Acidophil Stem Cell Adenoma

Exceptionally hyperprolactinemic patients might exhibit mild or no clinical features of acromegaly associated with biochemical evidence of slight serum GH elevation. This situation is due to the presence of the rare and aggressive acidophil stem cell pituitary adenoma.³⁴ The acidophilia is attributable to mitochondrial accumulation called oncocytic change. Immunohistochemical analysis is positive for PRL, and occasionally there is a scant positivity for GH. The definitive diagnosis requires electron microscopy, which depicts enlarged mitochondria. Scattered cells containing juxtanuclear fibrous bodies are similar to cells of sparsely granulated somatotroph adenomas. Misplaced exocytosis is present. The secretory granules are sparse and small, measuring 150 to 200 nm.

Nontumoral Lesions Associated With Hyperprolactinemia

Many nontumoral conditions can be mistaken for prolactinomas. Thyrotroph hyperplasia is associated with primary hypothyroidism due to loss of feedback (Fig. 11-3).³⁵ The correct diagnosis is important because this condition regresses with thyroid hormone replacement.³⁵ Idiopathic lactotroph hyperplasia is a rare cause of hyperprolactinemia that mistakenly can be taken for an expanding macroprolactinoma. The pituitary mass shape can help in the differential diagnosis. Inflammatory lesions such as lymphocytic hypophysitis (occurring mainly during pregnancy and puerperium) and sarcoidosis can be misdiagnosed as lactotroph adenoma.^36,37

Pituitary Prolactin-Secreting Carcinomas

Pituitary PRL-secreting carcinomas are exceedingly rare tumors that exhibit morphologic features indistinguishable from those of PRL-secreting adenomas. In addition to local invasiveness, distant intracranial and extracranial metastases in the nervous system and visceral metastases are the clues for the diagnosis of malignancy. Regarding intracranial lesions, sometimes it is difficult to distinguish between contiguity of an invasive prolactinoma and true metastasis from a PRL-secreting carcinoma.³

Physiologic Hyperprolactinemia

Throughout pregnancy, the size of a normal pituitary increases up to 136%, according to magnetic resonance imaging (MRI) studies.³⁸ This extensive growth is due to estrogen-induced hypertrophy and hyperplasia of lactotrophs, leading to progressive increase in PRL production and its hypersecretion during pregnancy.³⁹ Placental estrogen production stimulates lactotroph mitosis, PRL mRNA levels, and PRL synthesis, leading to a stepwise increase in serum PRL levels, achieving mean levels of 200 ng/mL at the end of pregnancy and up to 450 ng/mL in some cases. Serum PRL levels decline quickly after delivery but are maintained slightly increased in nursing women several months, especially after breastfeeding. At birth, newborn serum PRL concentrations are elevated nearly 10-fold, probably as a result of the stimulatory effect of maternal estrogen levels.⁴⁰

Because exercise and nonspecific stress are physiologic causes of hyperprolactinemia, there is a concern that the stress-induced PRL increase could lead to hormone elevation during venipuncture, and a period of rest before blood withdrawal is still recommended in many laboratories. A report by Vieira and coworkers,⁴¹ which included a large population, provided evidence that rest before blood collection may be needed in only a few patients.

Pharmacologic Hyperprolactinemia

Among medications that increase serum PRL, dopamine receptor blockers are the most potent. Neuroleptics (e.g., sulpiride, haloperidol, chlorpromazine, risperidone) and antiemetic drugs (e.g., metoclopramide, domperidone) can elevate serum PRL to levels that usually are detected with prolactinomas.⁴² Serotoninergic and antihistaminergic drugs are less potent than antidopaminergic medications. The calcium channel blocker verapamil elevates serum PRL levels probably by decreasing central dopamine generation, possibly through N-type calcium channels.⁴³ It was shown that protease inhibitors used for treatment of acquired immunodeficiency syndrome can cause hyperprolactinemia, but the mechanism is unknown.⁴⁴ A detailed inquiry about drug use is mandatory for all hyperprolactinemic patients.

Pathologic Hyperprolactinemia

Hyperprolactinemia is present in about 40% of acromegalic patients as a result of GH/PRL co-secretion by the same or by different tumor cells or secondary to hypothalamus-pituitary disconnection.⁴⁵ Because of the characteristic features of acromegaly, the differential diagnosis is usually not a problem. As already mentioned, in patients harboring the rare acidophil stem cell pituitary adenoma, serum GH is usually low compared with PRL levels, however, and acromegalic features are usually absent or minimally expressed.³⁴ In some cases, PRL resistance to dopamine agonists can be a clue for the differential diagnosis with prolactinomas.

Hyperprolactinemia secondary to impaired hypothalamic/tuberoinfundibular dopamine secretion or to stalk or even intrapituitary disconnection can be caused by tumors, inflammatory diseases, or trauma. In these cases, PRL is produced by normal lactotrophs and rarely exceeds 150 µg/L. The differential diagnosis of macroprolactinomas is mainly with clinically nonfunctioning pituitary adenomas (pseudoprolactinomas) and, to a lesser extent, with craniopharyngiomas.⁴⁶ Other tumoral lesions, such as meningiomas and chordomas, and nontumoral conditions, such as “empty sella” syndrome and even intrasellar aneurysms, can be associated with hyperprolactinemia, however (Fig. 11-4).⁴⁷ The differential diagnosis between macroprolactinomas and pseudoprolactinomas is crucial regarding their primary treatment—medical for macroprolactinomas and surgical for pseudoprolactinomas. Patients with nonfunctioning tumors treated with dopamine agonists were considered as having resistant macroprolactinomas, owing to the absence of tumor shrinkage even with the (obvious) PRL decrease to very low or undetectable levels (Fig. 11-5).⁴⁸ A clue to differentiate pseudoprolactinomas from true prolactinomas is the dramatic early PRL decrease with bromocriptine doses of 1.25 mg/day.

