Conservative Management of A Pituitary Tumor During Pregnancy Following Induction of Ovulation with Gonadotropins*

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FERTILITY AND SrERILITY Copyright" 1977 The American Fertility Society

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Vol. 28, No.1, January 1977 Printed in U.S.A.

CONSERVATIVE MANAGEMENT OF A PITUITARY TUMOR DURING PREGNANCY FOLLOWING INDUCTION OF OVULATION WITH GONADOTROPINS*

RAPHAEL JEWELEWICZ, M.D. EARL A. ZIMMERMAN, M.D. PETER W. CARMEL, M.D.

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Department of Obstetrics and Gynecology, Department of Neurology and Neurosurgery, and The International Institute for the Study of Human Reproduction, CoUege of Physicians and Surgeons, Columbia University, New York, New York 10032

Ovulation induced with human menopausal gonadotropin-human chorionic gonadotropin in a 27-year-old woman who had been amenorrheic for 7 years resulted in pregnancy. Although pretreatment neurologic evaluation was normal, significant loss of vision was found at 30 weeks' gestation, and a skull x-ray revealed enlargement and erosion ofthe sella turcica. As an attempt to delay surgery, 12 mg ofdexamethasone daily arrested further visual deterioration, and the pregnancy continued uneventfully for 36 weeks, when triplets were born. Five days after delivery the visual fields were normal. Trans-sphenoidal resection ofa prolactin-secreting chromophobe adenoma ofthe pituitary was carried out 6 months later. It is suggested that when disturbance in visual perception due to a pituitary tumor occurs during pregnancy, a course ofhigh-dose corticosteroids with frequent monitoring ofvisual fields and acuity might be tried before surgical intervention. Although further rapid deterioration in vision may dictate immediate surgical decompression, conservative management may result in stabilization, allowing the patient to carry the pregnancy to term and obviating the need for emergency surgery.

Progressive oligomenorrhea leading to amenorrhea with or without galactorrhea may be the first and only symptom of pituitary or parasellar tumors in women of reproductive age. In the early stages of tumor growth, which can last for many years, there may be no changes in the bony structure of the sella turcica and no neurologic or ophthalmologic signs to indicate a pituitary tumor. Many of these tumors may be associated with elevated plasma prolactin levels. 1 Infertility is a common complaint, and without treatment pregnancy is unusual in these patients. The introduction of the ovulation-inducing drug clomiphene citrate and the gonadotropins2 and the use ofbromocryptine to reduce abnormal prolactin

levels3 have changed the prognosis for these patients, and pregnancy is now possible. Treatment may also include radiotherapy or trans-sphenoidal surgery. 4 Since appreciable enlargement of the pituitary occurs during gestation,S a previously asymptomatic patient may develop acute neurologic and/or ophthalmologic symptoms during pregnancy. On the basis of these possibilities, our policy, as well as that of others,6 is not to induce ovulation and pregnancy in patients with pituitary tumors before the tumor is adequately treated. This approach has not been universally accepted, and in several institutions ovulation is induced in these patients and pituitary problems are treated as they arise. However, since many patients with presumably small pituitary tumors have no abnormal symptoms or signs except amenorrhea and infertility, one may, unfortunately, induce ovulation in these patients before the tumor is discovered. If the patient becomes

Accepted July 6, 1976. *Presented at the Thirty-Second Annual Meeting of The American Fertility Society, April 5 to 9, 1976, Las Vegas, Nev.

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JEWELEWICZ ET AL.

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pregnant, neurologic or ophthalmologic symptoms requiring immediate emergency treatment may appear. 7• 8 Recently one of our patients conceived after gonadotropin therapy and developed severe visual loss during pregnancy. She was treated conservatively and after delivery her vision improved significantly, but a pituitary tumor was diagnosed and a trans-sphenoidal resection was performed. This case and its management are described.

