Outline <ul><li>Case Presentation </li></ul><ul><li>The Clinical Problem </li></ul><ul><ul><li>Clinical Presentation </li></ul></ul><ul><ul><li>Causes of Hyperprolactinemia </li></ul></ul><ul><li>Strategies and Evidence </li></ul><ul><ul><li>Diagnostic Studies </li></ul></ul><ul><ul><li>Therapy </li></ul></ul><ul><ul><li> Microadenomas Macroadenomas Hypogonadism </li></ul></ul><ul><li>Areas of Uncertainty </li></ul><ul><li>Guidelines </li></ul><ul><li>Conclusions and Recommendations </li></ul>
Case Presentation <ul><li>A 22-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. </li></ul><ul><li>She takes no medications and has had no headaches, visual loss, dyspareunia, or decreased libido. </li></ul><ul><li>P.E. shows no abnormalities, except for the bilateral breast discharge . </li></ul><ul><li>A test for serum HCG is negative, the thyrotropin level is normal, and the serum prolactin level is 95 µg /l. </li></ul><ul><li>MRI reveals a mass, 3 mm in diameter, in the anterior lobe of the pituitary. </li></ul><ul><li>How should she be treated? </li></ul>
The Clinical Problem <ul><li>Prolactin-secreting tumors are benign neoplasms that account for about 40 % of all pituitary tumors. </li></ul><ul><li>Over 90 % are small, intrasellar tumors that rarely increase in size. </li></ul><ul><li>The primary action of prolactin is to stimulate lactation, but it is the effect of prolactin on gonadal function that warrants clinical attention. </li></ul><ul><li>Hypersecretion of prolactin leads to infertility and gonadal dysfunction by interrupting secretion of gonadotropin-releasing hormone , inhibiting the release of LH and FSH , and impairing gonadal steroidogenesis . </li></ul>
Prolactin inhibits oestrogen synthesis in the ovary <ul><li>In 20% of cases of secondary amenorrhoea, hyperprolactinaemia prevents ovulation by impairing normal follicular development, but little is known of the biochemical basis for this effect. </li></ul><ul><li>Bromocriptine can restore follicular growth and ovulation by inhibiting the release of prolactin from the pituitary. </li></ul><ul><li>The suckling stimulus causes an increase in prolactin levels, and ovarian follicles fail to develop fully, thus inducing an anovulatory state throughout lactation in many mammals. </li></ul><ul><li>We report here experiments with cultured granulosa cells which suggest that this contraceptive action of prolactin is due to its ability to interfere with the action of FSH on the synthesis of oestrogen . </li></ul>Nature. 1981 Apr 16;290(5807):600-2.
Clinical Presentation (1) <ul><li>The most common symptoms of hyperprolactinemia in premenopausal women are amenorrhea and infertility . </li></ul><ul><li>Galactorrhea occurs in about 80 % of such women, and some women with prolactinomas have infrequent menstrual flow (oligomenorrhea) or regular menses. </li></ul><ul><li>Hyperprolactinemia is often detected after discontinuation of an oral contraceptive, but there is no apparent relation between the use of oral contraceptives and the formation of prolactinomas. </li></ul><ul><li>The majority of prolactinomas in women are small at the diagnosis, and headaches and neurologic deficits are rare. </li></ul>
Clinical Presentation (2) <ul><li>In contrast, prolactinomas in men typically tend to be large at the time of diagnosis and may cause cranial-nerve dysfunction, visual loss, and hypopituitarism. </li></ul><ul><li>In men, hyperprolactinemia leads to impotence, infertility, and decreased libido, but these are rarely the initial symptoms; galactorrhea and gynecomastia are uncommon. </li></ul><ul><li>In both sexes, long-standing hyperprolactinemia leads to low bone density in the spine . </li></ul><ul><li>After prolactin has returned to the normal range, bone density will increase but does not reach normal values. </li></ul>
Prolactin-secreting tumors and hypogonadism in 22 men <ul><li>We studied 22 men with prolactin-secreting pituitary tumors and hypogonadism. Twenty complained of impotence, nine had visual impairment, and three experienced galactorrhea. None of the 17 p'ts undergoing operation or radiotherapy, or both, were subsequently normoprolactinemic. In all 13 p'ts treated with bromocryptine, major clinical improvement was associated with a decrease in serum prolactin levels and in nine with an increase in serum testosterone. </li></ul><ul><li>Two p'ts receiving testosterone replacement therapy showed improved potency only after bromocryptine was administered. </li></ul><ul><li>The results indicate that hyperprolactinemia frequently induces hypogonadism in men , that bromocryptine ameliorates symptoms of disease previously unchanged by operation or radiotherapy, and the impotence observed may not be solely the result of hypogonadism. </li></ul>N Engl J Med 1978;299:847-852.
