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A Spontaneous and Severe Hyperstimulation of the Ovaries Revealing a Gonadotroph Adenoma¹

Service d’Endocrinologie, Hopital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (S.C.-M., P.B.); Laboratoire de Biochimie Médicale, Hopital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris and Endocrinologie Cellulaire et Moléculaire de la Reproduction Centre National de la Recherche Scientifique Unité de Recherche Associée 1449, Université Paris VI (M.-L.K.); INSERM U-342, Hopital Saint-Vincent-de-Paul (N.L.); and Unité INSERM U-344 Hopital Necker Enfant-Malades (P.T.), Paris; and Service de Gynécologie Obstétrique, Hopital A Béclère (C.R.-B., R.F.), Clamart, France

Address all correspondence and requests for reprints to: Dr. Sophie Christin-Maitre, Service d’Endocrinologie, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.

	Abstract

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We report an unusual case of a gonadotroph adenoma in a 34-yr-old woman, revealed by a dramatic rise in the plasma estradiol (E₂) concentration (26,800 pmol/L; normal, <370), with nonsuppressed FSH and LH levels (4.9 and 2.4 mIU/mL, respectively). The PRL level was 503 ng/mL. The testosterone and progesterone levels were 7 and 17 nmol/L, respectively. The levels of inhibin , inhibin A, and inhibin B were increased compared to normal values in both the follicular (fp) and luteal (lp) phases of the menstrual cycle [inhibin , 1986 IU/L (fp normal, <700; lp normal, <1650); inhibin A, 254 pg/mL (fp normal, <20; lp normal, <120); inhibin B, 246 pg/mL (fp normal, <150; lp normal, <30 lp)]. Pituitary magnetic resonance imaging revealed a huge pituitary adenoma. After transphenoidal surgery, the patient presented with pituitary insufficiency and diabetes insipidus. RT-PCR of the tumor tissue was positive for LHß, FSHß, -subunit, and PRL. This case is of particular interest because 1) although the E₂ level was extremely high, the patient did not present with ascitis, suggesting that chronic elevated E₂ does not play a crucial role in the hyperstimulation symptoms; 2) the extreme rise in E₂ was related to the cosecretion of FSH and LH, confirming the two-cell two-gonadotropin theory; and 3) the rise in inhibin B is associated with FSH secretion, whereas the rise in inhibin A is probably due to luteinization.

	Introduction

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IN WOMEN, gonadotroph (LH and FSH) adenomas are usually diagnosed after the menopause and are generally revealed by local mass effects (1, 2, 3). Gonadotropin overproduction is usually not responsible for a clinically recognizable syndrome. We report an unusual case of a gonadotroph adenoma in a 34-yr-old woman presenting with grossly enlarged ovaries and a dramatic rise in the plasma estradiol (E₂) concentration (26,800 pmol/L).

	Case Report

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Mrs. B. came to the emergency room because of massive metrorragia. The ultrasound examination discovered a multicystic pelvic mass (20 x 11.5 x 8 cm) including the two ovaries. A coelioscopy revealed five cysts from 5–8 cm on each ovary. Endometrial biopsy revealed endometrial hyperplasia without atypia. In her past history, neither previous illness nor family history was reported. Menarche occurred at the age of 13 yr. She had been pregnant without using profertility drugs 13 and 9 yr before admission. The second child was breast fed for 6 months. Galactorrhea persisted, although the patient had stopped breastfeeding for the past 6 yr. Since the second delivery, her menses had been usually every 2 months. Clinically, she presented with facial hirsutism and spontaneous galactorrhea. The visual field examination revealed a bitemporal hemianopsia. The plasma E₂ level was 7000 pmol/L (2400 pg/mL). LH and FSH levels were 3 and 6.8 mIU/mL, respectively.

