MODERN TRENDS Edwilrd W M.D. allach~

Associate Editor FERTILITY AND STERILITY Copyright' 1977 The American Fertility Society

VoL 28, No.2, February 1977 Printed in U.s.A.

CURRENT CONCEPTS OF PROLACTIN PHYSIOLOGY IN NORMAL AND ABNORMAL CONDITIONS

DA YID F, ARCHER, M,D, Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Magee-Women's Hospital, Pittsburgh, Pennsylvania 15213

The past will not sleep. It works still. With every new fact a ray of light shoots up from the long-buried years. -Ralph Waldo Emerson, 1865 It becomes almost passe to write about the interest of physicians in the syndrome of amenorrhea and galactorrhea. As in all fields, eponymic classification of disorders occurs initially to describe the clinical symptomatology and then the patients await the improvements in isolation of hormones, specific assays, and increased knowledge concerning the pathophysiology of the disorder. So it has been with amenorrhea and galactorrhea. Classically, three clinical entities have been identified: (1) the Chiari-Frommel syndrome, the persistence of postpartum amenorrhea and galactorrhea for more than 1 year following delivery and without evidence of pituitary tumor; (2) the Ahumada-del Castillo syndrome, the spontaneous onset of amenorrhea and galactorrhea without pituitary adenoma; and (3) the ForbesAlbright syndrome, which is comparable to the above but with roentgenologic evidence of pituitary adenoma. 1 The medical literature is replete with other interesting associations of inappropriate breast secretion. Several of these have caught this author's fancy in the past. Case reports have included such titles as "Spontaneous Galactorrhea in a Virgin"2 and "Familial Galactorrhea in Three Sisters with Oligo-ovulation."3 Abnormal breast secretion and hyperprolactinemia have been found in association with primary hypothyroidism, as well as in the interesting triad of galactorrhea, precocious puberty, and hypothyroidism in Received January 6, 1977,

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which all symptoms cleared upon appropriate replacement with thyroid medication.4-7 Several other clinical situations have been identified in the etiology of galactorrhea. They include breast secretions following hysterectomy, after thoracotomy or chest wall trauma, after herpetic infection of the thoracic nerves, and following breast biopsies. 8 Abnormal lactation has also been reported to occur in Cushing's syndrome. 9 Some of the major organic causes of hyperprolactinemia are listed in Table 1. Recently, several therapeutic drugs have been found to result in increased serum prolactin (hPRL) levels and/or inappropriate breast secretions (Table 2). These include tricyclic antidepressants and other tranquilizers; foremost among them are the phenothiazines, such as Thorazine and Compazine. Breast secretion is apparent in a number of women taking oral contraceptives or following discontinuation of oral contraceptives. Postpill galactorrhea is often associated with persistent amenorrhea. 8 Reserpine and Aldomet (a-methyldopa) have also been documented to increase serum hPRL.lo, 11 The common denominator in all of the above case reports is inappropriate breast secretion (nonpuerperal). Forbes et al. I2 speculated in 1954 that increased prolactin secretion was responsible for the galactorrhea in those cases of pituitary adenoma which carry the eponym Forbes-Albright syndrome. However, 16 more years were required before pituitary hPRL was isolated and identified as a separate pituitary hormone distinct from human growth hormone (hGH).13, 14 Since that time,

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TABLE 1. Organic Causes of Hyperprolactinemia Pituitary adenoma Pituitary stalk section Hypothyroidism, primary Cushing's syndrome Chest wall trauma or infection Hysterectomy Renal disease Hypothalamic lesions

a rapidly expanding literature has accumulated on the physiology of pituitary hPRL secretion in normal and pathologic conditions. It is the purpose of this review to assess what is known about the control of prolactin secretion in humans as well as to document means of altering hPRL secretion (testing modalities) and to discuss current therapeutic regimens that may soon be available to the practicing physician. THE HYPOTHALAMIC-PITUITARY AXIS AND PROLACTIN SECRETION

The secretion of pituitary hPRL is regulated by a tonic inhibition secondary to a hypothalamic factor known as prolactin-inhibiting factor (PIF). Several reviews regarding the hypothalamic control of PRL secretion have been published documenting the extensive animal research in this area. 15 ,16 Interruption of the hypothalamic-pituitary portal system in humans by stalk section results in rapid and sustained elevation of serum hPRL levels, corroborating animal findings relative to a tonic hypothalamic inhibition of hPRL secretion. 17 Hypothalamic PIF is controlled by dopaminergic neurons which are found in the hypothalamic area. The median basal eminence of the hypothalamus has high concentrations of dopamine present.10 The neurosecretory fibers in this hypothalamic-hypophysiotropic area, when TABLE 2. Therapeutic Drugs Associated with Increases in Serum Prolactin Tranquilizers Phenothiazines Chlorpromazine (Thorazine) Prochlorperazine (Compazine) Tricyclic antidepressants Amitriptyline (Triavil) Imipramine (Tofranil) Meprobamate Haloperidol (Haldol) Steroids Estrogens Miscellaneous a-Methyldopa (Aldomet) Reserpine Amphetamines Isoniazid

February 1977 TYROSINE

TRYPTOPHAN

I

I

DIH YDROXYPHENYLALANINE

E

5-HYDROXYTRYPTOPHAN

I

I

DOPAMINE

SEROTONIN

NOREPINE;PHRINE PROLACTIN INHISITING FACTOR

1

I

PROLACTIN INHIBITING FACTOR

PROLACTIN RELEASING FACTOR

I

FIG. 1. Catecholamine metabolism of the hypothalamus involved in pituitary prolactin secretion.

