Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Describe the pathogenesis and clinical presentation of hyperprolactinemia.

2. Define the steps in diagnostic evaluation of hyperprolactinemia and identify pitfalls in diagnosis.

3. Explain the various pharmacologic and nonpharmacologic management approaches for hyperprolactinemia and management of prolactinomas during pregnancy.

Prolactin is a polypeptide hormone that is synthesized and secreted by lactotroph cells of the anterior pituitary gland. The primary biologic actions of prolactin are milk production, breast growth and development, and inhibition of ovulation. During pregnancy, rising levels of estrogen stimulate lactotroph hyperplasia, leading to increased prolactin secretion. Prolactin stimulates growth of mammary alveoli throughout pregnancy, and transitions to milk production after delivery. Lactotroph hyperplasia typically resolves within several months of parturition. Prolactin also suppresses ovulation by inhibiting the release of gonadotropin-releasing hormone from the hypothalamus. This, in turn, inhibits secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary, which are responsible for ovarian follicular development and ovulation.

Regulation of prolactin secretion is determined by multiple factors. Inhibitory control is primarily governed by dopamine, which is synthesized in the tuberoinfundibular cells of the hypothalamus and delivered to the anterior pituitary via the hypophyseal portal system.¹ In nonpregnant, nonlactating individuals, tonic release of dopamine adequately suppresses prolactin secretion. Alternatively, several factors stimulate prolactin release, including growth factors and neuropeptides. Thyroid hormone deficiency, specifically thyroxine (T₄) deficiency, disrupts the hypothalamic-pituitary-thyroid axis through loss of negative feedback. As a result of this, synthesis of hypothalamic thyrotropin-releasing hormone (TRH) is upregulated, causing increased expression of the PRL gene and increased secretion of prolactin from the anterior pituitary.² Estrogen is another prolactin-releasing factor that stimulates prolactin synthesis and release in a similar manner. This mechanism accounts for the physiologic hyperprolactinemia that occurs in pregnancy. After delivery, prolactin supports and maintains lactation via positive feedback pathways. Suckling during breastfeeding triggers a neural pathway that stimulates milk production.

The vast majority (~85%) of circulating prolactin exists in the monomeric form (23 kDa) and approximately 10% to 15% is found in the dimeric form ("big prolactin," ~50 kDa).^2,3 Macroprolactin ("big-big prolactin") refers to a form of prolactin with very high molecular mass (150-170 kDa). These multimers are largely composed of a prolactin monomer bound to an immunoglobulin G (IgG) autoantibody.⁴ Overall, big prolactin and macroprolactin exhibit lower affinity for prolactin receptors and therefore have significantly lower biologic activity than monomeric prolactin.^3,5

Epidemiology

The prevalence of hyperprolactinemia in the general adult population is very low, around 0.4%. However, the true prevalence is difficult to determine due to the lack of routine screening in addition to patients often being asymptomatic. Hyperprolactinemia can be found in 9% to 15% of women with amenorrhea and over 40% of women with both amenorrhea and galactorrhea.^6-8 Prolactinomas, or lactotroph adenomas, represent the most common cause of hyperprolactinemia in premenopausal women, accounting for approximately 75% of pituitary adenomas in women and 40% of all functioning pituitary adenomas.^9-12 Microadenomas are defined as less than 10 mm in diameter and account for the majority of pituitary tumors. They are much more common in women than in men (roughly 20:1), with the highest prevalence in women between ages 25 and 34 years.^11,13 Conversely, macroadenomas are at least 10 mm in diameter and are more common in men.⁸

Etiology

Physiologic Causes

The various etiologies of hyperprolactinemia can be broadly classified as physiologic, pathologic, or pharmacologic. The primary physiologic causes of significantly elevated serum prolactin levels are pregnancy and breastfeeding. However, mild elevations can be stimulated by eating, emotional or physical stress, exercise, and nipple stimulation. Furthermore, prolactin secretion changes with circadian rhythm; serum levels transiently rise in the evening, peak overnight, and reach a nadir shortly after awakening.²

