Current Management of the Amenorrhea-Galactorrhea Syndrome

MODERN TRENDS Edward Wwlach, M.D. Associ.de. E.ditor Vol. 29, No.6, ,June 1978 Printed in U.S.A.

FERTILITY AND STERILITY Copyright 1978 The American Fertility Society 'C

CURRENT MANAGEMENT OF THE AMENORRHEA-GALACTORRHEA SYNDROME

RAPHAEL JEWELEWICZ, M.D.* EARL A. ZIMMERMAN, M.D. Department of Obstetrics and Gynecology, Department of Neurology, and The Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, New York 10032

If a woman have milk, who is not with child, nor has brought forth, her menses are obstructed. -Hippocrates: Aphorism 39, Section V

NORMAL PHYSIOLOGY

The association of galactorrhea with amenorrhea has interested the medical profession for many years. I, 2 However, only recently was it discovered that prolactin is a distinct hormone 3, 4 which plays a major role in the etiology and pathophysiology ofthis syndrome. 5.9 The development of a sensitive and accurate radioimmunoassay5. 10, II for this hormone has increased appreciation of the hyperprolactinemic state with or without galactorrhea, and in many cases has aided greatly in the diagnosis and management of the disorder. In the last 5 years, the subject has been extensively reviewed in the medicalliterature. 5·9 • 12 Since this syndrome affects mostly women in the childbearing age, the obstetrician-gynecologist is usually the first physician faced with this problem. In this article we discuss our clinical experience with the diagnosis and treatment of amenorrheagalactorrhea over the last 5 years. At the onset we emphasize that one can only offer an approach to the problem in reference to treatment. The early diagnosis of prolactin-secreting microadenomas which interfere only with fertility has underscored our ignorance of the natural history of these tumors. Furthermore, the recent introduction of several new treatment modalities, incl uding the use of ergot alkaloids and microsurgery, will require time for full appreciation of their efficacy.

Prolactin was long recognized as an important hormone in lower vertebrates, but it was not until 1970 that prolactin was shown to be a distinct hormone in primates. 3 It is a protein hormone, synthesized and secreted by specific acidophilic cells in the anterior pituitary.13 Its molecular weight is approximately 21,000. 4 During the menstrual cyCle, prolactin levels are higher in the luteal phase than in the follicular phase. Several investigators have reported a midcycle surge of prolactin following the increase in estrogen levels and coinciding with the LH surge 7 ; however, this has not been substantiated by others. 14 Estrogens affect the lactotrophic cells and increase plasma prolactin levels. 15 Hyperplasia of the pituitary during pregnancy is associated with an increase in both the size and the number ofthe lactotrophic cells as a result of the increase in circulating estrogens. 16 Many types of stress (trauma, surgery) cause a considerable increase in prolactin levels. 17 Basal levels of prolactin in venous blood range from 1 to 25 ng/ml; the mean concentrations are slightly higher in women than in men. 9 It is of interest that there is circadian periodicity in prolactin concentration: it increases at night, reaches a maximal value between 1 A.M. and 6 A.M., and declines later in the morning. This pattern is not related to a specific phase of sleep, but is associated with sleep in general. 18 Prolactin levels increase during the last two trimesters of pregnancy, during the postpartum

Received December 5, 1977. *Reprintrequests: Raphael Jewelewicz, M.D., Columbia Uni· versity, 630 West 168th Street, New York, N. Y. 10032.

