prolactinoma in nejm2

Prolactinoma Prolactinoma 郝 立 智 醫 師 郝 立 智 醫 師 永康榮民醫院新陳代謝科 永康榮民醫院新陳代謝科 NEJM, Vol 349:2035-2041, Nov. 20, 2003, No. 21. HLJ Outline Outline • Case Presentation Case Presentation • The Clinical Problem The Clinical Problem – Clinical Presentation Clinical Presentation – Causes of Hyperprolactinemia Causes of Hyperprolactinemia • Strategies and Evidence Strategies and Evidence – Diagnostic Studies Diagnostic Studies – Therapy Therapy Microadenomas Macroadenomas Hypogonadism Microadenomas Macroadenomas Hypogonadism • Areas of Uncertainty Areas of Uncertainty • Guidelines Guidelines • Conclusions and Recommendations Conclusions and Recommendations HLJ Case Presentation Case Presentation • A 22-year-old woman who wants to become pregnant has A 22-year-old woman who wants to become pregnant has had had no menses no menses since she discontinued the use of an oral since she discontinued the use of an oral contraceptive one year ago, and recently, contraceptive one year ago, and recently, galactorrhea galactorrhea developed. developed. • She takes no medications and has had no headaches, visual She takes no medications and has had no headaches, visual loss, dyspareunia, or decreased libido. loss, dyspareunia, or decreased libido. • P.E. shows no abnormalities, except for the P.E. shows no abnormalities, except for the bilateral breast bilateral breast discharge discharge . . • A test for serum HCG is negative, the thyrotropin level is A test for serum HCG is negative, the thyrotropin level is normal, and the serum normal, and the serum prolactin prolactin level is level is 95 µg /l. 95 µg /l. • MRI reveals a mass, MRI reveals a mass, 3 mm 3 mm in diameter, in the anterior lobe in diameter, in the anterior lobe of the pituitary. of the pituitary. • How should she be treated? How should she be treated? HLJ The Clinical Problem The Clinical Problem • Prolactin-secreting tumors Prolactin-secreting tumors are benign neoplasms that are benign neoplasms that account for about account for about 40 % 40 % of all pituitary tumors. of all pituitary tumors. • Over Over 90 % 90 % are small, intrasellar tumors that rarely are small, intrasellar tumors that rarely increase in size. increase in size. • The primary action of prolactin is to stimulate lactation, The primary action of prolactin is to stimulate lactation, but it is the effect of prolactin on gonadal function that but it is the effect of prolactin on gonadal function that warrants clinical attention. warrants clinical attention. • Hypersecretion of prolactin leads to infertility and Hypersecretion of prolactin leads to infertility and gonadal dysfunction by gonadal dysfunction by interrupting secretion of interrupting secretion of gonadotropin-releasing hormone gonadotropin-releasing hormone , inhibiting the release , inhibiting the release of of LH and FSH LH and FSH , and , and impairing gonadal steroidogenesis impairing gonadal steroidogenesis . . HLJ Prolactin inhibits oestrogen synthesis in the ovary Prolactin inhibits oestrogen synthesis in the ovary • In In 20% 20% of cases of secondary amenorrhoea, of cases of secondary amenorrhoea, hyperprolactinaemia hyperprolactinaemia prevents ovulation by impairing normal prevents ovulation by impairing normal follicular development, but little is known of the follicular development, but little is known of the biochemical basis for this effect. biochemical basis for this effect. • Bromocriptine Bromocriptine can restore follicular growth and ovulation can restore follicular growth and ovulation by inhibiting the release of prolactin from the pituitary. by inhibiting the release of prolactin from the pituitary. • The The suckling stimulus suckling stimulus causes an increase in prolactin levels, causes an increase in prolactin levels, and ovarian follicles fail to develop fully, thus and ovarian follicles fail to develop fully, thus inducing an inducing an anovulatory state anovulatory state throughout lactation in many mammals. throughout lactation in many mammals. • We report here experiments with cultured granulosa cells We report here experiments with cultured granulosa cells which suggest that this which suggest that this contraceptive action of prolactin contraceptive action of prolactin is is due to its ability to due to its ability to interfere with the action of FSH on the interfere with the action of FSH on the synthesis of oestrogen synthesis of oestrogen . . Nature. 1981 Apr 16;290(5807):600-2. HLJ HLJ Clinical Presentation (1) Clinical Presentation (1) • The most common symptoms of hyperprolactinemia in The most common symptoms of hyperprolactinemia in premenopausal women are premenopausal women are amenorrhea and infertility amenorrhea and infertility . . • Galactorrhea Galactorrhea occurs in about 80 % of such women, and occurs in about 80 % of such women, and some women with prolactinomas have infrequent some women with prolactinomas have infrequent menstrual flow (oligomenorrhea) or regular menses. menstrual flow (oligomenorrhea) or regular menses. • Hyperprolactinemia is often detected after discontinuation Hyperprolactinemia is often detected after discontinuation of an oral contraceptive, but there is of an oral contraceptive, but there is no apparent relation no apparent relation between the use of oral contraceptives and the formation between the use of oral contraceptives and the formation of prolactinomas. of prolactinomas. • The majority of prolactinomas The majority of prolactinomas in women in women are small at the are small at the diagnosis, and headaches and neurologic deficits are rare. diagnosis, and headaches and neurologic deficits are rare. HLJ Clinical Presentation (2) Clinical Presentation (2) • In contrast, prolactinomas In contrast, prolactinomas in men in men typically tend to be large typically tend to be large at the time of diagnosis and may cause cranial-nerve at the time of diagnosis and may cause cranial-nerve dysfunction, visual loss, and hypopituitarism. dysfunction, visual loss, and hypopituitarism. • In men, hyperprolactinemia leads to impotence, infertility, In men, hyperprolactinemia leads to impotence, infertility, and decreased libido, but these are rarely the initial and decreased