Abstract
Summary
Paediatric pituitary adenomas are rare in children and adolescents and differ from adults in both clinical presentation and management. We present the case of a 14-year-old female with primary amenorrhoea secondary to a macroprolactinoma, showing a modest radiological and biochemical response to dopamine agonist (DA) therapy. Despite a 10-month duration of increasing DA therapy, initial symptoms of primary amenorrhoea and hyperprolactinaemia persisted, with new symptoms of weight gain, lethargy and low mood. A transsphenoidal resection of the macroprolactinoma was successfully performed, followed by the initiation of additional hormonal therapy. This case explores the unique challenges of treating a macroprolactinoma refractory to medical management in adolescence.
Learning points
Management of macroprolactinomas in childhood and adolescence can bring unique challenges, including a delay in sexual development, often presenting with primary or secondary amenorrhoea in girls.
DA therapy is typically the first-line therapy in treating macroprolactinomas; however, resistance in paediatric and adolescent patients is associated with tumour size and initial prolactin levels.
Surgical resection should be considered as a second-line therapy for adolescents unable to tolerate high-dose DA therapy or have inadequate response to DA therapy.
There are a range of potential surgical complications, including permanent or transient diabetes insipidus, meningitis, cerebrospinal fluid leakage and hypopituitarism.
Timely management of macroprolactinomas is important for secondary sex characteristics, bone development and psychological well-being.
Background
Prolactinomas are the most common pituitary adenomas, accounting for around 50% of all pituitary adenomas (1). Paediatric prolactinomas are rare, with an incidence of 0.1 per 1,000,000 population, which accounts for less than 2% of all intracranial tumours (2). Macroprolactinomas are classified as tumours ≥10 mm in diameter, while microprolactinomas are classified as <10 mm. Macroprolactinomas diagnosed in adolescence may present with symptoms of hyperprolactinaemia, including delayed puberty, such as amenorrhoea and galactorrhoea in females or gynaecomastia in males, and tumour mass effects, including headaches and visual field defects (3). Paediatric prolactinomas are typically diagnosed at the age when puberty begins and are found more frequently in girls although prolactinomas in boys tend to be larger and more aggressive. Clinical diagnosis and assessment of prolactinomas are based on serum prolactin (PRL) measurements and radiological evaluation of the pituitary gland (2).
Dopamine agonists (DAs) are widely used as the first-line treatment for macroprolactinomas, with dosage titrated according to serum PRL levels. Surgical resection is generally considered following resistance or intolerance to DA therapy (4). In rare cases, external radiation therapy is used in the treatment of malignant macroprolactinomas or for patients with a poor response to medical and surgical treatment (5).
We describe the challenging case of a medically refractory macroprolactinoma in an adolescent female with primary amenorrhoea. In contrast to adults, macroprolactinomas diagnosed in adolescence have their own unique issues, including delayed pubertal development, the implications of long-term medical treatment and the considerations of future fertility.
Case presentation
A 14-year-old female presented to her general practitioner with headaches and galactorrhoea. Her weight was 65 kg, height 164.6 cm and body mass index (BMI) 24.2 kg/m2. She had not reached menarche, with examination findings of Tanner Stage 2 breast development, along with the presence of axillary and pubic hairt. On physical examination, she had bitemporal hemianopia, which was confirmed on formal visual field testing (Fig. 1A and B). In addition, her appearance was not clinically cushingoid.
(A, B) Initial formal visual field testing demonstrates bitemporal hemianopia. (C, D) Repeat formal visual field testing after 7 months of DA therapy showed a 90% resolution.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0033
Past medical history included mild asthma, and there were no regular medications or known allergies. The paternal grandmother had a history of Conn’s syndrome, requiring an adrenalectomy. There was a family history of dyslipidaemia. She was performing well at school and lived with her parents.
Investigations
The results of the initial serum tests showed a grossly elevated PRL level of 26,286 mIU/L (Reference range (RR): 85–500). The remaining pituitary profile is outlined in Table 1. Magnetic resonance imaging (MRI) revealed a 28 × 18 × 15 mm pituitary mass with compression of the optic chiasm, almost 3 cm in vertical height and no extension to the cavernous sinuses (Fig. 2A and B).
Pituitary profile at presentation.
