ABSTRACT

Hyperprolactinemia is the most common hypothalamic-pituitary dysfunction, being an important cause of irregular menses and infertility amongst young women. Clinical and laboratorial investigation is crucial to determine hyperprolactinemia etiology and to indicate the proper treatment. Prolactinoma is the most common cause of pathological hyperprolactinemia, but physiological and pharmacological causes must be ruled out. Macroprolactinemia is a laboratorial pitfall that should be excluded in asymptomatic hyperprolactinemic individuals since treatment is not necessary. Hook effect is another laboratorial pitfall that may underestimate prolactin levels confounding the differential diagnosis between macroprolactinomas and non-functioning pituitary adenomas. Clinical treatment with dopamine agonists (DA) is effective in 80 to 90% of patients with prolactinoma leading to normal serum prolactin levels and tumor reduction. DA are usually well tolerated, nevertheless, valvopathy and psychiatric side effects should be actively evaluated. Normoprolactinemia after DA withdrawal is possible in around 30% of cases. Hypogonadism and infertility are usually reversed upon prolactin levels normalization due to DA treatment, allowing pregnancy in most patients. In micro and intrasellar macroprolactinomas, DA can be withdrawn after pregnancy confirmation. Pregnancy and menopause are associated with prolactinoma remission. Surgical treatment may be indicated in resistant/intolerant patients and symptomatic apoplectic tumors. In patients with non-invasive microadenoma or macroadenoma, surgical management could be offered as the first line treatment, considering high surgical remission. Radiotherapy is rarely performed and must be reserved to control tumor growth in aggressive cases. Temozolomide is an alternative treatment for resistant/aggressive prolactinomas not responding to high doses of dopamine agonists, multiple surgeries, and radiotherapy. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Prolactin secreting pituitary tumors are the most common type of hormone secreting pituitary tumors (1). They are also the only pituitary tumors which can be effectively managed primarily by medical means (2). Therefore, their identification and diagnosis are imperative to avoid unnecessary pituitary surgery.

PROLACTIN SECRETION

Prolactin is secreted by the lactotrophs in the anterior pituitary gland and its secretion is regulated by the hypothalamus. Unlike the other anterior pituitary hormones, the hypothalamic influence is predominantly of tonic inhibition (3).

The hypothalamus secretes prolactin-release-inhibiting factors (PIF) and prolactin-releasing factors (PRF). PIF is predominantly exerted by dopamine, with GABA having a minor role (4). Prolactin controls its own secretion through a short loop of negative feedback, stimulating the tuberoinfundibular dopamine (TIDA) neurons. Nevertheless, the nature of the physiological PRF is unclear. Thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), serotonin, histamine, oxytocin, and estrogens can act as a PRF. Other neurotransmitters and neuropeptides can also modulate prolactin secretion, as endothelin, TGF beta1, angiotensin, somatostatin, substance P, neurotensin, calcitonin, EGF, natriuretic atrial peptide, bombesin, cholecystokinin, acetylcholine, and vasopressin. (5)

CAUSES OF HYPERPROLACTINEMIA

The causes of hyperprolactinemia may be considered, in a simplified fashion, as resulting from four basic abnormalities. In some patients, however, it is not possible to elucidate the cause of hyperprolactinemia (6). Stress from venipuncture can cause a slight increase in serum prolactin levels in asymptomatic individuals and normal serum prolactin measured after resting for 30 minutes can rule out this condition (7). Nevertheless, routinely resting before venipuncture is usually not recommended (8). In addition, prolactin should not be measured after seizure, which could increase hormonal level (6).

Stimulation of Lactotrophs

Hypothyroidism may be associated with hyperprolactinemia, if there is an increase in TRH which can act as a PRL. Ectopic GHRH secretion can also cause hyperprolactinemia, due to stimulation of lactotrophs (11, 12). Estrogens act directly at the pituitary level, causing stimulation of lactotrophs, and thus enhance prolactin secretion. Furthermore, estrogens increase the mitotic activity of lactotrophs, increasing cell numbers. Pregnancy and breastfeeding are physiological causes of hyperprolactinemia (Figure 1). Injury to the chest wall can also lead to hyperprolactinemia. These results from abnormal stimulation of the reflex associated with the rise in prolactin that is seen normally in lactating women during suckling (6).