stimulated, elaborate hypothalamic releasing/ inhibiting factors such as gonadotropin-releasing hormone (Gn-RH) and/or PIF. Although dopamine and its metabolites (i.e., catecholamines, such as norepinephrine) appear to be the major neurotransmitter substance of the median eminence involved in hPRL secretion, the possibility exists for a second pathway in the hypothalamus involving serotonin (5-hydroxytryptamine) (see Fig. 1).10,18-20 Two recent reports in humans have documented increases in serum hPRL levels following administration of serotonin. 21, 22 It is possible that serotonin could decrease PIF or conversely could stimulate or increase a prolactin-releasing factor (PRF). Crude hypothalamic extracts from some avian species have been shown to have a positive effect (i.e., stimulation) on prolactin secretion from pituitary tissue in vitro, adding credence to this hypothesis. 15 It is conceivable that the regulation of hPRL secretion by the pituitary lactotroph does not depend on one hypothalamic factor alone, but is a result of a balance between PIF and PRF. A diagrammatic scheme of the hypothalamic-pituitary control of hPRL release is presented in Figure 2. Some hypothalamic releasing hormones have been isolated, identified, and synthesized. A tripeptide (pyroglutamyl-histidyl-prolinamide) has been synthesized and named thyrotropin-releasing hormone (TRH) on the basis of initial investigations which revealed that this substance increased the release of thyrotropin-stimulating hormone (TSH). Subsequently, TRH was found to cause a marked release of pituitary hPRL both in vitro and in vivo. 23-25 Although it was speculated that TRH might be the physiologic hPRL-releasing substance of the hypothalamus, most of the clinical data support the contention that release of hPRL is secondary to a reduction in hypothalamic PIF and not due to increased secretion of TRH in normal subjects. 26 , 27 Germane to this point is the failure to document an increase in TSH levels or an alteration of thyroid function

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HYPOTHALAMUS NEUROTRANSMITTER CELLS IN VENTROMEDIAL NUCLEUS AND MEDIAN EMINENCE DOPAMINE { EPINEPHRINE SEROTONIN

HYPOTHALAMIC·PITUITARY PORTAL CIRCULATION

PITUITARY PITUITARY LACTOTROPHS

_

• •~PROLACTIN

FIG. 2. Hypothalamic-pituitary relationship for prolactin secretion.

in breast-feeding women following nursing, which results in a rapid, marked rise in serum hPRL.28 PIF has not yet been isolated or identified. Currently some investigators believe that dopamine in actuality may be the hypothalamic PIF, since it can inhibit pituitary hPRL synthesis when infused via the hypothalamic-pituitary portal circulation. 29 It is conceivable that dopamine could be secreted directly from the nerve terminal into the hypothalamic-pituitary portal circulation rather than function at the synapse between nerves (Fig. 2). Pituitary hPRL responses are further modulated by both estrogen and thyroid hormones. Prolactin responses to both TRH and chlorpromazine are more marked in females than in males. 25 , 30 This sex difference can be minimized by the exogenous administration of estrogenic material to males. 31 Estrogen apparently promotes the release ofhPRL in two fashions: (1) reduction of hypothalamic PIF by estrogen, which has been documented in the rat,15 and (2) augmentation of the release of hPRL from the pituitary by a direct action on the pituitary lactotrophs. 32 ,33 Basal levels of hPRL are higher in females than in males at all ages except prior to puberty and following menopause. 25 ,34 During the menstrual cycle, hPRL levels are significantly higher in the luteal phase than in the preovulatory phase. Some investitors have reported what appears to be a midcycle surge of hPRL coincident with the follicle-

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stimulating hormone (hFSH) and luteinizing hormone (hLH) peak. 35-37 The addition of progesterone, corticosteroids, and androgens to in vitro pituitary cultures does not have a significant effect on hPRL synthesis or release, while estrogen results in a marked increase in hPRL release. 38 Thyroxin and triiodothyronine also modulate hPRL secretion. In primary hypothyroidism, basal hPRL levels are elevated and the hPRL response to exogenously administered synthetic TRH is exaggerated. 4, 39, 40 As the individual becomes euthyroidal with replacement therapy, basal hPRL levels return to normal and the hPRL response to TRH is normal,39 The hPRL response to TRH in hyperthyroidal individuals is blunted or absent. 4o However, the addition of thyroxin to pituitary cultures in vitro results in agumentation of prolactin secretion into the medium. 38 This dichotomy between in vivo and in vitro results is difficult to rationalize. The principal effect of thyroid hormones on hPRL secretion in clinical practice appears to be directly on the pituitary lactotroph, although a hypothalamic mechanism with increases in endogenous TRH cannot be excluded at the present time.

ETIOLOGY OF AMENORRHEA ASSOCIATED WITH HYPERPROLACTINEMIA

All studies of women with amenorrhea-galactorrhea syndromes have documented normal to low levels of peripheral gonadotropins, with low levels of circulating estrogens. 41 -43 The pathophysiologic changes with resultant amenorrhea could occur at three sites: the hypothalamus, pituitary, or ovary. Ovarian response to exogenous menopausal gonadotropins in the puerperium initially suggested a refractoriness of the ovary to gonadotropins, possibly secondary to the elevated levels of hPRL.44,45 Subsequent studies have shown that, in puerperal women, an estrogen response from the ovary can be elicited with increased dosage of menopausal gonadotropins. 46 Women with amenorrhea and elevated levels of hPRL have a normal ovarian response with ovulation and normal corpus luteum function following administration of human menopausal gonadotropins and human chorionic gonadotropins. 47 Elevation of serum hPRL in normal, menstruating women by the administration of synthetic TRH does not result in any alteration in the length of the menstrual cycle, nor in differences in hFSH, hLH, or progesterone levels between control and treated

