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Spontaneous Pregnancy in Women with a Prolactin-Producing Pituitary Adenoma*
FERTILITY AND STERILITY Copyright
Vol. 29, No.6, June 1978 Printed in U.S.A.
1978 The American Fertility Society
SPONTANEOUS PREGNANCY IN WOMEN WITH A PROLACTIN-PRODUCING PITUITARY ADENOMA*
JOHN A. SWANSON, M.D. FREDERICK K. CHAPLER, M.D.t BARRY M. SHERMAN, M.D. KENT CRICKARD, M.D. Divisions of Endocrinology, Departments of Obstetrics and Gynecology and Internal Medicine, University of Iowa School of Medicine, Iowa City, Iowa 52242
The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.
The pathophysiology and natural history of prolactin-producing adenomas of the pituitary gland are poorly understood. It is unclear whether the hyperprolactinemia results in infertility and/or amenorrhea through a central action on gonadotropin secretion or through direct alteration of ovarian function. Rarely has spontaneous pregnancy reportedly occurred in these individuals without prior therapy/ although ovulation induction and pregnancy have occurred in a few women following the use of human menopausal gonadotropins, and more recently bromocriptine. 2 We report two cases of spontaneous pregnancy occurring in individuals with amenorrhea-galactorrhea, hyperprolactinemia, and a radiographically abnormal sella.
at age 14 with somewhat irregular menses until 1971, when the patient had begun to use oral contraceptives. She discontinued the oral contraceptives, conceived, and had an uncomplicated pregnancy and delivery in October 1973. She resumed combination oral contraceptive therapy until January 1975 but remained amenorrheic after discontinuation. In July 1975 she noted the spontaneous onset of bilateral galactorrhea. On initial examination, positive physical findings included bilateral galactorrhea and a parous uterine size. Laboratory tests included a normal serum T4 concentration, a follicle-stimulating hormone (FSH) level of 4.3 mIU/ml (noFmal, 5 to 30 mIU/ml), a luteinizing hormone (LH) level of 30 mIU/ml (normal, 2 to 200 mIUlml) , and a prolactin level of 51.5 ng/ml (normal, 7.9 ± 6.9 ng/mI). Visual fields by Goldmann perimetry were normal, and tomograms revealed a depression in the left floor of the sella turcica which was thought to be abnormal and not just a variation of the sella. When admitted to University Hospitals in April 1976 for more extensive pituitary evaluation, the patient was noted to have a palpable uterine fundus at the umbilicus with audible fetal heart tones. Galactorrhea was no longer demonstrable. Ultrasound examination in May 1976 revealed a single fetus compatible with 23 weeks' gesta-
CASE REPORTS
Case 1. P. N., a 23-year-old white female, was first seen in the reproductive endocrinology clinic in January 1976. Menarche had occurred Received June 20, 1977; revised January 25, 1978; accepted February 17, 1978. *Supported by National Institutes of Health Grant RR59 from the General Clinical Research Centers Branch, Division of Research Resources. tReprint requests: Frederick K. Chapler, M.D., Department of Obstetrics and Gynecology, University of Iowa Hospitals, Iowa City, Iowa 52242.
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SWANSON ET AL.
tion. Repeat sella tomography (with appropriate pelvic and eye shielding) and visual field examination showed no change from the initial examination. The pregnancy progressed uneventfully, and on August 15, 1976, the patient delivered a 3340gm normal female infant. The patient did not breast-feed and was not given any medications to prevent postpartum breast engorgement. A visual field examination performed immediately postpartum was normal, and sella tomography repeated 8 weeks postpartum showed the persistent abnormality on the left. Serum prolactin levels measured 4 days and 2 months postpartum were 331 ng/ml and 198 ng/ml, respectively. Following delivery the amenorrhea and galactorrhea continued, and in February 1977 the patient was admitted to the clinical research center for more extensive evaluation. The serum T4 level was 9.3 JLg/dl (normal, 5 to 13 JLg/dl) , and the thyroid-stimulating hormone level was 7.9 mU/ml (normal). Thirty-minute blood sampling for 12 consecutive hours revealed a mean ± standard deviation) serum prolactin concentration of 42.6 ± 15.8 ng/ml. The serum 11deoxycortisol response to overnight metyrapone was normal, as were the serum growth hormone response to oral l-dopa and the prolactin response to intramuscular chlorpromazine. Visual fields were again normal, and tomographic pneumoencephalography confirmed the persistent defect in the left floor of the sella with no suprasellar extension. In March 1977 the patient underwent transsphenoidal pituitary surgery. A small area of bony erosion was noted in the left sella floor, and resection of a necrotic tumor mass was accomplished. Pathology confirmed an acidophilic pituitary adenoma. Postoperatively the patient did well, and on the 9th postoperative day, 30-minute blood sampling for 12 consecutive hours showed a mean prolactin of 9.5 ng/ml ± 3.1 ng/ml. All other pituitary functions remained normal. The galactorrhea ceased immediately and normal menses resumed 4 weeks postoperatively. Even though elevated prolactin levels and sellar changes were not documented prior to pregnancy, we believe that the patient's long history of amenorrhea and galactorrhea is supportive evidence that her tumor was present before conception. Case 2. B. W., a 24-year-old white female, was referred to the reproductive endocrinology clinic in June 1977 because of galactorrhea and hyperprolactinemia, both noted while the