Figure 1.

Mean prolactin levels throughout pregnancy. High estrogens levels during pregnancy stimulates the lactotrophs leading to hyperprolactinemia. Prolactin levels increase with gestational age. [Adapted from Hu et. Al (13)].

Figure 2.

Mechanism of hyperprolactinemia. Dopamine is the main regulatory factor of lactotrophs and exerts an inhibitory function. When dopamine does not reach the normal lactotrophs (for example, in pituitary stalk effect), hyperprolactinemia occurs. Hyperprolactinemia also occurs due to hyperestrogenism and increased levels of TRH (for example in primary hypothyroidism) (6).

CLINICAL MANIFESTATIONS OF HYPERPROLACTINEMIA

The symptoms associated with hyperprolactinemia may be due to several factors: the direct effects of excess prolactin, such as the induction of galactorrhea or hypogonadism, the effects of the structural lesion causing the disorder (i.e. the pituitary tumor), leading to, for example, headaches, visual field defects, or external ophthalmoplegia; or associated dysfunction of secretion of other anterior pituitary hormones (14).

Galactorrhea is an inconsistent marker of hyperprolactinemia (15). Approximately 50% of women with galactorrhea have normal prolactin and the incidence of galactorrhea in hyperprolactinemic patients is between 30% and 80%. In patients with extremely high prolactin levels and hypogonadism, galactorrhea may not be found, as minimum estrogen levels are necessary for this physical sign to occur. A woman with amenorrhea due to hyperprolactinemia does not develop the breast atrophy seen in postmenopausal women or women with amenorrhea who are gonadotropin-deficient or have primary ovarian failure. On examination, the breast and areola are well developed, and the Montgomery tubercles are hyperplastic. In male patients with hyperprolactinemia, there is usually no gynecomastia, but milk may be expressed from an entirely normal-sized male breast. The incidence of galactorrhea in men with hyperprolactinemia is low, less than 30% (i.e., it is much less common than in women). Nevertheless, the presence of galactorrhea in man with a pituitary mass is an important clinical clue for the presence of hyperprolactinemia and possible prolactinomas (3).

Women with hyperprolactinemia usually present with menstrual abnormalities – amenorrhea or oligomenorrhea – or anovulatory regular cycles. Mildly hyperprolactinemia may cause infertility due to luteal insufficiency, even in women with regular menses (16). Occasionally, patients may present with menorrhagia. Menstrual disorders are often not seen with mild hyperprolactinemia but it is unusual not to have menstrual problems if serum prolactin is greater than 180 ng/mL (3,600 mU/L) (17). In men, testosterone levels are usually low but can occasionally be normal (18)

The pathogenesis of the hypogonadal state in hyperprolactinemia is poorly understood. Results from an animal model study suggest that hyperprolactinemia inhibits gonadotropin-releasing hormone (GnRH) pulsatility by reducing kisspeptin input, considered the major controlling point of reproduction (19). Moreover, kisspeptin administration restored hypothalamic-pituitary-ovarian function in two hyperprolactinemic women (20) .

Suppression of gonadal function results from multiple mechanisms beyond GnRH inhibition via kisspeptin. These include reduced gonadotropin secretion due to impaired positive estrogen feedback on luteinizing hormone (LH) secretion in women (21), increased adrenal androgen secretion (22), and direct blockade of gonadotropin action at the gonadal level (23, 24). Additionally, prolactin reduces the normal pulsatility of LH, critical for gonadal function, and may disrupt LH and FSH actions at the gonads by inhibiting progesterone synthesis and stimulating adrenal androgen secretion (21-24).

Men often present clinical manifestations late in the course of the disease with symptoms of expansion of their pituitary tumor (i.e. headaches, visual defects, and external ophthalmoplegia) or symptoms from secondary adrenal or thyroid failure. Nevertheless, these men can usually present sexual impairment for many years before their diagnosis. It is unknown if macroprolactinomas are more commonly seen in men due to these delayed diagnosis and/or if prolactinoma´s pathogenesis is different in men (25). In contrast to women in whom microprolactinomas are most commonly seen, macroprolactinomas are usually found in men and the serum prolactin levels are usually much higher than those in women (26).

