Abordaje Del Paciente Con Hiperprolactinemia

Approach to the Patient with Prolactinoma
1 Renata S. Auriemma1, Rosa Pirchio1, Claudia Pivonello2, Francesco Garifalos1,3, Annamaria
2 Colao1,4, Rosario Pivonello1,3,4
3 1.Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di
4 Napoli, Naples, Italy; 2. Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy; 3.
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Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgad174/7089196 by guest on 16 April 2023
5 Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Unità di Andrologia e Medicina
6 della Riproduzione e Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di
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7 Napoli, Naples, Italy;4. Unesco Chair for Health Education and Sustainable Development, “Federico II”
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8 University, Naples, Italy.
10 Key words
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11 Prolactin, hyperprolactinemia, pituitary tumour, dopamine agonists, cabergoline, treatment
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12 withdrawal, pregnancy, menopause.
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13
14 Word count:
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15 Abstract: 253; Manuscript: 12117; Tables: 4; Figures: 6; References: 255

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16
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17 Address for correspondence
18 Rosario Pivonello, MD, PhD, Prof.

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19 Dipartimento di Medicina Clinica e Chirurgia
20 University Federico II
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21 Via Sergio Pansini 5
22 80131 Naples, Italy
23 Tel: +390817464983
24 Emal: rosario.pivonello@unina.it
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access
article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence
(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution
of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is
properly cited. For commercial re-use, please contact journals.permissions@oup.com 1
1 ORCID: 0000-0002-9632-1348
2 DISCLOSURE STATEMENT
3 AC has been Principal Investigator of Research Studies for Novartis, Ipsen, Pfizer, Lilly,
4 Merck and Novo Nordisk; consultant for Novartis, Ipsen, Pfizer, and received honoraria from
5 Novartis, Ipsen and Pfizer beyond the confines of this work. RPiv has been Principal
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6 Investigator of Clinical and/or Translational Research Studies for Novartis, HRA Pharma,
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7 Ipsen, Shire, Corcept Therapeutics, Cortendo AB, Janssen Cilag, Camurus, Strongbridge,
8 and Pfizer; Co-investigator of Research Studies for Pfizer; received research grants from
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9 Novartis, Pfizer, Ipsen, HRA Pharma, Shire, IBSA, Strongbridge Biopharma; has been an
occasional consultant for Novartis, Ipsen, Pfizer, Shire, HRA Pharma, Cortendo AB, Ferring,
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11 Strongbridge Biopharma, Recordati, Corcept Therapeutics, Crinetics Pharmaceuticals, ARH

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12 Healthcare, Biohealth Italia; and has received fees and honoraria for presentations from
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13 Novartis, Shire, Pfizer and Recordati beyond the confines of this work. RSA, RPir, CP and
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14 FG have nothing to declare.

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16 ABSTRACT
17 Prolactinomas are the most common pituitary tumour histotype, with microprolactinomas
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18 being prevalent in women and macroprolactinomas in men. Hyperprolactinemia is among
19 the most common causes of hypogonadotropic hypogonadism in both sexes, thus prompting
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20 medical advice for hypogonadism (infertility, oligo-amenorrhea, impotence,

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21 osteoporosis/osteopenia) in both sexes, and for signs and symptoms of mass effects
22 (hypopituitarism, visual loss, optic chiasm compression, cranial nerve deficits, headaches)
23 predominantly in men. Diagnostic workup involves a single PRL measurement and pituitary
24 imaging, but some laboratory artefacts, i.e., the hook effect and macroprolactin, can
25 complicate or delay the diagnosis. The treatment of choice for prolactinomas is represented
26 by dopamine agonists, mainly cabergoline, able to induce disease control, restore fertility in
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1 both sexes, and definitively cure one-third of patients, thus permitting treatment
2 discontinuation. Pregnancy and menopause may promote spontaneous PRL decline and
3 anticipate cabergoline discontinuation in women. Surgery and/or radiotherapy are indicated
4 in case of resistance to cabergoline not overcome by the increase in drug dose up to the
5 maximally tolerated or the patient’s personal choice of surgery. The evidence of resistance
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6 to cabergoline in invasive and proliferative tumours may indicate biological aggressiveness,
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7 thus requiring alternative therapeutic approaches mainly based on temozolomide use as
8 monotherapy or combined with radiotherapy. In uncontrolled patients, new medical
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9 approaches (alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide
therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors or immunotherapy) may be offered
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11 but the experience collected to date is still very scant. This article reviews different facets of
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12 prolactinomas and discusses approaches to the condition in more common clinical
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13 situations.
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16 CASE 1
17 In February 2019, a male patient aged 40 years old was referred to a neurologist due to
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18 intense and recurrent headaches. Among the exams performed to investigate the headache,
19 the brain MRI showed an intrasellar pituitary microadenoma 8x6x8 mm in size (tumour
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20 volume 1.96 cm3). The patient was then referred to endocrinological advice. Medical history
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21 revealed that the patient was the father of two children aged 4 years and 2 years,
22 respectively. Decreased libido and erectile dysfunction occurred over the last year. At the
23 first endocrinological assessment, pituitary function investigation revealed
24 hyperprolactinemia (PRL 900 µg/L, normal range 5-20 µg/L) and concomitant
25 hypogonadotropic hypogonadism (FSH 1.1 IU/ml, LH 1.3 IU/ml, testosterone= 175 ng/dl). A
26 concomitant seminal fluid examination revealed the presence of mild oligospermia, whereas
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1 at the dual-energy x-ray absorptiometry (DXA) scan bone mineral density was normal.
2 Therefore, the diagnosis of pituitary microadenoma with hyperprolactinemia was carried out,
3 and cabergoline therapy was started at the dose of 1 mg/week. The clinical course was
4 indolent over the following 6 months and responsiveness to cabergoline was acceptable,
5 with a significant decrease in PRL levels (180 µg/L, = -80%), together with a reduction in
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6 the headache intensity and frequency and an improvement in libido and erectile function.
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7 Therefore, given that PRL levels were progressively decreasing the treatment with
8 cabergoline was maintained at the same dose.
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9
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10 CASE 2
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In December 2009, a woman aged 26 years old was referred to endocrinological
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12 consultation for infertility. Medical history revealed oligo-amenorrhea and mild hirsutism
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13 (Ferriman-Gallway score= 9) over the last ten years, associated with progressive weight
14 gain in the last three years. At gynaecological ultrasounds performed over years, the ovaries
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15 displayed a multi-follicular aspect with no clear evidence of polycystic ovary syndrome,

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16 whereas hormonal assessment revealed normal androgen levels associated with mild
17 hyperprolactinemia (up to 36 µg/L, normal range 5-25 µg/L). The patient had received
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18 treatment with oral contraceptives for two years, from 2004 to 2006, with rapid relapse of
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19 the clinical syndrome after oral contraceptive withdrawal. At the first endocrinological
20 assessment, the patient reported amenorrhea over the last 9 months, recurrent headaches,
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21 and moderate hyperprolactinemia (PRL 126.7 µg/L). A pituitary MRI was performed and
22 revealed a microadenoma of 8 mm maximal diameter. The patient’s facial characteristics
23 (prominent frontal and zygomatic bones, enlarged nose, and mandibular prognathism) were
24 suggestive of concomitant GH hypersecretion, but GH and IGF-I levels were within the
25 normal range (GH= 0.3 µg/L, IGF-I= 206 µg/L). Therefore, the diagnosis of pituitary
26 microadenoma with hyperprolactinemia was carried out, and cabergoline therapy was
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1 started at the dose of 0.5 mg/week. The clinical course was indolent over the years and
2 responsiveness to cabergoline was optimal, with complete PRL normalization (PRL=18
3 µg/L), and a 50% shrinkage in pituitary tumour size, associated with full recovery of the
4 clinical syndrome. In November 2016, the pituitary MRI revealed a 50% increase in maximal
5 tumour diameter, from 3 mm to 6 mm, suggesting tumour re-growth, and PRL levels slightly
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6 increased up to 28 µg/L, as for suboptimal biochemical control, thus requiring an increase
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7 in cabergoline dose to 1 mg/week. One year later, PRL persisted stable at 27 µg/L and
8 pituitary MRI revealed a 25% decrease in maximal tumour diameter, but the patient reported
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9 persistent headache and asthenia. In September 2018, the patient was discovered to be
pregnant, therefore cabergoline was promptly withdrawn. The patient underwent regular
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11 endocrinological controls during gestation; no impairment in the visual field was recorded,
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12 and at term delivery without maternal and foetal complications occurred in March 2019. The
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13 patient skipped post-partum controls for one year during breast-feeding and required new
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14 endocrinological consultation only in March 2020, when the first PRL assessment 4 months
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15 after cessation of breast-feeding resulted as high as 30.7 µg/L.

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16 CASE 3
17 In November 2004, a male patient aged 35 years old was referred to ophthalmologic
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18 consultation due to the occurrence of visual disturbances, particularly the narrowing of the
19 visual field. Concomitant visual field examination revealed bitemporal hemianopsia. Medical
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20 history revealed that the patient was the father of two children aged 6 years and 4 years,
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21 respectively. Decreased libido and frequent headaches occurred over the last three years,
22 associated with weight gain in the last five years. A brain MRI was then performed to
23 evaluate the optic chiasm region, and a pituitary tumour 30 x 25 mm in size with intrasellar,
24 suprasellar, and right parasellar extension, partially obliterating the pontine cistern, was
25 seen. At the first endocrinological assessment, pituitary function investigation revealed
26 severe hyperprolactinemia (PRL= 8040 µg/L, normal range 5-20 µg/L) and
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1 hypogonadotropic hypogonadism (FSH<0.1 IU/ml, LH=<0.1 IU/ml, testosterone= 103 ng/dl),
2 whereas the remaining pituitary function was preserved despite pituitary compression by the
3 tumour mass. A concomitant seminal fluid examination revealed the presence of
4 azoospermia, whereas the DXA scan revealed the presence of osteopenia. Therefore, the
5 diagnosis of a PRL-secreting pituitary tumour was carried out, and in February 2005 the
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6 patient underwent trans-sphenoidal surgery as first-line treatment to decompress optic
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7 chiasm. The report of the histological examination lay for invasive prolactinoma with
8 chromophobic cells, sparsely granulated pattern, characterized by numerous mitoses (MI=3-
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9 7M/10 HPF) and Ki-67%/MIB-1 proliferation index as high as 10%. At the 1-month
postoperative evaluation, PRL was 386 µg/L, and pituitary MRI detected a macroadenoma
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11 32x20x28 mm in size (tumour volume 9.318 cm3), invading the cavernous sinuses bilaterally
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12 and the subarachnoid space of the pontine cistern. Aggressive biological behaviour due to
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13 rapid tumour regrowth and histological characteristics suggested the diagnosis of an atypical
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14 pituitary adenoma according to WHO classification (1). On the basis of this evidence,
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15 cabergoline therapy was promptly started at the dose of 1 mg/week and progressively
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16 increased to 2 mg/week during follow-up. Testosterone replacement therapy was
17 simultaneously started.
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18
19 INTRODUCTION
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20 Accounting for approximately 40% of the entire cohort of pituitary tumours, prolactinomas
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21 are the most common hormone-secreting pituitary adenomas; infertility, gonadal and sexual
22 dysfunction are the most relevant clinical features in both sexes (2). Prolactinomas are the
23 main pathologic cause of prolactin (PRL) excess, albeit several different conditions may
24 induce the increase in PRL levels and should be excluded before a diagnosis is made (Table
25 1). In clinical practice, microprolactinomas (< 10 mm in size) are more frequent than
26 macroprolactinomas (> 10 mm in size) and occur more frequently in women, in whom the
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1 disturbances of the menstrual cycle and infertility generally prompt rapid medical advice
2 leading to an early diagnosis, as in clinical case 2. Conversely, in men the rate of
3 macroprolactinomas with visual field defects, as in clinical case 3, and hypopituitarism at
4 first presentation is higher (4) and the mean age at diagnosis is at least 10 years delayed
5 as compared to women (2–5), given that the most important components of the clinical
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6 syndrome are the decrease of libido and/or erectile dysfunction, as in clinical case 3.
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7 In adults, the estimated prevalence of prolactinomas accounts for 60-100 per million
8 population (4, 6, 7). According to a recent review study including different patient series (8),
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9 where standardized incidence rates for pituitary tumours range from 4 to 7.39
cases/100.000/year, prolactinomas have been reported to represent 40-66% of all pituitary
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11 tumours (8). Patient age has been shown to differently influence incidence rates in men and
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12 women: indeed, between the age of 20 and 50 years the ratio between women and men is
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13 estimated to be 10:1, whereas after the sixth decade of life the frequency of prolactinomas
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14 is similar in both sexes (8-11). This difference may reflect the fact that in young females the
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15 clinical syndrome due to hypogonadism (infertility and oligo-amenorrhea) prompts early

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16 medical advice, particularly in case of pregnancy desire. Conversely, in elderly patients,
17 including post-menopausal women, and in men the diagnosis is due predominantly to mass
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18 effects from large tumours. In the paediatric and adolescent age, prolactinomas, albeit rare,
19 represent about 50% of all pituitary tumours (12, 13).