June 1978
patient was taking a combination oral contraceptive steroid pill. She had been taking the pills for 4 years and the galactorrhea had been present for 2 years. Her serum prolactin level, measured while she was taking these pills, was 52 ng/ml (normal, 7.9 ± 6.9 ng/ml). Two months after the patient discontinued the pill, her prolactin level remained elevated (43.7 ng/ml), galactorrhea persisted, and menses failed to resume. Additional laboratory tests at this time revealed normal levels of T 4, FSH, and LH. Because sellar tomography was reported as being normal, the patient received no specific therapy, but was told to return for repeat evaluation in 6 months. However, the patient returned 5 months later because of lower abdominal pain. Her galactorrhea and amenorrhea had continued. A slightly enlarged uterus was felt during pelvic examination, and a pregnancy test was positive. The patient's serum prolactin level was 143 ng/ml. Sellar tomography, with appropriate pelvic and eye shielding, revealed focal thinning of the anterior sella surface in anterior, posterior, and lateral cuts. This was interpreted as being consistent with changes secondary to a microadenoma. Review of her previous sella films showed these changes to be present, suggesting that the tumor had been present when the patient was initially seen. After careful deliberation, the patient requested and had an early pregnancy termination. The gestational age, based on uterine size and tissue examination, was estimated to be 10 weeks. Four weeks posttermination, the serum prolactin level was 44 ng/ml. The patient has agreed to be followed with repeat prolactin determinations and radiologic evaluations because she does not desire a pregnancy in the near future. She has also been advised not to take estrogen-containing pills. DISCUSSION
These cases demonstrate that spontaneous pregnancy can occur in patients with amenorrheagalactorrhea and hyperprolactinemia associated with pituitary tumors. This observation adds confusion to the problem of explaining the mechanism of why most patients with elevated prolactin levels have associated amenorrhea and anovulation. Obviously, hyperprolactinemia does not always interfere with normal hypothalamicpituitary-ovarian response, function, and interrelationships. It is important that this be recog-
Vol. 29, No.6
SPONTANEOUS PREGNANCY WITH PROLACTIN-PRODUCING PITUITARY ADENOMA
nized, as it is generally assumed that spontaneous pregnancy is a rare occurrence in patients who have elevated prolactin levels. We suspect that this happens more often than formerly appreciated. Pregnancy in a patient with a pituitary tumor may progress uneventfully, as it did in our first case, but rapid pituitary and prolactinoma growth can occur which may result in neurologic and/or ophthalmologic problems, necessitating immediate treatment. 3 ,4 This possibility currently serves as a contraindication to pregnancy in patients with a suspected pituitary adenoma. We, along with others,5 currently recommend transsphenoidal surgical removal of the tumor before attempting conception. If conception should occur spontaneously, before or without any other form of treatment, frequent visual field examination is the "follow-up" test of choice. Occasionally, repeat radiographic studies of the sella are indicated, but serum prolactin levels are of little value because of the superimposed normal increase in prolactin secretion during pregnancy. 6 This means of follow-up is in contradistinction
631
to following a similar type of patient in the nonpregnant state, i.e., serum prolactin levels being the most reliable and sensitive test, with sellar tomography a close second, and visual fields of much less value. REFERENCES 1. Husami N, Jewelewicz R, Vande Wiele RL: Pregnancy in
2. 3.
4.
5.
6.
patients with pituitary tumors. Fertil Steril 28:920, 1977 Child DR, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin, and pituitary tumours. Br Med J 4:87, 1975 Gemzell C: Induction of ovulation in infertile women with pituitary tumors. Am J Obstet Gynecol 121:311, 1975 Lamberts SWJ, Seldenrath HJ, Kwa HG, Birkenhager JC: Transient bitemporal hemianopsia during pregnancy after treatment of galactorrhea-amenorrhea syndrome with bromocriptine. J Clin Endocrinol Metab 44:180, 1977 Keye WR Jr, Chang RJ, Jaffe RB: Prolactin secreting pituitary adenomas in women with amenorrhea or galactorrhea. Obstet Gynecol Survey 32:727, 1977 Schenker JG, Ben-David M, Polishuk WZ: Prolactin in normal pregnancy: relationship of maternal, fetal, and amniotic fluid levels. Am J Obstet Gynecol 123:834, 1975
Vol. 29, No.6, June 1978 Printed in U.S.A.
