PRIMARY AMENORRHEA AND PITUITARY ADENOMAS

FERTIUTY AND STERILITY Copight c 1981 The American Fertility Society Vol. 35, No.6, June 1981 Printed in U.SA. PRIMARY AMENORRHEA AND PITUITARY ADENOMAS CAROLYN B. COULAM, M.D.* EDWARD R. LAWS, JR., M.D.t CHARLES F. ABBOUD, M.D.* RAYMOND V. RANDALL, M.D.* Department of Obstetrics and Gynecology, Department of Neurologic Surgery, Division of Endocrinology, Metabolism and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905 From 1972 to 1980,210 patients underwent transsphenoidal operation for removal of a prolactin-secreting tumor. Eight of the patients had primary amenorrhea. All eight patients had had a normal thelarche and pubarche without menarche, and all eight had hyperprolactinemia and abnormal findings on sella turcica tomography. After operation, only one patient did not have persistent hyperprolactinemia, and this patient was the only one who began spontaneous menses. The data indicate that, although prolactin hypersecretion interferes with menstrual function, it does not alter other pubertal development and that, if the source of the excessive prolactin can be removed, the removal alone may initiate spontaneous menses. In this report, however, patients with prolactin-secreting adenomas and primary amenorrhea had a high incidence of persistent hyperprolactinemia after operation (seven of eight patients). Fertil SteriI35:615, 1981 Among patients with primary amenorrhea, the incidence of pituitary tumors has been estimated to be approximately 2%.1 The association of amenorrhea and hyperprolactinemia among patients with pituitary tumors has been reported to be as high as 75%.2 Although four patients with primary amenorrhea associated with hyperprolactinemia have recently been described, 3 there have been no reports documenting the outcome of therapy for patients who have primary amenorrhea and pituitary adenoma. We wish to report our experience with eight patients who had primary amenorrhea and hyperprolactinemia and who underwent transsphenoidal operation for removal of a pituitaryadenoma. Received July 17, 1980; revised and accepted January 14, 1981. *Reprint requests: Carolyn B. Coulam, M.D., Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. t Department of Neurologic Surgery. *Division of Endocrinology, Metabolism and Internal Medicine. 615 MATERIALS AND METHODS s. Between January 31, 1972, and January 31, 1980, 210 patients (175 women and 35 men) underwent transsphenoidal operation for removal of a prolactin-secreting pituitary adenoma. Of the 175 women, 8 had primary amenorrhea. Their clinical data describing age at onset of thelarche, pubarche, and galactorrhea, as well as age at the time of diagnosis of pituitary adenoma, are outlined in Table 1. Prolactin Determinations. The assay for determining plasma levels of prolactin utilized a radioimmunoassay technique previously described. 4 The thotropin-releasing hormone stimulation test was performed by administering thotropinreleasing hormone, 400 mg intravenously as a bolus, and serum was sampled at 0, 30, and 60 minutes for the determination of prolactin concentration. Surgical Technique. A standard sublabial, transseptal microneurosurgical approach was used in each patient. The goal of operation was complete removal of the pituitary adenoma and

616 COULAM ET AL. June 1981 1 2 3 4 5 6 7 8 TABLE 1. Clinical Data of s with Primary Amenorrhea and Pituitary Adenoma Thelarche and pubarche 13 12 13 10 Age at onset of Galactorrhea Age at diagnosis of adenoma 17 20 18 18 None 18 22 27 13 15 As teenager; none 36 since On examination 20 only On examination 24 only preservation of normal anterior and posterior pituitary function. A tumor was discovered and removed in all but one patient. In this patient, a tumor was not found despite a thorough intrasellar exploration and multiple biopsy specimens, all of which revealed normal pituitary tissue. There were no complications of surgery, and postoperative hypopituitarism or diabetes insipidus did not occur. RESULTS s. All eight patients had had a normal thelarche and pubarche without subsequent menarche. Half of the patients had histories of galactorrhea ranging from less than 1 year to 10 years. In two patients, galactorrhea was noted only at the time of examination, and in two patients, no galactorrhea