IN THE NAME OF GOD

MANAGEMENT OF PROLACTINOMA

A 26-year-old woman who wants to become pregnant has had no menses since she discontinued the use of an oral contraceptive one year ago , and recently , galactorrhea developed . She takes no medications and has had no headaches, visual loss , . Physical examination shows no abnormalities ,except for the bilateral breast discharge. A test serum human chorionic gonadotropin is negative, the thyrotropin level is normal, and the serum prolactin level is 90 mg per liter. Magnetic resonance imaging(MRI) reveals a mass 8mm in diameter, in the anterior lobe of the pituitary . How should she be treated?

A 42 –year-old man presents with decreased libido, erectile dysfunction , and headaches. He reports no weight change, gynecomastia, fatigue, or other symptoms .He takes no medications. His prolactin level is 648 mg per liter . Magnetic resonance imaging(MRI) reveals a sellar mass 2.0 cm that is 5 mm below the optic chiasm and that extends bilaterally into the cavernous sinuses. What are the diagnostic and therapeutic considerations?

Prolactin

Prolactin Prolactin (PRL, luteotropic hormone) is secreted from lactortrophs of the anterior pituitary gland in both men and woman. It is a protein consisting of a single polypeptide biological action of the hormone is on the mammary gland where maintenance of milk production. Molecular weight of approximately 23.000 Daltons. . Women normally have slightly higher basal prolactin levels than men.

Synthesis and regulation

1-Diagnosis of hyperprolactinemia measurment of single serum prolactin or dynamic test? 2-Hook effect ? 3-Management of drug-induced hyperprolactinemia? 4-Asymptomatic microprolactinoma 5-Resistant and malignant prolactinoma? 6-Hyperprolactinemia and MRI 7-Bromocriptin or cabergoline? 8-Prolactinoma and pregnancy

Causes of hyper prolactinemia

To establish the diagnosis of hyperprolactinemia, a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress.

When there is a discrepancy between a very large pituitary tumor and a mildly elevated prolactin level, recommend serial dilution of serum samples to eliminate an artifact that can occur with some immunoradiometric assays leading to a falsely low prolactin value (“hook effect”).

Macroprolactin —  prolactin bound to immunoglobulin G (IgG), which is usually 150 to 170 kDa in size, compared with 23 kDa for monomeric prolactin . This entity is not of clinical significance directly, but patients can be misdiagnosed and treated as ordinary hyperprolactinemia. Misdiagnosis can be avoided by asking the laboratory to pretreat the serum with polyethylene glycol to precipitate the macroprolactin before the immunoassay for prolactin.

Prolactinoma is the most common type of hormone-producing tumor that can develop in pituitary gland The major effect is decreased levels of estrogen in women and testosterone in men. Although prolactinoma isn't life- threatening, it can impair vision, cause infertility and produce other effects.

Hyperprolactinemia in men, can cause hypogonadism decreased libido and energy and eventually loss of sexual hair, loss of muscle mass, and osteoporosis. Hyperprolactinemia in men may also be associated with erectile dysfunction, even when the serum testosterone concentration is normal.

Clinical manifestations of prolactinomas

Idiopathic hyperprolactinemia — In a substantial number of patients whose serum prolactin concentration is between 20 and 100 ng/mL , no cause can be found; they are considered to have idiopathic hyperprolactinemia. Although many of these patients may have microadenomas not visible on imaging studies, in most of them the serum prolactin concentrations change little during follow-up for several years.

Prolactin secretion by lactotroph adenomas is usually proportional to their size. Adenomas <1 cm in diameter are typically associated with serum prolactin values below 200 ng/mL , those approximately 1.0 to 2.0 cm in diameter with values between 200 and 1000 ng/mL , and those greater than 2.0 cm in diameter with values above 1000 ng/mL . Tumor size ranged from 56 to 84 mm and pre-treatment PRL from 1470 to 642387 ng/ml in Giant Prolactinomas reported. There are exceptions to this generalization, however, as occasional patients have a large lactotroph adenoma but only modest hyperprolactinemia. Such adenomas are generally less well differentiated and respond less well to dopamine agonists than the more typical tumors.

In premenopausal women, serum prolactin concentrations >100 ng/mL are likely to be associated with amenorrhea and low estradiol levels The symptoms correlate with the magnitude of the hyperprolactinemia. prolactin values of 50 to 100 ng/mL cause either amenorrhea or oligomenorrhea, while women with milder degrees of hyperprolactinemia (20 to 50 ng/mL may have normal menstrual cycles or oligomenorrhea but infertility due to insufficient luteal phase progesterone secretion.