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cycles. It should be pointed out that the circulating levels of hPRL in these studies never rose beyond the upper limits of normal values. 48 • 49 Prolactin is luteotropic in rats and rabbits, but only preliminary data are available regarding ovarian steroidogenesis in primates at this time. 50 Reduction of serum prolactin below the limits of assay sensitivity in rhesus monkeys, using 2bromo-a-ergocryptine (bromergocryptine [CB154], Sandoz Pharmaceuticals, East Hanover, N. J.), results in a shortening of the menstrual interval and a decrease in normal luteal phase levels of serum estradiol and progesterone. 51 A second study from the same department has documented normal-appearing corpora lutea with increased serum levels of progesterone in nursing postpartum rhesus monkeys at 2 through 3 weeks postpartum as compared with non-nursing controis. 52 These data suggest a possible luteotropic role for prolactin in primates. However, the exogenous administration of human chorionic somatomammotropin (hCS, hPL) to human volunteers, although slightly prolonging the menstrual cycle, was ineffective in prolonging luteal function as measured by urinary estrogens and pregnanediol excretion. 53 A current report indicates a possible association of luteal phase defects in women and elevated serum hPRL levels. 54 The addition of prolactin to the media of human granulosa cells cultured in vitro results in a decrease of progesterone biosynthesis. 55 A further study by McNatty et al. 56 demonstrated that levels of hPRL and progesterone in follicular cyst fluid have a negative correlation; low levels of hPRL are present with increased amounts of progesterone, and vice versa. At present the data are too preliminary to document a specific role for hPRL in human ovarian function. Most of the information currently available does not seem to substantiate any significant effect of hPRL as either a luteotropin or a luteolysin in women. Since increased hPRL secretion is due to a decrease in hypothalamic PIF, a dysfunction of the hypothalamus resulting in decreased PIF biosynthesis or secretion could secondarily alter normal hypothalamic synthesis or secretion of gonadotropin-releasing hormone, thereby altering pituitary hFSH or hLH secretion. The control of Gn-RH by the median eminence is stimulated by dopaminergic neurotransmitters. 57 In rodents, dopamine and epinephrine fail to alter FSH or LH secretion either following direct injection into the hypothalamic-pituitary portal system or in vitro

February 1977 pituitary cultures. 58 However, when median eminence material plus dopamine is added to in vitro rat pituitaries there is a significant increase in both FSH and LH levels in the incubation media. 59. 60 Several reports in humans have documented increases in serum levels of both hFSH and hLH following i-dopa administration. 6 1, 62 In these reports the acute administration of large amounts of i-dopa has been followed by a surge of hFSH and hLH comparable to the midcycle increase in gonadotropins. A concurrent decrease in serum hPRL and partial inhibition of galactorrhea in women who have amenorrhea-galactorrhea syndrome also occurs with i-dopa administration. Ovulation, as judged by serum progesterone levels and basal body temperatures, has occurred with pregnancy in several instances following this treatment. 61 ,62 The intravenous infusion of dopamine does not significantly alter basal hFSH levels but results in a decline of serum hLH, followed by a marked rebound of hLH upon discontinuation of the dopamine infusion. 63 These data are at variance with the above-cited animal studies concerning the dopaminergic control of LH secretion. 59, 60 No data are available as to changes in hypothalamic Gn-RH following dopamine infusion. Other supportive evidence for a hypothalamic etiology of the amenorrhea in hyperprolactinemic individuals is the lack of a positive feedback effect from exogenous estrogen, as well as failure of change in serum gonadotropin levels during and after the administration of clomiphene citrate. 64 , 65 Finally, the pituitary reserve or functional capacity in terms of gonadotropin response has been evaluated by the use of exogenous Gn-RH. Initially, a normal to low-normal response of hFSH and hLH was reported to occur in women with hyperprolactinemia. 66 A poor or even absent response was found to occur in individuals with demonstrable pituitary adenoma, and it was believed that this might be a reasonable diagnostic testing modality for differentiating pituitary adenoma from nonadenoma. 66 Subsequent studies have found an exaggerated response of hFSH and hLH to exogenous Gn-RH in women with elevated hPRL levels. 67 ,68 Since estrogen plays a major role in modulating the gonadotropin response to exogenous Gn-RH in women, it is possible that the hypoestrogenic state coincident with hyperprolactinemia alters or obtunds the normal hFSH and hLH release in some instances.

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The same situation occurs in normal puerperal females where there is no pituitary hFSH or hLH response to Gn-RH during the first 2 to 3 weeks postpartum, but gonadotropin responsiveness returns following this interim period. 69• 72 The exact role of hPRL per se in terms of pituitary gonadotropin response to exogenous Gn-RH is unknown at present, but in women with elevated serum hPRL levels the pituitary gonadotroph appears to be functionally intact as evaluated by exogenous Gn-RH stimulation. 68 Preliminary data support the contention that the diurnal (nocturnal) changes in hFSH and hLH are reasonably normal in individuals with hyperprolactinemia. 73 It appears that a hypothalamic dysfunction may be the principal cause of the associated amenorrhea in hyperprolactinemic states, but further investigation is warranted. ENDOCRINE EVALUATION OF PITUITARY RESERVE IN HYPERPROLACTINEMIC STATES

Although hyperprolactinemia can occur secondary to several diverse clinical etiologies, the primary diagnostic problem involves differentiating pituitary prolactin-secreting adenomas from "idiopathic" hyperprolactinemia-i. e., no demonstrable pituitary adenoma. The problem is compounded by the wide use of various drugs that have been associated with increases in serum prolactin; these drugs are listed in Table 2. After exclusion of exogenous drug therapy and local factors such as cystic mastitis or chest wall problems, a thorough endocrine evaluation of pituitary function is indicated, as outlined in Table 3. Assessment of the pituitary-thyroid axis is accomplished by measuring serum thyroxin (T 4 ) TABLE 3. Current Endocrine Assessment ofthe HypothalamicPituitary Axis in Hyperprolactinemic Conditions Assessment