was demonstrable, although one of these patients (patient 6) gave a history of noting galactorrhea as a teenager but not subsequently (Table 1). All patients demonstrated hyperprolactinemia, abnormal findings on tomography of the sella turcica (Table 2), and no other evidence of abnormal basal endocrine function (Table 3). Results of visual field examination were normal in each patient. The responses obtained from insulin tolerance tests and thotropin-releasing hormone stimulation tests are shown in Table 4. Pathologic Findings. Microadenomas (pituitary adenomas ~10 mm in diameter) ranging from 2 to 7 mm in diameter were removed from five patients (Table 5). One of these patients had an associated, partially empty sella syndrome. Suprasellar extension was documented at surgery in two patients with large tumors. One pathologic report described normal pituitary tissue, even though a pituitary tumor was seen at surgery. Follow~Up. Postoperative observation continued for as long as 3 years (Table 6). Only one patient (patient 2) did not have persistent hyperprolactinemia postoperatively, and this patient began spontaneous menses 5 weeks after operation. Her subsequent menses were regular, occurring every 28 days. * Three patients subsequently received radiation therapy. Only one pregnancy occurred, and this patient (patient 6) conceived while taking bromocriptine (Table 6). DISCUSSION Although several investigators have attempted to estimate the prevalence of pituitary adenomas in patients with various endocrinologic symptoms such as secondary amenorrhea,5-7 none has addressed the question in primary amenorrhea. Between 10% and 30% of all women complaining of menstrual irregularity, including secondary amenorrhea, have altered secretion of prolactin,5,8 and 35% of those with galactorrhea and amenorrhea have evidence of pituitary tumor on *She became pregnant and delivered, at term, 18 months after operation. TABLE 2. Roentgenographic Data of s with Primary Amenorrhea and Pituitary Adenoma 1 2 3 4 5 6 7 8 acomputed tomography. Prolactin nglml 91.7 264 2600 586 187 107 376 68.5 Results of sellar tomography eta scan Angiography Enlarged sella with decalcification Not done Negative Sellar expansion with deminerali- Not done Negative zation Enlarged sella with decalcification Positive Positive Sellar expansion with deminerali- Not done Negative zation Enlarged sella with asymmetry Negative Positive Intrasellar tumor Not done Positive Enlarged sella Positive Not done Sellar asymmetry Positive Not done

Vol. 35, No.6 PRIMARY AMENORRHEA AND PITUITARY ADENOMAS 617 TABLE 3. Endocrine Data of s with Primary Amenorrhea and Pituitary Adenoma Basal prolactin Follicle-stimu- Luteinizing hormone lating hormone Estrogen Thoxine A.M. Corticosteroids P.M. nglml fllildl fllildl 1 91.7 9.6 10 2 264 10 3 3 2600 5.3 6.7 4 586 25.2 2.7 5 187 16.1 2 6 107 16.8 2.1 7 376 3.6 <1 8 68.5 13.9 6.4 Normal,,;;;23 <2-25 1.4-15 ngldl fllildl fllildl 3.4 10.4 10 15 6.0 8.3 13 8.5 3.1 4.7 14 9.5 6.5 7.7 9 12 <3 5.3 25 16 4.4 5.6 17 13 7.5 5.8 15 14 4.4 8.0 23 15 4-60 5-13.5 7-28 2-18 radiologic examination of the sella turcica. 9 In one author's experience,3 4 of 29 patients with primary amenorrhea had hyperprolactinemia, and in only 1 of the 4 was a pituitary tumor demonstrated at surgery (although the tumor was not identified histologically). These four patients with primary amenorrhea have been reported to represent about 3% of women with hyperprolactinemia.3 In the present series, two of the eight patients had suprasellar extension of their pituitary adenomas (Table 5), representing a higher proportion of larger tumors than that described by others. 