Gonadotropin-secreting Pituitary Adenomas Research Articles

Reversible dementia in a case of functional gonadotropin-secreting pituitary adenoma: Different shades of gray.

Reversible dementia in a case of functional gonadotropin-secreting pituitary adenoma: Different shades of gray.

Gonadotroph adenomas as a cause of ovarian failure

Aims of study. The current analysis was undertaken to evaluate the clinical significance of gonadotropin-secreting pituitary adenoma in the development of ovarian insufficiency.
 Study design, materials and methods. This follow-up study included six observations of patients with prolonged amenorrhea caused by gonadotropin-secreting pituitary microadenoma.
 Results. In addition to amenorrhea, patients had complaints of headaches in history or at present, signs of psychotic depression, and neuroticism up to mental disorders in one case. There was found a dynamic decrease in the secretion of follicle stimulating and luteinizing hormones on the background of normal prolactin secretion, lowered antimullerian hormone levels, and signs of diminished ovarian reserve according to ultrasound. A tendency to a simultaneous decrease in thyroid stimulating hormone and free thyroxin concentrations was also noted. Performing MRI with contrast enhancement revealed pituitary microadenoma in all patients. They had no clinical signs of acromegaly or Cushing’s disease, with the secretion of adrenocorticotropic hormone, cortisol, somatotropic hormone and insulin-like growth factor-1 remaining normal, which excluded corticotroph or somatotroph adenomas.
 Conclusion. The clinical manifestation of gonadotroph adenomas, dependent on the secretory efficacy of gonadotropins and/or their subunits, is diverse. It includes the development of recurrent ovarian cysts, abdominal pain, metrorrhagia, and the development of persistent amenorrhea with psychosomatic disorders. If these symptoms are present, it is advisable to include pituitary MRI with contrast enhancement in the examination algorithm. Patients with gonadotroph adenomas are prescribed hormone replacement therapy and follow-up observation with dynamic MRI control of the tumor size (at 2–3-year intervals if no adenoma growth is seen).

Stężenia gonadotropin i α podjednostki w surowicy krwi u pacjentów z gruczolakami gonadotropowymi przysadki w zależności od immunoreaktywności guza

Although active gonadotropin-secreting pituitary adenomas are considered very rare, the vast majority of pituitary tumours diagnosed as "non-functioning" express gonadotropins or their free β or α subunits. However, systemic investigations comparing the serum concentrations of follitropin (FSH), lutropin (LH), and α-subunit (αSU) before surgery with the immunoreactivity of the respective substances in the excised tumours are still lacking. Immunostaining of FSH, LH, and αSU was compared in 43 surgically removed gonadotropin - expressing pitu-itary adenomas with serum concentrations of the above-mentioned substances before surgery in the same patients. The serum concentrations of FSH were elevated (> 11.6 mU/mL) in 8/12 (66.7%) cases of FSH-positive adenomas. By contrast, in FSH-negative tumours the elevation of FSH is absent. Moreover, only 1/25 (4%) patients with LH-positive adenoma had the elevated serum concentration of LH (51.5 mU/mL). The overproduction of LH was not observed in adenomas expressing free β LH or in LH-negative tumours. In patients with αSU-positive adenomas elevated serum levels of αSU were observed in 3/15 (20%) cases. No αSU elevations were observed in patients with αSU-negative adenomas. The mean serum FSH, LH, and αSU concentrations were higher in patients with FSH, LH, and/or αSU immunopositive tumours in comparison with immunonegative. However, the differences are not statistically significant. Although "silent" gonadotropinomas constitute a frequent subtype of pituitary adenomas, the "active" subtype (i.e. manifesting by gonadotropin excess) are rare (approx. 4% of all pituitary adenomas). Gonadotropinomas are difficult to diagnose before surgery. The measurement of gonadotropins including αSU is needed but often not sufficient for presurgical diagnosis.