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20
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21 THE INTERPLAY BETWEEN PROLACTIN AND FERTILITY
22 Hyperprolactinemia is the most common cause of secondary hypogonadism and infertility in
23 both sexes. In infertile women, PRL excess as the main cause of infertility has been found
24 to vary from 7 to 20% of cases, being lower than that reported in women with amenorrhea
25 and/or galactorrhea, but at least 10-fold higher than that of the general population (14). The
26 impact of PRL excess on the reproductive axis reflects its peculiar actions at both the central
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1 and peripheral levels (15). At the central level, PRL modulates the reproductive axis by
2 directly suppressing kisspeptin secretion, thus lowering GnRH activation and gonadotropins
3 secretion, so promoting hypogonadism and infertility (16, 17). At the peripheral level, PRL
4 plays a direct inhibitory effect on sexual hormone synthesis and secretion. In women, PRL
5 inhibits estrogen and progesterone synthesis (18-21). In men, PRL receptors have been
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6 identified on Leydig cells, Sertoli cells and epithelial cells of efferent ducts, suggesting a
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7 potential role for PRL in promoting steroidogenesis, spermatogenesis and
8 secretory/adsorptive functions of male reproductive organs (22). In infertile men, the
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9 prevalence of PRL increase as the main cause of infertility is still unknown, nevertheless
endocrine disorders, including hyperprolactinemia, reportedly account for only 2–4% of
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11 cases of male infertility (14).

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13 APPROACH TO PATIENT IDENTIFICATION
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14 Predisposition
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15 Although most pituitary adenomas occur in a sporadic setting, prolactinomas may arise from
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16 germline genetic mutations predisposing to pituitary tumour development in the context of
17 some inherited syndromes (23). The association with genetic defects may result in more
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18 aggressive clinical behaviour and poor responsiveness to standard treatment with dopamine
19 agonists (DA). Particularly, in the context of multiple endocrine neoplasia type 1 (MEN-1)
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20 and type 4 (MEN-4), and familial isolated pituitary adenomas (FIPA), prolactinomas are the
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21 most frequent pituitary tumour histotype. Overall, the efficacy of DA has been documented
22 in 51.5% of prolactinomas within MEN-1 (Table 2), but responsiveness to DA has been not
23 consistently reported across studies (24-28), varying from a scant (24, 25) to a good
24 response to DA (26-28), and from an aggressive (24, 25) to an indolent tumour clinical
25 behaviour leading to occasional tumour growth without clinical consequences (26-28). To a
26 similar extent, in the context of MEN-4 and FIPA prolactinomas are larger, more invasive,
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1 and less responsive to DA than their sporadic counterparts (29-32), suggesting a more
2 aggressive clinical behaviour as compared to sporadic tumours. In the context of Carney
3 Complex (CNC), prolactinomas are rare, but histology may reveal somatomammotroph
4 hyperplasia leading to the development of GH and/or PRL-secreting adenomas. In fact,
5 concomitant GH and PRL hypersecretion has been shown to occur in up to 64% of patients
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6 with CNC (33). To note, concomitant GH and PRL hypersecretion may occur independently
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7 on CNC, and the development of acromegaly in patients with a known prolactinoma is rare.
8 Altogether, these findings suggest that for those individuals with prolactinomas who are at
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9 risk for carrying a genetic mutation already diagnosed in a relative, genetic screening should
be offered after appropriate counselling and an explanation of the potential benefits deriving
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11 from early diagnosis (29).

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13 Clinical presentation at diagnosis
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14 Clinical features of prolactinomas are summarized in Figure 1. The pituitary adenoma per
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15 se may exert several compressive mass effects, resulting in headache, visual field defects
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16 and hypopituitarism (34, 35). Prolactin excess results in both sexes in weight gain, delayed
17 pubertal development, hypogonadism, infertility, galactorrhea, and osteopenia or

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18 osteoporosis (34, 35). Increased PRL levels underpin infertility in 7-20% of women and 2-
19 4% of men (14). Other signs and symptoms are gender-related and include in men libido
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20 reduction, erectile dysfunction, and gynecomastia; in women oligo-amenorrhea, vaginal

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21 dryness, irritability, and depression (34, 35). Particularly, in women the classical
22 amenorrhea–galactorrhea syndrome generally encourages rapid medical consultation, as in
23 clinical case 2, whereas weak symptoms of impotence and decreased libido in men might
24 be frequently underestimated, as in clinical case 1, leading to a diagnostic delay (35), as in
25 clinical case 3. However, different pathogenesis in men and women has also been
26 hypothesized, since rapidly growing prolactinomas with increased markers of cellular
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1 proliferation have been reported to occur more frequently in men (9, 36). These findings
2 have raised the question of whether prolactinomas are more aggressive in men than in
3 women, but the available evidence is still controversial. In men, prolactinomas are usually
4 large and invasive, with signs and symptoms of hypogonadism and mass effects being the
5 most frequent clinical features (37). Additionally, according to the last WHO classification
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6 (38) lactotroph tumours in men have a high probability of recurrence due to increased mitotic
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7 count and Ki-67 leading to elevated proliferative activity, or pluri-hormonal PIT-1-positive
8 immunostaining. The latter identifies tumours composed of a monomorphous population of
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9 poorly differentiated cells displaying various levels of immunoreactivity for several pituitary
tropines, including PRL together with GH, β-TSH, and α-subunit, and likely belonging to the
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11 acidophilic lineage of adenomas (38). These PIT-1 immunoreactive adenomas belonging to

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12 the acidophilic lineage display an intrinsic aggressive behaviour and a high degree of
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13 invasiveness, low rates of disease-free survival, and a high propensity for recurrence (38).
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14 Besides the hypogonadism-related signs and symptoms, PRL excess may exert extra-
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15 gonadal systemic effects. Given the direct actions of PRL and dopaminergic tone on
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16 pancreatic -cells and adipocytes, hyperprolactinemia may also induce an unfavourable
17 metabolic profile. Increased food intake and weight gain in patients with prolactinomas have
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18 been shown to promote altered body composition, insulin resistance, impaired glucose
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19 tolerance and adverse lipid profile, leading to visceral obesity and metabolic syndrome in
20 approximately one-third of patients (39-45). However, the potential impact of

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21 hyperprolactinemia-induced hypogonadism on body composition and metabolic profile
22 cannot be excluded. Indeed, men with testosterone and dihydrotestosterone levels in the
23 lower quartiles have been found to have a two-fold higher risk of developing obesity and
24 metabolic syndrome (46). Similarly, in 40 premenopausal hyperprolactinemic women, in
25 whom FSH, LH, and estrogen levels were in the normal range but their pulsatile secretion
26 was decreased due to hyperprolactinemia, PRL excess has been found associated with
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1 hyperinsulinemia and insulin resistance even independently of body weight, leptin and
2 adiponectin levels (44). The altered body composition, characterized by increased fat mass
3 and reduced lean mass (39, 40), together with the concomitant secondary hypogonadism
4 contribute to decreased bone density due to direct and indirect (i.e., hyperprolactinemia-
5 induced hypogonadism) effects of prolactin on bone physiology, early alterations in bone
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6 turnover markers, reduced bone mass mainly in trabecular rather than cortical bone, delayed
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7 peak bone mass acquisition, and high risk of vertebral fractures in both sexes (47-54).
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9 DIAGNOSTIC APPROACH
The diagnostic workup for hyperprolactinemia is shown in Figure 2. As reported in Table 1,
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11 a number of physiologic (pregnancy, breast-feeding, stress, exercise, food intake and sleep)
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12 and pathologic conditions (chronic kidney and liver failure, primary hypothyroidism,
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13 compression of the pituitary stalk by a non-PRL-secreting pituitary tumour or different
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14 parasellar mass, and granulomatous infiltration of the hypothalamus), as well as several

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15 drugs (mainly antidepressants, dopamine receptor blockers, dopamine synthesis inhibitors,

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16 oral contraceptives, gastrointestinal medications, neuroleptics and antipsychotics), can
17 induce symptomatic hyperprolactinemia (34, 55). Before a correct diagnosis of

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18 hyperprolactinemia is made, such conditions must be investigated and excluded. Attention
19 should be paid to medical history, concomitant medications, and biochemical assessment

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20 (34, 55). This is particularly true in the case of modest PRL elevations, which only
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21 occasionally may mask the presence of a prolactinoma (34), as in clinical case 2. To
22 ascertain the diagnosis of a PRL-secreting pituitary tumour, a single measurement of serum
23 PRL without excessive venepuncture stress is strongly recommended (34). Breast
24 examination in patients with galactorrhea should not be performed immediately before PRL
25 assessment as any nipple stimulation might result in PRL increase. A level above the upper
26 limit of normal (25 g/L in women, 20 g/L in men) raises diagnostic suspicion (34, 55).
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1 Conversely, dynamic testing of PRL secretion based on the administration of TRH, L-dopa,
2 nomifensine, and domperidone does not find clinical application nowadays (34). In uncertain
3 conditions, sampling can be repeated after overnight fasting on a different day in two to three
4 samples in time course at 15- to 20-min intervals to minimize the effect of PRL pulsatile
5 secretion (34). PRL levels >250 g/L generally confirm the diagnosis of prolactinoma, albeit
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6 PRL increase over 200 g/L can be also seen in case of non-PRL-secreting tumour mass,
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7 such as non-functioning pituitary tumours (34, 55). In presence of a serum PRL level >500
8 g/L, the diagnosis of macroprolactinoma can be ruled in (34). Once other causes of
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9 hyperprolactinemia (see above) have been excluded, a radiological confirmation with
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10 pituitary imaging, mainly based on gadolinium-enhanced magnetic resonance imaging
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11 (MRI) is required (55). Over the last 20 years, pituitary MRI has progressively replaced
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12 computed tomography (CT) with intravenous contrast enhancement, as the latter is less
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13 effective than MRI in visualizing small tumours on one hand, and in shaping the extension
14 of large or giant tumours on the other hand (55). Nowadays, a pituitary CT scan is
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15 recommended only when MRI is unavailable or contraindicated, such as in patients with

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16 cardiac pacemakers, implanted cardiac defibrillators, internal pacing wires, clips for cerebral,
17 carotid, or aortic aneurysm, cochlear implants, any implant held in by magnet, Swan-Ganz
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18 catheter, and pregnancy (55). In the last circumstance, the use of pituitary MRI is not
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19 recommended except in the case of clinical confirmation of tumour growth suggested by
20 sudden impairment in the visual field (34), and MRI should be performed without gadolinium
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21 after the second trimester of pregnancy (34). In those patients with macroadenomas
22 impinging the optic chiasm, a visual field examination is recommended, whereas visual
23 testing is not mandatory for patients with microadenomas (55).
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1 CHALLENGES IN DIAGNOSIS
2 The “hook effect”
3 Diagnostic workup for prolactinomas may be tangled by several challenges. The maximal
4 diameter of the prolactinoma reportedly correlates with PRL levels at baseline (56).
5 Therefore, in case of discrepancy between a very large pituitary tumour (> 3 cm in size) and
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6 a modestly increased PRL level, a 1:100 serum sample dilution is recommended to
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7 investigate and overcome a laboratory artefact responsible for falsely low PRL levels,
8 namely the “hook effect” (55). This phenomenon commonly occurs with the use of some
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9 immunoassays, such as the two-site monoclonal “sandwich” assay (57). The term “hook
effect” refers to the typical shape of the binding curve, which goes up as long as the analyte
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11 concentrations gradually increase in the sample, but at some critical point exceeding the
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12 capacity of the assay components, it turns going down (57). The “hook effect” may,
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13 therefore, mask a prolactinoma and suggest the incorrect diagnosis of a non-functioning
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14 pituitary tumour (57).