597

= 598

JEWELEWICZ AND ZIMMERMAN

TABLE 1. Causes of Galactorrhea Inhibition of PIF synthesis Drug-induced Phenothiazine derivatives Prochlorperazine (Compazine) Trifluoperazine (Stelazine) Thioridazine (Mellaril) Fluphenazine (Prolixin) Chlorpromazine (Thorazine) Trimeprazine (Temaril) Tricyclic antidepressants Amitriptyline (Triavil) Imipramine (Tofranil) Meprobamate (Equanil) Chlordiazepoxide (Librium) Haloperidol (Haldol) Reserpine (Serpasil) a-Methyldopa (Aldomet) Amphetamines Non-drug-induced Encephalitis or post-encephalitis Craniopharyngioma Tumor of the pineal gland Aneurysm Probably hypothalamic infarction Pseudotumor cerebri Inhibition of PIF transport Pituitary stalk section Tumors that secrete prolactin Pituitary tumors Chromophobe adenoma Associated with Cushing's syndrome Not associated with Cushing's syndrome Eosinophilic adenoma Associated with acromegaly Basophilic adenoma Non-pituitary tumors Excessive pituitary function without tumor Thyroid abnormalities Hypothyroidism Hyperthyroidism Gonadal abnormalities Physiologic or premature menopause Castration Removal of corpus luteum Withdrawal of gonadal steroids Estrogen-progestin combination Progesterone Progestin Neural stimulation Trauma to the skin and peripheral nerve Post-thoracotomy Postmastectomy Post-thoracoplasty Burns of the chest wall Herpes-Zoster Breast Small, chronic, breast abscess Cystic disease of the breast Oral or digital manipulation of the nipples Uterus or cervix Hysterectomy Uterine and adrenal tumors Spinal cord Tabes dorsalis Syringomyelia Psychogenic Pseudocyesis Miscellaneous Adrenal tumors Ovarian tumors Acute intermittent porphyria

June 1978

period, and particularly during lactation. 5. 19 An increase in prolactin levels during lactation is considered to be the mechanism by which ovulation is suppressed in breast-feeding mothers. Amniotic '"fluid contains very high levels of prolactin (up to 2 p.giml) , but its source and possible physiologic role are unknown. 6. 20 A multit':lde of drugs, mostly psychotropic drugs such as chlorpromazine, increase prolactin secretion and may cause galactorrhea. 21 A summary of known causes of galactorrhea is given in Table 1. HYPOTHALAMIC CONTROL OF PROLACTIN SECRETION

The hypothalamic control of prolactin secretion by the pituitary is predominantly inhibitory. Disruption of the hypophyseal portal system, which connects the anterior pituitary with the hypothalamus, or lesions affecting the medialbasal hypothalamus result in increased prolactin secretion, whereas the levels of other tropic hormones of the anterior pituitary are reduced. 19 The substance(s) which inhibits prolactin is called prolactin-inhibiting factor (PIF). Recent evidence suggests that dopamine formed by neurons in the arcuate nucleus in the medial-basal hypothalamus and secreted into portal blood22 is a major contributor to hypothalamic PIF activity. Dopamine may inhibit secretion by acting on receptors on lactotrophs in the anterior pituitary gland. 23 The administration of l-dopa, a precursor of dopamine, inhibits prolactin release,5. 24 and a direct action on the anterior pituitary has been confirmed by the inhibition by l-dopa of prolactin secretion after pituitary stalk section. 25 The administration of thyrotropin-releasing hormone causes a significant release of prolactin26 in addition to thyroid-stimulating hormone. A prolactinreleasing factor other than thyrotropin-releasing hormone is likely, since thyroid-stimulating hormone levels may be normal at a time when prolactin levels are elevated. Serotonin is also probably involved in prolactin release,27 but its mechanism is not known. CLINICAL ABNORMALITIES RELATED TO INCREASED PROLACTIN SECRETION

Galactorrhea was the only indicator of a possible disorder of prolactin secretion apparent to the clinician before immunoassays for prolactin became available. Although galactorrhea still remains the clinical hallmark of the disorder, it is now fairly well established that prolactin may