Parameters | Values | RR |
---|---|---|
Prolactin, mIU/L | 26,286 | 85–500 |
TSH, mIU/L | 1.05 | 0.4–4.0 |
FT4, pmol/L | 12.2 | 8–22 |
FT3, pmol/L | 4.6 | 4–9 |
ACTH, pmol/L | 13.2 | <12.1 |
Cortisol, nmol/L | 615 | 70–640 |
IGF-1, nmol/L | 30 | 21–88 |
FSH, IU/L | 5.0 | 1.5–10* |
LH, IU/L | 1.1 | 2.0–12* |
Oestradiol, pmol/L | 58 | 55–320 |
Testosterone, nmol/L | 2.5 | 0.2–1.8 |
SHBG, nmol/L | 21 | 30–110 |
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; IGF-1, insulin-like growth factor; LH, luteinising hormone; RR, reference range; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone.
Based off basal (early follicular) phase to reflect lower FSH/LH levels associated with hyperprolactinaemic amenorrhoea.
(A, B) Initial brain MRI demonstrates a pituitary mass of 28 × 18 × 15 mm, which superiorly displaces the optic chiasm with no extension to the cavernous sinuses (left – coronal T2, right – sagittal T1). White arrows indicate pituitary adenoma. (C, D) Preoperative brain MRI demonstrates a reduction in size of pituitary mass of 17 × 16 × 12 mm with no displacement of the optic chiasm (left – coronal T1, right – sagittal T1). White arrows indicate pituitary adenoma. (E, F) Post-operative brain MRI demonstrates debulking of the pituitary macroadenoma (left – coronal T2, right – sagittal T1). White arrows indicate pituitary adenoma resection.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0033
Treatment
Cabergoline treatment was commenced at 0.5 mg weekly and increased according to serum PRL (Fig. 3). Serum PRL significantly decreased from 26,286 to 24,432, 10,114 and 7,097 mIU/L after 1, 4 and 6 months, respectively (RR: 85–500). At 4 months post-initial therapy, MRI imaging demonstrated a significant shrinkage of the pituitary macroadenoma to 62% of the original size, measuring 24 × 15 × 13 mm. At 7 months post-initial therapy, repeat formal visual field testing was performed and showed a 90% resolution of initial visual hemianopia (Fig. 1C and D).
Serum prolactin trend in months following initial presentation, according to cabergoline (CBG) dose changes and surgery; black circle: no change to CBG dosage, red circle: increased CBG dosage, green circle: decreased CBG dosage. The PRL levels on initial presentation were 26,286 mIU/L and steadily decreased to 4,930 mIU/L following commencement and titration of CBG dosages up to 3 mg weekly. Surgical intervention was performed at 11 months post-initial presentation. Initial post-operative PRL was 738 mIU/L, and CBG was ceased. By 16 months, PRL had steadily increased again to 3,142 mIU/L, resulting in a re-introduction of CBG and subsequent long-term use.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0033
Despite further reductions in serum PRL, the level remained well above the normal range at 4,930 mIU/L (RR: 85–500) at 10 months post-initial therapy with cabergoline dosage at 3 mg weekly. Primary amenorrhoea persisted with new symptoms of progressive weight gain, lethargy and psychosocial changes of low mood, poor sleep and reduced performance at school. The emergence of new symptoms was attributed to adverse effects of high-dose cabergoline, and consequently, the decision was made not to increase the dosage beyond 3 mg weekly. On examination, her weight was 76.2 kg (12 kg increase since initial presentation), height 164.6 cm and BMI 28.1 kg/m2. A repeat brain MRI (10 months post-initial therapy) revealed minimal radiological improvement in the size of the pituitary macroadenoma, measuring 17 × 16 × 12 mm (Fig. 2C and D). At the chronological age of 15 years and 7 months, a bone X-ray was performed, which showed a bone age of 14 years. Genetic testing of multiple endocrine neoplasia-I (MEN1) was negative.
Given the insufficient response from medical therapy to adequately suppress serum prolactin levels and initiate menarche, alongside the perceived adverse effects from cabergoline, multidisciplinary input was sought, and a transnasal transsphenoidal excision was successfully performed at 11 months post-initial presentation. The post-operative MRI scan confirmed significant debulking of the pituitary macroadenoma, with the remaining pituitary tissue measuring 7 mm in height (Fig. 2E and F). Pathology identified a lactotroph PitNET/adenoma of the sparsely granulated lactotroph tumour subtype with infrequent mitoses and a Ki-67 index of 3%. Immunohistochemistry staining was positive for growth hormone, PRL, pituitary-specific positive transcription factor 1 (pit-1), somatostatin receptor type 2 (SSTR2) and SSTR5 (Fig. 4). Furthermore, SSTR2 and SSTR5 staining demonstrated an immunoreactivity score of 4/12 (6, 7). Desmopressin 100mcg daily was commenced for symptoms of diabetes insipidus and weaned as symptoms resolved. Initial post-operative PRL levels showed a significant decline to 738 mIU/L (RR: 85–500) (Fig. 3). The remainder of the pituitary profile is outlined in Table 2. Initial post-operative hypopituitarism was noted with low thyroid-stimulating hormone, luteinising hormone and follicle-stimulating hormone, which recovered over time.