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15 Noteworthy, current assay methodologies are mainly based on two-site immunometric

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16 assays, which are more sensitive and specific than previous competitive assays but are also
17 susceptible to some interferences such as the high-dose hook effect (58). Sandwich assays,
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18 generally performed in two steps or by diluting the samples, are able to avoid this
19 interference, so nowadays the high-dose hook effect persists in a very small minority of PRL
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20 assays (58). Nevertheless, consideration of the hook effect should be taken in PRL assay
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21 recommendations (58).
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23 Macroprolactin
24 Macroprolactin is an isoform of PRL with greater molecular weight and reduced biological
25 activity. In patients with asymptomatic hyperprolactinemia, the assessment for
26 macroprolactin can help endocrinologists in preventing incorrect diagnoses leading to
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1 inappropriate treatments, and in discriminating true hyperprolactinemia requiring a proper
2 therapeutic approach (55, 59). Although more than 80% of circulating PRL is monomeric (23
3 kDa), serum can also contain a covalently bound dimer and a larger polymeric form, known
4 as “big prolactin” (50 kDa) and “big-big prolactin” (150 kDa), respectively (55, 59). In most
5 cases, macroprolactin is composed of a complex formed by an IgG and a monomeric PRL
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6 (60,61); consequent hyperprolactinemia results from low renal PRL clearance and reduced
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7 dopaminergic tone (62). Macroprolactin is quite common, as it has been reported to cause
8 hyperprolactinemia in approximately 20% of cases (63). Therefore, the screening for
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9 macroprolactin with the use of polyethylene glycol (PEG) should be routinely offered, before
investigating alternative causes of PRL excess, in patients with asymptomatic
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11 hyperprolactinemia (55, 63). The overall prevalence of signs and symptoms of PRL excess
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12 in patients with macroprolactin is generally lower than that observed in patients with
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13 monomeric hyperprolactinemia (64). Indeed, menstrual disturbances, including both
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14 oligomenorrhea and amenorrhea, as well as galactorrhea and a combination of menstrual

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15 disturbances and galactorrhea have been reported to occur in 24%, 13% and 2% of patients
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16 with macroprolactin, respectively, presumably resulting from concomitant disorders, such as
17 polycystic ovary syndrome, pituitary tumours, etc., as compared to 26%, 29% and 34% of
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18 those with monomeric hyperprolactinemia, respectively (64), thus suggesting a potential
19 overlap in the clinical presentation mainly in terms of infertility features (64). Noteworthy,
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20 more than 60% of patients with macroprolactin reported no peculiar signs and symptoms of
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21 PRL excess (64). The coexistence of macroprolactin and pituitary incidentalomas may result
22 in a further diagnostic pitfall leading to an improper diagnosis of prolactinoma (62), but the
23 absence of a clinical syndrome specifically ascribable to hyperprolactinemia may assist in a
24 better diagnostic definition (64).
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1 Diagnosis at menopausal age
2 Menopause is associated with a physiologic decline of the stimulatory effects of estrogens
3 on PRL secretion and lactotroph cell proliferation, and a physiological reduction in circulating
4 PRL levels (65). Therefore, in postmenopausal women, when fertility does not represent a
5 foremost concern, the lack of the classical amenorrhea-galactorrhea syndrome due to PRL
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6 excess may result in the underestimation of the exact prevalence of prolactinomas (65).
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7 This is particularly true for women with microprolactinomas, although at least one-third of
8 those diagnosed at menopausal age have reported secondary amenorrhea in their medical
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9 history (65-67), suggesting that a scrupulous investigation of these symptoms during fertile
age might prompt an earlier diagnosis (65). Most patients (92%) with prolactinomas
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11 diagnosed after menopause have been found to harbour a pituitary macroadenoma, or even
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12 a giant pituitary tumour (66-68), leading predominantly to signs and symptoms of mass
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13 effect, such as headache and visual loss, with pituitary apoplexy occurring in approximately
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14 5% of cases (66-68). The evidence of large tumour size and frequent invasiveness of
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15 prolactinomas in postmenopausal women has raised the question of whether these tumours
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16 are biologically comparable to those of male patients (65), likewise characterized by rapid
17 growth rate and increased markers of cellular proliferation (9, 36), albeit a lower estrogen
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18 receptor α expression, together with low estrogen production, may per se promote lactotroph
19 cell proliferation and trigger the development of large, invasive pituitary tumours in
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20 postmenopausal women (69).

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21
22 Aggressive and malignant prolactinomas
23 Lactotroph tumours are the second-most frequent aggressive and malignant tumours (70).
24 According to the last WHO classification of pituitary tumours (38), pituitary adenomas have
25 been renamed with the term pituitary neuroendocrine tumours (PitNET) in replacement of
26 adenomas, and specific clinical, pathological, and radiological characteristics have been
15
1 proposed to identify aggressive and malignant PitNET, including prolactinomas. In this light,
2 attention should be paid to tumour invasiveness and proliferation. Invasion is defined on the
3 basis of histological and/or radiological evidence of cavernous or sphenoid sinus invasion,
4 whereas proliferation is defined on the basis of a mitotic count >2/10 HPF, Ki-67 3% and
5 >10 p53 strongly positive nuclei/10 HPF (71). Lactotroph tumours developing in patients
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6 younger than 20 years, mainly in males, and/or with a genetic predisposition have generally
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7 a poor prognosis because of a larger size, more frequent invasiveness, and overt resistance
8 to DA (70) leading to a high risk of recurrence and malignancy. Densely granulated PIT-1
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9 positive PRL-secreting pituitary tumours, mixed somatotroph–lactotroph tumours and pluri-
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10 hormonal PIT-1-positive acidophilic stem cell tumours (tumours of lactotroph differentiation
11
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often associated with hyperprolactinemia) are generally more invasive than sparsely
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12 granulated variants and less responsive to conventional medical therapy with DA, with
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13 overall reduced cure rates (38). The expression of proliferation markers (Ki-67 expression
14 ≥3%, mitotic count >2) is also correlated with tumour invasiveness and proliferation (70).
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15 Low estrogen receptors  expression and high vascular endothelial growth factor and
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16 epidermal growth factor expression are similarly correlated to tumour aggressiveness, and
17 the expression of some adhesion molecules such as E-cadherin, matrix metalloproteinase

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18 9, and abnormalities in chromosomes 1, 11, and 19 has also been correlated with tumour
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19 aggressiveness (38, 70). As for all PitNET subtypes, according to pathological and/or
20 radiological findings (71), lactotroph tumours can be classified based on a five degree-scale
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21 as: non-invasive and non-proliferative (grade 1a); non-invasive and proliferative (grade 1b);
22 invasive and non-proliferative (grade 2a); invasive and proliferative (grade 2b); metastatic
23 tumour (grade 3). Based on this classification, grade 2b (aggressive) lactotroph tumours
24 have a 20 times higher risk of progression compared to grade 1a tumours (71).
25 As for aggressive lactotroph tumours, malignant prolactinomas are the second most
26 frequent malignant pituitary tumours after ACTH-secreting pituitary carcinomas (72). The
16
1 exact incidence of PRL-secreting carcinomas is yet to be clearly defined, as that of all
2 pituitary carcinomas, known to be very rare (less than 0.2% of all pituitary tumours).
3 According to the recent European Society surveys (73, 74), malignant prolactinomas have
4 been reported to account for approximately 9% of patients with aggressive and malignant
5 pituitary tumours. The definition of malignant prolactinomas parallels that of all pituitary
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6 carcinomas and requires the confirmation of distant cerebrospinal, meningeal and/or
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7 systemic metastases (72).
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9 BACK TO THE CASES
CASE 1
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10
11 At the endocrinological assessment performed after 12 months of continuous treatment with

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12 cabergoline, PRL levels were fully normalized (PRL 8.6 µg/L) and pituitary MRI revealed a
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13 slight reduction in pituitary tumour volume (1.71 cm 3, = -13%). The pituitary evaluation
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14 revealed the restoration of normal gonadotropins and testosterone levels, which were
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15 associated with satisfactory libido and erectile function. Therefore, cabergoline was
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16 maintained at the same dose and the addition of testosterone replacement treatment was
17 not required. Pituitary evaluation performed over the years revealed the persistence of
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18 normoprolactinemia while on treatment with cabergoline, associated with a further reduction
in pituitary tumour volume (1.43 cm3, = -27% compared to the baseline). At the last
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19
20 endocrinological evaluation performed in February 2022, PRL levels were 10.6 µg/L and
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21 pituitary MRI revealed a further shrinkage in tumour volume (1.14 cm 3, = -42% compared
22 to the baseline). Nowadays, the patient is receiving cabergoline at the dose of 1.0 mg/week,
23 PRL being 6.7 µg/L. Occasionally headaches persist, whereas clinical symptoms of
24 decreased libido and erectile dysfunction did not recur after starting cabergoline treatment.
25 The clinical history of this patient is shown in Figure 3.
26
17
1 CASE 2
2 At endocrinological consultation in March 2020, evident facial disfigurement was associated
3 with macroglossia, soft tissue swelling, and arthralgia, thus suggesting the diagnosis of
4 acromegaly. In this suspicion, hormonal and MRI evaluations were immediately performed.
5 As expected, IGF-I was 3.9 x the upper limit of normal (ULN), and pituitary tumour was two-
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6 fold increased in maximal tumour diameter (9 mm vs 4.5 mm), whereas PRL was 30.7 µg/L,
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7 thus confirming the diagnosis of acromegaly. Metabolic, cardiological and respiratory
8 complications and colon polyps were excluded. Due to the COVID-19 pandemics, trans-
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9 sphenoidal surgery treatment was not possible at that time because of the restrictive
measures limiting or delaying routine non-urgent clinical procedures and was therefore
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10
11 postponed, considering that no peculiar symptoms ascribable to tumour mass effect were
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12 complained by the patient except for headaches. In fact, treatment with the somatostatin
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13 analogue lanreotide 120 mg every 28 days was started. IGF-I was normalized (0.9 x ULN)
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14 after 3-months of medical therapy, but the clinical syndrome associated with acromegaly
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15 persisted. Lanreotide was continued at the same dose until September 2020, when
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16 neurosurgery was feasible due to the restarting of routine procedures in Italian hospitals.
17 The report of the histological examination lay for pituitary GH-secreting tumour,
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18 immunohistochemically characterized by diffuse positivity for GH and focal for LH, rare cells
19 immunoreactive for PRL, and Ki-67 %/MIB-1 proliferation index <1 %. One month later, the
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20 post-operative assessment showed full PRL normalization (23 µg/L) but persistently
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21 elevated GH (12.6 µg/L) and IGF-I (1.2 x ULN), therefore lanreotide was restarted at the
22 dose of 90 mg every 28 days. In January 2021, biochemical and radiological complete
23 remission of acromegaly was documented and lanreotide was withdrawn. Five months later,
24 normal IGF-I values (118 µg/L, 0.4 x ULN) were still recorded. Nowadays, acromegaly
25 remission is still confirmed by IGF-I 0.4 x ULN (133 µg/L), with evidence of secondary empty
26 sella at MRI, and no medical treatment is required to maintain disease control in this patient.
18
1 Up to date, PRL levels are still within the normal range. The clinical history of this patient is
2 shown in Figure 4.
4 CASE 3
5 Despite the important reduction in pituitary tumour size during postsurgical treatment with
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6 cabergoline (7.030 cm3, = -24.5%), PRL normalization was never achieved during follow-
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7 up. In February 2012, PRL rapidly rose to 3500 µg/L, and a significant increase in tumour
8 size was registered (tumour volume= 20.827 cm3, = +66%), the tumour being still located
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9 at the cavernous sinus level, totally surrounding the right sinus and leading to the paresis of
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10 the III, IV and VI cranial nerves. Due to uncontrolled hyperprolactinemia and worsening
11
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neurological symptoms, the patient voluntarily underwent the second trans-sphenoidal
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12 surgery to achieve tumour debulking and cranial nerve decompression in March 2012. The
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13 second histological examination revealed an atypical prolactinoma with a sparsely
14 granulated pattern, Ki-67 %/MIB-1 proliferation index of 7%, and adenoma pleomorphism
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15 with "dot-like" reactivity for PRL at immunohistochemistry. Postoperative pituitary function

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16 assessment revealed the persistence of hyperprolactinemia (PRL 2523 µg/L), and
17 concomitant secondary hypocortisolism, for which proper replacement therapy was started.
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18 To counteract the biological aggressiveness, high-dose (3 mg/week) cabergoline therapy