libido, but these are rarely the initial symptoms; galactorrhea and gynecomastia are uncommon. symptoms; galactorrhea and gynecomastia are uncommon. • In both sexes, long-standing hyperprolactinemia leads to In both sexes, long-standing hyperprolactinemia leads to low bone density in the spine low bone density in the spine . . • After prolactin has returned to the normal range, After prolactin has returned to the normal range, bone bone density will increase but does not reach normal values. density will increase but does not reach normal values. HLJ Prolactin-secreting tumors and Prolactin-secreting tumors and hypogonadism in 22 men hypogonadism in 22 men • We studied 22 men with prolactin-secreting pituitary tumors and We studied 22 men with prolactin-secreting pituitary tumors and hypogonadism. Twenty complained of impotence, nine had visual hypogonadism. Twenty complained of impotence, nine had visual impairment, and three experienced galactorrhea. None of the 17 p'ts impairment, and three experienced galactorrhea. None of the 17 p'ts undergoing operation or radiotherapy, or both, were subsequently undergoing operation or radiotherapy, or both, were subsequently normoprolactinemic. In all 13 p'ts treated with bromocryptine, normoprolactinemic. In all 13 p'ts treated with bromocryptine, major clinical improvement was associated with a decrease in serum major clinical improvement was associated with a decrease in serum prolactin levels and in nine with an increase in serum testosterone. prolactin levels and in nine with an increase in serum testosterone. • Two p'ts receiving testosterone replacement therapy showed Two p'ts receiving testosterone replacement therapy showed improved potency only after bromocryptine was administered. improved potency only after bromocryptine was administered. • The results indicate that The results indicate that hyperprolactinemia frequently induces hyperprolactinemia frequently induces hypogonadism in men hypogonadism in men , that bromocryptine ameliorates symptoms of , that bromocryptine ameliorates symptoms of disease previously unchanged by operation or radiotherapy, and disease previously unchanged by operation or radiotherapy, and the the impotence observed may not be solely the result of hypogonadism. impotence observed may not be solely the result of hypogonadism. N Engl J Med 1978;299:847-852. HLJ Bone Marker and Bone Density Responses to Dopamine Bone Marker and Bone Density Responses to Dopamine Agonist Therapy in Hyperprolactinemic Males Agonist Therapy in Hyperprolactinemic Males • The aim of this prospective study was to evaluate the bone mineral The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. with different dopamine agonists. • Six p'ts received Six p'ts received bromocriptine bromocriptine at a dose of 2.5–10 mg/day; at a dose of 2.5–10 mg/day; • 7 p'ts received 7 p'ts received quinagolide quinagolide at a dose of 0.075–0.3 mg/day; at a dose of 0.075–0.3 mg/day; • 7 p'ts received 7 p'ts received cabergoline cabergoline at a dose of 0.5–1.5 mg/wk. at a dose of 0.5–1.5 mg/wk. • BMD, serum PRL, testosterone, dihydrotestosterone, and BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked osteocalcin (OC), and urinary cross-linked N N -telopeptides of type I -telopeptides of type I collagen (Ntx) levels were measured before and every 6 months collagen (Ntx) levels were measured before and every 6 months during treatment. during treatment. J Clin Endocrinol Metab 1998;83:807-813 [...]... 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 J Clin Endocrinol Metab 1998;83:807-813 HLJ • In conclusion, treatment with bromocriptine, quinagolide,... haloperidol-induced hyperprolactinemia may benefit from a switch to olanzapine 4 Long-term studies examining the health consequences of chronic hyperprolactinemia during antipsychotic treatment are needed Clin Ther 2000;22:1085-1096 HLJ Causes of Hyperprolactinemia (3) • Less commonly used antihypertensive agents that are associated with hyperprolactinemia include reserpine and methyldopa • Prolactin levels... Hyperprolactinemia (1) • 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 • 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,... switching from haloperidol to olanzapine are assessed HLJ Clin Ther 2000;22:1085-1096 • 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... 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 • However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia HLJ J Clin Endocrinol Metab 1998;83:807-813 Causes of Hyperprolactinemia... serum prolactin and GH concentrations in hypertensive p'ts were studied • Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations • 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... 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 • In some p'ts with primary hypothyroidism, mild hyperprolactinemia develops owing to the increased synthesis of TRH • Prolactin levels are elevated in chronic... lactotroph dopamine receptors HLJ Surgical Treatment of Prolactin-Secreting Pituitary Adenomas: Early Results and Long-Term Outcome • 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 • The aim of this study is to report a large series of p'ts operated for prolactinoma in the last... 0.9 yr Fiftynine 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 HLJ J Clin Endocrinol Metab 2002;87:3180-3186... Causes of Hyperprolactinemia (5) • When no cause of hyperprolactinemia can be identified, the diagnosis is idiopathic hyperprolactinemia • A prolactinoma may be present but may be too small to be detected radiographically • 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 • In one study, only 10 . decrease in serum prolactin levels and in nine with an increase in serum testosterone. prolactin levels and in nine with an increase in serum testosterone. • Two p'ts receiving testosterone replacement. impairing gonadal steroidogenesis impairing gonadal steroidogenesis . . HLJ Prolactin inhibits oestrogen synthesis in the ovary Prolactin inhibits oestrogen synthesis in the ovary • In In. oral contraceptives and the formation of prolactinomas. of prolactinomas. • The majority of prolactinomas The majority of prolactinomas in women in women are small at the are small at the