Vol. 29, No.6

CURRENT MANAGEMENT OF THE AMENORRHEA-GALACTORRHEA SYNDROME

be increased without recognizable clinical symptoms. In fact, only about 15% of female patients with elevated prolactin levels have gal actorrhea,28 and many patients with gross galactorrhea have normal prolactin levels. However, a pituitary tumor has been found in 50% of patients with significantly elevated prolactin levels. 29 At present the eponyms describing the various syndromes of amenorrhea and galactorrhea are only of historic interest. l , 2 Whenever amenorrhea and galactorrhea are found in conjunction with one another, the physician must rule out a pituitary tumor or a hypothalamic lesion. The association of this syndrome with diabetes insipidus points to a hypothalamic disorder affecting the secretion of gonadotropin-releasing hormone, PIF, and vasopressin. Clinical diabetes insipidus is not usually associated solely with destruction of the posterior lobe of the pituitary but requires destruction of the supraoptic and paraventricular nuclei or their pathways in the medial basal hypothalamus. 28 In a recent study it was found that 34% of women with amenorrhea-galactorrhea had radiographic evidence of a pituitary adenoma. 3o The adenomatous portion of the pituitary is the source of the hypersecreted hormoneY The tumors are usually chromophobic by tinctorial stain, although on occasion they may be acidophilic, particularly ifthey also secrete growth hormone. 3! Half of the tumors of acromegalic patients hypersecrete both hormones. 3! These tumors appear to grow very slowly over a span of many years and initially may produce few or no symptoms. The first clinical manifestation related to all pituitary tumors, whether or not they are associated with hyperprolactinemia, is a disturbance of gonadotropic function.:l2 Women in the reproductive age often develop irregular menses, oligomenorrhea, and then amenorrhea and galactorrhea. If such tumors occur prior to the age of menarche, primary amenorrhea may ensue. After menopause these early endocrine disturbances may not be appreciated and the patient may present with advanced hypopituitarism or visual field disturbances. Since amenorrhea and infertility and/or galactorrhea are among the earliest symptoms of a lesion in the hypothalamic-pituitary system, the gynecologist, as the first physician to be consulted, has an opportunity to recognize the problem at an early stage. Other common symptoms related to pituitary or parapituitary tumors are headaches, visual disturbances, and diplopia,

599

which may appear in more advanced stages of the disease. Depending on the cause, when there is destruction of more anterior pituitary function, patients develop cold intolerance and general weakness and fatigue as thyroid and adrenal deficiencies appear. Weight disturbance or diabetes insipidus may also be present in patients with hypothalamic disease. HOW DOES THE GYNECOLOGIST WORK UP THESE PATIENTS?

The possible association of galactorrhea with amenorrhea should be actively sought in a patient with menstrual irregularity. Patients with galactorrhea are often unaware of it. Therefore, the breast must be examined with milking pressure applied to the nipples. Once galactorrhea is found, blood prolactin levels need to be determined. Radioimmunoassays for prolactin are available in most medical centers and national commercial laboratories. Several resting samples on different days are desirable. In our own experience an initial single elevated value (less than 100 ng/ml) has been found in a normal person, possibly related to the stress of venipuncture, as repeat levels were normal. Normal levels of prolactin can also occasionally be found in patients with hyperprolactinemia as a consequence of falsely negative results (insensitive assay) or related to daily variations. Serial values obtained over several months were found useful in some patients with proven tumors whose levels ranged from 20 to 50 ng/ml. We have not found prolactin stimulation tests with chlorpromazine or thyrotropin-releasing hormone, or suppression with ldopa very helpful in distinguishing patients with lesions from normal subjects. These dynamic tests may be helpful in cases of suspected tumor when the prolactin levels are elevated and x-ray studies are normal or equivocal,31 or when a hypothalamic lesion is suspected and needs to be ruled out, especially when hyperprolactinemia cannot be explained by drug therapy or renal failure or by some obvious cause such as pregnancy. In most of the published series, when prolactin levels were above 200 ng/ml, a pituitary adenoma was found in over 90% of patients even when radiologic findings were normal. 33 Radiologic evaluation of the sellar region is essential in all patients with significant hyperprolactinemia or whenever a pituitary lesion is suspected. Recent experience with polytomography of the sella turcica has revealed that many such lesions are missed on routine x-rays of the skull. In a recent study it was shown that,

