help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2003-032029
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Piaditis, G.
Right arrow Articles by Kovacs, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Piaditis, G.
Right arrow Articles by Kovacs, K.
Related Collections
Right arrow Endocrine Oncology
Right arrow Female Endocrinology
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2097-2103
Copyright © 2005 by The Endocrine Society

Ectopic Bioactive Luteinizing Hormone Secretion by a Pancreatic Endocrine Tumor, Manifested as Luteinized Granulosa-Thecal Cell Tumor of the Ovaries

G. Piaditis, A. Angellou, G. Kontogeorgos, N. Mazarakis, T. Kounadi, G. Kaltsas, K. Vamvakidis, R. V. Lloyd, E. Horvath and K. Kovacs

Departments of Endocrinology and Diabetes (G.P., A.A., N.M., T.K., G.Ka.), Pathology (G.Ko.), and Surgery (K.V.), G. Gennimatas General Hospital, 115 27 Athens, Greece; Department of Pathology and Laboratory Medicine, Mayo Clinic Foundation (R.V.L.), Rochester, Minnesota 55905; and Department of Pathology, St. Michael’s Hospital (G.Ko., E.H., K.K.), University of Toronto, Toronto, Ontario, Canada M5B 1W8

Address all correspondence and requests for reprints to: Dr. George P. Piaditis, Department of Endocrinology and Diabetes Center, KOFKA Building, 1st Floor, G. Gennimatas General Hospital of Athens, 154 Messogion Avenue, 115 27 Athens, Greece. E-mail: edk-pgna{at}otenet.gr.


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
Endocrine pancreatic tumors are rare neoplasms consisting of multipotent cells capable of secreting various bioactive substances causing characteristic clinical syndromes. Ovarian stromal hyperthecosis is characterized by varying degrees of luteinized stromal cell proliferation after sustained LH and/or human chorionic gonadotropin stimulation, clinically manifested by symptoms/signs of virilization resembling the polycystic ovary syndrome (PCOS). We report a case of ectopic bioactive LH production from a pancreatic endocrine tumor in a 33-yr-old woman with rapidly developing symptoms/signs of hyperandrogenism and markedly elevated serum androgen and LH levels leading to hyperthecosis and bilateral luteinized granulosa-thecal cell tumors of the ovaries. Although the patient was initially thought to have either severe PCOS or an LH-secreting pituitary tumor, an LH-producing pancreatic endocrine tumor bearing somatostatin receptors was demonstrated on scintigraphy with [111In]octreotide and abdominal imaging. Symptoms and signs of hyperandrogenism resolved after the resection of the tumor. Immunohistochemistry, in situ hybridization, and electron microscopy studies confirmed LH synthesis by the tumor cell. Although extremely rare, ectopic LH production from nonpituitary endocrine tumors should be considered in the differential diagnosis of hyperandrogenism, particularly when associated with highly elevated serum LH levels.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
ENDOCRINE PANCREATIC TUMORS are rare neoplasms that can produce symptoms due to local expansion and hepatic metastases (nonfunctioning tumors) or more often due to the secretion of various bioactive substances accompanied by the development of characteristic clinical syndromes (functioning tumors) (1). Such tumors are able to synthesize and secrete insulin, glucagon, and, less frequently, pancreatic polypeptide, and they produce and secrete various peptide hormones, among which the more prevalent are ACTH, GHRH, PTHrP, and neurotensin (2, 3, 4, 5). Ovarian stromal hyperthecosis is characterized by varying degrees of luteinized stromal cell proliferation after sustained LH (6) and/or human chorionic gonadotropin (hCG) (7, 8) stimulation, clinically manifested by symptoms/signs of virilization in postmenopausal women (9) and occasionally in women of reproductive age resembling the polycystic ovary syndrome (PCOS) (10).

We report the case of a 33-yr-old woman who presented with symptoms/signs of virilization and bilateral ovarian luteinized granulosa-thecal cell tumors attributed to ectopic LH secretion from a pancreatic endocrine tumor. The progressive severe clinical symptoms and the persistently markedly elevated serum LH levels led to identification of the ectopic LH production source. Clinical and biochemical remission after resection of the tumor and morphological studies conclusively confirmed that the pancreatic tumor was the source of ectopic LH production in this patient. To our knowledge, this rare clinical entity secondary to ectopic production of bioactive LH has never been described.


