Keywords
prolactinoma - hyperprolactinemia - dopamine agonist - pregnancy
Introduction
Prolactin is secreted by the lactotroph cells of the pituitary gland. Its primary
function is the induction and maintenance of lactation in primed breast tissue. Although
not a significant effect, prolactin may also physiologically impact metabolism and
sexual functions.[1] Prolactin secretion is regulated through hypothalamic dopamine inhibition that is
counteracted with stimulatory effects by thyrotropin-releasing hormone (TRH), estrogen,
and breast/chest wall irritation. The prolactin is continuously maintained within
the normal physiologic range; however, it could be transiently elevated beyond the
normal level as a normal physiological response. Pathological elevation of prolactin
is relatively common. Many causes lead to prolactin elevation, with prolactinoma being
a common cause ([Table 1]).[1]
[2]
[3] Prolactinomas are lactotroph adenomas that account for around 40% of all pituitary
tumors. The reported population prevalence varies from 6 to 50 patients per 100,000
population. Generally, prolactinomas are more common in females than males, with a
ratio of 10:1. Most prolactinomas are sporadic, while around 5% are hereditary with
genetic underpinning. Hereditary prolactinomas are frequently encountered in the setting
of familial isolated pituitary adenomas or multiple endocrine neoplasia type 1.[2]
[3]
[4] The prevalence of prolactinoma in the Arab countries is mainly unknown, with very
scarce data. There are global and regional variations in management practices, perhaps
imposed by limited access to resources.[5]
Table 1
Causes of hyperprolactinemia
|
Prolactinomas
|
|
Growth hormone-producing adenoma with prolactin co-secretion
|
|
Hypothalamic dopamine deficiency
|
|
Defective transport mechanisms of dopamine (such as stalk effect, empty sell)
|
|
Lactotrophs insensitivity to dopamine due to medications such as antipsychotics
|
|
Chest wall/nipple trauma
|
|
Chronic kidney disease
|
|
Hypothyroidism
|
|
Polycystic ovarian syndrome
|
|
Idiopathic
|
Prolactinomas are categorized in terms of their size into microprolactinoma if they
measure < 1 cm in their largest diameter. On the contrary, prolactinomas with ≥ 1 cm
diameter are considered macroprolactinomas. Microprolactiniomas account for 90% of
the cases of prolactinomas, while macroprolactinomas represent around 10% of the cases.
Macroprolactinomas with a diameter of more than 4 cm are called giant prolactinomas,
which are relatively rare.[2]
[4]
A different classification of prolactinomas is based on their behavior. Most prolactinomas
are confined to the sella turcica. Less frequently, prolactinomas could be invasive
and aggressive, extending outside the sella turcica borders and invading the surrounding
structures. Generally, prolactinomas are dopamine agonist responsive, but some prolactinomas
might be dopamine agonist resistant. Rarely prolactin-producing tumors could be malignant,
where they could metastasize to local and distant areas in the body.[6]
[7]
[8] This review will discuss clinical presentation, diagnostic approach, and management
of suspected or confirmed prolactinomas.
Clinical Presentation
Patients with prolactinomas present with symptoms related to the high prolactin level
or symptoms associated with the mass effect of the adenoma ([Fig. 1]). Symptoms related to the increased prolactin included galactorrhea, which is reported
in up to 80% of female patients. Galactorrhea and gynecomastia are relatively rare
in males and reported in around 10% of the patients. Other symptoms related to high
prolactin levels are usually secondary to a relative state of hypogonadism. High prolactin
induces a relative hypogonadism state due to its inhibitory effect on the gonadotropin-releasing
hormone (GnRH). This relative hypogonadal state leads to amenorrhea and, more commonly,
oligomenorrhea in up to 90% of patients. In contrast, male patients usually present
with erectile dysfunctions. Both male and female patients could present with infertility
as the sole clinical presentation of hyperprolactinemia-induced hypogonadism. Younger
patients could have pubertal delay if the hyperprolactinemia-induced hypogonadism
starts before puberty. Moreover, prolonged high prolactin-induced hypogonadism could
lead to osteoporosis with fractures.[1]
[2]
[4]
[7]
Fig. 1 Clinical features of hyperprolactinemia/prolactinoma.