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19 was resumed, and the somatostatin analogue lanreotide was added at the dose of 120 mg
20 every 28 days in order to limit residue growth. Despite this combined therapy, PRL did not
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21 normalise (PRL 1225 µg/), thus requiring a further increase in cabergoline dose to 4.5
22 mg/week. Despite high-dose cabergoline, PRL persisted very high (PRL 988 µg/L) and a
23 dramatic headache together with sudden visual loss occurred, suggesting the potential
24 regrowth of the tumour. In December 2012, 9-months after the second neurosurgery, the
25 patient underwent the third trans-sphenoidal surgery, immediately followed by fractional
26 stereotaxic radiotherapy (25 fractions of 1.8 Gy each, for a total dose of 45 Gy, isodose
19
1 92.8%), which was performed on a lesion of 2.638 cm3, confirming the rapid tumour regrowth
2 after the third surgical procedure. After radiotherapy, cabergoline monotherapy was still
3 required at the dose of 3.5 mg/week, PRL being 376 µg/L. After radiotherapy secondary
4 hypocortisolism and hypogonadism were confirmed, whereas somatotropic and thyrotropic
5 axes were still preserved. High-dose cabergoline therapy was continued with a modest
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6 gradual reduction in PRL levels. As expected, one year after radiotherapy secondary
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7 hypothyroidism was diagnosed and L-thyroxine replacement was started, whereas IGF-I
8 levels were still within the normal range. PRL below 100 µg/L (84.7 µg/L) was achieved in
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9 March 2016, i.e., only 3-years after radiotherapy, with a slow and continuous PRL decrease
under cabergoline therapy being observed in the following years. Although never
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10
11 normalized, PRL nadir (38.8 µg/L) was registered in June 2021. Concomitantly, progressive
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12 tumour shrinkage was observed after radiotherapy reaching maximal efficacy in July 2022
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13 (tumour volume 0.619 cm3, = -76.5%). Nowadays, the patient is receiving cabergoline at
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14 the dose of 1.5 mg/week, PRL being 37 µg/L. Replacement therapies were constantly
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15 adjusted according to hormonal evaluations during follow-up. Particularly, testosterone

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16 replacement treatment allowed the complete recovery of signs and symptoms of
17 hypogonadism, confirming the relevant benefits provided by close monitoring and proper
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18 therapy. Clinical symptoms definitively disappeared, and the patient complained of

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19 headaches only occasionally. Since prolonged high-dose cabergoline therapy was
20 administered, echocardiography evaluations were regularly performed in order to study

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21 valves’ function and early detect possible insufficiency. Although high-dose cabergoline for
22 10 years, no valvular dysfunction occurred in this patient. At the last follow-up in July 2022,
23 nine years after radiotherapy, GH deficiency was lastly documented. The clinical history of
24 this patient is shown in Figure 5.
25
26
20
1 APPROACH TO PATIENT MANAGEMENT
2 Before DA became accessible for medical therapy, surgery and/or radiation therapy were
3 the treatment approaches of choice for prolactinomas (75). The introduction of DA in the
4 therapeutic algorithm for prolactinomas totally changed the natural course of these tumours,
5 offering a successful treatment strategy that progressively substituted surgery and
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6 radiotherapy in routine clinical management (75). DA, mainly cabergoline, are nowadays
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7 recommended as the treatment of choice to lower PRL levels, decrease tumour size, and
8 restore gonadal function for patients harbouring PRL-secreting tumours, regardless of
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9 tumour size (2, 4, 32, 75). However, multimodal therapy also including surgery and/or
radiotherapy may be required in patients resistant to DA or for those with aggressive
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10
11 prolactinomas (75).
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12
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13 Indications to treat patients with hyperprolactinemia
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14 The goals of treatment for prolactinomas include PRL normalization, decrease in tumour
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15 size and restoration of gonadal function (2, 4, 34, 55). In patients with prolactinomas
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16 effective treatments result in relief from the effects of tumour mass, including
17 hypopituitarism, visual field defects, headaches, and cranial nerve palsy; and relief from the
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18 effects of PRL excess, including hypogonadism, infertility, and osteopenia/osteoporosis (2).
19 Noteworthy, asymptomatic patients with microprolactinomas do not categorically require

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20 treatment (2, 34), since these tumours rarely grow up over years (76). Conversely,
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21 independently of tumour size, the presence of a clinical syndrome of PRL excess support
22 the introduction of PRL-lowering therapy (2,3). However, hypogonadal premenopausal
23 women with microadenomas without pregnancy desire may benefit from oral
24 contraceptives/sex hormone replacement instead of dopamine agonists (34). Caution
25 should be paid to periodic evaluation of PRL levels and potential growth of microadenomas
21
1 following treatment with oral estrogen therapy, albeit no clear evidence of tumour
2 enlargement after estrogen therapy has been provided so far (34).
3 The presence of a macroadenoma represents per se a strong indication of treatment, given
4 the known propensity of these tumours to grow (2). Additional indications for treatment
5 include tumour invasiveness and compression of adjacent structures, such as pituitary stalk
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6 or optic chiasm (2, 34).
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7
8 Medical treatment of prolactinomas: dopamine agonists
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9 Effects on PRL excess, tumour mass and gonadal status
DA represent the recommended treatment to achieve therapeutic goals (2, 5, 34). The use
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10
11 of DA is based on the intrinsic property of dopamine to bind type 2 dopamine receptors

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12 (D2DR), which are G-coupled receptor proteins whose activation is able to suppress PRL
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13 secretion in the pituitary lactotrophs, as well as PRL gene expression and lactotroph
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14 proliferation (77). Among DA, bromocriptine and cabergoline are the most commonly used
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15 compounds in clinical practice worldwide, whereas pergolide, quinagolide and lisuride are
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16 less frequently used or not available anymore (34). Cabergoline is strongly recommended
17 as the treatment of choice for prolactinomas of any size, given the proven greater efficacy
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18 over different DA either in PRL normalization and tumour shrinkage (34, 78-80), although
19 head-to-head comparison studies among different DA formulations are still limited. In

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20 patients with microprolactinomas and macroprolactinomas, cabergoline has been reported

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21 to induce PRL normalization and tumour shrinkage in 95% and 80%, respectively (81).
22 Regardless of tumour size, PRL normalization has been accomplished in 76% of patients
23 treated with bromocriptine, 87% of those treated with pergolide, and 89% of those treated
24 with cabergoline (81). While on cabergoline, tumour shrinkage has been shown to occur in
25 60% of patients previously treated with other DA (79). A similar biochemical and tumoral
22
1 effectiveness of cabergoline has been documented also in patients of paediatric and
2 adolescent age (2, 12).
3 Following treatment with cabergoline, amenorrhea, infertility, galactorrhoea and sexual
4 dysfunction have been reported to improve in 82%, 53%, 86% and 67%, respectively, of
5 women with prolactinomas (34, 55). The rapid amelioration of women's fertility justifies the
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6 advice to use mechanical contraception in patients without pregnancy desire (34, 55).
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7 Hypogonadism may persist only in a minority of women with prolactinomas and may require
8 replacement treatment (34, 55). Symptomatic hyperprolactinemic hypogonadal women may
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9 be cautiously administered estrogens/progesterone therapy but careful periodic observation
is recommended, although a negative outcome on tumour size has not been documented
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10
11 to date (82). In men receiving cabergoline, hypogonadism, seminal fluid parameters (sperm
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12 count and volume), decreased libido and erectile dysfunction have been reported to improve
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13 in 60%, 100% and 61% of cases, respectively (83-85). However, restoration of normal
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14 testosterone may be not sufficient to correct sexual dysfunction and seminal abnormalities,
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15 thus requiring testosterone replacement therapy (34, 55, 83-85). In these patients, attention
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16 should be paid to specific side effects of improper testosterone replacement treatment, such
17 as aggressiveness, hypersexuality, polycythaemia and prostate enlargement, generally

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18 caused by excessive dosages thus compelling proper dose adjustment (85). While on
19 testosterone replacement therapy, potential testosterone aromatization to estrogen may

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20 occur, virtually stimulating the proliferation and hyperplasia of lactotroph cells in the pituitary
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21 and inducing resistance to dopamine agonists (82). In case of persistent hypogonadism
22 despite PRL normalization following treatment with dopamine agonists, clomiphene citrate
23 may represent an option to improve sperm quality and restore fertility (82).
24
25
23
1 Effects on metabolic profile
2 Additional extra-pituitary and extra-gonadal effects of medical therapy with cabergoline
3 mainly include a metabolic gain (86). Long-term treatment with cabergoline has been
4 demonstrated to ameliorate or even recover metabolic consequences of PRL excess and
5 hypogonadism (39, 40, 87-90), such as altered body composition, insulin resistance,
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6 impaired glucose tolerance, and adverse lipid profile, known to trigger visceral obesity and
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7 metabolic syndrome (39-45). Long-term treatment with cabergoline has been shown to
8 significantly reduce body weight, BMI and waist circumference, thus improving visceral
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9 obesity (87-90). However, independently of the reduction in body weight, the impact on
visceral obesity is supported by the direct beneficial effects of DA on glucose metabolism,
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10
11 insulin resistance and lipid fractions. Indeed, both bromocriptine and cabergoline have been
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12 reported to induce a significant improvement in glucose metabolism and insulin resistance
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13 after 6 months of treatment for prolactinomas (39, 40, 87-90). Particularly, cabergoline
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14 significantly reduced fasting insulin and HOMA-IR in prolactinomas, predominantly when

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15 used at doses higher than 0.5 mg/week (87, 88). The positive impact on insulin metabolism
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16 is strengthened by the significant improvement seen also in insulin secretion and peripheral
17 sensitivity (88). That this favourable action can be directly attributed to cabergoline rather
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18 than to weight loss is confirmed by the evidence that cabergoline dose was the best predictor
19 of the per cent decrease in fasting insulin (89). In male patients with concomitant
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20 hypogonadism, known to negatively affect insulin metabolism, fasting insulin and indices of
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21 insulin resistance, secretion and sensitivity were found to improve after long-term treatment
22 with cabergoline and further ameliorated by testosterone replacement treatment (90). Even
23 in case of resistance to conventional cabergoline doses requiring high dose treatment
24 protocol (dose range 2-7 mg/week, median 3 mg/week), despite PRL normalization
25 occurring only in half of the patients, fasting insulin and indices of insulin secretion and
26 peripheral sensitivity significantly improved regardless from a concomitant amelioration of
24
1 fasting glucose and BMI, whereas pituitary surgery failed to achieve a similar outcome on
2 insulin metabolism (91). The improvement seen in the insulin profile parallels the
3 amelioration of lipid fractions (40, 87, 88, 90, 92-94). The reduction of total and LDL
4 cholesterol and triglycerides, together with the increase in HDL cholesterol occurring after
5 treatment with either bromocriptine or cabergoline, has been shown to be independent of
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6 changes in body weight (40, 87, 88, 90, 92-94). As for insulin metabolism, in male
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7 hyperprolactinemic patients with concomitant hypogonadism, treatment with cabergoline
8 has been demonstrated to significantly reduce total and LDL-cholesterol and triglycerides,
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9 without a further amelioration of lipids after testosterone replacement therapy (88).
Conversely, the use of a high-dose cabergoline schedule did not remarkably improve lipid
U
10
11 metabolism, whereas pituitary surgery was able to significantly reduce total cholesterol and
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12 triglycerides (91), suggesting that lipid fractions might be affected more markedly by the
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13 rapid correction of PRL excess rather than by DA.
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14 The direct consequence of the metabolic advantage induced by DA is a reduction by 20%

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15 in the prevalence of metabolic syndrome (87, 88, 90, 95).

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16
17 Safety and tolerability

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18 Over years, the longer half-life and the reduced incidence of side effects contributed to
19 progressively enhancing the use of cabergoline in preference to other DA in clinical practice.