Thyroid Ovary Adrenal

Growth hormone Prolactin

Serum levels of TSH, thyroxin, and triiodothyronine; if available, TSH response to TRH Serum levels ofhFSH, hLH, and estradiol; if available, hFSH and hLH response to Gn-RH Indirect evidence of adrenocorticotropic hormone response to Metyrapone stimulation Cortisol response to insulin hypoglycemia hGH response to Insulin hypoglycemia Arginine infusion Serum hPRL levels; if available, hPRL responses to l-dopa, chlorpromazine, and synthetic TRH; 24-hr profile of hPRL secretion

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and TSH. TSH reserve can be documented by the administration of TRH, but this compound is not currently available for routine clinical investigation. The pituitary-ovarian axis is evaluated by measuring peripheral levels of hFSH, hLH, and estradiol. In most instances reported to date, normal levels of hFSH have been found with lownormal levels of serum hLH. Dynamic testing of the pituitary by the administration of exogenous Gn-RH has resulted in normal to exaggerated release of hFSH and hLH in women with amenorrhea and galactorrhea, as previously described. 67 ,68 Pituitary adrenocorticotropic hormone function has been measured indirectly by either insulininduced hypoglycemia or metyrapone responses. The personal experience of the author has failed to document any significant alterations in either of these parameters in women with or without pituitary adenomas. An increase in the production of dehydroepiandrosterone sulfate has been reported in hyperprolactinemic women. This increase might be reflected in an increased level of urinary 17-ketosteroids. 74 The normal response to metyrapone should be a 2- to 3-fold increase in urinary 17 -hydroxysteroids over base line values. The hG H response to insulin-arginine is thought to be a reasonably sensitive index for documenting pituitary hypofunction. Absence of hGH response frequently occurs in postpartum hypopituitarism and pituitary adenomas. The current medical literature does not document a high degree of reliability using this test for incipient micro adenomas as opposed to adenomas readily apparent by roentgenographic means. 75 , 76

PROLACTIN RESPONSES TO PHARMACOLOGIC AND PHYSIOLOGIC STIMULI

Assessment of pituitary hPRL dynamics has been carried out by several groups. The administration of synthetic TRH not only increases TSH levels but also hPRL secretion. Individuals with evidence of pituitary adenoma have a poor or blunted hPRL response to TRH in 70% of cases described. 77 This poor response of pituitary hPRL following TRH has also been found in women without overt evidence of pituitary adenoma. 78 Chlorpromazine has been used as a means of testing the hypothalamic-pituitary axis for prolactin secretion. Theoretically, functional autonomy of the pituitary with an hPRL-secreting adenoma should not demonstrate any significant

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increase in serum hPRL levels in response to this stimulus. The expected increase in hPRL is secondary to a depletion of hypothalamic catecholamines by chlorpromazine, resulting in a decrease in hypothalamic PIF.lO Despite initial data documenting these changes in normal women, there are no published reports concerning the ability to discriminate pituitary adenomas on this basis.8.30 Other tests have relied on inhibition of hPRL secretion as a means of differentiating between adenoma and nonadenoma. Initially, acute water loading with resultant hypo-osmolality of the serum was described as differentiating functional hyperprolactinemia from adenoma. Subsequent reports have failed to substantiate the efficacy of this test in diagnostic studies. 79 The administration of l-dopa as previously described results in inhibition ofhPRL secretion. 15. 16 This drug acts both via the hypothalamus and directly on the pituitary lactotroph in inhibiting hPRL secretion. 80 . 81 The inhibition of hPRL secretion appears to be the same in adenoma and in idiopathic hyperprolactinemic conditions. 63 The constant infusion of l-dopa in normal individuals suppresses serum hPRL levels, and, upon discontinuation of infusion, there is a prompt rebound of hPRL levels above initial basal values. 8. 63 A comparable test in women with pituitary adenoma reduced serum hPRL, but after the infusion was discontinued hPRL levels returned to basal values without the anticipated rebound ofhPRL.63 This interesting finding needs further assessment in terms of etiology of pituitary adenomas. A new ergot derivative, bromergocryptine (CB-154), specifically lowers serum hPRL.1. 64. 82. 83 The mechanism of action is comparable to that of l-dopa, resulting in an increase in hypothalamic dopamine content as well as a direct inhibitory effect on the pituitary lactotroph. 1 It has the same drawback as a test modality as l-dopa, since it appears to suppress hPRL in both patients with adenoma and those without. 63 . 84 Physiologic changes in hPRL have also been utilized as a possible means of detecting pituitary hPRL-secreting adenomas. Stimulation of the breast in puerperal females results in an increase in serum hPRL via a neurosensory hypothalamicpituitary loop.8 It was theorized that alterations in this physiologic-neuroendocrine control circuit might be utilized diagnostically. However, nonpuerperal or never-pregnant females have variable hPRL responses to this stimulatory modality, and it was found to be of no clinical value. 79