Pathologic Causes

Pathologic hyperprolactinemia can arise from hypothalamic, pituitary, and systemic disorders. A comprehensive list of causes is summarized in Table 1. As previously mentioned, prolactinomas are the most common pathologic cause of hyperprolactinemia in premenopausal women. Generally, pituitary adenomas are benign and arise sporadically. They are classified by cell of origin (ie, lactotroph, somatotroph, thyrotroph, or gonadotroph) and tumor size, which have significant implications for clinical course and management. Adenomas arise from the monoclonal expansion of anterior pituitary cells and are often accompanied by hypersecretion of trophic hormones. Hormone secretion is determined by the cell of origin: lactotroph adenomas secrete prolactin and somatotroph adenomas secrete growth hormone. According to size classification, microadenomas are less than 10 mm and macroadenomas are 10 mm or more in diameter.

Table 1. Causes of Hyperprolactinemia

The differential diagnosis of a prolactin-secreting pituitary mass is not limited to prolactinomas. Although less common, certain types of growth hormone-secreting adenomas can secrete prolactin in addition to growth hormone.¹¹ Nonfunctioning pituitary adenomas do not secrete hormones but can nonetheless cause hyperprolactinemia by compressing the pituitary stalk, which interrupts dopamine delivery to the anterior pituitary. This effect, known as the "stalk effect," can be observed with any sellar (ie, pituitary) or parasellar mass (eg, Rathke cleft cyst and meningioma) that causes local compression of the pituitary stalk and disrupts dopaminergic inhibition of prolactin secretion.¹⁴ Typically, the associated hyperprolactinemia is mild to moderate (<150 ng/mL).^3,15 Other potential causes that can affect this region include stalk dysfunction from prior radiation therapy and stalk transection from trauma or surgery. Hypothalamic disorders cause hyperprolactinemia by disrupting the dopaminergic neurons themselves and thereby dopamine secretion. Such disorders of the hypothalamus include tumors (eg, craniopharyngioma and metastatic carcinoma) and infiltrative diseases (eg, sarcoidosis).

In addition to hypothalamic and pituitary causes, there are a few key systemic causes of hyperprolactinemia. As previously mentioned, primary hypothyroidism can cause elevated prolactin levels via elevated TRH if left untreated for a prolonged period.^3,15 Patients with chronic renal failure can develop hyperprolactinemia as a result of decreased renal clearance and increased prolactin secretion. Chest wall injuries from trauma, burns, or herpes zoster infection can cause mild elevations in serum prolactin concentrations. Irritation of the chest wall stimulates afferent neural pathways (similar to those involved in breastfeeding and the suckling reflex) that cause neurogenic stimulation of prolactin release.^3,16

Pharmacologic Causes

Several classes of pharmacotherapeutic agents disrupt dopaminergic inhibition of prolactin secretion, either directly or indirectly. Neuroleptic drugs are commonly implicated and antipsychotics are the most common cause of drug-induced hyperprolactinemia. This is seen with both first-generation (eg, haloperidol and fluphenazine) and second-generation (eg, risperidone and paliperidone) antipsychotics that display antagonist activity at dopamine D₂ receptors in the tuberoinfundibular pathway of the hypothalamus.¹⁷ Other classes of medications that can cause hyperprolactinemia, though to a lesser degree, include antiemetics (eg, metoclopramide) and certain antihypertensives (eg, methyldopa and verapamil).¹⁷ Generally, prolactin levels in medication-induced hyperprolactinemia do not exceed 100 ng/mL. However, some drugs, notably risperidone, phenothiazines, and metoclopramide, can be associated with very high levels (>200 ng/mL).¹⁵

Clinical Features

The clinical manifestations of hyperprolactinemia arise from both the direct and indirect effects of prolactin. The essential role of prolactin in lactogenesis is responsible for pathologic milk production that can be seen in patients with hyperprolactinemia. Although characteristic, galactorrhea is not a universal presenting symptom in premenopausal women, and even less common in men.¹⁵ Among patients harboring prolactinomas, galactorrhea can be observed in up to 50% of women and 35% of men.¹¹ Absence of galactorrhea may be attributed to the hypoestrogenic state associated with hyperprolactinemia-induced hypogonadism.³ Estrogen plays a key role in lactogenesis, particularly in priming breast tissue during pregnancy, and is necessary for milk production. Thus, patients with severe hyperprolactinemia causing a high degree of gonadotropin suppression may have insufficient circulating estrogen to produce milk.

