This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Colao, A. Articles by Lombardi, G. Search for Related Content PubMed PubMed Citation Articles by Colao, A. Articles by Lombardi, G.

Prolactinomas in Children and Adolescents. Clinical Presentation and Long-Term Follow-Up

Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (A.C., A.D.S., M.L.L., F.S., G.F., G.L.), Università "Federico II" di Napoli, 80131 Naples; Servizio di Endocrinologia Pediatrica (S.L.), Ospedale Regionale per le Microcitemie, 09121 Rome; Cagliari and Divisione di Pediatria (M.C.), Ospedale Bambin Gesù, Istituto di Recerca e Cura a Carattere Scientifico, Palidoro, 00100 Rome, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7–17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5–20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075–0.6 mg/day or by cabergoline at doses ranging from 0.5–3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery.

In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (±SE) at the time of diagnosis was 1080 ± 267 µg/L in patients with macroadenoma and 155 ± 38 µg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age.

In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PROLACTINOMAS are the most frequent pituitary tumors, and their frequency varies with age and sex, occurring most frequently in females between 20–50 yr old. In the pediatric/adolescent age, prolactinomas are rare, representing about half of all pituitary adenomas (which, overall, account for less than 2% of intracranial tumors) (1, 2). Therefore, the clinical presentation, response to medical treatment, and long-term outcome of children and adolescents with prolactinoma have been reported in only small series (3, 4) and in a number of isolated case reports (reviewed in Refs. 5, 6). It has been estimated that only 26 patients less than 18 yr old at diagnosis had been described between 1982 and 1991 (5, 6). In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma seen in our Institutions in the last 15 yr and whose age at diagnosis was less than 18 yr.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Twenty-six patients (9 males and 17 females, age 7–17 yr) were referred to our Institutions for suspected pituitary tumor or for persistence of hyperprolactinemia after surgery between 1980 and 1996. Their main clinical, hormonal, and radiological findings are summarized in Table 1. Assessment of clinical history, physical examination (including pubertal staging according to Tanner), and complete evaluation of hypothalamic-pituitary function were carried out in all patients. Gonadotropin, TSH, and PRL secretion was evaluated at baseline and after GnRH (100 µg, iv) and TRH (200 µg, iv) tests in all patients except those with compression of optic chiasm documented by computed tomography (CT) or magnetic resonance imaging (MRI), to avoid the risk of sudden impairment of visual field and acuity. Somatotropic function was evaluated by means of oral clonidine test (150 mg/m², per os) and/or measurement of serum insulin-like growth factor-I performed at baseline and then at yearly intervals. Evaluation of adrenal, gonadal, and thyroid functions was also performed at baseline and then at yearly intervals. At diagnosis, CT and/or MRI showed the presence of a macroadenoma in 15 patients and of a microadenoma in 11 patients (Table 1). Six patients (nos. 2, 4, 8, 10, and 23) came to our observation after surgery that did not lead to PRL normalization (normal values: 5–25 µg/L in females and 5–15 µg/L in males).

Circulating PRL, FSH, LH, GH, ACTH, and cortisol (serum and urinary) levels were assayed by commercially available RIA, whereas TSH and insulin-like growth factor-I (after ethanol extraction) levels were assayed by immunoradiometric assay.

Visual field was assessed by Goldmann-Friedmann perimetry and was performed at diagnosis and yearly during the follow-up in patients with visual field defects. CT and/or MRI were carried out at diagnosis and every 6–12 months. A greater than 30% decrease in tumor mass after treatment was considered significant shrinkage.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical presentation

Headache and/or visual field defects were the first symptoms in 7 males and 6 females with macroadenoma (in the latter, associated with primary or secondary amenorrhea). Menstrual disturbances were the first symptom in females with microprolactinoma (Table 1). Growth arrest was observed in a male patient with microprolactinoma (no. 7), whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Galactorrhea was observed in 12 patients (3 males and 9 females).

Radiological and hormonal findings

Five patients (nos. 2, 4, 8, 10, and 23) with macro- and 1 patient (no. 14) with microadenoma were investigated for tumor relapse after surgery. At diagnosis, serum PRL concentrations ranged from 145–3.300 µg/L in macro- and 70–500 µg/L in microadenomas. Impairment of other pituitary hormone secretion was documented in 7 patients, 5 of whom had undergone surgery (Table 1). Patients no. 3, 4, 8, and 10 became GH deficient in adult age.

