AMENORRHEA FOLLOWING THE USE OF ORAL CONTRACEPTIVES

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1 FERTILITY AND STERILITY Copyright' 1977 The American Fertility Society Vol. 28, No.7, July 1977 Printed in U.S.A. AMENORRHEA FOLLOWING THE USE OF ORAL CONTRACEPTIVES JACQUES VAN CAMPENHOUT, M.D.* PIERRE BLANCHET, M.D.t HUGUES BEAUREGARD, M.D. SAID PAPAS, M.D.t Infertility Center, Department of Obstetrics and Gynecology, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada Clinical aspects and the incidence of the various underlying etiologic factors were studied in 86 patients with post-oral contraceptive amenorrhea. Patients were divided into two groups according to the presence or absence of detectable galactorrhea. Group I was composed of 55 amenorrheic patients without detectable galactorrhea and group II included 31 patients with amenorrhea associated with galactorrhea. Both groups were comparable for age, gravidity, duration of intake of oral contraceptives, and duration of amenorrhea. The incidence of previous oligomenorrhea and late menarche was high in both groups. The most striking difference between the two groups was in the incidence of pituitary prolactin-secreting tumor--32% among patients with galactorrhea and less than 2% among patients without galactorrhea. Identification of galactorrhea and accurate diagnosis of its causes are mandatory for successful management of postpill amenorrhea. Post-oral contraceptive amenorrhea is a rare complication. Prospective studies on amenorrhea following the use of an oral contraceptive have yielded incidences of 0.2%, 0.7%,0.8%, and 2.2%.1.4 The purposes of this study were to evaluate some clinical aspects of this syndrome and to demonstrate the variety and incidence of underlying etiologic factors. MATERIALS AND METHODS Eighty-six patients with post-oral contraceptive amenorrhea of more than 6 months' duration were studied retrospectively. A complete case history was obtained for each patient and a thorough physical examination was made. Skull x-rays and tomographic sections of the sella turcica were obtained for all patients; the abnormal sellas were staged according to the Received January 3, 1977; revised April 11, 1977; accepted April 18, *To whom reprint requests should be addressed. tresearch Fellow in Infertility and Gynecologic Endocrinology, University of Montreal. 728 classification of Vezina and Maltais. 5 In stage I, the volume of the sella turcica is normal but there is a slight bulging ofits floor. In stage II, the sella is enlarged but does not show any erosion of the floor. Stages III and IV indicate various degrees of floor destruction. The letter A indicates suprasellar extension. Serum prolactin concentrations were determined by radioimmunoassay6 on at least three different occasions; prolactin levels below 25 nglml were considered normal. For most patients, plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and 17{3- estradiol were determined by radioimmunoassay.7.8 The normal values in our laboratory for normal menstruating women during the follicular phase, excluding the ovulatory peak, range from 7 to 18 mlu/ml for LH and from 5 to 12 miu/ml for FSH. The normal range for plasma estradiol is 60 to 120 pg/ml during the early follicular phase. In all patients with galactorrhea or hyperprolactinemia, the pituitary reserve in growth hormone (HGH) and adrenocorticotropic hormone (ACTH) was evaluated by measuring plasma cortisol and

