VOLUME
The
American
Journal
66
NUMBER 4
APRIL 1979
of Medicines EDITORIALS
Prolactin and Pituitary Tumors ALAN D. ROGOL, M.D., Ph.D. and RICHARD C. EASTMAN, The advent of sensitive, precise radioimmunoassays that followed the recent extraction and characterization of human pituitary prolactin has furthered our understanding of normal prolactin physiology, and has led to the definition of a variety of hyperprolactinemic conditions. In this editorial we will review the current understanding of the physiology of normal prolactin secretion, identify the clinical signs and symptoms of hypersecretion of prolactin in pathologic conditions and discuss the evaluation of patients found to be hyperprolactinemic. The prolactin-secreting cells of the anterior pituitary (lactotrophs) are kept under tonic inhibitory control by prolactin-inhibiting factor (PIF), produced by specialized neurosecretory cells in the hypothalamus. PIF reaches the pituitary through the capillaries of the hypothalamic-pituitary portal plexus and presumably acts directly on the pituitary lactotrophs to decrease prolactin secretion. Chemically, this inhibitory factor has been shown to be dopamine [l]. Other inhibitory factors may also exist but, to date, have not been defined. Normal regulation of prolactin secretion requires intact hypothalamic centers for synthesizing PIF and an intact hypothalamic-pituitary portal system, in addition to normal lactotrophs. Although prolactin-releasing factor(s) have been described biologically in lower animals, none has been isolated and chemically defined. Most investigators have found that the upper limit of the normal range for prolactin concentrations is 20 to 25 ng/ml of purified human prolactin in postmenarchial women. Values are slightly lower in prepubertal subjects and in postpubertal men [2]. Physiologic hyperprolactinemia occurs during the sleep-wake cycle. There is a nocturnal increase in prolactin concentration
M.D.
that has been shawn to be dependent on sleep rather than on circadian periodicity. Although there are some conflicting data, it is probable that a small increase in prolactin concentration occurs during the luteal phase of the normal menstrual cycle. Certainly there are more marked and sustained increases in prolactin concentration during pregnancy and postpartum lactation [l]. Both physical and emotional stress can lead to rapid and large increases in serum prolactin levels. A number of pharmacologic agents regularly cause prolactin concentrations to increase, and these may be classified into the following groups [3]: (1) Dopaminereceptor blockers (dopamine antagonists). The most common classes of drugs in this category are the phenothiazines (e.g., chlorpromazine) and the butyrophenones (e.g., haloperidol). (2) The dopamine-depleting agents [e.g., reserpine and alpha-methyl-dopa). (3) Miscellaneous agents (e.g., estrogens, thyrotropin-releasing hormone (TRH)). A variety of diseases affecting the hypothalamus and pituitary may result in hyperprolactinemia. Interference with hypothalamic function by infiltrative diseases such as histiocytosis X, basal meningitis, encephalitis and sarcoidosis, or by arterial-venous malformations and primary hypothalamic tumors have all been described [4,5]. Primary hypothyroidism is a recognized but relatively uncommon cause of hyperprolactinemia. Disorders which impair transport of PIF from the hypothalamus to the pituitary, such as stalk section or invasion by neoplasms, may lead to hyperprolactinemia. Pituitary tumors composed of lactotrophs may secrete prolactin, and other nonlactotroph pituitary tumors may produce hyperprolactinemia by compression of the pituitary stalk, presumably interfering with dopamine transport.
l;rom the Depurtments of Pediutrics und Phurmucofogy, ‘I’he Iiniversity of Virginiu School of Metlitine. Churlottesville, Virginia; und the Division of Endocrinology, Muine Medicul Center, Portlund, Muine. Requests for reprints should be uddressed to Dr. Alun II. Rogo!. Depurtments of Pediutrics und Phurmucology, ‘l’he University of Virginiu School of Medicine, Churlottesville. Virginiu z?w~.
