Clinically Nonfunctioning Pituitary Adenomas Research Articles

Association between Intracellular Calcium Signaling and Tumor Recurrence in Human Non-Functioning Pituitary Adenomas.

Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.

Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Immunohistochemical detection of prolactin in clinically non-functioning pituitary adenomas.

Approximately one third of pituitary adenomas are manifested neither by specific symptoms of hormone overproduction nor by elevated blood levels of pituitary hormones. However, these tumours, diagnosed before surgical intervention as clinically non-functioning pituitary adenomas (CNFPAs) express in majority different pituitary hormones, as can be revealed by means of immunohistochemical examination. One of the pituitary hormones which may be expressed in CNFPAs is prolactin (PRL) but the clinical and pathological data on this condition are very scarce. Sixty two pituitary adenomas, diagnosed before surgery as CNFPAs, were immunoassayed with antibodies against PRL, growth hormone (GH), luteinizing hormone (LH), follicle stimulating hormone (FSH), thyrotropin (TSH), alpha subunit (alpha-SU), corticotropin (ACTH) and dopamine receptor type 2. In a proportion of the patients the presurgical concentrations of insulin-like growth factor 1 (IGF-1) were estimated by means of enzyme-amplified chemiluminescence assay. Twenty-three (37.1%) of the examined CNFPAs presented the positive immunoreaction with anti-PRL antibody. Most cases concerned women. Only in two cases (one woman and one man), PRL was the unique hormone expressed in the tumour. In the remaining adenomas PRL immunopositivity was accompanied by GH expression - 17, LH or free bLH - 13, FSH - 2, free a subunit - 4 or by ACTH - 5 tumours. Seven (30.43%) of them were recurrent in comparison with 12.8% PRL-immunonegative recurrent CNFPAs. Dopamine receptors were positively immunostained in all the investigated PRL-immunopositive and all PRL-immunonegative adenomas. Our data confirm the observations that monohormonal silent prolactinomas are very rare but frequently silent PRL often co-expressed with GH or LH. Although in the whole population of patients with CNFPAs both sexes are equally represented, in the case of silent prolactinomas the female sex is prevalent. The observation of the higher rate of recurrent tumours within PRL-immunopositive adenomas versus PRL-immunonegative CNFPAs has to be confirmed on the larger material.

MON-309 Prevalence of Silent Corticotroph Adenomas in a Large Cohort of Nonfunctioning Pituitary Adenomas: Plasma Proopiomelanocortin(POMC) Levels and Response to Pasireotide LAR

Silent corticotroph adenomas (SCAs) are tumors of the TPIT anterior pituitary cell lineage that do not lead to biochemical or clinical Cushings syndrome. Thus, they present as clinically nonfunctioning pituitary adenomas (CNFPAs) and are only diagnosed pathologically. Since they are often aggressive tumors, identification of a peripheral blood marker of SCA activity would be useful for diagnosis and monitoring. Some data suggest that aberrant processing of POMC, the precursor of ACTH, underlies the lack of elevated biologically active ACTH and thus cortisol excess in SCAs. We hypothesized that these tumors could secrete POMC, resulting in elevated plasma levels of POMC in patients with SCAs. Therefore, we investigated plasma POMC levels as a potential marker of this tumor type and correlated with tumor ACTH immunoreactivity (IR), which may be detecting unprocessed POMC. We studied 267 patients (134M, 133F, age 56.3±13.6yr) with CNFPAs (Cushings excluded) prior to surgery and at enrollment in a prospective, observational study. We also studied 9 patients with known SCAs with residual macroadenomas after surgery. Peripheral blood was sampled for POMC, ACTH and cortisol levels. POMC was measured by in-house two-site ELISA (detects POMC and 22kD pro-ACTH) and ACTH and cortisol by Immulite(Siemens). POMC levels were compared to the 95%CI of the mean of 70 healthy subjects and considered elevated if ≥ the 97.5 percentile of 39 fmol/mL. Of the CNFPA cohort, 12/267 had elevated POMC levels (range 39-166 fmol/mL) and 4 of the 12 had elevated ACTH levels (> 50 pg/ml)(range 53.6-76 pg/ml). Of the 12 with elevated POMC, 9 underwent surgery and 6 of them had positive ACTH IR in their tumors. An additional 13 patients in the CNFPA cohort had weak ACTH IR tumors, but POMC <39 fmol/mL and normal ACTH. POMC levels were elevated in all 9 known SCA patients (range 40-996 fmol/mL), being highest in those with the most aggressive tumors. ACTH levels were elevated in 6 of them (range 50.6-397 pg/ml). POMC levels were lowered with surgery in 4 of 4 SCA patients followed longitudinally. Two SCAs were treated with monthly pasireotide LAR (40 mg escalated to 60 mg) for 8 months. Plasma POMC levels fell from 104 to 21 fmol/mL in 1 patient, but did not change in the 2nd, 124 to 112 fmol/mL. Both patients had no change in the size of their macroadenomas during treatment. In summary, patients with elevated plasma POMC levels were correctly identified as SCAs in most surgically treated patients and POMC levels were lowered by tumor removal in all who were tested longitudinally. Although POMC levels were not elevated in some other patients with weakly positive ACTH IR tumors, further characterization of these tumors by lineage specific transcription factors is underway to confirm them to be of corticotroph cell origin. These data suggest that plasma POMC measurements may have clinical utility in the evaluation of SCAs and this warrants further study.