Primary hypothyroidism can be associated with hyperprolactinemia, presumably due to high thyrotropin-releasing hormone levels that stimulate PRL release and presumably reduce prolactin metabolic clearance. Thyrotroph hyperplasia may occur, leading to pituitary enlargement mimicking a pituitary adenoma (see Fig. 11-3).³⁵ Cushing’s disease and adrenal insufficiency can be associated with hyperprolactinemia, which also can be present in Nelson’s syndrome.^49,50 Polycystic ovary syndrome also may be associated with hyperprolactinemia.⁵¹ Menstrual disturbances are prevalent in patients with polycystic ovary syndrome and in patients with prolactinomas, and sometimes the distinction between the two conditions may be difficult. The presence of mild hyperprolactinemia, negative pituitary imaging, high luteinizing hormone/follicle stimulating–hormone ratio, and clinical features suggestive of polycystic ovary syndrome can help in the differential diagnosis.

Uremia can be associated with hyperprolactinemia, mainly in patients with end-stage renal disease.⁵² The mechanism probably is related to reduced PRL clearance and to a presumably reduced dopaminergic tonus. Serum PRL elevation is mild but can be considerably increased in uremic patients taking drugs with a dopamine receptor–blocking effect. Hyperprolactinemia is present in up to 20% of patients with liver cirrhosis, probably due to an unbalanced estrogen-to-androgen ratio and to an altered dopaminergic tonus.⁵³ Nipple manipulation and chest-wall lesions, such as herpes zoster and surgical scars, may increase serum PRL via stimulation of neuron pathways going through the spinal cord.⁵⁴ In contrast to paraneoplastic adrenocorticotropic hormone (ACTH) secretion, ectopic production of PRL has rarely been described.⁵⁵ Finally, when all the above-mentioned causes are ruled out, hyperprolactinemia is considered idiopathic or functional. It is likely, however, that most patients with this condition harbor small microprolactinomas that went undetected with less-sensitive imaging tools used in the past, such as hypocycloidal polytomography and computed tomography (CT) and even with MRI. If there is no radiologic evidence of a prolactinoma at initial diagnosis of hyperprolactinemia, however, an identifiable adenoma is unlikely to develop in the long-term follow-up.⁵⁶ Nevertheless, a recent study by De Bellis et al.⁵⁷ points out the presence of anti-pituitary antibodies in 25.7% of patients with idiopathic hyperprolactinemia versus 0% in those with microprolactinoma, suggesting an autoimmune etiology for a subset of cases of idiopathic hyperprolactinemia.

Clinical Features

Hyperprolactinemia and its impact on the gonadotropic axis is the hallmark of microprolactinomas and macroprolactinomas and their clinical manifestations. Macroprolactinomas also may cause neurologic and visual disturbances and impairment of other pituitary functions owing to the tumor-mass effect (Table 11-2).⁵⁸ Loss of visual fields and impairment of visual acuity are the main ophthalmologic manifestations. Headache is the most common neurologic presentation; it is attributed to dural stretch or cavernous sinus invasion and less frequently as part of the clinical symptoms of pituitary apoplexy.⁵⁹ There are a few reports of special types of headache, such as the SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) syndrome secondary to prolactinomas, but the role of hyperprolactinemia as causative agent is obscure.⁶⁰ Other rare presentations of invasive macroprolactinomas are hydrocephalus,⁶¹ neuropsychiatric manifestations, and otoneurologic manifestations.^62,63

Women generally present with a correlation between the degree of serum PRL elevation and gonadal impairment, ranging from a short luteal phase to amenorrhea (Fig. 11-6). Most PRL-secreting pituitary adenomas are associated with amenorrhea, because hyperprolactinemia due to prolactinomas usually shows serum PRL levels greater than 100 ng/mL. Because hyperprolactinemia is present in about 20% of women with amenorrhea,⁶⁴ most patients with such menstrual disturbance and high serum PRL levels may harbor a prolactinoma. Because microprolactinomas can be associated with serum PRL levels between 40 and 100 ng/mL, and because PRL biological activity does not always correspond to routine laboratory assay levels,⁶⁵ some women with prolactinomas may exhibit milder forms of gonadotropic impairment such as anovulatory cycles and oligomenorrhea.⁶⁶ In addition to menstrual disturbances, hyperprolactinemic women complain of loss of libido, vaginal dryness, dyspareunia, and psychological distress.⁶⁷ Similar to other disorders associated with hypogonadism, osteoporosis is a frequent finding in women with hyperprolactinemia/prolactinomas, mainly in prolactinomas with long-standing hypogonadism. The relative risk of developing osteoporosis in premenopausal women with prolactinomas can be 4.5%.⁶⁸ Although a direct effect of PRL on bone has been considered, there is evidence that hyperprolactinemia is not a risk factor in itself for the development of osteoporosis, with the associated hypoestrogenism being the major determinant.⁶⁹

Galactorrhea is a frequent finding in women with hyperprolactinemia, but it can be absent, mainly in patients with macroprolactinomas associated with severe hypogonadism. Breast examination, if not adequate, also may fail to disclose mild galactorrhea. These facts may explain the discrepancy among series, which show a prevalence of galactorrhea ranging from 30% to 84%.64,70 Galactorrhea also may occur in normoprolactinemic women. A study including 235 patients with galactorrhea associated with diverse conditions showed that serum PRL was normal in 86% of women with idiopathic galactorrhea without amenorrhea.⁷¹ The mechanism is unknown, being attributed to different causes such as mammary hypersensitivity to PRL or “occult” transient hyperprolactinemia.