April 1676
The American Journal of Medicine
Volume 66
547
EDITORIAL-ROGOL,
EASTMAN
Pituitary tumors may also extend into the hypothalamus or may lead to increased prolactin concentrations by the secretion of other hormones that influence hypothalamic function such as in acromegaly or Cushing’s disease [1,2,4,5]. The tumorous causes of hyperprolactinemia have previously been classified into different eponymic syndromes: Chiari-Frommel; Argonz (AhumadaJ-de1 Castillo; and Forbes-Albright. Since there is considerable overlap among these syndromes-they may possibly represent a continuum of hypothalamic-pituitary dysfunction-we choose not to use this system of classification. The increased concentrations of circulating prolactin, irrespective of etiology, may interfere with pituitarygonadal function causing primary amenorrhea, oligomenorrhea, secondary amenorrhea, galactorrhea, infertility, estrogen deficiency, decreased libido and impotence [1,4,5].The detection of any increased prolactin concentration in such patients focuses attention on the hypothalamic-pituitary axis. Follow-up with roentgenograms of the sella turcica is indicated. Measurement of prolactin may also be of value as an index of hypothalamic-pituitary dysfunction in patients with diseases known to involve the hypothalamus (e.g., sarcoidosis) even when the patient has no symptoms of prolactin excess. Once hyperprolactinemia has been diagnosed, and in the absence of hypothyroidism, drug ingestion or infiltrative diseases of the hypothalamus, the likelihood of the individual patient harboring a pituitary tumor is substantially enhanced. If the standard anteroposterior and lateral skull roentgenograms do not demonstrate an abnormality of the sella, polytomography of the sella is indicated to look for subtle changes in the floor of the sella, consistent with a microadenoma [l]. The absolute level of prolactin may be useful in differentiating patients who have adenomas. The higher the prolactin concentration the greater the likelihood of a prolactinsecreting tumor. For example, Friesen found that concentrations of prolactin greater than 200 ng/ml are likely to be due to pituitary adenomas. Alsd, Kleinberg et al. [5] found that all of their patients with serum prolactin concentrations in excess of 300 ng/ml had pituitary tumors, and pituitary tumors were found in 57 per cent of the patients with prolactin concentrations above 100 ng/ml. However, since patients with microadenomas may have prolactin concentrations less than 100 ng/ml, polytomography is the most important means of identifying patients who might have pituitary tumors [5]. The usual provocative tests for prolactin modulation (L-dopa, chlorpromazine and thyrotropin-releasing hormone) are apparently not predictive of the exact etiology (“functional,” macro or microadenoma].
548
April 1979
The American Journal of Medicine
When a patient with hyperprolactinemia is found to have a microadenoma, the indications for further diagnostic studies and therapy are controversial. The goals of therapy must be clearly defined. The natural history of prolactin-producing microadenomas is largely unknown. The most common mandate for treating these patients is restoration of menses and fertility. In some patients the quantity of galactorrhea is bothersome but uncommonly incapacitating. The normal pituitary increases in volume during pregnancy, and there is concern that a tumor mass may also increase during pregnancy and cause optic nerve compression or hypothalamic-pituitary dysfunction. Recent reports have documented that pituitary adenomas can expand during pregnancy leading to visual deterioration requiring emergency neurosurgery. The threat of such an occurrence is established for tumors that produce an enlarged sella but may also be present in patients with microadenomas. Many authorities, therefore, recommend that the pituitary adenoma be treated before the patient is allowed to become pregnant: in most centers this recommendation has been extended to include patients with microadenomas. Presently, three modes of theraputic intervention for prolactin-producing pituitary adenomas are available: surgical resection (usually through the transsphenoidal approach) and irradiation therapy are aimed at removing or decreasing the mass of prolactin-secreting tissue. The dopamine agonists (e.g.. bromocriptine) suppress prolactin release. Although each modality may have specific indications and contraindications, it is beyond the scope of this editorial to weigh the pros and cons for each of these theraputic measures. A number of excellent reviews exist in which these issues are discussed in detail [1,4,5,6]. REFERENCES 1. Thorner MO: Prolactin. Clinics in Endocrinology and Metabolism (Besser GM, ed), Philadelphia, W. B. Saunders, 1977, p 201. 2. Frantz AG. Kleinberg DL. Noel CL: Studies on prolactin in man. Recent Prog Horm Res 28: 527,1972. 3. Fluckigcr E: Drugs and the control of prolactin secretion. Prolactin and Carcinogenesis (Boyns AR, Griffirhs K, edsl. Proceedings of the 4th Tcnovus Workshop, Cardiff Wales. Alpha Omega Alpha, 1972, p 162. 4. Hardy J: Transsphenoidal surgery of hppersecreting pituitary tumors. Diagnosis and Treatment of Pituitary Tumor> (Kohler PO, Ross GT, eds). International Congress Series No 303. Amsterdam Excerllta Medica. 1973. p 179. 5. Kleinberg DL, Noel GL. Frantz AG: Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 296: 589,1977. 6. Boyd AE III, Reichlin S, Turksay RN: Galactorrhea-amenorrhea syndrome: diagnosis and therapy. Ann Intern Med 87:
Volume 66
165,1977.