2 Vol. 28, No.7 AMENORRHEA FOLLOWING THE USE OF ORAL CONTRACEPTIVES 729 TABLE 1. Comparison of Clinical Data for Patients with Post pill Amenorrhea (Group I) and for Patients with Postpill Amenorrhea Associated with Galactorrhea (Group 11) Clinical data Group I: Groul/ II: 55 patients 31 patients Age (yr) Mean Range Gravidity 0 40 (72.7%) 22 (71.0%) 1 11 (20.0%) 7 (22.6%) 2 or more 4 (7.3%) 2 (6.4%) No. with previous 33 (60.0%) 15 (48.4%) oligomenorrhea No. with late menarche 6 (10.9%) 2 (6.4%) Duration of oral contraception (mo) Mean Range Duration of amenorrhea before investigation (mo) Mean Range HGH during hypoglycemia induced by the intravenous administration of 0.1 unit of insulin/kg of body weight, according to the methods and criteria described by Greenwood et al. 9 Patients were divided into two groups. Group I was composed of 55 amenorrheic patients without detectable galactorrhea. In group II, there were 31 patients with amenorrhea associated with galactorrhea. RESULTS As shown in Table 1, both groups were comparable for age and gravidity. The incidence of previous oligomenorrhea was 60% in group I and 48.4% in group II. Late menarche (16 years old or more) had occurred in 10.9% of group I patients and in 6.4% of group II patients. The duration of intake of the contraceptive pills varied from 3 months to 108 months in group I, with a mean of29 months, and from 1 month to 120 months in group II, with a mean of 34.5 months. The length of amenorrhea, defined as the time between the last contraceptive cycle and the investigation, varied from 6 months to 12 years in group I, with a mean of 17.5 months, and from 6 months to 6 years in group II, with a mean of27. 7 months. According to these clinical aspects, both groups were comparable. Of our 55 patients with postpill amenorrhea without galactorrhea (group I) (Table 2), 39 (70.9%) were classified as having hypothalamicpituitary dysfunction; the tomographic sections of the sella turcica and serum prolactin levels varying from 4 to 25 nglml, were normal. Plasm~ LH and FSH levels were low in 9 patients and within the normal range in 27 patients. Three patients had normal FSH levels with elevated LH levels (more the 25 miu/mi). Plasma estradiol levels were normal in eight patients and low in seven patients. In those patients, the investigation did not disclose any organic cause or evident psychogenic factor; the diagnosis of hypothalamic-pituitary dysfunction was thus made by exclusion. In seven patients of group I (12.7%) an evident psychologic factor, confirmed by a psychiatric consultation, was concomitant with the onset of amenorrhea; the sella turcica was normal in all of these patients and plasma prolactin levels ranged from 7 to 10 ng/ml. FSH and LH levels were low in three and normal in four. Estradiol levels were normal in three and low in four. In three patients (5.5%) primary ovarian failure was confirmed by high plasma FSH (> 70 miu/mi) and LH (> 80 miu/mi) levels and by the absence of follicles on bilateral ovarian biopsies. One patient (1.8%) had a stage IIA sella turcica and a serum prolactin level of 800 nglm1. Transsphenoidal sella exploration confirmed the diagnosis of a prolactin-secreting tumor. In the remaining five patients (9.1%), we found causes of amenorrhea probably unrelated to the pill: cirrhosis with hyponutrition; Addison's disease; hypopituitarism with selective deficiencies in ACTH, GH, and gonadotropin levels; obesity with diabetes; and simple obesity. All of those patients had normal or low gonadotropin levels, a normal sella turcica, and normal prolactin levels. The clinical and laboratory data of the 31 patients with amenorrhea associated with galactorrhea (group II) are presented in Tables 3 and 4. The galactorrhea was graded according to the description of Tolis et a1. 10 Nine patients (29%) were found to have very slight galactorrhea, detected only by the physician (grade I). Four patients (13%) had an induced milk flow of about TABLE 2. Etiologic Factors Found in Patients with Postpill Amenorrhea without Galactorrhea (Group 1) and in Patients with Postpill Amenorrhea Associated with Galactorrhea (Group II) Etiologic factor Pituitary tumor Hypothalamic-pituitary dysfunction Psychogenic Premature ovarian failure Primary hypothyroidism Other No. of cases Group I: Group II: 55 patients 31 patients