Hyperprolactinemia in men is predominantly associated with macroprolactinomas. The main clinical manifestations are hypogonadism, which is usually severe, along with loss of libido and reduced body hair growth, visual impairment, and headache.⁷² Only 22.5% of 80 patients with macroprolactinomas in our series sought medical assistance due to sexual complaints, whereas most patients requested appointments because of visual or neurologic disturbances. During the interview, 85% of the patients admitted, however, that loss of libido was of utmost importance.⁷³ In patients with microprolactinomas (n = 12), sexual dysfunction was the main complaint in 67% of the cases, but that number increased to 92% after the interview.⁷³ Testosterone replacement without serum PRL normalization seldom restores libido, an observation that points to a direct effect of PRL on sexual behavior, as previously suggested by animal models.⁷⁴ Galactorrhea is far less frequent in men than in women with prolactinomas.⁷⁵ It was disclosed in 15% and 25% of our patients with macroprolactinomas and microprolactinomas.⁷³ When present in men harboring pituitary tumors, however, it strongly suggests the presence of a prolactinoma (Fig. 11-7).⁷⁵ Osteoporosis also is present in hyperprolactinemic men.⁷⁶

Although the prevalence of prolactinomas in both genders is higher in the 20s and 30s, prolactinomas can occur in elderly and in younger individuals. Data on 44 young patients (12 males and 32 females, aged 16.3 ± 1.9 years at diagnosis) with pituitary adenomas showed a predominance of macroadenomas (61%) over microadenomas (39%). Of those, prolactinomas were the most prevalent (68% of cases).⁷⁷ Other series on prolactinomas diagnosed in childhood or adolescence showed that the prevalence of macroadenomas was also higher (15 versus 11 cases)⁷⁸ or similar (24 versus 23 cases) compared with microadenomas.⁷⁹ The predominance of larger tumors in children and adolescents points to molecular mechanisms influencing proliferation rather than the time course of the disease influencing the progression of prolactinoma size and invasiveness.

Laboratory Evaluation

Basal serum PRL evaluation usually confirms the clinical suspicion of a prolactinoma. Serum PRL usually ranges from 50 to 300 ng/mL in the presence of microprolactinomas and from 200 to 5000 ng/mL in the presence of macroprolactinomas (normal values range from 2 to 15 ng/mL). Values of 30 ng/mL have been associated with microprolactinomas, however, and values of 35,000 ng/mL have been found in patients harboring large and invasive macroprolactinomas. Stimulation tests with thyrotropin-releasing hormone and metoclopramide or suppression tests using levodopa, previously popular mainly for the differential diagnosis of microprolactinomas and so-called idiopathic hyperprolactinemia, give nonspecific results and have been largely abandoned.⁸⁰

Hyperprolactinemia secondary to hypothalamus-pituitary disconnection rarely exceeds 150 ng/mL, and lesions that mimic macroprolactinomas, especially nonfunctioning pituitary adenomas, generally exhibit serum PRL less than this value (pseudoprolactinomas).⁴⁶ A laboratory artifact may lead to an erroneous differential diagnosis between macroprolactinomas and pseudoprolactinomas, however. When serum PRL is evaluated by two-site immunometric assays, large amounts of antigen—PRL in this case—saturate capture and signal antibodies, impairing their binding and causing serum PRL to be underestimated (the so-called high-dose hook effect). Patients bearing macroprolactinomas with extremely high serum PRL levels (generally >10,000 ng/mL, depending on the assay measuring range) may present with falsely lower levels, within the 30 to 150 ng/mL range, causing the patient to be misdiagnosed as harboring a nonfunctioning pituitary adenoma. To avoid unnecessary surgeries (treatment of choice for nonfunctioning tumors), PRL assays with serum dilution or using two-step incubation are recommended in patients with macroadenomas who may harbor a prolactinoma.⁸¹

If such assays are not readily available, clinical clues pointing to prolactinomas are patient age younger than 50 years, presence of galactorrhea in male patients, and tumor shrinkage under dopamine agonist drugs, as shown by fast visual improvement in cases with chiasmal compression or rapid tumor reduction evidenced by MRI.⁷⁵