The
American
Journal
66
NUMBER 4
APRIL 1979
of Medicines EDITORIALS
Prolactin and Pituitary Tumors ALAN D. ROGOL, M.D., Ph.D. and RICHARD C. EASTMAN, The advent of sensitive, precise radioimmunoassays that followed the recent extraction and characterization of human pituitary prolactin has furthered our understanding of normal prolactin physiology, and has led to the definition of a variety of hyperprolactinemic conditions. In this editorial we will review the current understanding of the physiology of normal prolactin secretion, identify the clinical signs and symptoms of hypersecretion of prolactin in pathologic conditions and discuss the evaluation of patients found to be hyperprolactinemic. The prolactin-secreting cells of the anterior pituitary (lactotrophs) are kept under tonic inhibitory control by prolactin-inhibiting factor (PIF), produced by specialized neurosecretory cells in the hypothalamus. PIF reaches the pituitary through the capillaries of the hypothalamic-pituitary portal plexus and presumably acts directly on the pituitary lactotrophs to decrease prolactin secretion. Chemically, this inhibitory factor has been shown to be dopamine [l]. Other inhibitory factors may also exist but, to date, have not been defined. Normal regulation of prolactin secretion requires intact hypothalamic centers for synthesizing PIF and an intact hypothalamic-pituitary portal system, in addition to normal lactotrophs. Although prolactin-releasing factor(s) have been described biologically in lower animals, none has been isolated and chemically defined. Most investigators have found that the upper limit of the normal range for prolactin concentrations is 20 to 25 ng/ml of purified human prolactin in postmenarchial women. Values are slightly lower in prepubertal subjects and in postpubertal men [2]. Physiologic hyperprolactinemia occurs during the sleep-wake cycle. There is a nocturnal increase in prolactin concentration
M.D.
that has been shawn to be dependent on sleep rather than on circadian periodicity. Although there are some conflicting data, it is probable that a small increase in prolactin concentration occurs during the luteal phase of the normal menstrual cycle. Certainly there are more marked and sustained increases in prolactin concentration during pregnancy and postpartum lactation [l]. Both physical and emotional stress can lead to rapid and large increases in serum prolactin levels. A number of pharmacologic agents regularly cause prolactin concentrations to increase, and these may be classified into the following groups [3]: (1) Dopaminereceptor blockers (dopamine antagonists). The most common classes of drugs in this category are the phenothiazines (e.g., chlorpromazine) and the butyrophenones (e.g., haloperidol). (2) The dopamine-depleting agents [e.g., reserpine and alpha-methyl-dopa). (3) Miscellaneous agents (e.g., estrogens, thyrotropin-releasing hormone (TRH)). A variety of diseases affecting the hypothalamus and pituitary may result in hyperprolactinemia. Interference with hypothalamic function by infiltrative diseases such as histiocytosis X, basal meningitis, encephalitis and sarcoidosis, or by arterial-venous malformations and primary hypothalamic tumors have all been described [4,5]. Primary hypothyroidism is a recognized but relatively uncommon cause of hyperprolactinemia. Disorders which impair transport of PIF from the hypothalamus to the pituitary, such as stalk section or invasion by neoplasms, may lead to hyperprolactinemia. Pituitary tumors composed of lactotrophs may secrete prolactin, and other nonlactotroph pituitary tumors may produce hyperprolactinemia by compression of the pituitary stalk, presumably interfering with dopamine transport.
l;rom the Depurtments of Pediutrics und Phurmucofogy, ‘I’he Iiniversity of Virginiu School of Metlitine. Churlottesville, Virginia; und the Division of Endocrinology, Muine Medicul Center, Portlund, Muine. Requests for reprints should be uddressed to Dr. Alun II. Rogo!. Depurtments of Pediutrics und Phurmucology, ‘l’he University of Virginiu School of Medicine, Churlottesville. Virginiu z?w~.
