
Section 4: Problems with puberty and reproduction

One of the most important issues for the survivors of childhood cancer is the impact of their disease and its treatment on reproductive function and the implications for the health of their offspring.⁸⁸

4.1 Male puberty and fertility

4.1.1 NORMAL PHYSIOLOGY

The seminiferous epithelium of normal infant and child testes consists of immature Sertoli cells and spermatogonia. Primary spermatocytes, which degenerate and do not progress to spermatozoa, have been identified in some boys between the ages of 4 and 13 years.

Spermarche occurs at a median age of 13.4 years (range 11.7-15.3) at a time when median testicular size is 11.5 ml (range 4.7-19.6).⁸⁹

The prepubertal testis is approximately 2 ml in volume. The onset of puberty begins with enlargement of the testis at approximately 11.4 years. The longitudinal growth spurt starts when the testes are approximately of 8 ml volumes and maximal at approximately 12 ml. The normal adult testis is 15-25 ml. Azoospermia is likely if the volume of each adult testis is 10 ml or less.

4.1.2 DAMAGE TO TESTES AND FERTILITY PROBLEMS

Both prepubertal and postpubertal testes are susceptible to cytotoxic treatment by alkylating agents or radiotherapy to the gonads.^{90,
91, 92,
93, 94,
95, 96,
97, 98,
99, 100,
101, 102,
103, 104,
105, 106,
107, 108} Sertoli cells and germ cells are more susceptible than Leydig cells to chemotherapeutic or radiotherapeutic damage.^{92,
109} Evidence level 2++,2+,3

Decreased testicular volume (=<10 ml) is associated with impaired spermatogenesis in the postpubertal male. Testicular damage is also associated with elevated follicle stimulating hormone (FSH) and reduced serum inhibin B.^{90,
91} Evidence level 2++,2+,3

Direct irradiation to the testes causes permanently impaired spermatogenesis.^{110,
111, 112,
113} Leydig cell failure is unlikely below a threshold dose of 20 Gy.^{112,
114} Doses to the testes in excess of 20 Gy may result in delayed puberty.^{111,
112,
114} Evidence level 2++,2+,3

Total body irradiation causes permanently impaired spermatogenesis but has variable effects on Leydig cell function.^{96,
98, 114} Most prepubertal boys undergoing bone marrow transplantation with chemotherapy and hyperfractionated total body irradiation can expect to progress normally through puberty.¹¹⁴ Evidence level 3

Although there is evidence for impaired spermatogenesis after treatment for childhood cancer, it appears that the sperm that is produced, carries as much healthy DNA as sperm produced by the healthy population.¹¹⁵ Evidence level 2+

Most studies suggest that fertility outcomes are good for young people treated for leukaemia, and solid tumours except Hodgkin’s disease. Treatment for Hodgkin’s disease with multiple courses of alkylating agent based chemotherapy, irrespective of stage of puberty at treatment, is likely to be sterilising.^{94,
109,
116, 117,
118} Evidence level 2+

Sequential treatment regimens (alkylating agent based, alternating with anthracycline based), still carry a significant risk of infertility.¹¹⁹ Recovery of spermatogenesis has been documented after anthracycline based treatment alone.¹²⁰ Evidence level 2+

It is not possible to protect prepubertal testes from potentially toxic treatment nor is it currently appropriate to obtain germ cells for later use. It is also not currently possible to predict fertility outcome in individual male patients who are prepubertal at time of treatment.

Spontaneous progression through puberty is not a guarantee of future fertility.

With modern assisted reproductive technology (ART), in particular intracytoplasmic sperm injection (ICSI), a low sperm count should not preclude fertility.

Assessment of male pubertal development and fertility should include:

assessment of testicular volume using the Prader orchidometer
Tanner staging of secondary sexual development
measurement of serum FSH, luteinising hormone, testosterone, inhibin B (if available)
semen analysis.

Men who have evidence of impaired fertility should be referred for specialist assessment as they could benefit from ART.

Fertility counselling should be provided to survivors of childhood cancer.

4.1.3 FERTILITY PRESERVATION

Cryopreservation of semen from young patients (14-17 years of age) is as effective as that of semen from young adults (18-20 years).^{121,
122, 123} Cryopreservation of semen is dependent on the ability of the young patient to produce a specimen, and in the UK, consent for storage requires him to be “Gillick” competent. Evidence level 2+,3

Cryopreservation of semen should be offered to young male patients whose cancer therapy will include potentially gonadotoxic treatments.

