Vascularity in nontumorous human pituitaries and incidental microadenomas: A morphometric study

Vascularity in human pituitary 215

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AbstractThe aim of the present study was to determine the microvascular angioarchitecture inthe lateral and central portions of the anterior lobe as well as of the posterior lobe. Thepossible association between vascularity and age, sex, and pregnancy was also examined.In addition the vascular density of incidental microadenomas was investigated and com-pared to that of nontumorous gland. Blood vessels of 120 nontumorous pituitaries and11 incidental microadenomas obtained at autopsy were examined by immunohistochem-istry using the endothelial marker CD 34. Microvascular density (MVD) and microvesselsurface density (MSD) were determined by morphometry using an automatic computerimage analysis system. MVD and MSD were higher in the anterior than in the posteriorlobe. Age, gender, or pregnancy did not affect the angioarchitecture of these sites. Nostatistical differences in MVD and MSD were observed between central and lateral areasof the anterior lobe, although MVD appeared to be lower in the lateral zones. A markeddifference was noted in the vascularity of microadenomas compared to nontumorus tis-sue; both MVD and MSD were significantly lower in adenomatous tissue. Our studiessuggest that the capillary network of the anterior and posterior lobes differ. They alsoindicate that the microvascular architecture is not significantly affected by age, gender,or pregnancy. Lack of significant angiogenesis in pituitary microadenomas may underliethe low growth rate and infrequency of metastasis of pituitary adenomas.Key Words: Pituitary; angiogenesis, morphometry; microadenoma.

Introduction

A working knowledge of the pituitarycirculation is of importance if one wishesto understand the functional realtionshipbetween hypothalamus and pituitary, spe-cifically the details of adenohypophysealsecretory activity and its regulation by thehypophyseotropic area of the hypothala-mus [l]. The pituitary gland has a uniqueblood supply. The pars nervosa is suppliedby the inferior hypophyseal arteries, theinfundibular stem by the superior hypo-physeal arteries, and the pars distalis indi-rectly by a portal system originating in the

Vascularity in Nontumorous Human Pituitariesand Incidental Microadenomas: A Morphometric Study

Sergio Vidal, PHD,1,3 Bernd W. Scheithauer, MD2

and Kalman Kovacs, MD, PHD1

‘Department of LaboratoryMedicine, St. Michael’sHospital, University ofToronto, Toronto, Ontario,Canada, 2Department ofLaboratory Medicine andPathology, Mayo Clinic,Rochester, MN; 3Departmentof Anatomy, Laboratory ofHistology, University ofSantiago de Compostela,Lugo, Spain

Address correspondence to:Dr. Bernd W. ScheithauerDepartment of Pathology,Mayo Clinic, 200 FirstStreet, SW, Rochester, MN55905 USAE-mail:[email protected]

infundibular stem [2]. Our improved un-derstanding of the vascular anatomy of thepituitary as well as of the process of neuro-secretion has focused attention upon pitu-itary blood flow, particularly its directionand dynamics.

Previous studies in human and animalpituitaries have clearly demonstrated moreextensive blood flow in the posterior lobeas compared to the adenohypophysis [3–7].Three decades ago, Porter et al. [8] reportedthat blood flow in the anterior lobe of therat pituitary is not uniform throughout,but that differences exist between its centraland the lateral portions. Pituitary blood

Endocrine Pathology, vol. 11,no. 3, 215–227, Fall 2000© Copyright 2000 by HumanaPress Inc. All rights of anynature whatsoever reserved.1046–3976/00/11:215–227/$13.25

Clinical Research

216 Endocrine Pathology Volume 11, Number 3 Fall 2000

flow has been shown to vary in a numberof experimental situations, including mag-nesium deficiency [9] and hypothyroidism[10], and in Iysin vasopressin [11],hexadimethrine bromide [12], or bro-mocriptine administration [13]. It has alsobeen suggested that the process of agingmay affect pituitary blood flow regulation[14, 15].

By evaluating two different morphomet-ric parameters, microvessel density (MVD)and microvessel surface density (MSD),our study sought to determine (a) whetherdifferences exist in the regional vascularity ofthe autopsy-derived human pituitary and(b) whether age, gender, and pregnancyhave an effect. Incidental microadenomasencountered at autopsy were also studied.

