Understanding Prolactinoma: Epidemiology, Clinical Consequences, and Treatment Options

Prolactinoma Dr Marzieh Movahedi Rad Endocrinologist Mazandaran University of Medical Science

Agenda Epidemiology Clinical consequences of hyperprolactinemia Biochemical diagnosis and Imaging Medical treatment Surgical treatment Prolactinoma in special populations: pregnancy; men; children;menopause

Epidemiology A prolactinoma is the most common cause of chronic hyperprolactinemia once pregnancy, primary hypothyroidism, and drugs that raise serum prolactin (PRL) levels have been ruled out. Between the age of 20 and 50 years, the ratio between women and men is estimated to be 10:1, whereas after the fifth decade of life, both genders are equally affected . Although prolactinomas are rare at the pediatric and adolescent ages, they account for approximately half of all pituitary adenomas in that population . PRL-secreting carcinomas are extremely rare.

Epidemiology Prevalence: 50 per 100,000 incidence 3-5 new cases/100,000/year. Microadenomas (<10 mm ) are 4-5 fold more frequent than Macroadenomas ( 10 mm ) The ratio between macro- and microprolactinomas is approximately 1:8 in women, 4:1 in men (macroadenomas in 80% of cases) Giant prolactinomas (macroprolactinomas >40 mm;with notable extrasellar extension, very high serum levels of prolactin (usually >1,000 g/l) and no concomitant GH or ACTH secretion;good response to DA) are rare. Peak age of occurrence in women occurs at approximately 30 years, while most men are diagnosed after age 50.

Molecular pathogenetic mechanisms MEN1 germline mutation screening could be considered in: 1) Patients with a family history of pituitary adenomas . 2) Patients aged <30 years old with macroadenomas . Somatic mutation screening should not be routinely performed. Prolactinomas are mostly sporadic monoclonal neoplasms. Prolactinomas are very rarely associated with germline mutations : 1) Onset of disease usually occurs at a younger age. 2) Macroprolactinomas in individuals with multiple endocrine neoplasia type 1 (who have germline mutations in MEN1) are more aggressive\ resistant to therapy

Clinical consequences of hyperprolactinemia The most characteristic signs and symptoms found in patients with hyperprolactinemia are those related to hypogonadotropic hypogonadism and galactorrhea. Increased PRL levels decrease gonadotropin pulsatile secretion through inhibition of hypothalamic GnRH release .

Clinical consequences of hyperprolactinemia Women (Classic symptoms of prolactinomas) oligo- or amenorrhea :almost all patients (85-90%) Galactorrhea:84% of patients infertility Postmenopausal women They present with mass effects related to large tumors Although prolactinomas may also be discovered incidentally or because of a history of premature menopause

Some women present with non-puerperal galactorrhea in the presence of regular menstrual cycles and normal PRL levels This so-called idiopathic galactorrhea is estimated to be present in up to 40-50% of all women with non-puerperal galactorrhea In contrast, the finding of galactorrhea in men is highly suggestive of a prolactinoma

Clinical consequences of hyperprolactinemia Men Approximately 80% are diagnosed with a macroprolactinoma Half of men typically present with symptoms caused by the tumor mass Other half with symptoms of hypogonadism, including a loss of libido, ED, gynecomastia, infertility, and/or osteopenia Serum levels of prolactin are typically high, and are associated with low testosterone and osteoporosis if left untreated. Prolactinomas are generally more aggressive in men than in women, with higher proliferation (assessed by Ki-67), cellular atypia, angiogenic and proliferative features, and greater invasiveness.

Clinical consequences of hyperprolactinemia Mass effects Visual field defects (chiasmal compression depend on the extent of suprasellar extension) Headaches are a frequent symptom which is often associated with the lateralization of the tumor, and cluster-like headache may also occur as a major manifestation Hypopituitarism (from direct pituitary compression or more commonly from hypothalamic/stalk dysfunction) Cavernous sinus syndrome is rare and is generally observed in the context of pituitary apoplexy ,which is characterized by headache with a sudden and severe onset that is generally associated with visual disturbances or ocular palsy. Cerebrospinal fluid (CSF) rhinorrhea, hydrocephalus and seizures, can also occur.

Clinical consequences of hyperprolactinemia Bone disease Increased fracture risk is recognized as a clinical consequence of prolactinoma . Clinicians should initiate morphometric investigation by plain radiograph in patients with prolactinoma and back pain or decrease in height . Patients should be evaluated for changes in BMD by (DXA), depending on age, duration of hyperprolactinaemia and hypogonadism, and other risk factors . Baseline DXA is recommended in all patients with prolactinoma with : suspected long-standing (that is, >6 months) hypogonadism other risk factors for osteoporosis, including menopause and previous vertebral fracture.

Causes of hyperprolactinaemia

Causes of hyperprolactinaemia Medication use should be rigorously reviewed to exclude drug-induced hyperprolactinaemia. Primary hypothyroidism, renal insufficiency and liver failure should be recognized as causes of mild hyperprolactinaemia. Pregnancy should not be overlooked as a cause of hyperprolactinaemia.

