Hyperprolactinaemia
additional info:
- Serum prolactin should only be measured in patients with a pituitary mass or the clinical symptoms and signs of hyperprolactinaemia.
- Hyperprolactinaemia can cause galactorrhoea and impair reproductive function.
- Most prolactinomas are microprolactinomas.
- They usually do not grow sufficiently to cause hypopituitarism or visual field loss.
- Patients with a prolactinoma are usually successfully treated with a dopamine agonist such as cabergoline.
Physiology
- Prolactin is a Protein synthesized and secreted by Lactotrophs (acidophil cells) in the anterior pituitary
- Stimulation (releasing factors)
- Vasoactive intestinal polypeptide (VIP)
- Thyroid Releasing Hormone (TRH, short-term factor only)
- Estrogen
- Inhibition
- Hypothalamic Dopamine (Prolactin Inhibiting Factor or PIF)
- Stimulation (releasing factors)
- Prolactin Effects
- Prolactin increases with infant Breast Feeding
- Increases with each Breast Feeding episode
- Prolactin levels gradually level off after the first few months of regularly Breast Feeding
- Prolactin decreases to normal within 1-2 months of stopping Breast Feeding
- Prolactin stimulates milk secretion into the Breast alveoli in pregnancy and Lactation
- Oxytocin stimulates myoepithelial cells to contract, expressing Breast Milk from the nipple
- Prolactin response assumes prior Breast development
- Breast ducts, fat and stroma develop with Estrogen exposure
- Breast glands, alveoli and secretory tissues develop with Progesterone exposure
Causes of hyperprolactinaemia
| Examples | |
|---|---|
| Physiological (transient hyperprolactinaemia) – These increases are transient, and usually do not exceed twice the upper limit of normal reference ranges. | Pregnancy Lactation Exercise Coitus Chest wall/nipple stimulation Stress Seizure |
| Macroprolactinaemia – arises when immunoglobulins in serum bind prolactin to create high-molecular-weight forms of prolactin. – As clearance of these macroprolactin molecules is slower than monomeric prolactin, the serum prolactin concentration increases. – Macroprolactin is largely biologically inactive, so most patients with macroprolactinaemia are asymptomatic. | Immunoglobulin (IgG) binding prolactin |
| Hypothalamic/ pituitary lesions | Prolactinoma Non-functioning masses: – adenoma – craniopharyngioma – meningioma – Rathke’s cleft cyst Inflammatory/infiltrative lesions: – lymphocytic hypophysitis – Langerhan’s cell histiocytosis |
| Other illness | Hypothyroidism Chronic renal failure |
| Drugs | Antipsychotics (risperidone, amisulpride, paliperidone, haloperidol) Antiemetics (metoclopramide, domperidone) SSRI Opioids Oestrogens Antihypertensives (verapamil) |
COCP-associated galactorrhoea
- Literature from the 1980s suggest that 10–19% of women on a COCP experience galactorrhoea, with up to 30% experiencing hyperprolactinaemia.
- Some studies showed that COCPs use can increase serum prolactin levels, while some studies did not show any effect on prolactin levels.
- Galactorrhoea is usually seen in COCPs containing high oestrogen doses (35 μg), and is most apparent in the week of the placebo pills.
- In recent newer contraceptives with lower oestrogen doses, this is rarely observed.
- The proposed mechanism is the stimulatory effect of oestrogen and progesterone on prolactin secretion and the oestrogen-induced proliferation of lactotroph in the anterior pituitary gland.
Clinical features of hyperprolactinaemia
| Women | Men | |
|---|---|---|
| Breast | Galactorrhoea | Gynaecomastia Galactorrhoea |
| Reproductive | Oligo-amenorrhoea Infertility Osteopenia/osteoporosis | Erectile dysfunction Infertility Osteopenia/osteoporosis |
Confirm Hyperprolactinemia
- single raised prolactin level should always be repeated.
- A difficult venepuncture can cause a false-positive result;
- should be measured after fasting, but can be measured at any time of the day
- Macroprolactinaemia should be excluded, especially in asymptomatic patients.
- Evaluate for Physiologic Cause
- History
- Breast stimulation or Lactation
- Sexual Intercourse temporally related to lab test
- Excessive Eating, Exercise, Sleep or Stress
- Labs
- Thyroid Stimulating Hormone (Hypothyroidism)
- In primary hypothyroidism, such as Hashimoto’s thyroiditis, there is an increase in serum TRH levels, which stimulates hyperprolactinaemia, as well as TSH secretion.
- Reduced metabolic clearance in patients is also believed to contribute to high serum prolactin levels.
- Therefore, it is always good practice to correct abnormalities in thyroid biochemistry in women with galactorrhoea to see if symptoms resolve.