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results
 Discussion
 References
 
Case report

A 33-yr-old woman was referred to G. Gennimatas General Hospital of Athens with rapidly developing symptoms/signs of hyperandrogenism, secondary amenorrhea, infertility, and substantially elevated serum LH levels (220 IU/liter; normal range, 5–25 IU/liter). Her menarche was at the age of 15 yr; because she subsequently developed oligomenorrhea and mild hirsutism, the diagnosis of PCOS was made. The patient underwent a successful pregnancy and delivery at the age of 22 yr, after 3-month treatment with clomiphene citrate and hCG; her endocrine profile at that time was not available. After delivery, she developed oligomenorrhea again and secondary infertility despite treatment with clomiphene citrate/hCG or gonadotropins/hCG for 4 yr. Two years before admission to our hospital she developed severe acne, deepening of her voice, amenorrhea, and worsening hirsutism. Endocrine investigations revealed high serum androgen [free testosterone (FT), 18.01 pg/ml (62.46 pmol/liter; normal range, 0.7–3.6 pg/ml); {Delta}4-androstenedione ({Delta}4A), 13.99 ng/ml (48.87 nmol/liter; normal range, 0.5–2.8 ng/ml)] and LH (156.5 IU/liter) levels, but normal dehydroepiandrosterone sulfate [DHEA-S; 173.9 µg/dl (4.72 µmol/liter; normal range, 35–430 µg/dl)], FSH (5.3 IU/liter; normal range, 1–8 IU/liter), and prolactin (PRL; 8.4; normal range, <23 ng/ml) levels. Ovarian ultrasonography revealed a 2.8-cm left ovarian solid tumor and slight enlargement of the right ovary. Computer tomography (CT) and magnetic resonance imaging (MRI) of the pituitary did not reveal any pathology. The patient underwent resection of the left ovarian tumor and a wide wedge resection of the right; histology revealed a typical thecoma with nodular hyperthecosis of the resected right ovarian wedge. Postoperatively, androgen serum levels markedly decreased [total testosterone, 0.60 ng/ml (2.1 nmol/liter; normal range, 0.2–0.9 ng/ml); FT, 2.30 pg/ml (7.98 pmol/liter); {Delta}4A, 3.29 ng/ml (11.5 nmol/liter)], but serum LH levels remained markedly elevated at 220 IU/liter. Because pituitary imaging was negative, a presumptive diagnosis of severe PCOS was made, and the patient was started on treatment with a long-acting GnRH analog (triptorelin depot, 3.75 mg/month) for 3 months. This treatment was not associated with any substantial reduction of the elevated LH serum levels (LH, 98–220 IU/liter); in addition, serum androgens raised again to the postoperative levels [FT, 17.16–21.57 pg/ml (59.5–74.8 pmol/liter)]. For 4 months before her current admission, she received no medication.

On admission, she was found to be normotensive (125/75 mm Hg), but overweight (body mass index, 27 kg/m2). Clinical examination revealed marked acne on the face and neck, hirsutism, and virilism. Terminal hair was present beneath the chin, on the upper lip, the sideburn area, about the areola, and over the presternal region. The pubic hair extended along the midline to the umbilicus and involved the medial aspects of the thighs. Muscle bulk was increased, and she had mild (grade II) clitoromegaly, but no acanthosis nigricans; the rest of the clinical and gynecological examination showed no abnormalities. Routine hematology and biochemistry were normal. Serum androgen [{Delta}4A, 19.98 ng/ml (69.8 nmol/liter); FT, 21.57 pg/ml (74.8 pmol/liter); 17-hydroyprogesterone, 7.92 ng/ml (24 nmol/liter; normal range, 0.1–1.0 ng/ml)] and LH (203 IU/liter) levels were elevated, whereas estradiol (E2) [92.34 pg/ml (339 pmol/liter)], PRL (10.6 ng/ml), DHEA-S [254 µg/dl (6.9 µmol/liter)], and FSH (3 IU/liter) were within the normal range; SHBG [22.9 nmol/liter; normal range, 20–120 nmol/liter) levels were significantly reduced. She underwent an oral glucose tolerance test (75 g glucose, orally), which revealed normal glucose tolerance with mild hyperinsulinemia (insulin: 0 min, 11.3; 30 min, 65.4; 60 min, 101.3; 90 min, 107.1; 120 min, 113.6 µU/ml). Thereafter, the patient received octreotide, a long-acting somatostatin analog (200 µg/6 h for 3 d), which resulted in significant reduction of serum LH levels (before, 220 IU/liter; after, 104 IU/liter).

A repeated MRI scan of the pituitary showed no evidence of a pituitary lesion, and a transvaginal ultrasonographic pelvic examination revealed a normal uterus with an 8-mm endometrium and a 2.2-cm solid tumor of the right ovary. After substantial reduction of serum LH levels following the administration of octreotide, additional imaging with helical CT scan of the chest, CT and MRI of the abdomen, as well as a whole body [111In]octreotide scan (octreoscan) were suggested. However, because of the severity of the symptoms/signs of hyperandrogenism and their apparent relation to the tumor of the ovary, the patient decided to have a right ovariectomy in a private maternity hospital. Histology also disclosed a typical thecoma.