Follow-up (Table 2)

In 10 patients (nos. 1, 5, 7, 9, 12, 14, 16, 21, 22, and 25), BRC normalized serum PRL levels within 6–12 months and caused a variable, but significant, tumor shrinkage. The remaining patients were regarded as resistant or partially resistant to BRC. In 5 patients (nos. 1, 5, 14, 21, and 22), BRC caused intolerable side effects (Table 2) and had to be discontinued. CV treatment induced PRL normalization and tumor shrinkage only in 5 patients (nos. 13, 14, and 18–20). Ten patients (nos. 1–4, 8, 10, 11, 15, 17, and 23) were partially resistant also to CV and were given CAB, which normalized PRL concentrations in 6 of them (Table 2). Pregnancy occurred in patients no. 13 (once) and no. 17 (twice) while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. All patients are still on treatment. Only 4 patients (nos. 1, 3, 11, and 15) are presently moderately hyperprolactinemic and are symptomatic.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Treatment with dopamine-agonists is effective in normalizing PRL levels and in shrinking tumor mass in the majority of adult patients with prolactinoma (10). In children and adolescents, BRC has been used successfully be several investigators (3, 4, 5, 6, 8, 9). In our series, BRC induced normoprolactinemia in 10 of 26 patients. The poorly responsive patients were regarded as resistant or partially resistant to the drug. We recognize that many of them did not meet the criteria for being considered truly resistant, and we suspect that some of them were indeed not taking BRC appropriately. Poor compliance to any chronic treatment is a well-known phenomenon in children and adolescents. In addition, some patients required drug discontinuation for intolerable side effects, overall, regarding the gastrointestinal tract. All these patients were given CV or CAB, which were effective in reducing PRL secretion and tumor size in most of them.

In up to one third of women with microadenoma, hyperprolactinemia will prove self-limiting, and pregnancy might be one factor that triggers a return to normal function (11). However, all of our patients are still on treatment, and two of them became pregnant but remained hyperprolactinemic. We cannot predict whether some of our patients will be cured, but we believe that, for most (if not all) of them, dopamine-agonist treatment will be life-long (10).

Seven patients came to our observation immediately after surgery for persistence of hyperprolactinemia. They were first seen by the neurosurgeon for symptoms related to tumor expansion and then operated. As in adults (10), therapy with dopamine-agonists has been shown to be effective also in adolescent patients with large tumors and symptoms of tumor expansion (3, 5, 6). It is possible, therefore, that some of our patients could have avoided surgery if appropriately treated with dopaminergic drugs. Furthermore, none of the patients who underwent surgical resection of the adenoma as first treatment (with or without external radiotherapy) was cured, and many of them also developed associated pituitary hormone deficiencies. The high recurrence rate of prolactinomas after surgery compares favorably with that reported in the literature (1, 12). Thus, treatment with dopamine-agonists should be the first therapeutic option also in young patients with prolactinomas. Surgery should be reserved for those patients with large tumors not responsive to dopamine-agonist therapy. In particular, CAB has recently received attention for its better tolerability and compliance (13) and is effective also in patients poorly responsive or resistant to BRC and/or CV (7). CAB has a longer half-life than BRC, needs to be administered only once or twice a week, and causes normalization of serum PRL levels and restoration of gonadal function in the majority of patients with microprolactinoma (13). Low-dose CAB treatment produced marked tumor shrinkage in most macroprolactinoma patients (14, 15). We suggest that CAB should be the first-line treatment also in young patients with prolactinoma.

Received February 2, 1998.

Revised March 30, 1998.

