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Successful Pregnancy after Bromocriptine Therapy in an Anovulatory Woman Complicated with Ovarian Hyperstimulation Caused by Follicle-Stimulating Hormone-Producing Plurihormonal Pituitary Microadenoma

Departments of Obstetrics and Gynecology and Maternal and Perinatal Medicine (Y.M., H.A., S.M.), and Department of Neurosurgery (K.S.), Nagoya University Graduate School of Medicine, Nagoya 466-8550; Division of Pathology (T.N.), Clinical Laboratory, Nagoya University Hospital, Nagoya 466-8560; and Departments of Neurosurgery (I.T.) and Obstetrics and Gynecology (H.F., K.M.), Anjo Kosei Hospital, Anjo, Aichi 446-8602, Japan

Address all correspondence and requests for reprints to: Hisao Ando, M.D., Ph.D., Department of Obstetrics and Gynecology, Nagoya University School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: ando{at}med.nagoya-u.ac.jp.

Abstract

Gonadotropin-producing pituitary adenomas are extremely rare in reproductive-age women. We report here a case of gonadotroph microadenoma with ovarian hyperstimulation. It was found in a 29-yr-old infertile Japanese woman with enlarged multicystic ovaries. The patient had an elevated basal serum estradiol level (up to 6755 pM, or 1840 pg/ml). Serum FSH and prolactin were mildly elevated (15.4 IU/liter, 1.4 nM or 31.4 ng/ml), whereas LH was low (0.5 IU/liter). The FSH level was paradoxically elevated in response to TRH administration. Dynamic magnetic resonance imaging revealed a pituitary microadenoma. Daily administration of bromocriptine, a dopamine agonist, normalized the ovarian size, and the patient ovulated naturally. She conceived after 3 months of bromocriptine therapy and delivered a normal child. She underwent elective transsphenoidal pituitary surgery, 3 yr after the delivery. Immunostaining of the resected tumor showed that 80% and less than 5% of the tumor cells stained for FSH-ß and prolactin, respectively. Furthermore, RT-PCR suggested that dopamine type 2 receptor was expressed in the adenoma. Gonadotroph microadenoma should be considered in women with spontaneous ovarian hyperstimulation, even if they have no neurological symptoms or marked pituitary enlargement. In such cases, bromocriptine therapy may be an alternative to pituitary surgery.

SPONTANEOUS OVARIAN HYPERSTIMULATION is extremely rare, although exogenous gonadotropin stimulation may frequently cause ovarian hyperstimulation syndrome. In addition to a few pregnant women who have hypothyroidism or polycystic ovary syndrome or factor V Leiden mutation (1, 2, 3), only a limited number of cases of spontaneous ovarian hyperstimulation asttributable to the gonadotroph adenoma have been reported to date (4, 5, 6, 7, 8, 9, 10). Transsphenoidal tumor resection was performed in all of these macroadenoma cases. Some nonsurgical treatments for gonadotroph adenoma are also known, including GnRH analogs and dopamine agonist, although their effects have not been fully determined. We report here the first case of an infertile woman with a gonadotroph microadenoma causing ovarian hyperstimulation. This is also the first case of pregnancy and delivery after successful bromocriptine treatment of such a patient.

