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REDUCING THE BURDEN OF LATE EFFECTS IN SURVIVORS OF CHILDHOOD CANCER
TABLE 2. Risk-Based Screening for Potential
Endocrinopathies Following Cancer Treatment
Potential Late Effect Cancer Treatment Screening Tests
Thyroid Dysfunction Radiation impacting the
thyroid
Agents labelled with 131-I
Tyrosine kinase inhibitors
TSH, Free T4
Gonadal Dysfunction
(Female)
Gonadal Dysfunction
(Male)
Alkylating agents
Nitrosoureas
Cisplatin
Radiation to the gonads
Alkylating agents
Nitrosoureas
Cisplatin
Radiation to the gonads
Physical exam with
Tanner staging
LH
FSH
Physical exam with
Tanner staging
LH
FSH
Testosterone
Abbreviations: LH, luteinizing hormone; FSH, follicle stimulating hormone; TSH, thyroid
stimulating hormone.
Leydig cell dysfunction. Leydig cells are susceptible to
radiation-induced damage at higher doses than those associated
with germ cell dysfunction. Risk is directly related to testicular
radiation dose and inversely related to age at
treatment. 79 Although the majority of men who receive less
than 20 Gy fractionated radiation to the testes will produce
normal amounts of testosterone, most prepubertal males
who receive radiation doses of 24 Gy or greater to the testis
will develop Leydig cell failure. 80 Chemotherapy alone rarely
results in Leydig cell failure, although subclinical Leydig cell
dysfunction has been reported following treatment with alkylating
agents. 79
Leydig cell failure will result in pubertal delay or arrest, if it
occurs before or during puberty, and in reduced libido, erectile
dysfunction, decreased bone mineral density, and decreased
muscle mass if it occurs after completion of normal
puberty. Patients who are noted to have developed any of the
above symptoms after gonadotoxic therapy should be assessed
for Leydig cell failure.
Men treated with 20 Gy or more radiation to areas that may
affect the testes (flank/hemiabdomen, whole abdomen, inverted
Y, pelvic, prostate, bladder, iliac, inguinal, femoral,
testicular, total lymphoid, or TBI) should have periodic
screening with LH and an early-morning testosterone level
beginning at the time of puberty (e.g., by age 14; Table 2). 5
Elevated serum levels of LH with low levels of testosterone
are consistent with a diagnosis of Leydig cell failure.
Gonadal Dysfunction: Women
Because of the interdependence of sex steroid-producing
cells and oocytes within the ovarian follicle, ovarian failure
results in impairment of both sex hormone production and
fertility.
Ovarian dysfunction may result from treatment with gonadotoxic
chemotherapy, radiation affecting the ovaries, or
surgical removal of the ovaries. 81 Chemotherapy-induced
ovarian failure typically results from treatment with highdose
alkylators, 82,83 particularly when administered in preparation
for stem cell transplantation. 84 Risk is directly
correlated with cumulative dose and older age at exposure.
Women treated with radiation affecting the ovaries (spinal,
flank, hemiabdomen below the iliac crest, whole abdomen,
inverted Y, pelvis, vagina, bladder, iliac lymph nodes, total
lymphoid system, or total body) are at increased risk for ovarian
failure. 81-83 Doses to the ovary exceeding 10 Gy are associated
with a very high risk of ovarian failure. 82 When ovarian
transposition is performed before radiotherapy, however,
many younger women retain ovarian function. 79 Irradiation
at an older age confers a greater risk of ovarian failure.
Women who have normal ovarian function at the end of
treatment with potentially gonadotoxic therapy remain at
risk for premature menopause later in life and should be
counseled accordingly. 82
Although female survivors treated with high-dose alklyators
and/or pelvic irradiation have been shown to be less
likely to experience a pregnancy when compared with sibling
comparators, 85,86 those who do achieve pregnancy after treatment
with chemotherapy alone do not appear to have adverse
pregnancy outcomes. 87 Survivors treated with pelvic irradiation,
who become pregnant, however, are at a higher risk of
stillbirth and neonatal death and having offspring who are
premature, have low birth weight, and are small for gestational
age. 85,88
Among survivors of childhood cancer who achieve a successful
pregnancy, their offspring do not appear to be at increased
risk of congenital anomalies or genetic defects. 85,89,90
If ovarian failure occurs before pubertal onset, delayed puberty
and primary amenorrhea will result. In those in whom
ovarian function is lost during or after puberty, pubertal arrest,
secondary amenorrhea, and symptoms of menopause
will occur. If these symptoms are noted along with elevated
gonadotropins, a referral should be made to an endocrinologist
or gynecologist for consideration of hormone replacement
therapy.
All women treated with the gonadotoxic therapies mentioned
above should have periodic screening with LH and
FSH levels, as well as careful Tanner staging, to monitor pubertal
progression (Table 2). Elevated gonadotropin levels
are consistent with primary ovarian dysfunction. Although
plasma levels of anti-mullerian hormone (AMH) have been
shown to correlate with ovarian reserve in adult women,
there are no long-term data correlating AMH levels in children
and adolescents and subsequent ovarian function and
fertility. 91 Therefore, measurement of AMH levels is not currently
recommended in the clinical management of survivors
under age 25.
CONCLUSION
Research on survivorship-related issues has identifıed important
associations between certain therapeutic exposures
and long-term complications in survivors of childhood cancer.
This has facilitated the development of a number of
recommendations for early screening in asymptomatic sur-
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