Quantitative immunohistochemical assessment of clinically non-functioning pituitary adenomas

Introduction. Immunohistochemical staining is currently the gold standard of diagnostic and classification of pituitary adenomas. However, there are some discrepancies between immunohistochemical staining results and the clinical picture of pituitary adenomas. Pituitary adenomas with positive immunohistochemical reaction might not cause any endocrinological symptoms or changes in serum pituitary hormone levels. Such a discordance may be caused partly by clinically non-functioning pituitary adenomas (CNFPAs). The aim of our study was to establish the frequency of CNFPAs and identify their histological types using quantitative immunohistochemical assessment. Materials and methods. We enrolled in the study 72 patients with pituitary adenoma, and their medical history was evaluated retrospectively. The immunohistochemical panel of anterior pituitary hormones was introduced in all cases. The immunoreactivity index was calculated manually for each specimen. Results. 36.1% patients of the evaluated group presented as CNFPAs. Among the CNFPA patients we found 38.46% cases with positive immunohistochemical reaction for one or more anterior pituitary lobe hormones. In 23.07% of cases the adenomas were monohormonal, and in 15.38% they were plurihormonal. Conclusions. The morphometric method utilising the immunoexpression index introduced in this study provided a very precise recognition of pituitary adenoma pathology. In the case of CNFPAs the immuno-histochemical staining often reveals a positive reaction also for multiple pituitary hormones. Quantitative assessment limits the subjectivity of the examiner and allows objective results comparison, so it should become a standard in histopathological assessment of pituitary adenomas.

Prevalence, Clinical Features, and Natural History of Incidental Clinically Non-Functioning Pituitary Adenomas.