Abstract #851 A Case of Gonadotropin-Secreting Giant Pituitary Adenoma

Abstract #851 A Case of Gonadotropin-Secreting Giant Pituitary Adenoma

Leuprolide Injection Causing Pituitary Apoplexy: A Case Report

There is growing evidence to support occurrence of pituitary apoplexy following administration of gonadotropin releasing hormone (GnRH) agonists in patients with gonadotropin-secreting pituitary adenomas. We report a case of pituitary apoplexy after depot administration of the GnRH agonist leuprolide. The patient is a 78 year-old man with Gleeson 7, non-invasive prostate cancer who was treated with his first dose of leuprolide two days prior to presentation. He developed a severe headache four hours after leuprolide administration. Non-contrast Magnetic Resonance Imaging (MRI) brain showed a 1.2 cm T1 hyper intensity in the anterior pituitary, likely representing a hemorrhagic adenoma or cyst. 1 month later his repeat MRI of the brain showed resolution of the hemorrhage, as well as a 3 mm lesion within the pituitary thought to be a micro adenoma. What is unique in our case is the mild degree of symptoms manifested by intractable headaches with normal vision and cranial nerve examination, requiring no surgical intervention. There may be a correlation with the size of the adenoma and the severity of disease burden caused by the apoplexy.

Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma

Gonadotropin-releasing hormone (GnRH) agonists are widely used in hormone therapy for prostate cancer. We report a patient with pituitary apoplexy following this therapy as a rare complication and review the related literature. A 62-year-old man presented with elevated prostate specific antigen. Transrectal ultrasound guided biopsy of the prostate gland revealed adenocarcinoma. Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed FDG-uptake in the pituitary region. MRI also demonstrated a pituitary tumor, diagnosed as an incidental non-functioning adenoma. The patient received his first dose of GnRH agonist (leuprolide 11.25mg) against prostate cancer. He complained of a severe headache 10minutes after leuprolide administration and suffered from right third nerve palsy in the next 48hours. MRI demonstrated a high intensity area on T1-weighted images, diagnosed as pituitary apoplexy. The patient underwent transsphenoidal surgery. Pathology revealed predominantly necrotic tissue and a gonadotropin secreting pituitary adenoma. Overall, 15 patients, including ours, have been reported with pituitary apoplexy after GnRH agonists with pathologic gonadotropin secreting adenoma. Fourteen of 15 patients were male. Pituitary apoplexy developed within 4hours after administration of the agents in 8/15 patients. The combined data suggest that GnRH agonists have the potential to precipitate pituitary apoplexy in men with gonadotropin secreting adenoma. Therefore, prior to GnRH agonist therapy for prostate cancer, a known pituitary adenoma should be treated. Otherwise, the patients should be cautiously observed for any symptomatic change following drug administration.

The experimental study of miRNA in pituitary adenomas.

We investigated the differential miRNA expression in pituitary adenomas (both non-functioning and gonadotropin-secreting) and normal pituitaries. RNA was extracted and purified from pituitary adenomas (10 non-functioning and 10 gonadotropin-secreting) and from two normal pituitary tissue samples. The samples were analyzed by miRNA microarray. Gene expression was measured using realtime RT-PCR with SYBR GREEN I. In non-functioning pituitary adenomas, 25 miRNA genes were up-regulated (six by over 5-fold) and 15 were down-regulated (six by more than 10-fold). miR-124a was the most up-regulated gene (38.58-fold), and miR-31 the most down-regulated gene (21.5-fold). In gonadotropin-secreting pituitary adenomas, 16 miRNA genes were up-regulated (six by over 4-fold) and 13 were down-regulated (seven by more than 10-fold). miR-10b was the most up-regulated gene (48.73-fold), and miR-503 the most down-regulated gene (39.8-fold). Five genes were up-regulated in both subtypes: miR-523, miR-10b, miR-520b, miR-422a, and miR-422b. The RT-PCR results were consistent with those of the gene chips. We established miRNA expression maps of non-functioning and gonadotropin-secreting pituitary adenomas. The most strongly differentially expressed genes were miR-124a and miR-31 in non-functioning pituitary adenomas, and miR-10b and miR-503 in gonadotropin-secreting pituitary adenomas.

