Prolactinomas

Neuroendocrine regulation of prolactin secretion

Dopamine traverses the hypophyseal portal system from the hypothalamus to the anterior pituitary, where it binds the dopamine 2 receptor (D2R) and blocks prolactin secretion.

Suprasellar and infundibular lesions involving the stalk and pharmacological agents with antagonist activity at the D2R can result in an increase in prolactin secretion.

By contrast, thyrotrophin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) from the hypothalamus stimulate prolactin secretion in the pituitary, as does oestrogen.

Prolactin is systemically cleared by the kidney, so chronic kidney insufficiency can cause elevated serum levels of prolactin.

Clinical Presentation

Gonadal Dysfunction:

Symptoms include loss of libido, infertility, and erectile dysfunction in men, or new-onset menstrual irregularities and amenorrhoea in women.
In children and adolescents, delayed puberty or secondary amenorrhoea are key indicators.
Additionally, patients with suspected long-standing hypogonadism (more than six months) should be evaluated for bone mineral density changes using DXA scans.

Galactorrhoea:

The presence of breast milk secretion outside of pregnancy or lactation should prompt investigation, though its absence does not rule out the condition.

Imaging Findings:

The discovery of a sellar mass on an MRI or CT scan performed for other reasons necessitates an evaluation for hyperprolactinaemia.

Investigation

Diagnostic algorithm for prolactinoma.

Clinical signs and symptoms of hyperprolactinaemia, laboratory findings of hypogonadotrophic hypogonadism or sellar mass on MRI should all trigger evaluation of prolactin.

If moderately elevated blood levels are observed (≤200 ng/ml), diagnoses other than prolactinoma should be considered. Equivocal or questionable results inconsistent with clinical findings should prompt further investigation related to diagnostic procedures.

If prolactin levels are >200 ng/ml, prolactinoma is more probable than other diagnoses.

Imaging results inconsistent with clinical findings should prompt investigation for non-prolactinoma stalk effect, or high-dose hook effect. ULN, upper limit of normal.

Biochemical

Testing

Blood samples for prolactin should be obtained mid morning (i.e., not soon after awakening)

Not after stress, breast stimulation, or physical examination, which may increase PRL levels

Repeat testing

is recommended if levels are less than five times the upper limit of normal (ULN)
Cannulated sampling should be used if stress-induced elevation is suspected.
Clinicians must also exclude other causes such as medication use, primary hypothyroidism, renal insufficiency, and pregnancy.

Hormonal Screening

Patients should be screened for other pituitary hormone deficiencies (GH, TSH, and ACTH), particularly if they have macroadenomas.

Ruling Out Assay Artefacts

“Prolactin level > 200ng/ml”:

Indicates a very high prolactin level that exceeds the upper limits of the assay.
Call the lab and ask them to determine the actual value.

This usually requires the lab to run serial dilutions until the PRL is in a range that their assay can quantify (they may be able to do it with the specimen they have, or else the patient will need to have another blood draw).
The reasons this is important: treatment decisions:

PRL> 500 usually indicates that surgery alone will not be able to normalize the PRL
To assess response to treatment: it is essential to know what PRL level you are starting with to determine response to medication, surgery, XRT…

Macroprolactinaemia:

A situation where prolactin molecules polymerize and bind to immunoglobulins → Prolactin in this form has reduced biological activity but produced a laboratory finding of hyperprolactinemia.
This should be checked using polyethylene glycol (PEG) precipitation if clinical or imaging findings are discordant with results.
Clinical significance is controversial;
Asymptomatic patients usually do not require treatment

Hook Effect:

Extremely high PRL levels may overwhelm the assay (the large numbers of PRL molecules prevent the formation of the necessary PRL-antibody-signal complexes for radioimmunoassay) and produce falsely low results.
Therefore, for large (Giant) adenomas with a normal PRL level and a high clinical suspicion of hyperprolactinemia, have the lab perform several dilutions of the serum sample and re-run the PRL

The sample should be re-measured after a 1:100 dilution to prevent a false-low reading caused by antibody saturation.

Variations in secretion

Daily fluctuations can be as high as 30%
PRL levels should be rechecked if there is a reason to question a specific result

Intrinsic inaccuracies of radioimmunoassay

PRL levels should be rechecked if there is a reason to question a specific result

Heterophilic antibodies (seen in individuals routinely exposed to animal serum products) can cause anomalous results

Ruling out non-Tumorous Causes that can cause elevated prolactin

Physiological:

Pregnancy (the most common reason), lactation, exercise, and sleep.

Pathological:

Primary hypothyroidism, chronic renal insufficiency, and liver failure.

Pharmacological:

A rigorous review of medications is necessary, particularly dopamine antagonists (antipsychotics, metoclopramide) and certain antidepressants, which can cause significant elevations.

