This document summarizes endocrine morbidities that can result from cancer therapy involving radiation or chemotherapy. It discusses how the hypothalamic-pituitary axis, thyroid, parathyroids, gonads, and other endocrine glands can be affected. Specific risks include growth hormone deficiency, precocious puberty, hypothyroidism, thyroid cancer, ovarian dysfunction, and testicular damage leading to infertility. The risks depend on factors like treatment dose, age at treatment, and time since treatment. Regular screening is important to monitor for effects, and hormone replacement therapy may be needed. Protecting gonadal function through semen/oocyte cryopreservation is also discussed.

1. Endocrine Morbidity of
Cancer Therapy
Dr Kate Lissett
Department of Diabetes &
Endocrinology
Torbay

2. Why do I need to know?
• Increasing cure rates
• Endocrine abnormalities are a common
late effect
• Pre-treatment counselling
• Post-treatment screening
• Knowledge of side effects may allow
creation of better tolerated regimens

3. Which endocrine glands are
involved?
• Hypothalamo-pituitary dysfunction
• Thyroid dysfunction
• Thyroid carcinoma and nodules
• Parathyroid dysfunction
• Gonadal dysfunction

4. Hypothalamo-Pituitary Axis
Main insult is radiotherapy used in Rx of:
• Pituitary adenomas
• Craniopharyngiomas
• Intracranial tumours
• Nasopharyngeal carcinoma
• ALL
• TBI for BMT

5. Generally
GH
LH/FSH
ACTH
TSH
However ACTH may be lost before
LH/FSH
Hypothalamus more sensitive than
pituitary

7. Hypothalamo-Pituitary Axis
Incidence, extent and onset of
deficiencies determined by:
• irradiation dose
• fractionation
• age
• pre-treatment status

9. GH status Age @ n Time XRT IGF-I Change in
XRT since dose (ng / l) height
(yrs) XRT (yrs) (24/18 SDS post
Gy) XRT
GH 3.9 9 20 9/0 199 -2.1
deficiency
GH 5.6 11 19 9/3 205 -0.4
insufficiency
‘normal’ 12.9 12 12 3/8 314 -0.2
Reassessment of GH status in survivors of childhood ALL who
received cranial irradiation (Brennan et al 1998. Clin Endo;
48;777 - 783)

10. Hypothalamo-Pituitary Axis
Management:
• Screen for at least 10 years
• Screen growth rate and pubertal
development in children
• Regular biochemical screening in
adults and children receiving high
doses
• Basal and stimulation tests
• Rx is replacement

11. Precocious puberty
50 Gy to HP axis ⇒ gonadotrophin deficiency
< 50 Gy ⇒ early puberty
• Males have higher threshold
• Reduces time available for GH therapy
• Significant psychological sequlea
• Regular assessment of pubertal stage
• +/- Bone age
• +/- GnRH test
• Rx: GnRH analogues to delay puberty

12. Thyroid
• Hypothyroidism
• Graves disease
• Euthyroid Graves ophthalmopathy
• Atypical thyroiditis
• Thyroid cysts
• Nodules (single / multiple)
• Thyroid carcinoma

13. Hypothyroidism
• XRT for treatment of lymphomas, head
& neck cancer, craniospinal irradiation
and TBI
• Usually 30 - 50 Gy, multiple fractions
• May be transient + resolve
• Half of cumulative risk in first 5 years

14. Hypothyroidism
• 27 years after irradiation for Hodgkin’s
Disease
47% were hypothyroid
2% of the control population
(Hancock et al 1991, NEJM, 325; 595-605)
• 10 - 45% following XRT for head and neck
cancers
• 23 - 73% following TBI (single fraction)
• 10 - 28% following TBI (multiple fractions)

16. Hypothyroidism
Incidence of hypothyroidism dependant on
• dose and fractionation
• prior hemithyroidectomy and cervical
surgery
• age < 20 years
• time after XRT

17. Hypothyroidism
Management:
• Screen with twice yearly TFT initially
and yearly thereafter
• More frequent screening if
symptomatic
• Treat both definite and compensated
hypothyroidism
• Treatment is thyroxine