The objective of the study was to assess the prevalence and clinical features of incidentally discovered clinically non-functioning pituitary adenoma (CNFPA) and to analyze its natural history. A multicenter retrospective study in patients diagnosed with incidental CNFPA periodically followed-up in 3 specialized neuroendocrinology units from 1992 to 2015 was performed. Out of a total of 189 CNFPA patients, 57 cases (30.1%; 29 women; age at diagnosis 55.8±16.7 years) were incidental. Most patients (n=55, 96.5%) were diagnosed by magnetic resonance imaging (MRI). A sum of 71.9% (n=41) were macroadenomas; 2 of them (3.5%) were giant adenomas (≥4 cm). Patients with macroadenomas were older than those with microadenomas (59.5±16.7 vs. 46.4±18.1 years, p=0.007). Macroadenomas were more common in men (85.7% vs. 58.6%, p=0.023). Twenty-eight patients (49.1%) showed suprasellar extension; of these, 19 were accompanied by chiasmatic compression. Hypopituitarism was present in 14 (24.6%) patients; which was partial in 13 patients (22.8%) and complete in one patient (1.8%). The gonadal axis was the most frequently affected (n=13, 22.8%). Twenty four patients (42.1%) underwent surgery. Of the non-operated patients, 26 patients could be evaluated morphologically after a median follow-up of 15.5 months (interquartile range, 5.7-32.7 months). No significant changes were found in the maximum tumor diameter at the end of follow-up (1.2±0.6 vs 1.2±0.7 cm). The majority of CNFPAs evaluated (n=23, 88.5%) did not show any changes in size. In 2 cases (7.7%) tumor size decreased, and in one patient (3.8%) increased. In our series of CNFPA patients, approximately one-third were incidental. These tumors were diagnosed by MRI preferably from the 5th decade of life without sex predilection. Most of them were macroadenomas, more commonly diagnosed in men and at an older age, compared to microadenomas. The suprasellar extension with chiasmatic compression and hypopituitarism were frequent at diagnosis. Most of the non-operated incidental CNFPAs remain with stable tumor size over time, growth being an unusual event.

Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers.

Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.

"Silent" thyrotropin (TSH) expression in acromegaly and clinically non-functioning pituitary adenomas.

The pituitary adenomas secreting thyrotropin (TSH) are considered the rarest type of hormonally active pituitary tumour. In spite of that, many cases are described in the literature. On the other hand, the observations of the co-expression of TSH with other pituitary hormones (mostly with growth hormone [GH]) and "silent" expression of TSH in clinically non-functioning pituitary adenomas (CNFPA) are rather scarce. Among 93 examined pituitary adenomas, 22 of them were diagnosed as active acromegaly and 71 as clinically non-functioning pituitary adenomas (CNFPA). All of them were immunostained with antibodies against pituitary hormones, including the anti-TSH antibody. TSH-immunopositive adenomas are immunostained also to detect somatostatin receptor subtypes (SSTR 1-5). TSH immunopositivity was found in 4.2% of CNFPA (3/71 tumours) and in 13.6% (3/22) cases of somatotropinomas manifesting as active acromegaly. All of the examined TSH-immunopositive adenomas expressed SSTR subtypes except SSTR4. The symptoms of hyperthyroidism were not observed in any of the acromegalic patients co-expressing TSH with GH. Our data confirm the relative rarity of TSH expression or co-expression of TSH in pituitary tumours. In most cases TSH is co-expressed with GH in patients with acromegaly and is not accompanied by hyperthyroidism. The "silent" expression of TSH may occur also, although rarely in CNFPA. The strong expression of SSTR in TSH-immunopositive CNFPA ("silent thyrotropinoma") indicates the possibility of the treatment of these tumours with somatostatin analogues. (Endokrynol Pol 2016; 67 (5): 515-518).

Effect of Gonadotropin and Adrenocorticotropic Hormone Secretion on Invasiveness of Clinically Nonfunctioning Pituitary Adenomas: A Cell Culture Study

The aim of this study was to clarify the correlation between clinical features (especially cyst formation and cavernous sinus invasion) and minor secretion of anterior pituitary hormones, especially adrenocorticotropic hormone (ACTH) and gonadotropin, by clinically nonfunctioning pituitary adenomas (CNFPAs) in cell culture. We examined anterior pituitary hormones secreted by samples from 63 cases of CNFPAs grown in cell culture. Magnetic resonance imaging, including determination of the Knosp grade, cystic changes, and intraoperative cavernous sinus invasion, was performed. Detection of minor hormone secretion using cell culture showed that 61.9% (39/63) of CNFPAs secreted luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone, 44.4% (28/63) secreted ACTH, 57.1% (36/63) secreted prolactin, and 28.6% (18/63) secreted growth hormone; only 1 case of the null-cell adenoma was observed (1.6%). Cystic changes, Knosp grade 4 status, and cavernous sinus invasion were predominantly observed in cases of ACTH-secreting adenomas. Gonadotropin-secreting adenomas showed opposite characteristics to ACTH-secreting adenomas. Minor secretion of ACTH and gonadotropin may be related to clinical features, especially cystic changes and invasiveness of CNFPAs, suggesting that our cell culture method could be helpful for elucidating the mechanisms of pituitary cyst formation and the invasiveness of CNFPAs.