3 730 VAN CAMPENHOUT ET AL. July 1977 TABLE 3. Clinical and Laboratory Data for Patients with Post pill Amenorrhea-Galactorrhea and Pituitary Tumor Sella turcica Duration of Duration of Galactorrhea Patient stage oral amenorrhea contraception Grade Onset 1 I I 2 I III 3 I 5 20 I 4 I III 5 I 3 72 III 6 I III 7 I III 8 I 8 38 III 9 II I 10 I III aoc, Oral contraceptive intake. mo mo Prolactin Estradiol LH FSH nglml pglml mlu/ml mlu/ml During oca After OC After OC During OC During OC DuringOC < DuringOC ml and were unaware of it (grade 11). The last 18 patients (58%) had intermittent spontaneous galactorrhea (grade III). Spontaneous galactorrhea was noted before oral contraceptive use in three patients, during the intake of the pill in eleven, and concomitantly with the amenorrhea in the remaining four patients. Among these 31 patients, 10 (32.3%) were found to have a pituitary tumor as assessed by tomographic sections of the sella turcica and elevated serum prolactin levels (Table 3). All had normal ACTH and HGH pituitary reserve. Nine were operated upon by the trans-sphenoidal approach, and the diagnosis of pure prolactin-secreting tumor was proven by electronic microscopy. Patient 2 is awaiting surgery. The other 21 patients were diagnosed as having hypothalamicpituitary dysfunction with no evidence of tumor (Table 4). Among these, one patient (patient 31) had primary hypothyroidism as proven by low protein-bound iodine, T 3, and T4 levels, low 131{ uptake, and elevated plasma thyroid-stimulating hormone levels; the remaining 20 patients (64.5%) had completely negative evaluations except for the fact that 14 had high prolactin levels (ranging from 27.8 to 72.0 ng/ml). DISCUSSION Patients with post-oral contraceptive amenorrhea were divided into two groups according to the presence or absence of detectable galactorrhea. Clinical data (Table 1) showed no difference between the groups in terms of age and gravidity. The slight difference in terms of duration of oral contraception and length of amenorrhea before TABLE 4. Clinical and Laboratory Data for Patients with Post pill Amenorrhea-Galactorrhea and No Evidence of Pituitary Tumor Duration of Duration of Galactorrhea Patient oral amenorrhea Prolactin Estradiol LH FSH contraception Grade Onset mo mo nglml pglml mlulml mlulml I I I II I I III After Oca III During OC I III During OC II II III During OC III After OC III Before OC III During OC III Before OC III Before OC II III During OC " 48 7 III During OC aoc, Oral contraceptive intake. bprimary hypothyroidism.

