Endocrine Late Effects Guideline for Secondary Care Oncology

Overview

This specialist Guidelines summary aims to help healthcare professionals support patients with bone problems and osteoporosis; hot flushes; ovarian, pituitary, and testicular insufficiencies; and thyroid problems.

This summary is intended for use in a secondary care setting by oncologists. Refer to the full guideline for further information.

Bone Problems and Osteoporosis

• Any cancer patient may be at risk of poor bone health. The following are additional risk factors:
  • postmenopausal women and men >50 years of age
  • low body mass index (<19 kg/m²)
  • immobility
  • current smoking
  • alcohol consumption over three units per day
  • history of parental hip fracture
  • history of rheumatoid arthritis, inflammatory bowel disease, or diabetes
  • falls risk (peripheral neuropathy, cachexia, sarcopenia).

Cancers at High Risk of Bone Problems, Osteoporosis, and Fragility Fractures

• Haematological malignancies (lymphoma, leukaemia, myeloma)
• Gastric cancer.

Treatments Which May Be Followed by Bone Complications

• Glucocorticoid (GC) therapy
• High-dose methotrexate (cumulative dose >40,000 mg/m²)
• Chemotherapy—predominantly alkylating agents (for example, cyclophosphamide and chlorambucil), platinum compounds, and specific chemotherapies (for example,  ifosfamide)
• Ovarian suppression therapy or androgen deprivation therapy (ADT)
• Aromatase inhibitors (AI) and tamoxifen in premenopausal women
• Haematopoietic stem cell transplant
• Total body irradiation
• Radiotherapy to cancers of the brain, nasopharynx, orbit, and surrounding tissues, including proton therapy
• Gonadal radiotherapy
• Focal radiotherapy involving bones >40 Gy (pelvis/rib)
• Brachytherapy.

Symptoms of Bone Problems and Osteoporosis  

• Often asymptomatic
• Fragility fracture may present with pain
• Severe vitamin D deficiency may cause pain and proximal weakness
• Pelvic pain following pelvic radiotherapy may indicate insufficiency fractures.

Potential Actions

• At end of treatment (and ideally at start of treatment), all patients should be assessed for fracture risk by FRAX/Qfracture
• FRAX does not take any cancer treatments into consideration, so clinical judgement is required
• All patients at increased risk due to treatment should undergo a dual-energy X-ray absorptiometry (DXA) scan 1 year after the end of treatment
• All patients taking GCs, AI therapy, or ADT should follow current international algorithms
• Patients who have a low bone mineral density (BMD; T score <-1, Z-score <-2) should have screens for secondary causes of low bone mass, including blood tests for calcium, vitamin D, parathyroid hormone (PTH), alkaline phosphatase, and liver function tests, coeliac screen, serum and urine electrophoresis, assessment of gonadal status (oestradiol, 9am testosterone, luteinising hormone [LH] and follicle-stimulating hormone [FSH])
• All patients with pelvic pain following pelvic radiotherapy should have magnetic resonance imaging scan of pelvis to look for insufficiency fractures
• If clinical suspicion/high risk of vertebral fracture, should perform DXA or lateral thoracic/lumbar radiography.

Treatment

• Low bone mass/osteopenia (a T-score <-1 and >-2.5, or a Z-score <-2 in those less than 40 years old)
• Lifestyle advice (smoking, alcohol intake, weight bearing exercise for 30 minutes five times a week)
• Recommend intake of calcium: 700–1000 mg/day (supplements if diet insufficient) and ensure vitamin D >50 nmol/l (800 IU once daily, if replacement required)
• Manage secondary causes, for example, treat hypogonadism (premenopausal women and men) if no contraindications
• Osteoporosis (T-score ≤-2.5, fragility fracture or Z-score <-2 with history of fragility fractures). Follow FRAX tool and National Osteoporosis Guidelines Group
• For AI and ADT, follow guidelines
• Follow-up DXA scans should be determined by BMD and clinical risk.