Causes of hyperprolactinaemia Physiological prolactin increases : after exercise high-protein meals alcohol consumption pregnancy breast feeding sleep coitus Patients with PCOS require further evaluation of elevated serum levels of prolactin, as PCOS per se is rarely associated with hyperprolactinemia. High prolactin with lymphocytic hypophysitis could reflect either autoimmune cell actions or a stalk effect.

Causes of hyperprolactinemia Elevated serum levels of prolactin (up to six times ULN): hypothalamic pituitary lesion local trauma, surgery, radiation, skull fracture internal carotid artery aneurysm. Estrogens potently induce hyperprolactinemia, but the influence of oral contraceptives on prolactinoma development is controversial.

Causes of hyperprolactinaemia Stress (for example, due to venipuncture) can induce a twofold to fourfold rise in serum levels of prolactin that lasts for <1 h. Repeated or cannulated prolactin venipuncture sampling for testing is recommended. Prolactin co-secretion with GH in acromegaly or with TSH in thyrotropinoma is due to either plurihormonal adenoma or a stalk effect. Many drugs acting as dopamine antagonists or as serotonin agonists can cause hyperprolactinemia and galactorrhea.

Imaging : MRI MRI should be performed in patients with confirmed hyperprolactinaemia at diagnosis (if no other non-adenomatous causes for hyperprolactinaemia are evident), to demonstrate pituitary adenoma response to medical treatment, and to establish baseline status 3 6 months after surgery. Timing of MRI after medical therapy initiation depends on : Adenoma size Proximity to the optic chiasm Prolactin response to therapy Follow-up imaging frequency should be based on: clinical, biochemical ;histological factors, as well as previous imaging results

Prolactinomas are typically mildly hyperintense on T2- weighted MRI. Men might exhibit a heterogeneous T2 intensity signal that reflects necrosis and haemorrhage and that might be associated with increased serum levels of prolactin and less effective dopamine agonist response compared with a homogeneous adenoma.

Treatmentofmicroprolactinoma Dopamin Agonists DAs are the gold standard treatment for prolactinomas, as their use controls hormonal secretion and tumor growth in approximately 80% of cases . DA is initiated at a low dose (typically 0.25-0.5 mg of CAB 1-2/W), dose is escalated at 1-3 monthly intervals according to PRL levels and the reduction in tumor size. Doses range from 0.5 to 3.5 mg per week (maximum FDA approved dose is 2 mg weekly), bromocriptine doses range from 2.5 to 15 mg per day.

Cabergoline (CAB), a specific agonist of the dopamine receptor type 2 (D2R), is the first choice because of its better tolerability greater efficacy long half-life Bromocriptin and Quigulide less commonly used, depending on regional approval and availability

If a prolactinoma does not exhibit a favourable response in the first 36 months of treatment, it probably will not respond adequately to dopamine agonist therapy. Prediction of long-term response: Normoprolactinemia and tumour volume reduction of >25% after 3 months of cabergoline.

side effects Nausea and vomiting, GI symptoms Postural hypotension, dizziness, headache Nasal stuffiness and Raynaud's phenomenon They can be minimized by introducing the drug at a low dose at bedtime, taking it with food, and then escalating the dose very gradually.

Neuropsychiatric adverse effects: Mood changes or impulse control disorders. Changes in impulsivity are more common in men but occur in both men and women and are not dose-related CSF rhinorrhoea can rarely occur in patients with an invasive macroprolactinoma that is reduced in size with dopamine agonist therapy. If suspected, 2-transferrrin or -trace protein should be measured in nasal fluid; if confirmed, surgical repair is required . Dopamine agonist-induced apoplexy due to extensive shrinkage of a macroprolactinoma can lead to visual changes. In such cases, surgical repair is probably warranted.

cardiac valvulopathy If long-term treatment with high-dose (>2.0 mg per week) cabergoline is anticipated, perform baseline echocardiography to detect any pre-existing valve alterations. Baseline evaluation can be performed before starting cabergoline therapy or during the first few months of treatment. Repeat echocardiography every 2 3 years in patients treated with >2.0 mg per week of cabergoline . Perform echocardiography after 5 6 years in patients treated with 2.0 mg per week of cabergoline. Some workshop participants believed that these repeat examinations are not necessary in patients treated with<1.0 mg per week and who have no clinical signs of valvular dysfunction.

Monitoring of microadenoma treatment Measure PRL & evaluate the side effects after one month Improve gonadal function: Within a few months Decrease the dose after one year Discontinue medication: Normal PRL> 2 years and Normal MRI

Macroadenoma management Medical therapy regardless of size Reassess vision within one month if initially abnormal .(improvement may be observed within a few days) Adenoma size decrease within weeks or months and can continue for years. Repeat MRI 3 months later.

Hypogonadism Evaluation for restoration of gonadal function should be performed at least 6 months after normalization of prolactin serum levels. Recovery usually occurs in about 60% of men but more frequently in women. The presence of complete hypopituitarism reduces the chances of recovery from hypogonadism and could justify earlier hormone supplementation. Clomiphene has been used as an off-label treatment in men with hypogonadism.

