madman
Super Moderator
Italian Association of Clinical Endocrinologists (AME) and International Chapter of Clinical Endocrinology (ICCE). Position statement for clinical practice: prolactin-secreting tumors (2022)
Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio , Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini , Laurence Katznelson, Anton Luger and Catalina Poiana on behalf of AME
Abstract
Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.
1. Introduction
*1.a. Why this document
Prolactinomas are the most prevalent pituitary tumors. Medical therapy with dopamine agonists (DA) has been considered the first-line treatment for relieving symptoms, normalizing hyperprolactinemia, and reducing tumor size in the majority of patients, whereas surgery as a second-line treatment is indicated only for the minority of patients showing resistance or intolerance to DA, for patients with pituitary apoplexy, or based on patient’s preference (1). Technical advances have improved surgical outcomes, obtaining total removal of the tumor, a high rate of disease remission, and sparing normal pituitary function (2). Thus, the improvement of surgery could change in some prolactinomas the paradigm of DA chronic treatment as a first-line therapeutic strategy.
Prolactinoma is a clinical entity that includes different parameters: micro-and macroadenoma, males and females, patients with fertility consideration or postmenopausal, children or elderly patients, sensitivity or resistance to DA, presence of mass effect, and aggressive behavior (3). An individually tailored treatment is thus needed to manage a wide variety of settings, including the drawbacks of DA treatment in patients with psychiatric diseases.
To discuss all these aspects, a group of Italian experts has gathered together their clinical experience on the diagnostic and therapeutic challenges of prolactinoma patients, aiming to better define the most updated clinical approach and therapeutic options. Panelists were selected by the endorsing scientific societies (AME and ICCE) and included 15 endocrinologists with skill in the management of pituitary diseases (one skilled in scientific methodology), two neurosurgeons skillful in pituitary surgery and working in a high-volume pituitary center, one expert of laboratory medicine, and one neuroradiologist.
*1.b. Methodology
*1.c. Epidemiology, morbidity, and mortality
Prolactinomas are the most common pituitary adenoma, accounting for approximately 50% of all pituitary adenomas, with a prevalence of ∼50 per 100 000 population and an incidence of 3–5 new cases/100 000/year (8, 9). In autoptic series, a high prevalence of undiagnosed pituitary adenomas (almost all tiny tumors) has been detected (10.4%) and prolactinomas represented 40% of them (10).
Based on tumor size, they are classified as microprolactinomas (microP, <10 mm diameter) or macroprolactinomas (MP, ≥10 mm diameter). MicroPs are mainly observed in premenopausal women, whereas MPs are more common in men aged more than 50 years. Giant tumors (>40 mm) are rare (1–5% of all prolactinomas). They are diagnosed mostly in men aged between 20 and 50 years (median 42) and occasionally in older men or postmenopausal women and even in the pediatric population, with a reported male-to-female ratio of ∼9:1 (11, 12).
In a few cases, other pituitary hormones are secreted in excess beyond prolactin (PRL) (mostly growth hormone (GH)).
PRL-producing pituitary carcinomas are rare and defined by the presence of cerebrospinal, meningeal, or systemic metastases (13).
In clinical series of patients aged more than 65 years, prolactinomas account for 4–8% of pituitary adenomas but the prevalence may be actually underestimated in elderly women and men due to reduced attention to symptoms of hypogonadism (9, 11).
Pituitary adenomas are rare in children and adolescents and account for 3–4% of all intracranial tumors in this age group (14). The mean age at diagnosis was 16.1 ± 2.5 years (range: 4.5–20 years). The incidence of prolactinomas in this age group is 0.1 per 1 000 000 population, and they are more frequently diagnosed in girls than in boys (up to 80% of cases) (15). MPs are more prevalent than microPs in pediatric populations (58% vs 42%) (16). Prolactinomas are larger and more frequently invasive in boys than in girls as in the adult counterpart (16).
Prolactinomas can also belong to genetic syndromes (see below at 4.d), with reportedly higher aggressive behavior.
Prolactinomas are not associated with increased prevalence of diabetes, cardiovascular diseases, and cancer, as shown in a population-based cohort followed for 26 years in Tayside, Scotland (PROLEARS study) (17). Premature mortality was reported in patients bearing MP but not microP. The authors hypothesized that hypopituitarism-associated hormonal deficiencies or their overtreatment might contribute to adverse health outcomes.
2. Executive summary of recommendations (R)
*2.a. Diagnosis (see sections 4.a for R 1–11, 4.b for R 2, 4.c for R 12–15, 4.d for R 16)
*2.b. Treatment General aspects (see sections 5.a, 5.b, 5.c, 5.f)
-General aspects (see sections 5.a, 5.b, 5.c, 5.f)
-Microprolactinoma (see sections 5.b, 5.c)
-Macroprolactinoma (see sections 5.b, 5.c, 5.d, 5.f)
*2.c. Special cases
-Children (see section 5.e.i)
-Gonadal replacement, contraception, fertility, pregnancy, and menopause (see sections 5.b.iii, 5.e.ii, 5.e.iii, 5.e.iv
-Miscellany (see sections 5.e.v, 5.e.vi, 5.e.vii)
-DA resistance and aggressive disease (see sections 5.e.viii, 5.f)
3. Clinical issues
*3.a. Patients’ complaints that might lead to the evaluation for hyperprolactinemia
*3.b. Sequela of hyperprolactinemia
-Osteoporosis
-Quality of life (QoL)
4. Diagnostic issues
The diagnosis of hyperprolactinemia is established by measuring basal PRL levels. Hyperprolactinemia is the hallmark not only of PRL-secreting tumors but also of nonsecreting neoplasms of the hypothalamo-pituitary region and of a variety of disorders that must be excluded before prolactinoma is diagnosed.