Patients with macroprolactinomas could develop symptoms due to the adenoma mass effect.
Headache is the most common symptom in such patients. Visual impairment, typically
bi-temporal hemianopia, could result from optic chiasm compression by the macroadenoma.
If the tumor mass extends to the cavernous sinuses, it may compress the third, fourth,
fifth, and sixth cranial nerves, leading to ophthalmoplegia, which presents with double
vision. Aggressive prolactinomas that invade through the roof of the sphenoid sinus
could present with a CSF leak in the form of rhinorrhea. Rarely, a giant prolactinoma
that extends intracranially compress the cerebral cortex may cause a clinical presentation
similar to stroke and brain tumors such as hemiparesis. Macroprolactinomas could destroy
other pituitary cells, which results in variable degrees of hypopituitarism.[1]
[2]
[4]
[5]
[7]
Diagnostic Evaluation
The diagnosis of prolactinoma starts with the confirmation of hyperprolactinemia suggested
by the patient's clinical presentation. A single measurement of serum prolactin is
usually enough to establish the diagnosis of hyperprolactinemia. However, physiological
causes of transient prolactin elevation should be sought, particularly in patients
with high prolactin but no symptoms.[2]
[4] This is essential because many patients may get referred for evaluation based on
laboratory evidence of prolactin elevation without concerning clinical symptoms. Of
note, the transient physiological elevation of prolactin is usually mild compared
with pathologic causes in general. In such patients, repetition of prolactin level
measurement in a morning fasting sample with no physiologic stimuli of prolactin,
such as sleep disturbance and nipple stimulation, will be necessary.[9]
[10] Moreover, in such patients, special attention should be paid to the possibility
of macroprolactinemia, where the prolactin level is elevated due to multimeric prolactin,
which usually has no clinical consequences. Macroprolactinemiua has been reported
in up to 40% of all patients with hyperprolactinemia without symptoms.[11]
[12] On the contrary, pregnancy is a physiologic cause of significant prolactin elevation
that must be excluded in young females with hyperprolactinemia. Renal and liver impairment
may elevate the prolactin due to subnormal prolactin elimination from the circulation.
Therefore, baseline laboratory works for kidney and liver function is also advisable
in patients with hyperprolactinemia.[2]
[4]
Upon confirmation of persistent pathologic elevation of prolactin, which is usually
at least three times the upper end of the normal range, further investigation is necessary
to establish the cause and assess for possible complications. A baseline blood work,
including a full pituitary panel, is suggested, especially in patients suspected to
harbor macroprolactinoma or large sellar masses that could lead to hypopituitarism.[2]
[4]
[6]
[13] Because prolactinomas are the most common cause of hyperprolactinemia, all patients
with confirmed pathologically high prolactin should undergo a pituitary MRI, preferably
with contrast. If the MRI confirms macroadenoma, formal visual field testing is needed
to evaluate any compression of the optic chiasm ([Fig. 2]).[2]
[4]
Fig. 2 Diagnostic approach to hyperprolactinemia.