Dopamine 2 and somatostatin 1-5 receptors coexpression in clinically non-functioning pituitary adenomas.

This study investigated quantitated expression of dopamine 2 receptor (D2R) and somatostatin receptors of the five types (SSTR1-SSTR5) in a large series of clinically non-functioning pituitary adenomas (CNFAs). Co-expression of these receptors in individual adenomas was studied as well as correlation between receptor types. Adenoma tissue from 198 patients who underwent surgery for CNFAs was analyzed by immunohistochemistry and quantitative real-time PCR. D2R and SSTR1-3 mRNA was expressed in all 198 adenomas. SSTR4 and SSTR5 were detectable in 85 % and 61 % of adenomas, respectively. Expression of D2R was significantly higher than that of the somatostatin receptors. The median relative expressions were as follows from highest D2R >> SSTR3 > SSTR2 > SSTR1 > SSTR5 > SSTR4. High relative expression (ratio to beta-glucuronidase mRNA > 1) of D2R was found in 60 % of tumors, high expression of SSTR1 in 7.5 %, SSTR2 in 7 %, SSTR3 in 4 % and SSTR5 in 0.5 %. The quantity of D2R correlated positively with expression of SSTR2 and SSTR3, and negatively with SSTR1 and SSTR5. Among histological adenoma types, SSTR1 was significantly higher in null-cell adenomas and SSTR3 was lower in silent corticotroph adenomas. In conclusions, in CNFAs, high expression of somatostatin receptors is much less common than that of D2R, and co-expression of both these receptors is exceptional. D2R and SSTR3 seem to be the most promising targets for pharmacological treatment.

Increased Risk of Unfavorable Metabolic Outcome in Patients with Clinically Nonfunctioning Pituitary Adenomas.

The aim of this study was to investigate atherosclerotic risk markers in women with clinically nonfunctioning pituitary adenomas (CNFAs). Records of 47 women with CNFAs and 73 healthy women who were treated as outpatients between January 2010 and March 2014 were evaluated retrospectively. All study data were obtained from file records. Lipid parameters, mean platelet volume (MPV), total testosterone (TT), androstenedione (AS), and dehydroepiandrostenedione sulfate (DHEAS) were recorded. Insulin resistance (IR) was calculated with homeostatic model assessment-insulin resistance (HOMA-IR). Among the atherosclerotic risk markers, the HOMA-IR and AS levels were higher in patients with CNFAs than in healthy subjects (p=0.003, p=0.021, respectively). A positive correlation between AS and insulin/HOMA-IR levels was found among the metabolic parameters in the patients with CNFAs (p=0.001, r=0.550, p=0.004, r=0.498, respectively). The data showed that patients with CNFAs had high atherosclerotic risk markers such as insulin resistance and hyperandrogenemia. Insulin resistance may also cause hyperandrogenemia in patients with CNFAs.

Nadekspresja protymozyny alfa w gruczolakach przysadki jest związana z nawrotowością a nie z proliferacją komórek i inwazyjnością guza