The magnitude of PRL levels can be useful in determining the etiology of hyperprolactinemia. PRL levels generally correlate with prolactinoma size, namely up to 150 ng/mL in most patients with microP and higher than 200–250 ng/mL in patients with MP. An increase in PRL levels can be caused by non-secreting pituitary lesions (the so-called pseudoprolactinomas), such as nonsecreting adenomas, as well as other tumoral, infectious, and inflammatory processes involving the hypothalamus, the perisellar region, the pituitary stalk, and the pituitary itself or a primary empty sella. This ‘stalk effect’ is due to the disconnection between the hypothalamus and the pituitary gland, with the consequent impairment of the inhibitory dopaminergic pathways and an increase in PRL levels. In pituitary macroadenomas, PRL levels below 100 ng/mL can be attributed to this phenomenon, whereas PRL concentrations between 100 and 200 ng/mL represent a ‘gray zone’ that should prompt differential diagnosis between prolactinoma and pseudoprolactinoma (56, 57, 58, 59).
*4.a. The conundrum of PRL assays and laboratory workup (R 1–10)
-Pre-analytical requirements
PRL secretion is pulsatile, and levels are physiologically higher during sleep and in the early morning (60).
Emotional stress, venipuncture, exercise, walking, and a protein-rich diet all stimulate PRL secretion (61). Thus, specimens collected after an overnight fast, at least 2 h after awakening when the patient is resting, provide the most reliable PRL assessment (62). The insertion of an i.v. catheter 15–20 min before sampling for PRL assay in the diagnostic phase is a simple and practical tool in cases of mild hyperprolactinemia (63).
-Analytical specifications
-Endocrine workup in patients with prolactinoma
*4.b. The hunt for non-tumoral causes of hyperprolactinemia (R 2,11)
-Secondary non-endocrine diseases
-Endocrine diseases different from prolactinomas
-Medication effects
-Idiopathic hyperprolactinemia
*4.c. Imaging of PRL-producing lesions when and how (R 11–14)
-Technical specifications
-Prolactinomas on MRI
-Follow-up imaging
*4.d. When to suspect and how to screen for genetic diseases (R 15)
5. Therapeutic issues
*5.a. Aims of treatment
*5.b. Pharmacologic treatments
-5.b.i. Dopaminergic drugs (R 20–23, 27–31, 33–34)
*Microadenomas
The aim of the treatment is to revert the effects of hyperprolactinemia, that is, spontaneous galactorrhea, and to restore gonadal function, that is, ovulatory menses in females, normal testosterone levels and sexual potency in males, and libido in both sexes. Treatment should be offered also to regularly cycling females with pathological hyperprolactinemia and anovulatory menses desiring pregnancy, and males with pathological hyperprolactinemia and normal testosterone levels complaining of erectile dysfunction. Tumor shrinkage is not an issue in this setting because significant or persistent growth is uncommon according to studies of the natural history of untreated microPs (112), even in the presence of local tumor invasion. Amenorrheic premenopausal women not desiring pregnancy may be treated only with oral contraceptives, without DA, provided that patients do not complain of symptoms suggestive of tumor size increase and/or galactorrhea, PRL levels do not substantially increase, and evidence of tumor enlargement is not observed while on this treatment (1).
In females, Cab should be administered at the lowest dose capable of restoring regular menses and suppressing galactorrhea. The clinical response occurs within 12 weeks in about 80–90% of patients. In the steady-state, this target is usually maintained with 0.25 mg twice a week or 0.5 mg once a week, according to tolerability or the patient’s preference. Female patients should be informed that treatment can early restore ovulation. Contraception may be thus required if needed. In a review of 14 prospective studies in patients with hyperprolactinemic disorders, Cab was successful in normalizing PRL levels in 73–96% (113). In addition, tumor shrinkage was reportedly observed in 50–100% of Cab-treated microP (113).
Wide variability exists in clinical response. Some females require full PRL normalization to resume ovulatory menses, whereas, in others, the clinical response may be observed despite still pathological PRL values. At variance, in males usually, testosterone levels are normalized and sexual activity is fully regained only after the normalization of PRL levels which may require several weeks. Accordingly, Cab dose should be individually tailored, with up-titration to 1.0–2.0 mg/week (or even more) or down titration to the lowest effective dose.
DA should be discontinued in pregnancy (see below at 5.e.iii) and might be withheld in some particular cases, such as perimenopausal women, asymptomatic postmenopausal women, or asymptomatic men without hypogonadism in whom simple observation with periodic monitoring of PRL could be considered (114, 115, 116, 117).
*Macroprolactinomas
The aims of the treatment in these patients are the quick relief of neuro-ophthalmologic symptoms when present, the normalization of PRL levels, and tumor shrinkage. The first is a compulsory aim in all patients, whereas the second and third ones should be pursued but are not always obtained.
Cab is always the first-line option in MP, even in patients bearing huge adenomas and/or severe neurologic symptoms or visual defects. In these patients, the thorough up-titration of Cab can quickly improve neurological and visual symptoms and lower abruptly PRL levels.
Cab is effective at doses ranging from 0.5 to 2 mg weekly in most MP (118). A marked decline in PRL levels and tumor shrinkage may be obtained with a very low Cab dose (0.5 mg/week) even in patients bearing very large adenomas and very high PRL levels.