Subject and Methods

Serum LH and FSH levels were measured by immunoradiometric assays using Spac-S LH and FSH kits from Daiichi Pharmaceutical Company Ltd. Radioisotope Laboratory (Tokyo, Japan). The detection limit in both of these assays was 0.5 IU/liter. No cross-reactivity with TSH, human CG, FSH, or LH was detectable. Glycoprotein hormone -subunit was measured by a two-site chemiluminescent immunoassay. Estradiol, progesterone, and testosterone levels were determined by RIA using a kit from Diagnostic Products (DPC; Los Angeles, CA). The detection limit of the DPC estradiol kit was 29.4 pM (8 pg/ml; measurement range, 29.4–13,950 pM). The interassay variation was less than 7% coefficient of variation. The cross-reactivity with estrone and estriol was 1.03% and 0.32%, respectively. The detection limit of the DPC progesterone kit was 0.06 nM (0.02 ng/ml; measurement range, 0.06–127 nM). The measurement range of the DPC testosterone kit was 0.14–55.5 nM (4–1,600 ng/dl). The cross-reactivity with cortisol and estradiol was 0.005% and 0.02%, respectively. Prolactin (PRL) was measured by RIA using PRL Riabead II from Dainabot (Tokyo, Japan). The measurement range was 0.01–9.10 nM (0.3–200 ng/ml). No cross-reactivity was detectable at concentrations under 3,000 IU/liter for LH, 1,000 IU/liter for FSH, and 1 IU/liter for TSH. GH was measured by immunoradiometric assay using a kit from Daiichi Radioisotope Laboratory. An enzyme immunoassay was used for the determination of serum TSH values, with an AIA-PACK TSH kit (TOSOH Medics, San Francisco, CA). The cross-reactivity with LH was 0.17%; and that with human CG, FSH, and human GH was less than 0.01%. The TRH test was performed to evaluate the response of the anterior pituitary gland. Five hundred micrograms of TRH were administered iv, and serum FSH and LH levels were measured at 0, 15, 30, 60, 90, and 120 min.

Magnetic resonance imaging (MRI) was performed with a Vizard System (1.5-tesla MRI imaging system; Toshiba Medical Systems, Tokyo, Japan). Magnevist (Nihon Schering, Tokyo, Japan) was used as a contrast agent for dynamic MRI. X-Ray computed tomography (CT) was performed using an Xvigor (Toshiba Medical Systems). Iopamiron 300 (Nikon Schering, Tokyo, Japan) was used as a contrast medium. Three-dimensional (3D)-image manipulation and reconstruction for x-ray CT was performed by using Xtension, version 2.2 (Toshiba Medical Systems).

A transsphenoidal specimen of the pituitary tumor was fixed in 10% buffered formalin and embedded in paraffin. Sections of 3-µm thickness were stained with hematoxylin-eosin. Immunohistochemical staining was carried out as described elsewhere (11), based on the labeled streptavidin-biotin method, using the Ventana’s BenchMark IHC Staining System (Ventana Medical Systems, Tucson, AZ). The primary antibodies used were as follows: antihuman FSH-ß subunit mouse monoclonal antibody (clone C10/M3504; DAKO Corp., Carpinteria, CA), antihuman LH-ß subunit mouse monoclonal antibody (clone C93; DAKO Corp.), antihuman ACTH mouse monoclonal antibody (clone 02A3; DAKO Corp.), antihuman PRL rabbit polyclonal antibody (DAKO Corp.), antihuman GH rabbit polyclonal antibody (DAKO Corp.), and antihuman dopamine type 2 receptor (D2R) protein (amino terminus) goat polyclonal antibody (D2DR sc-7522; Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The Basic DAB Detection Kit (Ventana Medical Systems), which yielded a brown product from diaminobenzidine/copper sulfate, was used to detect FSH-ß and other hormones. For negative control experiments, the primary antibody was replaced by mouse IgG. Stained sections were observed under a BH2 microscope from Olympus Corp. (Tokyo, Japan) and photographed using Superia 100 film (Fujicolor; Fuji Photo Film Co., Ltd., Tokyo, Japan) and an Olympus Corp. camera.