Hyperprolactinemia in premenopausal women can also cause galactorrhea Hyperprolactinemia in premenopausal women can also cause galactorrhea. The presence of galactorrhea alone does not require treatment unless the patient finds it bothersome. Postmenopausal women have markedly low estradiol levels, and galactorrhea is rare. Hyperprolactinemia in these women is clinically recognized only in the unusual situation when a lactotroph adenoma becomes so large as to cause headaches or impair vision.

Hyperprolactinemia in men, can cause decreased libido and energy and eventually loss of sexual hair, loss of muscle mass, and osteoporosis. Hyperprolactinemia in men may also be associated with erectile dysfunction, even when the serum testosterone concentration is normal. The mechanism is unknown, but the erectile dysfunction usually improves dramatically when the hyperprolactinemia is corrected .

in a symptomatic patient with suspected drug- induced hyperprolactinemia, discontinuation of the medication for 3 d or substitution of an alternative drug, followed by remeasurement of serum Prolactin. If the drug cannot be discontinued and the onset of the hyperprolactinemia does not coincide with therapy initiation, obtaining a pituitary MRi to differentiate between medication-induced hyperprolactinemia and symptomatic hyperprolactinemia due to a pituitary or hypothalamic mass .

Medication-induced hyperprolactinemia is usually associated with prolactin levels ranging from 25 to 100ng /ml, but metoclopramide, risperidone, and phenothiazines can lead to prolactin levels exceeding 200 ng/ml.

The first step in treatment of medication-induced hyperprolactinemia is to stop the drug if this is clinically feasible. If this is not possible, a drug with a similar action that does not cause hyperprolactinemia should be substituted, and if this is not feasible considering the cautious administration of a dopamine agonist in consultation with the patient’s physician.

it is important to determine whether patients with hyperprolactinemia also have acromegaly because prolactin is elevated in up to 50% of patients with GH-secreting tumors.

TREATMENT

A dopamine agonist drug should usually be the first treatment for patients with hyperprolactinemia of any cause, including lactotroph adenomas (prolactinomas) of all sizes, because these drugs decrease serum prolactin concentrations and decrease the size of most For most patients with hyperprolactinemia, cabergoline is first choice of drug, and bromocriptine is second choice for lactotroph adenomas .  Dopamine agonists decrease prolactin secretion and reduce the size of the lactotroph adenoma in more than 90 percent of patients. Both effects are mediated by the binding of the drug to cell-surface dopamine receptors, leading to reductions in the synthesis and secretion of prolactin and in adenoma cell size .

The fall in serum prolactin typically occurs within the first two to three weeks of therapy with a dopamine agonist ,in patients with macroadenoma, it always precedes any decrease in adenoma size .The decrease in adenoma size can, in many patients, be detected by imaging within six weeks after initiation of treatment; in some patients, however, a decrease is not apparent for six months.

Following the decrease in serum prolactin and adenoma size in patients with macroadenomas, visual and pituitary function often return to normal. Vision usually begins to improve within days after the initiation of treatment. Improvement of menses and fertility in women and of testosterone secretion, sperm count, and erectile function in men requires several weeks of treatment .Patients with macroadenomas who are hypothyroid and/or hypoadrenal may also have a return of these functions to normal .

The principal side effects of dopamine agonist drugs are nausea, postural hypotension, and mental fogginess. Less common side effects include nasal stuffiness, depression, Raynaud phenomenon, alcohol intolerance, and constipation. Nausea appears to be more common with bromocriptine than cabergoline. Cerebrospinal fluid (CSF) rhinorrhea may occur during dopamine agonist treatment for very large lactotroph adenomas that extend inferiorly and invade the floor of the sella .

If the patient cannot tolerate the first dopamine agonist administered because of side effects, another can be tried. In women, nausea can be avoided by vaginal administration resistant to cabergoline. Cardiac ultrasonography approximately every two years in patients who take larger than typical doses of cabergoline (eg, greater than 2 mg per week) is recommended.

If dopamine agonists have been unsuccessful or the patient cannot tolerate them, transsphenoidal surgery or ovulation induction with clomiphene citrate can be considered . For women not pursuing pregnancy, estrogen and progesterone replacement can be considered; men can consider testosterone therapy. Estrogen is also a reasonable option for women with hyperprolactinemia and amenorrhea due to other causes, including antipsychotic agents. Since estrogen treatment might pose a slight risk of increasing the size of the adenoma, the serum prolactin concentration should be measured periodically in these patients. Estrogen should not be used as the sole treatment for lactotroph macroadenomas.

  Transsphenoidal surgery should be considered in patients with microadenomas when dopamine agonist treatment has been unsuccessful in lowering the serum prolactin concentration, symptoms or signs due to hyperprolactinemia persist even after several months of treatment, and gonadal steroid replacement is not an option, eg, when pregnancy is desired.