Responsiveness to DA is very common but cannot be predicted with certainty (119). The attempt to create retrospectively a predictive score combining demographic, biochemical and tumoral parameters was unsuccessful (120). Accordingly, it is worthwhile to begin treatment and monitor PRL values and tumor size. It has been reported that the first PRL values obtained during treatment (either evaluated as an absolute value or as a percent decrease from baseline or as lowering below a predefined threshold, according to different series) as well as early tumor shrinkage (with different cut-offs in different series) are good predictors of long-term DA efficacy (120), either evaluated at 6 months (121) or even earlier (122, 123, 124). On the contrary, it was recently reported but not yet confirmed that heterogeneity of prolactinoma T2 signal at diagnosis could be used as a negative predictor factor of hormonal response to DA (87).
In responsive patients, Cab achieves progressive PRL decrease and tumor shrinkage for years, reaching hormone normalization and tumor shrinkage up to its disappearance or empty sella in most. In these highly responsive patients, Cab dose may be progressively lowered (to 0.25–0.5 mg/ week or even administered at longer intervals). On the other hand, a stepwise dose up-titration may be necessary for some resistant patients in whom the average Cab dose does not achieve hormonal and tumoral targets (125). An extreme uptitration (up to 7–12 mg/week) is anecdotic. It is reasonable to continue with further dose increases whenever this is followed by a substantial PRL decrease, whereas it is recommended to go back to the lowest dose that caused the lowest PRL levels without an increase in tumor size, in order to avoid side effects.
Some patients experience an extremely rapid decrease in tumor size with a significant improvement in visual fields within 24–72 h. Improvements in visual fields generally parallel the changes observed at imaging, whereas reductions in PRL levels usually forerun any tumor shrinkage.
In MP patients, there is usually a positive correlation between PRL levels and adenoma size. In most cases, PRL reduction and tumor shrinkage follow a parallel course during Cab treatment, although there are exceptions: in some patients, PRL decrease is faster than tumor size reduction, in others, PRL decrease is accompanied by an improvement of visual fields without a significant change of tumor volume. In very rare cases, PRL levels decrease in spite of tumor size increase (95).
Patients with persisting neuro-ophthalmologic symptoms, tumor size increase/reincrease during treatment, or PRL reincrease despite carrying on treatment (‘escape phenomenon’) should be referred to neurosurgery (see below at 5.c).
*Follow-up.
In most severe cases, controls should be performed at short intervals:
• Neuro-ophthalmologic examination and clinical evaluation should be tightly evaluated within the first month in order to guide the timing of neurosurgical interventions when needed.
• PRL levels should be evaluated weekly or monthly for the first 3 months and then at longer intervals if treatment is effective.
• MRI control should be performed according to ophthalmologic and PRL changes on treatment
*Side effects, intolerance to treatment, and precautions to be taken (R 21–23)
Most adverse events of DA are mild or moderate in severity
The most typical side effects of DA are nausea, vomiting, postural hypotension, drowsiness, somnolence, nasal stuffiness, headache, Raynaud’s phenomenon, and constipation. Nausea and postural hypotension occur frequently with Br, even at the lowest doses at the beginning of treatment, and require shifting to Cab.
Cab is generally better tolerated than Br, any side effect usually subsides over time but in a few cases (3–4%) they may persist, requiring Cab down titration or withdrawal and referral to neurosurgery.
Care should be exercised when administering DA concomitantly with other medications known to lower blood pressure. DA should be used with caution in patients with a history of neuropsychiatric disease.
DA-induced neuropsychiatric symptoms may be much more worrisome, including psychosis (or exacerbation of pre-existing psychosis) and ICD, such as compulsive gambling, shopping or eating, and hypersexuality, which are resolved after either DA reduction or cessation (126, 127, 128, 129, 130). These features can have devastating effects on the patient and his/her social environment. The exact incidence of DA-induced psychosis occurrence or exacerbation is not known but is likely to be less than 1% (56), whereas the true prevalence of ICD remains unclear. In an uncontrolled study of 308 patients with prolactinoma treated with Cab for at least 3 months, 17% developed an ICD (131), a figure higher than in patients with non-secreting pituitary adenoma and no history of DA therapy and far lower than in patients with Parkinson’s disease who usually are treated with higher doses of Cab. No association with DA type, dose, or duration of treatment was noted. A recent Australian paper evaluated specific neuropsychological questionnaires in 113 patients with hyperprolactinemia (prolactinoma in 95%) and 99 normal controls and reported a 50% increase of relative risk in patients (up to 60%) compared to a surprisingly high prevalence of ICD in the control group (40%) (132). It has been suggested that patients (and family members/caregivers) should be forewarned of the possible development of ICD while on DA therapy
In patients bearing large invasive MP extending through the sellar diaphragm and eroding the sellar floor, CSF nasal leakage has been rarely reported during DA treatment, either within the first few weeks or later after several months (34). This extremely severe complication is due to rapid tumor shrinkage that allows the leakage of CSF through an emerging tumor-induced gap in the skull base. The patient should be alerted to seek medical advice in case of watery nasal discharge. Analysis of fluid for beta-2 transferrin or beta trace protein is a well-known, specific method for detecting the presence of CSF (133) but unfortunately, it is not largely available. CSF leakage should prompt urgent evaluation by an ENT or a neurosurgeon (134).
Cab and pergolide (but not Br due to its lower affinity to serotonin 2B receptor) have been associated with valvular heart disease in patients with Parkinson’s disease (135, 136, 137). A recent meta-analysis observed a statistically significant increased risk of tricuspid valvular dysfunction with the use of Cab but in no patient tricuspid valve dysfunction was diagnosed as a result of clinical symptoms. In addition, there was no significant increase in any other valvulopathy (138). Neither treatment duration nor cumulative dosage was associated with an increased risk of tricuspid valve lesions of any severity and the clinical significance of these findings is therefore questionable.