February 1977 There is a circadian rhythmicity to hPRL secretion. Increases in serum hPRL levels are found between 2 A.M. and 5 A.M. and are associated with deep sleep (non-barbiturate-induced).85.86 The increase in hPRL is distinct from that found with hGH and occurs 2 to 4 hours following the nocturnal rise in hGH. Several reports have documented absence of the nocturnal hPRL surge in women with pituitary adenoma. 87 . 88 This lack of normal rhythmicity may indicate autonomous function ofhPRL secretion, since rapid, wide oscillations in serum hPRL levels have been found to occur with hPRL-secreting adenomas. 79 It is apparent that provocative tests of pituitary function and/or reserve do not aid greatly in determining small intrasellar hPRL-secreting adenomas, i.e., "microadenomas." Levels ofhPRL in excess of 300 ng/ml are highly suggestive of pituitary adenomas. However, only 30% of pituitary adenomas of the chromophobic (acidophilic) variety are associated with increased hPRL secretion. 89 This means that most adenomas do not manifest any significant change in serum hPRL. Currently, hypocycloidal polytomography of the sella turcica with frontal and lateral views is the best means of documenting pituitary microadenomas. 9o Computerized axial tomography and standard skull x-rays are not adequate to discern the small functioning microadenomas ofthe pituitary with any degree of reliability.78 Furthermore, amenorrhea, breast secretion, and reasonably normal levels of hPRL, without evidence of pituitary adenoma, have been documented in women. Breast tissue is a specific target tissue for hPRL, and the main physiologic action of hPRL is initiation of milk biosynthesis. hPRL, like other protein hormones, is bound to a cell membrane receptor to elicit its intracellular effect. Current investigation has indicated that 50% binding of hPRL to cell membrane receptors can occur with concentrations ofhPRL comparable to approximately 8 ng/ml of serum hPRL.91 This implies that breast secretion is feasible if the endogenous hormonal milieu is appropriate, despite the presence of normal levels of serum hPRL. Whether or not the amenorrhea can also be explained on this basis remains to be determined.

THERAPEUTIC MODALITIES FOR ELEVATED SERUM PROLACTIN

Although l-dopa can reduce the elevated levels of serum hPRL, the therapeutic effect is of short duration and there are attendant side effects, most

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notably nausea and vomiting. 92 For these reasons, l-dopa is not recommended as a therapeutic modality at this time. Two ergot derivatives have been found to result in a rapid and sustained inhibition of serum hPRL. These are 2-bromo-a-ergocryptine (bromergocryptine, CB-154) and 2-chloro-6-methylergoline-813-acetonitrile methane sulfonate (Lergotrile, Compound 83636; Eli Lilly and Co" Indianapolis, Ind.).l. 64. 82. 83. 93 Most clinical data have been compiled with bromergocryptine. Published reports have documented its efficacy in reducing serum hPRL with resumption of menses, ovulation, and pregnancy in women. 1. 64. 82. 83 Only preliminary clinical reports are available for Lergotrile, which is now in initial clinical trials. 93 These therapeutic modalities are useful only in individuals without overt evidence of pituitary microadenoma, although bromergocryptine has been used with success in patients with definite microadenoma. 84 Pregnancy is contraindicated in the presence of a pituitary microadenoma. There are reports of rapid enlargement of pituitary microadenomas during pregnancy and in the puerperium, necessitating emergency neurosurgical procedures. 94 . 95 Although ovulation with resultant pregnancy could be accomplished with exogenous menopausal gonadotropin therapy in women with pituitary micro- or macroadenomas, the appropriate conservative management is either neurosurgical removal of the adenoma (trans-sphenoidally if possible) ,or radiation therapy, prior to attempting ovulation induction. 47 The failure rate for radiation therapy appears to be approximately 20%.96 It is difficult to acquire any firm data on the neurosurgical success rate for hPRL-secreting microadenomas, but in the author's personal experience it is approximately 35%.97 The reasons for this low success rate are unknown, and it is hoped that a more aggressive approach may yield better results. Compounding this is the fact that none ofthe women has developed evidence of hypopituitarism following surgery, except for transient episodes of diabetes insipidus. A more radical neurosurgical approach, although resulting in clinical improvement, might result in increased instances of hypopituitarism.

sive investigation. Development of sensitive, specific radioimmunoassays for hPRL and improved roentgenographic techniques have increased the diagnostic acumen for incipient pituitary microadenomas. Several modalities of treatment are available at the present time which can result in improvement in the clinical symptoms ofthe amenorrheagalactorrhea syndromes. Eponymic classification of amenorrhea-galactorrhea syndromes should be discarded and appropriate diagnostic studies initiated to determine the etiology of the inappropriate breast secretion and/or elevated serum hPRL level.

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SUMMARY

Currently the physiology and pathophysiology of pituitary prolactin secretion are under inten-

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galactorrhea: results of therapy with 2-bromo-a-ergocryptine (CB-154). Am J Obstet Gynecol 122:85, 1975 Maizels G: Spontaneous galactorrhea in a virgin. J Obstet Gynaecol Br Commonw 74:933,1967 Wider JA, Marshall JR, Ross GT: Familial galactorrhea in three sisters with oligo-ovulation. JAMA 209:669,1969 Ross F, Nusynowitz ML: A syndrome of primary hypothyroidism, amenorrhea and galactorrhea. J Clin Endocrinol Metab 28:591, 1968 Bayliss PFC, Van't HoffW: Amenorrhea and galactorrhea associated with hypothyroidism. Lancet 2:1399, 1969 Edwards CRW, Forsyth lA, Besser GM: Amenorrhea, galactorrhea, and primary hypothyroidism with high circulating levels of prolactin. Br Med J 3:462, 1971 Van Wyk JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism. J Pediatr 57:416, 1960 Frantz AG: Prolactin secretion in physiologic and pathologic human conditions measured by bioassay and radioimmunoassay. In Lactogenic Hormones, Fetal Nutrition and Lactation, Edited by JB Josimovich, M Reynolds, E Cobo. New York, John Wiley and Sons, 1974, p 379 Mahesh VB, Dalla Pria S, Greenblatt RB: Abnormal lactation with Cushing's syndrome-a case report. J Clin Endocrinol Metab 29:978, 1969 Frohman LA: Neurotransmitters as regulators of endocrine function. Hosp Practice 10:54, 1975 Archer DF: The role of pituitary prolactin in amenorrhea and galactorrhea. Contemp Obstet Gynecol 7:71, 1976 Forbes AP, Henneman PH, Griswold GC, Albright F: Syndrome characterized by galactorrhea, amenorrhea and low urinary FSH: comparison with acromegaly and normal lactation. J Clin Endocrinol Metab 14:265, 1954 Frantz AG, Kleinberg DL: Prolactin: evidence that it is separate from growth hormone in human blood. Science 170:745,1970 Hwang P, Guyda H, Friesen H: Purification of human prolactin. J BioI Chem 247:1955, 1972 Nicoll CS, Fiorindo RP, McKennee CT, Parsons JA: Assay of hypothalamic factors which regulate prolactin secretion. In Hypophysiotropic Hormones of the Hypothalamus: Assay and Chemistry, Edited by J Meites. Baltimore, Williams & Wilkins Co, 1970, p 115