Accepted April 14, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Partington MD, Dudley HD, Laws ER, Scheithauer BW. 1994 Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery. J Neurosurg. 80:209–216.[Medline]
2. Mindermann T, Wilson CB. 1995 Pediatric pituitary adenomas. Neurosurgery. 36:259–269.[Medline]
3. Blackwell RE, Younger BJ. 1986 Long-term medical therapy and follow up of pediatric adolescent patients with prolactin-secreting macroadenomas. Fertil Steril. 45:713–716.[Medline]
4. Howlett TA, Wass JAH, Grossman A, et al. 1989 Prolactinomas presenting as primary amenorrhoea and delayed or arrested puberty: response to medical therapy. Clin Endocrinol (Oxf). 30:131–140.[CrossRef][Medline]
5. Oberfield SE, Nino M, Riddick L, et al. 1992 Combined bromocriptine and growth hormone (GH) treatment in GH-deficient children with macroprolactinoma in situ. J Clin Endocrinol Metab. 75:87–90.[Abstract]
6. Tyson D, Reggiardo D, Sklar C, David R. 1993 Prolactin-secreting macroadenomas in adolescents. Response to bromocriptine therapy. Am J Dis Child. 147:1057–1061.[Abstract/Free Full Text]
7. Colao A, Di Sarno A, Sarnacchiaro F, et al. 1997 Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab. 82:876–883.[Abstract/Free Full Text]
8. Dalzell GW, Atkinson AB, Carson PJ, Sheridan B. 1987 Normal growth and pubertal development during bromocriptine treatment for a prolactin-secreting pituitary macroadenoma. Clin Endocrinol (Oxf). 26:169–172.[CrossRef][Medline]
9. DeShepper J, Smitz J, Loeb H. 1989 Normalization of growth hormone deficiency during bromocriptine treatment for hyperprolactinemia. J Pediatr Endocrinol. 3:273–276.
10. Molitch ME, Thorner MO, Wilson C. 1997 Management of prolactinomas. J Clin Endocrinol Metab. 82:996–1000.[Free Full Text]
11. Jeffcoate WJ, Pound N, Sturrock NDC, Lambourne J. 1996 Long-term follow-up of patients with hyperprolactinemia. Clin Endocrinol (Oxf). 45:299–303.[CrossRef][Medline]
12. Dyer EH, Civit E, Visot A, Delalande O, Derome P. 1994 Transsphenoidal surgery for pituitary adenomas in children. Neurosurgery. 34:207–212.[Medline]
13. Webster J, Piscitelli G, Polli A, et al. 1994 A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med. 331:904–909.[Abstract/Free Full Text]
14. Biller BMK, Molitch ME, Vance ML, et al. 1996 Treatment of prolactin-secreting macroadenoma with once-a week dopamine agonist cabergoline. J Clin Endocrinol Metab. 81:2338–2343.[Abstract]
15. Colao A, Di Sarno A, Landi ML, et al. 1997 Long-term and low dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab. 82:876–883.

This article has been cited by other articles:

				M. P. Gillam, M. E. Molitch, G. Lombardi, and A. Colao Advances in the Treatment of Prolactinomas Endocr. Rev., August 1, 2006; 27(5): 485 - 534. [Abstract] [Full Text] [PDF]

				V. M. Kelly, K. Arif, S. Ralston, N. Greger, and S. Scott Bloody Nipple Discharge in an Infant and a Proposed Diagnostic Approach Pediatrics, April 1, 2006; 117(4): e814 - e816. [Abstract] [Full Text] [PDF]

				A. Barlier and P. Jaquet Quinagolide - a valuable treatment option for hyperprolactinaemia Eur. J. Endocrinol., February 1, 2006; 154(2): 187 - 195. [Abstract] [Full Text] [PDF]

				A. Colao, G. Vitale, P. Cappabianca, F. Briganti, A. Ciccarelli, M. De Rosa, S. Zarrilli, and G. Lombardi Outcome of Cabergoline Treatment in Men with Prolactinoma: Effects of a 24-Month Treatment on Prolactin Levels, Tumor Mass, Recovery of Pituitary Function, and Semen Analysis J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1704 - 1711. [Abstract] [Full Text] [PDF]

				M. De Rosa, S. Zarrilli, G. Vitale, C. Di Somma, F. Orio, L. Tauchmanova', G. Lombardi, and A. Colao Six Months of Treatment with Cabergoline Restores Sexual Potency in Hyperprolactinemic Males: An Open Longitudinal Study Monitoring Nocturnal Penile Tumescence J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 621 - 625. [Abstract] [Full Text] [PDF]

				J. J. Pinzone, L. Katznelson, D. C. Danila, D. K. Pauler, C. S. Miller, and A. Klibanski Primary Medical Therapy of Micro- and Macroprolactinomas in Men J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3053 - 3057. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Colao, A. Articles by Lombardi, G. Search for Related Content PubMed PubMed Citation Articles by Colao, A. Articles by Lombardi, G.