The use of the lowest effective dose of Cab and serial cardiac ultrasonographic examinations are suggested in patients taking larger doses of Cab. Current data do not support major concerns about the risk of valvulopathy in hyperprolactinemic patients who are chronically treated with DA at standard doses (≤2 mg/week) (139). Subclinical valvular abnormalities detected by ultrasonography are not an indication for discontinuation of DA treatment. If valve lesions are detected during follow-up, further evaluation is indicated to distinguish Cab-induced etiology from other causes of valvulopathy.
-5.b.ii. How long to treat (R 33, 34, 58, 59)?
-5.b.iii. Restoration of gonadal function and fertility when and how (R 40–42, 44)
Hypogonadism is often present at diagnosis of PRLsecreting adenoma as PRL regulates gonadal steroid secretion. Chronically elevated PRL levels and hypogonadism are associated with reduced BMD and osteoporosis (45, 46). Moreover, untreated hypogonadism increases mortality in both sexes, due to cardiovascular diseases, while gonadal replacement therapy restores the standard mortality rate (147, 148).
Even though DA very often obtains reversal of hypogonadism, especially in microP and MP with normal TSH-thyroid and ACTH-adrenal function (149), gonadal replacement therapy may be necessary for patients with persistent hypogonadism despite lowering/normalization of PRL levels or being resistant to DA.
*Premenopausal women
In spite of estrogen sensitivity of lactotrophs, in microP patients using oral contraceptives or ERT, tumor size rarely increases even without DA treatment (149, 150, 151). Women with microP who do not require fertility restoration may be treated only with estroprogestinic preparations (or estrogen alone in hysterectomized women) rather than DA.
Tumor growth is more concerning in patients with MP. Therefore, in cases with persistent amenorrhea, a thorough case-by-case evaluation is required, with very close monitoring of tumor size and PRL levels if estrogen therapy is prescribed (151), due to the potential estrogen-induced decrease of DA efficacy. ERT should be continued at least until the age of physiologic menopause or longer evaluating the individual risk profile, and taking into account the risk of osteoporosis.
DA treatment restores fertility in most women, even before menses occur (152). When normal menses are not restored, recombinant gonadotropins may be used for ovulation induction (149).
Males
In males, impaired BMD and anemia are the main consequences of long-term PRL-induced hypogonadism. Commonly, normalization of PRL and testosterone levels improves anemia as well as other manifestations of hypogonadism and is associated with bone health status improvement (153).
There are not enough data regarding predictors of long-lasting/persisting hypogonadism. In a recent retrospective study with a follow-up of only 2 years, hypogonadism persisted in 74% of patients after PRL normalization with Cab; the higher PRL levels and tumor size, the lower the chance of normalizing testosterone levels (154). In another study, long-term treatment (median: 3 years) was necessary to obtain normalization of hyperprolactinemia and reversal of hypogonadism (155).
Even though there is a potential risk that testosterone aromatization into estrogen could stimulate proliferation and hyperplasia of prolactinoma cells, thus inducing DA resistance (156), this occurrence is very rare (157), and the usefulness in this setting of aromatase inhibitors as add-on treatment was reported (158). TRT is thus indicated in the case of hypogonadism persistence (159). Reports on the adequate timing for starting TRT are missing. Clinical experience suggests that in patients with pituitary failure, age-adjusted TRT should be quickly added to adrenal and thyroid replacement therapies, in order to improve clinical conditions and restore normal libido. As for isolated hypogonadism, an individual evaluation should guide the start of TRT. Given all these data, an early TRT may be suggested (within 3–6 months after the start of DA), provided that PRL levels are progressively decreasing and tumor size is shrinking.
TRT should be started soon also in patients partially sensitive to DA. In these cases, tighter control of PRL levels (or MRI if needed) is suggested.
In male patients, treatment with clomiphene citrate or gonadotropins may be considered to restore or induce fertility, respectively. Clomiphene citrate increases serum testosterone levels and improves sperm motility, even in the absence of normal PRL levels (160).
*5.c. Neurosurgery feasibility and appropriateness (R 17–19, 26, 29, 30, 32)
*5.d. Radiation treatments (R 35–38)
*5.e. Special cases
-5.e.i. Children (R 39)
-5.e.ii. Women requiring contraception or sex hormone replacement therapy (R 41–43)
-5.e.iii. All about pregnancy from ovulation to breastfeeding (R 44–57)
-5.e.iii. All about pregnancy from ovulation to breastfeeding (R 44–57)
-Before conception
-During pregnancy (Microprolactinoma/Macroprolactinoma)
-Delivery
-Obstetrical outcome
-Breastfeeding
-After pregnancy
-5.e.iv. Postmenopausal women (R 58–59)
-5.e.v. Women with personal or familial history of breast cancer (R 60)
-5.e.vi. Patients with a psychiatric disease (R 61–63)
-5.e.vii. Treatment of osteoporosis (R 64)
-5.e.viii. Resistance to treatment and aggressive disease from definition to multimodal treatment (R 65–69)
*5. f. Therapeutic strategy possible shift to surgery as a first-line option (R 16–20, 25–27, 33)
6. Conclusions and perspectives
We are facing a paradigm change in the management of prolactinomas. Both DA and neurosurgery might now be regarded as a first-line therapeutic option in certain clinical and neuroradiological scenarios, such as a non-invasive adenoma, regardless of size. In this clinical situation and when feasible, a shared decision should be implemented with full provision of information about the benefits and risks of both treatment options, taking into account the patient’s preferences and values. Whereas most endocrinologists are potentially able to manage DA treatment, reported data clearly show that the best surgical results are obtained by neurosurgeons with a high caseload of pituitary operations (at least 50 pituitary operations per year) (242, 243, 244).