Material and Methods

PatientsOne hundred thirty-one formalin-fixed,

paraffin-embedded human pituitariesremoved at autopsy were obtained from thearchival files of the Departments of Pathol-ogy of St. Michael’s Hospital and the MayoClinic. All patients died of nonendocrinecauses. Within the study group, histologicexamination revealed incidental pituitaryadenomas in 11 glands (12%).

The pituitaries were divided into 10groups: group 1, adult men less 39 yr(n = 8); group 2, adult women less 39 yr(n =10); group 3, men ranging from 40to 59 yr (n = 16); group 4, women rang-ing from 40 to 59 yr (n = 29); group 5,men ranging from 60 to 79 yr (n = 12);group 6, women ranging from 60 to 79yr (n = 13); group 7: men ranging from 80to 90 yr (n = 8); group 8, women rangingfrom 80 to 90 yr (n = 24); group 9, preg-nant women ranging in the second or thirdtrimester of pregnancy (n = 10); and group

10, incidental pituitary adenomas encoun-tered in six men and five women rangingfrom 60 to 79 yr (n = 11).

Immunohistochemistry

Five micron sections of the horizontallycut glands were used for immunohis-tochemical staining by the streptavidin–biotin–peroxidase complex method [16].For the demonstration of endothelial cells,a rabbit polyclonal antibody raised againsthuman CD34 (Immunotech, France) wasapplied. Before staining, sections weretreated by antigen retrieval in a microwaveoven in 0.1 M citrate buffer for 15 min.Immunostains were performed using a1:30 dilution of antibody at room tempera-ture overnight. The reaction product wasvisualized with diaminobenzidine. Slideswere counterstained with methyl green andmounted. Details of immunohistochem-istry and control procedures have beendescribed in previous publications [17,18].

Morphometric Study

Geographically, the pituitaries weredivided into three regions correspondingto the lateral wings and central areas of theadenohypophysis, as well as the posteriorlobe. In each area, CD34 immunostainedsections were examined using a computerimage analysis system (Microimage, MediaCybernetics). Quantitation consisted ofarea and perimeter measurements for everymicrovessel in each field. Both MVD andMSD were thus determined. The countswere performed using a Provis AX70microscope (Olympus) attached to anOlympus DP 10 digital camera. Imageswere taken utilizing a ×40 apochromatobjective and subsequently captured digi-tally at a resolution of 386 pixels. Prior tomeasurements being taken of vessel counts,


each image was processed digitally toexaggerate the contrast between microvesselsand their lumens.

In each nontumorous pituitary, a totalof 20 randomly chosen fields (correspond-ing to 6.7 mm2 of pituitary tissue) wereassessed. The same approach was appliedto nontumorous pituitary tissue surround-ing the 11 incidentally discovered adenomas.With regard to the microadenomas, thevascularity in the entire adenomatous areawas examined. The measured parametersincluded MVD (the percentage of pituitaryoccupied by vessels) and MSD (the per-centage of the vessel circumference in directcontact with pituitary tissue).

Statistic Study

Provided that the criteria of normal dis-tribution were met (SPSS statistic pro-gram), comparisons between the differentgroups were performed by one-way analy-sis of variance (ANOVA) and the Student’st test as a multiple comparison method.Differences of p < 0.05 were considered sta-tistically significant.

Results

Immunohistochemical staining of theCD 34 antigen resulted in homogeneousreactivity confined entirely to endothelialcells (Figs. 1–4). Positivity was well definedand easy to quantify.

Nontumorous Pituitaries

Our morphometric study demonstrateddifferences in the microvascular architec-ture of the anterior and posterior lobes ofthe nontumorous gland. These were appar-ent in both sexes, in all age groups, and inpregnancy. In general, MVD was higherin the anterior lobe, which is in accordancewith the greater percentage of the vessel

wall in contact with pituitary tissue at thissite (Figs. 5–8). Neither age- nor gen-der-dependent changes were noticeable inthe anterior or posterior lobes.