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16. Meites J, Lu K-H, Wuttke W, Welsch CW, Nagasawa H, Quadri SK: Recent studies on functions and control of prolactin secretion in rats. Recent Prog Horm Res 28:471, 1972 17. Turkington RW, Underwood LE, VanWyk JJ: Elevated serum prolactin levels after pituitary-stalk· section in man. N Engl J Med 285:707,1971 18. Turkington RW, Maclndoe JH: Prolactin release-effector mechanisms in clinical disorders of prolactin secretion. In Lactogenic Hormones, Fetal Nutrition and Lactation, Edited by JB Josimovich, M Reynolds, E Cobo. New York, John Wiley and Sons, 1974, p 413 19. Kamberi lA, Mical RS, Porter JC: Effects of melatonin and serotonin on the release of FSH and prolactin. Endocrinology 88:1288,1971 20. Lu K-H, Meites J: Effects of serotonin precursors and melatonin on serum prolactin release in rats. Endocrinology 93:152, 1973 21. Maclndoe JH, Turkington RW: Stimulation of human prolactin secretion by intravenous infusion of L-trytophan. J Clin Invest 52:1972, 1973 22. Kato Y, Nakai Y, Imura H, Chihara K, Ohgo S: Effect of 5-hydroxytryptophan (5-HTP) on plasma prolactin levels in man. J Clin Endocrinol Metab 38:695,1974 23. Tashjian AH Jr, Hoyt RF Jr: Transient controls of organspecific functions in pituitary cells in culture. In Molecular Genetics and Developmental Biology: Proceedings of the Symposium ofthe Society of General Physiologists, Woods Hole, September 1971, Edited by M Sussman. Englewood Cliffs NJ, Prentice-Hall, 1972, p 353 24. Bowers CY, Friesen HG, Hwang P, Guyda HJ, Folkers J: Prolactin and thyrotropin release in man by synthetic pyroglutamyl-histidyl-prolinamide. Biochem Biophys Res Commun 45:1033, 1971 25. Jacobs LS, Snyder PJ, Utiger RD, Daughaday WH: Prolactin response to thyrotropin-releasing hormone in normal subjects. J Clin Endocrinol Metab 36:1069, 1973 26. L'Hermite M, Robyn C, Golstein J, Rothenbuchner G, Birk J, Loos U, Bonnyns M, Vanhaelst L: Prolactin and thyrotropin in thyroid diseases: lack of evidence for a physiological role ofthyrotropin-releasing hormone in the regulation of prolactin secretion. Horm Metab Res 6: 190, 1974 27. Bowers CY, Friesen HG, Folkers K: Thyrotropin releasing hormone and the release of prolactin. In Biological Rhythms in Neuroendocrine Activity, Edited by M Kawakami. Tokyo, Igaku Shoin Ltd, 1974, P 102 28. Gautvik KM, Tashjian AH Jr, Kourides lA, Weintraub BD, Graeber CT, Maloof F, Suzuki K, Zuckerman JE: Thyrotropin-releasing hormone is not the sole physiologic mediator of prolactin release during suckling. N Engl J Med 290:1162, 1974 29. MacLeod RM, Lehmeyer JE: Studies on the mechanism of the dopamine-mediated inhibition of prolactin secretion. Endocrinology 94:1077, 1974 30. Buckman MT, Peake GT: Estrogen potentiation ofphenothiazine-induced prolactin secretion in man. J Clin Endocrinol Metab 37:977, 1973 31. Carlson HE, Jacobs LS, Daughaday WH: Growth hormone, thyrotropin and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pretreatment. J Clin Endocrinol Metab 37:488, 1973 32. Abu-Fadil S, DeVane G, Siler TM, Yen SSC: Effects of oral contraceptive steroids on pituitary prolactin secretion. Contraception 13:79, 1976