Occasionally, hyperprolactinemia may occur in prepubertal or peripubertal children, when it may present with delayed or arrested puberty, headache, visual field defects, or growth arrest. Children and adolescents often present with larger and more aggressive prolactinomas, especially in boys (27). In this population, there is a high prevalence of genetic abnormalities in lactotroph tumors, therefore a recent consensus for pituitary adenomas in children and adolescents recommends offering genetic testing to all pediatric patients to inform management and family surveillance (28). MEN1 and AIP mutations should be screened, as the most prevalent genetic conditions in this population are MEN 1 and FIPA (29). More rarely, mutations in the genes CKDN1B, MAX, and SDHx variants could be seen.

Persistent hyperprolactinemia could negatively impact skeletal health, not only because of the hypogonadism. In vitro studies suggest that prolactin excess acts in the osteoblast increasing the expression of RANKL and reducing osteoprotegerin (30, 31). In animal models, prolactin influences bone physiology by three different mechanisms: increasing intestinal calcium absorption, by a direct effect on bone cells, and through hypogonadism (32). Both men and women with prolactinoma can present with persistent impaired bone mineral density (BMD), despite long-term control of hyperprolactinemia and hypogonadism (33).Therefore, it has been suggested that all patients with prolactinoma should be submitted to a bone health evaluation at diagnosis with DXA scan, morphometric vertebral fracture (VF) assessment, and 25 (OH) vitamin D levels. In patients with controlled hyperprolactinemia and without bone impairment at baseline, DXA scan should be performed every 18-24 months. If patients remains with an uncontrolled prolactinoma and presented at baseline with osteopenia/osteoporosis or VFs, the follow up with bone health assessment should be more frequent, every 12-18 months, including DXA morphometry and 25 (OH) vitamin D measurements (34).

DIFFERENTIAL DIAGNOSIS

It is important to exclude other causes of hyperprolactinemia: pregnancy, lactation, hypothyroidism, use of drugs that either deplete central dopamine or block dopamine receptors, and renal and hepatic failure. Ruling out these important causes, and any hypothalamic lesion, three common diagnostic possibilities remain: the presence of microadenoma, macroadenoma or no visible tumor at all. If patients do not harbor an identifiable tumor, they are described as having idiopathic hyperprolactinemia. It is likely, however, that patients with this condition may harbor small microprolactinomas, which were undetected with less sensitive imaging tools used in the past, and even with magnetic resonance imaging (MRI) (3). Figure 5 presents a diagnostic flowchart for hyperprolactinemia.

A microadenoma is described as having a maximum diameter of up to 10mm (the maximal diameter of the normal pituitary gland) while a macroadenoma has a diameter larger than 10 mm. Giant adenomas are defined as the presence of the largest diameter of the tumor being larger than 4 cm (35). A microadenoma is often visualized using MRI. Usually, the serum prolactin level is below 200 ng/mL (4000 mU/L) in patients with microadenomas. A macroadenoma that secretes prolactin is usually associated with a serum prolactin level of more than 200 ng/mL (4000 mU/L). If the patient has a macroadenoma and a serum prolactin level of less than 200 ng/mL (4000mU/L), consideration should be given to the possibility that a nonfunctioning pituitary adenoma is present, and the hyperprolactinemia is a result from the deprivation of some lactotrophs of dopaminergic inhibition (3). However, a laboratory artifact may lead to a mistaken differential diagnosis between macroprolactinomas and nonfunctioning pituitary adenomas. When prolactin is evaluated by two-site immunometric assays, large amounts of prolactin saturate both the capture and the signal antibodies, impairing their binding, causing serum prolactin to be underestimated (the so-called “high-dose hook effect”). Therefore, patients bearing macroprolactinomas, usually > 4cm in the maximal diameter, with extremely high serum prolactin levels (generally >1,000 ng/mL [>180,000 mU/L]) may present with falsely low levels, e.g. 30-120 ng/mL (600-2,400 mU/L) range, causing the patient to be misdiagnosed as harboring a nonfunctioning pituitary adenoma. In order to avoid unnecessary surgery (treatment of choice for non-functioning tumors), prolactin assays with serum dilution are recommended in patients with macroadenomas who may harbor a prolactinoma (36). Recent assays do not manifest the hook effect at PRL concentrations as high as 14,750 ng/mL (around 295,000 mIU/L) (37).