Bone Marker and Bone Density Responses to Dopamine Agonist Therapy in Hyperprolactinemic Males <ul><li>The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. </li></ul><ul><li>Six p'ts received bromocriptine at a dose of 2.5–10 mg/day; </li></ul><ul><li>7 p'ts received quinagolide at a dose of 0.075–0.3 mg/day; </li></ul><ul><li>7 p'ts received cabergoline at a dose of 0.5–1.5 mg/wk. </li></ul><ul><li>BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N -telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment. </li></ul>J Clin Endocrinol Metab 1998;83:807-813
<ul><li>At study entry, BMD values were lower in p'ts than controls at both lumbar spine (0.82 ± 0.03 vs. 1.18 ± 0.01 g/cm2; P < 0.001) and femoral neck (0.85 ± 0.02 vs. 0.92 ± 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 p'ts at the lumbar spine and in 6 of them at the femoral neck level. </li></ul><ul><li>A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration ( P < 0.01). </li></ul><ul><li>In the 20 p'ts, serum OC levels were significantly lower (2.1 ± 0.1 vs. 9.3 ± 2.4 µg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 ± 1.1 vs. 96.4 ± 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. </li></ul><ul><li>A significant inverse correlation was found between serum PRL and OC ( P < 0.01), but not Ntx, levels. </li></ul>J Clin Endocrinol Metab 1998;83:807-813
<ul><li>After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 p'ts, as shown by the normalization of serum T (from 2.2 ± 0.2 to 5.0 ± 0.2 µg/L) and dihydrotestosterone (0.3 ± 0.02 vs. 0.5 ± 0.01 nmol/L) levels, without any significant difference among groups. </li></ul><ul><li>A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of p'ts. </li></ul><ul><li>A slight, although significant, increase in BMD values was recorded in all p'ts after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment , whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents. </li></ul>J Clin Endocrinol Metab 1998;83:807-813
<ul><li>In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. </li></ul><ul><li>However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia. </li></ul>J Clin Endocrinol Metab 1998;83:807-813
Causes of Hyperprolactinemia (1) <ul><li>The secretion and release of prolactin are mediated by dopamine , and any process that disrupts dopamine secretion or interferes with the delivery of dopamine to the portal vessels may cause hyperprolactinemia. </li></ul><ul><li>Normal prolactin levels in women and men are below 25 µg/l and 20 µg/l, respectively. There is a 10-fold increase in prolactin during pregnancy , and levels rise after exercise, meals, and stimulation of the chest wall. </li></ul><ul><li>Physical and psychological stress increases the secretion of prolactin, but rarely exceeds 40 µg/l. </li></ul><ul><li>Breast examination is infrequently associated with elevation of the prolactin level. </li></ul>
Causes of Hyperprolactinemia (2) <ul><li>Metoclopramide, phenothiazines, and butyrophenones antagonize lactotroph dopamine receptors, leading to prolactin levels that exceed 100 µg /l. </li></ul><ul><li>Risperidone causes a similar elevation, and MAOIs and TCAs raise prolactin levels through effects on the delivery of dopamine to the portal vessels. </li></ul><ul><li>Serotonin-reuptake inhibitors may cause hyperprolactinemia, but the prolactin levels rarely exceed the normal range. </li></ul><ul><li>Nearly 10 % of p'ts taking verapamil have elevated prolactin levels, but other CCBs are not associated with hyperprolactinemia. </li></ul>
The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in p’ts with schizophrenia. <ul><li>BACKGROUND: There is relatively little comparative information on elevations in plasma prolactin level (PRL) with conventional versus novel antipsychotic agents. </li></ul><ul><li>OBJECTIVE: This paper examines the comparative effects on PRL of olanzapine, risperidone, and haloperidol based on data from 3 multicenter, double-blind, randomized clinical trials. Magnitude of response, dose dependency, time course, effects of sex and age, and response to switching from haloperidol to olanzapine are assessed. </li></ul>Clin Ther 2000;22:1085-1096
<ul><li>METHODS: The effects of olanzapine, risperidone, and haloperidol on PRL were assessed in schizophrenia or related psychoses participating in 3 double-blind clinical trials: (1) a 6-wk acute trial comparing olanzapine 5 to 20 mg/d (n = 1,336) and haloperidol 5 to 20 mg/d (n = 660), with a 1-year, open-label olanzapine extension for responders; (2) a 54-wk study comparing olanzapine 5 to 20 mg/d (n = 21), risperidone 4 to 10 mg/d (n = 21), and haloperidol 5 to 20 mg/d (n = 23) in early illness; and (3) a 28-wk study comparing olanzapine 10 to 20 mg/d (n = 172) and risperidone 4 to 12 mg/d (n = 167). </li></ul><ul><li>RESULTS: PRL elevations were significantly greater with risperidone than with either olanzapine or haloperidol in study 2. and significantly greater than with olanzapine in study 3 (all, P < 0.001). PRL elevations were significantly greater with haloperidol than with olanzapine in study 1 (P < 0.001 ). A dose-response relationship was not consistently confirmed with any of the drug treatments. Risperidone-associated PRL elevations peaked relatively early in treatment. In haloperidol- and risperidone-treated p'ts, the mean change in PRL was greater in women than in men. PRL decreased significantly when treatment was switched from haloperidol to olanzapine. </li></ul>Clin Ther 2000;22:1085-1096
<ul><li>CONCLUSIONS: </li></ul><ul><li>This side-by-side analysis of 3 independent studies suggests that with the 3 antipsychotic drugs studied, PRL is elevated moderately by olanzapine (mean change, 1-4 ng/mL), intermediately by haloperidol (mean change, approximately 17 ng/mL), and strongly by risperidone (mean change, 45-80 ng/mL). </li></ul><ul><li>No consistent dose-response relationship was observed, and the time course and sex-dependency of the response differed between the 3 agents. </li></ul><ul><li>P'ts with haloperidol-induced hyperprolactinemia may benefit from a switch to olanzapine . </li></ul><ul><li>Long-term studies examining the health consequences of chronic hyperprolactinemia during antipsychotic treatment are needed </li></ul>Clin Ther 2000;22:1085-1096
Causes of Hyperprolactinemia (3) <ul><li>Less commonly used antihypertensive agents that are associated with hyperprolactinemia include reserpine and methyldopa . </li></ul><ul><li>Prolactin levels may also be mildly elevated after the administration of estrogen . </li></ul><ul><li>The magnitude of medication-induced elevations in the prolactin level is variable, and the level returns to normal within days after the cessation of therapy. </li></ul><ul><li>Medication-induced hyperprolactinemia is associated with levels of prolactin in the range of 25 to 100 µg /l. </li></ul>
Effects of methyldopa on prolactin and GH <ul><li>The effects of administration of methyldopa on serum prolactin and GH concentrations in hypertensive p'ts were studied. </li></ul><ul><li>Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. </li></ul><ul><li>Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In p'ts treated with methyldopa for two to three wks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive p'ts. </li></ul><ul><li>In contrast, p'ts treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal. </li></ul>Br Med J 1976;1:1186-1188.