More commonly, hyperprolactinemia presents with symptoms of central hypogonadism secondary to inhibition of the hypothalamic-pituitary-gonadal axis. Therefore, disruption of the menstrual cycle manifested as oligomenorrhea or amenorrhea is the most common clinical symptom in premenopausal women. In the long-term, persistently elevated prolactin levels can lead to reduced bone mineral density due to loss of estrogen protection.¹²

Clinical manifestations often correlate with the degree of hyperprolactinemia. Mild elevations in prolactin levels (<50 ng/mL) may only cause subtle luteal phase defects, manifesting as a short luteal phase associated with decreased progesterone secretion by the corpus luteum.^18,19 Moderate elevations (51-100 ng/mL) typically cause oligomenorrhea or amenorrhea, and high elevations (>100 ng/mL) are often associated with symptoms of overt hypogonadism and estrogen deficiency.^12,20

Patients harboring pituitary adenomas exhibit varied clinical features, and this is largely attributed to several important factors, including cell of origin, tumor size, sex, and age. Hormone-secreting pituitary tumors cause distinct clinical syndromes associated with symptoms of excess hormone secretion. As previously mentioned, some growth hormone-secreting tumors cosecrete prolactin. These patients display features of both acromegaly and hyperprolactinemia.¹¹ Conversely, nonfunctioning adenomas do not secrete hormones and are not associated with endocrine symptoms. These patients often present later in the course of the disease after the tumor has grown sufficiently large to create a mass effect, including pituitary stalk compression and disruption of dopaminergic neurons leading to hyperprolactinemia.¹¹

Pituitary macroadenomas commonly present with neurologic symptoms, such as headache and changes in vision. The most common presenting symptoms of pituitary macroadenomas are visual defects, which may include vision loss, diplopia, and impaired depth perception.¹⁰ These symptoms may be insidious, relapsing-remitting, and either unilateral or bilateral. Because the pituitary gland is located inferior to the optic chiasm, chiasmal compression initially causes bitemporal vision loss predominantly affecting the superior quadrants.^11,14 Tumor growth may further damage the optic chiasm and lead to worsening visual symptoms and optic nerve atrophy. Visual field defects may expand to involve the inferior temporal quadrants, resulting in bitemporal hemianopia, and even the nasal fields, which can lead to blindness.¹¹

Diagnosis and Evaluation

Measurement of Prolactin

According to the Endocrine Society and Pituitary Society guidelines, a single measurement of serum prolactin elevated above the upper limit of normal is usually sufficient to establish a diagnosis of hyperprolactinemia, if the sample was obtained without excessive venipuncture stress.^15,21 The normal range of serum prolactin levels varies slightly among men, premenopausal women, and postmenopausal women, and typically levels are marginally higher in women. Laboratories may report different reference intervals for prolactin because these values are determined by and specific to the bioassay. Generally, physiologic prolactin levels do not exceed 25 ng/mL in premenopausal women or 20 ng/mL in postmenopausal women and men. Small elevations can be observed in response to meals, emotional or physical stress, exercise, and nipple stimulation. Furthermore, serum levels transiently rise in the evening and are lowest shortly after awakening.² As such, the Pituitary Society recommends that sampling should ideally be performed in the morning, at least 1 hour after awakening or eating.²¹

Measurement of serum prolactin is obtained with a 2-site sandwich immunoassay that uses 2 antiprolactin antibodies to capture and detect prolactin molecules. This test can occasionally yield a false result in the presence of extremely high levels of prolactin (>5000 ng/mL), a well-documented phenomenon known as the "hook effect."^3,10,16 In this type of immunoassay, the analyte is "sandwiched" between 2 antiprolactin antibodies, one that anchors the molecule to the well and another that generates a signal for detection. When the analyte concentration in the sample greatly exceeds the antibody concentrations, prolactin molecules may completely saturate both antibodies and prevent formation of the heterotrimeric immune complex. This results in artifactually low concentrations (typically <200 ng/mL), when, in fact, prolactin levels are significantly higher. A high index of suspicion is therefore necessary for those with large pituitary adenomas and disproportionally low levels of prolactin. To overcome this potential artifact, the test should be repeated using a 1:100 dilution of the original sample.^10,16