An integrated network among hub and spoke centers able to manage even complex cases in multidisciplinary teams should be implemented.
Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio , Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini , Laurence Katznelson, Anton Luger and Catalina Poiana on behalf of AME
Abstract
Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.
1. Introduction
*1.a. Why this document
Prolactinomas are the most prevalent pituitary tumors. Medical therapy with dopamine agonists (DA) has been considered the first-line treatment for relieving symptoms, normalizing hyperprolactinemia, and reducing tumor size in the majority of patients, whereas surgery as a second-line treatment is indicated only for the minority of patients showing resistance or intolerance to DA, for patients with pituitary apoplexy, or based on patient’s preference (1). Technical advances have improved surgical outcomes, obtaining total removal of the tumor, a high rate of disease remission, and sparing normal pituitary function (2). Thus, the improvement of surgery could change in some prolactinomas the paradigm of DA chronic treatment as a first-line therapeutic strategy.
Prolactinoma is a clinical entity that includes different parameters: micro-and macroadenoma, males and females, patients with fertility consideration or postmenopausal, children or elderly patients, sensitivity or resistance to DA, presence of mass effect, and aggressive behavior (3). An individually tailored treatment is thus needed to manage a wide variety of settings, including the drawbacks of DA treatment in patients with psychiatric diseases.
To discuss all these aspects, a group of Italian experts has gathered together their clinical experience on the diagnostic and therapeutic challenges of prolactinoma patients, aiming to better define the most updated clinical approach and therapeutic options. Panelists were selected by the endorsing scientific societies (AME and ICCE) and included 15 endocrinologists with skill in the management of pituitary diseases (one skilled in scientific methodology), two neurosurgeons skillful in pituitary surgery and working in a high-volume pituitary center, one expert of laboratory medicine, and one neuroradiologist.
*1.b. Methodology
*1.c. Epidemiology, morbidity, and mortality
Prolactinomas are the most common pituitary adenoma, accounting for approximately 50% of all pituitary adenomas, with a prevalence of ∼50 per 100 000 population and an incidence of 3–5 new cases/100 000/year (8, 9). In autoptic series, a high prevalence of undiagnosed pituitary adenomas (almost all tiny tumors) has been detected (10.4%) and prolactinomas represented 40% of them (10).
Based on tumor size, they are classified as microprolactinomas (microP, <10 mm diameter) or macroprolactinomas (MP, ≥10 mm diameter). MicroPs are mainly observed in premenopausal women, whereas MPs are more common in men aged more than 50 years. Giant tumors (>40 mm) are rare (1–5% of all prolactinomas). They are diagnosed mostly in men aged between 20 and 50 years (median 42) and occasionally in older men or postmenopausal women and even in the pediatric population, with a reported male-to-female ratio of ∼9:1 (11, 12).
In a few cases, other pituitary hormones are secreted in excess beyond prolactin (PRL) (mostly growth hormone (GH)).
PRL-producing pituitary carcinomas are rare and defined by the presence of cerebrospinal, meningeal, or systemic metastases (13).
In clinical series of patients aged more than 65 years, prolactinomas account for 4–8% of pituitary adenomas but the prevalence may be actually underestimated in elderly women and men due to reduced attention to symptoms of hypogonadism (9, 11).
Pituitary adenomas are rare in children and adolescents and account for 3–4% of all intracranial tumors in this age group (14). The mean age at diagnosis was 16.1 ± 2.5 years (range: 4.5–20 years). The incidence of prolactinomas in this age group is 0.1 per 1 000 000 population, and they are more frequently diagnosed in girls than in boys (up to 80% of cases) (15). MPs are more prevalent than microPs in pediatric populations (58% vs 42%) (16). Prolactinomas are larger and more frequently invasive in boys than in girls as in the adult counterpart (16).
Prolactinomas can also belong to genetic syndromes (see below at 4.d), with reportedly higher aggressive behavior.
Prolactinomas are not associated with increased prevalence of diabetes, cardiovascular diseases, and cancer, as shown in a population-based cohort followed for 26 years in Tayside, Scotland (PROLEARS study) (17). Premature mortality was reported in patients bearing MP but not microP. The authors hypothesized that hypopituitarism-associated hormonal deficiencies or their overtreatment might contribute to adverse health outcomes.
2. Executive summary of recommendations (R)
*2.a. Diagnosis (see sections 4.a for R 1–11, 4.b for R 2, 4.c for R 12–15, 4.d for R 16)
*2.b. Treatment General aspects (see sections 5.a, 5.b, 5.c, 5.f)
-General aspects (see sections 5.a, 5.b, 5.c, 5.f)
-Microprolactinoma (see sections 5.b, 5.c)
-Macroprolactinoma (see sections 5.b, 5.c, 5.d, 5.f)
*2.c. Special cases
-Children (see section 5.e.i)
-Gonadal replacement, contraception, fertility, pregnancy, and menopause (see sections 5.b.iii, 5.e.ii, 5.e.iii, 5.e.iv
-Miscellany (see sections 5.e.v, 5.e.vi, 5.e.vii)
-DA resistance and aggressive disease (see sections 5.e.viii, 5.f)
3. Clinical issues
*3.a. Patients’ complaints that might lead to the evaluation for hyperprolactinemia
*3.b. Sequela of hyperprolactinemia
-Osteoporosis
-Quality of life (QoL)
4. Diagnostic issues
The diagnosis of hyperprolactinemia is established by measuring basal PRL levels. Hyperprolactinemia is the hallmark not only of PRL-secreting tumors but also of nonsecreting neoplasms of the hypothalamo-pituitary region and of a variety of disorders that must be excluded before prolactinoma is diagnosed.