Prothymosin alpha (ProTα) is a peptide initially considered as a thymic hormone, but further studies have shown its wide distribution in different tissues and organs. It has a prevalent nuclear localisation and is thought to be involved in the control of proliferation and apoptosis. In earlier studies, the overexpression of ProTα was found in several human tumours, including pituitary adenomas. The present study deals with the relations of ProTα to the pituitary adenoma hormonal phenotype, proliferation, recurrence and invasiveness. Sixty two pituitary adenomas were included in the study. The invasiveness of the tumours was estimated before surgery by means of magnetic resonance imaging. The paraffin sections of the tumours were immunostained with an antibody against the C-terminal fragment (101-109) of ProTα and with anti-Ki-67 antibody. The hormonal phenotype of the investigated pituitary adenomas had been established previously by means of immunostaining with antibodies to pituitary hormones (GH, PRL, FSH, LH, TSH, ACTH and α-subunit). Strong immunostaining with anti-ProTα antibody occurred in the subpopulation of cell nuclei and the walls of intratumoural blood vessels. ProTα index is higher in clinically non-functioning pituitary adenomas (CNFPA) compared to any type of functioning adenomas. There was no difference in the percentage of ProTα- positive cell nuclei in non-invasive vs. invasive adenomas, but it was significantly more frequent in recurrent than in primary tumours. Moreover, the decrease of ProTα index was found in somatotroph tumours treated with somatostatin analogues vs. untreated ones. The percentage of ProTα nuclei did not correlate with Ki-67 index. The overexpression of nuclear ProTα in pituitary adenomas is related to tumour recurrence, but not to proliferation or invasiveness.

Correlation Between Histological Subtypes and MRI Findings in Clinically Nonfunctioning Pituitary Adenomas

Clinically nonfunctioning pituitary adenomas (CNFPAs) consist of several histological subtypes, including null cell adenoma (NCA), silent gonadotroph cell adenoma (SGA), silent corticotroph adenoma (SCA), and other silent adenomas (OSA) (i.e., GH, TSH, and prolactin adenomas). To detect possible correlations between MRI findings and the subtypes, we retrospectively studied 390 consecutive patients with CNFPA who underwent surgery between 2008 and 2010. They were classified into three groups: NCA/SGA (313 cases), SCA (39 cases), and OSA (36 cases); in addition there were two unusual cases of plurihormonal adenoma. Three MRI findings were less common in NCA/SGA than in the other groups (P < 0.0001): giant adenoma (>40 mm), marked cavernous sinus invasion (Knosp grade 4), and lobulated configuration of the suprasellar tumor. When these MRI findings were negative in patients older than 40 years old, 91.0% (212/233) were NCA/SGA. These MRI findings were frequently noted despite a low MIB-1 index in SCA. OSA showed a high MIB-1 index and a preponderance in younger patients. In conclusion, although SCA and OSA consisted of only 20% of CNFPAs, their frequency significantly increased when the tumor was large, invasive, and lobulated, and the patient was younger than 40 years old.

A STUDY OF THE CORRELATION BETWEEN MORPHOLOGICAL FINDINGS AND BIOLOGICAL ACTIVITIES IN CLINICALLY NONFUNCTIONING PITUITARY ADENOMAS

The aims of this study are to review the histology of the clinically nonfunctioning pituitary adenomas (CNFPAs) we have observed and to determine whether or not the frequency of cavernous sinus invasion is different among each type of morphology. In addition, several proliferative markers, including Ki67, p53, E-cadherin, matrix metallo-proteinase 9 and pituitary tumor derived fibroblast growth factor receptor 4 (ptd-FGFR4), were also investigated in invasive and non-invasive tumors. Our consequent 213 CNFPAs were diagnosed as follows: 64% were silent gonadotroph adenomas, 18% were null cell adenomas, 12% were silent corticotroph adenomas, 4% were silent Subtype 3 adenomas, and 1% were other types of adenomas. Female patients or younger patients showed a significant preponderance in silent corticotroph adenomas and in silent Subtype 3 adenomas, respectively. Cavernous sinus invasion occurs most frequently in silent corticotroph adenomas (85%) followed by Subtype 3 adenomas (67%), null cell adenomas (38%), and silent gonadotroph adenomas (11%). There were no significant differences in the Ki67, p53, E-cadherin, matrix metallo-proteinase 9, and ptd-FGFR4 expression between tumors with and without cavernous sinus invasion. From a clinical standpoint, it is quite important to differentiate morphological type in CNFPAs to aid the clinician in assessing the clinical behavior and prognosis of the tumor. Therefore, we suggest that all CNFPAs be examined not only by conventional light microscopy but also by immunohistochemistry, preferably by electron microscopy, to achieve a correct morphological diagnosis.

Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma.

This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA). Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment. A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels. Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.