Augmentation of prolactin secretion by estrogen in hypogonadal women <ul><li>The effect of estrogen on PRL release and gonadotropin suppression was assessed in six experiments performed on four hypogonadal women. </li></ul><ul><li>Ethinyl estradiol at a dose of 1 ug/kg/day induced a significant elevation of serum PRL levels within the 1st wk of treatment. There was a further rise until a plateau was reached in about 3-4 wk to levels of more than 3 times the initial concentration. This was accompanied by a pattern of increased episodic fluctuation. </li></ul><ul><li>The corresponding serum LH and FSH fell progressively during the study period. </li></ul><ul><li>These data indicate that a positive feedback relationship between estrogen and PRL release exists in humans. </li></ul>J Clin Invest 1974;53:652-655.
Causes of Hyperprolactinemia (4) <ul><li>Craniopharyngioma , acromegaly , granulomatous infiltration of the hypothalamus , severe head trauma , and large nonfunctioning pituitary tumors may also lead to hyperprolactinemia. </li></ul><ul><li>In p'ts with acromegaly, prolactin may be secreted along with GH. The development of large nonfunctioning pituitary tumors can compress the pituitary stalk and lead to prolactin levels in the range of 25 to 200 µg/l , with increases to levels of less than 100 µg/l in most cases. </li></ul><ul><li>In some p'ts with primary hypothyroidism , mild hyperprolactinemia develops owing to the increased synthesis of TRH. </li></ul><ul><li>Prolactin levels are elevated in chronic renal failure because of decreased clearance of the hormone. </li></ul>Br Med J 1976;1:1186-1188.
Causes of Hyperprolactinemia (5) <ul><li>When no cause of hyperprolactinemia can be identified, the diagnosis is idiopathic hyperprolactinemia . </li></ul><ul><li>A prolactinoma may be present but may be too small to be detected radiographically. </li></ul><ul><li>In one third of p'ts with idiopathic hyperprolactinemia, the level of prolactin later returns to the normal range, and in nearly half , it remains unchanged. </li></ul><ul><li>In one study, only 10 % of p'ts with idiopathic hyperprolactinemia had radiographic evidence of a pituitary tumor during a follow-up period of six years . </li></ul>
Clinical history and outcome of 59 p'ts with idiopathic hyperprolactinemia <ul><li>OBJECTIVE: To investigate the clinical course of hyperprolactinemia without demonstrable cause. </li></ul><ul><li>DESIGN: Prospective study of all p'ts with idiopathic hyperprolactinemia first seen between 1974 and 1985. </li></ul><ul><li>SETTING: Outp't Department of University Hospital. </li></ul><ul><li>P'ts: Fifty-nine p'ts followed for 6 to 190 months (median 78 months). Medical treatment given only in case of anovulatory infertility or hypogonadism. </li></ul><ul><li>OUTCOME MEASURES: Development of pituitary (micro)prolactinoma, PRL levels, and clinical signs of menstrual dysfunction. </li></ul>Fertil Steril 1992;58:72-77.
<ul><li>RESULTS: </li></ul><ul><li>With exception of one woman in whom it probably had been missed by hypocycloidal tomography, no demonstrable prolactinoma developed. </li></ul><ul><li>Prolactin levels rose in two p'ts, one using oral contraceptives and the other with prolactinoma. </li></ul><ul><li>At the end of follow-up, 15 of 16 p'ts using a dopaminergic drug had a normal cycle; 13 had normal final PRL levels. From the 43 p'ts off medication, 28 (66%) had normal PRL levels and 23 (54%) had a normal cycle. </li></ul><ul><li>There were no significant differences between women who had and had not been pregnant. </li></ul><ul><li>Dopaminergic medication had no appreciable influence on the course of the disease. </li></ul>Fertil Steril 1992;58:72-77.
<ul><li>CONCLUSION: </li></ul><ul><li>In idiopathic hyperprolactinemia, progression to pituitary prolactinoma seldom , if ever, occurs. </li></ul><ul><li>There is a high tendency to spontaneous cure , and pregnancy or medication have no apparent effect. </li></ul><ul><li>Frequent pituitary imaging was found to be not necessary in our p't population. </li></ul><ul><li>It may best be reserved for situations in which the PRL level in symptomatic hyperprolactinemia is inconsistent with pituitary imaging results. </li></ul>Fertil Steril 1992;58:72-77.