Histologic slides of pituitary biopsy. (A) Haematoxylin and eosin, (B) PRL expression, (C) SSTR2 expression and (D) SSTR5 expression.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0033
Post-operative pituitary profile.
Parameters | Values | RR |
---|---|---|
Prolactin, mIU/L | 738 | 85–500 |
TSH, mIU/L | 0.07 | 0.35–6.00 |
FT4, pmol/L | 11.4 | 8.0–22.0 |
FT3, pmol/L | 2.3 | 4.0–9.0 |
ACTH, pmol/L | 9.5 | <12.1 |
Cortisol, nmol/L | 761 | 70–650 |
IGF-1, nmol/L | 19 | 21–88 |
FSH, IU/L | 0.9 | 1.5–10* |
LH, IU/L | 0.1 | 2.0–12* |
Testosterone, nmol/L | 0.1 | 0.2–1.8 |
SHBG, nmol/L | 19 | 30–110 |
GH, mIU/L | 0.5 | 0–30 |
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; GH, growth hormone; IGF-1, insulin-like growth factor; LH, luteinising hormone; RR, reference range; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone.
Based off basal (early follicular) phase to reflect lower FSH/LH levels associated with hyperprolactinaemic amenorrhoea.
Outcome and follow-up
Five months after her operation, PRL levels were reduced but remained significantly elevated at 3,142 mIU/L. Symptoms of fatigue persisted post-operatively, although improvements in mood and energy were seen with regular physical exercise. Treatment was reattempted with cabergoline 0.5 mg weekly, and subsequently increased to 3.5 mg weekly according to PRL levels. While secondary pubertal characteristics had developed, the patient remained amenorrhoeic and was commenced on a combined oestrogen and progestin transdermal patch at 50/140 μg twice a week. Future clinical management will involve ongoing surveillance of PRL levels and visual field testing. Surveillance MRI scans will be performed to determine changes in tumour size and character.
Discussion
This case report highlights the challenges in treating refractory hyperprolactinaemia in an adolescent patient with macroprolactinoma despite high-dose DA therapy. Transsphenoidal surgical resection demonstrated initial efficacy in reducing hyperprolactinaemia, as has been previously reported in the literature; however, macroprolactinoma in this age group is often resistant to multimodal therapy and requires long-term medical treatment. Managing an adolescent patient with amenorrhoea further requires consideration of timely treatment and the addition of hormonal therapy to support normal pubertal development.
Pituitary adenomas are rare in childhood and adolescence, with a prevalence of 2–6% of all intracranial brain tumours (8). In contrast to the adult population, macroprolactinomas are more prevalent than microprolactinomas and present with different features in children and adolescents (9). Hyperprolactinaemia from pituitary prolactinomas results in reduced gonadotropin secretion through suppression of the hypothalamic hormone kisspeptin (10). Therefore, during the developmental and pubertal period, young patients typically present with delayed or arrested puberty, growth failure, amenorrhoea (primary or secondary) or galactorrhoea. Tumour mass effects are more commonly seen in boys and may present as headache and visual field defects (11). Weight gain is another common symptom, which was also present in our patient as she progressed, with the previous literature reporting 46% patients being overweight or obese at diagnosis of a macroprolactinoma and 23% having weight gain as a presenting symptom (12).
Similar to adults, DA therapy is the first-line for treating macroprolactinomas in children and adolescents, with cabergoline as the recommended DA of choice given its efficacy and low adverse effect profile (1, 11). While DA therapy can provide effective sole treatment of microprolactinomas, this is more difficult to achieve in larger adenomas. An observational study of 28 paediatric patients reported that all adenomas <13.5 mm responded well to conventional DA therapy, while all adenomas >30 mm or between 13.5 and 30 mm with extension/invasion developed DA resistance and were more likely to require surgical resection (13). The largest cohort study of paediatric patients with macroprolactinomas (n = 77) reported that the use of DA therapy (alone or following surgery) failed to normalise PRL levels in 26% cases. Factors found to be associated with DA resistance were young age, increased tumour size, higher initial prolactin levels and the presence of a MEN1 mutation (12).