Two months later, the patient was readmitted to this hospital for additional investigation. Although postoperative serum androgen and E2 levels fell within or below the normal range [total testosterone, 0.39 ng/ml (1.38 nmol/liter); FT, 1.5 pg/ml (5.2 pmol/liter); {Delta}4A, 0.9 ng/ml (3.14 nmol/liter); E2, 8.17 pg/ml (30 pmol/liter)], serum LH remained grossly elevated (LH, 238.8 IU/liter; FSH, 48.4 IU/liter). Both the CT and MRI scans of the abdomen revealed a 7-cm tumor at the tail of the pancreas (Fig. 1Go), which corresponded to a well-demarcated intense uptake of a whole body octreoscan (Fig. 2Go); a CT of the adrenals was normal. On view of these findings, a presumptive diagnosis of ectopic LH secretion from a pancreatic endocrine tumor possessing somatostatin receptors was made. The patient underwent surgical exploration and removal of the pancreatic tumor.



View larger version (54K):
[in this window]
[in a new window]
  		FIG. 1. Abdominal MRI showing a 7-cm tumor at the tail of the pancreas (arrows). The tumor appears hypointense on T1-weighted (left) and hyperintense on T2-weighted (right) images.

 


View larger version (70K):
[in this window]
[in a new window]
  		FIG. 2. The octreoscan shows an abdominal, well-demarcated intense uptake of [111In]octreotide corresponding to a 7-cm tumor at the tail of the pancreas.

 
Postoperatively, serum LH levels although significantly decreased (LH, 89.8 IU/liter) still remained within the range usually seen in postmenopausal women. After 2-month administration of long-acting GnRH analog (triptorelin depot, 3.75 mg/month), serum LH levels decreased significantly (6 IU/liter), but failed to suppress completely, suggesting that part of the tumor was left behind. A subsequent whole body octreoscan and abdominal MRI identified a residual tumor of 1.5 cm in the pancreas. Follow-up studies during the last 3 yr showed no change in the size of the remaining tumor.

Histology

For light microscopy, formalin-fixed, paraffin-embedded tissue samples were used; sections 4 µm thick were stained with hematoxylin and eosin.

Immunohistochemistry

The standard avidin-biotin-peroxidase complex technique was applied on paraffin sections of the pancreatic tumor. Details of the technique have been previously described (11). Primary antisera included general endocrine markers and related antigens (chromogranin, synaptophysin, neuron-specific enolase, and S-100 protein), endocrine hormones and peptides (insulin, glucagon, somatostatin, pancreatic polypeptide, cholecystokinin, vasoactive intestinal polypeptide, and hCG), and pituitary hormones [GH, PRL, ACTH, ß-TSH, ß-FSH, ß-LH, and {alpha}-subunit of glycoprotein hormones ({alpha}-SU)]. The proliferation index was estimated using the Ki-67 antibody (cone MIB-1). For the ovarian tumors, immunohistochemistry for {alpha}- and ß-inhibin was also used (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Antibodies used for immunohistochemistry

 
Electron microscopy

For electron microscopy, selected samples of the pancreatic tumor were appropriately fixed in glutaraldehyde, postfixed in osmium tetroxide and embedded in a mixture of Epon-Araldite. Ultrathin sections, stained with uranyl acetate and lead citrate, were studied with a Phillips 410LS electron microscope (Phillips Electronic Instruments, Rahway, NJ) (11).

In situ hybridization

The technique was performed using sequences of oligonucleotide probes for ß-LH and {alpha}-SU as described previously (12, 13, 14). Briefly sections from the pancreatic tumor were deparaffinized, treated with prehybridization washes, and incubated with 1x106 cpm 35S-labeled probes in hybridization buffer for 18 h. They were subsequently washed in 2x and 0.5x standard saline citrate and dehydrated in alcohol. Autoradiography was carried out with Kodak NTB2 emulsion (Eastman Kodak Co., Rochester, NY). After 2 wk, they were developed and counterstained with hematoxylin. Negative controls for in situ hybridization used oligonucleotide and sense probes for ß-LH and {alpha}-SU. For positive controls, normal anterior pituitary tissue was used.

Dispersed cell cultures

Pancreatic tumor tissue was mechanically dissected in PBS solution and digested in solution containing DMEM/Ham’s F-12, collagenase type 2 (1 mg/ml), and gentamicin (100 µg/ml). There were three enzymatic digestions of 30 min each; then the dispersed cells were placed in 24-well plates (100,000 cells/well plate and 200,000 cells/well plate). After incubation at 37.5 C in 5% CO2 for 24 h, cells were treated with somatostatin for 1–4 h. Consequently, the supernatant was collected, and the LH concentrations were measured and compared with the basal levels of the untreated controls.

Hormone assays

Serum LH, FSH, and hCG concentrations were determined by two-site monoclonal antibody immunoradiometric assays (CIS Bio-International, Saclay, Paris, France), and all other hormones were determined by double antibody RIAs: {Delta}4A with Diagnostic System Laboratories kits (Webster, TX); total testosterone with Byk-Sangtec kits (Dietzenbach, Germany); E2, FT, DHEA-S, and insulin with Diagnostic Products Corp. kits (Los Angeles, CA); 17-hydroyprogesterone with a CIS Bio-International kit; and SHBG with an Orion Diagnostica kit (Espoo, Finland). The LH assay showed no cross-reaction with hCG, FSH, TSH, or {alpha}- and ß-LH subunits.