Strategies and Evidence--Diagnostic Studies (1) <ul><li>A single measurement of the prolactin level in a blood sample obtained at any time of the day is usually adequate to document hyperprolactinemia. </li></ul><ul><li>Because of the pulsatile nature of prolactin secretion and the effect of stress, a test that shows a level of 25 to 40 µg/l should be repeated before hyperprolactinemia is diagnosed. </li></ul><ul><li>Most causes of hyperprolactinemia can be ruled out on the basis of the history and physical examination, a pregnancy test, and assessments of thyroid function and renal function. </li></ul><ul><li>Provocative tests with the use of insulin-induced hypoglycemia, levodopa, and TRH are not helpful in the evaluation of p'ts for hyperprolactinemia. </li></ul>
Strategies and Evidence--Diagnostic Studies(2) <ul><li>When other causes of hyperprolactinemia have been ruled out, the diagnosis of a prolactinoma is confirmed by gadolinium-enhanced MRI . </li></ul><ul><li>CT with IV contrast enhancement is an alternative, but MRI is more effective in revealing small adenomas and the extension of large tumors. </li></ul><ul><li>Prolactinomas are classified as microadenomas if they are less than 10 mm in diameter ( Figure 1A ) and as macroadenomas if they are 10 mm or greater in diameter ( Figure 1B ). </li></ul><ul><li>Macroadenomas that extend beyond the sella should undergo visual-field examination and testing of anterior pituitary function. </li></ul>
<ul><li>Figure 1. Gadolinium-Enhanced, T1-Weighted Coronal MRI Scans Showing a Microadenoma and a Macroadenoma. </li></ul><ul><li>The microadenoma (arrow, Panel A) is a hypodense intrasellar mass, 4 mm in diameter. The macroadenoma (arrow, Panel B) is a mass, 1 cm in diameter, with extension toward the optic chiasm. </li></ul>
Strategies and Evidence--Diagnostic Studies (3) <ul><li>In general, serum prolactin levels parallel tumor size fairly closely. Macroadenomas are typically associated with levels of over 250 µg /l , and in some cases the level exceeds 1000 µg /l. </li></ul><ul><li>Care must be taken in interpreting a moderate elevation of the prolactin level (<100 µg /l) in the presence of a macroadenoma. </li></ul><ul><li>The discrepancy between a large tumor and a mildly elevated level of prolactin may be due either to compression of the pituitary stalk by the tumor or to an artifact in the immunoradiometric assay for prolactin. </li></ul><ul><li>This artifact (called the " hook effect ") can be eliminated by serial dilution of the serum samples. </li></ul>
High prolactin levels may be missed by immunoradiometric assay in p'ts with macroprolactinomas. <ul><li>OBJECTIVE: Large amounts of antigen may produce falsely low values in immunoradiometric assays due to the so-called high dose, hook effect. The study was designed to identify the clinical and biochemical features of pituitary macroadenomas in whom a high dose PRL hook effect was documented. </li></ul><ul><li>DESIGN: The clinical and biochemical features of four p'ts with the high dose PRL hook effect were compared with those of 54 p'ts with pituitary non-functioning adenomas and 11 with macroprolactinomas who underwent transsphenoidal microsurgery between 1989 and 1994. </li></ul>Clin Endocrinol (Oxf). 1996 Mar;44(3):305-9.
<ul><li>MEASUREMENTS: The presence of the high dose PRL hook effect was confirmed by an increase in the initial PRL concentration when the immunoradiometric assay was processed after dilutions of the serum. This phenomenon was observed in 5.8% (4/69) of p'ts with pituitary macroadenomas. Undiluted median (range) PRL levels were 9140 (1530-83850), 1530 (162-3210) and 2110 mU/l (1470-45,000) in p'ts with macroprolactinoma, non-functioning macroadenoma and the hook effect, respectively. In p'ts with the hook effect, the median PRL levels increased to 384,720 (317,520-950,000) mU/l when the assay was performed after serum dilution. The proportion of males was 9.9% (1/11) in the macroprolactinoma group, 46.3% (25/54) in the non-functioning macroadenoma group and 100% (4/4) in p'ts with the hook effect. p'ts with prolactinoma and non-functioning adenoma had mean tumour sizes of 20 +/- 9 and 27 +/- 11 mm (SD), respectively, while in the hook effect group it was 51 +/- 10 mm. </li></ul>Clin Endocrinol (Oxf). 1996 Mar;44(3):305-9 .
<ul><li>CONCLUSION: </li></ul><ul><li>This study suggests that the high dose PRL hook effect is observed particularly in p'ts with very large tumors. </li></ul><ul><li>The immunoradiometric PRL assay must be performed with serum dilution in order to overcome the high dose PRL hook effect in all new p'ts with pituitary macroadenomas who may have a prolactinoma. </li></ul>Clin Endocrinol (Oxf). 1996 Mar;44(3):305-9 .
Strategies and Evidence -- Therapy <ul><li>The decision to provide treatment is based on the size of the tumor, the presence or absence of gonadal dysfunction, and the p't's desires with respect to fertility. </li></ul><ul><li>Primary therapy for all prolactinomas is a dopamine agonist . </li></ul><ul><li>Transsphenoidal surgery does not reliably lead to long-term cure, and recurrence of hyperprolactinemia is common. </li></ul><ul><li>The dopamine agonists approved for use in the United States are bromocriptine and cabergoline. </li></ul><ul><li>Bromocriptine is an ergot derivative that has been used for two decades and is now off patent. </li></ul><ul><li>Cabergoline is a nonergot agonist with a high affinity for lactotroph dopamine receptors. </li></ul>
Surgical Treatment of Prolactin-Secreting Pituitary Adenomas: Early Results and Long-Term Outcome <ul><li>Medical therapy with dopaminergic drugs is the preferred initial treatment for symptomatic PRL-secreting adenomas; but in recent years, there has been a renewed interest in surgery. </li></ul><ul><li>The aim of this study is to report a large series of p'ts operated for prolactinoma in the last 10 yr. A total of 120 consecutive p'ts (93 female, 27 male) underwent surgery from January 1990 to December 1999. Their mean age at surgery was 29.7 ± 0.9 yr. Fifty-nine p'ts (49.2%) had a microadenoma, and the remaining 61 (50.8%) had a macroadenoma, of which 24 (20%) were intrasellar and 37 (30.8%) were extrasellar adenoma. MRI signs of invasion of the cavernous sinus were detected in 18 p'ts (15.0%). Thirty-one p'ts (25.8%) had never been treated before, whereas the remaining 89 (74.2%) had received dopaminergic drugs. </li></ul>J Clin Endocrinol Metab 2002;87:3180-3186.