There is a correlation between the prolactin level and the prolactinoma size. Patients
with prolactinomas, in general, will usually have prolactin levels more than three
to four times the upper end of the normal range of the assay. On the contrary, pathologic
prolactin elevation due to the stalk effect in the setting of a sellar mass on the
MRI will have persistent prolactin elevation but less than triple or quadruple the
upper end of the assay. The stalk effect results from the interference of a sellar
tumor with dopamine trafficking in the pituitary stalk, leading to loss of inhibition
of prolactin secretion leading to hyperprolactinemia.[14]
[15]
However, in patients with a confirmed sellar mass on MRI and relatively mild prolactin
elevation, special attention must be paid to the possibility of the hook effect. The
hook effect should be suspected when there are specific clinical symptoms of high
prolactin and a macroadenoma on the pituitary MRI. In contrast, the prolactin level
does not match the adenoma size and the clinical presentation.[6] The hook effect is an inherent pitfall of immunoassay when the measured antigen
level is significantly elevated. The very high level of the measured antigen leads
to independent saturation of the trapping and detecting antibodies that interfere
with the needed antigen sandwiching to detect its actual level in correlation to the
test measured signal. Lack of sandwiching effect leads to sudden drop out in the assay
signal and loss of the correlation between the actual measured antigen level and the
test signal. In such patients, the measurement of the prolactin level after sample
dilution is needed and enough to exclude the possibility of the hook effect. Although
the hook effect is rare with newer assays, it should always be kept in mind and excluded
confidently if suspected.[6]
[16]
[17]
Management
Management Strategy
The management of prolactinomas depends mainly on the patient's clinical presentation
and the prolactinoma size. The preferred treatment option for all types of prolactinomas
is medical therapy, in particular with dopamine agonists (DA) ([Fig. 3]).[2]
[4]
[6]
[10]
Fig. 3 Management of prolactinoma.
Patients with hyperprolactinemia due to microprolactinoma do not need treatment if
asymptomatic. Microprolactinomas are confined to the sella turcica and usually do
not cause any complications in terms of mass effect. However, in a symptomatic patient
with microprolactinoma, treatment with a dopamine agonist is indicated to normalize
the prolactin level and improve the patient's symptoms. Alternatively, patients with
amenorrhea or oligomenorrhea due to high prolactin from microprolactinomas could be
treated with oral contraceptive pills as a symptomatic treatment instead of dopamine
agonists.[6]
In contrast, all patients with macroprolactinomas should receive treatment with dopamine
agonists to improve their clinical symptoms from the prolactin elevation and induce
prolactinoma size reduction to prevent complications in terms of mass effect.[2]
[4]
Dopamine Agonist Therapy
The two widely used dopamine agonists are cabergoline and bromocriptine. Bromocriptine
is reported to be effective in up to 80% of patients. In comparison, cabergoline is
effective in up to 90% of the patients in normalizing the prolactin level and tumor
reduction. Moreover, around 70% of patients who were unresponsive to bromocriptine
will usually respond to cabergoline. Therefore, cabergoline is the recommended first-line
therapy in most patients with prolactinoma.[2]
[4]
[6]
[18]
[19]
[20] The usual starting dose of cabergoline is 0.5 mg once weekly with titration every
8 to 12 weeks until the prolactin level normalizes and the prolactinoma size starts
to reduce. Dopamine agonists are generally safe with mild side effects that are usually
tolerable.[4]
Dopamine agonists are usually continued for at least 2 years to induce significant
prolactinoma size reduction or complete tumor resolution. Up to 30% of such patients
will have sustainable long-term normal prolactin levels. Patients with considerable
size reduction or disappearance of the adenoma on the follow-up MRI are more likely
to achieve a sustainable prolactin level normalization after discontinuation of the
dopamine agonists.[2]
[21]
[22]
However, some patients may require long-term treatment. Patients with relapsed hyperprolactinemia
after DA discontinuation should be restarted on dopamine agonist if symptomatic with
the possibility of long-term treatment.[19]
[23] In females, DA could be discontinued safely upon menopause if the adenoma size is
not a concern to cause a mass effect. High prolactin levels in postmenopausal women
are usually of no clinical significance.[24]
[25] However, male patients with persistent symptomatic prolactin elevation likely require
long-term treatment with DA to prevent the hypogonadism state and its complications.[26]
[27]
Role of Surgery
Trans-sphenoidal pituitary surgery (TSS) as a treatment modality for prolactinoma
is rarely required, as most cases respond very well to DA. However, TSS is an option
in patients with resistant prolactinomas or intolerance to DA. Resistant prolactinoma
is defined as failure to achieve normal prolactin level and prolactinoma size reduction
by at least 50% on a maximally tolerated DA dose. Another indication for surgical
treatment of prolactinoma is in patients with acute apoplexy if they have neurological
complications requiring urgent de-compressive surgery.[2]
[4]
[28]
[29]
Challenges in Prolactinoma Management
Managing prolactinoma could be challenging. Giant and invasive prolactinomas present
with severe symptoms that require timely intervention. DA remains the first-line treatment
option in such patients as a significant number of them will show an improvement within
a few weeks of DA initiation. Surgical intervention alone is unlikely to cure such
tumors. Nonetheless, de-compressive debulking surgery could be an option if DA is
ineffective after a few weeks or if the patient's clinical condition requires immediate
surgical intervention. Radiotherapy could be of value in some patients after surgery
as a means of loco-regional control of the tumor.[2]
[4]
[30]
[31] Another challenging prolactinoma subtype is malignant prolactinoma. Albeit rare,
it constitutes a challenging disease as the experience in its management is limited.