A fragment of the resected tumor tissue was fresh-frozen for use in later experiments. Total RNA from the resected tumor tissue and the tissue of a human female’s pituitary prolactinoma, which was provided by the tissue bank of the Department of Neurosurgery of Nagoya University with approval of the Institutional Review Board, was extracted with an RNeasy Mini Kit (QIAGEN, Valencia, CA) according to the manufacturer’s protocol. RNA concentrations were quantified using a spectrophotometer at 260 nm. Half a microgram of total RNA was reverse-transcribed, and the cDNA product was amplified by PCR using Ready-To-Go RT-PCR Beads (Amersham Pharmacia Biotech, Piscataway, NJ). Reverse transcription was performed at 42 C for 30 min; and after denaturation at 96 C for 5 min, 35 cycles of PCR (96 C for 30 sec, 60 C for 30 sec, and 72 C for 1 min) were performed. The following forward and reverse oligonucleotide primer sequences were used for human D2R: 5'-GGTCTACATCAAGATCTACATTGTCCTCC-3' and 5'-TGGCGAGCATCTGAGTGGCTTTCTTCTCC-3', which amplify fragments from both the short and long splicing variants, 420 and 507 bp; for -subunit, 5'-CGCTACAGGAAAACCCATTCTTCTCCCAGCCCG-3' and 5'-AGTACTGCAGTGGCACGCCGTGTG-3', which amplify a 227-bp fragment; for FSH-ß, 5'-GACCAGGATGAAGACACTCC-3' and 5'-CAAAGGAGCAGTAGCTGGGC-3', which amplify a 380-bp fragment; for LH-ß, 5'-CCTGGCTGTGGAGAAGGAGG-3' and 5'-TCACAGGTCAAGGGGTGGTC-3', which amplify a 288-bp fragment.

Case Report

A 29-yr-old nulligravid Japanese woman consulted the Department of Obstetrics and Gynecology, Anjo Kosei Hospital, with complaint of infertility. She was 150 cm tall and weighed 40 kg. She had irregular menstrual periods, and her basal body temperature record indicated anovulatory cycles. X-Ray CT (Fig. 1A) and transvaginal ultrasound (Fig. 1B) revealed multicystic megaovaries measuring 110 x 100 x 65 mm (right) and 50 x 62 x 72 mm (left). Ascites was not found in these examinations. Routine blood analysis did not show evidence of elevated hemoconcentration.

View larger version (79K): [in this window] [in a new window]   Figure 1. Images of the ovaries before/after bromocriptine therapy. A, CT examination revealed that the abdominal cavity was occupied by huge multicystic ovaries. B, Transvaginal ultrasonographic examination showed bilateral multicystic megaovaries. C, After bromocriptine administration, the size of both ovaries decreased to normal, and the patient spontaneously ovulated and then successfully conceived.

Serum FSH was inappropriately high, considering the high serum estradiol levels, and both serum FSH and LH levels were elevated in response to TRH (Table 1). We suspected gonadotropinoma and performed a pituitary imaging study to examine this possibility, although the patient did not have visual disturbance or other neurological signs; confrontational screening of visual fields by finger counting was normal. The imaging study revealed a microadenoma in the anterior pituitary lobe.

The patient also began to have regular menstrual periods again and successfully became pregnant. Her course of pregnancy was uneventful, but both ovaries gradually became enlarged in spite of the continued bromocriptine treatment until the 34th week of gestation. Her estradiol level was high (up to 58,000 pM or 15,800 pg/ml), but her serum FSH level remained in the normal range (5.1–8.4 IU/liter). She delivered a healthy male baby weighing 2,980 g.

In the postpartum period, the patient’s serum FSH level became reelevated, and both ovaries became enlarged and multicystic, as when she first visited. Therefore, she again started to take bromocriptine. She ovulated a few times during this period but failed to get pregnant. During the next 3 yr, in spite of an increased dosage of bromocriptine (up to 10 mg), her ovaries did not decrease in size, and her serum FSH and estradiol levels did not decrease (FSH, 15.7 IU/liter; LH < 0.5 IU/liter; estradiol, 3,051 pM or 831 pg/ml; progesterone, 16.9 nM or 5.4 ng/ml). Although she had no neurological symptoms that indicated macroadenoma in the pituitary gland and no change in pituitary size in MRI studies, transsphenoidal pituitary surgery was performed after preoperative evaluation of the tumor by 3D-CT, because she strongly desired to conceive another child as soon as possible. The tumor was successfully removed and the postoperative course was uneventful, except for transient diabetes inspidus.

Three months after the surgery, the serum FSH level decreased to within the normal range (from 15.7 to 7.8 IU/liter) and the paradoxical elevation of FSH was not observed (Table 1). Both ovaries were reduced in size, and the patient’s ovulatory cycle recovered 6 months after the operation, although her menstrual cycle was not regular.