<ul><li>After surgery, normalization of PRL levels occurred in 77 p'ts (64.2%). Logistic regression analysis showed that the only predictive factor of unsuccessful surgery was a high preoperative PRL level . Recurrence of hyperprolactinemia occurred in 13 of the 77 cured p'ts (16.9%) during a mean follow-up of 50.2 ± 3.0 months; the 5-yr disease-free survival was 75.9%. Extrasellar extension of the tumor and presence of a postoperative PRL response to TRH were associated with a lower risk of relapse. </li></ul><ul><li>In summary, surgery normalized PRL levels and relieved symptoms of hyperprolactinemia in most p'ts. Recurrence of hyperprolactinemia occurred within 4 yr after surgery . </li></ul><ul><li>Transsphenoidal surgery can be offered as a definitive therapy, especially to intrasellar tumors . </li></ul>J Clin Endocrinol Metab 2002;87:3180-3186.
Long term follow-up of women with surgically treated prolactin- secreting pituitary tumors <ul><li>To examine the long term effectiveness of transsphenoidal microsurgery for p'ts with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. </li></ul><ul><li>Hyperprolactinemia recurred in 12 of 31 p'ts (39%) who had normal PRL concentration 6 wks after surgery. </li></ul><ul><li>None of the p'ts with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 wks after surgery occurred more frequently in cured p'ts than in those who had a recurrence. </li></ul>N Engl J Med 1983;309:280-283
<ul><li>PRL responses to TRH were normal in cured p'ts 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. </li></ul><ul><li>The PRL responses to chlorpromazine- and insulin- induced hypoglycemia were blunted in p'ts with normal as well as elevated PRL levels. </li></ul><ul><li>P'ts with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in PRL 5 yr after surgery. </li></ul><ul><li>The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for p'ts with PRL-secreting tumors. </li></ul>N Engl J Med 1983;309:280-283
Microadenomas (1) <ul><li>Both bromocriptine and cabergoline decrease prolactin secretion and reduce the size of tumors, but on the basis of its safety record in pregnancy, bromocriptine is the treatment of choice when restoration of fertility is the p't's goal. </li></ul><ul><li>Bromocriptine normalizes the secretion of prolactin in 82 % of women with microadenomas and restores menses and fertility in over 90 %. Therapy is initiated with a dose of 0.625 mg administered at bedtime with a snack. After one wk, a morning dose of 1.25 mg is added to the regimen. </li></ul><ul><li>At wkly intervals, the dose is increased by 1.25 mg, for a total dose of 5.0 mg, and the immunoradiometric assay for prolactin is repeated after one month . </li></ul>
Microadenomas (2) <ul><li>A daily dose of 5.0 to 7.5 mg is usually required to restore menses and normalize the level of prolactin, and for maximal effect, the drug should be administered twice daily. Side effects, including nausea, orthostatic hypotension, and depression, are minimized if the therapy is initiated at night. </li></ul><ul><li>Intravaginal administration is associated with diminished GI side effects, and the effect of the drug lasts for 24 hours . Some vaginal irritation may occur, but, in general, this approach is well tolerated. </li></ul><ul><li>In most women, a regimen of 2.5 to 5.0 mg daily is necessary to normalize the level of prolactin. </li></ul>
Vaginal bromocriptine in hyperprolactinemic p'ts and puerperal women. <ul><li>Fifteen hyperprolactinemic and 7 puerperal women were treated with bromocriptine per vaginam (2.5-5 mg) because of absolute intolerance to the oral administration of this drug. In both groups the prolactinemia was normalized without the typical side effects of bromocriptine. Three p'ts reported vaginal burning , but only one discontinued the therapy because of the intensity of the symptom. </li></ul><ul><li>This study suggests that vaginal bromocriptine should be considered as a useful alternative for the treatment of hyperprolactinemia. </li></ul>Acta Obstet Gynecol Scand 1991;70:493-495.
Effectiveness of vaginal bromocriptine in treating women with hyperprolactinemia. <ul><li>Tx of hyperprolactinemia with oral bromocriptine has been associated with a high incidence of side effects. The authors recently demonstrated that, in normal women, the vaginal route of administration was an effective and safe alternative to oral bromocriptine. </li></ul><ul><li>To evaluate the effectiveness of vaginal bromocriptine in treating women with hyperprolactinemia, the authors treated 15 hyperprolactinemic women with daily vaginal administration of 2.5 mg . Serum PRL levels and vital signs were measured daily for 6 days, then wkly for 4 wks. GI side effects were limited to a single episode of mild nausea, and two cases of transient constipation. </li></ul><ul><li>In all p'ts there was a dramatic initial reduction in PRL in response to a single 2.5 mg dose. In 13 p'ts, PRL levels were maintained within the normal range with daily administration of 2.5 mg, whereas in two p'ts, PRL levels remained higher than normal despite an increase dose to 5 mg. </li></ul><ul><li>These results suggest that short term use of vaginal bromocriptine is a safe and effective method for hyperprolactinemia . </li></ul>Fertil Steril. 1989 Feb;51(2):269-72.