April 1676
The American Journal of Medicine
Volume 66
547
EDITORIAL-ROGOL,
EASTMAN
Pituitary tumors may also extend into the hypothalamus or may lead to increased prolactin concentrations by the secretion of other hormones that influence hypothalamic function such as in acromegaly or Cushing’s disease [1,2,4,5]. The tumorous causes of hyperprolactinemia have previously been classified into different eponymic syndromes: Chiari-Frommel; Argonz (AhumadaJ-de1 Castillo; and Forbes-Albright. Since there is considerable overlap among these syndromes-they may possibly represent a continuum of hypothalamic-pituitary dysfunction-we choose not to use this system of classification. The increased concentrations of circulating prolactin, irrespective of etiology, may interfere with pituitarygonadal function causing primary amenorrhea, oligomenorrhea, secondary amenorrhea, galactorrhea, infertility, estrogen deficiency, decreased libido and impotence [1,4,5].The detection of any increased prolactin concentration in such patients focuses attention on the hypothalamic-pituitary axis. Follow-up with roentgenograms of the sella turcica is indicated. Measurement of prolactin may also be of value as an index of hypothalamic-pituitary dysfunction in patients with diseases known to involve the hypothalamus (e.g., sarcoidosis) even when the patient has no symptoms of prolactin excess. Once hyperprolactinemia has been diagnosed, and in the absence of hypothyroidism, drug ingestion or infiltrative diseases of the hypothalamus, the likelihood of the individual patient harboring a pituitary tumor is substantially enhanced. If the standard anteroposterior and lateral skull roentgenograms do not demonstrate an abnormality of the sella, polytomography of the sella is indicated to look for subtle changes in the floor of the sella, consistent with a microadenoma [l]. The absolute level of prolactin may be useful in differentiating patients who have adenomas. The higher the prolactin concentration the greater the likelihood of a prolactinsecreting tumor. For example, Friesen found that concentrations of prolactin greater than 200 ng/ml are likely to be due to pituitary adenomas. Alsd, Kleinberg et al. [5] found that all of their patients with serum prolactin concentrations in excess of 300 ng/ml had pituitary tumors, and pituitary tumors were found in 57 per cent of the patients with prolactin concentrations above 100 ng/ml. However, since patients with microadenomas may have prolactin concentrations less than 100 ng/ml, polytomography is the most important means of identifying patients who might have pituitary tumors [5]. The usual provocative tests for prolactin modulation (L-dopa, chlorpromazine and thyrotropin-releasing hormone) are apparently not predictive of the exact etiology (“functional,” macro or microadenoma].
548
April 1979
The American Journal of Medicine
When a patient with hyperprolactinemia is found to have a microadenoma, the indications for further diagnostic studies and therapy are controversial. The goals of therapy must be clearly defined. The natural history of prolactin-producing microadenomas is largely unknown. The most common mandate for treating these patients is restoration of menses and fertility. In some patients the quantity of galactorrhea is bothersome but uncommonly incapacitating. The normal pituitary increases in volume during pregnancy, and there is concern that a tumor mass may also increase during pregnancy and cause optic nerve compression or hypothalamic-pituitary dysfunction. Recent reports have documented that pituitary adenomas can expand during pregnancy leading to visual deterioration requiring emergency neurosurgery. The threat of such an occurrence is established for tumors that produce an enlarged sella but may also be present in patients with microadenomas. Many authorities, therefore, recommend that the pituitary adenoma be treated before the patient is allowed to become pregnant: in most centers this recommendation has been extended to include patients with microadenomas. Presently, three modes of theraputic intervention for prolactin-producing pituitary adenomas are available: surgical resection (usually through the transsphenoidal approach) and irradiation therapy are aimed at removing or decreasing the mass of prolactin-secreting tissue. The dopamine agonists (e.g.. bromocriptine) suppress prolactin release. Although each modality may have specific indications and contraindications, it is beyond the scope of this editorial to weigh the pros and cons for each of these theraputic measures. A number of excellent reviews exist in which these issues are discussed in detail [1,4,5,6]. REFERENCES 1. Thorner MO: Prolactin. Clinics in Endocrinology and Metabolism (Besser GM, ed), Philadelphia, W. B. Saunders, 1977, p 201. 2. Frantz AG. Kleinberg DL. Noel CL: Studies on prolactin in man. Recent Prog Horm Res 28: 527,1972. 3. Fluckigcr E: Drugs and the control of prolactin secretion. Prolactin and Carcinogenesis (Boyns AR, Griffirhs K, edsl. Proceedings of the 4th Tcnovus Workshop, Cardiff Wales. Alpha Omega Alpha, 1972, p 162. 4. Hardy J: Transsphenoidal surgery of hppersecreting pituitary tumors. Diagnosis and Treatment of Pituitary Tumor> (Kohler PO, Ross GT, eds). International Congress Series No 303. Amsterdam Excerllta Medica. 1973. p 179. 5. Kleinberg DL, Noel GL. Frantz AG: Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 296: 589,1977. 6. Boyd AE III, Reichlin S, Turksay RN: Galactorrhea-amenorrhea syndrome: diagnosis and therapy. Ann Intern Med 87:
Volume 66
165,1977.