Another laboratory pitfall concerns the presence of high serum PRL levels in subjects with few or no symptoms related to PRL excess. Human PRL in circulation manifests as marked size heterogeneity, with three forms (23 kD, 50 kD, and 150 to 170 kD) that are indistinguishable by routine assays.⁸² The 23-kD form (little PRL) is the most common form, but serum PRL can be elevated secondary to the presence of 150- to 170-kD aggregates with low biological activity (big-big PRL), leading to macroprolactinemia, a term coined by Jackson and colleagues⁸³ in the 1980s. Less frequently, the 50-kD form (big PRL) can be the prevalent circulating form.^84,85 The presence of molecular aggregates with low biological activity, such as big-big PRL, should be suspected when high serum PRL levels are detected in patients without or with scarce signs and symptoms related to hyperprolactinemia.^4,86 Precipitation with polyethylene glycol is an excellent screening method.⁸⁷ The predominant molecular form recovered (i.e., assayed after the precipitation) is the highly biologically active little PRL. The gel filtration chromatography confirms the presence of big-big PRL (Fig. 11-8), but being a costly and time-consuming method, it is performed for practical clinical purposes only when polyethylene glycol precipitation results are inconclusive. Macroprolactinemia is a common finding, occurring in 8% to 42% of all cases of hyperprolactinemia.⁴ The pathogenesis of macroprolactinemia is still unknown. It could be in part a complex of monomeric PRL with immunoglobulin G⁸⁹; anti-PRL autoantibodies were identified in patients with idiopathic hyperprolactinemia.⁸⁹

Big-big PRL biological activity is still controversial in the literature. Studies in vitro with rat Nb2 cell bioassays show either the presence or the absence of biological activity.⁴ To explain the dissociation of presence of activity in vitro but not in vivo, we can speculate that because of its large molecular weight, macroprolactin does not cross the capillary barrier, and it is unable to reach target cells. Additionally, the PRL receptor forms of rat cells are different from those of humans, so a bioassay using cells harboring human PRL receptors which addresses the biological activity of macroprolactin should be of interest. As a matter of fact, a study by Glezer et al.⁹⁰ showed that sera of individuals with macroprolactinemia presented lower biological activity in a bioassay using a mouse cell transfected with the long form of human PRL receptor as compared to the rat Nb2 bioassay (Fig. 11-9). Moreover, in a recent publication, Hattori et al.⁸⁹ claim that the level of bioactivity of macroprolactin in the Nb2 bioassay is present due to the dissociation of monomeric PRL from the autoantibodies, as a result of the longer incubation and more dilute assay conditions. Despite these controversies in the literature concerning the biological activity of PRL aggregates, most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia and do not need any treatment. To avoid unnecessary medical or surgical procedures, macroprolactin screening is mandatory when clinical features and serum PRL assay results are conflicting.

Assessment of other pituitary functions is mandatory, mainly in the presence of macroprolactinomas. Insulin-like growth factor 1 must be followed either to verify GH deficiency or to disclose the rare cases of prolactinomas that progress with PRL/GH co-secretion.⁹¹ Gonadotropin assessment may explain cases with persistent amenorrhea or sexual impairment despite PRL normalization. Although less frequently affected, thyrotropic and adrenocorticotropic axes also must be evaluated. Thyrotropin assessment also may disclose primary hypothyroidism as the cause of hyperprolactinemia.³⁵ Because restoration of pituitary function may occur after adenoma removal by surgery or tumor shrinkage attained by medical therapy,^92,93 these assessments have to be repeated after such procedures to avoid unnecessary hormone replacement.

Imaging

MRI is currently the gold-standard imaging method for diagnosis and treatment follow-up of micro- and macroprolactinomas, although CT scan still have a place for sellar region assessment. MRI is superior to CT for tumor boundary delineation, especially regarding its associations with the optic chiasm and cavernous sinus (Fig. 11-10). Additionally, tumor consistency, presence of hemorrhage, and presence of cystic lesions are better shown by MRI, especially comparing T1-weighted and T2-weighted images. CT has the advantage of showing bone erosion and calcifications and may help surgical planning.⁹⁴ Although MRI is currently the most sensitive imaging method for microprolactinomas, tumors measuring less than 2 mm may remain undetected by this technique. This fact is well known for the usually tiny ACTH-secreting adenomas leading to Cushing’s disease, with about 50% of them not identified by MRI.⁹⁵ It is probable that many of the so-called idiopathic hyperprolactinemic patients harbor a small microprolactinoma. Procedures such as dynamic imaging with gadolinium enhancement (Fig. 11-11) and spoiled gradient recalled acquisition technique (SPGR)⁹⁶ may contribute to improve MRI sensitivity for such tiny adenomas.

MRI can disclose the so-called pituitary incidentaloma, a term coined by Reincke in 1990 to describe incidentally discovered pituitary masses by imaging performed to evaluate conditions not linked to pituitary disease, including head trauma and sinusitis. Controversies exist in the literature concerning the definition of pituitary incidentalomas.⁹⁷ Molitch⁹⁸ included patients who presented with symptomatic pituitary disease and who were diagnosed only when a sellar mass was incidentally disclosed. In our opinion, the term incidentaloma should be reserved for cases with no endocrine or mass effects of a pituitary adenoma.⁴ Incidental imaging findings of pituitary adenomas, mainly microadenomas, are present in up to 27% of autopsy findings in the general population.¹¹ Other imaging pitfalls include normal anatomic variations such as asymmetric sphenoid septum with bulging of the sellar floor or displacement of the pituitary stalk,⁹⁹ artifacts such as clips and prostheses, and global pituitary enlargement—either physiologic, as shown in puberty or even in young adults¹⁰⁰ and pregnancy,¹⁰¹ or pathologic, as seen in primary hypothyroidism ³⁵ and mental depression.¹⁰²