600

JEWELEWICZ AND ZIMMERMAN

of 20 hyperprolactinemic patients who had evidence of a pituitary tumor on polytomography, 14 had a "normal" lateral skull x_ray.34 Therefore, whenever x-rays seem indicated, polytomography is ordered. Serial tomograms are usually not desirable as changes occur slowly, the test is expensive, and delivers about 10 times the radiation delivered for plain films. Yearly coneddown lateral views of the sella may be desirable if serial films are needed. If tomograms are indicative or suggestive of a pituitary or parapituitary tumor, thyroid function is screened by blood tests, and the visual fields are examined. These tests are useful guides to additional endocrine dysfunction and hypothalamic disturbance. The patient is then referred for further endocrine and neurologic evaluation. The physician should keep in mind the small possibility that the syndrome can be caused by a hypothalamic lesion which is not associated with obvious diabetes insipidus, visual field defects, or other neurologic symptoms. Computerized axial tomography of the brain with special attention to the sella and hypothalamus may be reassuring, if negative, in ruling out a hypothalamic tumor and in some cases suprasellar extension of a pituitary adenoma or even the empty sella syndrome. At the present time, however, contrast studies such as cerebral arteriography and/or pneumoencephalography may be required for adequate evaluation of this region. It is often advantageous to manage these patients as a team including a gynecologist, endocrinologist, neurologist, neurosurgeon, and radiologist who understand the specific problems involved.

WHO SHOULD BE TREATED?

In many patients with amenorrhea-galactorrhea and elevated prolactin levels a slight irregularity suggestive of a small pituitary tumor is found on poly tomography. However, these patients are usually asymptomatic except for the lack of menses, the presence of galactorrhea, and probably infertility. In such a patient treatment is often dictated by her desire. If the patient is not interested in pregnancy, a semiannual follow-up, including thyroid and prolactin determinations and visual field examination, may be all that is required. The patient is carefully examined and questioned for the occurrence of any visual disturbances or headaches. A good rapport with the patient and reassurance may be all that is needed. Since these tumors grow

June 1978

very slowly, tomograms should probably not be repeated for several years. In the great majority of patients these tumors are probably sedentary and cause no changes over many years. However, if a considerable increase in prolactin is found, if the patient experiences headaches or visual field disturbances, or if other changes occur, further evaluation may be required. The problem has different implications in the patient interested in establishing a pregnancy. During pregnancy physiologic enlargement of the pituitary occurs, mainly due to glandular hypertrophy.35 Normally this pituitary hypertrophy does not affect the adjacent structures and compression of the optic chiasma does not occur. However, when an adenoma is present in the pituitary, expansion of the tumor and/or normal gland due to pregnancy may press on the optic chiasma or its blood supply and cause visual symptoms. 36 In most instances these symptoms regress spontaneously within several days after delivery.37 But there have been several reports in the literature that emergency hypophysectomy in pregnant patients with pituitary tumors was required to alleviate pressure on the optic chiasma and avert permanent visual compromise. 38 The need for such drastic measures is quite rare, and the great majority of patients with microadenomas have uneventful pregnancies. In the presence of radiologic or neurologic evidence of extrasellar extension of a pituitary tumor or a parapituitary tumor the patient should be fully investigated and treated before ovulation is induced and pregnancy attempted. However, when the tumor is small (a "microadenoma"), the sella turcica is intact or only minimally affected, and neurologic symptoms are absent, ovulation may be induced medically and the patient followed closely during pregnancy. This approach is not universally accepted, and several investigators and clinicians believe that any patient with a suspected pituitary tumor, no matter how small, should be operated upon prior to attempting pregnancy.39 Transsphenoidal excision of microadenomas, using microsurgical techniques, gives excellent results and very low morbidity. After removal of the microadenoma, 70% of patients resume normal ovulatory cycles and conceive spontaneously.39, 40 The other means of treatment is radiation therapy, which at present appears as effective for microadenomas as does neurosurgeryY The disadvantage of radiotherapy is the time required for reduction of prolactin levels (months or years).