Gonadotroph pituitary macroadenoma inducing ovarian hyperstimulation syndrome: successful response to octreotide therapy

We report a young woman with spontaneous ovarian hyperstimulation syndrome (OHSS), headaches, visual field defect and pituitary macroadenoma. She underwent transsphenoidal surgery with remission of OHSS. Immunohistochemical staining was positive for β-FSH and β-LH. Recurrence occurred after four years. The patient was treated with octreotide administration and conventional radiation therapy. Octreotide was effective in normalizing estradiol levels and resolving OHSS. This is a rare description of octreotide administration as an effective treatment modality of OHSS caused by gonadotropin-secreting pituitary adenomas.

Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery

Gonadotropin-secreting pituitary adenomas carry a high risk of local recurrence or progression (R/P) of remnant tumor after first surgery. The clinical characteristics and the long-term outcome of these silent adenomas, which show no signs of endocrine hyperfunction, differ from those of other types of pituitary adenomas. However, to date, no study has focused specifically on gonadotropic adenomas. To identify prognostic factors of R/P of remnants, we studied the postoperative outcome of 32 gonadotropic pituitary adenomas, defined on immunohistochemical staining, according to their clinical and radiological characteristics as well as the Ki-67 labeling index (LI). The Ki-67 LI failed to provide independent information for the identification of patients at risk of progression of remnants or recurrence. Multivariate survival analysis (Cox regression) showed that neither invasiveness nor remnant tumors nor hyposomatotropism influenced tumor recurrence. The strongest predicting factors of R/P were the antero-posterior (AP) diameter in the sagittal plane (P = 0.014), and the age of the patient at surgery (P = 0.047), with younger patients being at greater risk. Hazard ratios were 2.11 for each 5 mm increase in AP diameter and 0.57 for every 10 years of age. The two simple clinical criteria revealed by our study, the AP diameter of the tumor and the age of the patient, should be helpful in planning clinical management and radiological monitoring after first surgery of gonadotropic adenomas, while awaiting the identification of other pathological parameters.

Effectiveness of treating ovarian hyperstimulation syndrome with cabergoline in two patients with gonadotropin-producing pituitary adenomas

To report the effect of cabergoline on ovarian hyperstimulation syndrome associated with gonadotropin-secreting pituitary adenomas. Case report. Outpatient practice. Two women with menstrual irregularity, enlarged ovaries, high E(2), and normal gonadotropin levels. Cabergoline treatment and transsphenoidal surgery. Estradiol levels, transvaginal ultrasonography, and pituitary magnetic resonance imaging. Transsphenoidal surgery showed pituitary adenoma staining for LH in both patients. Cabergoline was effective in reducing E(2) levels and decreasing ovarian size but ineffective in shrinking the pituitary adenomas. This is the first description of the effectiveness of cabergoline as the primary treatment of spontaneous ovarian hyperstimulation syndrome in patients with gonadotropin-producing pituitary adenomas.

Lack of Somatostatin Analogs Effectiveness in Gonadotropin-Secreting Pituitary Adenomas