Stalk Effect:

Moderate elevations (usually less than six times ULN) can be caused by any sellar mass compressing the pituitary stalk, which disrupts the normal flow of dopamine (the prolactin inhibitor) from the hypothalamus to the pituitary.
PRL is the only pituitary hormone primarily under inhibitory regulation
Injury to or compression of the hypothalamus or pituitary stalk from surgery or compression by any type of tumour can cause modest elevation of PRL due to decrease in prolactin inhibitory factor (PIF).
There is no Class I evidence to support a threshold to distinguish between stalk effect and a prolactinoma.

Mean PRL in non-functioning pituitary adenomas was 39 ng/ml, with a majority of patients with stalk effect having PRL< 200ng/ ml.
Rule of thumb: the percent chance of an elevated PRL being due to a prolactinoma is equal to one half the PRL level.

Persistent post-op PRL elevation may occur even with total tumour removal as a result of stalk injury (usually ≤ 90ng/ml; stalk effect doubtful if PRL> 150).
For stalk effect, follow these patients, do not use bromocriptine
Differentiating stalk effect from prolactinoma

A TRH stimulation test can be used as stalk compression shows a normal prolactin rise with TRH, whereas patients with prolactinomas do not

Significance of prolactin levelsᵃ

PRL (ng/ml)	Interpretation	Situations observed in
3–30ᵇ	Normal	Non-pregnant female
10–400	Normal	Pregnancy (see)
2–20	Normal	Postmenopausal female
25ᵇ–150	Moderate elevation	- Prolactinoma - "Stalk effect" - Other causesᵈ
>150ᶜ	Significant elevation	Prolactinomaᵈ

ᵃ Ectopic sites of prolactin secretion have rarely been reported (e.g. in a teratoma)
ᵇ Normal values vary, use your lab’s reference range
ᶜ Some authors recommend 200 ng/ml as the cutoff for probable prolactinomas
ᵈ For differential diagnosis of hyperprolactinemia, see

Imaging

MRI with dynamic gadolinium-based contrast is the gold standard for initial diagnosis.

Prolactinoma size typically correlates with serum prolactin levels;

Any discrepancy should trigger investigation into assay artefacts like the hook effect (requiring sample dilution) or macroprolactinaemia.

Classification:

Microprolactinomas (<10 mm)
Macroprolactinomas (≥10 mm)
Giant prolactinomas (>40 mm)

Prolactin level correlates with size of prolactinomas:

1-550 mU/L is normal
If PRL is < 200ng/ml, ≈ 80% of tumours are microadenomas, and 76% of these will have normal PRL after surgery;
If PRL> 200, only ≈ 20% are microadenomas

Correlation:

Generally, the size of the pituitary adenoma correlates with the degree of prolactin elevation;
A significant discrepancy (e.g., a large mass with low prolactin) should trigger a search for the hook effect or reconsidering a "stalk effect" diagnosis.

Medical Management

Dopamine agonists (DAs)

General

First-line Treatment

Surgery can be beneficial, however as second-line following the failure or complication of dopamine agonist treatment. (Visual deterioration, Apoplexy, or lack of response to DA).

Specifically cabergoline, are the preferred primary therapy due to their high efficacy and long half-life.

Effective at

Lowering prolactin

Shrinking tumours

Improving clinical symptoms.

Dosing

Treatment often starts with low doses, escalating slowly to improve tolerability.

Options

Bromocriptine

Bind to dopamine receptors (D1 + D2) in lactotrophs → inhibit release of Prolactin + dec. lactotrophs cell growth and division → reduce prolactin levels + shrink tumour

Pregnancy issues:

Dopamine agonist

Can inc. fertility by removal prolactin suppression on GnRH
Can cause 3.3% congenital anomalies and 11% spontaneous abortion

Pregnancy → elevates oestrogen levels → sti. hyperplasia of lactotrophs → risk of tumour size inc.

Microadenomas <3%
Macroadenomas 30%

Surgery should be done <6months of starting

Prolong use causes fibrosis
Using drug > 1 yr reduce surgical cure by 50%

Dose

1.25mg PO ON → increase by 2.5mg per day based on prolactin levels
Check prolactin levels

Every 4 wks. microadenoma
Every 4 days for macroadenoma

Cabergoline

Selective D2 dopamine agonist

Better than bromocriptine

Controlling prolactin levels
H/A + GI symptoms better

Take care if have

Compulsive gambling and sexual
Cardiac valve disease

Because cabergoline can activate 5-HT2B receptors that induces myofibroblast to cause valvular fibroplasia
This is seen in Parkinson treatment as doses used are 10x for adenomas

Eclampsia/pre-eclampsia
Uncontrolled HTN
Mental disease

Has compulsive gambling and sexual

Dose

0.25mg PO 2x/week → inc. 0.25mg every 4 weeks based on prolactin levels

Outcome

Response rate

Use for 4 yrs

< 2 yrs: 95% recurrence rate

Prolactin levels (ng/ml)	Recommendation
<20	Maintain
20-50	Reassess dose
>50	Consider surgery

Dopamine Agonists are highly effective and the recommended first-line treatment in the majority of cases.