Although MVD did not significantlydiffer between the central and lateral por-tions of the anterior lobe, in both sexes thelateral wing appeared to have lower counts(Figs. 9 and 10). Similarly, no statisticallysignificant differences were noted in theMSD of the two regions in both sexes. Asshown in the Fig. 11, in men the percent-age of the vascular circumference in contactwith pituitary tissue decreased with age inthe lateral wing as compared to the centralarea. In contrast, in the lateral wing ofwomen, the MSD in this zone slightlyincreased with age as compared with thecentral area. Lastly, in contrast to the non-pregnant female groups, the lateral wingof pregnant women had a slightly higherMSD than did the central region (Fig. 12).

Incidental Microadenomas

Staining for CD 34 showed that inci-dental microadenomas had a very differ-ent microvascular architecture than thenontumorous adenohypophyses (Figs. 3and 4). Our morphometric study clearlyfound both the MVD and MSD to be sig-nificantly lower in microadenomas as com-pared to nontumorous anterior pituitarytissue (Figs. 13 and 14). In contrast no sig-nificant differences were noted in themicrovascular architecture of the non-tumorous adenohypophysis and that ofadenohypophysial tissue surroundingincidental micoradenomas.

Discussion

In each organ, the microcirculation isspecifically organized to serve its specialneeds. The purpose of pituitary vessels is


Fig. 1. CD34 immunoreactivity in the lateral wing of nontumorous adenohypophysis. Bar: 50 µm.Fig. 2. Immunostaining shows CD34 immunoreactivity in the endothelial cells of the posterior lobe.Bar: 50 µm.Fig. 3. Adenoma border. Compared to the nontumorous adenohypophysis (NTP)microvessel density is decreased in the microadenoma (MA). Immunostaining forCD34. Bar. lOO µm.Fig. 4. Immunostaining for CD34 adenohypophysial microadelloma\showing,ai marked decrease in the num-ber of vessels. Bar: 50 µm.

(a) to transport nutrients to the tissue, (b)to carry away waste products, (c) to deliverspecific stimulating or inhibiting factors to

the cells, and (d) to carry the secretoryproducts of these cells to distant sites. Spe-cific architectural features of the microcir-


Fig. 5. Pituitary microvessel density in men. Data are expressed as percentage of pituitary occupied by ves-sels and represent the mean + SEM. Statistical significance *p < 0.05, **p < 0.005, ***p < O.OOOI comparedanterior lobe (AL) vs paired posterior lobe (PL).

Fig. 6. Pituitary microvessel density in women. Data are expressed as percentage of pituitary occupied byvessels and represent the mean + SEM. Statistical significance *p < 0.05, **p < 0.005; ***p < O.OOO1 com-pared AL vs paired PL.


culation are obviously related to blood flowin each organ. In the pituitary, blood flow,metabolism, and functional activity areclosely associated [1,19]. One can safelyassume that the quantity of hypothalamicsecretagogues reaching the anterior lobedepend not only on their rate of produc-

Fig. 7. Pituitary microvessel surface density in men. Data are expressed as percentage of pituitary in contactwith vessels and represent the mean + SEM. Statistical significance *p < 0.05 and ***p < 0.0005 comparedanterior lobe (AL) vs paired posterior lobe (PL).

Fig. 8. Pituitary microvessel surface density in women. Data are expressed as percentage of pituitary incontact with vessels and represent the mean + SEM. Statistical significance *p < 0.05; **p < 0.005; ***p < 0.0001compared AL vs paired PL.

tion, but also upon the amount of bloodtransported to this structure. Various tech-niques, such as autoradiographic, thermo-electric, indicator uptake, and hydrogenclearance methods, have been used quan-titatively to assess pituitary blood flow[1,20–22]. Interestingly, several aspects of


Fig. 9. Pituitary microvessel density in men. Data are expressed as percentage of pituitary occupied by ves-sels and represent the mean + SEM. Statistical significance *p < 0.05, **p < 0.005, ***p < 0.0001 comparedcentral area (MAA) and lateral wing (LWA) of the adenohypophysis vs paired PL.

Fig. 10. Pituitary microvessel density in women. Data are expressed as percentage of pituitary occupied byvessels and represent the mean + SEM. Statistical sign)ficance *p < 0.05, **p < 0.005, ***p < 0.0001 com-pared central area (MAA) and lateral wing (LWA) of the adenohypophysis vs paired PL.


determining blood flow in different por-tions of the human pituitary. Similar dif-ferences were observed with respect toMSD in the two lobes. It is possible thatthese characteristics of the microvascu-lature not only affect pituitary blood flowbut also the relationship between bloodsupply and the very different parenchymacomprising both lobes.