10 This observation may be important in understanding the natural history and growth rate of these tumors. It has been proposed that the recent increase in the diagnosis of pituitary adenomas is most likely due to advances in diagnostic technology.ll Prepubertal girls not having the clinical landmarks of menstrual irregularity or galactorrhea to prompt the use of the new diagnostic procedures would be expected to have large tumors at the time of eventual diagnosis. Two large studies of autopsy findings have given incidences of asymptomatic pituitary adenoma of 9% and 22.5%.12, 13 However, to date, there is no similar autopsy study of women with amenorrhea and galactorrhea. There are isolated reports of tumors becoming manifest after many years of amenorrhea (23 years in one study).14 In the same study,14 however, five macroadenomas were diagnosed after amenorrhea of 2 years or less. The growth rates of these tumors, therefore, appear to be variable. Our experience in treatment is in agreement with that of Jaquet et al.,15 who reported that clinical response was related to tumor size. Hardy et al. 16 reported transsphenoidal microsurgical treatment of80 patients with prolactin-producing pituitary adenomas, of whom five had primary amenorrhea. Postoperatively, three began to menstruate. Hardy17 has now operated upon 14 patients with primary amenorrhea, and eight of these began to menstruate following operation. In the present series, only one patient had a normal level of serum prolactin after the operation, and this patient was the only one to menstruate spontaneously. In contrast, in another study,18 41 (79%) of 52 women less than 50 years old who had secondary amenorrhea associated with a prolactinoma of 10 mm or less in diameter had return of menses, 2 patients became pregnant without antecedent menses, and 2 were lost to follow-up. Seven patients who did not have a return of menses had persistent elevation of serum prolactin values after operation. The poor rate of clinical resolution in our series might be accounted for in TABLE 4. Pituitary Reserve Testing of s with Primary Amenorrhea and Pituitary Adenoma Insulin tolerance test Thotropin-releasing hormone stimulation Glucose Human growth hormone Corticosteroids Thoid-stimulating hormone Prolactin 1 Normal Normal Normal Normal Abnormal 2 Normal Normal Normal Normal Abnormal 3 Normal Normal Normal Normal Abnormal 4 Not done Not done Not done Not done Not done 5 Normal Normal Normal Normal Abnormal 6 Not done Not done Not done Not done Not done 7 Normal Normal Normal Normal Abnormal 8 Normal Normal Normal Normal Abnormal

618 COULAM ET AL. June 1981 TABLE 5. Pathologic Findings in s with Primary Amenorrhea and Pituitary Adenoma Finding 1 Microadenoma (2 mm) 2 Microadenoma (7 mm) 3 Macroadenoma (15 mm) with suprasellar extension 4 Microadenoma (5 mm) 5 Cystic macroadenoma with 1 ml of fluid and suprasellar extension 6 Microadenoma with partially empty sella 7 Macroadenoma (diffuse intrasellar tumor) 8 'Normal pituitary (no adenoma found) part by concomitant lactotroph hyperplasia in the "normal" gland. This was noted by Ezrin et al.19 in of 15 pituitary glands harboring prolactinsecreting. tumors. All eight of our patients had spontaneous and appropriate thelarche and pubarche. This observation suggests that either (1) the excess prolactin developed during puberty (after thelarche and pubarche but before menarche) or (2) the hyperprolactinemia developed before puberty but did not cause a disturbance of the hypothalamicpituitary-gonadal axis of sufficient magnitude to interfere with- the initiation of puberty. It might be tempting to speculate that the increase in estrogen during puberty is related to or evokes the initiation of hyperprolactinemia. Evidence against this speculation is the presence of relatively low levels of estrogen in the sera of our patients (Table 3). Most investigators have ascribed the hypogonadism to defects in gonadotropin regulation,20 although others have postulated a direct gonadal effect of prolactin.21 The data on our eight patients indicate that none had low serum levels of follicle-stimulating hormone and that only one had a low value for luteinizing hormone, whereas five had low serum levels of estrogen. These data suggest that the low levels of estrogen are a result of an inhibitory effect of prolactin at the ovarian level and that the low production of steroid then inhibits the central cyclicity of gonadotropin secretion. Moreover, the amelioration of this defect and the onset of spontaneous menses in the one patient who became normoprolactinemic suggest that the hypogonadism can be reversed by decreasing the serum prolactin level. This concept is supported by the observation that the one postoperative pregnancy occurred in a hyperprolactinemic patient when serum prolactin levels were decreased by bromocriptine. Thus, in our patients with primary amenorrhea and pituitary adenoma, transsphenoidal