Breast development began more than three years ago; breasts and pubic hair are now Tanner stage IV. Growth has decelerated slightly (her height is at the 50th percentile for age) and weight has been steady at the 95th percentile. She has no complaint of hirsutism, acne, or galactorrhea. She denies cyclic abdominal pain, cold intolerance, constipation, change in skin or hair texture, decreased energy level, sexual activity, and taking medications or using illicit drugs or alcohol. She has pursued interscholastic sports, but not seriously.
She has no appreciable hirsutism, acne, striae, or acanthosis nigricans. Inspection of the external genitalia shows a normal vulva without clitoromegaly. A digital pelvic exam confirms a patent vaginal canal and palpable cervix. The only other change she notes is difficulty with vision during the past year. Indeed, although a prior vision screening examination yielded 20/20 acuity, her best effort at this visit demonstrates 20/100 acuity. Visual fields by confrontation seem normal.
The history of amenorrhea in this well-developed girl intrigues you, and you conclude that it deserves attention. A single episode of menses suggests normal anatomy, and you ponder the differential diagnosis of secondary amenorrhea. Is this symptom independent of her earlier complaint of headache, or is it related—somehow?
Down into the cellar for a diagnosis
You order tests of thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone (FSH), prolactin, dehydroepiandrosterone, and testosterone. TSH, gonadotropin, and testosterone levels are normal, but the prolactin level returns markedly elevated at 183 ng/mL (normal, 2.8 to 29.2 ng/mL). Dehydroepiandrosterone is also elevated at 14.8 ng/mL (normal, 1.5 to 7 ng/mL).
Magnetic resonance imaging (MRI) of the brain confirms your suspicion. A mass 0.8 x 1.2 cm is visualized within the left pituitary fossa. It does not appear to impinge on the optic chiasm, but does displace the left internal carotid artery and cavernous sinus. Reproductive endocrinologic and neurosurgical consultations are obtained and treatment for prolactinoma is initiated.
A prolactinoma is a benign tumor of the pituitary gland that leads to hypersecretion of the hormone prolactin. The tumor is rare in children compared to its prevalence among adults, although pituitary tumors do constitute approximately 2.7% of supratentorial tumors of childhood. In younger age groups, adrenocorticotropic hormone-secreting tumors are the most common pituitary adenomas, whereas prolactinoma predominates by adolescence.Girls are affected more often—by a ratio as high as 4.5:1—although prolactinomas are usually larger in boys by the time they are identified.
In addition to its lactogenic effect, prolactin may affect the hypothalamic-pituitary-gonadal axis. Presenting symptoms of prolactinoma reflect hyperprolactinemia or mass effect, and often include headache, arrested growth, and delayed puberty. In girls, amenorrhea or galactorrhea may be the initial complaint; boys may rarely demonstrate gynecomastia. Enlargement of the pituitary may cause compression of the optic chiasm, resulting in visual disturbances such as bitemporal hemianopia (tunnel vision).
Under normal circumstances, prolactin is secreted episodically from the pituitary gland and regulated by chronic dopamine inhibition, yielding a serum concentration of 1 to 20 ng/mL. Many physiologic and pathologic factors affect secretion of prolactin; stress, exercise, routine breast examination, a number of medications (phenothiazines, benzodiazepines, cimetidine, and metoclopramide, for example), and illicit drugs may cause a modest elevation. Hormonal changes of pregnancy, hypothyroidism, and polycystic ovary syndrome can also cause hyperprolactinemia. These clinical scenarios typically elevate the prolactin level to 30 to 100 ng/mL. Concomitant rise in dehydroepiandrosterone may occur as a result of prolactin receptors in the adrenal gland. A prolactin level >100 ng/mL suggests a prolactin-secreting tumor and should be further explored by brain imaging.
Because routine head CT may provide suboptimal images of the sellar region or lack the sensitivity to detect very small lesions, pituitary pathology is best defined by MRI. Once a prolactinoma is delineated radiologically, it is classified on the basis of its size as a microadenoma (<1 cm in diameter) or a macroadenoma (>1 cm). Size often correlates with the degree of hyperprolactinemia and may influence the approach to management.
Both microadenomas and macroadenomas must be treated if symptoms are to be relieved, normal menstrual cycles and fertility restored, and the patient protected from further complications. Because a microadenoma does not necessarily progress to a macroadenoma, the decision to treat is based on the clinical scenario. Direct extension of a macroadenoma poses an ongoing risk of loss of vision, destruction of the pituitary, and hypopituitarism—mandating more urgent need for treatment. In addition, most adolescents with a prolactinoma are estrogen-deficient and therefore suffer significant bone loss if not treated.
Dopamine agonist therapy has replaced surgery as the mainstay of treatment for adolescents with prolactinoma. Bromocriptine, once daily, or cabergoline, twice weekly, decreases the level of circulating prolactin, ultimately shrinking the tumor in most patients. Common side effects—including headache, nausea, and dizziness secondary to postural hypotension—are less likely when using newer, long-acting formulations of these drugs. Duration of therapy depends on the patient's response, although few prolactinomas are self-limited. Despite the striking reduction in the size of the tumor prompted by medication, it is never eliminated and lifelong pharmacotherapy is often required to sustain remission.
When a prolactinoma is refractory to medical management or a patient cannot tolerate dopamine agonist medications, then trans-sphenoidal surgery or, more rarely, radiation therapy may be required. These alternatives are avoided as first-line interventions because they carry a high risk of severe complications, especially in cases of macroadenoma.
It is essential to provide long-term follow-up for patients with prolactinoma. Routine monitoring of clinical status, measurement of the prolactin level, examination for visual field changes, and observation of the appearance of the tumor with MRI should be performed every three to six months during the initial phase of therapy. Especially close surveillance is needed during pregnancy and in the peripartum period. Dopamine agonist therapy is discontinued upon recognition of pregnancy, thereby increasing the risk that a macroadenoma will expand and related complications will develop.
Pituitary adenomas, including prolactinomas, are rarely fatal, but associated endocrinopathy may exert a profound effect on the patient's quality of life. Early evaluation and intervention are necessary to prevent permanent consequences of unrestrained tumor growth, especially during vulnerable periods of rapid sexual and skeletal development.
Pediatricians, and parents, often attribute headache to psychosocial stressors, particularly in adolescents, based on a consistent history and physical exam. This may often be true, but these patients should nevertheless be followed carefully for evolving symptoms or clinical changes that suggest an alternative cause. Before you conclude that the problem is all in the patient's head, consider this: It just might be.