Vol. 29, No.6

CURRENT MANAGEMENT OF THE AMENORRHEA·GALACTORRHEA SYNDROME

601

INDUCTION OF OVULATION IN PATIENTS WITH

MANAGEMENT OF THE PREGNANT PATIENT WITH A

AMENORRHEA-GALACTORRHEA

PITUITARY TUMOR

Amenorrhea and galactorrhea may be a final stage in ovulatory and menstrual disorders caused by prolactin-secreting pituitary tumors. Initially the patient may ovulate, but she gradually develops an inadequate luteal phase, oligo-ovulation, and, finally, anovulation with resultant amenorrhea. 28 , 42 A few patients have conceived spontaneously and others have been successfully treated with clomiphene citrate on the assumption that their oligo-ovulation was "idiopathic," and many conceived. However, with a full-blown syndrome of amenorrheagalactorrhea and elevated prolactin levels, the chances of spontaneous conception are small. In these patients, after adequate work-up, ovulation must be induced. Generally, when the prolactin level is high, clomiphene citrate or its combination with human chorionic gonadotropin is not effective. 43 Human menopausal gonadotropin and human chorionic gonadotropin are effective, yielding a pregnancy rate of about 60%. However, this therapy is complex and expensive. 44 The introduction of bromocriptine (2-brom-aergocriptine), a dopamine agonist, has revolutionized the treatment ofhyperprolactinemic amenorrhea-galactorrhea and infertility45 in other countries. Bromocriptine (2.5 mg to 7.5 mg daily) acts directly on the lactotrophs in the pituitary to suppress prolactin secretion. The side effects are minimal: postural hypotension, dizziness, nausea, and vomiting. These unpleasantries disappear within several days to 1 week. Over 90% of women receiving bromocriptine for hyperprolactinemic amenorrhea-galactorrhea resume ovulatory cycles within 6 to 8 weeks of treatment. 46 This drug is given until pregnancy is confirmed, then it is discontinued. This results in a gradual increase in blood prolactin levels, which does not interfere with pregnancy. The possibility of a teratogenic effect of bromocriptine has been raisedY It has been suggested that bromocriptine be given intermittently during the follicular and preovulatory phases of the cycle in patients who resume menses and ovulation, thus avoiding exposure of the conceptus to the drug. This regimen was as effective as continuous treatmentY Most recently, bromocriptine treatment was extended to normoprolactinemic amenorrheic patients with promising results. 47 Although bromocriptine is used extensively in Europe and Canada, in the United States its use is still limited to scientific investigation.

Some patients with small pituitary tumors conceive spontaneously, whereas in others ovulation may be induced medically by the use of clomiphene citrate, gonadotropins, or ergolines. 48 Even if a patient was treated for a pituitary tumor prior to pregnancy, she should be followed closely. Pregnant patients with a suspected microadenoma who have not been treated should be followed carefully for an expanding pituitary tumor and the appearance of visual or neurologic symptoms. In addition to routine prenatal follow-up examinations, these patients are carefully questioned for visual disturbances and headaches. Visual fields are routinely tested at monthly intervals starting in the second trimester of pregnancy. Most of the patients have no problems, and the pregnancy, labor, and parturition are uneventful. If visual symptoms appear, the patient should be hospitalized and followed closely. Neurosurgical consultation should be obtained, as sellar decompression by transsphenoidal surgery may become necessary to save vision. 38 We avoided surgery in one patient by the administration of high doses of glucocorticoids (dexamethasone, 4 mg three times daily), which probably reduced swelling and pressure on the optic chiasma. 48 If there is premature labor adrenal steroids are also useful to reduce pulmonary problems in the newborn. 49 If visual deterioration is severe or progresses, hypophysectomy is recommended. The possibility of termination of the pregnancy must be kept in mind, since in most instances there is spontaneous regression of visual symptoms after delivery,37 Improvement of visual fields following bromocriptine therapy was recently reported iIi two nonpregnant patients with amenorrhea-galactorrhea. 50 Since the drug may reduce pituitary size, Besser et al. 46 have speculated that daily doses of 60 mg may be useful in patients who develop visual symptoms during pregnancy. POSTPARTUM FOLLOW-UP