The efficacy of dopamine agonist therapy in adult giant prolactinomas: results of data synthesis

Data Item	Cases Included in Analysis	Result
Patient Age	474	39.1 years
Sex	413	83.3% Male (344), 16.7% Female (69)
Tumour maximal diameter (mm) (pre-treatment)	273	55.2 mm
Average decrease in tumour diameter (%)	264	80.1%
VFD improvement rate (%)	280	71.1%
Average prolactinaemia (pre-treatment)	334	6979 ng/ml
Average prolactinaemia (post-treatment)	317	433 ng/ml
Average percentage reduction (post-treatment)	334	94.6%

Side effects

Headache

Fatigue

Orthostatic hypotension with dizziness

Peripheral vasodilation

Night mares

Should stop using is develop psychosis and vasospasm

Neuropsychiatric Monitoring:

Patients and their families must be warned about potential impulse control disorders, such as compulsive gambling or hypersexuality, which may require dose adjustment or discontinuation.

Cardiac Screening:

For patients on high-dose (>2.0 mg per week) or long-term cabergoline, baseline and periodic echocardiography are suggested to monitor for rare cardiac valve changes.

Treatment Withdrawal

Withdrawal of dopamine agonist therapy can be considered if a patient has had normal prolactin levels for at least two years and a substantial reduction in tumour size.

Approximately 20% of patients remain in remission after discontinuation, though they require lifelong annual prolactin monitoring.

Monitoring and Follow-up

Imaging Frequency:

For macroprolactinomas, a follow-up MRI is typically performed 3–6 months after starting DA therapy.
For stable microprolactinomas, serial imaging beyond one year is often unnecessary unless prolactin levels rise.

Hormone Replacement:

If hypogonadism persists for more than six months despite normalised prolactin, sex hormone replacement therapy (HRT) or testosterone should be considered.

Bone Health:

Patients with long-standing hypogonadism should be evaluated for changes in bone mineral density using DXA scans.

Surgical Intervention

Transsphenoidal surgery (TSS) is an alternative first-line option

Indications:

Microprolactinomas and well-encapsulated macroprolactinomas

When performed by an expert neurosurgeon.

Intolerant or resistant to DAs
Rapidly progressive vision loss or apoplexy
Soft indication

Cystic prolactinoma

Pros

Can prevent having medication for life

Cons:

If the lesion is not central and small cure rate is low

Outcomes:

Surgery offers a high chance of immediate cure (up to 93% for microprolactinomas) and may be preferred by young women to avoid decades of medical therapy.

Special Situations

Pregnancy: DAs are generally discontinued once pregnancy is confirmed to limit fetal exposure. Patients with macroprolactinomas require monthly clinical follow-ups and visual field checks every three months, as they are at higher risk for tumour expansion during pregnancy.
Aggressive Prolactinomas: For tumours resistant to standard doses and surgery, options include dose escalation, radiation therapy, or the chemotherapeutic agent temozolomide.
Cystic Lesions: These may still respond to DAs, though they often require differentiation from non-functioning cystic lesions causing a "stalk effect".

Differential diagnosis of elevated prolactin (PRL) level (hyperprolactinemia)ᵃ

Pregnancy-related

During pregnancyᵇ: 10–400 ng/ml
Postpartum: PRL decreases ≈ 50% (to ≈ 100 ng/ml) in the first week postpartum, usually back to normal in 3 weeks
In the lactating female: suckling increases PRL (critical for lactogenesis; once initiated, nonpregnant PRL levels can maintain lactation)
First 2–3 months postpartum: basal PRL = 40–50 ng/ml, suckling → increases ×10–20. 3–6 months postpartum: basal PRL levels become normal/slightly elevated, and double with suckling. PRL should normalize by 6 months after weaning

Pituitary adenoma

Prolactinoma: larger prolactin microadenomas and macroadenomas usually produce PRL >100 ng/ml
Stalk effect: rule of thumb, the percent chance of an elevated PRL being due to a prolactinoma is equal to one half the PRL level
Some tumors secrete both PRL and GH

Drugs: dopamine receptor antagonists (e.g., phenothiazines, metoclopramide), oral contraceptives (estrogens), tricyclic antidepressants, verapamil, H2 antagonists (e.g., ranitidine), some SSRIs (esp. paroxetine)

Primary hypothyroidism: TRH, a prolactin releasing factor (PRF), will be elevated

Empty sella syndrome

Transient elevations in human serum prolactin (HSP): occur following 80% of generalized motor, 45% of complex partial, and only 15% of simple partial seizures. Peak levels reached in 15–20 minutes, gradually return to baseline over the subsequent hour

Breast or chest-wall trauma/surgery: usually ≤50 ng/ml

Excessive exercise: usually ≤50 ng/ml

Stress: in some cases, stress of having blood test is enough to elevate PRL, anorexia nervosa

Ectopic secretion: reported in renal cell/hepatocellular tumors, uterine fibroids, lymphomas

Infiltrating hypothalamic tumors

Renal failure

Cirrhosis

Macroprolactinemia

Notes:

ᵃ Hyperprolactinemia from causes other than prolactinomas rarely exceeds 200 ng/ml
ᵇ Always rule out pregnancy as a cause of amenorrhea & hyperprolactinemia in a female with reproductive potential