Indications for surgery Resistant to dopamine agonists Women desiring pregnancy might also prefer immediate surgery particullary macroprolactinomas to avoid symptoms from enlargement during pregnancy. Invasive macroprolactinomas or giant prolactinomas with spontaneous or dopamine agonist-induced CSF rhinorrhoea.(Due to increased risk of morbidity and mortality, surgical resection of these large prolactinomas should be restricted.) Rapid or Progressive vision loss with large prolactinomas. large cystic or hemorrhagic components to ensure immediate decompression of visual pathways.

Negative predictor of postoperative remission: Male sex Suprasellar extension Prolactin serum level of >282 ng/ml

Radiation therapy Radiation therapy should be reserved for: poor mass shrinkage in response to dopamine agonists non-resectable residual adenoma tissue after surgery contraindications for surgery . Response to radiotherapy can take several years . Potential adverse effects even after many years : hypopituitarism, optic neuropathy, cranial nerve palsy, second brain tumours

Aggressive prolactinomas and therapy resistance Aggressive prolactinomas are defined as : Invasive adenomas with unusually rapid growth rate Adenomas with clinically relevant growth despite maximal tolerated dopamine agonist doses. In patients with aggressive prolactinomas and documented persistent adenoma growth despite exhausting all treatment modalities, the chemotherapeutic agent temozolomide is recommended. Response to temozolomide should be evaluated after 3 months and treatment continued for at least 6 months in responsive patients.

Resistance Refractory lack of normalization of prolactin serum levels lack of relevant mass shrinkage ( 30%reduction in maximum diameter) If prolactin is not controlled even by dose escalation to maximally tolerated doses of dopamine agonists and surgery is considered for debulking, the term suggested is refractory prolactinoma. when treated with standard dopamine agonist doses (7.5 10 mg per day of bromocriptine or 2.0 mg per week of cabergoline) for at least 6 month.

Pregnancy and fertility Patients desiring fertility and undergoing pituitary surgery before pregnancy should be informed of the potential risk of hypopituitarism and its impact on fertility . To reduce exposure of the developing fetus to dopamin agonist therapy, dopamine agonists should be discontinued as soon as pregnancy is confirmed. Pregnancy in patients with microprolactinomas is usually uneventful, and patients should be followed clinically every 3 months .

Pregnancy and fertility In patients with large macroprolactinomas, maintenance of dopamine agonist therapy during pregnancy is also an option. In patients with macroprolactinoma, adenoma response to dopamine agonist therapy should be confirmed prior to conception. In those without mass response, surgery should be considered prior to conception .

Pregnancy and fertility Patients with macroprolactinoma have a risk of : clinically relevant adenoma expansion apoplexy during pregnancy. Patients should be : Visit monthly during pregnancy and questioned about local mass effects, Visual field evaluation ever 3 months . Patients with suspicion of clinically relevant adenoma growth during pregnancy should undergo MRI without gadolinium.

Pregnancy and fertility Re-initiation of dopamine agonist therapy that was discontinued at conception should be considered in patients with clinically relevant adenoma growth. In patients with an enlarged adenoma that does not respond to re-initiation of dopamine agonist therapy, consideration should be given to pituitary surgery or delivery if the pregnancy is sufficiently advanced. Serum levels of prolactin should not be used to assess for adenoma growth during pregnancy.

Breast feeding Do if micro (macro)adenomas remained stable in size during pregnancy Dopamine agonists should not be taken during breast feeding, because breast feeding fails. Contraindicated in women who have neurologic symptoms at the time of delivery, because they should be treated with dopamin agonists

Prolactinomas in children and adolescents In addition to the clinical signs and symptoms present in adults (that is, secondary amenorrhoea and galactorrhoea), delayed puberty due to hypogonadotrophic hypogonadism should trigger evaluation for hyperprolactinaemia in children. As apoplexy and aggressive prolactinoma behaviour are more common in children than in adults, high clinical suspicion warrants prompt investigation. Surgery should be considered in patients in whom vision is threatened, if severe neurological symptoms or CSF leakage is present, or if the mass is resistant to dopamine agonist therapy.

Patients with an underlying psychiatric disorder Prolactin should be measured prior to initiation of a antipsychotic drug . Serum levels of prolactin more than ten times ULN are uncommon in antipsychotic-mediated hyperprolactinaemia and should trigger suspicion for a prolactinoma. Dose reduction or switching to a second-generatin antipsychotic that does not cause hyperprolactinaemia, such as aripiprazole,distinguishes prolactinoma from drug-induced hyperprolactinaemia in most patients . When antipsychotics are withdrawn, drug-induced hyperprolactinaemia resolves within 48 96 h.

Prolactinomas and menopause Menopause is associated with a physiological decrease in circulating levels of prolactin Women with well-controlled microprolactinoma entering menopause should undergo a trial of dopamine agonist withdrawal. In postmenopausal women with macroprolactinoma, treatment should be targeted to controlling adenoma growth. Current evidence does not support microprolactinoma treatment in asymptomatic postmenopausal women.