Regarding the functional evaluation of prolactinomas by imaging, in-vivo imaging by single-photon emission computed tomography using radiolabeled high-affinity benzamine derivatives to D2 receptors, such as iodine 123–methoxybenzamide or iodine 123–epidepride, could serve as a response predictor to dopamine agonist treatment.103,104 Positron emission tomography using 18-fluorodeoxyglucose, carbon 11–methionine, or dopamine D2 receptor ligands also has been used for in-vivo assessment of the metabolic rate and D2 receptor density of macroprolactinomas and other pituitary tumors.¹⁰⁵ These methods are expensive and time consuming, however, and are better reserved for the study of tumors without a hormone marker, such as clinically nonfunctioning pituitary adenomas. Regarding prolactinomas, such techniques currently should be reserved for investigational purposes or for special cases, such as searching for metastases in the rare malignant prolactinomas.¹⁰⁶ Fig. 11-12 is a flow diagram for the diagnostic evaluation of hyperprolactinemia.

Surgical Therapy

Pituitary surgery by the transsphenoidal approach was used at the beginning of the 20th century and was reintroduced in the early 1960s and greatly improved when the surgical microscope was introduced.2,108 More recently, endonasal endoscopic surgery has become available. Compared to the classic transsphenoidal approach, endoscopic pituitary surgery seems to reduce the time of hospitalization, but improvement of surgical results remains to be demonstrated.^109,110 These developments made the selective removal of the pituitary adenoma possible, sparing the normal gland, along with low complication and mortality rates, mainly for surgeons with more than 500 operations.¹¹¹ Besides serum PRL normalization, this surgical modality aims at reducing or eliminating the mass effect of expanding macroadenomas, often leading to the resolution of neurologic and visual manifestations. The transcranial surgical approach is reserved solely for tumors with a predominance of extrasellar location expanding out of the midline.¹¹²

The surgical success in normalizing serum PRL levels depends on the experience and ability of the surgeon and on the tumor size and invasiveness. Preoperative serum PRL levels, usually associated with tumor dimension and location, were found to be paramount in predicting surgical remission, being the only predictive factor in multivariate analysis in some reports.113,114 Consequently, the best results were achieved in microprolactinomas with a preoperative serum PRL less than or equal to 100 ng/mL. A study on the initial outcome of 219 women with prolactinomas operated on by transsphenoidal microsurgery showed a remission rate of 92% of cases with preoperative PRL less than or equal to 100 ng/mL and 91% with intrasellar microadenomas, but only 59% in women with microadenomas with cavernous sinus extension, leading to an overall remission rate of 82% for microadenomas. Of the women with macroprolactinomas, 88% with intrasellar adenomas, 86% with moderate suprasellar extension, and 80% with focal sphenoid sinus invasion achieved remission. Surgical remission in patients with diffuse sphenoid sinus invasion, cavernous sinus invasion, and major suprasellar extension was poor, however, ranging from 0% to 44%.¹¹³ In another large series of 120 patients with prolactinomas (93 women and 27 men) who underwent pituitary surgery by the transsphenoidal route, PRL normalization occurred in 78% of patients with microadenomas, in 87.5% of patients with intrasellar macroadenomas, and in 27% of patients with extrasellar macroadenomas.¹¹⁴

A compilation of 50 published series showed that postsurgical serum PRL normalization was achieved in 73.7% of 2137 microprolactinomas and 33.9% of 2226 macroprolactinomas.¹¹⁵ Comparison among the series is difficult, however, because many authors do not mention preoperative serum PRL levels, the tumor size, and degree of invasiveness. The grade of clinical improvement in cured patients is high, mainly in smaller tumors. Menses and fertility restoration is high, and pregnancy rates ranged from 75% to 90% in different series. Some patients can achieve menstrual regulation and even become pregnant without full PRL normalization.^114,116 Sexual improvement in men is less likely to occur, probably owing to irreversible gonadotropic damage caused by the higher frequency of extrasellar and invasive prolactinomas compared with women. Nonetheless, pituitary function generally is preserved in intrasellar adenomas and is restored by the removal of suprasellar adenomas causing hypothalamus-pituitary disconnection.¹¹⁴ In addition, neurologic and visual amelioration often is achieved after pituitary surgery.

Many patients bearing prolactinomas have undergone treatment with dopamine agonist drugs before surgery. The effect of previous medical therapy on surgical outcome is still a matter of debate. Some reports point to poorer results compared with nontreated patients117,118; others do not show significant differences.^113,114 There is also evidence, however, of improvement of surgical results in the medically pretreated group.^119,120 Because the issue of dopamine agonist–induced fibrosis remains unresolved, it is unclear whether the negative outcome was caused directly by the drug or whether it was biased by a tendency to treat medically large and invasive tumors, which present with the poorest surgical results.

An important caveat of surgical treatment is prolactinoma recurrence. This issue was raised in the early 1980s when an article from the Montreal group reported recurrence rates in surgically “cured” patients to be 50% for microprolactinomas and 80% for macroprolactinomas.¹²¹ Subsequently, several reports on this issue were published but with less impressive figures. A literature compilation reported recurrence rates of 18.2% of 809 microprolactinomas and 22.8% of 465 macroprolactinomas.¹¹⁵ In our series, the recurrence of hyperprolactinemia in surgically cured patients was 27% for microprolactinomas and 17% for macroprolactinomas.¹¹⁶ Median time to recurrence varied among the different surgical series, from 1 to 7 years. Concerning recurrence predictors, many studies pointed to higher postoperative serum PRL levels in patients who recurred compared with patients without recurrence,^113,121,122 whereas others did not find serum PRL levels to be a predictor of late outcome.¹²³ Another marker of recurrence is the absence of PRL response to dynamic tests, especially to thyrotropin-releasing hormone.^114,123 These findings raise the question whether, in prolactinomas, serum PRL increase after surgical normalization represents true recurrence or important but incomplete tumor removal.