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V. B. A., age 27, was referred to us for evaluation of secondary amenorrhea and primary infertility of 7 years' duratIon. Thelarche had occurred at age 13 and menarche at age 14. She had had regular menstrual periods until age 20, when her periods suddenly stopped. At that time she married and, since she was not interested in becoming pregnant, was given oral contraceptives, which she took until age 23. During that time she had had regular menstrual periods and no complaints. Desirous of pregnancy, she stopped the oral contraceptives but menstruation did not resume. Her gynecologist had the impression that she had developed "postpill amenorrhea" and advised her to wait. After 3 years, during which she neither menstruated nor conceived, she was evaluated at another hospital. Thyroid and adrenal function tests were said to have been normal. Urinary gonadotropin levels ranged from 6 to 16 mIU/24 hours (bioassay-normal values). A hysterosalpingogram was normal. Routine x-rays of the skull revealed a normal sella turcica. ;Laparoscopy revealed small, inactive ovaries. The patient failed to respond to several cycles of clomiphene citrate. When first seen at this institution (November 10, 1972), her general physical examination revealed only moderate obesity (height, 5 feet 4% inches; weight, 173 lb). There was no galactorrhea. Pelvic examination was normal. Some 'thick ce~ical mucus was present. The vaginal smear showed a moderate to low estrogen effect. The patient did not experience withdrawal bleeding after intramuscular administration of 100 mg of progesterone. The plasma luteinizing hormone (LH) level, determined by radioimmunoassay, was 20 nglml (normal, 32 to 260 nglml; LER 907); the follicle-stimulating hormone (FSH) level was 103 nglml (normal, 50 to 380 nglml). The response to a single injection of 50 ILg of synthetic gonadotropin-releasing hormone (GnRH;

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Abbott Laboratories, North Chicago, Ill.) indicated normal pituitary function (Fig. 1). These findings suggested hypothalamic (idiopathic?) hypogonadotropic amenorrhea, and the patient was advised to undergo gonadotropin therapy for induction of ovulation. After receiving a total dose of 80 vials of human menopausal gonadotropin (HMG) (Pergonal) and 10,000 IU of human chorionic gonadotropin (HCG), she ovulated and conceived. At 14 weeks' gestation the uterus appeared significantly larger than expected, and sonographic diagnosis of a quadruplet gestation was made. Despite bed rest, the patient aborted at 191h weeks' gestation. During this pregnancy she did not complain of headaches or visual disturbances. Four months later, another cycle of HMG-HCG was given (Pergonal, four ampules/day for 11 days :::>

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MANAGEMENT OF PITUITARY TUMOR DURING PREGNANCY

and 10,000 IU of HCG) and the patient again conceived (Fig. 2). At 8 weeks' gestation the uterus. appeared larger than expected, and a multiple· gestation was suspected. Sonography at 16 weeks revealed triplets, and the patient was advised to have complete bed rest at home. At 22 weeks' gestation, during a routine prenatal visit, she complained of slightly blurred vision, but she had no headaches, and a complete neurologic examination was negative. During the following biweekly visit she had no complaints, but during the 30th week of gestation she again complained

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of slightly blurred vision while reading, and occasional mild headaches. A complete neurologic examination at that time revealed bitemporal visual loss on confrontation fields, which was worse in the left eye. The optic discs were normal on fundoscopy. Visual acuity was 20170 in the left eye and did not correct, and 20/20 in the right eye. A routine skull x-ray series demonstrated enlargement of the sella turcica with erosion of the floor and the dorsum along the lamina dura (Fig. 3). Formal visual fields showed significant loss of vision in the entire field of the left eye and

FIG. 3. X-ray of the sella turcica demonstrating enlargement and erosion of the floor and the dorsum along the lamina dura.

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JEWELEWICZ ET AL.

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FIG. 4. Visual fields at 30 weeks' gestation.

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FIG. 6. Visual fields 9 days after delivery.

minimal loss in the right outer upper temporal quadrant in the right eye (Fig. 4). She was immediately hospitalized. Treatment with dexamethasone (Decadron), 12 mglday in divided doses, was begun and, after 3 days of treatment, visual acuity had improved to 20/40 in the left eye, remained 20/20 in the right eye, and the headaches disappeared. The visual acuities and fields were tested twice weekly and remained unchanged for the next 6 weeks. Blood pressure and fasting blood sugar also remained normal. The patient's condition remained stable for 6 weeks and the pregnancy progressed uneventfully. After 36¥.! weeks' gestation she developed spontaneous labor and the membranes ruptured spontaneously. Although the first fetus was in vertex presentation, the head was high. An x-ray of the abdomen revealed that the second fetus was in transverse position, and the third a breech. In view of the patient's condition and the possibility, of a complicated vaginal delivery, cesarean section was performed. Three baby girls in excellent condition, weighing 1800, 1570, and 2200 gm, were delivered. Apgar scores ranged from 7 to 9. The newborns did very well and showed no evidence of adrenal insufficiency. On arising 3 days after delivery, the patient noticed that her vision had improved. On the following day the visual fields were markedly improved and the visual acuity was 20/20 (Fig. 5). Nine days after delivery the visual fields were normal (Fig. 6). The dexamethasone dose was gradually reduced and was discontinued 10 days after delivery.