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20 Adverse effects of cabergoline are generally less frequent, less severe, and of shorter
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21 duration as compared to other DA (2), and mainly include nausea or vomiting, headache,
22 dizziness, vertigo, and arterial hypotension (2, 96). Noteworthy, DA use has been found
23 associated, albeit rarely, with the occurrence of compulsive behaviour and psychosis.
24 Particularly, even at low doses bromocriptine has been reported to induce mania in
25 postpartum women and psychotic reactions in patients with pre-existing mental disorders
26 (96). Conversely, similar findings have been very occasionally reported following treatment
25
1 with cabergoline (96). Based on this evidence, the use of DA to achieve normal PRL levels
2 in patients with antipsychotic-induced hyperprolactinemia is still questionable, as DA might
3 exacerbate underlying psychosis (34).
4 Given the high binding affinity of cabergoline for serotonin receptor subtype 2B, whose
5 activation reportedly promotes fibroblast proliferation and mitogenesis at the cardiac valve
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6 level (97, 98), over the last fifteen years several independent studies (99-120) have
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7 investigated the potential association between the use of cabergoline and the development
8 of clinically relevant cardiac valve disease in patients with prolactinomas, as previously
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9 demonstrated in patients with Parkinson’s disease (121-123). Noteworthy, the experience
collected in patients with Parkinson’s disease has demonstrated that cardiac valve disease
U
10
11 occurred in 29% to 39% of patients, usually receiving cabergoline at doses as high as 3-5
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12 mg/day and mean weekly doses up to 25 mg and taking median cumulative doses ranging
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13 from 2600 to 6700 mg (121-123). Conversely, standard doses of cabergoline routinely used
M
14 for patients with prolactinomas do not exceed 2 mg/week in most cases, and only a minority
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15 of patients require higher doses to achieve disease control. A recent meta-analysis

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16 investigating the prevalence of cardiac valvulopathy did not confirm a similar association
17 and found no significant increase in the prevalence of any valvular disease in patients with
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18 hyperprolactinemia receiving cabergoline at standard doses as compared to controls, apart
19 from a slight increase in mild (i.e., non-clinically relevant) tricuspid regurgitation (124). Based
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20 on these findings and considering that the cabergoline dose threshold at which valve
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21 abnormalities can occur is yet to be fully elucidated, a standard transthoracic
22 echocardiogram before starting treatment with cabergoline (or pergolide) is still
23 recommended (125). Nevertheless, given that the evidence of clinically relevant valve
24 disease is nearly absent, and that generally the use of cabergoline at doses  2 mg/week is
25 not associated with pathological changes in leaflet thickness, restriction, or retraction (125),
26 a transthoracic echocardiogram should be repeated every 5 years in patients treated with
26
1 cabergoline doses  2 mg/week, or yearly in those receiving higher doses (125).
2 Cabergoline duration and cumulative dose have been shown to exert no significant impact
3 on cardiac valvulopathy in prolactinomas (126).
5 Resistant and aggressive prolactinomas
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6 According to International Guidelines (34), resistance to DA occurs in case of failure to
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7 achieve PRL normalization and at least ≥ 50% reduction in tumour size at maximally
8 tolerated doses. Following treatment with DA, some patients may display discordant
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9 responses, as PRL normalization may be not associated with a reduction in tumour size or
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10 vice versa (34); other patients may display partial responsiveness and require higher than
11
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standard doses of DA to achieve a satisfactory response (34). However, the definition of
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12 resistance to DA is still open to question, as there is no full consensus about the definition
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13 of the DA dose to which the drug should be up-titrated before classifying a patient as
14 resistant to DA (127), and specifically, if this dose should be ≥2.0 mg/week for cabergoline
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15 and ≥15 mg/day for bromocriptine (127).

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16 Primary resistance to DA in prolactinomas is rare, accounting for 20-30% of patients treated
17 with bromocriptine and nearly 10-20% of those receiving cabergoline (127, 128). Secondary
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18 resistance to DA has been seldom reported in patients with prolactinomas, but its
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19 occurrence has been generally linked to poor prognosis and potential aggressive or
20 malignant progression of the pituitary tumour (129-135). Several molecular mechanisms

A
21 may cause the development of resistance to DA (136). Among them, genetic variants,
22 intracellular signalling alterations and the expression of the small single-stranded non-
23 coding RNA molecules microRNA (miRNA), that function in RNA silencing and post-
24 transcriptional regulation of gene expression, may lead to a decreased number of D2DR, a
25 decreased affinity of D2DR for DA, or an altered signal transduction rising resistance to DA
26 (136). Particularly, a decreased mRNA stability and synthesis of D2DR due to genetic
27
1 alterations, such as the gene variant NcoI T+, has been reported to cause resistance to DA
2 (137). On the other hand, estrogens may affect the balance between the short (D2S) and
3 long (D2L) isoforms of D2DR, increasing the expression of the latter and thus limiting the
4 effectiveness of DA (138-140). Intracellular signalling may be negatively affected by
5 cytoskeleton proteins, such as Filamin-A (141) or -arrestins (142, 143), known to act as
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6 scaffolds for signalling molecules involved in D2DR signal transduction in lactotroph tumours
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7 and in dopaminergic neurotransmission. More recently, resistance to DA has been found
8 associated with an increased expression of miR-93-5p (144, 145) and miR-1299 (146), or a
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9 reduced expression of miR-145 (147).
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10 Resistance to DA may require different therapeutic approaches to be overcome. In patients
11
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resistant to a certain DA, dose escalation to maximally tolerated doses is recommended
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12 (34), as in clinical case 3. Cabergoline doses as high as 12 mg/week have been needed to
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13 overthrow resistance (148). Alternatively, the switch from different DA to cabergoline may
14 increase responsiveness to medical therapy (34). Indeed, six-month treatment with

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15 cabergoline at a dose range of 0.5-3 mg/week has been shown to induce PRL normalization
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16 in nearly 63% and tumour shrinkage in more than 44% of patients with proven resistance to
17 long-term bromocriptine or quinagolide (149), thus demonstrating that patients unresponsive

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18 to different DA may benefit from chronic administration of cabergoline. Successful disease

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19 control resulted in the restoration of gonadal function in 70% of patients (149).
20 Nevertheless, some patients may require a multi-modal therapeutic approach, including the
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21 association of medical therapy and surgery, ultimately combined with radiotherapy,
22 particularly in presence of aggressive tumours (34, 150), as in clinical case 3. Such a
23 treatment strategy has successfully controlled 56% of patients (151). Resistance to
24 cabergoline represents the first clear indication for surgery in prolactinomas (152), together
25 with pituitary apoplexy, intolerance to DA, persistent chiasmal compression despite optimal
26 medical therapy, cerebrospinal fluid leak while on DA and psychiatric conditions in
28
1 macroadenomas (152). Interestingly, surgical debulking has been found to prompt a
2 significant decrease in PRL levels while reducing the weekly cabergoline dose by 50% (153).
3 In experienced hands, initial remission rates with surgery were approximately 40% and 75%
4 for macroprolactinomas and microprolactinomas, respectively, and long-term remission
5 rates were approximately 65% and 80% for macroprolactinomas and microprolactinomas,
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6 respectively (35). However, the improvement of surgical techniques over years has
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7 progressively increased the successful use of neurosurgery also as a first-line treatment in
8 prolactinomas, resulting as effective as cabergoline in patients with enclosed adenomas not
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9 located laterally from the gland and not invasive to the cavernous sinus (154). In these
patients, the surgical approach could increase cure rates and reduce the requirement of
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10
11 dopamine agonists for those not cured by first-line surgery, also limiting medical costs and
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12 side effects of chronic dopamine agonist treatment (155). Conversely, tumours invasive to
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13 cavernous sinus have been reported to be associated with a higher risk of venous bleeding
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14 and a lower remission rate as compared to enclosed tumours (154). So far, surgery (83%)
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15 has been shown to provide similar outcomes as compared to dopamine-agonists (91%) in

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16 terms of achievement of biochemical control in patients with microprolactinomas, but not in
17 those with macroprolactinomas, in whom the rate of biochemical control is higher in

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18 medically treated (77%) as compared to surgically treated (60%) patients, according to a
19 recent meta-analysis (154). Altogether, this evidence supports the use of surgery as a viable
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20 first-line therapeutic choice for patients with enclosed and not invasive prolactinomas, also
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21 suggesting an adequate tailoring of treatments based on tumour characteristics, size and
22 invasiveness.
23 Radiotherapy, in any form, is nowadays considered a third-line treatment and is reserved
24 for those patients with macroadenomas resistant to either medical therapy or surgery, as in
25 clinical case 3, mainly because of the long latency to therapeutic efficacy and the frequent
26 occurrence of hypopituitarism (34).
29
1 Aggressive and malignant prolactinomas refractory to all treatment strategies may benefit
2 from the administration of the oral alkylating chemotherapeutic agent temozolomide (Figure
3 6), whose efficacy in terms of tumour growth control accounts for up to 50% of patients with
4 prolactinomas (156). According to the European Society survey of 166 patients, including
5 38 with aggressive lactotroph tumours, the use of temozolomide in aggressive
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6 prolactinomas resulted in complete regression in 5%, partial regression in 45%, stable
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7 disease in 26% and tumour progression in 24% of cases (73). Temozolomide is nowadays
8 recommended as first-line chemotherapy for aggressive pituitary tumours and pituitary
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9 carcinomas, following documented tumour growth (157). Responsiveness to temozolomide
may be predicted by the evaluation of O(6)-methylguanine methyl transferase (MGMT)
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10
11 status by immunohistochemistry by expert neuropathologists, as high MGMT expression is

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12 generally suggestive of a lack of response (158). Indeed, tumour regression has been
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13 documented in 46% of tumours with low MGMT expression, but only in 23.5% of those with
M
14 high MGMT expression (157). The first evaluation of the response to temozolomide should
D
15 be done after the first 3 cycles (157). If radiological progression is demonstrated,

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16 temozolomide treatment should be stopped (158). Conversely, in patients proven to respond
17 to first-line temozolomide after 3 cycles, treatment can be continued for at least 6 months or
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18 longer time if a sustained therapeutic benefit is observed (157). As for all chemotherapeutic
19 agents, close monitoring of haematological parameters, liver function tests and careful
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20 clinical observation should be performed for potential adverse effects (fatigue, nausea,
A
21 vomiting, etc.) (157). The effectiveness of temozolomide has been shown to increase when
22 combined with radiotherapy given its radio-sensitizing properties, thus offering a further
23 therapeutic option for those individuals with aggressive or malignant prolactinomas (156,
24 157). Indeed, tumour regression has been documented in 71% of patients receiving
25 temozolomide and radiotherapy combined treatment, but only in 34% of those receiving
26 temozolomide monotherapy (157). The combination of temozolomide and radiotherapy can
30
1 be offered to patients with rapid tumour growth in whom maximal doses of radiotherapy have
2 not been reached (158). However, disease progression has been reported to occur in 38%
3 of cases despite treatment with temozolomide (158). A second trial of 3 cycles of
4 temozolomide can be attempted in patients developing recurrence following the initial
5 response to the drug (157). Alternatively, a trial with other systemic cytotoxic therapy can be
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6 proposed in patients with rapid tumour progression while on temozolomide (157).
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7
8 Management after treatment withdrawal
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9 In selected cases, treatment with DA for prolactinomas may result in a complete cure and
can be definitively stopped. Specifically, after bromocriptine discontinuation persistent
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10
11 normoprolactinemia reportedly ranged from 7% to 44% (159-1665), thus indicating a wide

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12 variability in the long-term outcome after bromocriptine withdrawal. Recurrence of
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13 hyperprolactinemia generally occurred within three months after bromocriptine
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14 discontinuation (159-165). However, symptomatic tumour regrowth has been reported to

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15 occur in less than 10% of cases (166, 167), and to be influenced by the duration of previous
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16 DA treatment (163). Tumour re-expansion was successfully managed by bromocriptine
17 restarting (167). A greater success has been demonstrated after cabergoline withdrawal
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18 (Table 3). Preliminary studies (168-173) have reported the persistence of
19 normoprolactinemia after cabergoline withdrawal to range from 10–31% of patients. In a

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20 prospective study, 36-48 months after cabergoline discontinuation persistent

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21 normoprolactinemia was found in 19 out of 25 (76%) patients with non-tumoral
22 hyperprolactinemia, 73 out of 105 (70%) of those with microprolactinomas, and in 45 out of
23 70 (64%) of those with macroprolactinomas (174). The median time to recurrence of
24 hyperprolactinemia ranged from 12 to 18 months (174). The Kaplan-Maier estimate of
25 disease recurrence at five years was significantly lower in patients with non-tumoral
26 hyperprolactinemia as compared to those harbouring a pituitary tumour, and in patients with
31
1 no evidence of tumour remnant at MRI before cabergoline withdrawal as compared to those
2 with residual tumour (174). The role of tumour mass as the main determinant of long-term
3 remission was confirmed by the finding that the maximal diameter during cabergoline
4 treatment was the best predictor of the PRL level at the last follow-up visit after treatment
5 discontinuation, with a 19% hazard rate for the recurrence of hyperprolactinemia for each
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6 millimetre increment in the maximal tumour diameter (174). Nowadays, the achievement of
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7 a residual tumour maximal diameter smaller than 3.1 mm in size associated with nadir PRL
8 levels <5.4 μg/L is considered the best predictor of long-term remission from
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9 hyperprolactinemia after cabergoline withdrawal (175).
Altogether, these findings guided the advice that after therapy with DA for at least 2 years a
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10
11 trial of progressive DA dose lowering and discontinuation can be started if PRL levels are
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12 normal and the tumour volume is evidently shrunk (55).
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13 As shown in Table 3, the application in clinical practice of the aforementioned criteria for DA
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14 discontinuation in prolactinomas has resulted in a substantial progressive increase in the

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15 long-term remission rate after treatment withdrawal up to 75% of patients (176-184).

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16 Nevertheless, the pooled proportion of patients with persisting normoprolactinemia after DA
17 withdrawal was 21% in a systematic review and meta-analysis (185), where remission rates
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18 were confirmed to be higher in idiopathic hyperprolactinemia (32%) and microprolactinomas
19 (21%) as compared to macroprolactinomas (16%).