	Materials and Methods

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RIAs were used to measure plasma concentrations of testosterone, androstenedione, progesterone, and 17-hydroxyprogesterone using ³H RIA kits from Biomérieux (Charbonnières-les-Bains, France). LH, FSH, E₂, GH, and -subunit were measured by immunoradiometric assays (Biomérieux). Anti-Mullerian hormone was measured using a two-site enzyme-linked immunosorbent assay (INSERM U293, Montrouge, France). The in vitro FSH bioactivity (B) was measured using a cell line expressing the human FSH receptor combined to a luciferase reporter gene, as previously described (4). Inhibin levels were measured by two-site enzyme-linked immunosorbent assays specific to inhibin , inhibin A, and inhibin B, as previously described (5, 6, 7). Tumor tissue was cut into two fragments: one was embedded in Bouin, and the other was deep frozen until nucleic acid extraction. Immunostaining was performed using monoclonal antibodies [Immunotech, Marseille, France; anti-FSH, anti-LH, anti-PRL, anti-TSH (1:500), and anti--subunit (1:500)]. Total ribonucleic acid (RNA) was extracted from tumor tissue and from normal pituitary tissue using RNA-PLUS (Bioprobe Systems, Montreuil, France). RNAs were transcribed into complementary DNA, which was used as a template for PCR amplifications using 0.75 U Taq polymerase (Appligene-Oncor, Illkirch, France). Forward (F) and reverse (R) oligonucleotide primer sequence were: for LHß: F1, 5'-CCTGGCTGTGGAGAAGGAGG-3'; R1, 5'-TCACAGGTCAAGGGGTGGTC-3' (8); for FSHß: F2, 5'-GACCAGGATGAAGACACTCC-3'; R2, 5'-CAAAGGAGCAGTAGC TGGGC-3' (9); and for -subunit: F3, 5'-CGCTACAGGAAAACCCATTCTTCTCCCA GCCCG-3'; R3, 5'AGTACTGCAGTGGCACGCCGTGTG-3' (10). Seven microliters of each PCR mixture were used for electrophoresis analysis of PCR products on agarose gel (1.5%) with DNA markers.

	Results

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Hormonal evaluation

The patient’s hormonal evaluation (Table 1) revealed a very high plasma E₂ level of 26,800 pmol/L. The PRL level was 503 ng/mL; hCG was not detectable. The testosterone, androstenedione, progesterone, and 17-hydroxyprogesterone levels were high: 7, 26.7, 17, and 38.5 nmol/L, respectively. The anti-Mullerian hormone level, a product of granulosa cells (11) was 2.97 ng/mL. The bioactive/immunoactive FSH ratio was not statistically different from that in cycling women. The levels of inhibin , inhibin A, and inhibin B were increased: 1986 IU/L, 254 pg/mL, and 246 pg/mL, respectively. The remaining anterior pituitary functions were intact. The TSH level was 1.66 µIU/mL; the free T₄ level was 10.9 pmol/L. During an ACTH test, the cortisol level reached 925 nmol/L, 60 min after iv 250 µg ACTH (Syntropin, Novartis Pharma, Rueil Malmaison, France). Acromegaly was excluded by an oral glucose tolerance test as GH levels decreased to 0.1 mIU/mL within 2 h. The level of insulin-like growth factor I was in the normal range. Calcemia, measured in the case of a potential type Ia multiple endocrine neoplasm, was normal (2.4 mmol/L).

As shown in Fig. 1 (a and b), pituitary magnetic resonance imaging (MRI) revealed a huge intra- and suprasellar lesion measuring 3 x 3 x 4 cm, impinging upon the optic chiasm. The upper limit of the tumor reached the foramen of Monro. The tumor invaded the sphenoidal sinus and laterally the left cavernous sinus. The imaging characteristics were those of a pituitary macroadenoma.

View larger version (80K): [in this window] [in a new window]   Figure 1. T1-weighted coronal (a) and sagittal (b) MRI (450/15) showing an intra- and suprasellar lesion, invading the left cavernous sinus, measuring 4 x 3 x 4 cm. T1-weighted coronal (c) MRI (450/15) was performed 3 months after surgery.