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Three months after delivery the patient was readmitted for evaluation of her pituitary status. At that time her plasma prolactin level was 900 ng/ml (normal, 1 to 25 ng/ml); resting plasma growth hormone level, 0.9 nglml (normal, 0 to 5 ng/ml); LH level, 0.8 mIUlml (normal, 2 to 30 mIUI ml); FSH level, 1.2 mIU/ml (normal, 3 to 10 mIUI mI). All other test results, including thyroid and adrenal function tests, were normal. The results of the physical and neurologic examinations were normal, except for the presence of galactorrhea. Visual fields and acuities were also normal. Skull x-rays revealed no change in the sella. An attempt to perform a pneumoencephalogram failed, but computerized transaxial tomography confirmed the presence of an intrasellar tumor and did not indicate suprasellar extension. Six months after delivery the patient was readmitted, and a trans-sphenoidal resection of the pituitary tumor was performed. Examination of the tumor by routine histologic stains revealed sheets of cells which stained typically for chromophobe adenoma. No eosinophilia was present. Deparaffinized, formalin-fixed sections (5 /Lm) were allowed to react with antiserum to growth hormone and prolactin by the immunoperoxidase technique. 9 Many of the tumor cells contained products reactive to prolactin (Fig. 7) but none to growth hormone. The patient's postoperative course was uneventful. Visual fields were normal, as were thyroid and adrenal function. The prolactin level decreased to 157 nglml 5 days after surgery. At this writing, 9 months after surgery, the patient is in good health. However, her plasma prolactin level on January 16, 1976, was 169 ng/ml, and radiotherapy is contemplated.

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VA 20/20 VA 20/20 FIG. 5. Visual fields 4 days after delivery.

DISCUSSION

Amenorrhea with or without galactorrhea may be the only symptom ora small pituitary or parasellar tumor, which may be dormant for many

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MANAGEMENT OF PITUITARY TUMOR DURING PREGNANCY

FIG. 7. Photomicrograph of a section of the chromophobe adenoma surgically removed from the patient and immunostained for· prolactin. The immunoperoxidase technique reveals black products reactive to the hormone in the tumor cells (x 600).

years. Neuro-opthalmologic and standard radiologic signs may be absent, and the only hint that such a tumor exists may be an elevated plasma prolactin level or abnormal tomograms. 10 Since anovulatory infertility is a frequent complaint of patients with sellar or parasellar diseases, the gynecologist must rule out a tumor in the region of the pituitary gland before inducing ovulation and pregnancy. This task is not simple. Recently it has been recognized that many patients with amenorrhea and galactorrhea may have a small adenoma of the pituitary gland without obvious abnormalities on a routine x-ray of the sella turcica. In a study of 20 patients, Vezina and Suttonl l found that routine x-rays showed normal pituitary fossae in 14; all of these patients had radiologic evidence of pituitary tumor after careful tomography. Had tomography of the sella region been performed in our patient the tumor might have been demonstrated prior to induction of ovulation. The tumor might also have been