Although the occurrence of relapses contributes to the decrease of long-term surgical cure rate of prolactinomas, many patients with recurrent hyperprolactinemia remain asymptomatic and have no evidence of tumor regrowth.113,124 Relapse can be transient. From a cohort of 44 patients with surgically cured microprolactinomas, 8 (18.2%) experienced recurrence and were followed up. Only two of the eight patients experienced permanent relapse.¹²⁵ Additional therapy is reserved only for patients with symptomatic recurrence.

Surgical treatment for prolactinomas is indicated for cases with persistent intolerance or hormonal or tumor resistance to dopamine agonists (see later); pituitary apoplexy¹²⁶; tumor growth during medical therapy¹²⁷; cerebrospinal fluid (CSF) leakage due to dopamine agonist–induced tumor shrinkage of invasive macroprolactinomas^128,129; and (rarely) visual loss on medical therapy, secondary to optic chiasm herniation resulting from tumor retraction.¹³⁰ Additionally, surgery is an excellent alternative for patients harboring microprolactinomas, especially patients with serum PRL less than or equal to 100 ng/mL, with poor compliance to medical therapy.^113,131

Medical Therapy

The knowledge that dopamine is a powerful inhibitor of PRL secretion has yielded insights regarding use of dopamine agonists in hyperprolactinemia treatment.

Radiotherapy

The efficacy of conventional radiation therapy for prolactinomas is lower than medical or surgical treatment. Our results of 19 patients submitted to radiotherapy after medical/surgical failure showed that only 3 (16%) achieved serum PRL normalization 5, 6, and 15 years after the procedure.¹¹⁶ A study with 63 patients treated with radiation after noncurative surgery showed that only 30% had normal PRL levels by 10 years.¹⁹⁸ A compilation from the literature shows serum PRL normalization in less than one third of patients 5 to 15 years after conventional radiotherapy, with hypopituitarism occurring in 5.5% to 93.3% of cases.¹⁹⁹ This prevalence is probably greater because many series have underestimated GH deficiency in adults. Other complications associated with conventional radiotherapy include optic nerve lesions, neurologic dysfunctions, cerebrovascular disease, and the development of other intracranial tumors.

There are emerging data on gamma-knife radiosurgery for prolactinomas. In one retrospective investigation, the authors examined the results of gamma-knife radiosurgery for tumor remnants after unsuccessful open surgery and medical treatment in 20 patients with prolactinomas. Serum PRL levels decreased into the normal range in five cases (25%). Patients treated with dopamine agonists during gamma-knife radiosurgery did significantly less well compared with the untreated group, suggesting a “radioprotective” effect of the drug.²⁰⁰ This event is also suggested by a recent study²⁰¹ showing serum PRL normalization in 26% of 23 patients in an average time of 24.5 months, with new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two cases (7%). Best results were achieved in patients with tumor volume less than 3.0 cm³ and who are not receiving dopamine agonist at the time of treatment. Another study including 128 patients estimated the efficacy of gamma-knife radiosurgery as the primary therapy for prolactinomas. The mean follow-up time was 33.2 months (range, 6 to 72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months after gamma-knife radiosurgery. Clinical cure was achieved in 67 cases (52%). Nine infertile women became pregnant 2 to 13 months after irradiation, and all gave birth to normal infants. There was no visual deterioration related to gamma-knife radiosurgery. This study points to better results in terms of PRL normalization but does not mention the impact of treatment on pituitary function, besides mentioning five women who experienced “premature menopause.”²⁰² More data and follow-up time are required to assess the superiority of gamma-knife radiosurgery compared with conventional radiotherapy. To date, in the author’s opinion, radiation therapy for prolactinomas is reserved for cases with medical and surgical failures, especially for invasive tumors.

Therapeutic Perspectives

As a result of the efficacy of medical and surgical therapies, most patients with prolactinomas can be controlled adequately. A subset of patients resistant to dopamine agonists, especially patients harboring invasive macroadenomas, who are not expected to be surgically cured, pose an important therapeutic problem. Radiotherapy use is generally limited, efficacious only in the long term, and usually leads to hypopituitarism.

Many studies did not find tumor enlargement in patients with “idiopathic” hyperprolactinemia or microprolactinomas, before or after menopause.153,203 When pregnancy is not a concern, and galactorrhea is not disturbing, sexual steroid replacement can be considered for those patients, who must be followed carefully. Additionally, testosterone may be given to men harboring resistant microprolactinomas and even partially resistant macroprolactinomas, with monitoring of PRL levels and with imaging. The introduction of an aromatase-inhibitor drug may be considered if there is evidence of tumor growth or serum PRL increase.²⁰⁴

Prolactinomas usually do not respond to somatostatin.²⁰⁵ It has been shown, however, that a selective analogue of the somatostatin receptor subtype 5 (SSTR5) inhibited PRL secretion in human prolactinoma cell culture.²⁰⁶ Nevertheless, another in-vitro study did not show better response of this selective analogue compared with quinagolide.²⁰⁷ A recent publication by Fusco et al.²⁰⁸ pointed to an efficacy comparable to cabergoline of a selective analogue of SSTR5, BIM-23206, and the chimeric somatostatin/dopamine D2 receptor ligant, BIM-23A760, in responsive prolactinomas but not in resistant ones. Also the “universal” somatostatin ligand SOM230 (pasireotide) was ineffective in cabergoline-resistant adenomas.²⁰⁸ In summary, although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands do not appear to be highly effective in suppressing PRL in tumors resistant to dopamine agonists.