Important Points

• Low threshold for referral to metabolic bone clinic, particularly in young patients, hypogonadism, and insufficiency fractures
• Presence of new fragility fracture (particularly vertebral fracture) is high risk of further fracture
• Withdrawal of denosumab treatment has been associated with rebound vertebral fractures—if denosumb to be stopped, liaise with specialist
• If suspected radiation induced fracture, refer to rheumatology or metabolic bone clinic (or fracture clinic, if unstable fracture on X-ray)
• DXA scan cannot distinguish between osteoporosis and severe vitamin D deficiency; DXA should only be performed in those who are vitamin D replete.

Hot Flushes and Hormone Replacement Therapy/Testosterone Replacement Contraindicated  

Cancers Whose Treatment Can Cause Hot Flushes and Hormone Replacement Therapy/Testosterone Replacement May Be Contraindicated

• Breast cancer
• Prostate cancer
• Ovarian/endometrial cancer.

Treatments Which May Be Followed by Hot Flushes and Hormone Replacement Therapy/Testosterone Replacement Contraindicated 

Androgen Deprivation Treatments

• LH blockers (for example, goserelin, leuprorelin, decapeptyl) for prostate cancer, which block LH production in the pituitary gland, thereby stopping the testicles from producing testosterone
• Anti-androgens (flutamide, bicalutamide) which block testosterone receptors on prostate cancer cells
• Gonadotrophin releasing hormone receptor blocker (degarelix), which acts at the hypothalamus to stop the pituitary from producing LH.

Hormone Treatments for Breast Cancer

• Tamoxifen (stops oestrogen reaching the cancer cells)
• AIs (for example, exemestane, anastrozole, letrozole), which work in postmenopausal women by stopping the body converting androgens into oestrogen
• LH blockers (goserelin).

Symptoms of Hot Flushes

• Hot flushes may range from a sensation of rising heat (particularly in the face), through to drenching sweats and panic attacks
• Cancer treatments may induce permanent or temporary ovarian/testicular insufficiency
• During hormonal treatment for prostate cancer, men can experience tiredness, impotence, breast tenderness, weight gain, memory disturbance, and mood changes
• Men may be at risk of heart disease or diabetes if ADT is for more than 6 months
• Consider bone health—see the section, Bone Problems and Osteoporosis.

History Detailing

• Type of cancer: is it hormone sensitive, or was ovarian/testicular insufficiency induced by treatment (surgery or chemotherapy)?
• What are the patient’s risk factors—osteoporosis, cardiovascular risks?
• Are there any risks if hormone replacement therapy (HRT) treatment is given, for example, risks of recurrence or blocking cancer treatment effects? (see below)
• Ask about erectile dysfunction or vaginal dryness and lack of libido, sexual dysfunction, dyspareunia, psychological concerns, and fertility issues, as patients may not otherwise disclose these concerns.

Non-pharmaceutical Management for Men and Women

• Stress can be clearly identified as a trigger for flushing in some patients, and cannabidiol and acupuncture may usefully reduce this
• Consider practical interventions, such as reducing spicy food, caffeine, and alcohol intake, and sleeping in or wearing natural fibres, such as cotton.

Treatment in Women

Risks of Hormone Replacement Therapy

• Women with breast cancer who are treated with HRT are three times more likely to have cancer recurrence.

Ovarian and Endometrial Cancer

• Some ovarian/endometrial cancers (particularly low grade) have oestrogen receptors and can be treated with tamoxifen and AIs
• Following successful curative cancer treatment there is no contraindication for HRT
• Topical low-dose vaginal oestrogen is considered an acceptable treatment for patients using AIs with dyspareunia and vaginal dryness who have already tried simple lubricants.

Alternatives to HRT

• Drug options: clonidine (25–75 mcg orally twice daily or via patch), venlafaxine (37.5–75 mg daily)
• Weak selective serotonin reuptake inhibitors, such as citalopram (10–20 mg once daily) or gabapentin (300 mg three times daily) have also been shown to be beneficial
• There is a theoretical concern that paroxetine/fluoxetine may interfere with tamoxifen metabolism; use alternatives where possible.