4 Vol. 28, No.7 AMENORRHEA FOLLOWING THE USE OF ORAL CONTRACEPl'IVES 731 TABLE 5. Incidence of Pituitary Tumors in Patients with Post pill Amenorrhea-Galactorrhea and in Patients with Amenorrhea-Galactorrhea Unrelated to Oral Contraceptives Postpill Non-postpill No. of patients No. of tumors 10 (32.3%) 16 (41%) investigation was not statistically significant. The incidence of late menarche and previous oligomenorrhea was high in both groups of patients. Our total incidence of previous oligomenorrhea was 55.8%. Shearman,11 Furuhjelm and ~m:lstrom,12 and Steele et a1. 13 found, respectively, InCIdences of29.1 %,35.4%, and 63% in comparable series. In comparing both groups as shown in Table 2, it is evident that the incidence of pituitary tumor was much higher when galactorrhea was associated with postpill amenorrhea. In fact, we found 10 cases of prolactin-secreting tumor among 31 patients with postpill amenorrhea-galactorrhea, which represents an incidence of 32.3% pituitary tumors; in group I the incidence was less than 2%. This incidence of pituitary tumor is surprisingly high, compared with that reported in the literature. Furuhjelm and Carlstrom12 and Beaconsfield et a1. 14 found no pituitary tumor among their cases. In his 103 patients with postpill amenorrhea, Shearman ll found a 2% incidence of pituitary tumors. Our high incidence of pituitary tumor has three possible explanations. First, we routinely use tomographic sections of the sella turcica in every case of amenorrhea, since pituitary adenomas smaller than 10 mm are usually undetectable by classic skull x-rays. Second, serum prolactin levels are determined in all patients with amenorrhea (repeatedly in patients with galactorrhea). Furthermore, all patients are carefully examined in order to elicit minimal bilateral milk discharge. In this regard, it must be stressed that 13 patients of group II were unaware of the presence of galactorrhea. Although this incidence of pituitary tumor in postpill amenorrhea-galactorrhea might seem strikingly high, it is possible and even probable that some of the patients classified as having no evidence of pituitary tumor on the basis of normal tomographies of the sella turcica in fact have prolactin-secreting microadenomas which wou~d b~come radiologically evident on follow-up, considering the fact that serum prolactin levels were elevated in 14 cases. It should be stressed at this point that all patients included in this study were referred for their clinical syndrome without any previous investigation or diagnosis. In comparing our 31 cases referred for postpill amenorrhea-galactorrhea with 39 undiagnosed cases referred for amenorrhea-galactorrhea unrelated to pills, we found no statistically significant difference in the incidence of pituitary tumors (respectively, 32.3% and 41%) (Table 5). Because of the 16-fold higher risk of a pituitary tumor in postpill amenorrhea associated with galactorrhea, we recommend a careful search for galactorrhea in every patient with postpill amenorrhea. When galactorrhea is present... ' ~nvest~gation of the hypothalamic-pituitary axis, IncludIng repeated prolactin assays and tomographic sections of the sella turcia, is mandatory. When galactorrhea cannot be elicited, the probability of finding a pituitary prolactin-secreting tumor is low. In our series, one amenorrheic patient without galactorrhea had a very high level of prolactin and an easily recognizable pathologic pituitary fossa. Furthermore, among 77 hyperprolactinemic patients operated upon for prolactin-secreting pituitary tumors in our hospital, galactorrhea was undetectable in only 10%. Thus, considering the low incidence of pituitary tumor in the absence of galactorrhea among patients with postpill amenorrhea and taking into account that many patients will resume spontaneous menstrual cycles within 1 year after cessation of oral contraceptives, it seems to us acceptable in the absence of galactorrhea to reassure the patient and to wait 1 year before requesting an expensive and not readily available endocrine work-up. REFERENCES 1. Golditch 1M: Post contraceptive amenorrhea. Obstet Gynecol 39:903, Pettersson F, Fries H, Nillius SJ: Epidemiology of secondary amenorrhea. AmJ Obstet GynecoI117:80, Larsson-Cohn U: The length of the fu'st three menstrual cycles after combined oral contraceptive treatment. Acta Obstet Gynecol Scand 48:416, Evrard JR, Buxton BH, Erickson D: Amenorrhea following oral contraception. Am J Obstet Gynecol 124:88, Vezina JL, Maltais R: La selle turcique dans l'acromegalie. Etude radiologique. Neurochirurgie [Suppl2[ 19:35, Hwang P, Guyda H, Friesen H: A radioimmunoassay for human prolactin. Proc Natl Acad Sci USA 68:1902, Midgley AR: Radioimmunoassay: a method for human chorionic gonadotropins and human luteinizing hormone. Endocrinology 79:10, Hotchkiss J, Atkinson LE, Knobil E: Time course of serum estrogen and luteinizing hormone (LH). Concentrations during the menstrual cycle of the rhesus monkey. Endocrinology 89:177, 1971

5 732 VAN CAMPENHOUT ET AL. July Greenwood FC, Landon J, Stamp TC: The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin. J Clin Invest 45:429, Tolis G, Somma M, Van Campenhout J, Friesen HG: Prolactin secretion in sixty-five patients with galactorrhea. Am J Obstet GynecoI118:91, Shearman RP: Secondary amenorrhea after oral contraceptives. Contraception 11:123, Furuhjelm M, Carlstrom K: Amenorrhea following use of combined oral contraception. Acta Obstet Gynecol Scand 52:373, Steele SJ, Mason B, Brett A: Amenorrhea after discontinuing combined oestrogen progestogen oral contraceptives. Br Med J 4:343, Beaconsfield P, Dick R, Ginsburg J, Lewis P: Amenorrhea and infertility after the use of oral contraceptives. Surg Gynecol Obstet 138:571, 1974

PROLACTIN-SECRETING PITUITARY MICROADENOMA: DETECTION AND EVALUATION*t

FERTILITY AND STERILITY Copyright 1978 The American Fertility Society Vol. 29, No.3, March 1978 PrinlRd in U.s.A. PROLACTIN-SECRETING PITUITARY MICROADENOMA: DETECTION AND EVALUATION*t R. HERBERT WIEBE,