Transsphenoidal surgery is commonly required as a second-line treatment for macroprolactinomas. Clinicians should work within a multidisciplinary team when considering the indications and risks for surgery. Typical indications include resistance or intolerance to DA therapy, neuro-ophthalmologic deficits such as rapid loss of vision or pituitary apoplexy, while potential surgical complications include hypopituitarism, cerebrospinal fluid leakage or meningitis (5). A systematic review and meta-analysis consisting of 275 paediatric patients reported 41.5% patients with a macroprolactinoma underwent surgical intervention, compared to only 12.1% patients with a microprolactinoma (14). Larger tumours are more likely to require surgical intervention, as reported in a series of 22 paediatric patients, with all macroprolactinomas over 20 mm requiring surgical intervention for poor response to DA therapy or due to pituitary apoplexy (14). In addition, the previous literature suggests surgical remission is more difficult to achieve in paediatric patients, with higher post-surgical recurrence rates of hyperprolactinaemia (38%) (9) compared with adults (25%) (1). Of note, patients with cavernous sinus invasion are more likely to require long-term adjuvant medical therapy (15).
In cases where patients remain symptomatic and tumour growth cannot be controlled despite medical and surgical management, further treatment with repeated surgery or temozolomide chemotherapy and subsequent stereotactic radiotherapy can be considered (14). Currently, there remains limited evidence available for radiotherapy in paediatric patients, with most cases reserved for last-resort treatment options due to risks of hypopituitarism and the potential for secondary malignancies (16). In adult studies, radiation therapy has been reported to be effective in controlling tumour growth in up to 89% patients with functioning pituitary adenomas; however, high rates of hypopituitarism are reported, with an incidence of 30% at 5 years after radiation therapy (17).
Genetic mutation testing is recommended in all children and adolescents who present with macroprolactinoma, as MEN1 and aryl hydrocarbon receptor-interacting protein (AIP) germline abnormalities have been linked to both familial and sporadic forms of prolactinomas. Incidence of MEN1 and AIP mutations has been reported at 5 and 4%, respectively, in patients diagnosed with macroprolactinoma before age 20 years (12). In cases of known MEN1 in patients under 21 years, approximately 34% of patients have a pituitary adenoma and 70% of these are prolactinomas (18). Furthermore, MEN1 mutations are linked to the development of more aggressive and DA-resistant macroprolactinomas, whereas AIP mutations have no such associations (12).
Another challenge highlighted in this case is the management of hyperprolactinaemia resulting in amenorrhoea for adolescent females. Currently, there is limited evidence on an ideal regimen for pubertal induction in females with hyperprolactinaemic amenorrhoea. Typically, for patients without secondary pubertal characteristics, unopposed oestrogen should be introduced prior to progestin to allow for full breast development and other physical changes in puberty (19). Furthermore, clinicians may need to initiate sensitive discussions regarding future fertility planning. Whilst substantial data demonstrate good outcomes of DA therapy and surgical resection restoring fertility in over 90% patients with micro- or macroprolactinomas, evidence remains limited for those unresponsive to these treatments (20, 21). Additional hormonal therapies such as clomiphene citrate, gonadotropin stimulation or in vitro fertilisation have been suggested to facilitate ovulation and pregnancy in these patients (22). Patients with persistent hyperprolactinaemia and absent or irregular menstrual cycles should consult fertility specialists for comprehensive family planning.
Conclusion
This case presents the challenges of managing hyperprolactinaemia and amenorrhoea in an adolescent patient with macroprolactinoma despite multimodal therapy with medical and surgical intervention. While the literature is widely published on the management of adult-onset macroprolactinomas, the efficacy and challenges of treatment options differ significantly in children and adolescents. As described in our case report, clinicians managing adolescent patients with macroprolactinomas should carefully weigh the benefits and risks of available treatment options, prioritise timely management and consider the potential consequences of pubertal delay on growth and well-being.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
NZ contributed to data collection, intellectual input, manuscript drafting and finalising. SJG was the physician responsible for the patient and contributed to data collection, intellectual input, manuscript editing and finalising. EW contributed to data collection, intellectual input, manuscript editing and review. MD contributed to intellectual input and review. WV contributed to data collection, intellectual input, manuscript editing and review. TW contributed to intellectual input, manuscript editing and review.
Patient consent
Written informed consent was obtained from the patient/patient’s mother for publication of this case report.