Treatment in Men with Prostate Cancer on ADT

• NICE recommends medroxyprogesterone 20 mg per day to be offered initially for 10 weeks
• If medroxyprogesterone is not effective, consider changing to cyproterone acetate, with a 50 mg starting dose, and if necessary, upward titration within the range 50–150 mg/day in one to three divided doses
• Consult with oncologist if testosterone remains low, symptoms are debilitating, and ADT is completed (testosterone replacement may be suggested).

Ovarian Insufficiency

Primary ovarian insufficiency is when the ovary is damaged. Secondary ovarian insufficiency is when damage occurs to the pituitary/hypothalamus.

Cancers That May be Followed by Ovarian Insufficiency

• Cancers of the brain, nasopharynx, orbit and surrounding tissues
• Ovarian/gynaecological cancer
• Haematological malignancies
• Colorectal/anal cancer
• Breast cancer
• Pancreatic cancer
• Bladder cancer.

Treatments That May be Followed by Ovarian Insufficiency

• Chemotherapy—predominantly alkylating agents (for example, cyclophosphamide and chlorambucil), platinum compounds, and specific chemotherapies (for example, ifosfamide)
• Surgery—bilateral oophorectomy, pituitary, hypothalamus
• Radiotherapy (including proton beam)—ovarian, abdominal, pelvic, brain, head, orbits, nasopharynx, pituitary, hypothalamus
• Total body irradiation.

Symptoms of Oestrogen Insufficiency

• Amenorrhoea and oligomenorrhoea
• Fertility problems
• Osteoporosis/fragility fracture
• Hot flushes, night sweats, palpations
• Vaginal dryness
• Reduced libido/pain during sex
• Problems with memory and concentration
• Joint stiffness, aches, and pains
• Recurrent urinary tract infection.

History Detailing

• If premenopausal, is the patient menstruating and is it a regular menstrual cycle?
• If the patient is a young adult, have they started menstruating, completed puberty, and have they grown to an appropriate height?
• Is the patient experiencing hot flushes?
• Is there any dyspareunia or vaginal dryness?
• Is there any post-coital bleeding?
• Are there any psychological issues or sexual problems?
• Are there any fertility issues or concerns?

Oligo/amenorrhoea

• Can be primary when the ovary is damaged (high LH/FSH) or secondary when damage is to the pituitary/hypothalamus (low normal LH/FSH). Both have low oestradiol (<100 pmol/l).

Blood Tests for:

• LH, FSH, oestradiol (day 1–5 if menstruating)
• Consider exclusion of other causes of amenorrhoea, for example, polycystic ovary syndrome, elevated prolactin.

Potential Actions

• If under 50 years of age, in the absence of contraindications start oestrogen replacement
• Contraindications include:
  • breast cancer, endometrial cancer, and presence of BRCA mutations
  • thrombophilia
• If unsure seek specialist advice
• If young adult, refer to endocrinology
• If secondary ovarian insufficiency, refer to endocrinology as further pituitary surveillance is needed
• Tamoxifen causes amenorrhoea but pregnancy can still occur and LH/FSH is not a robust indicator of ovarian function
• Contraception is recommended in premenopausal women.

Oestrogen Replacement

• Consider HRT first line (more physiological) unless contraception is required, then the combined oral contraceptive pill or HRT, with alternative method of contraception
• Oestradiol is important for the prevention of menopausal symptoms and bone protection
• Usual risks of HRT do not apply to young women (there is currently no data in this age group)
• Women with a uterus must have progestogen (cyclical, continuous, or impregnated intrauterine contraceptive device) together with oestrogen replacement.

Vaginal Dryness

• Consider treatments such as topical oestrogen, Replens, and Dermol 500 wash in the standard way
• Cervical screenings may be challenging and painful; seek specialist advice as required.

Hot Flushes

• Blood tests for:
  • LH, FSH, oestradiol
  • oestrogen replacement if under 50 years of age, if not contraindicated
  • if oestrogen replacement is contraindicated or not wanted, see the section, Hot Flushes and Hormone Replacement Therapy/Testosterone Replacement Contraindicated.