Results

Endocrinological evaluation of pituitary adenoma

The serum estradiol level was constantly high (up to 6,755 pM, or 1,840 pg/ml). The serum FSH was mildly elevated (15.4 IU/liter), but LH was low (0.5 IU/liter). Furthermore, FSH and LH were paradoxically elevated after TRH administration (Table 1).

Imaging evaluation of pituitary adenoma

MRI revealed that the pituitary fossa was within the normal size range (Fig. 2A). Microadenoma tissue was demonstrated in the right side of the pituitary by dynamic MRI (Fig. 2B). The location of the tumor was imaged in detail by 3D-processing from the helical x-ray CT images (Fig. 2, C–F). The tumor was 7 mm in diameter and was located in the right anterior lower part of the pituitary fossa.

View larger version (100K): [in this window] [in a new window]   Figure 2. Images of the pituitary microadenoma. A, On simple MRI, the anterior lobe of the pituitary was 7 mm in diameter in sagittal slices. B, On dynamic MRI, the left half of the anterior lobe was clearly enhanced after 115 sec of contrast medium infusion, and the existence of a pituitary microadenoma in the right side (arrow) was confirmed. C, Posterior view on 3D-CT. The image includes the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior clinoid process. The pituitary stalk (arrow) is shifted to the left. D, Posterior view at the pituitary fossa on 3D-CT. The left half of the pituitary fossa includes the anterior (arrows) and the posterior pituitary lobes as well as the pituitary stalk attributable to the presence of adenoma tissue in the lower right part of the pituitary fossa. E, Coronal section at the center of the pituitary fossa on 3D-CT. The right half of the pituitary fossa was occupied by the adenoma (7 mm in diameter, milky white, white arrows). The milky-white area on the left side (black arrow) is the posterior lobe, and it has the same CT value as the tumor tissue. The image of the anterior lobe in red has been diminished in this panel to show the adenoma tissue more clearly. F, Midsagittal section of pituitary fossa on 3D-CT. Adenoma tissue (arrows) is located in the front side of the pituitary fossa. R, right; L, left; A, anterior; P, posterior. Note: In the 3D-CT panels (C–F), five CT-value bands were created and colored as follows: beige corresponds to areas with CT values of -700 to -200, e.g. mucosal membrane of the paranasal sinus; white corresponds to areas with CT values of 35–65, e.g. bone; red corresponds to areas with CT values of 65–80, e.g. anterior pituitary lobe; milky white corresponds to areas with CT values of 80–100, e.g. adenoma tissue, pituitary stalk, posterior pituitary lobe; gold corresponds to areas with CT values of 100–270, e.g. blood vessels.

Histologic examination revealed tumor cells with round nuclei and clear cytoplasm. The cells had proliferated in trabecular or nest-like patterns, as is typical for pituitary adenomas (Fig. 3A). Immunohistochemical analysis showed positive reactivity for FSH in the cytoplasm of the majority of the adenoma cells (Fig. 3B). Some of the tumor cells were positive for PRL (Fig. 3C). However, no reactivity for TSH, GH, ACTH, LH, or D2R was detected (data not shown).

View larger version (92K): [in this window] [in a new window]   Figure 3. Pathology of the resected gonadotroph microadenoma tissue. A, In hematoxylin-eosin staining, characteristic adenoma cells with a round nucleus and clear cytoplasm are seen. The cells have proliferated in trabecular or nest-like patterns. B, In immunohistochemistry, more than 80% of the cells were stained with brown deposits with anti-FSH-ß monoclonal antibody. C, Less than 5% of the cells were stained with anti-PRL monoclonal antibody. Scale bar, 50 µm.

The presence of FSH-ß, LH-ß, and -subunit mRNAs in the tumor tissue was demonstrated by RT-PCR, using specific sets of primers for each mRNA (Fig. 4; lanes 1–3). Two fragments were amplified by the D2R primers, corresponding to the long and short splicing variants of D2R (Fig. 4; lane 4).