18. Hyperthyroidism
a) Graves disease
• 1677 pts treated with XRT for
Hodgkin’s
• 34 developed Graves disease
• Predicted 7.2 - 20.4
Hancock et al 1991, NEJM 325; 595-605.
b) Radiation induced thyroiditis - transient
and frequently asymptomatic
• Identification and treatment as for the
unirradiated patient

19. Thyroid dysfunction and medical
therapy
Interferon & IL2
∀ ⇑ Incidence autoimmune
hypothyroidism, hyperthyroidism and
thyroiditis
5 flurouracil
∀ ⇑ tT3 / tT4 as a result of ⇑ TBG
L- asparaginase
∀ ⇓ tT3 / tT4 as a result of ⇓ TBG,
also ? ⇓ TSH secretion from pituitary

20. Thyroid Carcinoma
• Association followed an observation that
9/28 children with thyroid Ca had
received irradiation for thymic
enlargement
(Duffy & Fitzgerald 1950,Cancer, 3; 1018-32)
• Confirmed on further epidemiological
studies

21. Meta-analysis of 58,000 patients, XRT
field involving thyroid, predominantly
childhood therapy
• Correlation between XRT dose and risk
of thyroid Ca (RR 7.7/Gy, absolute risk
4.4/Gy/10,000 pt yrs)
• No significant increased excess risk
above 10 Gy
• Little risk if XRT exposure after 20 yrs
of age
(Ron et al 1995, Radiation Research, 141; 259-77)

22. Thyroid Carcinoma
• Increased risk observed in adults treated
with XRT for Hodgkin’s Disease
• Peak incidence of thyroid carcinoma 15-19
yrs post XRT, rare before 5 yrs
• Histological types similar to that occurring
in unirradiated patients
• Increased frequency multicentric lesions,
local invasion, distant metastasis but
similar rate of progression

23. Thyroid nodules
• Pathology:
focal hyperplasia
single or multiple adenomas
chronic lymphocytic thyroiditis
colloid nodules and fibrosis
• Prevalence of palpable nodules:
1-5% in general population
20-30% in irradiated population

24. Thyroid nodules
• Management:
• T4 to suppress TSH reduces incidence
of recurrent benign radiation induced
nodules
• In clinic
Regular thyroid palpation
FNA of palpable lesions
Further Mx on histology

25. Parathyroid dysfunction
• Increased risk hyperparathyroidisnm
following XRT of neck
- retrospective studies only
• Long latency period (25-47 years)
• ? many cases subclinical in both
irradiated and unirradiated population
• Dose response relationship supports
hypothesis
• Clinically: monitor Ca levels regularly

26. Gonadal Dysfunction-XRT
TESTIS
• Germinal epithelium > sensitivity than
Leydig cells
• Immature cells are most sensitive
• < 0.8 Gy oligospermia
• > 0.8 Gy azospermia
• < 3 Gy spermatozoa counts fall at 60-70
days

27. Gonadal Dysfunction-XRT
• Quicker fall with > 4 Gy as spermatids
damaged
• Spontaneous recovery from remaining
stem cells
Complete recovery at 9-18 months
with < 1 Gy, 30 months with 2-3 Gy, 5
years with 4 Gy
• TBI and chemotherapy for BMT results
in azospermia, ?recovery

28. Gonadal Dysfunction-XRT
Leydig cells
• More resistant to XRT
• Significant LH rise with
> 0.75 Gy single
2.0 Gy fractionated
No change in testosterone
“compensated Leydig cell dysfunction”
• LH normalises over 30 months

29. Gonadal Dysfunction-XRT
• > doses result in more marked
insufficiency
• 10-20 Gy permanent testosterone
deficiency
• Replacement therapy with testosterone,
especially important for puberty

30. Gonadal Dysfunction-
Chemotherapy
TESTIS
• Complex
• Damage and recovery dependant on
drug and dosage
• Germ cells more sensitive than Leydig
cells

31. Table of cytotoxic agents known to be gonadotoxic
Cytotoxic Drug Generic Drug Name
Group
Alkylating Agents Cyclophosphamide
Chlorambucil
Mustine
Melphalan
Busulphan
Carmustine
Lomustine
Antimetabolites Cytarabine
Vinca Alkaloids Vinblastine
Others Procarbazine
Cisplatin