Fertility

• If the patient is seeking fertility assistance, or they wish to review options for future fertility in the context of ovarian insufficiency, refer to local fertility services
• If the patient is sexually active, advise the use of contraception even if they are not menstruating, as there is still a small chance of returning ovarian function and unplanned pregnancy
• Discuss risks of sexually transmitted infections if the patient is sexually active.

Pregnancy

• If the patient becomes pregnant, refer to obstetrics
• Pregnancies should be considered high risk if there is previous:
  • pelvic/chest radiotherapy
  • chemotherapy, for example, bleomycin, busulphan, carmustine, lomustine—can cause restrictive lung defects
  • anthracyclines and chest radiotherapy—can cause cardiac decompensation.

Psychological Issues

• Ask the patient if they have any concerns regarding mood, quality of life, and/or sexual dysfunction
• If concerns are present, refer to mental health and wellbeing services or specialist psychosexual counselling.

Osteoporosis/Fragility Problems

• See the section, Bone Problems and Osteoporosis.

Pituitary Insufficiency

• If a patient has undergone surgery or radiotherapy that may have affected the pituitary or hypothalamus, refer to endocrinology for assessment/pituitary surveillance.

Cancers That May be Followed by Pituitary insufficiency

• Brain tumours either close to or involving the hypothalamus or pituitary
• Cancers of nasopharynx, orbit, and surrounding tissues
• Haematological malignancies
• Brain tumours or metastatic cancer treated with dexamethasone for 4 weeks or longer
• Brain metastases (most frequently lung, breast, kidney, melanoma, and bowel).

Treatments That May be Followed by Pituitary Insufficiency

• Neurosurgery either close to or involving the hypothalamus or pituitary
• Radiotherapy (including proton beam) to cancers of nasopharynx, orbit, and surrounding tissues
• Total body irradiation
• New cancer treatments: biological therapies, immunotherapies
• Dexamethasone for 4 weeks or longer.

Symptoms of Pituitary Insufficiency

• Fatigue, weakness, depression
• Anorexia and weight loss
• Sexual dysfunction: reduced libido, erectile dysfunction, irregular or lack of periods, vaginal dryness, hot flushes
• Fertility problems
• Symptoms of hypothyroidism
• Patients at risk of hypopituitarism should be under the care of an endocrinologist.

Blood Tests

• Conduct a 9am cortisol test in patients not on dexamethsone or other glucocorticoid therapies
• If 9am cortisol is <100 nmol/l, start hydrocortisone at a dose of 15 mg in the morning and 5 mg at 3pm; this will mean the patient is protected; refer urgently to endocrinology
• If 9am cortisol is between 100–350 nmol/l, the patient needs further urgent assessment; refer urgently to endocrinology
• Check thyroid function levels. A free thyroxine (fT4) below the normal range with a low/normal or mildly elevated level of thyroid stimulating hormone (TSH) suggests secondary hypothyroidism. (state on blood request form ‘?secondary hypothyroidism due to pituitary insufficiency’)
• Do not start levothyroxine until cortisol status is known, as this may precipitate an adrenal crisis
• In men, check 9am testosterone and sex hormone binding globulin (SHBG); if testosterone is low and LH and FSH are not raised, this suggests secondary hypogonadism. See the section, Testicular Insufficiency
• In premenopausal women with absent menstrual cycle, check LH, FSH, and oestradiol; if oestradiol is low and LH and FSH are not raised, this suggests secondary hypogonadism. Refer to endocrinology 
• In postmenopausal women, check FSH; if FSH is low/normal, this suggests hypopituitarism.

Important Points

• Consider hypophysitis if there is evidence of hypopituitarism during and after use of immunotherapies
• Headache, cognitive problems, and neurological symptoms may indicate recurrence, second tumour, or consequence of cranial irradiation
• New acute neurological symptoms, suspicion of cerebrovascular accident, ventriculoperitoneal shunt blockage (headache, symptoms suggestive of infection). Refer to neuro-oncology/neurosurgery urgently
• Patients treated with total body irradiation or cranial/head radiotherapy may develop asymptomatic hypopituitarism; regular screening is required for growth hormone deficiency and secondary hypogonadism, hypothyroidism, and hypoadrenalism
• Patients with hypopituitarism are at risk of cardiovascular disease, diabetes, and hyperlipidiaemia
• Hypopituitarism following radiation may evolve over many years; most deficiencies occur within 10 years but can occur later; ongoing follow up is required
• Ensure patients with secondary adrenal insufficiency have a MedicAlert card and are aware of sick day rules; refer to the Pituitary Foundation website for further information
• Thirst and polyuria can be suggestive of diabetes insipidus
• Exclude diabetes mellitus, and hypercalcaemia
• Diabetes insipidus is not associated with cranial irradiation or any other cancer therapy, so may suggest tumour or metastases affecting the hypothalamus or pituitary
• Cognitive dysfunction and memory issues can occur at a young age after cranial irradiation
• Consider referring to local services for neuro-psychometric testing, or to community services if employment or benefits support is needed.

Testicular Insufficiency

Primary testicular insufficiency is when the testes are damaged. Secondary testicular insufficiency is when damage occurs to the pituitary/hypothalamus.

Cancers That May be Followed by Testicular Insufficiency

• Cancers of the brain, nasopharynx, orbit, and surrounding tissues
• Testicular cancer
• Colorectal/anal cancer
• Prostate cancer
• Bladder cancer
• Haematological malignancies.

Treatments That May be Followed by Testicular Insufficiency

• Chemotherapy—predominantly alkylating agents (for example, cyclophosphamide and chlorambucil), platinum compounds, and specific chemotherapies (for example, ifosfamide)
• Surgery—bilateral orchidectomy, pituitary, hypothalamus
• Radiotherapy (including proton beam)—testicular, abdominal, pelvic, brain, orbits, nasopharynx, pituitary, hypothalamus
• Total body irradiation.

Symptoms of Testosterone Insufficiency

• Reduced libido
• Erectile dysfunction
• Fertility problems
• Reduced frequency of shaving
• Reduced muscle bulk
• Osteoporosis/fragility fracture
• Hot flushes, night sweats, palpitations
• Problems with memory and concentration.

History Detailing

• If the patient is an adult, do they have any issues with libido, erectile function, lack of shaving?
• If the patient is a young adult, have they progressed through puberty and grown to an appropriate height?
• Any there any psychological issues or sexual problems?
• Are there any fertility issues or concerns?
• Are they experiencing hot flushes?

Bloods Tests for Testosterone Insufficiency

• LH, FSH, 9am testosterone, SHBG (to calculate free testosterone, which may be helpful, for example, in obese patients)
• Exclude other causes of low testosterone, for example, elevated prolactin
• Testicular insufficiency is primary when the testes are damaged (high LH/FSH), or secondary when damage is to the pituitary/hypothalamus (low normal LH/FSH); both have low testosterone
• High FSH and normal testosterone can indicate sertoli cell damage, which only affects sperm production (no effect on testosterone)
• Do not check testicular function at the time of significant intercurrent illness, or while a patient is undergoing active cancer-related treatment.

Potential Actions

• If blood tests show low 9am testosterone (on two occasions), refer to endocrinology.

Testosterone Replacement

• Testosterone can be replaced with testosterone gel, or short- or long-acting injections
• Monitor annual testosterone level, full blood count (due to risk of secondary polycythaemia) and prostate/prostate-specific antigen screening.

Fertility

• Elevated FSH in the presence of normal testosterone may indicate sertoli cell damage and fertility issues
• Fertility should be discussed with the patient at risk or with evidence of testicular insufficiency and before starting testosterone replacement
• If semen was stored prior to cancer therapy, advise the patient to contact the storage facility to arrange a check of current fertility status and confirm they have up-to-date details and consent
• If patient interested in knowing their fertility status, arrange semen analysis with appropriate counselling
• If the patient is seeking fertility assistance, or wishes to review options for future fertility, refer to local fertility services with expertise in male factor infertility
• Psychological support may be needed to discuss abnormalities in semen analysis and loss of fertility
• If the patient is sexually active, advise them to use contraception
• Discuss risks of sexually transmitted infections if sexually active.

Sexual Function

• Patients who have undergone the following may experience sexual dysfunction:    
  • surgery to spinal cord, sympathetic nerves, or pelvis 
  • radiotherapy to the testes or pelvis  
  • patients who are hypogonadal.

Psychological Issues

• Ask the patient if they have any concerns regarding mood, quality of life, or sexual dysfunction; if appropriate, refer to mental health and wellbeing services or specialist psychosexual counselling.

Osteoporosis/Fragility Problems

See the section, Bone Problems and Osteoporosis.

Thyroid Problems

• Breast cancer screening is recommended for women over 25 years of age who received mediastinal irradiation; refer to local breast screening services.

Cancers That May be Followed by Thyroid Problems

• Brain/head and neck cancers
• Pituitary tumours
• Thyroid cancer
• Breast cancer
• Haematological malignancies.

Treatments That May be Followed by Thyroid Problems

• Surgery leading to thyroid removal
• Head and neck, mediastinal, cervical spine radiotherapy (including proton beam)
• Bone marrow transplant, with or without total body irradiation
• Therapeutic meta-iodobenzylguanidine
• New cancer treatments: biological therapies, immunotherapies.

Symptoms of Thyroid Problems

• Fatigue
• Weight loss or weight gain
• Heat or cold intolerance
• Diarrhoea or constipation
• Anxiety, tremors, sweating
• Dry hair or skin
• Hair loss
• Menstrual disturbance
• Neck lump.

History Detailing

• Symptoms of thyroid overactivity?
• Symptoms of thyroid underactivity?
• Neck swelling or neck lump?

Hypothyroidism

• Is primary when the thyroid is damaged (high TSH, low/normal fT4)
• Is secondary when there is hypothalamic—pituitary damage (low fT4, low/normal or mildly elevated TSH)
• If the patient is at risk of secondary hypothyroidism an fT4 level must be requested.
• Blood tests for:
  • TSH, fT4
  • autoantibodies (thyroid peroxidase antibodies antibody) if considering an autoimmune cause
  • 9am cortisol test to confirm adequate level before commencing replacement if at risk of hypopituitarism (See the section, Pituitary Insufficiency)
  • no need for imaging for hypothyroidism.

Potential Actions

Primary Hypothyroidism

• Repeat thyroid function tests as thyroid disease may evolve if thyroiditis is present
• Consider levothyroxine replacement if clinical or subclinical hypothyroidism (TSH >7 with normal T4)
• Start with a low dose (50 mcg)
• Primary hypothyroidism—titrate up to normalise TSH.

Secondary Hypothyroidism

• TSH is not a valid marker of thyroid status and should be ignored; titrate using fT4, aiming for the middle of the fT4 normal range
• Caution if at risk of cardiac dysfunction, for example, prior anthracyclines or mediastinal radiotherapy.

Hyperthyroidism

• Blood tests for:
  • TSH, fT4
  • TSH-receptor antibody.

Potential Actions

• Consider repeating if investigations and clinical signs are suggestive of thyroiditis
• Refer to secondary care for further investigations and antithyroid therapy
• May require beta blockade for symptom control.

Secondary Thyroid Nodule/Cancer Surveillance

• Childhood/young adult cancer survivors who received mediastinal/neck radiotherapy should be advised to see their GP urgently if a neck mass develops
• For patients presenting with a new thyroid or neck mass, refer urgently to neck or thyroid lump service as per local protocols
• Conduct an annual neck examination by palpation for patients who have undergone radiotherapy that may have treated the neck
• Use of thyroid ultrasound in surveillance is contentious. Seek local thyroid specialist advice. See ighg.org/guidelines/topics/thyroid-cancer/recommendations.

Pregnancy and the Thyroid

• Where preconception planning is feasible, optimise thyroid function prior to a pregnancy
• If the patient becomes pregnant, manage levothyroxine replacement as for all patients with thyroid dysfunction in pregnancy
• Refer early to appropriate antenatal/obstetric services
• Refer to cardiology if the patient is at risk of cardiac dysfunction, for example, prior anthracyclines or mediastinal radiotherapy.