In view of the importance of blood flowto pituitary function, it has been postu-lated that vascular alterations may explainchanges in endocrine activity known tooccur with advancing aging [14,15]. Theseinclude slight decrease in pituitary thy-rotropin release and/or gradual declines inblood levels of growth hormone/insulin-like growth factor 1 in a signifcant pro-portion of elderly women and men [23,24]. Perhaps related to these manifesta-tions, Sano et al. [ 14] reported the changesin pituitary morphology accompanyingaging. These authors observed perivascu-

Fig. 11. Pituitary microvessel surface density in men. Data are expressed as percentage of pituitary in contactwith vessels and represent the mean + SEM. Statistical sign)ficance *p < 0.05; **p < 0.005; ***p < 0.0001compared central area (MAA) and lateral wing (LWA) of the adenohypophysis vs paired PL.

pituitary microvascular architecture havebeen ignored, most notably angiogenesis.To our knowledge, the present study isthe first morphologically to demonstratemarked differences in the structure of theanterior and posterior lobes. That differ-ence did exist was previously suggested bya laser–Doppler flow study during trans-sphenoidal adenomectomy [7]. Using CD34 immunostaining combined with auto-mated morphometry, we appear to havedemonstrated an inverse correlationbetween MVD and blood flow as reportedto occur in the anterior and posteriorpituitary [7]. Given the higher blood flowknown to occur in the posterior lobe [3–7], our finding of a significantly lower MVDat this site was unexpected. Relative to theconcept that blood flow equals the volumeflow divided by the cross-sectioned area ofthe vascular bed, our results provide strongphysiologic support for the concept thatthe capillary network plays a major role in


lar fibrosis in the adenohypophysis of mostaging men. Although we found no signifi-cant age-related changes in microvasculararchitecture in both sexes, an effect ofpituitary blood flow upon pituitary dys-function cannot be excluded. Jakubowski[1] suggested that decrease in blood flowper unit of adenohypophysial weightoccurring during estrogen treatment couldbe due to a disproportionate increase inparenchyma relative to vascular supply. Asimilar scenario may occur in the pituitaryduring aging, since possible changes inpituitary weight are not accompanied byalteration in microvascular architecture.Degens [25] observed that the restingblood flow of the skeletal muscle was mini-mally affected by age but blood flow dur-ing or following exercise was decreased dueto a reduced vasodilatory capacity andcapillarization. The explanation may notbe as simple as vasculature and blood flow.

For example, several authors have reportedage-related changes in the production ofhypothalamic as well as in the expressionof their receptors upon pituitary cells [26–28].These changes could certainly affect pitu-itary function as well.

Prior studies have demonstrated thatblood flow in the anterior lobe is not uni-form throughout the gland, being higherin the central area than in the lateral wing[6,8,29]. Different hypotheses have beenformulated to explain this finding. Ourfindings demonstrate no correlationbetween anterior lobe microvascular archi-tecture and the lack of uniform blood flow.Specifically, we observed no statistical dif-ferences in the two morphometric param-eters analyzed (MVD and MSD) in thecentral and lateral portions of the lobe. Itis of note, however, that in both sexeshigher MVD values were observed in thecentral area. Although these differences

Fig. 12. Pituitary microvessel surface density in women. Data are expressed as percentage of pituitary incontact with vessels and represent the mean + SEM. Statistical significance *p < 0.05, **p < 0.005; ***p < 0.0001compared central area (MAA) and lateral wing (LWA) of the adenohypophysis vs paired PL.