32. Gonadal Dysfunction-
Chemotherapy
Cyclophosphamide monotherapy
52/116 (45%) testicular dysfunction
Correlation with dose
80% post-pubertal patients receiving
a dose > 300 mg/kg had gonadal
dysfunction

33. Gonadal Dysfunction-
Chemotherapy
Lymphomas
• MVPP for Hodgkin's
> 90% azospermia,
⇑ LH, normal testosterone
• ABVD less gonadotoxic
• NHL regimens less toxic
? Related to ⇓ dose alkylating
agents or absence of procarbazine

34. Gonadal Dysfunction-
Chemotherapy
Testicular Cancer
• 170 patients with germ cell carcinoma
cis/carboplatin based regimens
• 24% azospermia, 24% oligospermia
pre-treatment

35. Gonadal Dysfunction-
Chemotherapy
• Of those normospermic recovery over
long period: 48% & 80%
spermatogenesis at 2 & 5 years
respectively
• Similar results from lung/osteosarcoma
pts treated with cisplatin

37. Gonadal Dysfunction-
Chemotherapy
? Transmissible genetic damage
• Demonstrated to occur in animals
• Humans ⇑ abnormal spermatozoa
• No ⇑ frequency of birth defects
• No alteration in sex ratio or birth
weights
• ? Selection bias against abnormal
sperm

38. Gonadal Dysfunction-XRT
OVARY
• Effects are age and dose dependent
• Ovarian dose < 4 Gy infrequently
associated with permanent premature
ovarian failure (POF)
• 97% POF from ovarian dose of 5 -10.5 Gy
but 91% > 40 years, 20% > 50 years
(Doll & Smith 1968. Br J Radiol, 41; 362-8)

39. Gonadal Dysfunction-XRT
• < 40 years of age, estimated dose for
POF = 20 Gy
• > 40 years of age, estimated dose for
POF = 6 Gy
(Lushbaugh et al 1976. Cancer, 37; 1111-25)
• Also loss of ovarian steroidogenesis
with symptomatic of oestrogen
deficiency

40. Gonadal Dysfunction-XRT
UTERUS
• XRT involving uterus during childhood
can result in failure to carry a child ⇒
term
• 20-30 Gy to abdomen reduced uterine
length and loss of response to
physiological dose exogenous E2
• ? Vascular aetiology
• Implications for IVF +/- donor oocytes

41. Gonadal Dysfunction-
Chemotherapy
OVARY - Hodgkin’s disease
• MVPP, COPD, ChlVPP ⇒ 38-57% POF
• Age > 35 yrs at Rx; POF inevitable
• Retrospective study
• > 1000 women, chemotherapy in
childhood, menstruating at 21 years
• 42% menopausal at age 31, 5%
controls
(Byrne et al 1992. Am J Obs Gyn 166; 788-93)

42. Gonadal Dysfunction-
Chemotherapy
• Newer regimes – ABVD
• Results vary depending on age of
patients treated
• 0 - 44% of patients develop POF
• One study (mean age 25) revealed no
reduction in fertility followiABVng D
Hematol Oncol 2007; 25: 11–15

43. Gonadal Dysfunction-
Chemotherapy
• Damage dose and age dependent
• With ⇑ age ⇒ permanent amenorrhoea
at smaller doses
• Oligomenorrhoea post-therapy can ⇒
POF or resolve spontaneously
• Evolution of ovarian dysfunction
consistent with destruction of a fixed no.
of oocytes

44. Gonadal Dysfunction-
Chemotherapy
• Older women smaller pool of oocytes ⇑
premature ovarian failure
• Younger women frequently have normal
ovarian function but premature
menopause
• < 50 yrs therapy HRT (osteoporosis,
IHD, symptoms)
• No evidence of ⇑ birth defects

45. Gonadal Dysfunction-
Chemotherapy
Protection of Gonadal Function
Testis: Cryostorage of semen
• ? prepubertal, ⇓ testicular function in
malignant disease
• ? suppression of testicular function
(pre / post Rx)
• ? harvest stem cells & re-implant

46. Gonadal Dysfunction-
Chemotherapy
Ovary:
• Cryopreservation of oocytes
• Cryopreservation of strips of ovarian
tissue
• Protection of ovary with GnRH
analogues

47. •From Anderson R., and Wallace H. Clinical Endocrinology “Accepted Article”