The magnitude of PRL levels can be useful in determining the etiology of hyperprolactinemia. PRL levels generally correlate with prolactinoma size, namely up to 150 ng/mL in most patients with microP and higher than 200–250 ng/mL in patients with MP. An increase in PRL levels can be caused by non-secreting pituitary lesions (the so-called pseudoprolactinomas), such as nonsecreting adenomas, as well as other tumoral, infectious, and inflammatory processes involving the hypothalamus, the perisellar region, the pituitary stalk, and the pituitary itself or a primary empty sella. This ‘stalk effect’ is due to the disconnection between the hypothalamus and the pituitary gland, with the consequent impairment of the inhibitory dopaminergic pathways and an increase in PRL levels. In pituitary macroadenomas, PRL levels below 100 ng/mL can be attributed to this phenomenon, whereas PRL concentrations between 100 and 200 ng/mL represent a ‘gray zone’ that should prompt differential diagnosis between prolactinoma and pseudoprolactinoma (56, 57, 58, 59).
*4.a. The conundrum of PRL assays and laboratory workup (R 1–10)
-Pre-analytical requirements
PRL secretion is pulsatile, and levels are physiologically higher during sleep and in the early morning (60).
Emotional stress, venipuncture, exercise, walking, and a protein-rich diet all stimulate PRL secretion (61). Thus, specimens collected after an overnight fast, at least 2 h after awakening when the patient is resting, provide the most reliable PRL assessment (62). The insertion of an i.v. catheter 15–20 min before sampling for PRL assay in the diagnostic phase is a simple and practical tool in cases of mild hyperprolactinemia (63).
-Analytical specifications
-Endocrine workup in patients with prolactinoma
*4.b. The hunt for non-tumoral causes of hyperprolactinemia (R 2,11)
-Secondary non-endocrine diseases
-Endocrine diseases different from prolactinomas
-Medication effects
-Idiopathic hyperprolactinemia
*4.c. Imaging of PRL-producing lesions when and how (R 11–14)
-Technical specifications
-Prolactinomas on MRI
-Follow-up imaging
*4.d. When to suspect and how to screen for genetic diseases (R 15)
5. Therapeutic issues
*5.a. Aims of treatment
*5.b. Pharmacologic treatments
-5.b.i. Dopaminergic drugs (R 20–23, 27–31, 33–34)
*Microadenomas
The aim of the treatment is to revert the effects of hyperprolactinemia, that is, spontaneous galactorrhea, and to restore gonadal function, that is, ovulatory menses in females, normal testosterone levels and sexual potency in males, and libido in both sexes. Treatment should be offered also to regularly cycling females with pathological hyperprolactinemia and anovulatory menses desiring pregnancy, and males with pathological hyperprolactinemia and normal testosterone levels complaining of erectile dysfunction. Tumor shrinkage is not an issue in this setting because significant or persistent growth is uncommon according to studies of the natural history of untreated microPs (112), even in the presence of local tumor invasion. Amenorrheic premenopausal women not desiring pregnancy may be treated only with oral contraceptives, without DA, provided that patients do not complain of symptoms suggestive of tumor size increase and/or galactorrhea, PRL levels do not substantially increase, and evidence of tumor enlargement is not observed while on this treatment (1).
In females, Cab should be administered at the lowest dose capable of restoring regular menses and suppressing galactorrhea. The clinical response occurs within 12 weeks in about 80–90% of patients. In the steady-state, this target is usually maintained with 0.25 mg twice a week or 0.5 mg once a week, according to tolerability or the patient’s preference. Female patients should be informed that treatment can early restore ovulation. Contraception may be thus required if needed. In a review of 14 prospective studies in patients with hyperprolactinemic disorders, Cab was successful in normalizing PRL levels in 73–96% (113). In addition, tumor shrinkage was reportedly observed in 50–100% of Cab-treated microP (113).
Wide variability exists in clinical response. Some females require full PRL normalization to resume ovulatory menses, whereas, in others, the clinical response may be observed despite still pathological PRL values. At variance, in males usually, testosterone levels are normalized and sexual activity is fully regained only after the normalization of PRL levels which may require several weeks. Accordingly, Cab dose should be individually tailored, with up-titration to 1.0–2.0 mg/week (or even more) or down titration to the lowest effective dose.
DA should be discontinued in pregnancy (see below at 5.e.iii) and might be withheld in some particular cases, such as perimenopausal women, asymptomatic postmenopausal women, or asymptomatic men without hypogonadism in whom simple observation with periodic monitoring of PRL could be considered (114, 115, 116, 117).
*Macroprolactinomas
The aims of the treatment in these patients are the quick relief of neuro-ophthalmologic symptoms when present, the normalization of PRL levels, and tumor shrinkage. The first is a compulsory aim in all patients, whereas the second and third ones should be pursued but are not always obtained.
Cab is always the first-line option in MP, even in patients bearing huge adenomas and/or severe neurologic symptoms or visual defects. In these patients, the thorough up-titration of Cab can quickly improve neurological and visual symptoms and lower abruptly PRL levels.
Cab is effective at doses ranging from 0.5 to 2 mg weekly in most MP (118). A marked decline in PRL levels and tumor shrinkage may be obtained with a very low Cab dose (0.5 mg/week) even in patients bearing very large adenomas and very high PRL levels.