Macroprolactinemia

As previously discussed, multiple forms of prolactin exist. Monomeric or little prolactin (23 kDa) has the highest biologic activity and accounts for the vast majority of circulating prolactin. Big prolactin (dimeric form) and big-big prolactin (macroprolactin) are larger variants that are functionally inactive due to their low bioactivity.⁴ Macroprolactin has a high molecular mass (150-170 kDa) and is usually associated with antiprolactin autoantibodies (largely IgG).⁴ Big-big prolactin contributes to hyperprolactinemia because of slower renal clearance and increased half-life.¹⁶

Macroprolactinemia can be found in up to 40% of patients with hyperprolactinemia and is an important diagnostic consideration that can help avoid misdiagnosis, unnecessary testing, and inappropriate treatment.¹⁶ Macroprolactin exhibits reduced biologic activity yet high immunological reactivity. Most conventional immunoradiometric assays detect macroprolactin but are unable to differentiate it from monomeric prolactin. Therefore, patients with macroprolactinemia often have elevated levels of serum prolactin without the typical symptoms of prolactin excess.^3,10,22,23 The Endocrine Society recommends screening for macroprolactinemia in patients with asymptomatic hyperprolactinemia.¹⁵ Per the Pituitary Society guidelines, screening is reasonable in patients who exhibit moderate hyperprolactinemia, for example in the range of 50 to 100 ng/mL, associated with less typical symptoms.²¹ Detection of macroprolactin is best done by polyethylene glycol precipitation, a process that is efficient, effective, and inexpensive.^15,16

Evaluation

Upon diagnosis of hyperprolactinemia, evaluation should begin with a thorough history, being sure to elicit information about obstetric history, menstrual history, medications, thyroid function, and renal function. Next, a thorough review of systems is crucial for identifying any recent development of characteristic symptoms, particularly headaches and visual changes. Physical examination findings are valuable as well, evaluating for galactorrhea. Visual field defects on neuro-ophthalmology examination, specifically bitemporal hemianopsia, are suggestive of a pituitary mass compressing the optic chiasm.¹¹

In the initial evaluation of symptomatic hyperprolactinemia, both the Endocrine Society and the Pituitary Society recommend first excluding the following nonphysiologic causes: medication use, renal failure, hypothyroidism, and parasellar tumors.^15,21 Therefore, in addition to patient history and clinical findings, laboratory tests should be obtained to assess thyroid, kidney, and liver function.^21,24 Women of reproductive age should also undergo a pregnancy test.^3,11 If the cause of hyperprolactinemia still cannot be ascertained, pituitary imaging with gadolinium-enhanced MRI should be obtained to evaluate for a pituitary mass. Notably, the absence of a visible tumor does not necessarily exclude the presence of a microadenoma.²¹

The presence of a pituitary mass on imaging should be correlated with serum prolactin levels, as there is a strong correlation between tumor size and degree of prolactin secretion observed with prolactinomas. Generally, prolactin levels associated with microprolactinomas do not exceed 200 ng/mL and macroprolactinomas between 1 and 2 cm range from 200 to 1000 ng/mL. However, microprolactinomas can be associated with any serum concentration of prolactin. Levels greater than 200 to 250 ng/mL are strongly indicative of a macroprolactinoma, but are not diagnostic until levels surpass 500 ng/mL.^3,11,15 After eliminating potential artifact caused by the "hook effect," those with macroadenomas and disproportionally low prolactin levels should undergo evaluation for other types of pituitary masses.^2,11 Most often, these are found to be nonfunctioning pituitary macroadenomas, but other secretory pituitary tumors should first be ruled out through further laboratory evaluation. Elevated levels of insulin-like growth factor-1 or plasma corticotropin suggest the presence of a somatotroph or corticotroph adenoma, respectively. Finally, if there is no evidence of a sellar mass on imaging, the diagnosis of idiopathic hyperprolactinemia is made in the absence of an identifiable cause of hyperprolactinemia.