Studies show that the human PTTG induces angiogenesis via basic fibroblast growth factor induction²⁰⁹ and that estrogen is involved in paracrine regulation of pituitary tumorigenesis by PTTG. Selective estrogen receptor modulators, such as tamoxifen and raloxifene, and inhibitors, such as ICI 182780, abolished estrogen-induced pituitary PTTG expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated PRL-secreting pituitary tumor growth by 41% in rats. Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%.¹⁷ These findings may indicate a role for selective antiestrogens in prolactinoma treatment, including resistant ones.

The development of PRL receptor antagonists could also represent an option for medical treatment of resistant macroprolactinomas without mass effect, because they should be able to block the actions of PRL, if not its production.²¹⁰ One therapeutic approach would be the association of dopamine agonists and PRL receptor–antagonist drugs in cases of macroprolactinomas exhibiting tumor shrinkage but not PRL normalization when on dopamine agonist monotherapy.

The alkylating agent temozolomide has been experimentally used in many tumors. Its product of hydrolyzation, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide, is thought to exert a cytotoxic effect by DNA alkylation. Temozolomide can be given orally and is currently approved in the United States for the treatment of patients with refractory anaplastic astrocytoma and for the treatment of newly diagnosed patients with glioblastoma multiforme, as an adjunct to radiotherapy. Three case reports recently published describe patients with invasive prolactinoma or PRL-secreting carcinoma resistant to conventional therapy who responded to this drug211–213 (Fig. 11-17). More data is needed to assess the efficacy and tolerability of this promising drug in a larger cohort of aggressive, resistant prolactinomas.

Finally, there is evidence that nerve growth factor expression is reduced in resistant prolactinomas and that this growth factor restores p53 function in pituitary cell lines.²¹⁴ Nerve growth factor administration to athymic mice with transplanted human bromocriptine-resistant prolactinomas results in the expression of dopamine D2 receptors in the tumor and restores sensitivity to subsequent treatment with bromocriptine. This could be a promising therapy for patients who are refractory to dopamine-agonist treatment.²¹⁵

Prolactinomas and Pregnancy

The development of efficacious medical and surgical therapies for prolactinomas has made pregnancy possible for women bearing such tumors. Gestational risks due to the possibility of tumor growth during pregnancy, mainly in women with macroadenomas, raise a concern, however. The management of pregnancy in patients with prolactinomas submitted to different therapies is brought into focus here.

Regarding microprolactinomas, a study including 91 pregnancies mostly induced by bromocriptine, without previous surgery or radiotherapy, indicated symptomatic tumor growth in 5.5% of cases.²¹⁶ In a compilation of pregnancies in 246 women with microprolactinomas treated with bromocriptine only, tumor growth symptoms were reported in 1.6% of patients, although an asymptomatic increase of the tumor was shown in 4.5% of the cases. None of the patients needed surgical intervention during pregnancy.²¹⁷ We followed 71 term pregnancies, and the results were similar.^218,219 Of the 22 patients with previous surgery, none presented symptoms of tumor growth; of the 41 pregnant patients who underwent treatment with bromocriptine alone, only 1 (2.4%) presented with headaches in the third month of pregnancy, which regressed with drug reintroduction. Seven patients got pregnant without treatment and did not develop any complications. There was an asymptomatic increase of the tumor in one case with previous surgery and in two cases with bromocriptine alone, as assessed by scanning postpartum. Because of the low risk of tumor growth during pregnancy in patients with microprolactinomas, there is no need to perform periodic imaging or ophthalmologic examinations. These assessments should be reserved for cases with clinical complaints suggesting tumor growth, such as headache or visual field changes.

The risk of complications during pregnancy is much greater with macroprolactinomas. One study revealed symptomatic tumor growth in 41.3% of 56 pregnancies occurring in 46 patients who were medically treated only, compared with 7.1% of 70 pregnancies that occurred in 67 women who previously had been submitted to surgery or radiotherapy.²¹⁶ A review from the literature pointed to symptoms related to tumor growth in 15.5% of 45 patients with macroprolactinomas treated with bromocriptine only. The incidence of complications was only 4.3% in the 46 patients who underwent surgery or radiotherapy before pregnancy. Additionally, asymptomatic tumor growth was seen in 8.9% of the patients without prior surgery or radiotherapy.²¹⁷ We followed 51 term pregnancies in patients with macroprolactinomas.^218,219 Of those, 21 were in patients with previous surgery, and none of the patients presented with symptoms or signs of tumor growth. Of the 30 patients treated with pregestational bromocriptine only, 11 (37%) manifested complaints related to tumor growth: all of them presented with headaches, and seven had visual alterations (Fig. 11-18). Pituitary imaging after delivery was performed in 23 other patients, and an asymptomatic growth of the tumor was observed in 4 more cases.