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20 In patients with evidence of recurrence of hyperprolactinemia after treatment

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21 discontinuation, DA must be restarted. However, a second withdrawal may be attempted if
22 patients have received cabergoline for 2 additional years (186, 187). Evidence from previous
23 studies has documented a successful outcome, defined as the achievement of
24 normoprolactinemia, in 30% of cases (186, 187).
25 Altogether, these findings suggest that more than one-third of patients totally fulfilling the
26 criteria for drug discontinuation may exhibit persistent normoprolactinemia over time.
32
1 However, a careful follow-up after therapy withdrawal remains strongly recommended to
2 identify as soon as possible the recurrence of hyperprolactinemia and/or tumour regrowth
3 requiring prompt treatment restarting (55).
5 Management in pregnancy
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6 Given the great efficacy of DA in restoring fertility almost immediately after treatment starts,
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7 mechanical contraception should be recommended in women beginning DA therapy and
8 without pregnancy desire (34, 55). For those women with macroprolactinomas wishing
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9 pregnancy, conception should be planned after the achievement of PRL normalization
together with a marked reduction in tumour mass, primarily to minimize the risk of optic
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10
11 chiasm compression in case of tumour expansion during pregnancy (34, 55). Noteworthy,
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12 the risk of tumour enlargement during pregnancy is modest and however influenced by
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13 tumour size and previous treatments (188). In fact, tumour growth has been reported to
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14 occur in 2.4% of microadenomas and 4.7% of macroadenomas treated with surgery or

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15 radiotherapy before pregnancy, as compared to 21.0% of those with macroadenomas not

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16 receiving prior surgery or radiotherapy (188). In pregnant women, tumour re-expansion can
17 be suspected in case of persistent or worsening headaches or abnormal visual field testing

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18 (188). In such cases, PRL cannot be used as a biomarker of disease activity, as PRL levels
19 beyond the threshold do not suggest unquestionably tumour growth and cannot prompt
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20 therapeutic concerns per se, unless PRL increases up to the levels measured at diagnosis,
A
21 thus advising a pituitary MRI for a more accurate diagnostic assessment (189).
22 The low risk of tumour enlargement during pregnancy has provided the reason why women
23 with prolactinomas must be instructed to withdraw DA as soon as pregnancy is confirmed
24 (34, 55), as in clinical case 2. In fact, in humans, bromocriptine has been demonstrated to
25 cross the placenta (188); data collected in animal models have confirmed a similar effect for
26 cabergoline but definitive confirmation in humans is still lacking (188). However, exposure
33
1 to bromocriptine or cabergoline within the first 6 weeks of gestation has been found not to
2 increase the risk for unfavourable maternal and foetal outcomes, including spontaneous
3 abortions, ectopic pregnancies, trophoblastic disease, multiple pregnancies, or congenital
4 malformations (188,190, 191). To a similar extent, long-term follow-up studies (up to 12
5 years) on children born from mothers treated with bromocriptine or cabergoline before
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6 pregnancy have rarely reported abnormalities in physical or mental development (192, 193).
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7 The use of DA during pregnancy is not officially approved, with the only exception of
8 bromocriptine, whose use is approved for conception (194). Nevertheless, in selected
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9 patients with macroadenomas who become pregnant while on DA and who have not had
prior therapy, it may be cautious to continue DA throughout the pregnancy, especially if the
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10
11 tumour is invasive or abutting the optic chiasm (34). In patients experiencing symptomatic
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12 growth of a prolactinoma during pregnancy treatment restarting is recommended, and
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13 bromocriptine is the therapy of choice (34, 194), based on the large experience over years
M
14 not documenting any increased risk for maternal and foetal outcomes (191). The experience
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15 with the use of cabergoline throughout pregnancy is still scant and limited to a few studies,
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16 however resulting in at-term delivery in most cases, while pre-term delivery and intrauterine
17 death occurred in less than 7% of cases (192, 193).

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18 After pregnancy, an absolute restriction of breastfeeding is not mandatory, as it has been
19 demonstrated to be not associated with an increased risk of tumour expansion (191, 195).
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20 However, in patients harbouring large residual tumours abutting the optic chiasm,
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21 breastfeeding should be adequately considered and tailored based on tumour
22 characteristics, invasiveness and size. Nevertheless, DA cannot be used until the desired
23 breastfeeding has been completed (34).
24 Noteworthy, pregnancy may contribute to triggering spontaneous remission from
25 hyperprolactinemia (191, 194, 196-202). As shown in Table 4, approximately 39% of
26 patients with prolactinomas have been reported to experience a spontaneous fall in PRL
34
1 levels following pregnancy and breast-feeding (192, 194, 196-202), with permanent
2 discontinuation of cabergoline being reported in up to 66% of patients with
3 microprolactinoma, 70% of those with macroprolactinoma and in 100% of women with non-
4 tumoral hyperprolactinemia (191). Older maternal age, lower PRL at diagnosis and tumour
5 size at diagnosis have been found to be the main determinants for the achievement of
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6 normoprolactinemia (201). A role for vascular and molecular mechanisms has been
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7 hypothesized to explain the naturally occurring remission from hyperprolactinemia after
8 pregnancy. The acute decrease in blood pressure and the hemodynamic changes directly
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9 caused by the delivery and placental expulsion could lead to the auto-infarction of
prolactinomas, thus inducing a decrease in PRL secretion (191). On the other hand, the
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10
11 expression of estrogen receptors, known to affect lactotroph growth and differentiation, may
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12 play a role in the reduction in tumour size after pregnancy (203-206).
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13
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14 Management in menopause
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15 In postmenopausal women, prolactinomas are rarely diagnosed (207-211). With the

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16 beginning of menopause, the physiological state of hypogonadism is generally associated
17 with the spontaneous decline in the stimulatory effects of estrogens on PRL secretion and
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18 lactotroph cell proliferation, resulting in the reduction of circulating PRL levels (208, 209).
19 Consequently, in postmenopausal women microprolactinomas can remain undiagnosed for

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20 a long time as they lack specific features of hormonal hypersecretion (210, 211). In absence
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21 of signs and symptoms of PRL excess and given the reportedly low risk of enlargement for
22 microprolactinomas, postmenopausal women may not require medical treatment with DA
23 (207). To a similar extent, patients with microprolactinomas diagnosed at fertile age and
24 passing through menopause may be successfully discontinued from DA. Indeed,
25 spontaneous remission from hyperprolactinemia after DA withdrawal has been reported to
35
1 occur in two-thirds of postmenopausal women, mainly those with microprolactinomas,
2 whereas the observed recurrence rate was 33% of patients (212-215).
3 However, most women of menopausal age harbour macroadenomas or giant tumours,
4 responsible for a clinical picture mainly characterized by signs and symptoms of mass
5 effects rather than PRL excess (216-218). Headache and visual loss have been reported to
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6 be the most common features at presentation; pituitary apoplexy due to very large tumours
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7 has been experienced in approximately 5% of cases (217-219). Therefore, in
8 postmenopausal women with macroprolactinomas treatment with DA should be cautiously
SC
9 maintained to counteract tumour enlargement (207). In selected patients with
macroprolactinomas not abutting the optic chiasm and stable in size while on low DA doses,
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10
11 a trial of DA withdrawal can be contemplated, nonetheless offering careful monitoring of

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12 tumour progression (207).
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13 The use of DA during menopause might be further supported by the evidence that these
M
14 compounds could improve cardiometabolic and bone health in these patients, as already
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15 documented in men with prolactinomas and in women with hypothalamic amenorrhea (86,
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16 219, 220). In this light, the choice to discontinue DA should be carefully weighed considering
17 their beneficial effects at peripheral levels, regardless of PRL and tumour control (207).
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18
19 AREAS OF UNCERTAINTY AND FUTURE LANDSCAPE

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20 Despite the remarkable effectiveness of DA in the therapeutic management of

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21 prolactinomas, patients with aggressive or malignant tumours are still orphans of successful
22 drugs able to overcome resistance to standard treatments or disease recurrence.
23 Aside from surgery, radiotherapy, and chemotherapy with temozolomide, alternative
24 treatment schedules have been investigated or are nowadays tested in clinical and
25 preclinical models, but the experience is still too scant to draw definitive conclusions. Among
26 them, alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide
36
1 therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors and immunotherapy, appeared to
2 offer promising results, as shown in Figure 6.
3 The rationale for the use of selective estrogen receptor modulators (SERMs, Figure 6) in
4 prolactinomas rose from the evidence that estrogens affect PRL homeostasis in the
5 hypothalamus, anterior pituitary, and posterior pituitary (221, 2232). Prolonged exposure
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6 and high doses of estrogens result in an increase in PRL levels; such effects are mediated
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7 by estrogen receptors (ER) alpha and beta, which are expressed on lactotroph cells and
8 induce cell proliferation in cultured lactotrophs (221, 222). In vitro tamoxifen has been shown
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9 to prevent tumour growth and suppress PRL synthesis in the rat pituitary gland (223, 224).
In patients with giant, invasive, resistant prolactinomas the use of SERMs, such as
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10
11 tamoxifen and raloxifene, has been found associated with a decrease in PRL levels by at
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12 least 20% of baseline values (225-227), and an additive effect to bromocriptine (225, 226)
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13 or cabergoline (227) has been documented. Nevertheless, high heterogeneity in the
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14 achievement of complete biochemical control, defined as PRL normalization, has been

D
15 reported, varying from 0% (225) to 58.3% (226) and to 71% (227), and data about tumour
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16 outcomes were not available.
17 Different steroid hormones, mainly progesterone, have been recently investigated as

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18 potential treatments for resistant prolactinomas (228). Whereas in rats the binding of nuclear
19 progesterone receptors reportedly triggers classical, genomic pathways able to prevent the
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20 hypertrophic and hyperplastic effects of estrogens by reducing the number of proliferating

A
21 cells and increasing cell death (229), the activation of membrane progesterone receptors
22 (mPRα, Figure 4), belonging to the progestin and adipoQ receptor family and mediating non-
23 genomic progesterone effects, has been proposed to induce a rapid DA release in
24 hypothalamic dopaminergic neurons (229). The consequent binding of DA to D2DR in the
25 rat pituitary lactotrophs might activate TGFβ1 and decrease cAMP levels, thus inhibiting
26 PRL secretion (228). The simultaneous mPRα activation in the lactotroph cell membrane
37
1 might induce the inhibition of the adenylyl cyclase activity and cAMP levels, the
2 phosphorylation of ERK and the activation of TGFβ1, resulting in the inhibition of PRL
3 secretion (229). These promising preclinical results in rats are still waiting for clinical
4 confirmation in humans.
5 However, in patients with DA-resistant prolactinomas a higher expression of somatostatin
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6 receptors (SSTRs, Figure 6) has been demonstrated as compared to those DA-sensitive
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7 (230). SSTR5 and SSTR1 have been found to be highly expressed in DA-resistant tumours
8 compared to SSTR2 and SSTR3 (230, 231). Interestingly, in DA-sensitive adenomas SSTR
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9 expression was neglectable as compared to D2DR expression (230). At high concentrations,
selective binding of SSTR5 by BIM-23268, but not that of SSTR2 by octreotide or BIM-
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10
11 23197, has been demonstrated to inhibit PRL secretion with similar and not additive effects
N
12 to DA (230). The in vitro investigation of pasireotide-mediated PRL suppression has led to
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13 the conclusion that pasireotide potently inhibited PRL secretion in primary cultures of GH
M
14 and PRL co-secreting adenomas (232) but was almost ineffective in DA-resistant
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15 prolactinomas (231), whereas the use of the chimeric SSTR-DR compound BIM-23A760
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16 was associated with an approximately 20% decrease in PRL levels, suggesting partial
17 effectiveness of this drug (231).