Figure 3.

Hook effect. In the left image, usual antigen concentrations leading to regular assay dose-response. In the right image, very high antigen concentrations saturate capture and signal antibody, leading to falsely low signal and prolactin level (38).

An additional condition that interferes in the parallelism of serum PRL concentrations and prolactinoma dimensions is cystic prolactinomas, defined if 45% of lesion are the predominantly cystic sellar lesions (>50% of the volume being cystic) (39). In these lesions, serum prolactin levels are lower, but usually greater than 94 ng/mL. Differential diagnosis is important to determine the correct therapeutic intervention and includes Rathke’s cleft cysts, non-prolactin secreting cystic adenomas, craniopharyngiomas, and arachnoid cysts (40).

Another laboratory pitfall concerns the presence of high serum prolactin levels in subjects with few or no symptoms related to prolactin excess. Human prolactin circulates as monomeric prolactin and in larger forms, which are indistinguishable by routine assays. Monomeric prolactin is the most common form, but serum prolactin can be elevated due to the presence of aggregates with low biological activity, such as big-big prolactin, leading to so-called macroprolactinemia. The presence of molecular aggregates with low biological activity, macroprolactin, should be suspected when high serum prolactin levels are detected in patients without or with few signs and symptoms related to hyperprolactinemia. Precipitation with polyethylene glycol (PEG) is an excellent screening method. Chromatography confirms the presence of macroprolactin but is an expensive and time-consuming method; it is performed only when PEG precipitation results are inconclusive. Macroprolactinemia is a common finding, present in almost 20% of the samples with hyperprolactinemia (41). Big-big prolactin biological activity is still controversial in the literature (42). Studies in vitro with rat Nb2 cells bioassays show either the presence or the absence of biological activity. In two studies with cell cultures expressing the human PRL receptor, macroprolactin did not show biological activity (43, 44). Most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia, and do not need any treatment. Therefore, to avoid unnecessary medical or even surgical procedures, macroprolactin screening is important to consider when clinical features and serum prolactin assay results are not consonant with one another (45). Moreover, standardization of monomeric prolactin levels after PEG precipitation is crucial to evaluate conditions that could be associated with macroprolactinemia, as prolactinomas. Therefore, monomeric prolactin levels point to real hyperprolactinemia, even in the presence of macroprolactinemia (46, 47).

Figure 4.

Total serum of prolactin levels includes all forms of prolactin (macroprolactin, dimeric prolactin, and monomeric prolactin). When macroprolactinemia is suspected, polyethylene glycol (PEG) can be used to precipitate macroprolactin and enable the evaluation of monomeric prolactin in the supernatant serum (47).

Figure 5.

A flowchart for the diagnosis of hyperprolactinemia. In the presence of galactorrhea, loss of libido, infertility, menstrual cycle abnormality, erectile disfunction or hypogonadotropic hypogonadism, serum prolactin level should be evaluated. If hyperprolactinemia is confirmed, systemic diseases, physiological, and pharmacological causes of hyperprolactinemia should be excluded. After that, a sellar MRI should be performed.

For detailed information on pituitary imaging see the Endotext chapter entitled “Radiology of the Pituitary” (48).

The anatomy of the pituitary is optimally assessed by contrast-enhanced MRI. MRI allows imaging of the optic chiasm, the cavernous sinuses, the pituitary (both the normal gland and tumors), and its stalk. In addition, aneurysms of the carotid are immediately obvious. Thus, MRI allows accurate measurement of the size of the pituitary and of any tumor and its relationship to the optic chiasm and cavernous sinuses. Cisternal herniation is also readily seen. If MRI is not available, CT scanning is also helpful, but the resolution is worse, and it is less satisfactory for delineating the relationship of the diaphragm sellae with the optic chiasm (49).

Figure 6.