Generally, malignant prolactinoma requires a multimodal treatment approach, including
surgery and radiotherapy; chemotherapeutic agents such as temozolomide, tyrosine kinase
inhibitors, and DA.[2]
[4]
[30]
[31] Management of patients with giant, invasive, and malignant prolactinomas is better
at centers of excellence in pituitary tumor management. In such centers, a multidisciplinary
team approach involving experts from different specialties is vital in patients' care.[30]
Management during Pregnancy
Management of prolactinomas during pregnancy requires proper preconception evaluation
and close follow-ups. High estrogen levels during pregnancy usually increase in the
prolactinoma size. However, women with microprolactinomas could conceive safely without
expected complications, as the adenoma size will increase in less than 10% of cases.
In such patients, the DA is usually discontinued upon pregnancy confirmation. Visual
field assessment and MRI evaluation may be needed if the patient develops symptoms
suggestive of mass effect.[2]
[4]
[32]
[33]
In contrast, up to 20% of the women with macroprolactinomas will have significant
size growth of the adenoma during pregnancy. The growth of macroprolactinomas that
extend outside the sella turcica may lead to a substantial mass effect. Generally,
in such patients, it is advisable to delay pregnancy until prolactinoma regresses
in size with DA and becomes confined to the sella turcica. Alternatively, transsphenoidal
surgery could be an option for such patients before they conceive.[2]
[4]
[32]
[33] Patients with intrasellar macroprolactinomas, such as microprolactinomas, could
conceive safely without needing DA. Such patients are followed by visual field testing
every trimester, and a pituitary MRI is to be done if any symptoms suggest a mass
effect from the adenoma. The resumption of DA will be necessary for some patients.
Surgical intervention during pregnancy is reserved for apoplexy or macroadenomas unresponsive
to dopamine agonists ([Fig. 4]).[2]
[4]
[32]
[33]
Fig. 4 Management of prolactinoma during pregnancy.
If for any reason, a patient with macroprolactinoma with extra sellar extension becomes
pregnant without proper planning, then such patients should continue dopamine agonists
during pregnancy. Both cabergoline and bromocriptine are safe, with more robust data
for bromocriptine than cabergoline.[5]
[32]
[34]
Conclusions
Prolactinoma is the most common pituitary tumor. The clinical presentation of prolactinomas
is either due to the high prolactin state or the adenoma mass effect. Diagnosis of
prolactinomas is established with the confirmation of persistent pathologic hyperprolactinemia
and exclusion of other causes of high prolactin levels. Subsequently, a pituitary
MRI is required to characterize the prolactinoma size and extension within the sella
turcica. Further investigation may include visual field assessment and laboratory
investigations for hypopituitarism. Prolactinoma management is mainly medical with
dopamine agonists, as most of these tumors are responsive. Surgical intervention is
rarely required with specific indications. Patients with resistant, invasive, and
malignant prolactinomas achieve better outcomes in specialized institutions and should
be referred to centers with good patients' volume and multidisciplinary teams.