Treatment with bromocriptine (Parlodel, Novartis Pharma; 10 mg daily) was first attempted. The plasma PRL level was normalized in 72 h, but the visual field did not improve nor did the tumor volume decrease even after 3 weeks of treatment. Transphenoidal surgery was then performed, and a partially necrotic adenoma was extracted. Immunostaining of the tumor tissue was positive for FSHß (10%), LHß (50%), and -subunit (50%). As shown in Fig. 2, each PCR product from the normal human pituitary and the tumor fragment displayed the expected size, corresponding to FSHß (380 bp), LHß (288 bp), and -subunit (227 bp). RT-PCR was also positive for PRL (373 bp; data not shown). After surgery, the patient normalized her visual field and presented with pituitary insufficiency and diabetes insipidus, as shown in Table 1. A tumor remnant could be seen on MRI, as shown in Fig. 1c. Three months after surgery, the FSH level started to rise (6.2 mIU/mL), and a 10-day progestin withdrawal test was positive. The patient was, therefore, subsequently treated with radiotherapy (55 Gy).

View larger version (54K): [in this window] [in a new window]   Figure 2. RNAs extracted from the tumor tissue (P for patient) and from a normal human pituitary fragment used as positive control (C2) were agarose electrophoresed and visualized using ethidium bromide. C1 corresponds to a negative control. A, Amplification using F1/R1 and F2/R2 primers; B, amplification using F3/R3 primers. M represents DNA markers (X174 digested with HaeIII). The size of the FSHß fragment is 380 bp, that of the LHß fragment is 288 bp, and that of the -subunit fragment is 227 bp.

	Discussion

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In our patient, the FSH bioactivity/immunoactivity ratio was not increased. Only few cases of increased FSH bioactivity have been previously reported in gonadotroph adenomas (14, 15). An indirect measurement of FSH bioactivity is the evaluation of inhibin secretion. Lahlou et al. (16) have previously shown that plasma immunoreactive inhibin levels are correlated with tumor volume in men. Recent studies have shown that during the normal menstrual cycle, inhibin A is preferentially secreted during the luteal phase (6). In contrast, inhibin B is secreted during the follicular phase (7) and could represent a marker of follicular reserve and growth (17). In our patient, both inhibin A and B were elevated. Inhibin B rose in relation with FSH stimulation, whereas the high inhibin A and progesterone levels suggest that the follicles were luteinized. The increased progesterone level in our patient was probably secondary to LH stimulation.

Concerning the treatment of this adenoma, a GnRH agonist was not used because of the potential risk of the initial flare-up effect. Under such treatment, an increase in tumor size with the risk of pituitary apoplexy has been reported (18). Furthermore, the efficacy of GnRH agonist treatment has not been proven (19). Interestingly, no reduction in size has been reported after antagonist treatment of gonadotroph adenomas (20, 21). The bromocriptine therapy was remarkably efficient in reducing PRL levels, but the volume of the adenoma was not modified, consistent with failure of tumor shrinkage with dopamine agonist therapy previously shown in 76 of 84 well characterized gonadotroph adenomas (22). Finally, 4 months postsurgery, the plasma FSH level started to rise, and a progestin withdrawal test was positive, in keeping with incomplete surgical treatment of the macroadenoma. Therefore, the patient was subsequently treated with pituitary radiotherapy.

Although the plasma E₂ level in our patient was extremely high, she presented without ascitis or edema as it is usually the case in ovarian hyperstimulation syndrome (OHSS) induced by gonadotropin therapy. This clinical case report illustrates the fact that chronic E₂ elevation does not play a crucial role in the clinical presentation of OHSS. It is now well recognized that angiogenic factors, such as vascular endothelial growth factor, play a key role in the pathophysiology of OHSS.

In conclusion, we report a very unusual gynecological presentation of a gonadotroph adenoma. This case emphasizes the importance of measuring E₂, inhibin B, and gonadotropin levels in the presence of multicystic ovaries. These measurements would probably increase the frequency of early diagnosis of gonadotroph adenoma in premenopausal women.

	Acknowledgments

 
We thank Dr. R. Casper for helpful discussion of the manuscript, and Prof. Mikol and Dr. Seret-Beguet for performing immunocytochemistry on the tumor tissue.

	Footnotes

 
¹ This work was supported in part by a grant from Délégation à la Recherche Clinique Project AOB 94045 and CRC Grant 96108.

Received March 18, 1998.

Revised June 18, 1998.

Accepted July 8, 1998.

	References

Top Abstract Introduction Case Report Materials and Methods Results Discussion References

 

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