Microadenomas (3) <ul><li>Women should be advised to use a mechanical contraception until two regular menstrual periods have occurred, and bromocriptine should be stopped when one menstrual cycle has been missed. </li></ul><ul><li>Used in this fashion, bromocriptine has not been associated with an increased incidence of spontaneous abortion, ectopic pregnancy, or congenital malformation. </li></ul><ul><li>Among infants of mothers who conceived after taking cabergoline, the incidence of congenital malformations is no higher than that in the general population, but the number of pregnancies studied has been small. </li></ul><ul><li>Until there is more information about cabergoline-induced pregnancy, cabergoline should not be used as a therapy for infertility. </li></ul>
Pregnancy outcome after cabergoline treatment in early wks of gestation. <ul><li>We collected information on 61 pregnancies in 50 women treated with cabergoline. These pregnancies resulted in 12 (19.7%) early terminations (five induced abortions, six spontaneous abortions, one hydatidiform mole) and 49 (80.3%) live births. In one case, malformations were suspected by a gynecologist based on ultrasound at 12 gestational wks and the pregnancy was terminated; additional information was not available. There was one case of trisomy 18. The frequency of spontaneous and induced abortions and major congenital malformations was comparable with rates in the general population. </li></ul><ul><li>The data did not indicate any potential adverse effect of the drug on pregnancy . </li></ul><ul><li>The data from this study in combination with previous reports can exclude a congenital malformation risk greater than 10% associated with pregnancy exposure to cabergoline. </li></ul>Reprod Toxicol. 2002 Nov-Dec;16(6):791-3.
Microadenomas (4) <ul><li>The risk of symptomatic enlargement of a microadenoma during pregnancy is about 1 %. </li></ul><ul><li>Formal visual-field testing is not necessary during pregnancy, nor is serial measurement of prolactin levels, because increased levels do not correlate reliably with tumor enlargement. </li></ul><ul><li>Lactation is not associated with tumor growth . </li></ul><ul><li>Women wishing to breast-feed their infants should not be given bromocriptine. </li></ul>
Microadenomas (5) <ul><li>Transsphenoidal surgery is an option in an infertile p't who cannot tolerate bromocriptine or in whom bromocriptine is ineffective. </li></ul><ul><li>Surgery for microadenomas has a success rate of 74 %, but higher rates have been achieved among carefully selected p'ts with prolactin levels that were lower than 200 µg /l, small tumors, and a short duration of amenorrhea . </li></ul>
Microadenomas (6) <ul><li>In 95 % microadenomas, the tumors do not progressively increase in size, so that suppression of tumor growth is not an indication for therapy . When pregnancy is not an issue, either bromocriptine or cabergoline will restore menses and eliminate galactorrhea. </li></ul><ul><li>Bromocriptine is less expensive but requires administration twice daily; about 5 % p'ts cannot tolerate bromocriptine, and in 10 % it is not effective. </li></ul><ul><li>Cabergoline appears to be more effective in decreasing prolactin secretion and restoring ovulatory cycles; it is effective in 70 % of p'ts who do not have a response to bromocriptine and is associated with fewer side effects. </li></ul><ul><li>Cabergoline therapy is begun at a dose of 0.25 mg administered twice wkly , and the dose is increased monthly until prolactin secretion normalizes, to a maximal dose of 1 mg twice wkly ; doses ranging from 0.25 to 0.5 mg twice wkly are usually sufficient to normalize the prolactin level. </li></ul>
Microadenomas (7) <ul><li>The use of a dopamine agonist should be continued unless the p't becomes pregnant, and the prolactin level should be checked yearly . In some p'ts, the drug may ultimately be discontinued. In approximately 25 % of women treated with bromocriptine for at least 24 months , the prolactin level remains normal after the discontinuation of therapy. </li></ul><ul><li>If the prolactin level does not return to the normal range with therapy, or if the p't cannot tolerate the first dopamine agonist, changing to the other drug may be effective. </li></ul>
Long-term follow-up of p'ts with hyperprolactinaemia. <ul><li>AIM: To determine the frequency with which hyperprolactinaemic illness tends to resolve with time. </li></ul><ul><li>STUDY DESIGN: A retrospective case-notes review from a specialist endocrine unit in a provincial teaching hospital and tertiary referral centre. </li></ul><ul><li>P'ts: Seventy women with hyperprolactinaemia referred to the unit in the 15 year period between May 1979 and May 1994. All those with a non-pituitary cause or with macroadenoma had been excluded, as were those who did not have high-resolution imaging, or who were on treatment at the time of referral. </li></ul><ul><li>INTERVENTION: Intermittent course of treatment with dopamine receptor agonists according to individual need. </li></ul>Clin Endocrinol (Oxf). 1996 Sep;45(3):299-303.
<ul><li>ENDPOINTS: Latest serum PRL in those who had discontinued treatment, and whether serum PRL tended to be lower in any particular group. </li></ul><ul><li>RESULTS: There was a significant fall in median PRL concentration from 2000 (714-8000) to 1000 mU/l (220-5600) in the 31 women who had discontinued therapy (P < 0.0005), and serum PRL was normal (< 700 mU/l) in 11 of them. Serum PRL also fell to normal in three of ten women who had no treatment at all. Final PRL concentration was normal in 35% of women who had had at least one pregnancy during the period of follow-up compared to 14% who had not (P < 0.05). </li></ul><ul><li>CONCLUSIONS: These data confirm the findings of others that hyperprolactinaemia will prove self-limiting in up to one-third of women , and that pregnancy may be one factor which triggers a return to normal function. </li></ul>Clin Endocrinol (Oxf). 1996 Sep;45(3):299-303.