February 1977 33. Rakoff JS, Siler TM, Sinha YN, Yen SSC: Prolactin and growth hormone release in response to sequential stimulation by arginine and synthetic TRF. J Clin Endocrinol Metab 37:641,1973 34. Ehara Y, Yen SSC, Siler TM: Serum prolactin levels during puberty. Am J Obstet GynecoI121:995, 1975 35. L'Hermite M, Delvoye P, Nokin J, Vekemans M, Robyn C: Human prolactin secretion, as studied by radioimmunoassay: some aspects of its regulation. In Prolactin and Carcinogenesis: Proceedings ofthe Fourth Tenovus Workshop, Cardiff, March 1972, Edited by AR Boyns, K Griffiths. Cardiff Wales, Alpha Omega Alpha Publishing, 1972, p 81 36. Ehara Y, Siler T, VandenBerg G, Sinha YN, Yen SSC: Circulating prolactin levels during the menstrual cycle: episodic release and diurnal variation. Am J Obstet Gynecol 117:962, 1973 37. Robyn C, Delvoye P, Nokin J, Vekemans M, Badawi M, Perez-Lopez FR, L'Hermite M: Prolactin and human reproduction. In Human Prolactin: Proceedings of the International Symposium on Human Prolactin, Brussels, June 1973, Edited by JL Pasteels, C Robyn. New York, American Elsevier Publishing Co, 1973, p 167 38. Meites J: Control of mammary growth and lactation. In Neuroendocrinology, Edited by L Martini, WF Ganong. New York, Academic Press, 1966, p 669 39. Edwards CRW, Forsyth lA, Besser GM: Amenorrhea, galactorrhea, and primary hypothyroidism with high circulating levels of prolactin. Br Med J 3:462, 1971 40. Jacobs LS, Daughaday WH: Physiologic regulation of prolactin secretion in man. In Lactogenic Hormones, Fetal Nutrition and Lactation, Edited by JB Josimovich, M Reynolds, E Cobo. New York, John Wiley and Sons, 1974, p 351 41. Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Washwa SR, Josimovich JB: Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 119: 466, 1974 42. Franks S, Murray MAF, Jequier AM, Steele SJ, Nabarro JDN, Jacobs HS: Incidence and significance of hyperprolactinaemia in women with amenorrhoea. Clin Endocrinol (Oxf) 4:597, 1975 43. Spark RF, Pallotta J, Naftolin F, Clemens R: Galactorrhea-amenorrhea syndromes: etiology and treatment. Ann Intern Med 84:532, 1976 44. Zarate A, Canales ES, Soria J, Ruiz F, MacGregor C: Ovarian refractoriness during lactation in women: effect of gonadotropin stimulation. Am Obstet Gynecol 112: 1130, 1972 45. Zarate A, Canales ES, Soria J, Ikon C, Garrido J, Fonseca E: Refractory postpartum ovarian response to gonadal stimulation in nonlactating women. Obstet Gynecol 44: 819, 1974 46. Nakano R, Mori A, Kayashima F, Washio M, Tojo S: Ovarian response to exogenously administrated human gonadotropins during the postpartum period. Am Obstet GynecoI121:187, 1975 47. Archer DF, Josimovich JB: Ovarian response to exogenous gonadotropins in women with elevated serum prolactin. Obstet Gynecol 48:155, 1976 48. Zarate A, Schally AV, Soria J, Jacobs LS, Canales ES: Effect of thyrotropin releasing hormone (TRH) on the menstrual cycle in women. Obstet Gynecol 43:487, 1974 49. J ewelewicz R, Dyrenfurth I, Warren M, Frantz AG, Vande Wiele RL: Effect of thyrotropin-releasing hormone (TRH)

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upon the menstrual cycle in women. J Clin Endocrinol Metab 39:387,1974 50. Josimovich JB, Archer DF: Primate lactogenic hormones and functions. In Lactation, a Comprehensive Treatise, Edited by B Larson. New York, Academic Press. In press 51. Espinosa-Campos J, Butler WR, Knobil E: Inhibition of corpus luteum function in the rhesus monkey by 2-broma-ergocryptine (CB-154) (abstr 63). Presented at The Endocrine Society 57th Annual Meeting, New York, 1975 52. Weiss G, Dierschke DJ, Karsch FJ, Hotchkiss J, Butler WR, Knobil E: The influence oflactation on luteal function in the rhesus monkey. Endocrinology 93:954, 1973 53. Josimovich JB, Stock RJ, Tobon J: Effects of primate placental lactogen upon lactation. In Lactogenic Hormones, Fetal Nutrition and Lactation, Edited by JB Josimovich, M Reynolds, E Cobo. New York, John Wiley and Sons, 1974, P 335 54. Corenblum B, Pairaudeau N, Shewchuk AB: Prolactin hypersecretion and short luteal phase defects. Obstet Gynecol 47:486, 1976 55. McNatty KP, Hunter WM, McNeilly AS, Sawers RS: Changes in the concentration of pituitary and steroid hormones in the follicular fluid of human graafian follicles throughout the menstrual cycle. J Endocrinol 64:555, 1975 56. McNatty KP, Sawers RS, McNeilly AS: A possible role for prolactin in control of steriod secretion by the human graafian follicle. Nature 250:653, 1974 57. McCann SM, Krulich L, Cooper KJ, Kalra PS, Kalra SP, Libertun C, Negro-Vilar A, Orias R, Ronnekleiv 0, Fawcett CP: Hypothalamic control of gonadotropin and prolactin secretion, implications for fertility control. J Reprod Fertil [Suppl] 20:43, 1973 58. Kamberi lA, Mical RS, Porter JC: Effect of anterior pituitary perfusion and intraventricular injection of catecholamines and indoleamines on LH release. Endocrinology 87:1, 1970 59. Schneider HPG, McCann SM: Possible role of dopamine as transmitter to promote discharge of LH-releasing factor. Endocrinology 85:121, 1969 60. McCann SM, Ojeda SR, Fawcett CP, Krulich L: Catecholaminergic control of gonadotropin and prolactin secretion with particular reference to the possible participation of dopamine. Adv Neurol 5:435,1974 61. Zarate A, Canales ES, Jacobs LS, Maneiro PJ, Soria J, Daughaday WH: Restoration of ovarian function in patients with the amenorrhea-galactorrhea syndrome after long-term therapy with L-dopa. Fertil Steril 24:340, 1973 62. Ayalon D, Peyser R, ToaffR, Cordova T, Harell A, Franchimont P, Lindner HR: Effect of L-dopa on galactopoiesis and gonadotropin levels in the inappropriate lactation syndrome. Obstet Gynecol 44:159, 1974 63. Leblanc H, Lachelin GCL, Abu-Fadil S, Yen SSC: Effects of dopamine infusion on pituitary hormone secretion in humans. J Clin Endocrinol Metab 43:668, 1976 64. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhea and hypogonadism with bromocriptine. Br Med J 25:419, 1974 65. Glass MR, Shaw RW, Butt WR, Logan Edwards R, London DR: An abnormality of oestrogen feedback in amenorrheagalactorrhea. Br Med J 3:274,1975 66. Zarate A, Canales ES, Soria J, Garrido J, Jacobs LS, Schally AV: Pituitary secretory reserve in patients with