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
Pancreatic tumor

Histology. The pancreatic tumor admitted for histology was ovoid, well demarcated, and encapsulated, measuring 6.5 x 4.5 x 4.5 cm. On sectioning, it was solid, soft, and yellow, showing a homogeneous, partly lobular appearance. Histological examination was consistent with the diagnosis of a well-differentiated pancreatic endocrine tumor. The tumor consisted of highly cellular solid nests or anastomosing trabecules, separated by delicate, vascularized connecting tissue (Fig. 3Go). The tumor cells were small and round with spherical nucleus and focally conspicuous nucleolus. Mitotic figures were rare.



View larger version (92K):
[in this window]
[in a new window]
  		FIG. 3. Endocrine tumor of the pancreas (left; hematoxylin-eosin stain; x2.5). The well differentiated neoplasm consisted of cellular, solid trabecular nests separated by delicate vascularized connective tissue (right; hematoxylin-eosin stain; x10).

 
Immunohistochemical and electron microscopic analysis. The tumor was immunoreactive for the general endocrine markers, mostly for synaptophysin chromogranin and neuron-specific enolase. The tumor cells were strongly immunoreactive for ß-LH and {alpha}-SU (Fig. 4Go). Immunostain for S-100 protein disclosed several scattered cells representing sustentacular cells. The proliferation index assessed by Ki-67 was less than 1%. Immunostains for insulin, glucagon, somatostatin, pancreatic polypeptide, vasoactive intestinal polypeptide, hCG, GH, PRL, ACTH, ß-TSH, and ß-FSH were negative. By electron microscopy, the tumor consisted of polyhedral or polar cells with spherical nuclei. The cytoplasm contained moderately developed Golgi apparatus and several parallel profiles of rough endoplasmic reticulum. A fair number of mitochondria and scarce secretory granules of 100–150 nm mostly accumulated in the cytoplasmic processes (Fig. 5Go).



View larger version (82K):
[in this window]
[in a new window]
  		FIG. 4. Variably strong immunoreactivity for ß-LH (left) and {alpha}-SU (right) pancreatic endocrine tumor cells (avidin-biotin-peroxidase complex technique; magnification, x20).

 


View larger version (128K):
[in this window]
[in a new window]
  		FIG. 5. Electron micrograph demonstrating endocrine cells with spherical nucleus and moderately developed membranous organelles. The sparse 100- to 150-nm secretory granules are present mainly in cytoplasmic processes (magnification, x11,000).

 
In situ hybridization and dispersed cell cultures. In situ hybridization showed positivity in the tumor cells with the ß-LH and {alpha}-SU mRNA antisense probes, whereas the sense probes produced no staining (Fig. 6Go). Experiments with dispersed cell cultures after incubation with somatostatin resulted in suppression of LH secretion by approximately 90–95%. Maximum suppression was observed within 1 h (Table 2Go).



View larger version (85K):
[in this window]
[in a new window]
  		FIG. 6. Expression of ß-LH mRNA (left) and {alpha}-SU mRNA (right) in pancreatic tumor cells by in situ hybridization (magnification, x20).

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Dispersed cell culture results

 
Ovarian tumors

Histological and immunohistochemical analysis. By light microscopy, the ovarian tumors were composed of clusters or sheets of ovoid or polyhedral cells with ample acidophilic cytoplasm and discerning cytoplasmic borders. The nuclei were small and round, possessing small nucleoli. Among the tumor cells, eosinophilic proteinaceous material was focally present. By immunohistochemistry, the tumor cells were selectively positive for {alpha}- and ß-inhibin, showing strong and diffuse cytoplasmic reactivity. The adjacent parenchyma of both ovaries included multiple atretic cystic follicles, showing luteinization of the inner theca; some of them were in various stages of regression. In addition, multiple primary ovarian follicles were noted. The initially resected right ovarian wedge also showed foci of nodular hyperthecosis. Based on the histological findings, the diagnosis of luteinized granulosa-thecal cell tumor was made.


   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
Pancreatic endocrine tumors are rare neoplasms that can occur either sporadically or as part of the multiple endocrine neoplasia type 1 syndrome (1). Approximately 80% of these tumors secrete a variety of peptide hormones associated with characteristic clinical entities, among which the best known are insulinoma, glucagonoma, somatostatinoma, Zollinger-Ellison (gastrinoma) syndrome, Cushing’s syndrome, and acromegaly (1).