Microadenomas (8) <ul><li>When fertility is not a concern, another option is to treat microadenomas with an oral contraceptive that contains estrogen and a progestin. This therapy will not normalize bone density, but it may prevent progressive bone loss . </li></ul><ul><li>Although estrogen can induce lactotroph hyperplasia , short-term use of oral contraceptives in women with microadenomas does not appear to be associated with tumor growth. </li></ul><ul><li>A woman with a microadenoma who is taking estrogen will need to have her prolactin levels measured yearly . </li></ul><ul><li>MRI should be repeated if clinical signs of tumor expansion appear or if the prolactin level exceeds 250 µg /l . </li></ul>
The effect of combined estrogen/progestogen treatment in women with hyperprolactinemic amenorrhea. <ul><li>Eleven women with hyperprolactinemic amenorrhea were treated with a combined estrogen/progestogen preparation (Loestrin 30) for 3 months as hormone replacement therapy because of estrogen deficiency, with a view to protection against osteoporosis . </li></ul><ul><li>Serum prolactin levels rose during the 1st month of treatment (p < 0.05) but did not rise significantly further during the 2nd and 3rd months. The levels rose in proportion to pretreatment levels by 28% (median), and fell significantly but not completely during the 1-wk treatment-free intervals. After the study period, prolactin values appeared to remain stable in those women who continued longer on treatment, and returned to around pretreatment values in those who stopped. In one woman there was radiological evidence of pituitary tumor growth during treatment. </li></ul>Gynecol Endocrinol. 1992 Sep;6(3):183-8.
<ul><li>This study shows that estrogen/progestogen treatment in standard contraceptive dosage usually leads to only moderate and non-progressive stimulation of pituitary activity in women with hyperprolactinemic amenorrhea, but occasional excessive growth of a prolactinoma can occur and treatment needs to be monitored . </li></ul><ul><li>Women with relatively high prolactin levels seem to be at particular risk. Safer variations of estrogen therapy such as lower dosage or combination with a protective low dose of a dopamine agonist should also be considered. </li></ul>Gynecol Endocrinol. 1992 Sep;6(3):183-8.
Macroadenomas (1) <ul><li>Because of the large potential for growth , a macroadenoma is an absolute indication for therapy. Treatment should be initiated with a dopamine agonist and should be managed by an endocrinologist. </li></ul><ul><li>Both of the dopamine agonists that are currently available provide effective therapy for macroadenomas, but, as in p'ts with microadenomas, bromocriptine should be used when fertility is the goal of treatment. </li></ul>
Macroadenomas (2) <ul><li>A macroadenoma that is confined to the sella is not likely to enlarge sufficiently during pregnancy to cause clinically serious complications, and p'ts with intrasellar macroadenomas who wish to become pregnant should be followed in the same way as p'ts with microadenomas. </li></ul><ul><li>When suprasellar extension of a macroadenoma is detected in a p't who wishes to become pregnant, there is a 15 to 35 % risk of tumor enlargement during gestation. </li></ul>
Macroadenomas (3) <ul><li>These tumors should be surgically debulked before pregnancy , and after surgery, therapy with bromocriptine should be initiated. </li></ul><ul><li>Bromocriptine has been used throughout pregnancy in a small number of p'ts, without major complications or fetal abnormalities, and its use is probably less harmful than surgical intervention during pregnancy. </li></ul><ul><li>Visual-field testing should be performed at least once every three months during pregnancy , and MRI should be repeated if symptoms of tumor enlargement develop. </li></ul>
Hypogonadism (1) <ul><li>When fertility is not an issue, the goals of treatment are restoration of gonadal function and reduction tumor size. </li></ul><ul><li>Either dopamine agonist can be used, but cabergoline may be more effective in reducing the prolactin levels, decreasing the size of the tumor, and eliminating visual-field abnormalities. </li></ul><ul><li>There have been no studies that directly compared the efficacy of cabergoline with that of bromocriptine for the treatment of macroadenomas, but cabergoline has been shown to be effective for bromocriptine-resistant tumors. </li></ul>
Hypogonadism (2) <ul><li>Macroadenomas require higher doses of bromocriptine (usual range, 7.5 to 10.0 mg daily) or cabergoline (usual range, 0.5 to 1.5 mg twice wkly) than microadenomas. </li></ul><ul><li>With both dopamine agonists, a decrease in prolactin levels occurs within 2 to 3 wks after treatment begins and usually precedes a decrease in the size of the tumor and the restoration of anterior pituitary function. </li></ul><ul><li>The length of time necessary to achieve a reduction in tumor size ranges from wks to years. </li></ul><ul><li>Visual-field testing should be repeated one month after the initiation of therapy, and MRI should be repeated after six months of treatment. Prolactin levels should be measured yearly . </li></ul>
Hypogonadism (3) <ul><li>When the prolactin level has been normal for two years and the size of the tumor has decreased by at least 50 %, the dose of cabergoline or bromocriptine can be gradually decreased, with close follow-up to R/O tumor enlargement. </li></ul><ul><li>After two years of uninterrupted therapy , even low doses of these medications inhibit prolactin secretion and control tumor growth. </li></ul><ul><li>In macroadenomas , discontinuation of the drug usually leads to renewed expansion of the tumor and to a recurrence of hyperprolactinemia and should therefore be undertaken with extreme caution. </li></ul>
Withdrawal of bromocriptine after long-term therapy for macroprolactinomas: effect on plasma prolactin and tumor size <ul><li>The present study describes the effect on plasma prolactin values and tumor size of bromocriptine withdrawal in 12 p'ts who had been treated for macroprolactinomas for a period of 3.5-7 (mean 4.9) years. </li></ul><ul><li>Pretreatment plasma prolactin values ranged from 12,000 to 210,000 (mean: 66,000) mU/l. </li></ul><ul><li>Immediately before bromocriptine withdrawal, plasma prolactin values were in the normal range (less than 350 mU/l for men; less than 450 mU/l for women). </li></ul><ul><li>Bromocriptine treatment was associated with tumour reduction in all cases. </li></ul>Clin Endocrinol (Oxf) 1991;34:175-178.