pituitary surgery established the diagnosis of pituitary adenoma and removed the mass effect of the tumor in seven of eight patients. Further measures are usually necessary to correct the physiologic abnormality. Earlier diagnosis and therapy, when the tumors are smaller, may be more likely to result in normal postoperative values for prolactin. This, in tum, should prompt earlier and more aggressive investigation of patients with primary amenorrhea, and such investigation should include measurement of levels of plasma TABLE 6. Follow-Up of s with Primary Amenorrhea and Pituitary Adenoma Postoperative prolactin concentration 1 Wk 3Mo 6Mo 1 Yr 2Yr 3 Yr Menses Other treatment nglml 1 97.7 37.3 38.2 26.4 24.8 4.5 None, treatment with Bromocriptine began 21/2 oral contraceptives postop 2 10.1 Spontaneous, 5 wk postop, Pregnancy, delivered 3.6 kg boy every 28 days 18 mo postop 3 988 764 313 194 None, treatment with Radiation treatment (4500 rads) oral contraceptives 6 mo postop; bromocriptine recommended 2 postop 4 492 134.7 None Radiation treatment (4500 rads) 3 mo postop; bromocriptine recommended 6 mo postop 5 48.3 46.2 43.9, 108 3.0 None Bromocriptine began 18 mo postop with subsequent regular menses 6 19.0 30.6 None Bromocriptine began 6 mo postop (delivered 3.3 kg girl, 18 mo postop) 7 1 67.0 None None 8 54.4 52.9 None Bromocriptine recommended 4 mo postop with subsequent regular menses

Vol. 35, No.6 PRIMARY AMENORRHEA AND PITUITARY ADENOMAS 619 prolactin and polytomograms of the sella turcica, and high resolution computed tomography with contrast medium. REFERENCES 1. McDonough PG: Pediatric and adolescent gynecology: menarchal delay. In Current Problems in Obstetrics and Gynecology, Vol 1, No 1, Edited by RW Kistner. Chicago, Year Book Medical Publishers, 1977, p 1 2. Nader S, Mashiter K, Doyle FH, Joplin GF: Galactorrhoea, hyperprolactinaemia and pituitary tumours in the female. Clin Endocrinol (OxO 5:245, 1976 3. Kemmann E, Jones JR: Hyperprolactinemia and primary amenorrhea. Obstet Gynecol 54:692, 1979 4. Kao PC, Jiang N-S, Abboud CF: Radioimmunoassay of human homologous prolactin in serum with commercially available reagents. Clin Chern 23:1563, 1977 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. Tyson JE, Zacur HA: Diagnosis and treatment of abnormal lactation. Clin Obstet Gynecol 18:65, 1975 7. Spark RF, Pallotta J, Naftolin F, Clemens R: Galactorrhea-amenorrhea syndromes: etiology and treatment. Ann Intern Med 84:532, 1976 8. Canales ES, Forsbach G, Soria J, Zarate A: Infertility due to hyperprolactinemia and its treatment with ergocryptine. Fertil Steril 27:1335, 1976 9. Bergh T, Nillius SJ, Wide L: Hyperprolactinaemia in amenorrhoea: incidence and clinical significance. Acta Endocrinol (Kbh) 86:683, 1977 10. Chang RJ, Keye WRJr, YoungJR, Wilson CB, Jaffe RB: Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977. Coulam CB, Annegers JF, Abboud CF, Laws ER Jr, Kurland LT: Pituitary adenoma and oral contraceptives: a case-control study. Fertil Steril 31:25, 1979 12. Costello RT: Subclinical adenoma of the pituitary gland. Am J Pathol 12:205, 1936 13. McCormick WF, Halmi NS: Absence of chromophobe adenomas from a large series of pituitary tumors. Arch Pathol 92:231, 1971 14. Rowe TC, Shearman RP, Fraser IS: Antecedent factors and outcome in amenorrhea-galactorrhea. Obstet Gynecol 54:535, 1979 15. J aquet P, Grisoli F, Guibout M, Lissitzky J -C, Carayon P: Prolactin secreting tumors: endocrine status before and after surgery in 33 women. J Clin Endocrinol Metab 46:459, 1978 16. Hardy J, Beauregard H, Robert F: Prolactin-secreting pituitary adenomas: transsphenoidal microsurgical treatment. In Progress in Prolactin: Physiology and Pathology, Vol 2, Edited by C Robyn, M Harter. New York, Elsevier North Holland, 1978, p 361 17. Hardy J: Personal communication 18. Randall RV, Laws ER Jr, Abboud CF: Unpublished data 19. Ezrin C, Kovacs K, Horvath E: Hyperprolactinemia: morphologic and clinical considerations. Med Clin North Am 62:393, 1978 20. Murray FT, Osterman J, Sulewski J, Page R, Bergland R, Hammond JM: Pituitary function following surgery for prolactinomas. Obstet Gynecol 54:65, 1979 21. McNatty KP, Sawers RS, McNeilly AS: A possible role for prolactin in control of steroid secretion by the human Graafian follicle. Nature 250:653, 1974