Cushing’s syndrome may be caused by ACTH (15) or CRH (3), and acromegaly is GHRH mediated in most cases (4, 16), whereas ectopic GH secretion is rarely observed (17). Less commonly secreted peptide hormones have also been noted, including PTH-like peptide (5), calcitonin (18, 19), calcitonin gene-related peptide (20), proopiomelanocortin-derived peptides (21), neuropeptide Y (22), and ghrelin (23). In some cases, hormone precursors are produced and secreted by the pancreatic tumors instead of the intact hormone, whereas the excessive production of many of these hormones may not be associated with characteristic signs and symptoms.

Until recently, only one case of pancreatic endocrine tumor with ectopic LH production has been reported in a 40-yr-old woman (24). Although this woman was of reproductive age, there was no hirsutism or acne, and her serum levels of all androgens were within the normal range, in contrast with our case, in whom severe hirsutism and greatly elevated serum androgens levels were observed. The findings in the previously reported case suggest that either the LH molecules secreted by the tumor were not bioactive or the LH receptors were desensitized by the greatly elevated LH levels (644 IU/liter). The latter explanation seems more likely, because the LH secreted by the tumor was shown to be bioactive using a heterologous bioassay. It is probable that when extremely elevated LH levels exceed a critical level, they can induce LH receptor desensitization. However, this may not be the case in our patient, partly because of the much lower LH levels (203 IU/liter). Although LH receptor desensitization is a well-characterized phenomenon after prolonged elevation of hCG/LH levels (25), this is not always the case, because men with an hCG-producing tumor and greatly elevated serum hCG levels (>3.5 x 103 IU/liter) retain serum testosterone levels well above the normal range (26). In addition, long-standing elevation of LH levels in transgenic mice was associated with hyperandrogenemia and thecal-interstitial cell hypertrophy (27), whereas complete desensitization of the LH receptor is not observed even after the administration of high LH or CG doses in different animal models (28).

The findings in our case are in agreement with the above observations and show that the human ovaries may retain a significant steroidogenic activity, besides chronically and greatly elevated LH levels. This may be related to the gradual and progressive increase in LH production defined by the benign nature and slow growth potential of the tumor. At the early stages of LH tumor development, LH levels rise but still remain below a critical level, capable of inducing receptor desensitization, retaining full biological activity capable of inducing profound proliferation and luteinization of ovarian stromal cells. Thereafter, as the LH tumor size increases, the LH concentration exceeds that critical level and may thus cause LH receptor desensitization. However, as mentioned above, LH receptor desensitization is not complete, and the remaining, even small, LH bioactivity may justify the significantly raised ovarian androgen levels because of the preceding ovarian stromal cells hyperplasia (mass effect). Nevertheless, ectopic bioactive LH production causing ovarian hyperthecosis and bilateral thecomas has not been reported to date.

The present case offers a unique opportunity to investigate the effect of long-standing, elevated, ectopically produced bioactive LH by a pancreatic endocrine tumor on ovarian function and histology in a woman of reproductive age. Ectopic secretion of bioactive hCG is a strong stimulus of ovarian or testicular steroidogenesis (6, 7, 8). The same holds true for ectopic secretion of bioactive LH, which was confirmed in our case by the clinical picture and significantly elevated serum androgen levels. Excessive LH production by the pancreatic tumor was documented by the increased serum and cell culture medium LH levels measured by an assay specific for LH (immunoradiometric assay) as well as by immunohistochemical analysis and in situ hybridization. In addition, electron microscopic studies confirmed the presence of secretory granules in the cytoplasm of pancreatic tumor cells. The positive octreoscan as well as the somatostatin-induced reduction of LH secretion in vivo and in vitro provided evidence that functional somatostatin receptors were present in the tumor cells, a common finding in endocrine tumors. Thus, scintigraphy with [111In]octreotide should be recommended when the suspicion of an ectopic source arises, because many endocrine tumors have somatostatin receptors and can be identified by a positive scan (29).

Two other cases of ectopic bioactive LH secretion, both by adrenocortical tumors, causing precocious puberty and increased LH and testosterone levels in two young boys, have been reported (30, 31). After tumor removal, the signs and symptoms of precocious puberty resolved, and the previously elevated serum LH and testosterone levels returned to normal in both cases, suggesting that LH secretion by the adrenocortical tumor was the cause of precocious puberty. Although large quantities of LH were found in tumor extracts and there was positive immunohistochemistry for LH in the tumor cells, electron microscopy and in situ hybridization studies were not performed.

The pathogenesis of pancreatic endocrine tumors is unknown. A number of somatic mutations of different oncogenes or tumor suppressor genes, such as K-ras, p53, c-erbB2, Rb (retinoblastoma gene), DPC4 (Smad4), CDKN2A/16p, and multiple endocrine neoplasia type 1 gene, that have been identified in other malignant neoplasms are claimed to be either rare or absent in pancreatic endocrine tumors (32, 33, 34). Various growth factors, among them steroidogenic factor-1 (SF-1), have been implicated in gonadotroph cell proliferation and differentiation. SF-1 is expressed and located in the nuclei of gonadotroph cells of the normal pituitaries (35). Targeted disruption of SF-1 gene in mice results in loss of GnRH receptor expression and selective impairment of gonadotroph cell development (36). Studies of human pituitary tumors showed that SF-1 expression is characteristic of FSH-/LH-producing adenomas as well as of null cell adenomas and oncocytomas that are known to produce ß-FSH/ß-LH subunits (37).