1978 The American Fertility Society
SPONTANEOUS PREGNANCY IN WOMEN WITH A PROLACTIN-PRODUCING PITUITARY ADENOMA*
JOHN A. SWANSON, M.D. FREDERICK K. CHAPLER, M.D.t BARRY M. SHERMAN, M.D. KENT CRICKARD, M.D. Divisions of Endocrinology, Departments of Obstetrics and Gynecology and Internal Medicine, University of Iowa School of Medicine, Iowa City, Iowa 52242
The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.
The pathophysiology and natural history of prolactin-producing adenomas of the pituitary gland are poorly understood. It is unclear whether the hyperprolactinemia results in infertility and/or amenorrhea through a central action on gonadotropin secretion or through direct alteration of ovarian function. Rarely has spontaneous pregnancy reportedly occurred in these individuals without prior therapy/ although ovulation induction and pregnancy have occurred in a few women following the use of human menopausal gonadotropins, and more recently bromocriptine. 2 We report two cases of spontaneous pregnancy occurring in individuals with amenorrhea-galactorrhea, hyperprolactinemia, and a radiographically abnormal sella.
at age 14 with somewhat irregular menses until 1971, when the patient had begun to use oral contraceptives. She discontinued the oral contraceptives, conceived, and had an uncomplicated pregnancy and delivery in October 1973. She resumed combination oral contraceptive therapy until January 1975 but remained amenorrheic after discontinuation. In July 1975 she noted the spontaneous onset of bilateral galactorrhea. On initial examination, positive physical findings included bilateral galactorrhea and a parous uterine size. Laboratory tests included a normal serum T4 concentration, a follicle-stimulating hormone (FSH) level of 4.3 mIU/ml (noFmal, 5 to 30 mIU/ml), a luteinizing hormone (LH) level of 30 mIU/ml (normal, 2 to 200 mIUlml) , and a prolactin level of 51.5 ng/ml (normal, 7.9 ± 6.9 ng/mI). Visual fields by Goldmann perimetry were normal, and tomograms revealed a depression in the left floor of the sella turcica which was thought to be abnormal and not just a variation of the sella. When admitted to University Hospitals in April 1976 for more extensive pituitary evaluation, the patient was noted to have a palpable uterine fundus at the umbilicus with audible fetal heart tones. Galactorrhea was no longer demonstrable. Ultrasound examination in May 1976 revealed a single fetus compatible with 23 weeks' gesta-
CASE REPORTS
Case 1. P. N., a 23-year-old white female, was first seen in the reproductive endocrinology clinic in January 1976. Menarche had occurred Received June 20, 1977; revised January 25, 1978; accepted February 17, 1978. *Supported by National Institutes of Health Grant RR59 from the General Clinical Research Centers Branch, Division of Research Resources. tReprint requests: Frederick K. Chapler, M.D., Department of Obstetrics and Gynecology, University of Iowa Hospitals, Iowa City, Iowa 52242.
629
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SWANSON ET AL.
tion. Repeat sella tomography (with appropriate pelvic and eye shielding) and visual field examination showed no change from the initial examination. The pregnancy progressed uneventfully, and on August 15, 1976, the patient delivered a 3340gm normal female infant. The patient did not breast-feed and was not given any medications to prevent postpartum breast engorgement. A visual field examination performed immediately postpartum was normal, and sella tomography repeated 8 weeks postpartum showed the persistent abnormality on the left. Serum prolactin levels measured 4 days and 2 months postpartum were 331 ng/ml and 198 ng/ml, respectively. Following delivery the amenorrhea and galactorrhea continued, and in February 1977 the patient was admitted to the clinical research center for more extensive evaluation. The serum T4 level was 9.3 JLg/dl (normal, 5 to 13 JLg/dl) , and the thyroid-stimulating hormone level was 7.9 mU/ml (normal). Thirty-minute blood sampling for 12 consecutive hours revealed a mean ± standard deviation) serum prolactin concentration of 42.6 ± 15.8 ng/ml. The serum 11deoxycortisol response to overnight metyrapone was normal, as were the serum growth hormone response to oral l-dopa and the prolactin response to intramuscular chlorpromazine. Visual fields were again normal, and tomographic pneumoencephalography confirmed the persistent defect in the left floor of the sella with no suprasellar extension. In March 1977 the patient underwent transsphenoidal pituitary surgery. A small area of bony erosion was noted in the left sella floor, and resection of a necrotic tumor mass was accomplished. Pathology confirmed an acidophilic pituitary adenoma. Postoperatively the patient did well, and on the 9th postoperative day, 30-minute blood sampling for 12 consecutive hours showed a mean prolactin of 9.5 ng/ml ± 3.1 ng/ml. All other pituitary functions remained normal. The galactorrhea ceased immediately and normal menses resumed 4 weeks postoperatively. Even though elevated prolactin levels and sellar changes were not documented prior to pregnancy, we believe that the patient's long history of amenorrhea and galactorrhea is supportive evidence that her tumor was present before conception. Case 2. B. W., a 24-year-old white female, was referred to the reproductive endocrinology clinic in June 1977 because of galactorrhea and hyperprolactinemia, both noted while the