Responsiveness to DA is very common but cannot be predicted with certainty (119). The attempt to create retrospectively a predictive score combining demographic, biochemical and tumoral parameters was unsuccessful (120). Accordingly, it is worthwhile to begin treatment and monitor PRL values and tumor size. It has been reported that the first PRL values obtained during treatment (either evaluated as an absolute value or as a percent decrease from baseline or as lowering below a predefined threshold, according to different series) as well as early tumor shrinkage (with different cut-offs in different series) are good predictors of long-term DA efficacy (120), either evaluated at 6 months (121) or even earlier (122, 123, 124). On the contrary, it was recently reported but not yet confirmed that heterogeneity of prolactinoma T2 signal at diagnosis could be used as a negative predictor factor of hormonal response to DA (87).
In responsive patients, Cab achieves progressive PRL decrease and tumor shrinkage for years, reaching hormone normalization and tumor shrinkage up to its disappearance or empty sella in most. In these highly responsive patients, Cab dose may be progressively lowered (to 0.25–0.5 mg/ week or even administered at longer intervals). On the other hand, a stepwise dose up-titration may be necessary for some resistant patients in whom the average Cab dose does not achieve hormonal and tumoral targets (125). An extreme uptitration (up to 7–12 mg/week) is anecdotic. It is reasonable to continue with further dose increases whenever this is followed by a substantial PRL decrease, whereas it is recommended to go back to the lowest dose that caused the lowest PRL levels without an increase in tumor size, in order to avoid side effects.
Some patients experience an extremely rapid decrease in tumor size with a significant improvement in visual fields within 24–72 h. Improvements in visual fields generally parallel the changes observed at imaging, whereas reductions in PRL levels usually forerun any tumor shrinkage.
In MP patients, there is usually a positive correlation between PRL levels and adenoma size. In most cases, PRL reduction and tumor shrinkage follow a parallel course during Cab treatment, although there are exceptions: in some patients, PRL decrease is faster than tumor size reduction, in others, PRL decrease is accompanied by an improvement of visual fields without a significant change of tumor volume. In very rare cases, PRL levels decrease in spite of tumor size increase (95).
Patients with persisting neuro-ophthalmologic symptoms, tumor size increase/reincrease during treatment, or PRL reincrease despite carrying on treatment (‘escape phenomenon’) should be referred to neurosurgery (see below at 5.c).
*Follow-up.
In most severe cases, controls should be performed at short intervals:
• Neuro-ophthalmologic examination and clinical evaluation should be tightly evaluated within the first month in order to guide the timing of neurosurgical interventions when needed.
• PRL levels should be evaluated weekly or monthly for the first 3 months and then at longer intervals if treatment is effective.
• MRI control should be performed according to ophthalmologic and PRL changes on treatment
*Side effects, intolerance to treatment, and precautions to be taken (R 21–23)
Most adverse events of DA are mild or moderate in severity
The most typical side effects of DA are nausea, vomiting, postural hypotension, drowsiness, somnolence, nasal stuffiness, headache, Raynaud’s phenomenon, and constipation. Nausea and postural hypotension occur frequently with Br, even at the lowest doses at the beginning of treatment, and require shifting to Cab.
Cab is generally better tolerated than Br, any side effect usually subsides over time but in a few cases (3–4%) they may persist, requiring Cab down titration or withdrawal and referral to neurosurgery.
Care should be exercised when administering DA concomitantly with other medications known to lower blood pressure. DA should be used with caution in patients with a history of neuropsychiatric disease.
DA-induced neuropsychiatric symptoms may be much more worrisome, including psychosis (or exacerbation of pre-existing psychosis) and ICD, such as compulsive gambling, shopping or eating, and hypersexuality, which are resolved after either DA reduction or cessation (126, 127, 128, 129, 130). These features can have devastating effects on the patient and his/her social environment. The exact incidence of DA-induced psychosis occurrence or exacerbation is not known but is likely to be less than 1% (56), whereas the true prevalence of ICD remains unclear. In an uncontrolled study of 308 patients with prolactinoma treated with Cab for at least 3 months, 17% developed an ICD (131), a figure higher than in patients with non-secreting pituitary adenoma and no history of DA therapy and far lower than in patients with Parkinson’s disease who usually are treated with higher doses of Cab. No association with DA type, dose, or duration of treatment was noted. A recent Australian paper evaluated specific neuropsychological questionnaires in 113 patients with hyperprolactinemia (prolactinoma in 95%) and 99 normal controls and reported a 50% increase of relative risk in patients (up to 60%) compared to a surprisingly high prevalence of ICD in the control group (40%) (132). It has been suggested that patients (and family members/caregivers) should be forewarned of the possible development of ICD while on DA therapy
In patients bearing large invasive MP extending through the sellar diaphragm and eroding the sellar floor, CSF nasal leakage has been rarely reported during DA treatment, either within the first few weeks or later after several months (34). This extremely severe complication is due to rapid tumor shrinkage that allows the leakage of CSF through an emerging tumor-induced gap in the skull base. The patient should be alerted to seek medical advice in case of watery nasal discharge. Analysis of fluid for beta-2 transferrin or beta trace protein is a well-known, specific method for detecting the presence of CSF (133) but unfortunately, it is not largely available. CSF leakage should prompt urgent evaluation by an ENT or a neurosurgeon (134).
Cab and pergolide (but not Br due to its lower affinity to serotonin 2B receptor) have been associated with valvular heart disease in patients with Parkinson’s disease (135, 136, 137). A recent meta-analysis observed a statistically significant increased risk of tricuspid valvular dysfunction with the use of Cab but in no patient tricuspid valve dysfunction was diagnosed as a result of clinical symptoms. In addition, there was no significant increase in any other valvulopathy (138). Neither treatment duration nor cumulative dosage was associated with an increased risk of tricuspid valve lesions of any severity and the clinical significance of these findings is therefore questionable.