Differential diagnosis of hyperprolactinemia (50). (A) A patient with IgG4-related hypophysitis and hyperprolactinemia due to stalk pituitary effect. Serum PRL 56.1 (< 19.4) ng/mL. Sellar MRI sagittal T1 weighted without contrast showed a thickened pituitary stalk and the absence of the neurohypophysis signal. (B) A patient with a giant aneurysm (12x11x12mm) of the left internal carotid artery, depicted at a sellar MRI coronal T2 weighted (B-1) and at an arteriography (B-2) Serum PRL 68.2 (5.2-26.5) ng/mL. (C) A woman with galactorrhea, amenorrhea, serum PRL 151 (5.2-26.5) ng/mL and visual complains. Sellar MRI coronal T1 weighted after contrast showed a macroadenoma with suprasellar expansion on the left and cavernous sinus invasion on the right. Diagnosis of a non-functioning pituitary adenoma was confirmed after surgery.

TREATMENT OF HYPERPROLACTINEMIA

Therapeutic strategy must consider several aspects, such as the patient’s clinical presentation, the differences between microadenomas and macroadenomas concerning their natural history, the desire for pregnancy, and the patient’s treatment preference, if applicable. Medical treatment with DA drugs is highly effective at lowering serum levels of prolactin and reducing adenoma size in both microprolactinomas and macroprolactinomas. Traditionally, pituitary surgery, usually by the transsphenoidal approach, is discussed in detail in the Endotext chapter entitled “Surgical Treatment of Pituitary Adenomas” (51)) and is generally reserved for prolactinomas resistant to DA drugs. Nevertheless, recent international guidelines for management of prolactinomas discuss surgical resection of microprolactinomas and well-circumscribed macroprolactinomas as primary treatment, especially in young women (45). Pituitary macroadenoma parasellar invasiveness is usually evaluated in MRI by Knosp classification, grades 0 and 1 considered non-invasive (52). This recommendation considers cost-effectiveness, avoiding long-term DA treatment and the availability of a dedicated neurosurgeon. A meta-analysis published in 2020 found that 36% of microprolactinomas presented disease remission after DA withdrawal and 83% after surgery (53). For patients with macroprolactinomas, surgical remission was 60%, inferior to medical treatment (77%) (53), but the remission rate differs depending on the invasiveness of the adenoma. A retrospective cohort study of 78 cases found late remission rates of 64.9% in patients with Knosp 0/2, compared to 47.1% and 25% in patients with Knosp 3 and 4, respectively (54). Therefore, DA is still the first line treatment for invasive macroprolactinomas and giant prolactinomas, but surgery could be an option for those non-invasive prolactinomas and, a dedicated neurosurgeon and patients’ preference. If the initial treatment with surgery is chosen, there is no indication for pre-treatment with DA. Transsphenoidal approach is also indicated to correct significant side effects of DA treatment such as cerebral spinal fluid leakage, apoplexy, and optic chiasm herniation (45).

For children and young people under 19 years of age, cabergoline is the first line treatment. Surgery should be offered if the patient is intolerant or resistant to high dose cabergoline or if the patient develops deteriorating vision on cabergoline (55).

Radiotherapy for prolactinomas generally brings poor results, especially regarding normoprolactinemia restoration, and is currently reserved only for macroadenomas refractory both to medical and surgical treatment (3).

Dopamine Agonist Drug Therapy

The first DA ergot compound to be used in clinical practice was bromocriptine, a peptide ergot. It was introduced in the early 1970s in Europe, and thus there is more than 40 years of experience using such compounds in the treatment of hyperprolactinemia. Bromocriptine has the advantage of having a long duration of action compared to dopamine itself or oral compounds such a levo-dopa (56).

Bromocriptine has a similar mode of action to dopamine in stimulating dopamine receptors on the prolactin-secreting pituitary cells – D2 receptors. Stimulation of these receptors leads to inhibition of both prolactin secretion and synthesis. Subsequently a variety of other compounds have been developed which are useful additions. These include quinagolide and cabergoline (3).