June 1978
patient was taking a combination oral contraceptive steroid pill. She had been taking the pills for 4 years and the galactorrhea had been present for 2 years. Her serum prolactin level, measured while she was taking these pills, was 52 ng/ml (normal, 7.9 ± 6.9 ng/ml). Two months after the patient discontinued the pill, her prolactin level remained elevated (43.7 ng/ml), galactorrhea persisted, and menses failed to resume. Additional laboratory tests at this time revealed normal levels of T 4, FSH, and LH. Because sellar tomography was reported as being normal, the patient received no specific therapy, but was told to return for repeat evaluation in 6 months. However, the patient returned 5 months later because of lower abdominal pain. Her galactorrhea and amenorrhea had continued. A slightly enlarged uterus was felt during pelvic examination, and a pregnancy test was positive. The patient's serum prolactin level was 143 ng/ml. Sellar tomography, with appropriate pelvic and eye shielding, revealed focal thinning of the anterior sella surface in anterior, posterior, and lateral cuts. This was interpreted as being consistent with changes secondary to a microadenoma. Review of her previous sella films showed these changes to be present, suggesting that the tumor had been present when the patient was initially seen. After careful deliberation, the patient requested and had an early pregnancy termination. The gestational age, based on uterine size and tissue examination, was estimated to be 10 weeks. Four weeks posttermination, the serum prolactin level was 44 ng/ml. The patient has agreed to be followed with repeat prolactin determinations and radiologic evaluations because she does not desire a pregnancy in the near future. She has also been advised not to take estrogen-containing pills. DISCUSSION
These cases demonstrate that spontaneous pregnancy can occur in patients with amenorrheagalactorrhea and hyperprolactinemia associated with pituitary tumors. This observation adds confusion to the problem of explaining the mechanism of why most patients with elevated prolactin levels have associated amenorrhea and anovulation. Obviously, hyperprolactinemia does not always interfere with normal hypothalamicpituitary-ovarian response, function, and interrelationships. It is important that this be recog-
Vol. 29, No.6
SPONTANEOUS PREGNANCY WITH PROLACTIN-PRODUCING PITUITARY ADENOMA
nized, as it is generally assumed that spontaneous pregnancy is a rare occurrence in patients who have elevated prolactin levels. We suspect that this happens more often than formerly appreciated. Pregnancy in a patient with a pituitary tumor may progress uneventfully, as it did in our first case, but rapid pituitary and prolactinoma growth can occur which may result in neurologic and/or ophthalmologic problems, necessitating immediate treatment. 3 ,4 This possibility currently serves as a contraindication to pregnancy in patients with a suspected pituitary adenoma. We, along with others,5 currently recommend transsphenoidal surgical removal of the tumor before attempting conception. If conception should occur spontaneously, before or without any other form of treatment, frequent visual field examination is the "follow-up" test of choice. Occasionally, repeat radiographic studies of the sella are indicated, but serum prolactin levels are of little value because of the superimposed normal increase in prolactin secretion during pregnancy. 6 This means of follow-up is in contradistinction
631
to following a similar type of patient in the nonpregnant state, i.e., serum prolactin levels being the most reliable and sensitive test, with sellar tomography a close second, and visual fields of much less value. REFERENCES 1. Husami N, Jewelewicz R, Vande Wiele RL: Pregnancy in
2. 3.
4.
5.
6.
patients with pituitary tumors. Fertil Steril 28:920, 1977 Child DR, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin, and pituitary tumours. Br Med J 4:87, 1975 Gemzell C: Induction of ovulation in infertile women with pituitary tumors. Am J Obstet Gynecol 121:311, 1975 Lamberts SWJ, Seldenrath HJ, Kwa HG, Birkenhager JC: Transient bitemporal hemianopsia during pregnancy after treatment of galactorrhea-amenorrhea syndrome with bromocriptine. J Clin Endocrinol Metab 44:180, 1977 Keye WR Jr, Chang RJ, Jaffe RB: Prolactin secreting pituitary adenomas in women with amenorrhea or galactorrhea. Obstet Gynecol Survey 32:727, 1977 Schenker JG, Ben-David M, Polishuk WZ: Prolactin in normal pregnancy: relationship of maternal, fetal, and amniotic fluid levels. Am J Obstet Gynecol 123:834, 1975