Stromal hyperthecosis (SHT) is characterized by nonneoplastic proliferation of luteinized ovarian stromal cells frequently accompanied by some degree of stromal hyperplasia (SHP). Luteinized granulosa-thecal cell tumors are rare steroid-producing tumors of the ovaries usually occurring in postmenopausal women (80%). They are small, less than 3 cm in size, and with rare exceptions, unilateral. They originate in stromal luteinized cells as in SHT and are accompanied by SHP in approximately 92% of cases, suggesting that SHP may be the first disorder of the disease, followed by SHT and subsequently by the development of luteinized granulosa-thecal cell tumors. Our case supports this sequence of events. Although the cause of SHT and luteinized granulosa-theca cell tumor formation is obscure, it is general knowledge that LH and/or hCG are the main factors in the development of the disease. Ovarian interstitial cells have specific high-affinity receptors for LH; during protracted stimulation they undergo dramatic morphological changes, as shown by in vitro studies (6). hCG-secreting trophoblastic tumors as well as pregnancy induce extensive luteinization of the ovarian stroma and may result in hyperthecosis and, rarely, formation of ovarian granulosa-thecal cell tumor, also known as pregnancy thecoma or luteoma (7, 8, 38). Activating mutations of the gene encoding the LH receptor (39) or the {alpha}-subunit of Gs (40) have been identified in a number of Leydig cell tumors of both men and women. However, the most convincing evidence for the casual role of LH in SHT and ovarian tumor formation was provided by recent studies using transgenic mice. Targeted overexpression of LH in transgenic mice leads to infertility, PCOS, ovarian hyperemia, and ovarian granulosa and stromal tumors (27, 41). In these mice, the first histological finding before tumor development was marked ovarian SHP. Gonadotropin hypersecretion was suggested as a mechanism for tumor formation in ovaries transplanted to the spleen in ovariectomized rats (42), in women receiving long-standing human menopausal gonadotropin treatment for infertility (43), and in ovaries of inhibin-deficient transgenic mice (44).

However, LH excess alone cannot explain the development of the disease in either pre- or postmenopausal women, because hyperthecosis is a very rare condition in both, and in premenopausal women, immunoreactive serum LH concentrations are within the normal range. These findings suggest that the causes of stromal cell tumor formation are likely to be heterogeneous, and other factors may also be involved in the development of the disease. One of them may be insulin resistance/hyperinsulinemia, a very common finding in women with SHT, correlated with the ratio of bioactive/immunoreactive LH (45). It is conceivable that alterations in other stimulating factors, such as SF-1, steroidogenic acute regulatory protein, Mullerian duct inhibitory factor, GATA-binding proteins, and FOG-2 (friend of GATA), may also play a role in neoplastic transformation. In our case, both ovarian tumors were strongly immunopositive for {alpha}- and ß-inhibin, which are involved in steroidogenesis and tumor formation (46, 47).

In summary, we have reported a rare case of a pancreatic endocrine tumor secreting bioactive LH accompanied by luteinized granulosa cell tumors of both ovaries. We want to call attention to this clinical entity in women presenting with symptoms/signs of hyperandrogenism and luteinized granulosa-thecal cell ovarian tumors associated with highly elevated LH levels.


   Footnotes
 
First Published Online February 1, 2005

Abbreviations: {Delta}4A, {Delta}4-Androstenedione; CT, computer tomography; DHEA-S, dehydroepiandrosterone sulfate; E2, estradiol; FT, free testosterone; hCG, human chorionic gonadotropin; MRI, magnetic resonance imaging; PCOS, polycystic ovary syndrome; PRL, prolactin; SF-1, steroidogenic factor-1; SHP, stromal hyperplasia; SHT, stromal hyperthecosis; {alpha}-SU, {alpha}-subunit of glycoprotein hormone.

Received November 20, 2003.