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amenorrhea associated with galactorrhea. Ann Endocrinol (Paris) 35:535, 1974 67. Wentz AC, Jones GS, Rocco L, Matthews RR: Gonadotropin response to luteinizing hormone releasing hormone administration in secondary amenorrhea and galactorrhea syndromes. Obstet Gynecol 45:256, 1975 68. Archer DF, Sprong JW, Nankin HR, Josimovich JB: Pituitary gonadotropin response in women with idiopathic hyperprolactinemia. Fertil Steril 27:1158, 1976 69. Nakano R, Kayashima F, Mori A, Kotsuji F, Hashiba N, Tojo S: Gonadotropin response to luteinizing hormone releasing factor (LRF) in puerperal women. Acta Obstet Gynecol Scand 53:303,1974 70. Canales ES, Zarate A, Garrido J, Ikon C, Soria J, Schally AV: Study on the recovery of pituitary FSH function during puerperium using synthetic LRH. J Clin Endocrinol Metab 38:1140, 1974 71. LeMaire WJ, Shapiro AG, Riggall F, Yang NST: Temporary pituitary insensitivity to stimulation by synthetic LRF during the postpartum period. J Clin Endocrinol Metab 38:916,1974 72. Tolis G, Guyda H, Rochefort JG: Pituitary responsiveness to gonadotropin releasing factor (GnRH) in puerperium. Endocrinol Res Commun 2:521, 1975 73. Kapen S, Boyar R, Freeman R, Frantz A, Hellman L, Weitzman ED: Twenty-four hour secretory patterns of gonadotropins and prolactin in a case of Chiari-Frommel syndrome. J Clin Endocrinol Metab 90:234,1975 74. Giusti G, Bossi F, Borsi L, Cattaneo S, Grannotte P, Lanza L, Pazzagli P, Vigiani G, Serio L: In Prolactin and Human Reproduction, Edited by PG Crosignani. New York, Academic Press. In press 75. Kase N, Andriole JP, Sobrinho L: Endocrine diagnosis of pituitary tumor in galactorrhea syndromes. Am J Obstet GynecoI114:321,1972 76. Wiebe RH, Hammond CB, Borchert LG: Diagnosis of prolactin-secreting pituitary microadenoma. Am J Obstet Gynecol 126:993, 1976 77. Snyder PJ, Jacobs LS, Rabello MM, Sterling FSH, Shore RN, Utiger RD, Daughaday WH: Diagnostic value of thyrotropin-releasing hormone in pituitary and hypothalamic disease,s: assessment of thyrotropin and prolactin secretion in 100 patients. Ann Intern Med 81:751, 1974 78. Archer DF, Josimovich JB: Unpublished observations 79. Archer DF, Josimovich JB: Response of serum prolactin to exogenous stimulation. Fertil Steril 26:627,1975 80. MacLeod RM, Lehmeyer JE: Studies on the mechanism of the dopamine-mediated inhibition of prolactin secretion. Endocrinology 94:1077,1974 81. Diefenbach WP, Carmel PW, Frantz AG, Ferin M: Suppression of prolactin secretion by L-dopa in the stalksectioned rhesus monkey. J Clin Endocrinol Metab 43: 638, 1976 82. del Pozo E, Brun del Re R, Varga L, Friesen H: The inhibition of prolactin secretion in man by CB-154 (2-broma-ergocryptine). J Clin Endocrinol Metab 35:768, 1972 ~3. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 4:694,1975 84. Corenblum B, Webster BR, Mortimer CB, Ezrin C, Shewchuk A: Possible anti-tumor effect of2-bromo-ergocryptine (CB-154 Sandoz) in two patients with large prolactinsecreting pituitary adenomas. Clin Res 23:614A, 1975

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85. Sassin JF, Frantz AG, Weitzman ED, Kapen S: Human prolactin: 24-hour pattern with increased release during sleep. Science 177:1205, 1972 86. Sassin JF, Frantz AG, Kapan S, Weitzman ED: The nocturnal rise of human prolactin is dependent on sleep. J Clin Endocrinol Metab 37:436, 1973 87. Boyar RM, Kapan S, Weitzman ED, Hellman L: Pituitary microadenoma and hyperprolactinemia: a cause of unexplained secondary amenorrhea. N Engl J Med 294: 263, 1976 88. Malarkey WB, Johnson JC: Pituitary tumors and hyperprolactinemia. Arch Intern Med 136:40, 1976 89. Friesen H, Tolis G, Shiu R, Hwang P: Studies on human prolactin: chemistry, radioreceptor assay and clinical significance. In Human Prolactin: Proceedings of the International Symposium on Human Prolactin, Brussels, June 1973, Edited by JL Pasteels, C Robyn. New York, American Elsevier Publishing Co, 1973, p 11

February 1977 90. Vezina JL, Sutton TJ: Prolactin-secreting pituitary microadenomas: roentgenologic diagnosis. Am J Roentgenol Radium Ther Nucl Med 120:46, 1974 91. Shiu RPC, Friesen HG: Properties of a prolactin receptor from the rabbit mammary gland. Biochem J 140:301, 1974 92. Leblanc H, Yen SSC: The effect of L-dopa and chlorpromazine on prolactin and growth hormone secretion in normal women. Am J Obstet Gynecol 126:162, 1976 93. Lemberger L, Crabtree R, ClemensJ, Dyke RW, Woodburn RT: The inhibitory effect of an ergoline derivative (Lergotrile, Compound 83636) on prolactin secretion in man. J Clin Endocrinol Metab 39:579,1974 94. Child DF, Gordon H, Hoplin GF: Pregnancy, prolactin, and pituitary tumors. Br Med J 4:87,1975 95. Shewchuk A: Personal communication 96. Ontjes DA, Ney RL: Pituitary tumors. CA 26:330, 1976 97. Archer DF, Maroon JC: Unpublished observations