Gonadotropin-secreting pituitary adenomas are rare. Sur- gery remains the treatment of choice, whereas medical therapy is used when surgery has failed, is contraindicated, or is refused. Recently, data suggesting a possible inhibitory effect of somatostatin analogs (SSAs) in these adenomas and their overall effectiveness is controversial. Moreover, although a subset of gonadotropinomas is partially respon- sive to SSAs in terms of hormone inhibition, SSA efficacy on tumor shrinkage is less clear. We report the case of a 55-year-old patient, with a pituitary mass of 55 47 mm, with high levels of alpha-subunit (7.2 U/L) and follicle-stimulating hormone (FSH) (67.7 U/L). Before sur- gery, octreotide LAR (20 mg intramuscularly every 28 days) was administered for 3 months. An OctreoScan revealed significant tumor uptake, but serum FSH, alpha-subunit levels, and tumor size were not decreased. Tumor specimens were studied by immunohistochemistry and by reverse transcriptase-polymerase chain reaction (RT-PCR). The adenomatous cells expressed SSTR subtype sst2A, agreeing with the OctreoScan result. RT-PCR analysis confirmed selective expression of sst2A as well as sst1 mRNAs. This report shows that in patients with a gonadotropinoma, responsiveness to an SSA is not always predicted by scintigraphy, and in vitro expression of SSTRs may be dissociated from the in vivo response to SSAs in terms of hormone secretion and tumor growth. On the basis of this case, we reviewed the literature on this subject and analyzed it in this report.

Impaired estrogen-induced negative feedback on gonadotropin secretion in patients with gonadotropin-secreting and nonfunctioning pituitary adenomas.

Several in vitro studies suggest that gonadotropin-secreting pituitary adenomas (Gn-omas) and non functioning pituitary adenomas (NFPA) originate from gonadotroph cells. Patients with Gn-oma and NFPA frequently show abnormal gonadotropin response to TRH. The aim of the study was to investigate whether the estrogen-induced negative feedback is operating in either patients with Gn-oma or NFPA. Serum gonadotropin levels were evaluated at 24 h after ethinylestradiol administration (1 mg per os; EE2 test) in seven patients with a diagnosis of Gn-oma, based on the presence of high follicle-stimulating hormone (FSH) and/or lutenising hormone (LH) levels with normal or high levels of sex steroids, in 22 patients with NFPA with normal or low levels of gonadotropin and sex steroids, and 30 sex- and age-matched healthy subjects. A normal response to EE2 test was arbitrarily defined as a serum LH and FSH decrease of at least 40 and 30% below basal levels. Among patients with Gn-oma, only one had a normal FSH inhibition and another, a normal LH inhibition. Among the 22 patients with NFPA, the EE2 test caused a normal FSH or LH reduction in 10 and 15, respectively, while a normal reduction of both FSH and LH was observed in nine. The study demonstrates that estrogen-induced negative feedback of gonadotropin secretion is disrupted in almost all patients with Gn-oma and in half of those with NFPA. This defective feedback is reminiscent of the resistance to thyroid hormones and glucocorticoids observed in patients with thyroid-stimulating hormone- (TSH-) and adrenocorticotropic hormone- (ACTH-)secreting adenomas, respectively.

Absence of activating mutations in the GnRH receptor gene in human pituitary gonadotroph adenomas.

The monoclonal origin of gonadotropin-secreting pituitary adenomas has been well demonstrated but only few molecular abnormalities have so far been recognized in these tumors. For many years, several authors have suggested a role for GnRH and/or GnRH receptors (GnRH-R) in the development of these pituitary adenomas. To test the hypothesis that mutant genes encoding a constitutively activated GnRH-R might be involved in the pathogenesis of these tumors, the sequence of the GnRH-R gene was analyzed in tumoral pituitary tissue obtained from ten patients (six female, four male). The pituitary gonadotropin-secreting adenoma was associated with in vivo hypersecretion of FSH, LH and/or free alpha-subunit (n = 7) or was clinically silent (normal plasma levels of gonadotropins or free alpha-subunit, n = 3). In all cases, immunocytochemical studies of the removed adenoma confirmed their gonadotroph nature by revealing positivity for FSH, LH and/or alpha-subunit. Genomic DNA was extracted from the pathological tissue obtained at neurosurgery. Eight sequencing primers were used to amplify the three exons of the GnRH-R gene from tumoral DNA. The entire coding sequence of the GnRH-R gene was sequenced in the ten adenomas. No mutation was found in any of the tumor specimens examined. In conclusion, mutations in the GnRH receptor coding sequence occur infrequently if at all in gonadotropin-secreting pituitary adenomas.