Accepted December 6, 2004.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

  1. Solcia E, Kloppel G, Sobin LH 2000 WHO: histological typing of endocrine tumors. Springer: Berlin, New York
  2. Le Bolic MF, Heymann MF, Lecomte M, Berger N, Berger F, Louvel A, De Micco C, Patey M, De Mascarel A, Burtin F, Saint-Andre JP 1996 Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia type I. Am J Surg Pathol 20:1378–1384[CrossRef][Medline]
  3. Beuschlein F, Hammer GD 2002 Ectopic pro-opiomelanocortin syndrome. Endocrinol Metab Clin North Am 31:191–234[CrossRef][Medline]
  4. Doga M, Bonadonna S, Burratin A, Giustina A 2001 Ectopic secretion of growth hormone-releasing hormone (GHRH) in neuroendocrine tumors: relevant clinical aspects. Ann Oncol 12(Suppl 2):S89–S94
  5. Bouvet M, Nardin SR, Burton DW, Lee NC, Yang M, Wang X, Baranov E, Behling C, Moossa AR, Hoffman RM, Deftos LJ 2002 Parathyroid hormone-related protein as a novel tumor marker in pancreatic adenocarcinoma. Pancreas 24:284–290[CrossRef][Medline]
  6. Erickson FC, Magoffin DA, Dyer AC 1985 The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 6:371–399[Abstract/Free Full Text]
  7. Nagamani M, Kaspar HG, Dinh TV, Hannigan EV, Smith E 1990 Hyperthycosis of the ovaries in a woman with a placental site trophoblastic tumor. Obstet Gynecol 76:931–935[Medline]
  8. Erkola R, Seppala P, Klemi PJ 1985 Virilization during pregnancy due to bilateral hyperthycosis. A case report. Horm Res 21:83–97[Medline]
  9. Braithwaite SS, Erkman-Balis B, Avila TD 1978 Postmenopausal virilization due to ovarian stromal hyperthycosis. J Clin Endocrinol Metab 46:295–300[Abstract/Free Full Text]
  10. Wentz AC, Grutaia JP, Jones GS, Migeon CJ 1976 Ovarian hyperthycosis in the adolescent patients. J Pediatr 88:488–493[CrossRef][Medline]
  11. Kontogeorgos G, Horvath E, Kovacs K, Killinger DW, Smyth HS 1991 Null cell adenoma of the pituitary with features of plurihormonality and plurimorphous differentiation. Arch Pathol Lab Med 115:61–64[Medline]
  12. Lloyd RV, Cano M, Chandler WF, Barkan AL, Horvath E, Kovacs K 1989 Human growth hormone and prolactin secreting pituitary adenomas analyzed by in situ hybridization. Am J Pathol 134:605–613[Abstract]
  13. Lloyd RV, Jin L, Fields K, Chandler WF, Horvath E, Stefaneanu L, Kovacs K 1991 Analysis of pituitary hormones and chromogranin A mRNAs in null cell adenomas, oncocytomas and gonadotroph adenomas by in situ hybridization. Am J Pathol 139:553–564[Abstract]
  14. Jameson JL, Lindell CM, Habener JF 1987 Gonadotropin and thyrotropin {alpha}- and ß-subunit gene expression in normal and neoplastic tissues characterized using specific messenger ribonucleic acid hybridization probes. J Clin Endocrinol Metab 64:319–327[Abstract/Free Full Text]
  15. Becker M, Aron DC 1994 Ectopic ACTH syndrome and CRH-mediated Cushing’s syndrome. Endocrinol Metab Clin North Am 23:585–606[Medline]
  16. Faglia G, Aroso M, Bazzoni N 1992 Ectopic acromegaly. Endocrinol Metab Clin North Am 21:575–595[Medline]
  17. Melmed S, Ezrin C, Kovaks K, Goodman RS, Frohman LA 1985 Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor. N Engl J Med 312:9–17[Medline]
  18. MacLeod MK, Vinic AL 1992 Calcitonin immunoreactivity and hypercalcitoninemia in two patients with sporadic, nonfamilial, gastroenteropancreatic neuroendocrine tumors. Surgery 111:484–488[Medline]
  19. Machens A, Haedecke J, Hinze R, Thomusch O, Schneyer U, Dralle H 2000 Hypercalcitoninemia in a sporadic asymptomatic neuroendocrine tumor of the pancreatic tail. Dig Surg 17:522–524[CrossRef][Medline]
  20. Takami H, Shikata J, Kakudo K, Ito K 1990 Calcitonin gene-related peptide in patients with endocrine tumors. J Surg Oncol 43:28–32[Medline]
  21. Roth, KA, Newell DC, Dorin RI, Eberwine JH, Hoffman AR 1988 Aberrant production and regulation of proopiomelanocortin-derived peptides in ectopic Cushing’s syndrome. Horm Metab Res 20:225–229[Medline]
  22. Waeber G, Hurlimann J, Nicod P, Grouzmann E 1995 Immunolocalization of neuropeptide Y in human pancreatic endocrine tumors. Peptides 16:921–926[CrossRef][Medline]
  23. Corbetta S, Peracchi M, Cappiello V, Lania A, Lauri E, Beck-Peccoz P, Spada A 2003 Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab 88:3117–3120[Abstract/Free Full Text]
  24. Hirshberg B, Conn PM, Uwaifo GI, Blauer KL, Clark BD, Nieman LK 2003 Ectopic luteinizing hormone secretion and anovulation. N Engl J Med 348:312–317[Free Full Text]