Patients with microadenomas who achieve normal serum prolactin concentrations should be treated for at least one year. Serum prolactin measurements should be obtained at least every 12 months . giant adenomas (>3 cm) may behave more aggressively, as shown by case reports of rapid, substantial regrowth within weeks of discontinuation of dopamine agonist medication. In a meta-analysis of 19 studies with a total of 743 patients, the overall rate of remission (persistent normoprolactinemia) after withdrawal of dopamine agonist therapy was only 21 percent.

Discontinuation should probably not be considered if the adenoma was initially >2 cm, if it can still be visualized by MRI during treatment, or if the prolactin has not become normal during treatment. .

Hyperprolactinemia in premenopausal women can also cause galactorrhea Hyperprolactinemia in premenopausal women can also cause galactorrhea.. Postmenopausal women have markedly low estradiol levels, and galactorrhea is rare. Hyperprolactinemia in these women is clinically recognized only in the unusual situation when a lactotroph adenoma becomes so large as to cause headaches or impair vision.

clinicians not treat asymptomatic patients harboring microprolactinomas with dopamine agonists.

clinicians not treat patients with Asymptomatic medication- induced hyperprolactinemia.

If the drug cannot be discontinued or substituted and the patient has hypogonadal symptoms or low bone mass, estrogen or testosterone therapy should be considered

Careful clinical and biochemical follow-up therapy may be tapered and perhaps is continued in patients who have been treated with dopamine agonists for at least 2yr, who no longer have elevated serum prolactin, and who have no visible tumor remnant on MRI.

In patients who begin dopamine agonist therapy, follow-up includes: 1) periodic prolactin measurement starting 1 month after therapy to guide treat ment intensification to achieve normal prolactin level and reversalof hypogonadism; 2) repeat MRI in 1yr (or in 3 months in patients with macroprolactinoma, if prolactin levels continue to rise while patient is receiving dopaminergic agents, or if new symptoms.

Careful clinical and biochemical follow-up, therapy may be tapered and perhaps discontinued in patients who have been treated with dopamine agonists for at least 2 yr, who no longer have elevated serum prolactin, and who have no visible tumor remnant on MRI. The risk of recurrence after withdrawal ranges from 26 to 69% , and all studies have shown that recurrence is predicted by prolactin levels at diagnosis and by tumor size.

For patients who after2yr of therapy have achieved normal prolactin levels and no visible tumor remnant and for whom dopamine agonists have been tapered or discontinued, follow-up includes: 1) measurement of serum prolactin levels every3months for the first year and then annually thereafter; and 2) MRI if prolactin increases above normal levels . in women with microprolactinomas, it may be possible to discontinue dopaminergic therapy when menopause occurs.

The majority of patients with prolactinomas treated with standard doses of dopamine agonists respond with normalization of prolactin levels and a reduction in tumor size. However, some patients do not respond satisfactorily . dopamine agonist resistance includesa failure to achievea normal prolactin level on maximally tolerated doses of dopamine agonist and a failure to achieve a 50% reduction in tumor size.

Microadenomas are less resistant to dopamine agonists than are macroadenomas. Ten percent of patients with microadenomas and 18% of patients with macroadenomas do not achieve normal prolactin levels on cabergoline . Furthermore, men are more likely than women to be dopamine agonist resistant .The mechanism of dopamine agonist resistance is not completely understood. There is a decreased number Of d2 receptors expressed on resistant prolactinoma.

Increasing the cabergoline dose to as much as 11 mg/ wk has been necessary in a few patients to overcome resistance. Although high doses of cabergoline may be necessary to overcome resistance, caution must be exhibited with protracted use of high-dose cabergoline because of the potential risk of cardiac valvular regurgitation.

Although cabergoline is the first-line treatment for patients with prolactinoma, approximately 10% of patients are resistant to that drug. On the other hand, approximately 25% are resistant to bromocriptine, and 80% of these patients may achieve prolactin normalization on cabergoline .

Transsphenoidal surgery to symptomatic patients with prolactinomas who cannot tolerate high doses of cabergoline or who are not responsive to dopamine agonist therapy is recommended.

Seven to fifty percent of surgically resected prolactin- secreting tumors recur. Side effects of surgery, which are less commonly encountered with experienced pituitary surgeons, include hypopituitarism, diabetes insipidus, cerebrospinal fluid leak, and local infection .

Malignant prolactinoma is defined as one that exhibits metastatic spread within or outside the central nervous system. Malignant prolactinomas are rare, and approximately 50 have been described . In patients with malignant prolactinomas, we suggest temozolomide therapy.

Patients with malignant prolactinomas, are treated with temozolomide or radiation therapy.

Pregnancy and prolactinoma

Women with prolactinomas are instructed to discontinue dopamine agonist therapy as soon as they discover that they are pregnant . Routine pituitary MRI during pregnancy is dicouraged in patients with microadenomas or intrasellar macroadenomas unless there is clinical evidence for tumor growth such as visual field compromise.