Serum FSH bioactivity and inhibin levels in patients with gonadotropin secreting and nonfunctioning pituitary adenomas.

It has been reported that serum FSH bioactivity and inhibin levels can be used as markers of the presence of true gonadotropin-secreting pituitary adenoma (Gn-oma). To verify this hypothesis, we have investigated the bioactivity of FSH and serum inhibin alpha-alpha and alpha-beta A levels in a series of patients with either Gn-oma or nonfunctioning pituitary adenoma (NFPA). Nine patients with Gn-oma (6 men and 3 women), 21 with NFPA (9 men and 12 women) and 30 normal subjects were included in the study. We studied FSH biological activity (FSH-B) by using Sertoli cell aromatase bioassay (SAB) and alpha-alpha and alpha-beta A inhibin levels by two noncompetitive immunometric assays (IEMA). In male patients with Gn-oma, serum immunoreactive FSH (FSH-I) and FSH-B levels ranged from 5.1 to 35.5 U/L and from 8.3 to 48 U/L, respectively, FSH B/I ratio being elevated in 2 (2.5 and 4.1; normal male range: 0.3-1.5), while female patients with Gn-oma had serum FSH-I and FSH-B levels ranging from 43.2 to 162 U/L and from 41.2 to 112.8 U/l, respectively, with a normal FSH B/I ratio. In male patients with NFPA, FSH-I and FSH-B levels ranged from 2.7 to 10.7 U/l and from 2.4 to 11.4 U/l while in females they ranged from 3.4 to 67.9 and from 4.6 to 60.8 U/l, respectively. FSH B/I ratio was elevated in 1 male (3.3) and normal in the remaining patients with NFPA. Serum alpha-alpha inhibin levels were normal or low in patients with Gn-oma and NFPA, while alpha-beta A inhibin concentrations were slightly elevated in 1 of 6 postmenopausal women (0.9; normal range < 0.7 U/ml). The present study confirms and extends previous reports indicating that male patients with Gn-oma may secrete FSH molecules with increased bioactivity. However, this abnormality was also observed in one male patient with NFPA. Moreover, the measurement of inhibin levels does not appear to be a reliable in vivo marker of pituitary tumors of gonadotroph origin, as it was normal or low in almost all patients with either Gn-oma or NFPA.

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas: Warnet A , Harris AG, Renard E, Martin D, James-Deidier A, Chaumet-Riffaud P, and the French Multicenter Octreotide Study Group. Neurosurgery 1997;41:786–797

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas: Warnet A , Harris AG, Renard E, Martin D, James-Deidier A, Chaumet-Riffaud P, and the French Multicenter Octreotide Study Group. Neurosurgery 1997;41:786–797

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. French Multicenter Octreotide Study Group.

The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas. Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume of > or = 20% of the initial measurement); opposite changes were defined as deterioration. Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy. The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

Usefulness of thyrotropin-releasing hormone test, SMS 201-995, and bromocriptine in the diagnosis and treatment of gonadotropin-secreting pituitary adenomas.