The use of the lowest effective dose of Cab and serial cardiac ultrasonographic examinations are suggested in patients taking larger doses of Cab. Current data do not support major concerns about the risk of valvulopathy in hyperprolactinemic patients who are chronically treated with DA at standard doses (≤2 mg/week) (139). Subclinical valvular abnormalities detected by ultrasonography are not an indication for discontinuation of DA treatment. If valve lesions are detected during follow-up, further evaluation is indicated to distinguish Cab-induced etiology from other causes of valvulopathy.
-5.b.ii. How long to treat (R 33, 34, 58, 59)?
-5.b.iii. Restoration of gonadal function and fertility when and how (R 40–42, 44)
Hypogonadism is often present at diagnosis of PRLsecreting adenoma as PRL regulates gonadal steroid secretion. Chronically elevated PRL levels and hypogonadism are associated with reduced BMD and osteoporosis (45, 46). Moreover, untreated hypogonadism increases mortality in both sexes, due to cardiovascular diseases, while gonadal replacement therapy restores the standard mortality rate (147, 148).
Even though DA very often obtains reversal of hypogonadism, especially in microP and MP with normal TSH-thyroid and ACTH-adrenal function (149), gonadal replacement therapy may be necessary for patients with persistent hypogonadism despite lowering/normalization of PRL levels or being resistant to DA.
*Premenopausal women
In spite of estrogen sensitivity of lactotrophs, in microP patients using oral contraceptives or ERT, tumor size rarely increases even without DA treatment (149, 150, 151). Women with microP who do not require fertility restoration may be treated only with estroprogestinic preparations (or estrogen alone in hysterectomized women) rather than DA.
Tumor growth is more concerning in patients with MP. Therefore, in cases with persistent amenorrhea, a thorough case-by-case evaluation is required, with very close monitoring of tumor size and PRL levels if estrogen therapy is prescribed (151), due to the potential estrogen-induced decrease of DA efficacy. ERT should be continued at least until the age of physiologic menopause or longer evaluating the individual risk profile, and taking into account the risk of osteoporosis.
DA treatment restores fertility in most women, even before menses occur (152). When normal menses are not restored, recombinant gonadotropins may be used for ovulation induction (149).
Males
In males, impaired BMD and anemia are the main consequences of long-term PRL-induced hypogonadism. Commonly, normalization of PRL and testosterone levels improves anemia as well as other manifestations of hypogonadism and is associated with bone health status improvement (153).
There are not enough data regarding predictors of long-lasting/persisting hypogonadism. In a recent retrospective study with a follow-up of only 2 years, hypogonadism persisted in 74% of patients after PRL normalization with Cab; the higher PRL levels and tumor size, the lower the chance of normalizing testosterone levels (154). In another study, long-term treatment (median: 3 years) was necessary to obtain normalization of hyperprolactinemia and reversal of hypogonadism (155).
Even though there is a potential risk that testosterone aromatization into estrogen could stimulate proliferation and hyperplasia of prolactinoma cells, thus inducing DA resistance (156), this occurrence is very rare (157), and the usefulness in this setting of aromatase inhibitors as add-on treatment was reported (158). TRT is thus indicated in the case of hypogonadism persistence (159). Reports on the adequate timing for starting TRT are missing. Clinical experience suggests that in patients with pituitary failure, age-adjusted TRT should be quickly added to adrenal and thyroid replacement therapies, in order to improve clinical conditions and restore normal libido. As for isolated hypogonadism, an individual evaluation should guide the start of TRT. Given all these data, an early TRT may be suggested (within 3–6 months after the start of DA), provided that PRL levels are progressively decreasing and tumor size is shrinking.
TRT should be started soon also in patients partially sensitive to DA. In these cases, tighter control of PRL levels (or MRI if needed) is suggested.
In male patients, treatment with clomiphene citrate or gonadotropins may be considered to restore or induce fertility, respectively. Clomiphene citrate increases serum testosterone levels and improves sperm motility, even in the absence of normal PRL levels (160).
*5.c. Neurosurgery feasibility and appropriateness (R 17–19, 26, 29, 30, 32)
*5.d. Radiation treatments (R 35–38)
*5.e. Special cases
-5.e.i. Children (R 39)
-5.e.ii. Women requiring contraception or sex hormone replacement therapy (R 41–43)
-5.e.iii. All about pregnancy from ovulation to breastfeeding (R 44–57)
-5.e.iii. All about pregnancy from ovulation to breastfeeding (R 44–57)
-Before conception
-During pregnancy (Microprolactinoma/Macroprolactinoma)
-Delivery
-Obstetrical outcome
-Breastfeeding
-After pregnancy
-5.e.iv. Postmenopausal women (R 58–59)
-5.e.v. Women with personal or familial history of breast cancer (R 60)
-5.e.vi. Patients with a psychiatric disease (R 61–63)
-5.e.vii. Treatment of osteoporosis (R 64)
-5.e.viii. Resistance to treatment and aggressive disease from definition to multimodal treatment (R 65–69)
*5. f. Therapeutic strategy possible shift to surgery as a first-line option (R 16–20, 25–27, 33)
6. Conclusions and perspectives
We are facing a paradigm change in the management of prolactinomas. Both DA and neurosurgery might now be regarded as a first-line therapeutic option in certain clinical and neuroradiological scenarios, such as a non-invasive adenoma, regardless of size. In this clinical situation and when feasible, a shared decision should be implemented with full provision of information about the benefits and risks of both treatment options, taking into account the patient’s preferences and values. Whereas most endocrinologists are potentially able to manage DA treatment, reported data clearly show that the best surgical results are obtained by neurosurgeons with a high caseload of pituitary operations (at least 50 pituitary operations per year) (242, 243, 244).
An integrated network among hub and spoke centers able to manage even complex cases in multidisciplinary teams should be implemented.