  25. Ascoli M, Fanelli F, Segaloff DF 2002 The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23:141–174[Abstract/Free Full Text]
  26. Rieu M, Reznik Y, Vannetzel JM, Mahoudeau J, Berrod JL, Kuhn JM 1995 Testicular steroidogenesis in adult men with human chorionic gonadotropin-producing tumors. J Clin Endocrinol Metab 80:2404–2409[Abstract]
  27. Risma KA, Hirshfield AN, Nilson JH 1997 Elevated luteinizing hormone in prepubertal transgenic mice causes hyperandrogenemia, precocious puberty and substantial ovarian pathology. Endocrinology 138:3540–3547[Abstract/Free Full Text]
  28. Tang PZ, Tsai-Morris CH, Dufau ML 1998 Regulation of 3ß-hydroxysteroid dehydrogenase in gonadotropin-induced steroidogenic desensitization of Leydig cells. Endocrinology 139:4496–4505[Abstract/Free Full Text]
  29. Lamberts SW, Bakker WH, Renbi JC, Krenning EP 1990 Somatostatin receptor imaging in the localization of endocrine tumors. N Engl J Med 323:1246–1249[Abstract]
  30. Gadner H, Weber B, Riechm H 1974 Adrenocortical carcinoma with ectopic LH production. Z Kinderheillkd 118:63–70[CrossRef]
  31. Romer TE, Sachnowska K, Savage MO, Woziewicz B, Lowe DG, Kula KK, Janas R, Malendowicz L, Besser GM 1998 Luteinizing hormone secreting adrenal tumour, as a case of precocious puberty. Clin Endocrinol (Oxf) 48:367–372[CrossRef][Medline]
  32. Wang DG, Johnston CF, Buchanan KD 1997 Oncogene expression in gastroenteropancreatic tumors. Cancer 80:668–675[CrossRef][Medline]
  33. Calender A 2000 Molecular genetics of neuroendocrine tumors. Digestion 62(Suppl 1):3–18
  34. Delle Fave G, Corleto VD 2001 Oncogenes, growth factors, receptor expression and proliferation markers in digestive neuroendocrine tumors. A critical reappraisal. Ann Oncol 12 (Suppl 2):S13–S17
  35. Parker KL, Schimmer BP 1997 Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 19:361–377
  36. Asa SL 2001 Transgenic and knockout mouse models clarify pituitary development, function and disease. Brain Pathol 11:370–383
  37. Asa SL, Ezzat S 1998 Cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19:798–827[Abstract/Free Full Text]
  38. Young RH, Scally R 1982 Ovarian sex cord-stromal tumors. Recent progress. Int J Gynecol Pathol 1:101–104[Medline]
  39. Liu G, Duranteau L, Carel JC, Monroe J, Doyle DA, Shenker A 1999 Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med 341:1731–1736[Free Full Text]
  40. Candida MB, Fragoco V, Latronico C, Carvalho FM, Zerbini MC, Marcondes JAM, Araujo LMB, Lando VS, Frazzatto ET, Mendonca BB, Villares SMF 1998 Activating mutation of the stimulatory G protein (gsp) as a putative cause of ovarian and testicular human stromal Leydig cell tumors. J Clin Endocrinol Metab 83:2074–2078[Abstract/Free Full Text]
  41. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nilson JH 1995 Targeted over-expression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries and ovarian tumors. Proc Natl Acad Sci USA 92:1322–1326[Abstract/Free Full Text]
  42. Biskind MS, Biskind GS 1966 The regulation of the secretion of follicle-stimulating hormone. In: Harris GW, Donovan BT, eds. The pituitary gland. London: Butterworths; 49–58
  43. Willemsen W, Kruitwagen R, Bastiaans B, Hanselaar T, Rolland R 1993 Ovarian stimulation and granulosa-cell tumor. Lancet 341:986–988[CrossRef][Medline]
  44. Kananen K, Wati R, Paukku T, Markkula M, Rainio EM, Huhtanemi I 1997 Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin {alpha}-subunit promoter/simian virus 40 T-antigen fusion gene. Endocrinology 138:3521–3531[Abstract/Free Full Text]
  45. Nagamani M, Osuampke C, Kelver ME 1999 Increased bioactive luteinizing hormone levels and bio/immuno ratio in women with hyperthecosis of the ovaries: possible role of hyperinsulinemia. J Clin Endocrinol Metab 84:1685–1689[Abstract/Free Full Text]
  46. Kumar TR, Wang Y, Matzuk MM 1996 Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 137:4210–4216[Abstract]
  47. Rilianawati, Paukku T, Kero J, Zhang FP, Rahman N, Kananen K, Huhtaniemi I 1998 Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin {alpha}-subunit promoter/simian virus 40 T-antigen fusion gene. Mol Endocrinol 12:801–809[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Piaditis, G.
Right arrow Articles by Kovacs, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Piaditis, G.
Right arrow Articles by Kovacs, K.
Related Collections
Right arrow Endocrine Oncology
Right arrow Female Endocrinology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals