Top 10 Advice and Guidance requests in endocrinology

In the first of a new series sharing expert insights on the most common Advice and Guidance (A&G) requests in key specialties, consultant endocrinologists Dr Anna Mitchell and Professor Simon Pearce highlight the 10 most common requests received in their Endocrinology A&G service and explain how these are managed

Note all 10 requests feature hypothetical cases created for illustrative purposes

1. Elevated prolactin level

Q: This 29-year-old woman has been trying to conceive for 12 months without success. Prolactin 952 mIU/L [reference range 102-496], bioactive monomeric prolactin 690 mIU/L [75-381], LH 4.2 IU/L, FSH 6.3 IU/L, TSH 2.3 mU/L [0.3-4.7]. Her menstrual cycle has been slightly irregular but she denies galactorrhoea. She gets occasional headaches. Should I book an urgent pituitary MRI? She is concerned about a pituitary tumour.

A: More than half of patients with a mildly raised prolactin will have a drug-induced or physiological hyperprolactinaemia. Check the patient is not pregnant or breastfeeding. Other physiological causes include the stress of venepuncture and anything that causes nipple stimulation (nipple piercings, exercise or stimulation during sexual activity).

Drug causes include oestrogens, antiemetics, particularly metoclopramide, opiates, antidepressants (SSRIs, SNRIs, tricyclics) and antipsychotics. Many culprit drugs cause prolactin levels up to 1,500 mIU/L, while some antipsychotics can result in levels up to 4,000 mIU/L. If there is amenorrhoea or galactorrhoea, offending drugs may need to be discontinued or oestrogen hormone replacement considered.

If there are no relevant drugs and physiological factors are not obvious, then it is worth repeating the measurement once or twice more, when the patient is feeling relaxed. A single normal measurement is sufficient to be reassured. If the prolactin remains modestly elevated (<1,000 mIU/L) then please refer and we will obtain a cannulated prolactin measurement; if it is consistently over 1,000 mIU/L in the absence of an obvious cause, then we will organise pituitary MRI. A high prolactin per se will not cause subfertility in the absence of oligo-amenorrhoea.

2. High parathyroid hormone (PTH) level

Q: My GP partner ordered blood tests on this 47-year-old man with learning difficulty in supported living as part of an annual health check; PTH was elevated at 17.6 pmol/L [2.0–6.4], with a calcium of 2.24 mmol/L [2.2-2.6], PO4 0.92 mmol/L [0.8-1.5], normal U&E, LFT, blood count, HbA1c and lipid profile. Please advise whether the PTH needs repeating or additional investigations are required.

A: It is rarely necessary to measure PTH in a patient with normal serum calcium, so we would not advise repeating it. Vitamin D insufficiency is the commonest cause of an isolated rise in PTH and it would be reasonable to just start a replacement dose of colecalciferol, 800-1,000 units (20-25 mcg) daily if the patient is not already taking it. Given the patient’s situation, it is not necessary to measure serum vitamin D before starting a daily supplement, as the probability of insufficiency is extremely high for people in care environments, as also for those of non-White ethnicity.

Other frequent causes of high PTH include bisphosphonate or denosumab use, renal impairment (CKD 4 or 5) and less commonly dietary calcium deficiency. Rarely coeliac disease may present with high PTH due to a combination of vitamin D deficiency and calcium malabsorption, but microcytic anaemia would commonly accompany this.

It is not necessary to monitor serum calcium or vitamin D levels in patients just taking a replacement dose of colecalciferol, in the absence of complicating factors such as malabsorption or bariatric surgery, anti-convulsant use or more complex metabolic bone diseases.

3. Low testosterone level

Q: This 56-year-old man consulted me recently about low libido. His serum testosterone level was 5.7 nmol/L [6.7-25.7]. He has hypertension, obesity (BMI 34) and chronic back pain. Would you consider testosterone therapy for him?

A: Low libido is often multifactorial, including owing to medications, comorbid physical conditions and psychosexual factors. Opiate use in particular can result in low serum testosterone levels, mediated through gonadotropin (LH and FSH) suppression.

It is important to enquire about non-prescribed testosterone or anabolic steroid use; gonadal suppression may take a year or more to recover. Obesity and obstructive sleep apnoea are also common culprits. Normochromic anaemia and elevated LH and FSH would mark out true primary hypogonadism from that mediated by functional axis suppression.

As with many hormones, there are normal diurnal variations in testosterone levels, with levels falling during the daylight hours, and following food. It is worth rechecking the testosterone level first thing in the morning (8-9 am), having fasted overnight. Any value in the reference range excludes hypogonadism.

Screening for sleep apnoea using the Epworth Sleepiness Scale or STOP-BANG score is worthwhile. If the early morning testosterone level remains below the reference range, particularly if associated with anaemia or elevation of gonadotrophins, then please refer. A haematocrit above 50% is a relative contraindication to testosterone use and goes against a diagnosis of hypogonadism.

4. Low TSH level with normal FT4 (subclinical hyperthyroidism)

Q: This 84-year-old woman was found to have serum TSH <0.05 mU/L (0.3–4.2) with free T4 18.3 pmol/L (10.0–22.0) during a routine older person review. She reports losing half a stone in weight over the last 5 years but is otherwise well. Does she need further investigation?

A: Low or fully suppressed TSH can reflect subclinical hyperthyroidism, or be an effect of medications (steroids, opiates, levodopa, metformin, and of course levothyroxine) or comorbidity including malignancy, inflammatory diseases or frailty. Occasionally it can reflect iodine load from CT scan contrast, angiography or amiodarone use.

It is important to measure serum free T3 in this situation, as elevation would mean T3-thyrotoxicosis and we would recommend treatment for that, such as antithyroid drugs or radioiodine. If free T3 is within reference range, and medications are not implicated, then it is sufficient to simply recheck TSH, FT4 and FT3 in three months’ time and then twice each year. Around 50% will spontaneously normalise over time and this is more likely in those with a TSH in the 0.05–0.3 mU/L range than in those with a fully suppressed TSH (<0.05). We would only need to see this patient if she has a goitre, the free T3 or free T4 became elevated, or if she developed a potential complication of hyperthyroidism such as atrial fibrillation (AF) or osteoporosis.

Not relevant to this case, but low TSH with normal FT4 is also frequently seen in the first trimester of pregnancy.

5. High TSH level on levothyroxine

Q: This 23-year-old woman has been on levothyroxine since the age of 20. She is currently taking 250 mcg daily and her recent serum TSH level was 20.4 mU/L (0.3–4.2). Does she warrant clinic review?

A: In individuals taking levothyroxine for primary hypothyroidism, the target TSH is a level in the reference range. In people with a raised TSH, the first thing that should be addressed is concordance, and how the medication is taken. Assuming good concordance, the dose of levothyroxine should be titrated up with repeat TSH measurement every 6 to 8 weeks until within the reference range. Most people need around 1.6 mcg levothyroxine per kilogram of body weight, although some people will need more to achieve biochemical euthyroidism.

Erratic historical TSH results give a clue to a compliance problem. People on levothyroxine should be educated to take levothyroxine on an empty stomach, with water, then wait at least 30 minutes before having food, drink or other medications. Iron and calcium supplements, proton pump inhibitors and antacids in particular interfere with the absorption of levothyroxine, so it should be taken well away from these.

Autoimmune conditions commonly co-exist and if TSH is persistently elevated, coeliac disease and pernicious anaemia/atrophic gastritis should be excluded with tissue transglutaminase and gastric parietal cell or intrinsic factor antibody tests.

Levothyroxine can be taken at any time of day. If the patient misses a dose one day, it is safe to take a double dose of levothyroxine the next day to ‘catch up’. Otherwise healthy people who really struggle to take tablets daily can take a large weekly dose of levothyroxine, but this should be avoided in those with ischaemic heart disease or AF.

6. High LH level

Q: A colleague in reproductive medicine checked an LH level in this 35-year-old woman who suffers with health anxiety and is concerned about her prospects for fertility, and the level has come back at 57 iu/L. She has regular periods at the moment but the result came through to her on the NHS App and she is now very concerned that she is menopausal.

A: Individuals with regular periods are likely to be ovulating and therefore, from a hormone perspective, they should be reassured that their fertility prospects are likely to be normal. LH levels vary hugely across the menstrual cycle. In an individual with regular periods, a one-off high LH level is likely to indicate an LH surge related to ovulation.

Ovulation and ovarian reserve could be checked with a day 21 progesterone and measurement of antimullerian hormone (AMH), respectively, but this is not necessary unless she has failed to conceive.

7. Interpretation of serum cortisol levels

Q: This 24-year-old woman came to see us complaining of feeling tired all the time. We checked her morning cortisol level and it was high at 820 nmol/L. TSH was 2.9 mU/L. What further investigations are needed?

A: A 9 am cortisol is used to screen for adrenal insufficiency in people with relevant symptoms. It is important to have a low threshold for considering this diagnosis as it is inevitably fatal if unrecognised. The symptoms of adrenal insufficiency are often insidious with weight loss being almost invariable; fatigue, malaise, nausea, skin pigmentation and light-headedness on standing are among other common features.

In the above scenario, the clinical concern was adrenal insufficiency and this has been effectively excluded. High serum cortisol levels can be seen in people who are stressed or anxious. Women who are on the combined contraceptive pill or who are pregnant are also expected to have high morning cortisol levels due to induction of serum cortisol-binding globulin. This does not require further investigation.

Serum cortisol levels need to be interpreted in the context of steroid medication (oral, inhaled, topical or injected) and opiate use. 9 am serum cortisol levels over 300 nmol/L effectively exclude adrenal insufficiency, whereas levels less than 150 nmol/L could indicate adrenal insufficiency and need urgent referral or discussion with endocrinology (depending on how the patient is feeling, and exogenous steroid use).

Morning cortisol levels between 150–299 nmol/L are a grey area and it is worth repeating the level once or twice, but if cortisol is persistently at these levels consider referral for synacthen testing. In addition, hyponatraemia would indicate a high likelihood of adrenal insufficiency and warrants immediate referral in this situation.

8. U2 thyroid nodules

Q: This 64-year-old woman complained of a persistent sore neck, so a neck ultrasound scan was requested. This has highlighted two ‘U2’ thyroid nodules in the left lobe of the thyroid. These are 1 cm and 1.5 cm in size. Her TSH is normal. Do these nodules require any follow up?

A: A ‘U2’ thyroid nodule is a nodule that has confidently benign sonographic appearances. All individuals with thyroid nodules should have a TSH checked to ensure that they are biochemically euthyroid, and thyrotoxic patients should be referred to endocrinology for review. In someone who is euthyroid and has an asymptomatic, incidental U2 thyroid nodule on scan, no further investigations or management are needed. Red flags requiring urgent referral of a thyroid lump are stridor or breathlessness, persistent hoarseness of the voice, dysphagia with a large goitre or recent rapid growth in a palpable nodule. People with these symptoms should be referred to a neck lump clinic, usually via ENT.

9. Thyroiditis on ultrasound scan

Q: This 43-year-old woman had a neck ultrasound performed for left-sided lymphadenopathy that has since resolved. The scan reported a diffusely enlarged thyroid with a heterogeneous echotexture consistent with thyroiditis. Only small reactive lymph nodes were seen on scan. Does this need further investigation?

A: Hashimoto (autoimmune) thyroiditis may present with positive thyroid peroxidase (TPO) antibodies or heterogeneous echotexture on ultrasound scan, many years before hypothyroidism is apparent. This patient should have serum TSH checked and assuming this is normal, will simply need an annual TSH check. The eventual risk of hypothyroidism is around 50% after 20 years follow up.

Measuring TPO antibodies once would not be unreasonable to confirm the diagnosis, but there is no value in checking TPO serially.

10. Hypoglycaemia in the non-diabetic patient

Q: This 34-year-old woman is using a continuous glucose monitoring (CGM) device and intermittent fasting to lose weight. She has noticed that her sugar level can drop as low as 3.1 mmol/L at times associated with a feeling of shakiness, weakness and hunger. If she has a snack, these symptoms go away. Reviewing her levels, she has also noted a couple of low levels overnight (down to 2.9 mmol/L). She is not diabetic and she does not take any regular medications. Please see her to investigate spontaneous hypoglycaemia.

A: CGM use in people without diabetes is growing in the private sector but is not evidence-based. Hypoglycaemic symptoms associated with a plasma glucose ≤2.5 mmol/L in someone without diabetes raise a suspicion of spontaneous hypoglycaemia. Manifestations include both sympathetic (eg sweating, shakiness) and neuroglycopenic symptoms (eg, confusion, aggression, seizures, change of consciousness).

To warrant investigation for spontaneous hypoglycaemia, patients must fulfil Whipple’s triad, namely symptoms and/or signs consistent with hypoglycaemia, a low plasma glucose concentration (usually 2.5 mmol/L or less), and resolution of those symptoms after eating.

In healthy individuals who are not on oral hypoglycaemic agents or insulin, it is common to see glucose levels in the high 2s or low 3s and this is not pathological. It is normal to feel a bit shaky and hungry on fasting, and recovery following food does not signify pathological hypoglycaemia.

We would only want to investigate this patient if her glucose levels dropped to <2.5 mmol/L associated with clear neuroglycopenic symptoms as listed above.

Dr Anna Mitchell and Professor Simon Pearce are consultant endocrinologists at Newcastle upon Tyne NHS Hospitals Trust and Newcastle University