Follow-up of patients with pituitary or parapituitary tumors after delivery is not different from that during the nonpregnant state. As noted, in most cases where visual symptoms appeared during pregnancy, regression was spontaneous within several days after delivery. At present there is no other information on the long-term effects of pregnancy on pituitary tumors. A ques-

JEWELEWICZ AND ZIMMERMAN

602

tion that frequently arises in these patients is whether to breast-feed, and at present no adequate information is available on which to base an answer. Some believe that it is contraindicated since suckling stimulates the lactotrophs and theoretically might further aggravate the tumor. Others believe that lactation for the customary limited time is unlikely to further a tumor already stimulated by pregnancy. Among our patients with pituitary tumors who conceived, several nursed without any problems. CONCLUSIONS

Greater awareness by physicians ofthe amenorrhea-galactorrhea syndrome and its relationship to pituitary and/or parapituitary tumors, and new diagnostic techniques, have increased considerably the number of patients diagnosed. When the tumors are small, causing no apparent symptoms except for amenorrhea and/or galactorrhea, no treatment may be needed. Whenever pregnancy is contemplated, obvious tumors should be adequately treated before pregnancy is attempted. However, in cases of microadenomas, where the only symptoms are hyperprolactinemia, amenorrhea, and galactorrhea, ovulation may be induced medically with good prospects of pregnancy. During the pregnancy these patients are followed carefully for an emerging tumor and the appearance of neurologic and visual symptoms. The majority of patients will have uneventful pregnancies. Those who develop symptoms can be treated conservatively or, if necessary, by microsurgery. The development of new neurosurgical techniques and the introduction of the ergolines have improved significantly the prospects of resumption of normal menstrual function and fertility in women with amenorrhea-galactorrhea.

SUMMARY

Management of the amenorrhea-galactorrhea syndrome has changed considerably in the last 5 years. Better understanding of the neuroendocrine physiology of the central nervous system in general, and of the hypothalamic-pituitary region in particular, have contributed significantly to our understanding of the pathophysiology of this syndrome. Greater awareness by physicians, improved neuroradiologic techniques, and the development of immunoassays for prolactin have markedly improved our diagnostic

June 1978

abilities. Many more patients are being diagnosed as having a pituitary tumor. The recent introduction of microneurosurgical techniques and the new medications (ergolines) are changing the treatment of this syndrome. Women in the childbearing age-who are affected most often---can expect successful treatment in the majority of cases with res~mption of normal menstrual function and fertility. However, certain risks are still posed, particularly during pregnancy. In spite of improved diagnosis and treatment, the natural history of prolactin-secreting pituitary tumors and the long-range effects are still not fully appreciated. More experience in time will be needed before the indications for and the efficacy of various treatment regimens are fully known. REFERENCES 1. Argonz J, del Castillo EB: A syndrome characterized

2.

3.

4.

5. 6. 7.

8.

9.

10. 11.

12.

13.

by estrogenic insufficiency, galactorrhea and decreased urinary gonadotropins. J Clin Endocrinol Metab 13: 79, 1953 Forbes AP, Henneman PH, Griswold GC, Albright F: Syndrome characterized by galactorrhea, amenorrhea, and low urinary FSH: comparison with 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 170:45, 1970 Niall HD, Hogan MC, Tregear GW, Segal GV, Hwang P, Friesen H: The chemistry of growth hormone and the lactogenic hormone. Recent Prog Horm Res 29:387,1973 Frantz AG, Kleinberg DL, Noel GL: Studies on prolactin in man. Recent Prog Horm Res 28:527,1972 Friesen H, Hwang P: Human prolactin. Annu Rev Med 24:251, 1973 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 of the Fourth Tenovus Workshop, Edited by AR Boyns, K Griffith. Cardiff, Wales, Alpha Omega Alpha Publishing, 1977, p 81 Boyd AE III, Reichlin S, Turksoy R: Galactorrhea-amenorrhea syndrome: diagnosis and therapy. Ann Intern Med 87:165, 1977 Antunes JL, Housepian EM, Frantz AG, Holub DA, Hvi R, Carmel PW, Quest PD: Prolactin-secreting pituitary tumors. Ann Neurol 2:148, 1977 Hwang P, Guyda H, Friesen H: A radioimmunoassay for human prolactin. Proc Nat! Acad Sci USA 68:1902,1971 Jacobs LS, Mariz IK, Daughaday WH: A mixed heterologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 34:484, 1972 Spark RJ, Pallotta J, Naftolin F, Clemens R: Galactorrhea-amenorrhea syndromes: etiology and treatment. Ann Intern Med 84:532, 1976 Pasteels JL, Ganesset P, Dangny A, Ectors F, Nicoll CS, Varavndhi P: Morphology of the lactotropes and somatotropes of man and rhesus monkeys. J Clin Endocrinol Metab 34:959, 1972

Vol. 29, No.6

CURRENT MANAGEMENT OF THE AMENORRHEA-GALACTORRHEA SYNDROME

14. Ehara G, Siler T, VandenBerg G, Sinha YN, Yen SSC: Circulating prolactin levels during the menstrual cycle: episodic release and diurnal variation. Am J Obstet GynecoI117:962,1973 15. Abu-Fadil S, DeVane G, Siler T, Yen SSC: Effect of oral contraceptive steroids on pituitary prolactin secretion. Contraception 13:79, 1976 16. GoluboffLG, Ezrin C: Effect of pregnancy on the somatotroph and the prolactin cell of the human adenohypophysis. J Clin Endocrinol Metab 29:1533,1969 17. Noel GL, Suh KK, Stone JG, Frantz AG: Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 35: 840, 1972 18. Sassin JF, Frantz AG, Weitzman ED, Kapen S: Human prolactin: 24 hour pattern with increased release during sleep. Science 177:1205, 1972 19. Macleod RM: Regulation of prolactin secretion. In Frontiers in Neuroendocrinology, Vol 4, Edited by L Mantini, WF Ganong. New York, Raven Press, 1975, p 169 20. Tyson JE, Hwang P, Guyda H, Friesen HG: Studies of prolactin secretion in human pregnancy. Am J Obstet GynecoI113:14,1972 21. Archer DF: Current concepts of prolactin physiology in normal and abnormal conditions. Fertil Steril 28:125, 1977 22. Ben-Jonathan N, Oliver C, Weiner HJ, Mical R, Porter JC: Dopamine in hypophysial portal plasma of the rat during the estrous cycle and throughout pregnancy. Endocrinology 100:452, 1977 23. Shaar CJ, Clemens JA: The role of catecholamines in the release of anterior pituitary prolactin in vitro. Endocrinology 95:1202, 1974 24. Kleinberg DL, Noel GL, Frantz AG: Chlorpromazine stimulation and L-dopa suppression of plasma prolactin in man. J Clin Endocrinol Metab 33:873, 1971 25. 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 26. Jacobs LS, Synder FJ, Utiger PD, Daughaday WH: Prolactin response to thyrotropin-releasing hormone in normal subjects. J Clin Endocrinol Metab 36:1064, 1973 27. Frohman LA: Neurotransmitters as regulators of endocrine function. Hosp Pract 10:54, 1975 28. Zimmerman EA, Robinson AG: Hypothalamic neurons secreting vasopressin and neurophysin. Kidney Int 10:12, 1971 29. L'Hermite M, Caufriez A, Vekemans M, Denayer P, Robyn C: Pharmacological and pathological aspects of human prolactin secretion. Prog Reprod BioI 2:244, 1977 30. Kleinberg DL, Noel GL, Frantz AG: Galactorrhea: a study of 235 cases including 48 with pituitary tumors. N Engl J Med 296:589, 1977 31. Zimmerman EA, Defendini R, Frantz AG: Prolactin and growth hormone in patients with pituitary adenomas: a correlative study of hormones in tumor and plasma by immunoperoxidase technique and radioimmunoassay. J Clin Endocrinol Metab 38:577,1974 32. Hankinson J, Banna M: Pituitary and parapituitary tumors. In Major Problems in Neurology, Vol 16. Philadelphia, WB Saunders Co, 1976, p 18