Management

Overview

The indications for treatment of hyperprolactinemia vary and rely on several factors including etiology, clinical presentation, and severity. Dopamine agonist therapy is the first-line approach for most causes of hyperprolactinemia, including prolactinomas and idiopathic hyperprolactinemia. Management of systemic causes of hyperprolactinemia (eg, primary hypothyroidism and chronic renal failure) should focus on treatment of the underlying disorder, as prolactin levels will usually correct once the disorder is adequately treated.

Drug-Induced Hyperprolactinemia

Drug-induced hyperprolactinemia typically resolves after the offending drug is discontinued or, if not feasible, substituted with an alternative medication. After discontinuation, prolactin levels are expected to normalize within 3 to 4 days, at which time a repeat measurement should be obtained to confirm the diagnosis.^15,16,21 This approach can be used for patients in whom medication-induced hyperprolactinemia is suspected; decreased prolactin levels on repeat testing would confirm the diagnosis. Both the Endocrine Society and the Pituitary Society suggest discontinuation or substitution, if safe to do so, for patients experiencing symptoms of prolactin excess.^15,21 However, antipsychotics are the most common cause of drug-induced hyperprolactinemia and often cannot be safely discontinued. Therefore, antipsychotic-induced hyperprolactinemia should be comanaged with the patient's psychiatric care team. Importantly, any changes involving an antipsychotic should be decided in consultation with the treating psychiatrist.

When discontinuation is not an option, patients may be switched to a different medication that poses less risk of hyperprolactinemia. Alternative options for neuroleptic agents may include lower-potency antipsychotics (eg, quetiapine and olanzapine) or aripiprazole, an atypical antipsychotic with both partial agonist and antagonist activity at dopamine receptors (D₂). This unique mechanism allows it to function as both a prolactin-sparing antipsychotic and treatment for hyperprolactinemia.²⁵ There is growing evidence to support the efficacy of adjunctive aripiprazole, particularly in patients taking risperidone.^15,25

If none of the aforementioned options are possible, the Endocrine Society and the Pituitary Society cautiously suggest considering dopamine agonist therapy.^15,21 However, this remains controversial and is probably best avoided in patients with antipsychotic-induced hyperprolactinemia due to the risk of exacerbating existing or underlying psychosis.^12,15

Medical Management of Prolactinomas

The primary goals of therapy for patients with prolactinomas are to normalize prolactin levels, restore normal function of the hypothalamic-pituitary-gonadal axis, and reduce tumor size (for macroadenomas only).³ Macroprolactinomas are almost always an indication for treatment, largely due to concern of compression of or invasion into nearby structures.

The mainstay of treatment is medical management with dopamine agonists. Currently, cabergoline and bromocriptine are the only agents approved for treatment of hyperprolactinemia in the United States, with cabergoline strongly preferred over bromocriptine. Both are ergot alkaloid dopamine agonists. Cabergoline has a longer half-life than bromocriptine due to its higher affinity for dopamine D₂ receptors, allowing for a more convenient dosing regimen. The recommendations for dopamine agonists begin at very low doses and increase gradually to use the lowest effective dose.²⁴ The starting dose is 0.25 mg twice weekly for cabergoline and 1.25 mg once daily for bromocriptine. Both medications are titrated incrementally as tolerated until normoprolactinemia is achieved.¹⁵ Maximum doses typically do not exceed 3 to 3.5 mg weekly for cabergoline and 10 mg daily for bromocriptine.^3,24 Several randomized controlled trials have demonstrated the greater efficacy, less frequent dosing regimen, and more favorable side effect profile of cabergoline compared with bromocriptine.^26,27 Furthermore, cabergoline has been demonstrated to be more effective in terms of normalizing serum prolactin levels, restoring menses and ovulation, and reducing tumor size.^11,27

The most common adverse effects associated with dopamine agonists are nausea, headache, dizziness or vertigo, gastrointestinal disturbances (abdominal pain, dyspepsia, and gastritis), and fatigue.²⁷ Orthostatic hypotension is an uncommon but serious side effect, minimized with careful attention to dosing. Although cabergoline and bromocriptine have similar side effects, severe side effects are less likely with cabergoline, allowing better tolerability.²⁷ Side effects of bromocriptine can be attenuated by dividing the daily dose into 2 or 3 administrations. Alternatively, intravaginal administration of bromocriptine may be effective for those experiencing intractable nausea. Neuropsychiatric symptoms are also a possible side effect of dopamine agonist therapy. These are rare but may include psychotic symptoms, which are much more common in those with history, and disordered impulse control, which is significantly more common in men.²⁸