Cabergoline has an extremely long biological half-life and thus, generally only needs to be administered either once or twice per week, with a weekly dose of 0.5 to 2.0 mg. In addition to its long biological half-life, cabergoline is generally better tolerated than bromocriptine, increasing the patient’s adherence. Therefore, cabergoline is currently considered the first-choice drug for the treatment of prolactinomas. In a study comparing bromocriptine (2.5 to 5.0 mg twice daily) to cabergoline (0.5 to 1.0 mg twice weekly) in 459 hyperprolactinemic women with amenorrhea, stable normoprolactinemia was achieved in 83% of patients on cabergoline and in 59% patients on bromocriptine (57). Ovulatory cycles or pregnancy occurred in 72% of cases on cabergoline and in 52% of cases on bromocriptine. Drug withdrawal due to adverse effects was reported in 3% of cases on cabergoline and in 12% of cases on bromocriptine. Regarding tumor size, a decrease in at least 50% was obtained in 64% of patients on bromocriptine and in 93% of patients on cabergoline (Figure 7). This important beneficial effect of DA treatment can rapidly relieve mass effect symptoms such as visual impairment, without the need for surgical decompression (Figure 8) (57). Doses higher than 2 mg per week of cabergoline may be used in cases with partial response (58).

In men, cabergoline treatment can reverse hypogonadotropic hypogonadism in about 50-65% of the cases (59, 60). Higher baseline testosterone, prolactin normalization, smaller initial tumor size, absence of cystic components, absence of visual field or ACTH deficits at diagnosis are related to the ability of the gonadal axis to recover (61). Constantinescu et al found that testosterone levels <213 ng/dL at 6 months was the best independent predictor of persistent hypogonadism at one year (60), reinforcing the Pituitary consensus that recommends testosterone replacement in men with ongoing hypogonadism despite dopamine agonist therapy for more than 6 months (45).

Figure 7.

A 32 yrs-old female patient with hyperprolactinemia (PRL 80 ng/mL), irregular menses and galactorrhea had a sellar MR showing a pituitary lesion of 0.8 cm on maximal diameter (A). After cabergoline introduction (0.5 mg/week), PRL levels normalized, paralleled with menses restoration and remission of galactorrhea. Tumoral dimensions reduction are shown: tumoral maximal diameter of 0.6 cm after two years of treatment (B) and no lesion visualization after seven years on cabergoline (C) (57).

Figure 8.

A 28 yrs-old man with headache, erectile disfunction, visual loss, and hyperprolactinemia. At diagnosis prolactin level was 4808 ng/mL (< 19.4 ng/mL) and a sellar MRI, coronal T1-weighted after contrast, depicted a macroadenoma, measuring 39x31 mm, with suprasellar expansion and the optic chiasma was not identified (A-1). Visual field demonstrated residual vision in the upper nasal field in the left eye and temporal hemianopsia in the right eye (A-2). 48 hours after cabergoline 0.5 mg, prolactin levels dropped to 591.6 ng/mL and three weeks later, on 1.5 mg/week, there was visual improvement confirmed by a visual field (B-2). Sellar MRI showed a reduction in tumor dimensions: 29x24 mm. The suprasellar expansion diminished and the optic chiasma was abutted (B-1). Prolactin levels were lower (90.4 ng/mL). After two years of clinical treatment, neuroophthalmological evaluation was completely not visible anymore in sellar MRI ©.

SIDE EFFECTS

Side effects of DA therapy usually occur at the start of treatment and frequently disappear with continued therapy. If treatment is started with full doses or increased too quickly, dizziness, nausea, and postural hypotension may occur. To avoid such effects, DA must always be taken during a meal. Administration should be started at night, with a snack, when the patient retires to bed. Doses can be gradually increased afterwards (62).

Cabergoline and pergolide were associated with a higher risk of cardiac valvopathy in patients with Parkinson’s disease. These DA also have an agonist effect on serotonin receptor 5HT2B, present in fibroblast of cardiac valves and chordae tendineae. Fibroblast’s proliferation occurs after this receptor activation, leading to valve insufficiency, especially of tricuspid and pulmonary valves. This proposed mechanism was already described in carcinoid syndrome. Nevertheless, the mean cabergoline dose for Parkinson’s patients is 3 mg a day, much higher than the usual dose for hyperprolactinemia. Stiles et al in 2018 published a meta-analysis including 836 cabergoline-treated hyperprolactinemic patients and 1388 healthy controls from 13 published studies and there was an increase in tricuspid regurgitation; however, no patient had clinical symptoms due to tricuspid disease (63). Although moderate and severe tricuspid regurgitation was heavily influenced by data from one center (64), data from meta-analysis could not rule out an effect on cardiac valvular dysfunction of cabergoline used at “endocrine” dosages to treat hyperprolactinemia.