603

33. Martin JB, Reichlin S, Brown GM: Clinical Neuroendocrinology. Philadelphia, FA Davis Co, 1977, p 141 34. Vezina JL, Sutton TJ: Prolactin secreting adenomas: roentgenologic diagnosis. Am J Roentgenol Radium Ther Nucl Med 120:46, 1974 35. Erdheim J, Stumme E: Uber die Schwangerschaftsveriinderung der hypophyse. Beitr Pathol 46:1,1909 36. Child DF, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin and pituitary tumors. Br Med J 4:87,1975 37. Falconer MA, Stafford-Bell MA: Visual failure from pituitary and parasellar tumors occurring with favorable outcome in pregnant women. J Neurol Neurosurg Psychiatry 38:919, 1975 38. Kajtar T, Tomkin GH: Emergency hypophysectomy in pregnancy after induction of ovulation. Br Med J 4:88, 1971 39. Hardy J: Transsphenoidal surgery of hypersecreting pituitary tumors. In Diagnosis and Treatment of Pituitary Tumors, Edited by PW Kohler, GT Ross. New York, American Elsevier, 1973, p 179 40. Trijillo J, Brodkey J, Kaufman B, Pearson OH: Results of surgical treatment of galactorrhea-amenorrhea syndrome. Presented at the Fifty-Ninth Annual Meeting of the Endocrine Society, Chicago Ill, 1977, abstr 330 41. Kliman B, Kjellberg RN: Proton beam therapy of pituitary tumors in women with galactorrhea-amenorrhea and elevated serum prolactin. Presented at the Fifty-Ninth Annual Meeting of the Endocrine Society, Chicago Ill, 1977, abstr 329 42. Seppala M, Hirvonen E, Ranta T: Hyperprolactinemia and luteal insufficiency. Lancet 1:229, 1976 43. Husami N, Jewelewicz R, Vande Wiele RL: Pregnancy in patients with pituitary tumors. Fertil Steril 28:920, 1977 44. Jewelwicz R: Management of infertility resulting from anovulation. Am J Obstet Gynecol 122:909, 1975 45. Del Pozo E, Varga L, Wyss M, Tolis G, Friesen H, Wenner R, Vetter L, Vettweiler A: Clinical and hormonal response to bromocriptin (CB-154) in the galactorrhea syndrome. J Clin Endocrinol Metab 39:18,1974 46. Besser GM, Thorner MO, Wass JAH, Mortimer CN, Yeo T: Therapeutic use of bromocriptin and growth hormone release inhibiting hormone. Prog Reprod BioI 2:261, 1977 47. Coelingh Bennink HJT, Van Der Steeg HJ: Ovulation induction by bromocryptine (abstr). Fertil Steril '28:347, 1977 48. Jewelewicz R, Zimmerman EA, Carmel PW: Conservative management of a pituitary tumor during pregnancy following induction of ovulation with gonadotropins. Fertil Steril 28:35, 1977 49. Liggins GC, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50: 515, 1972 50. Vaidya R, Aloorkar S, Sheth A: Therapeutic regression of putative pituitary hyperplasia and/or microadenoma with CB-154 (abstr). Fertil Steril 28:363, 1977