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suspected earlier if prolactin levels had been measured. Whenever there is evidence of such a tumor, it should be adequately treated before ovulation is induced and pregnancy attempted. There is general agreement that physiologic enlargement of the pituitary occurs during pregnancy, probably due to an increase in the cells associated with prolactin secretion. 12 Normally, this physiologic enlargement does not compress the optic chiasm or nerve. However, when a small adenoma is present, expansion of the tumor and! or the normal gland may press on the optic chiasm or its blood supply and cause visual symptoms. In most cases these symptoms regress promptly after deliveryP Thus, if surgery can be avoided during pregnancy, there is a good chance that the visual symptoms will subside after delivery, and definitive treatment can be carried out later on a nonpregnant patient. In our patient we were faced with such a problem. Visual disturbances were discovered after 30 weeks of gestation. Since she carried triplets, it was expected that labor would start before term. Our aim and that of the patient was to maintain the pregnancy as long as possible with the least interference. Although surgery was discussed at 30 weeks, the patient did not want to accept the risk to the pregnancy ifit could be postponed until after delivery. It should be noted that, although hypophysectomy during pregnancy has been carried out, it is a procedure not without risk. 7 By treating the patient with high doses of corticosteroids we hoped to reduce possible swelling in or around the optic chiasm, at least temporarily. A secondary effect of the corticosteroids may have been enhanced maturation of the fetal lungs. 14 The "wait and see" approach was monitored by frequent visual field examinations, since considerable and rapid visual deterioration would have required immediate surgical decompression. This conservative treatment enabled the patient to continue the pregnancy another 61;2· weeks, when viable children were born, and avoided the risk of surgery during pregnancy. Although successful pituitary surgery has been performed in pregnant women, the case presented suggests that adrenal steroid therapy given under close observation may be an alternative method of management in this situation. The significant improvement in vision after delivery is indirect evidence that the pressure on the optic chiasm was due not only to the tumor but to pituitary enlargement caused by the pregnancy. Although microsurgical techniques have significantly reduced morbidity and mortality, 15 it is preferable not to operate during pregnancy.

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JEWELEWlCZ ET AL.

CONCLUSIONS

1. Infertile women who are suspected of having a pituitary tumor require a complete neurologic and radiologic evaluation including tomography of the sella turcica, visual field examination and visual acuity tests, and plasma prolactin measurement before treatment is begun. 2. If a pituitary tumor is proven, it should be adequately treated by surgery, radiation, or both, before ovulatory cycles are induced. 3. If a tumor is suspected but unproven and pregnancy occurs, careful follow-up, including repeated examinations of the visual fields, is important. 4. If disturbances in visual perception and headaches occur during pregnancy, the patient should be hospitalized; after proper evaluation, a course of high-dose corticosteroids might be tried with frequent monitoring of visual fields and acuities. Although further rapid deterioration in vision may dictate immediate surgical decompression, the case presented suggests that conservative management may result in stabilization and some improvement that may allow the patient to carry the pregnancy safely to term and may obviate the need for emergency surgery. REFERENCES 1. Child DF, Nader S, Mashiter K, Kjeld M, Banks L, Fraser

TR: Prolactin studies in "functionless" pituitary tumours. Br Med J 1:604, 1975

January 1977 2. Jewelewicz R: Management of infertility resulting from anovulation. Am J Obstet Gyneco1122:909, 1975 3. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhea and hypogonadism with bromocriptine. Br Med J 2:419, 1974 4. Child DF, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin and pituitary tumours. Br Med J 4:87,1975 5. Erdheim J, Stumme E: Uber die Schwangerschaftsveranderung der Hypophyse. Beitr Pathol 46:1, 1909 6. Gemzell C: Induction of ovulation in infertile women with pituitary tumors. Am J Obstet GynecoI121:311, 1975 7. Kajtar T, Tomkin GH: Emergency hypophysectomy in pregnancy after induction of ovulation. Br Med J 4:88, 1971 8. Von Luft H: Zusammenhange zwischen Hypophysentumor und Schwangerschaft. Zentralbl Gynaekol 90:1501, 1968 9. Zimmerman EA, Defendini R, Frantz AG: Prolactin and growth hormone in patients with pituitary adenomas: a correlative study of hormone in tumor and plasma by immunoperoxidase technique and radioimmunoassay. J Clin Endocrinol Metab 38:577,1974 10. Frantz AG, Kleinberg DL, Noel GL: Studies on prolactin in man. Recent Prog Horm Res 28:527, 1972 11. Vezina JL, Sutton TJ: Prolactin-secreting pituitary microadenomas: roentgenologic diagnosis. Am J Roentgenol Radium Ther Nucl Med 120:46, 1974 12. Goiuboff LG, Ezrin C: Effect of pregnancy on the somatotroph and the prolactin cell of the human adenohypophysis. J Clin Endocrinol Metab 29:1533, 1969 13. Falconer MA, Stafford-Bell MA: Visual failure from pituitary and parasellar tumours occurring with favorable outcome in pregnant women. J Neurol Neurosurg Psychiatry 38:919, 1975 14. 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 15. Hardy J: Transsphenoidal hypophysectomy. J Neurosurg 34:582, 1971