Different guidelines suggest protocols for screening cardiac valve chances. British Society of Echocardiography, the British Heart Valve Society, and the Society for Endocrinology recommend that a standard transthoracic echocardiogram should be performed before a patient starts DA therapy for hyperprolactinemia, repeating this exam at 5 years after starting cabergoline in patients taking a total weekly dose less than or equal to 2 mg, or annually if the dose is greater than 2 mg a week (65). More recently, in the Pituitary Society consensus, many participants believed that it was not necessary for such a close follow up, and proposed repeating an echocardiography every 2-3 years in patients treated with > 2.0 mg/week, 5-6 years if ≤ 2.0 mg/week, and if the treatment dose is < 1.0 mg/week, repeat examinations are not necessary (45).

Regarding pergolide, it was withdrawn from the market. Quinagolide, the only non-ergot derived DA, is only available in Europe.

Impulse control disorders (ICD) have been associated with DA treatment, due to dopamine receptor type 3 activation, even in patients with no previous psychiatric disorder. The DA dose is not predictive of ICD risk and should be actively evaluated (66). Some of the common behaviors in ICD are hypersexuality, compulsive buying, gambling, and punding (repetitive, purposeless behavior, often involving mechanical or compulsive tasks, like sorting, collecting, or disassembling objects) (67). In five series of cases, summing up 543 patients with prolactinoma, ICD frequency varied from 8 to 61%, being hypersexuality the most common and associated with male gender (67). Prolactin-mediated hypogonadism is another risk factor for hypersexuality in men, possibly by rapid increase in testosterone levels, after prolactin normalization (67). DA withdrawn or dosage decrease led to an improvement of psychiatric symptoms. The patient must be evaluated by psychiatry and DA treatment should be reevaluated on an individualized basis (68).

CAN DOPAMINE AGONIST DRUGS BE WITHDRAWN WITHOUT RECURRENCE OF HYPERPROLACTINEMIA?

One of the drawbacks of medical treatment of prolactinomas is the need for long-term therapy in most of the cases. As a matter of fact, treatment with bromocriptine and other DA drugs generally is considered as “symptomatic” since DA discontinuation often leads to recurrence of hyperprolactinemia and to tumor regrowth in most patients at least after short-term use.

Nevertheless, remission and normoprolactinemia after DA withdrawal can occur, especially after long-term treatment. Four meta-analyses, published between 2010 and 2022, reviewed patients treated with cabergoline and bromocriptine (69-72). The recurrence rates after DA withdrawal varied from 25-100%, this great variability may be in part explained by the heterogeneity of the studies and population. The patients with higher chance for remission were those treated for a time greater than 2 years, that used cabergoline over bromocriptine, had lower dose of cabergoline at withdrawal and had significant reduction in tumor size (at least 50%). Recurrence after DA withdrawal is usually not associated with tumor growth and not necessarily needs to be treated, especially if the elevation is not accompanied by hypogonadism (73). A second attempt to DA withdrawal, after additional 24 months of treatment was also described, with lower rates of success (74).

Although the exact mechanism of prolactinomas remission is not completely understood, it could also be linked to the natural history of the disease. Periodic withdrawal of DA is recommended, especially in cases with normal serum prolactin levels and tumor reduction. Prolactinoma remission is also described after pregnancy and menopause. It is suggested that estrogen-induced necrosis could lead to decreased tumor size and PRL decrease after delivery (3). Regarding menopause, the remission rate in a series with 99 patients was 73% (75). The possible mechanism underlying the remission is still not clear, but the reduction in estrogen levels and a subsequent decrease in prolactin production may play an important role.