4.1.4 PROGENY

The offspring of male Wilms’ tumour survivors have no apparent excess risk for birth defects.¹²⁴ Evidence level 2+,3

Spontaneously conceived offspring of patients treated for cancer in childhood have no excess of congenital anomalies or other diseases.^{100,
125} Evidence level 2+,3

4.2 Female puberty and fertility

4.2.1 NORMAL PHYSIOLOGY

Oogonia arising from primordial germ cells in the yolk sac reach a complement of 6-7 million by the sixth month of gestation; these represent the total fixed number of germ cells available.¹²⁶ Primordial follicles consist of a primary oocyte surrounded by a single layer of spindle-shaped cells. By the time of birth, the pool of primordial follicles has already been reduced to 2-4 million by ongoing apoptosis and further attrition leaves approximately 400,000 by the time of menarche.

The onset of female puberty is characterised by the appearance of breast buds (breast stage 2, B2) which may be as early as 8.4 years of age or delayed until 13.5 years of age.¹²⁷ Any girl with breast buds before the age of 8.4 years has precocious puberty, whilst the absence of breast development in a girl older than 13.5 years requires endocrine assessment to ascertain the cause of the delay.

During childhood, increased amplitude, frequency and duration of gonadotrophin secretion, will result in consonant pubertal progression, taking an average two years to menarche (at B3 or B4),¹²⁷ at mean age 12.4 years (range 10-14.5).

For the first year after menarche, menstrual cycles are often anovulatory. Ovulatory cycles, and thus the potential for fertility, can occasionally occur in girls whose sexual development is not quite complete.

4.2.2 PUBERTY

Radiotherapy to the hypothalamus/pituitary may result in delayed puberty; the risk increasing with higher doses (greater than 30-40 Gy). Lower doses (less than 30 Gy) are more commonly associated with precocious puberty especially in young girls.^{11,
23, 27,
33, 35,
128} Evidence level 2+

Girls treated with cranial irradiation should have their pubertal status assessed three to four times a year from the end of treatment as part of a routine clinical assessment.

4.2.3 REPRODUCTIVE DYSFUNCTION

In the female, chemotherapy and radiotherapy may affect uterine growth, damage the ovary and hasten oocyte depletion, resulting in loss of hormone production, uterine dysfunction and a premature menopause.¹²⁹

Treatment of Hodgkin’s disease with chemotherapy alone is less likely to be damaging to reproductive function in girls than it is in boys.^{91,
100,
116} Evidence level 2+,3

Cyclophosphamide when used alone as conditioning treatment for bone marrow transplantation, is not associated with long term gonadal function impairment.¹⁰³ High dose busulfan is a major cause of ovarian failure.¹³⁰ Evidence level 3

Whole abdominal, pelvic or total body irradiation is likely to result in impairment of ovarian function.^{98,
103,
114,
124,
131, 132,
133} Evidence level 2+,3

Uterine distensibility and blood flow are irreversibly affected by high dose pelvic or abdominal irradiation in childhood.¹³⁴ Non-invasive assessment may predict potential for pregnancy following ovum donation and embryo transfer. Evidence level 3

Physiological sex steroid replacement improves uterine function. Women who have had total body irradiation may benefit from assisted reproductive technology.¹³⁵ Evidence level 3

Most studies are reassuring about female reproductive outcome after chemotherapy alone for childhood cancer although these young women may be at risk of a premature menopause due to reduced ovarian reserve, and may benefit from hormone replacement therapy (HRT).^{104,
116,
136, 137,
138, 139} Evidence level 2++,2+,3

Women who have evidence of impaired fertility should be referred for specialist assessment as they could benefit from assisted reproductive technology.

4.2.4 PROGENY

Female survivors of Wilms’ tumours who have been treated with abdominal radiation, are at an increased risk for a variety of reproductive problems including fetal loss, early delivery, and birth defects in offspring.^{124,
140} Evidence level 3

Flank irradiation is associated with low birth weight in subsequent offspring.^{102,
141, 142} Evidence level 3

Females successfully treated for childhood acute lymphoblastic leukaemia have a nearly normal reproductive pattern during young adulthood,¹³⁸ without increased risk of congenital anomalies in the offspring.¹⁴³ Spontaneously conceived offspring of patients treated for cancer in childhood have no excess of congenital anomalies or other diseases.^{100,
125,
142} Evidence level 2+,3

4.2.5 BREAST HYPOPLASIA

A field of radiation that includes prepubertal breast tissue may result in significant breast hypoplasia and asymmetry.¹⁴⁴ Evidence level 3