View larger version (150K): [in this window] [in a new window]   Figure 4. RT-PCR from the resected gonadotroph microadenoma tissue. Total RNA from the tumor tissue was amplified with FSH-ß primers (lane 1), LH-ß primers (lane 2), -subunit primers (lane 3), and D2R primers (lane 4). The presence of FSH-ß, LH-ß, and -subunit mRNAs was demonstrated in lanes 1–3 (380 bp, 288 bp, and 227 bp, respectively). In lane 4, long and short splicing variants of D2R mRNA (507 bp and 420 bp, respectively) were amplified. As a positive control, total RNA from human prolactinoma tissue was amplified with D2R primers (lane 5). As a negative control, total RNA from rat placenta was amplified with D2R primers (lane 6). M, Size marker (100-bp DNA ladder).

Gonadotroph pituitary adenomas are recognized, mostly in men and postmenopausal women, as clinically nonfunctioning sellar masses. Only seven premenopausal cases of spontaneous ovarian hyperstimulation attributable to gonadotroph macroadenoma have been reported (4, 5, 6, 7, 8, 9, 10), including a prepubertal case (7). There is only one successful postoperative pregnancy case report, which appeared while we were preparing this manuscript (10). The present report describes the first successful pregnancy after nonsurgical treatment. Moreover, this is also the first report of an FSH-producing functional pituitary microadenoma.

The most typical endocrinological abnormality in our case was the paradoxical response of FSH after TRH administration (12). As shown in the reported cases of macroadenomas, serum FSH elevation is not essential for the diagnosis of FSH-producing tumors (13). In the current case, serum FSH was mildly elevated and was not suppressed in spite of the high estradiol level.

In all previously reported cases of gonadotroph adenoma, transsphenoidal surgical resection was the first choice for treatment because of the neurological symptoms. Pituitary radiotherapy, GnRH analogs, dopamine agonist, or somatostatin analog were attempted only when patients had residual tumor or recurrent clinical symptoms. The effect of these nonoperative therapies remains controversial; and thus, there is no established treatment regimen at present (14, 15, 16, 17, 18). In the current case, the administration of bromocriptine, a dopamine agonist, improved the status of the hormonal levels and led to ovarian size reduction and recovery of the ovulatory cycle, followed by successful pregnancy. Although the mechanism of the effects of bromocriptine has not been clearly demonstrated, there have been some case reports in which bromocriptine was also effective for FSH-producing pituitary adenomas (19, 20, 21). Moreover, in vitro studies have shown that bromocriptine can suppress the release of gonadotropins and free -subunits from gonadotroph tumors (22). It is also interesting that D2R gene expression was detected by in situ hybridization, not only in prolactinomas but also in some other kinds of pituitary tumors (23, 24). In the current case, we could demonstrate the existence of D2R mRNA in the tumor cells, in contrast with the negative results of immunohistochemistry. This may have been attributable to the differing sensitivities of the two methods or to the absence of D2R protein expression with decreased D2R gene transcription. Unfortunately, the second trial of bromocriptine administration after delivery was unsuccessful. We consider that possible bromocriptine resistance arising before the operation, down-regulation of D2R protein, or spontaneous evolution of the tumor might explain this lack of response.

In the current case, histologic evaluation revealed that PRL was also secreted in a minor population of the tumor cells. It has been pointed out that a variety of plurihormonal pituitary adenomas may exist. The hormones most commonly expressed are GH, PRL, and one or more glycoprotein hormones, most often TSH. However, FSH- or LH-secreting plurihormonal adenomas are quite rare (25, 26, 27, 28).

In conclusion, we encountered a very rare case of FSH-secreting microadenoma, complicated with ovarian hyperstimulation and infertility. Gonadotroph adenoma with endocrinological symptoms might exist more frequently than expected, considering the recently increasing case reports thereof. Precise hormonal profiling and detailed intracranial examination are required for diagnosis. Gonadotroph adenomas may be sensitive to bromocriptine therapy via D2R, as demonstrated in the present case.

Footnotes

This work was supported in part by a grant-in-aid for Scientific Research (to H.A. and to S.M.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Abbreviations: CT, Computed tomography; D2R, dopamine type 2 receptor; 3D, three-dimensional; MRI, magnetic resonance imaging; PRL, prolactin.

Received November 19, 2002.

Accepted January 30, 2002.

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