Hyperprolactinaemia

Introduction

Hyperprolactinaemia occurs when there is an elevated level of prolactin in the blood.¹

It is the most common type of hypothalamic-pituitary dysfunction and it is an important condition to consider in young women with fertility issues or irregular menstruation.²

Normal prolactin levels are generally <400mU/L in males and <500mU/L in females, but specific cut-offs vary between local hospital clinical laboratories.³

Aetiology

Normal physiology

Prolactin is secreted by lactotroph cells in the anterior pituitary gland.²

Prolactin secretion is regulated by the hypothalamus, and this is predominantly under inhibitory control by hypothalamic dopamine.¹ Conversely, thyrotropin-releasing hormone (TRH), serotonin and oestrogens can act to stimulate prolactin release.^2,4

The primary function of prolactin is to stimulate breast tissue proliferation during pregnancy and breast milk production post-partum. Prolactin also inhibits luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion.⁵

Causes of hyperprolactinaemia

There are many different causes of elevated prolactin levels. These can be broadly divided into physiological, drug-related and pathological causes.^1,5

Physiological causes

Physiological causes include stress, sexual intercourse, pregnancy, lactation and exercise.⁶ These increases are usually temporary and do not normally exceed twice the upper limit of normal prolactin levels.⁵

Drug related causes

Numerous medications are associated with elevated prolactin levels. These include antipsychotics (e.g. risperidone, haloperidol), antidepressants (SSRIs, MAO inhibitors and tricyclics) and certain antiemetics (domperidone and metoclopramide).

Verapamil, phenytoin, opioids and oestrogens can also cause hyperprolactinaemia.^4,5

Pathological causes

Prolactinomas are tumours originating from the lactotroph cells of the anterior pituitary gland. They are the most common cause of pathologically elevated prolactin.² Prolactinomas can be microprolactinomas (<10mm size) or macroprolactinomas (>10mm size).^{1, 5}

Other masses of the pituitary gland or hypothalamus can cause hyperprolactinaemia due to compression of the pituitary stalk. These include meningiomas, craniopharyngiomas or a growth hormone-secreting pituitary adenoma, causing acromegaly.⁴

Several other disorders are known to cause hyperprolactinaemia. These include chronic kidney disease, cirrhosis, polycystic ovarian disease, hypothyroidism, and sarcoidosis.^2,6 Epileptic seizures may also cause a transient hyperprolactinaemia.⁵

Clinical features

History

Typical symptoms associated with hyperprolactinaemia include:^1,2

• Symptoms due to the direct effects of raised prolactin: amenorrhoea, oligomenorrhoea, infertility, galactorrhoea, reduced libido, erectile dysfunction in men.
• Symptoms due to tumour (usually macroprolactinomas): headache, visual disturbances +/- other pituitary deficiencies or excess (e.g. growth hormone co-secretion)

Other important areas to cover in the history include:

• Obstetric history: current or recent pregnancy; history of infertility
• Menstrual history
• History of hypothyroidism, renal or liver disease
• Drug history: to identify any drugs that may cause hyperprolactinaemia
• Family history: about 20% of patients with multiple endocrine neoplasia type 1 (MEN1) have prolactinomas.¹ Prolactinomas can also occur with familial isolated pituitary adenomas (FIPA).²

Clinical examination

Typical clinical findings of hyperprolactinaemia may include:^1,2,5

• Visual field defects: classically bitemporal hemianopia (caused by a pituitary adenoma compressing the optic chiasm)
• Cranial nerve palsies
• Gynaecomastia
• Galactorrhoea
• Clinical signs associated with concomitant dysfunction of other pituitary hormones (e.g. change in appearance and interdental spacing in acromegaly)
• Clinical signs of underlying systemic disorders (e.g. hair loss, bradycardia in hypothyroidism)

Investigations

Laboratory investigations

Relevant laboratory investigations include:¹

• Serum prolactin: to confirm the diagnosis of hyperprolactinaemia
• Pregnancy test: to exclude pregnancy, a common physiological cause of hyperprolactinaemia
• Thyroid function tests: to identify hypothyroidism
• Urea & electrolytes: to identify reduced renal function (chronic kidney disease)
• Pituitary function testing: to assess pituitary function and possible hypopituitarism

Imaging

An MRI pituitary is used to investigate for a pituitary adenoma or hypothalamic mass. 

Management

Not all patients require treatment, but the underlying cause of hyperprolactinaemia should always be addressed if possible.

Physiological and drug related hyperprolactinaemia do not typically require treatment.^{5, 7} In symptomatic drug-related hyperprolactinaemia, stopping the causative drug should be considered.⁶

The main aim of treatment is to normalise prolactin levels, re-establishing normal ovulation in women and normal sexual function and testosterone in men.³

Management of prolactinomas

Medical management

Dopamine agonists are the first line treatment of macroprolactinomas and microprolactinomas.

Dopamine agonists bind to dopamine receptors and are effective inhibitors of prolactin secretion.^1,3,7 These medications lower prolactin levels, shrink tumour size and restore normal gonadal function.

The two most frequently used in practice are cabergoline and bromocriptine. Side effects include nausea, fatigue, dizziness and rarely, mood changes, impulse control disorders, CSF rhinorrhoea, and cardiac valvulopathy.⁷

Surgical management

Transsphenoidal surgery is usually indicated for those patients who are resistant to dopamine agonists or cannot tolerate the side effects. However, the cure rate with surgery for macroprolactinomas is poor at about 30%.^3,4

Radiotherapy

This is sparingly used and reserved for patients with macroprolactinomas not responding to medical or surgical treatment.

Complications

Hypogonadism secondary to hyperprolactinaemia can lead to:⁶

• Infertility and erectile dysfunction
• Osteoporosis: spinal bone density is decreased by roughly 25% in women with hyperprolactinemia

Patients with a pituitary mass causing elevated prolactin may suffer from acute pituitary failure due to haemorrhage or infarction of the pituitary gland (pituitary apoplexy). This is characterised by a sudden onset of neurological symptoms such as headache, visual disturbances and cranial nerve palsies.^1,4

Key points

• Hyperprolactinaemia is defined as an elevated level of prolactin in the blood
• Hyperprolactinaemia can arise from physiological, drug related and pathological causes
• Prolactinomas are the most common pathological cause of hyperprolactinaemia
• Prolactinomas are prolactin-secreting tumours of the pituitary gland
• Clinical features of hyperprolactinaemia include amenorrhoea, galactorrhoea, reduced libido, headache and visual disturbances (when caused by a pituitary tumour)
• Relevant investigations include serum prolactin levels and MRI pituitary
• Dopamine agonists are the first line treatment for prolactinomas
• Transsphenoidal surgery can be considered if medical treatment fails
• Complications include infertility, osteoporosis and pituitary apoplexy

Reviewer

Dr Gabriela Mihai

Clinical Lecturer in Endocrinology at Queen Mary University of London

Editor

Dr Chris Jefferies

References

1. Tidy C. Hyperprolactinaemia and Prolactinoma. Patient.info. Published 2023. Available from: [LINK]
2. Glezer A, Bronstein M. Hyperprolactinemia. Endotext. Published 2022. Available from: [LINK]
3. BMJ Best Practice. Prolactinoma. Published 2022. Available from: [LINK]
4. Owen K, Turner H, Wass J. Oxford Handbook of Endocrinology and Diabetes: Oxford University Press; 2022.
5. Chen AX, Burt MG. Hyperprolactinaemia. Aust Prescr. 2017;40(6):220-4.
6. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273-88.
7. Molitch M, Drummond J, Korbonits M. Prolactinoma Management. Endotext. Published 2022. Available from: [LINK]