The time course of response varies, as dopamine agonists display a dose-response relationship. Both agents significantly reduce prolactin levels in the first 2 to 3 weeks of treatment. Serum concentrations within the normal range are typically not achieved until approximately 4 weeks of cabergoline therapy and 6 weeks of bromocriptine therapy.²⁷ Resistance to dopamine agonist treatment is not uncommon, and may be seen in as many as 10% of patients treated with cabergoline and 25% with bromocriptine.²⁷ Although universal criteria have not yet been established, resistance is generally defined as a failure to achieve normal prolactin levels or significant tumor volume reduction using standard doses of dopamine agonists.^15,21 Furthermore, resistance encompasses a spectrum of clinical responses to dopamine agonist therapy; whereas partially resistant individuals may simply require higher than normal effective doses, those with complete resistance may not achieve adequate control even with maximally tolerated doses.^15,29,30 Both the Endocrine Society and Pituitary Society guidelines recommend increasing to maximally tolerated doses before referring patients for neurosurgery.^15,21

Clinical and biochemical follow-up are used to guide dosing adjustments and to ensure an adequate treatment response.^15,21 This includes monitoring serum prolactin levels regularly starting 1 month after treatment and obtaining repeat imaging to visualize tumor shrinkage. Patients with microprolactinomas should have pituitary imaging repeated after 1 year and those with macroprolactinomas after 3 months.^15,21 Earlier imaging is also warranted for those who exhibit new symptoms or an inappropriate treatment response.¹⁵ Visual field assessment should be performed periodically in patients with existing visual defects or macroadenomas who are at risk for chiasmal compression.^15,21 Lastly, any comorbidities should be routinely assessed and managed during this follow-up period as well.¹⁵

The cost of dopamine agonist medication is noteworthy to mention because of its potential impact on a patient's decision. Hyperprolactinemia is often diagnosed in premenopausal women and may require lifelong therapy. Two studies conducted cost-utility analyses that highlighted the massive discrepancy in average treatment costs between bromocriptine and cabergoline in the United States.^31,32 Zygourakis and colleagues³² estimated the average cost for the first year of bromocriptine or cabergoline treatment to be $3935 and $6042, respectively. The true cost discrepancy may be up to 2-fold, although this is determined by several factors such as the dose, response, and overall success of treatment.^31,32

Treatment of microprolactinomas primarily aims to achieve symptom resolution and is therefore largely determined by clinical presentation at the time of diagnosis. For asymptomatic patients, the Endocrine Society suggests not treating with dopamine agonists, given the low likelihood of tumor growth and adverse effects of the medication.^11,15 However, microadenomas causing hypogonadal symptoms or secondary amenorrhea can be treated with either dopamine agonists or oral contraceptives. Oral contraceptives are also an option for hormone replacement therapy in patients at risk for bone loss from long-term antipsychotic-induced hyperprolactinemia.

The management of premenopausal women with microprolactinomas and associated hypogonadism requires careful consideration of the patient's goals of care. If immediate fertility is desired, dopamine agonists should be administered to restore ovulation and infertility. Alternatively, if pregnancy is not desired for a foreseeable period, oral contraceptives can be a safe, effective, and potentially preferable option for treating symptoms of central hypogonadism and estrogen deficiency. Although there are no randomized controlled trials to date comparing these 2 treatments, studies have demonstrated no significant deleterious effect on either tumor growth or prolactin levels with oral contraceptive therapy.^33,34

Withdrawal of Therapy and Follow-Up

The Endocrine Society and Pituitary Society guidelines outline recommendations for withdrawal of dopamine agonist therapy and subsequent follow-up to detect possible recurrence.^15,21 According to the Endocrine Society guidelines, dopamine agonist therapy may be tapered and potentially withdrawn after a minimum treatment period of 2 years, if prolactin levels have remained within the normal range and there is no evidence of residual tumor on imaging.¹⁵ Colao and colleagues³⁵ found that individuals who meet these criteria have the lowest likelihood of recurrence (26%-30%). According to the Pituitary Society guidelines, tapering and discontinuation can be considered in patients who have undergone 3 years of treatment, maintained normoprolactinemia, and achieved significant reduction in tumor size.²¹ Factors that influence recurrence risk include tumor size, prolactin levels at diagnosis, and visible tumor remnants at the time of withdrawal.^35,36 Recurrence most often occurs within the first year, and is more common with macroadenomas than microadenomas. Furthermore, those treated with bromocriptine are more likely to recur compared with those treated with cabergoline.^35,36

After therapy has been tapered and discontinued, close follow-up is essential to identify possible recurrence. The Endocrine Society guidelines recommend measurement of serum prolactin levels every 3 months for the first year followed by yearly measurements.¹⁵ If serum concentrations become elevated again, pituitary imaging should be obtained. Women with microadenomas may be able to discontinue therapy after the onset of menopause; these patients should be monitored periodically for tumor growth with imaging.¹⁵

Surgical Management

Surgery is generally reserved for patients with macroprolactinomas who either fail medical management or are unable to tolerate the adverse effects of dopamine agonist therapy. Other indications for surgical management include cystic pituitary adenomas that are unresponsive to medical therapy and tumors that exhibit significant mass effect.³⁷ Some women with macroprolactinomas do not achieve tumor shrinkage with dopamine agonist therapy or are unable to tolerate the medications. For these patients, both the Endocrine Society and the Pituitary Society recommend counseling and evaluation for surgical intervention before attempting pregnancy.^15,21

The preferred approach for pituitary resection is endoscopic endonasal transsphenoidal surgery with an experienced pituitary neurosurgeon. Several studies have demonstrated a higher risk of recurrence associated with macroadenomas, likely due to incomplete resection.¹¹ The recurrence rate for microadenomas is about 20%, whereas for macroadenomas is closer to 50% or possibly even greater.³⁸ Rarely, patients may fail both medical and surgical therapy, and in these instances, the next step in management would be radiotherapy.

Management in Pregnancy

Both the Endocrine Society and the Pituitary Society recommend that women with prolactinomas discontinue dopamine agonist therapy if they become pregnant.^15,21 Some studies have shown that bromocriptine is likely safe in pregnancy. However, there remains insufficient evidence to justify its continuation throughout gestation, given that bromocriptine readily crosses the placenta and the overall risk of clinically significant tumor growth during pregnancy is low.³⁹

For the general management of pregnant women with prolactinomas, the Endocrine Society and the Pituitary Society recommend against serial prolactin measurements and routine pituitary imaging.^15,21 However, those who develop new symptoms during gestation (eg, new-onset visual changes or persistent headaches) should undergo formal visual field evaluation and a noncontrast MRI of the pituitary region.

Overall, the risk of tumor growth during gestation is determined by adenoma size. Molitch³⁹ found that there was a very low incidence of symptomatic tumor growth for microadenomas (2.7%); comparatively, this was much lower than for macroadenomas (22.9%). Importantly, among women harboring macroprolactinomas, those who underwent surgery or radiation before conception exhibited significantly lower risk compared with those who did not (4.8% vs 22.9%).

Therefore, it may be beneficial for some women with macroprolactinomas to continue dopamine agonist therapy in pregnancy, particularly if there is suprasellar invasion.¹⁵ Per the Endocrine Society guidelines, in women with macroadenomas who have not had surgery or radiation before pregnancy and become pregnant while on dopamine agonist therapy, continued treatment should be considered.¹⁵

Rarely, patients may need to resume dopamine agonist therapy during pregnancy if new symptoms develop that are concerning for tumor enlargement. The Endocrine Society and Pituitary Society guidelines recommend that these patients immediately undergo formal visual field examination and MRI of the pituitary region without gadolinium contrast.^15,21

Conclusion

Hyperprolactinemia is not uncommon among reproductive-age women and can be attributed to various etiologies associated with a spectrum of clinical manifestations. In evaluating patients with hyperprolactinemia, it is important to perform a thorough workup to assess whether the cause is physiologic, pathologic, or pharmacologic in nature. The etiology and diagnosis largely determine treatment (if needed) and future management. When treatment is indicated, medical management can be highly effective and is preferred, although surgery or radiotherapy may be required for some patients.

REFERENCES