Five patients with gonadotropin-secreting pituitary adenomas were studied. The utility of gonadotropin response to TRH stimulation in the diagnosis and follow-up of these tumors was evaluated, as well as the effects of somatostatin analogue SMS 201-995 and bromocriptine on gonadotropin release. Three patients had FSH and LH secreting adenomas while the other two tumors secreted FSH and alpha-subunit. Transsphenoidal resection of the pituitary adenomas were performed in all patients. Following preoperative TRH administration (400 micrograms i.v.), marked increases were observed in FSH levels in two cases, in LH levels in three and in alpha-subunit in one. The FSH and LH responses to t.his stimulus persisted in the same patients after surgery. Following acute bromocriptine administration (5 mg orally), FSH was reduced in all cases by 19% to 46%, LH in three cases by 50-67% and alpha-subunit in one by 33%. In patient no. 5, with persistent high FSH levels in the immediate postoperative period, long-term bromocriptine treatment was administered (15 mg/d orally), resulting in normalization of FSH levels 6 months later, although the size of the tumor was not reduced. After acute SMS 201-995 administration (100 micrograms sc) FSH decreased in two cases by 38% and 76%, LH in three by 30-56% and alpha-subunit in one by 20%. We conclude that gonadotropin response to TRH stimulation is useful in the diagnosis and follow-up of patients with gonadotroph adenoma. Bromocriptine and SMS 201-995 may be effective as coadjuvant treatment following surgery and radiotherapy in these patients, although long-term studies will be necessary to confirm these proposals.

Concanavalin A affinity chromatography of human serum gonadotropins: evidence for changes of carbohydrate structure in different clinical conditions.

We have studied the carbohydrate of circulating human gonadotropins (FSH and LH) in different clinical conditions using Concanavalin A (Con A) affinity chromatography. This technique permits separation of molecules differing in the extent of carbohydrate branching. The proportion of molecules that does not bind to Con A was greater in circulating FSH than in LH, reflecting a higher content of multiantennary and/or bisected biantennary complex carbohydrate structures in serum FSH. No significant difference in gonadotropin binding pattern to Con A was found between normal controls and patients with chronic uremia or gonadotropin-secreting pituitary adenomas. On the contrary, sera from postmenopausal women and fetuses contained a greater proportion of FSH and LH that bound to Con A, indicating a shift from multiantennary and/or bisecting structures to hybrid and/or high mannose forms, i.e. to the secretion of less mature forms. International Reference Preparations, derived from pituitary extracts, were more retained on Con A than circulating hormones, suggesting that carbohydrate chains of the intrapituitary hormone stock are less mature than those present in the circulation. Less mature forms were also found in FSH, but not in LH, from normal controls after GnRH injection. Finally, a higher proportion of unbound forms, i.e. complex carbohydrate chains, was found in healthy subjects presenting with an immunologically anomalous variant of LH. In conclusion, the current data show that the hormonal status of the individual may differently affect carbohydrate branching of gonadotropins. Alteration in glycosylation is likely to be involved in masking at least one epitope specific for intact LH dimer, thus indicating that it may modulate the tertiary structure of glycoprotein hormones.

Reduction in size of a thyrotropin- and gonadotropin-secreting pituitary adenoma treated with octreotide acetate (somatostatin analog)

Reduction in size of a thyrotropin- and gonadotropin-secreting pituitary adenoma treated with octreotide acetate (somatostatin analog)

Reduction in size of a thyrotropin- and gonadotropin-secreting pituitary adenoma treated with octreotide acetate (somatostatin analog).

TSH as well as alpha-subunit, secretion has been shown to decrease after the administration of the somatostatin analog octreotide acetate (SMS 201-995). We have studied a 59-yr-old, male patient with a TSH- and gonadotropin-secreting tumor who, because of severe cardiomyopathy, was treated with long-term somatostatin analog rather than surgical resection of the pituitary tumor. Thirteen weeks of treatment with thrice daily sc injection of 100 micrograms octreotide acetate resulted in decreased TSH and alpha-subunit secretion, normal serum thyroid hormone levels, reduction in LH and testosterone level, and significant tumor size reduction. Long-term treatment for 51 weeks has not been associated with any significant side effects. We have shown that octreotide acetate may be a therapeutically valuable modality for certain patients with neoplastic inappropriate secretion of TSH (NIST). A probable effect of octreotide acetate on neoplastic gonadotropes, as evidenced by the reduction of the LH level with a concomitant decrease in testosterone level, is, likewise, suggested.