- Urine Pregnancy Test
- Comprehensive Metabolic Panel (Electrolytes, Serum Creatinine, hepatic panel)
- Evaluate for liver disease and renal disease
- Consider reproductive Hormone levels if Hypogonadism is present
- Serum Estrogen
- Serum Testosterone
- Follicle Stimulating Hormone
- Luteinizing Hormone
- Thyroid Stimulating Hormone (Hypothyroidism)
- MRI of the pituitary
- pituitary mass more than 1 cm in diameter should have investigations assessing other pituitary hormones and have visual field testing.
- bone mineral density
- in hypogonadal patients.
- History
Management
- Some patients do not require treatment.
- Patients with physiological hyperprolactinaemia, macroprolactinaemia, asymptomatic microprolactinoma or drug-induced hyperprolactinaemia usually do not require treatment.
- If hyperprolactinaemia is secondary to hypothyroidism, treating the patient with thyroxine should normalise prolactin.
Drug-induced hyperprolactinaemia
- In patients with symptomatic drug-induced hyperprolactinaemia the first consideration is whether the drug can be withdrawn, or replaced with an alternative that does not cause hyperprolactinaemia.
- If the risks of stopping the drug are greater than the potential benefits, any hypogonadism can be treated with appropriate sex hormone replacement.
- Symptomatic patients should be treated.
- No strict serum prolactin threshold for treatment; intervention depends on individual risk factors.
- Mild asymptomatic hyperprolactinaemia may not need active intervention but should be monitored, including gonadal hormone levels.
- Moderate to severe hyperprolactinaemia, symptomatic cases, or low gonadal hormones warrant active intervention.
Reducing Antipsychotic Dose
- Prolactin elevation is dose-dependent.
- Lowering the dose may help but carries a risk of relapse, especially in psychotic disorders.
- Switching to another antipsychotic may be more effective than dose reduction (e.g., risperidone-related cases).
Switching to a Prolactin-Sparing Antipsychotic
- Options include quetiapine, clozapine, olanzapine, aripiprazole.
- Usually restores normal prolactin levels within weeks.
- Consider risks vs. benefits; not ideal for treatment-resistant patients.
- Cross-tapering recommended to prevent relapse.
Addition of Aripiprazole
- A partial dopamine agonist that lowers prolactin levels.
- Effective in up to 79% of cases.
- Usually effective at 5 mg/day, but some may need higher doses.
- Normalisation occurs within 3 months.
- Side effects: Headache, hypersomnia, insomnia.
- Less effective in sulpiride- or amisulpride-induced cases.
- Preferred over dopaminergic agents due to better safety in psychosis.
Addition of a Dopaminergic Agent (Bromocriptine or Cabergoline)
- Typically used for pituitary adenomas but can be considered for antipsychotic-induced cases.
- No clear evidence of worsening psychosis, but case reports exist.
- Cabergoline is preferred over bromocriptine due to better efficacy and tolerability.
- Should be used if aripiprazole fails or in confirmed pituitary adenoma.
- Close liaison with an endocrinologist is advised.
Hormonal Replacement (Oestrogen/Testosterone)
- Consider in long-term hypogonadism or osteoporosis.
- Should be managed by a specialist.
Prolactinoma
- Common cause of hyperprolactinaemia.
- Usually small, benign, and endocrinologically silent.
- Prolactin-secreting adenomas account for 40% of all pituitary tumours.
- Over 90% are small, intrasellar tumours that rarely enlarge.
- Asymptomatic pituitary tumours are highly prevalent:
- 14.4% in autopsy studies.
- 22.5% in radiological studies.
- Endocrinologically Active Pituitary Adenomas
- Associated with very high prolactin levels and related symptoms.
- Prolactin levels >2000 mIU/L suggest a possible pituitary adenoma.
- Prolactin levels >4000 mIU/L strongly indicate a pituitary adenoma.
- Prolactin levels correlate with tumour size.
- Clinical Features of Large Pituitary Adenomas
- Pressure effects on surrounding structures can lead to:
- Headache.
- Visual field defects (e.g., bitemporal hemianopia).
- Diplopia (double vision).
- Pressure effects on surrounding structures can lead to:
- Diagnosis
- MRI scan is the preferred imaging modality.
- Small adenomas can be missed on imaging.
- Treatment
- first-line treatment of a prolactinoma: dopamine agonist
- Cabergoline and Bromocriptine
- recommended in all patients with a macroprolactinoma and most patients with a symptomatic microprolactinoma
- Cabergoline normalises prolactin in up to 95% of patients, reduces tumour size in about 90% and controls symptoms in the majority of patients.
- It can be extremely effective, even in a patient with a giant prolactinom
- first-line treatment of a prolactinoma: dopamine agonist
- Correction of sex hormone deficiency also improves bone mineral density, although bisphosphonate therapy can occasionally be required.
- Thyroid dysfunction–induced hyperprolactinaemia should resolve with thyroxine use.