could not be enough to justify changes inthe blood-flow values between lateral andcentral areas, they may relate to strongercontrol exerted by hypothalamic factorsupon the central zone. Porter et al. [30]showed that the concentration of dopam-ine in the central zone was higher than inthe lateral region, suggesting that this find-ing may account for the relative prepon-derance of prolactin-producing cells in thelateral portions of the gland. In the presentstudy, no statistical differences were foundin MSD between the middle and lateralareas. However, minor differences wereobserved between males and females.Unlike men, the MSD in women wasslightly higher in the lateral than in thecentral regions. Since in the female ante-rior lobe the MVD is higher in the centralarea, our data suggest that the microvessels

in the lateral area have a more irregularperimeter than those of the central part.Gender differences have been reported inadenohypophysial endocrine cells afterpuberty. It is reasonable to suggest thatsuch differences may be estrogen-induced.Although it is not possible to draw adefinitive conclusion from the presentstudy, our results are consistent that estro-gen-effect upon the lateral regions under-lie the differences. For example, it has beenshown that estrogens can increase bloodflow, in both reproductive and endocrineorgans [29,31,32]. Furthermore, Elias andWeiner [33] observed that estrogen treat-ment induced lactotroph hyperplasia andangiogenesis in the lateral area of the ratadenohypophysis. These observations areconsistent with our findings in the preg-nant pituitary, which is not under estro-

Fig.13. Microvessel density in pituitary microadenomas. Data are expressed as percentage of pituitary occu-pied by vessels and represent the mean + SEM. Statistical significance ***p < 0.0001 compared normaltumor-free adenohypophyses (60–79 yr-old men and 60–79 yr old women) and nontumorous adenohypo-physis surrounding adenomas vs microadenomas.


gen influence. We noted that the percent-age of vessel wall in direct contact withpituitary tissue was lower in the lateral thanin the central areas of the anterior lobe.Although this effect could be attributableto lack of estrogens, the marked increasein the percentage of lactotrophs reportedto occur in pregnant pituitary [34,35]could also explain these results, sincelactotrophs are particularly numerous inthe lateral wings.

The present study also showed that,compared to normal anterior lobe tissue,adenohypophysial microvascular architec-ture was drastically altered in the inciden-tal microadenomas. As a rule, these aresmall tumors and are a frequent autopsyfinding in the elderly. They are benign,well-demarcated tumors, which either lackimmunoreactivity for pituitary hormonesor stain for prolactin, follicle-stimulating

hormone (FSH), luteinizing hormone(LH), or α-subunit [36]. Our findingsshowed that the vascularity of micro-adenomas was significantly lower than thatof nontumorous adenohypophysis. In con-trast, no significant differences in vascu-larity were observed between anterior lobetissue of normal tumor-free pituitaries andthat surrounding adenomas. This observa-tion confirms the results of previous stud-ies of surgical material showing thatpituitary adenomas are less vascularizedthan nontumorous pituitaries [37,38].Jugenburg et al. [38] suggested that lackof significant angiogenesis may underlie theslow pace of pituitary tumor growth andthe rarity of metastasis. The basis for thelow vascularity of pituitary adenomas isunclear. Recently Lloyd et al. [39] reporteddecreased expression of vascular endothe-lial growth factor (VEGF), the most sig-

Fig. 14. Microvessel surface density in pituitary rnicroadenomas. Data are expressed as percentage of pitu-itary in contact with vessels and represent the mean + SEM. Statistical significance ***p < 0.0001 comparednormal tumor-free adenohypophyses (60–79-yr-old men and 60–79-yrs-old women) and nontumorousadenohypophysis surrounding adenomas vs microadenomas.


nificant factor inducing angiogenesis, inadenomas as compared to nontumoralpituitaries. In a previous study, we dem-onstrated von Hippel–Lindau protein(VHL-P) in adenomatous pituitary cells[40]. Both in vivo and in vitro VHL-P havebeen shown to interact directly with thetranscription factor Spl to repress VEGFtranscription. Since angiogenesis is the resultof a delicate balance between factors thatstimulate or inhibit endothelial cell prolif-eration, it is conceivable that adenomatouspituitary cells could produce very little orno stimulating factors and/or that they syn-thesize factors that suppress angiogenesis.

AcknowledgmentsThis study was supported in part by the

Research Council of St. Michael’s Hospi-tal, Mr. and Mrs. Stephen Jarislowsky, andthe Lloyd Carr-Harris Foundation. Dr.Sergio Vidal was supported by a researchgrant from the University of Santiago deCompostela, Spain. The authors areindebted to Mr. Fabio Rotondo and Mrs.Arlene Stewart for the technical assistanceand the staff of St. Michael’s Health SciencesLibrary for their contribution in this study.

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Vascularity in nontumorous human pituitaries and incidental microadenomas: A morphometric study