Prolactinomas Resistant to Dopamine Agonists

About 15% of patients with prolactinomas are resistant to DA therapy. The Pituitary Society Consensus defined resistance as lack of normalization of prolactin serum levels or lack of relevant mass shrinkage (≥30% reduction in maximum diameter) when treated with standard dopamine agonist doses (7,5-10mg per day of bromocriptine or 2.0 mg per week of cabergoline) for at least 6 months (45). A refractory prolactinoma is an adenoma not controlled even by dose escalation to maximally tolerated doses of DA. The main resistant mechanism is reduction of D2R tumor expression (76, 77), although D2R polymorphism (78, 79) and low filamin A (80) expression could also be implied. If a patient has been responsive and then becomes unresponsive, a pituitary carcinoma should be ruled out. The approach to the resistant prolactinoma includes escalation to maximally tolerated cabergoline dose and if necessary complementary approaches such as pituitary surgery, radiotherapy, and drugs such as temozolomide (81). Pituitary surgery, usually by transsphenoidal approach, aims for complete tumor removal or at least a vast debulking, which may lead to serum prolactin normalization with DA reintroduction in partially resistant cases.

Radiotherapy is indicated in aggressive cases not controlled by surgery or drugs (82). The alkylating agent temozolomide has proven efficacy in aggressive pituitary adenomas and carcinomas, mainly the prolactin secreting ones. Complete and partial response was obtained in 56% of 32 cases reviewed in literature (81). Figure 9 illustrates sellar MR of a young man with an invasive/aggressive macroprolactinoma, resistant do dopamine agonist, multiple surgeries, and radiotherapy.

Other therapies reported in case series or single reports were pasireotide, lapatinib, and tamoxifen (83). More recently, inhibitory checkpoint immunity (ICI) drugs appear to be an alternative for those cases resistant to temozolomide, especially carcinomas (84). Different treatment protocols have been employed, the most frequent involving initial combination therapy with ipilimumab (CTLA4- inhibitor) and nivolumab (PD-1 inhibitor). An observational cohort study analyzed 6 cases of functioning lactotroph tumors treated with ICI and a favorable response was observed in two patients (partial response and stable disease), whereas the other 4 underwent a further increase in prolactin levels and radiological progression of the disease (85). So far, no markers have been proved to be good predictors for treatment response (86).

Figure 9.

26 yrs-old man complaining of visual disturbance was submitted to a sellar MRI (A): sellar mass with 5 cm in the maximal diameter with supra, infra and left parasellar invasion. Serum PRL levels were above 1000 ng/mL. After one year on cabergoline, 0.5 mg/day, there was no tumor reduction and PRL levels were around 800 ng/mL. He was then submitted to transsphenoidal surgery and radiotherapy in another medical service. Sellar MRI (B) two months after the surgery showed a pituitary mass with 3.1 cm in the maximal diameter. Despite chiasmal decompression, visual dysfunction was not reversed, and during his follow-up, anterior pituitary function was lost. PRL levels on cabergoline, 1.5 mg/week, were 250 ng/mL. After two more years, sellar MRI depicted a lesion of 2.9 cm. in the maximal diameter (C). There was a progressive rise of PRL levels despite increased cabergoline doses (0.5 mg/d) and another sellar MRI (D), after two years, depicted a lesion of 3.1 cm in the maximal diameter. Another surgery was indicated.

CONCLUSION

Dopamine-agonist therapy for hyperprolactinemia leads to a reversal of the hyperprolactinemic hypogonadal state without risk of the development of pituitary insufficiency, thus allowing pregnancy in former infertile patients. Dopamine-agonist therapy is effective not only in patients with microadenomas but also in most patients with large prolactin-secreting tumors in reducing tumor size. Moreover, drug withdrawal after long-term treatment is possible in almost 30% of cases, especially after pregnancy and menopause. Surgery, radiotherapy, and antiblastic drugs, such as temozolomide, should be reserved for resistant/aggressive cases.

ACKNOWLEDGEMENTS

We respectfully acknowledge the invaluable contributions of Dr. Marcello D. Bronstein, a distinguished neuroendocrinologist whose enduring legacy is reflected in his extensive authorship of numerous manuscripts and book chapters, and whose impact continues to shape our work.

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