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18 This evidence has encouraged the clinical application of treatment with the first-generation
19 somatostatin analogue octreotide (233, 234) and the novel somatostatin analogue
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20 pasireotide (235, 236) as alternative therapeutic approaches for resistant prolactinomas, but
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21 with discordant results. Indeed, the addition of octreotide LAR to cabergoline has been
22 reported to induce a remarkable tumour shrinkage but only modest inhibition of PRL
23 secretion in selected patients (233, 234), as in clinical case 3, whereas anecdotal cases
24 reporting the use of pasireotide monotherapy in resistant aggressive prolactinomas have
25 documented the achievement of long-term biochemical and tumoral control (235, 236),
38
1 suggesting the potential application of pasireotide in the therapeutic algorithm of resistant
2 prolactinomas.
3 The known expression of SSTRs and the evidence for uptake of radiolabeled somatostatin
4 analogues, such as 68Ga-DOTATATE (237), in prolactinomas have also fostered the
5 investigation of peptide receptor radionuclide therapy (PRRT) effectiveness in aggressive
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6 prolactinomas. Treatments with 111Ind-DTPA-Octreotide (238, 239), 68Ga-DOTATATE
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7 (240), and 17Lu-DOTATOC (239) in patients resistant to multiple surgeries, radiotherapy
8 and medical therapy with temozolomide have been reported to variably reduce tumour
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9 volume and PRL levels in some cases (238, 239), or to be almost ineffective in other cases
(240), leading to the conclusion that proper identification of candidates to PRRT and timing
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10
11 of treatment is mandatory in order to increase the therapeutic efficacy of this promising

N
12 approach.
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13 The modest and partial effectiveness of hormonal and peptide receptor treatments in
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14 aggressive and malignant prolactinomas provided the basis to extend research studies to
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15 other alternative therapeutic strategies, sharing the oncological experience.

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16 Cytotoxic chemotherapies have been tested in PRL-secreting carcinomas, but with no
17 evident success. Several chemotherapy protocols, based on the use of carboplatin (241) or
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18 associations of lomustine/5-fluorouracil (241), lomustine/procarbazine/etoposide (240),
19 carboplatin/etoposide (242), 5FU/oxaliplatin (237) and cisplatin/procarbazine/lomustine/

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20 vincristine (243), have been shown to produce a modest tumoral response, sometimes
A
21 requiring permanent discontinuation due to haematological toxicity (244).
22 To a similar extent, mTOR inhibitors (Figure 6) have been proposed for aggressive
23 prolactinomas after the activation of the PI3K/AKT/mTOR pathway has been demonstrated
24 in murine GH3 cell lines and in PRL-secreting pituitary tumours (245). In GH3 cell lines, both
25 cabergoline and the mTOR inhibitor everolimus monotherapies have been shown to inhibit
26 cell proliferation and PRL secretion, but combined treatment has been found to produce a
39
1 synergistic effect only on the suppression of PRL levels but not on cell proliferation (245). At
2 immunohistochemistry evaluation, elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6
3 have been demonstrated in tumour tissues (245). The administration of everolimus in
4 association with cabergoline in a patient with an aggressive prolactinoma resulted in PRL
5 decrease and tumour regression in five months, followed by tumour stabilization and PRL
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6 re-increase for 12 months (245).
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7 The effectiveness of the anti-angiogenic anti-VEGF agent bevacizumab (Figure 6) in
8 aggressive or malignant prolactinomas is yet to be investigated. In pituitary adenoma tissue
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9 samples, western blot analysis has demonstrated high expression of VEGF in approximately
59% of 197 different pituitary tumours, mainly in PRL, ACTH, FSH-secreting and non-
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10
11 functioning pituitary adenomas (246). In aggressive ACTH-secreting (246, 247) or non-

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12 functioning (248) adenomas resistant to multiple surgical, chemotherapy and radiotherapy
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13 approaches, the use of bevacizumab as monotherapy (248) or in combination with
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14 temozolomide (245) has resulted in remarkable hormonal reduction (245, 248) and tumour
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15 stabilization (248), raising the question of whether similar results can be expected also in
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16 prolactinomas.
17 After epidermal growth factor receptor 2 (HER2)/ErbB2 overexpression has been

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18 demonstrated in murine models of prolactinoma and ErbB receptor ligands have been
19 shown to regulate PRL gene expression (249), the use of the tyrosine kinase inhibitor (TKI,
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20 Figure 6) gefitinib, an EGFR antagonist (249), and lapatinib, a dual TKI of both epidermal
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21 growth factor receptor (EGFR)/ErbB1 and HER2 (250), has been tested on cell proliferation
22 and PRL secretion in animal and human models. Suppressed cell proliferation (249, 250),
23 blocked PRL gene expression (250), inhibited PRL mRNA expression and secretion (250),
24 and reversed EGF-mediated somatotroph-lactotroph phenotype switching (250) have been
25 demonstrated to occur following treatment with gefitinib or lapatinib. Based on this evidence,
26 clinical trials investigating the effects of targeted tyrosine kinase inhibitor (TKI) treatment in
40
1 aggressive resistant (251) or malignant (252) prolactinomas have been proposed. Tumour
2 shrinkage (251) or stabilization (252) were reported, with PRL levels not always paralleling
3 tumour outcomes, suggesting the potential application of such target therapy in well-
4 selected patients with aggressive prolactinomas or carcinomas.
5 Lastly, a high expression of programmed death-ligand 1 (PD-L1, Figure 6) has been
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6 demonstrated in functioning pituitary tumours, mainly PRL-secreting, and has been
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7 correlated with aggressive behaviour (253). In clinical practice, the association of anti-PD-
8 L1 nivolumab and anti-CTLA4 ipilimumab has been reported to induce a significant reduction
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9 in pituitary tumour volume and the dominant liver metastasis and hormonal values in a
patient with ACTH-secreting carcinoma (254). The evidence about the use of immune
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10
11 checkpoint inhibitors in patients with prolactinomas nowadays is limited to four cases, in

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12 which the use of immune checkpoint inhibitors resulted in complete/partial radiological
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13 response in 50% and complete biochemical response in 33% (255).
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14
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15 CONCLUSIONS
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16 The approach to the patient with prolactinoma is uncomplicated in most cases. The peculiar
17 clinical picture, mainly characterized by hypogonadism concerns in both sexes, together

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18 with signs and symptoms of mass effect in presence of a macroadenoma, suggests the
19 diagnosis of a PRL-secreting pituitary tumour, and a single PRL assessment together with
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20 a pituitary MRI are sufficient to carry out the correct diagnosis. Nevertheless, some pitfalls,
A
21 namely the hook effect and macroprolactin, may tangle and confound the diagnostic workup.
22 Similarly, in menopausal age the lack of fertility concerns may mask the presence of a
23 prolactinoma leading to a diagnostic delay. Therapeutic management of prolactinomas is
24 primarily based on using cabergoline as first-line and often sole medical therapy required to
25 control PRL excess and tumour mass and restore fertility. In patients treated with
26 cabergoline for at least two years and achieving residual tumour maximal diameter <3.1 mm
41
1 in size and nadir PRL levels <5.4 μg/L, cabergoline can be totally curative and definitively
2 withdrawn, with long-term remission being seen in approximately 40% of cases and disease
3 relapse occurring within the first 12 months after treatment discontinuation in most patients.
4 Some physiologic conditions in women, such as menopause and pregnancy, may prompt a
5 spontaneous decline in PRL levels allowing treatment withdrawal. However, 10-20% of
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6 prolactinomas display resistance to cabergoline, which may be overcome by increasing the
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7 drug dose to the maximally tolerated or offering pituitary surgery and radiotherapy.
8 Resistance to cabergoline is a common feature of aggressive or malignant prolactinomas,
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9 defined on the basis of tumour invasiveness and proliferation. Aggressive and malignant
prolactinomas generally require a combination of medical therapy with surgery and
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10
11 radiotherapy. Unfortunately, intrinsic biological aggressiveness due to a high proliferation

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12 rate in some cases may limit the effectiveness of the multimodal approach compelling the
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13 use of alternative therapeutic strategies. Temozolomide is nowadays considered the
M
14 treatment of choice for patients with aggressive or malignant prolactinomas, but

D
15 responsiveness to treatment appears to be influenced by the MGMT expression in the

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16 tumour. The effectiveness of temozolomide can be enhanced by combining this
17 chemotherapy with radiotherapy, but this approach is nowadays reserved for patients with
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18 rapid tumour growth in whom maximal doses of radiotherapy have not been reached. In
19 case of ineffectiveness of all available therapeutic strategies, new medical approaches,

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20 including alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide

A
21 therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors or immunotherapy, may be
22 considered but the experience collected to date is still too scant to draw definitive
23 conclusions. Future studies will clarify the potential applications of such treatments, driving
24 endocrinologists in the choice of the best-tailored therapy for patients with aggressive and
25 malignant prolactinomas.
26
42
1 FINANCIAL SUPPORT
2 None.
4 DATA AVAILABILITY
5 Data sharing is not applicable to this article as no datasets were generated or analysed
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6 during the current study.
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7
8 AFFIRMATION OF ORIGINALITY AND AUTHORSHIP
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9 The work submitted for publication is original and has not been published elsewhere for print or
10 electronic publication consideration. The authors affirm that each person listed as the authors
11
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participated in the Work in a substantive manner. RSA gave substantial contributions to the
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12 conception and design of the work, the acquisition, analysis, and interpretation of literature, and
A
13 to the drafting of the manuscript. RPir, CP and FG gave substantial contributions to the
M
14 acquisition and interpretation of literature and to the drafting of the figures. AC and RPiv gave
D
15 substantial contributions in revising the manuscript critically for important intellectual content.
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16 RPiv provided the final approval of the version to be published. All authors consent to the
17 investigation of any improprieties that may be alleged regarding the Work. Each author further
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18 releases and holds harmless the Endocrine Society from any claim or liability that may arise
19 therefrom.
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20
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15 246. Wang Y, Li J, Tohti M, Hu Y, Wang S, Li W, Lu Z, Ma C. The expression profile
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29 HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for
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9 Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and
10 Nivolumab. J Clin Endocrinol Metab. 2018 Oct 1;103(10):3925-3930
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11 255. Ilie MD, Vasiljevic A, Jouanneau E, Raverot G. Immunotherapy in aggressive
12 pituitary tumors and carcinomas: a systematic review. Endocr Relat Cancer. 2022
May 27;29(7):415-426.
U
13
14
N
15 Table 1: Causes of hyperprolactinemia
A
Physiologic Pathologic
Coitus Pituitary stalk section
M
Physical exercise Primary hypothyroidism

Lactation Granuloma
Pregnancy Infiltrative diseases: sarcoidosis, histiocytosis
D
Sleep Cranial/hypothalamic radiation

Stress Trauma
TE
Pituitary disease
Idiopathic hyperprolactinemia
Acromegaly
EP
Hypophysitis
Macroadenoma (impingement of pituitary stalk)
Macroprolactinemia
CC
Prolactinoma
Surgery*
Trauma*
Rathke’s cleft cyst*
A
Hypothalamic: tumors*: craniopharyngioma, germinoma,

hypothalamic metastases, meningioma
Systemic Disease
Surgery, Herpes Zoster, Chest or spine lesions
Chronic kidney
Liver insufficiency
Liver cirrhosis
Epilepsy/seizure
Polycystic ovarian syndrome
Breast and nipple stimulation
68
Drugs
Anaesthetics (benzodiazepines, ketamine, propofol)
Anticonvulsants (phenytoin)
Antidepressants (amoxapine, imipramine, amitriptyline, fluoxetine)
H2 Antihistamines (cimetidine, ranitidine)
Antihypertensive (-metildopa, reserpine, verapamil)
Dopamine receptor blockers (metoclopramide, sulpiride, domperidone)
Estrogens/oral contraceptives/oral contraceptives withdrawal)
PT
Neuroleptics/antipsychotics (perphenazine, fluphenazine, flupenthixol, promazine,
haloperidol, loxapine, chlorpromazine, pimozide, risperidone)
Opiates (methadone, morphine, heroin)
RI
*Via stalk effect
SC
U
N
1
A
2
M
3
D
TE
EP
CC
A
69
1 Table 2: responsiveness to treatment with dopamine agonists in patients with prolactinomas
2 in the context of a Multiple Endocrine Neoplasia type 1 (MEN-1)
3
Author, yr (Ref) Patients Prolactinomas (%) Micro Macro DA responders
(%)
Burgess, 1996 (24) 165 18* 7 5 7 (58.3)**
PT
Verges, 2002 (25) 324 84 (26) 13 71 35 (42)
de Laat, 2015 (26) 323 50 (15.5) 30 20 31 (59.6)
RI
Goroshi, 2016 (27) 18 8 (44.4) 3 5 8 (100)
SC
Vannucci, 2017 (28) 22 7 (31.8) 5 2 5 (71.4)
TOTAL 852 167 (19.6) 58 103 86 (51.5)
U (34.7) (61.7)
4
N
*
5 6 patients with normal pituitary scan
A
**
6 calculated on 12 patients with tumor evidence at pituitary scan
7
M
D
TE
EP
CC
A
70
R
SC
1

2 Table 3: Prevalence of long-term remission from hyperprolactinemia after DA withdrawal: an overview of the literature.
U
3
N
Remission (%)
A
Author, year Patient no Therapy Duration (mos) Follow-up NTHP Micro Macro Overall
(Ref) (mos)
M
Johnston, 1984 15 BRC 42 12 NA NA NA 7
(159)
Zarate,
(164)
1983 ED 16 BRC 24 24 - 17 100 37.5
Moriondo, 1985 36 BRC 24 30 - 22 - 22