<ul><li>The following observations were made upon withdrawal of bromocriptine: </li></ul><ul><li>(1) In 11 p'ts hyperprolactinaemia redeveloped although plasma prolactin levels remained below 600 mU/l in two of these p'ts during a follow-up period of 1 year. In the other nine p'ts bromocriptine treatment was reinstituted after 4-12 wks. </li></ul><ul><li>(2) Hyperprolactinaemia was associated with tumour reexpansion in one case and increased density of the tumour in two cases. </li></ul><ul><li>(3) In one p't plasma prolactin remained undetectable during a follow-up period of 1 year and no tumor re-expansion was found. </li></ul><ul><li>It is concluded that tumor regrowth is uncommon and of small extent after cessation of long-term bromocriptine treatment for macroprolactinomas. </li></ul>Clin Endocrinol (Oxf) 1991;34:175-178.
Hypogonadism (4) <ul><li>Given the potential for growth of macroadenomas, the use of estrogen is generally discouraged . </li></ul><ul><li>If a macroadenoma does not respond to medical therapy, transsphenoidal surgery should be undertaken. </li></ul><ul><li>Surgery is rarely curative, however, and therapy with a dopamine agonist will be necessary afterward to normalize prolactin secretion. </li></ul><ul><li>External radiation may be required if substantial tumor tissue remains after surgery, major side effects are hypopituitarism, damage to the optic nerve, and neurologic dysfunction. </li></ul>
Areas of Uncertainty <ul><li>There is limited information regarding the effects of the discontinuation of therapy for prolactinoma. Studies of p'ts with microadenomas or macroadenomas that were treated with bromocriptine over a period of 24 to 48 months have shown that in 6 to 37 % of p'ts, prolactin levels remain normal after the withdrawal of bromocriptine. </li></ul><ul><li>Elsewhere in this issue of the Journal, Colao et al. report that prolactin levels remained normal in over 60 % of p'ts after the withdrawal of cabergoline. Although there are no precise criteria for predicting whether drug withdrawal will be successful, this prospective analysis of cabergoline withdrawal and the retrospective studies conducted with bromocriptine suggest that lifelong treatment of hyperprolactinemia may not be inevitable. </li></ul><ul><li>Possible explanations for the persistence of normal prolactin levels after drug withdrawal include a cytocidal effect of the dopamine agonist and the natural history of the tumor . </li></ul>
Necrotic changes in prolactinomas after long term administration of bromocriptine <ul><li>Six prolactinoma p'ts were studied endocrinologically and their tumors were examined histologically after long term bromocriptine therapy. In p't 1 with a large prolactinoma, a marked reduction in size and a remarkable decrease in elevated serum PRL levels occurred after bromocriptine treatment for 8 months. </li></ul><ul><li>The histological findings consisted of two components, i.e. shrunken island-like cell nests and acellular spaces . Some degenerative and necrotic tumor cells, hyaline substance, and fibrosis were observed with light and electron microscopy in these acellular spaces. </li></ul><ul><li>Island-like cell nests consisted of atrophic cells having disproportionally scanty cytoplasm. The same histological findings were observed in four other p'ts. However, in another p't whose tumor decreased in size only slightly during bromocriptine therapy, the specimen had few acellular spaces. </li></ul><ul><li>Thus, long term bromocriptine treatment of p'ts with prolactinomas may result in necrosis of some adenoma cells in some p'ts. </li></ul>J Clin Endocrinol Metab 1984;59:463-470.
Guidelines <ul><li>There are no formal guidelines for the management of prolactinoma. </li></ul>
Conclusions and Recommendations (1) <ul><li>The diagnosis of a prolactinoma is established on the basis of a sustained elevation of serum levels of prolactin and radiographic evidence of a pituitary adenoma after other causes of hyperprolactinemia have been ruled out. </li></ul><ul><li>The indications for therapy include infertility , the presence of a macroadenoma , and hypogonadism . </li></ul><ul><li>The primary therapy for all prolactinomas is a dopamine agonist . Bromocriptine and cabergoline are both effective in reducing the size of the tumor and restoring gonadal function, but bromocriptine should be used when pregnancy is the goal ( Figure 2 ). </li></ul>
<ul><li>Figure 2. Management of Prolactinoma in Women. </li></ul>
Conclusions and Recommendations (2) <ul><li>Cabergoline is more expensive than bromocriptine but easier to administer, usually better tolerated, and effective in p'ts who do not have a response to bromocriptine. Surgery is rarely curative in p'ts with prolactinomas and should be recommended only when medical therapy is ineffective. </li></ul><ul><li>Although discontinuation of drug therapy for macroadenomas usually leads to recurrent hyperprolactinemia and expansion of the tumor, the dose of the medication can often be decreased after two years or more of therapy . </li></ul><ul><li>My approach is to taper the medication at three-month intervals (reducing the wkly dose of cabergoline by 0.25 mg or the daily dose of bromocriptine by 2.5 mg), check the prolactin level after each dose reduction, and obtain an MRI scan six months after the initiation of tapering, in order to rule out tumor enlargement. </li></ul>
Conclusions and Recommendations (3) <ul><li>The young woman described in the vignette has a prolactin-secreting microadenoma . There is no indication to test for anterior pituitary dysfunction or to perform formal visual-field testing. She should be treated with bromocriptine and should use mechanical contraception until regular menstrual cycles have been established. </li></ul><ul><li>When she becomes pregnant, the bromocriptine should be discontinued, though the medication is likely to be needed again, after pregnancy and lactation. </li></ul><ul><li>For p'ts who have been receiving drug therapy for two years or more , I would attempt to discontinue the medication, with reassessment of prolactin levels, to determine an ongoing need for treatment. </li></ul>