These data show the higher risk of tumor growth in macroprolactinomas during pregnancy, necessitating a stricter follow-up (Fig. 11-19). The first recommendation should be the use of a nonhormonal contraceptive along with a dopamine agonist until tumor shrinkage has been shown within sellar boundaries. The duration of previous treatment with dopamine also might be important. A follow-up study of 37 pregnancies showed signs of tumor growth in 7, all of them treated with bromocriptine for less than 1 year. No tumor enlargement was found in the 14 macroprolactinoma patients treated for a longer time, suggesting that the duration of bromocriptine use before conception might be a good prognostic factor in pregnancy.²²⁰

After pregnancy has been confirmed, the dopamine agonist can be withdrawn, and the patient must be monitored closely for symptoms related to tumor growth. If there is a suspected tumor expansion, the confirmation can be made through MRI, after the fourth month of gestation, and by visual field testing (see Fig. 11-19). Monitoring serum PRL levels during pregnancy does not seem to be useful, because they are not always related to tumor behavior during gestation. The reintroduction of bromocriptine in such cases often leads to clinical amelioration and tumor reduction. In 9 of 11 patients who exhibited complications during pregnancy, bromocriptine reintroduction brought complete resolution of the symptoms related to tumor growth.²¹⁹ Surgery also can be employed as treatment for symptomatic tumor growth in pregnancy. Several authors have reported good results, although the increased risk of spontaneous abortion in patients who undergo surgery is well known.²¹⁹

The safety of bromocriptine reintroduction or even maintenance during pregnancy is supported by a large experience with this dopamine agonist reported in the literature. A large review²²¹ consisted of 2587 pregnancies and did not show an increase of maternal or fetal morbidity or mortality. Since then, some authors have favored the maintenance of bromocriptine in pregnancy to prevent complications in patients with macroprolactinomas without previous surgery or radiotherapy.²²² It is our policy to indicate such an approach only when the patient gets pregnant after a short treatment period, mainly without confirmation of tumor shrinkage or when the tumor is outside sellar boundaries. Surgery is indicated before pregnancy in cases without tumor reduction during treatment with dopamine agonists or in patients who developed tumor growth in previous gestations.²¹⁹

Treatment Planning and Follow-Up

Based on the previously described evidence, to date the gold-standard therapy for either microprolactinomas or macroprolactinomas is medical treatment with dopamine agonist drugs (Fig. 11-20). Physicians must motivate patients to embark on such long-term treatment based on the overall better results compared with surgery and, mainly based on more recent data,^147,191 the possibility of drug withdrawal for a substantial number of patients with maintenance of normoprolactinemia. Surgical treatment of prolactinomas is indicated for patients with persistent intolerance or hormonal or tumor resistance to more than one dopamine agonist drug—in particular if pregnancy is desired—or if the tumor has grown during medical treatment. In cases of resistance, rare conditions, such as acidophil stem cell adenoma or PRL-secreting carcinomas, must be considered. Malignant prolactinomas respond only temporarily, if they respond at all, when patients are switched to another dopamine agonist drug or undergo surgery. Surgical therapy also is indicated frequently in pituitary apoplexy, in dopamine agonist–induced CSF leakage occurring in invasive macroprolactinomas, and in the exceedingly rare occurrence of visual loss secondary to optic chiasm herniation during medical therapy. Additionally, surgery in skilled hands may be considered for patients not willing to be submitted to long-term medical therapy, especially patients harboring microprolactinomas and serum PRL levels less than 100 ng/mL. Radiotherapy, either conventional or stereotactic, is reserved for prolactinomas not responsive to medical or surgical treatment, particularly regarding the invasive ones.

There is evidence that, in general, estrogen replacement is not harmful for women harboring microprolactinomas. This approach may be used when fertility is not an issue for patients with intolerance or resistance to medical therapy and not cured by or not willing to undergo pituitary surgery. In addition, women successfully treated medically may use hormonal contraceptives if they have not adapted to barrier methods. Menopausal women bearing microprolactinomas can interrupt dopamine agonist drug use and are allowed to start hormone replacement therapy if it is indicated.²⁰³ Although there is evidence of a PRL role in carcinogenesis in animal models, mainly carcinoma of the mammary gland, human data are still highly controversial.^230–233 It is now apparent that human mammary epithelial cells can synthesize PRL endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary PRL and probably not affected by dopamine agonist drugs. To date, the maintenance of high serum PRL levels in premenopausal and postmenopausal women is not a concern with regard to carcinogenesis. Finally, for macroprolactinomas that are not adequately controlled, the use of estrogens is generally discouraged, given their potential for inducing growth.

There are many therapeutic perspectives for resistant/aggressive prolactinomas: specific somatostatin or somatostatin/dopamine analogues, selective anti-estrogen drugs, cytotoxic drugs such as temozolomide, and PRL-receptor antagonists. Nevertheless, more studies are needed in order to assess their places in the treatment algorithm.

The follow-up planning for patients with prolactinomas depends on the tumor size and clinical, laboratory, and imaging response to therapy. Many patients are clinically controlled even if serum PRL levels are still above the normal range and do not need further drug dose increases. For microprolactinomas and especially for macroprolactinomas, significant tumor shrinkage or “disappearance” on MRI is a good prognostic marker, and in such cases, imaging reassessment can be performed sporadically. Medically or surgically controlled patients must be reassessed periodically, clinically and hormonally, to identify patients who may discontinue the dopamine agonist drug with maintenance of normoprolactinemia or patients with recurrence of hyperprolactinemia.

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