PT
(160)
Wang, 1987 24 BRC 24 12-48 40 8.7 4.3 10
(162)
E
Rasmussen, 75 BRC 24-65 6 NA NA NA 44

CC
1987 (161)
Van’t Verlaat, 12 BRC 36-84 12 - - 9 9
1991 (1613)
A
Passos, 2002 131 BRC 48 42 - 26 16 20.6

(1635)
Remission from 2/5
309 28/133 (21%) 17/108 (15.7%) 19.1
Bromocriprine (40%)
Ferrari, 1992 127 CAB 40-84 12 8.1 7 10 7.9
(171)
Muratori, 1997 26 CAB 12 38-60 - 19 - 19
(172)
71
R
SC
Cannavò, 1999 37 CAB 24 12 - 15.4 9.1 13.5

U
(173)
Colao, 2003 175 CAB 48 24-60 76 70 64 68.5
N
(174)
Colao, 2007 194 CAB 36-45 48 74 66 47 60
A
(175)
M
Kharlip, 2009 46 CAB 52 52 25 48 45 45.6
(177)
Sala, 2016 (181) 74 CAB 66-79 12 - 56 50 54
Espinosa-
Cárdenas, 2020
ED
50 CAB 60 132-408 - 18.7 38.3 32
(183)
PT
Kim, 2021 (184) 44 CAB 12-120 12-97 - 78.9 63.6 75
Remission from 238/479

773 43/93 (46.2%) 119/253 (47%) 48.5
E
Cabergoline (49.7%)
Biswas, 2005 89 Both 37 12 - 36 - 36
CC
(169)
Guitelman, 2006 100 Both 24-60 60 - 20 3 15
(176)
A
Huda, 2010 40 Both 108 12 - 22.5 - 22.5

(176)
Barber, 2011 60 Both 90 3-36 - 36 7 28.3
(179)
Anagnostis, 26 Both 79 24 - 60 50 57.7
2012 (180)
Teixeira, 2017 50 Both 11885 - - 78 44.4 72
(182)
72
R
SC
Total 1447 45/98 (45.9%) 381/853 145/423

U
(44.6%) (34.3%)
Abbreviations: NTHP, non-tumoral hyperprolactinemia; BRC, bromocriptine; CAB, cabergoline; NA, not available
N
1
A
2
M
ED
E PT
CC
A
73
1
2 Table 4: spontaneous remission from hyperprolactinemia after pregnancy: overview of
3 literature
Author, yr (Ref) Patient no Remission rate (%)
PT
Crosignani, 1989 (196) 54 17
Crosignani, 1992 (197) 176 29
RI
Jeffcoate, 1996 (198) 70 35
SC
Huda, 2010 (199) 40 10
Auriemma, 2013 (191) 91 68
Domingue, 2014 (200) 73

U 41
N
Araujo, 2017 (201) 25 12
A
O'Sullivan, 2020 (2002) 47 25
M
Sant' Anna, 2020 (193) 194 10

D
Total 770 27.8

TE
6
EP
CC
A
74
1 LEGEND TO FIGURES
2 Figure 1: clinical characteristics of patients with prolactinoma. Pituitary tumour per se exerts
3 several compressive mass effects, leading to headache, visual field defects and
4 hypopituitarism. Prolactin excess results in both sexes in weight gain, delayed pubertal
5 development, hypogonadism, infertility, galactorrhea, and osteopenia or osteoporosis. Other
PT
6 signs and symptoms are gender-related and include in men libido reduction, erectile
RI
7 dysfunction, and gynecomastia; in women oligo-amenorrhea, vaginal dryness, irritability,
8 and depression. Created with Biorender.com.
SC
9
Figure 2: diagnostic workup for hyperprolactinemia. Scarceness or absence of the peculiar
U
10
clinical syndrome of PRL excess in patients with PRL levels <250 g/L should suggest the
11
N
A
12 screening for macroprolactin before performing a pituitary MRI (left). In patients with overt
clinical syndrome of PRL excess and PRL values >250 g/L the diagnosis of a prolactinoma
M
13
14 can be ruled in and a pituitary gadolinium-enhanced MRI is strongly recommended (right),

D
15 to investigate for the presence of a microadenoma or a macroadenoma. Discrepancy

TE
16 between PRL levels and tumour size, particularly in case of tumour size > 3 cm, should
17 suggest a potential hook effect and requires the reassessment of the sample with serum
EP
18 dilution (at least 1:100, middle). Created with Biorender.com.

CC
19
20 Figure 3: Biochemical and radiological evolution of patient no 1. The left panel shows
A
21 changes in PRL levels from diagnosis to the last follow-up. The right panel shows changes
22 in tumour size from the first available MRI to the last follow-up.
23
75
5 Figure 6: Alternative medical treatment in resistant prolactinoma: molecular mechanisms
PT
6 explored in murine models. Temozolomide elicits cytotoxicity through the methylation of
RI
7 DNA guanine and adenine residues, leading to single- and double-strand DNA breaks.
8 Prolonged exposure to estrogens induces the growth of lacotroph cells and PRL synthesis,
SC
9 this latter by binding the estrogen receptors (ER) alpha and beta, abundantly expressed on
lactotroph cells, and by activating the estrogen responsive elements (ERE) and other
U
10
11 transcription factors (TF). Tamoxifen, by competing with estrogens at the receptor site and
N
12 blocking the promotional role of estrogens, has been shown to prevent tumour growth and
A
13 suppress PRL synthesis in the rat pituitary gland. Synthetic progestins have been recently
M
14 investigated as potential treatments for resistant prolactinomas because of their capability

D
15 to bind the membrane progesterone receptors (mPRα), by mediating non-genomic

TE
16 progesterone effects, and inducing a rapid DA release by hypothalamic dopaminergic
17 neurons. The consequent binding of DA to D2DR in the rat pituitary lactotrophs might
EP
18 activate the Transforming growth factor beta 1 (TGFβ1) transcription and decreases the
19 adenylate cyclase (AC) and cAMP levels, leading to the inhibition of PRL secretion.
CC
20 Similarly, somatostatin analogues, with high binding affinity to SSTR5, BIM-23268 and
A
21 pasireotide, and chimeric compounds, binding SSTR5/D2DR, BIM-23A760, have been
22 demonstrated to reduce PRL synthesis by reducing AC and cAMP levels in rat pituitary cell
23 lines. Everolimus, the mTOR inhibitor, by decreasing the downstream molecules p70S6k
24 and 4eBP1, induces cell proliferation inhibition as a consequence of reduced protein
25 synthesis. The blocking of vascular endothelial growth factor (VEGF) by bevacizumab and
26 of epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2)
76
1 tyrosine kinase phosphorylation by lapatinib and gefitinib, inhibits the activation of
2 proliferative signalling. Finally, the blocking of PD-L1 with nivolumab and of CTLA4 with
3 ipilimumab can prevent the immune escape of lactotroph tumour cells. Created with
4 Biorender.com.
PT
RI
SC
U
N
A
M
D
TE
EP
6
7 Figure 1
8 170x119 mm ( x DPI)
CC
9
A
77
78
PT
RI
SC
U
N
170x113 mm ( x DPI)
170x74 mm ( x DPI)
A
Figure 2
Figure 3
M
D
TE
EP
CC
A
1
2
3
4
5
6
7
79
PT
RI
SC
U
170x78 mm ( x DPI)
N
170x92 mm ( x DPI)
Figure 4 A
Figure 5
M
D
TE
EP
CC
A
1
2
3
4
5
6
7
8
80
PT
RI
SC
U
N
170x119 mm ( x DPI)
A
Figure 6
M
D
TE
EP
CC
A
1
2
3

Abordaje Del Paciente Con Hiperprolactinemia

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Abordaje Del Paciente Con Hiperprolactinemia

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Approach to the Patient with Prolactinoma

1 Renata S. Auriemma1, Rosa Pirchio1, Claudia Pivonello2, Francesco Garifalos1,3, Annamaria

2 Colao1,4, Rosario Pivonello1,3,4

3 1.Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di

6 della Riproduzione e Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di

15 Abstract: 253; Manuscript: 12117; Tables: 4; Figures: 6; References: 255

17 Address for correspondence

18 Rosario Pivonello, MD, PhD, Prof.

19 Dipartimento di Medicina Clinica e Chirurgia

21 Via Sergio Pansini 5

22 80131 Naples, Italy

11 Strongbridge Biopharma, Recordati, Corcept Therapeutics, Crinetics Pharmaceuticals, ARH

14 FG have nothing to declare.

18 being prevalent in women and macroprolactinomas in men. Hyperprolactinemia is among

20 medical advice for hypogonadism (infertility, oligo-amenorrhea, impotence,

3 anticipate cabergoline discontinuation in women. Surgery and/or radiotherapy are indicated

8 monotherapy or combined with radiotherapy. In uncontrolled patients, new medical

therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors or immunotherapy) may be offered

23 first endocrinological assessment, pituitary function investigation revealed

8 cabergoline was maintained at the same dose.

15 displayed a multi-follicular aspect with no clear evidence of polycystic ovary syndrome,

22 revealed a microadenoma of 8 mm maximal diameter. The patient’s facial characteristics

2 responsiveness to cabergoline was optimal, with complete PRL normalization (PRL=18

15 after cessation of breast-feeding resulted as high as 30.7 µg/L.

25 seen. At the first endocrinological assessment, pituitary function investigation revealed

3 tumour mass. A concomitant seminal fluid examination revealed the presence of

8 chromophobic cells, sparsely granulated pattern, characterized by numerous mitoses (MI=3-

16 increased to 2 mg/week during follow-up. Testosterone replacement therapy was

2 leading to an early diagnosis, as in clinical case 2. Conversely, in men the rate of

3 macroprolactinomas with visual field defects, as in clinical case 3, and hypopituitarism at

cases/100.000/year, prolactinomas have been reported to represent 40-66% of all pituitary

15 clinical syndrome due to hypogonadism (infertility and oligo-amenorrhea) prompts early

16 medical advice, particularly in case of pregnancy desire. Conversely, in elderly patients,

19 represent about 50% of all pituitary tumours (12, 13).

21 THE INTERPLAY BETWEEN PROLACTIN AND FERTILITY

22 Hyperprolactinemia is the most common cause of secondary hypogonadism and infertility in

8 secretory/adsorptive functions of male reproductive organs (22). In infertile men, the

endocrine disorders, including hyperprolactinemia, reportedly account for only 2–4% of

11 cases of male infertility (14).

16 germline genetic mutations predisposing to pituitary tumour development in the context of

25 behaviour leading to occasional tumour growth without clinical consequences (26-28). To a

2 aggressive clinical behaviour as compared to sporadic tumours. In the context of Carney

4 hyperplasia leading to the development of GH and/or PRL-secreting adenomas. In fact,

11 from early diagnosis (29).

17 pubertal development, hypogonadism, infertility, galactorrhea, and osteopenia or

20 reduction, erectile dysfunction, and gynecomastia; in women oligo-amenorrhea, vaginal

22 amenorrhea–galactorrhea syndrome generally encourages rapid medical consultation, as in

24 be frequently underestimated, as in clinical case 1, leading to a diagnostic delay (35), as in

26 hypothesized, since rapidly growing prolactinomas with increased markers of cellular

8 immunostaining. The latter identifies tumours composed of a monomorphous population of

11 acidophilic lineage of adenomas (38). These PIT-1 immunoreactive adenomas belonging to

16 pancreatic -cells and adipocytes, hyperprolactinemia may also induce an unfavourable

20 approximately one-third of patients (39-45). However, the potential impact of

21 hyperprolactinemia-induced hypogonadism on body composition and metabolic profile

24 metabolic syndrome (46). Similarly, in 40 premenopausal hyperprolactinemic women, in

5 induced hypogonadism) effects of prolactin on bone physiology, early alterations in bone

The diagnostic workup for hyperprolactinemia is shown in Figure 2. As reported in Table 1,

14 parasellar mass, and granulomatous infiltration of the hypothalamus), as well as several

15 drugs (mainly antidepressants, dopamine receptor blockers, dopamine synthesis inhibitors,

16 oral contraceptives, gastrointestinal medications, neuroleptics and antipsychotics), can

17 induce symptomatic hyperprolactinemia (34, 55). Before a correct diagnosis of

18 hyperprolactinemia is made, such conditions must be investigated and excluded. Attention

19 should be paid to medical history, concomitant medications, and biochemical assessment

21 occasionally may mask the presence of a prolactinoma (34), as in clinical case 2. To