References
- 1↑
Petersenn S, Fleseriu M, Casanueva FF, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 2023 19 722–740. (https://doi.org/10.1038/s41574-023-00886-5)
- 2↑
Hoffmann A, Adelmann S, Lohle K, et al. Pediatric prolactinoma: initial presentation, treatment, and long-term prognosis. Eur J Pediatr 2018 177 125–132. (https://doi.org/10.1007/s00431-017-3042-5)
- 3↑
Casanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol 2006 65 265–273. (https://doi.org/10.1111/j.1365-2265.2006.02562.x)
- 4↑
Michail M, Ioannis K, Charoula M, et al. Clinical manifestations, evaluation and management of hyperprolactinemia in adolescent and young girls: a brief review. Acta Biomed 2019 90 149. (https://doi.org/10.23750/abm.v90i1.8142)
- 5↑
Iglesias P & Diez JJ Macroprolactinoma: a diagnostic and therapeutic update. QJM 2013 106 495–504. (https://doi.org/10.1093/qjmed/hcs240)
- 6↑
Ilie M-D, Tabarin A, Vasiljevic A, et al. Predictive factors of somatostatin receptor ligand response in acromegaly – a prospective study. J Clin Endocrinol Metab 2022 107 2982–2991. (https://doi.org/10.1210/clinem/dgac512)
- 7↑
Gatto F, Feelders RA, van der Pas R, et al. Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. J Clin Endocrinol Metab 2013 98 E66–E71. (https://doi.org/10.1210/jc.2012-2609)
- 8↑
Aguilar-Riera C, Clemente M, González-Llorens N, et al. Pituitary macroadenomas in childhood and adolescence: a clinical analysis of 7 patients. Clin Diabetes Endocrinol 2023 9 5. (https://doi.org/10.1186/s40842-023-00153-6)
- 9↑
Yang A, Cho SY, Park H, et al. Clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of prolactinomas in children and adolescents at a single center. Front Endocrinol 2020 11 527. (https://doi.org/10.3389/fendo.2020.00527)
- 10↑
Sonigo C, Bouilly J, Carré N, et al. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J Clin Invest 2012 122 3791–3795. (https://doi.org/10.1172/jci63937)
- 11↑
Korbonits M, Blair JC, Boguslawska A, et al. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 2, specific diseases. Nat Rev Endocrinol 2024 20 290–309. (https://doi.org/10.1038/s41574-023-00949-7)
- 12↑
Salenave S, Ancelle D, Bahougne T, et al. Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients. J Clin Endocrinol Metab 2015 100 1177–1186. (https://doi.org/10.1210/jc.2014-3670)
- 13↑
Alikasifoglu A, Celik NB, Ozon ZA, et al. Management of prolactinomas in children and adolescents; which factors define the response to treatment? Pituitary 2022 25 167–179. (https://doi.org/10.1007/s11102-021-01184-x)
- 14↑
Arya VB, Aylwin SJB, Hulse T, et al. Prolactinoma in childhood and adolescence-tumour size at presentation predicts management strategy: single centre series and a systematic review and meta-analysis. Clin Endocrinol 2021 94 413–423. (https://doi.org/10.1111/cen.14394)
- 15↑
Andereggen L, Frey J, Andres R, et al. First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center. J Endocrinol Invest 2021 44 2621–2633. (https://doi.org/10.1007/s40618-021-01569-6)
- 16↑
Burman P, Van Beek AP, Biller BM, et al. Radiotherapy, especially at young age, increases the risk for de novo brain tumors in patients treated for pituitary/sellar lesions. J Clin Endocrinol Metab 2017 102 1051–1058. (https://doi.org/10.1210/jc.2016-3402)
- 17↑
Xu Z, Lee Vance M, Schlesinger D, et al. Hypopituitarism after stereotactic radiosurgery for pituitary adenomas. Neurosurgery 2013 72 630–637. (https://doi.org/10.1227/neu.0b013e3182846e44)
- 18↑
Goudet P, Dalac A, Le Bras M, et al. MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 2015 100 1568–1577. (https://doi.org/10.1210/jc.2014-3659)
- 19↑
Harrington J & Palmert MR An approach to the patient with delayed puberty. J Clin Endocrinol Metab 2022 107 1739–1750. (https://doi.org/10.1210/clinem/dgac054)
- 20↑
Maiter D Prolactinoma and pregnancy: from the wish of conception to lactation. Ann Endocrinol 2016 77 128–134. (https://doi.org/10.1016/j.ando.2016.04.001)
- 21↑
Ono M, Miki N, Amano K, et al. Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro-and macroprolactinomas. J Clin Endocrinol Metab 2010 95 2672–2679. (https://doi.org/10.1210/jc.2009-2605)
- 22↑
McGarrigle HHG, Sarris S, Little V, et al. Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea. Br J Obstet Gynaecol 1978 85 692–697. (https://doi.org/10.1111/j.1471-0528.1978.tb14949.x)