The Morphology of the Pituitary Gland: A Meta-Analysis with Implications for Diagnostic Imaging

The objective of this meta-analysis was to present transparent data on the morphology of the pituitary gland (PG) using the available data in the literature. The main online medical databases, such as PubMed, Embase, Scopus, and Web of Science, were searched to gather all relevant studies regarding PG morphology. The mean overall volume of the PG was found to be 597.23 mm3 (SE = 28.81). The mean overall height of the PG was established to be 5.64 mm (SE = 0.11). The mean overall length of the PG was found to be 9.98 mm (SE = 0.26). In the present study, the PG’s overall morphology and morphometric features were analyzed. Our results showed that, on average, females from Asia have the highest volume of PG (706.69 mm3), and males from Europe have the lowest (456.42 mm3). These values are crucial to be aware of because they represent the normal average properties of the PG, which may be used as reference points when trying to diagnose potential pathologies of this gland. Furthermore, the present study’s results prove how the PG’s size decreases with age. The results of the present study may be helpful for physicians, especially surgeons, performing procedures on the PG.


Introduction
The pituitary gland (PG) is a small bean-shaped organ located at the base of the brain. It was termed the "master gland" because of the numerous hormones that emanate from it and help to regulate vital functions such as the growth of various tissues, blood pressure, and reproduction. It is located in the sella turcica, which is the saddle-like bony formation on the upper surface of the body of the sphenoid. The PG consists of the anterior pituitary lobe (or adenohypophysis), the intermediate lobe, and the posterior pituitary lobe (or neurohypophysis).
During the fourth week of gestation, Rathke's pouch originates from the roof of the stomodeum. It proliferates to produce the pars distalis (anterior pituitary), the pars intermedia (intermediate lobe), and the pars tuberalis [1,2]. Furthermore, between the fifth and sixth week of gestation, the diencephalon neuroectoderm produces the median eminence, the infundibular stem, and the pars nervosa [3].
The "norm" in anatomy is not as precise a concept as one would wish and could be considered an approximation [4]. It is known that pituitary size depends on age, gender, certain diseases, and even race. There is a trend for larger pituitary volumes among females and during puberty, followed by a progressive decrease in size after adolescence [5]. Furthermore, pituitary height was proposed as the best single surrogate parameter of pituitary size and is maximal in young adults and changes with chronic functional alterations [6]. PG volume may also change in patients with various nutritional disorders and neuroendocrine and psychiatric diseases such as schizophrenia, depression, and psychotic disorders [7][8][9][10]. Moreover, morphological changes in the PG due to hormone-related factors, such as the intake of estrogens, pregnancy, and the postpartum phase, have also been a repeated topic of discussion [11,12]. Magnetic resonance imaging (MRI) allows for a detailed examination of PG morphology because of its excellent contrast resolution. Some of the standard methods used in MRI measuring the PG volume are based on stereological techniques using point counting, planimetry, and the elliptic formula [13].
Pituitary disorders cause a broad spectrum of hormonal and neurological symptoms due to the gland's location close to vital neurovascular structures and the essential hormonal control it provides [14]. Therefore, the objective of this meta-analysis was to present transparent data on the morphology of the PG using the available data in the literature. These results could provide physicians with reliable knowledge about the PG's morphology and morphometry, enabling the recognition of pathological changes in the gland.

Search Strategy
The main online medical databases, such as PubMed, Embase, Scopus, and Web of Science, were searched to gather all relevant studies regarding PG morphology. The following search terms were used: ((pituitary gland) OR ((hypophysis)) AND (anatomy))) OR ((pituitary gland[Title/Abstract]) AND (morphometry[Title/Abstract])). The search terms were adjusted for each database to maximize the number of studies found. The date, language, article type, and text availability conditions were not applied. An additional search was conducted through the references of the identified studies at the end of the search stage to ensure the precision of the process. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed during the study. The critical appraisal tool for anatomical meta-analysis (CATAM) was also used to provide the highest-quality findings [15].

Eligibility Assessment
Initially, after the search of the databases and an additional manual search through the references, 21,365 studies were identified and first reviewed by two independent reviewers. After removing the duplicates and irrelevant records, a total of 318 articles qualified for the full-text evaluation. Papers such as case reports, case series, conference reports, reviews, letters to editors, and studies that provided incomplete or irrelevant data were excluded to minimize potential bias and maintain an accurate statistical methodology. The inclusion criteria involved original studies, both cadaveric and based on radiological imagining, with extractable numerical data on the morphology of the PG. Studies examining the PG in only one dimension were also considered. The results obtained on the cadavers did not differ statistically significantly from those obtained using magnetic resonance imaging (p > 0.05); therefore, an overall analysis could be performed. A total of 247 articles were excluded from the study because they were case reports or case series (n = 38) or because they did not have relevant or sufficient data regarding the morphometric parameters of the PG (n = 210). Finally, a total of 72 studies were included in this meta-analysis. The AQUA Tool, which was specifically designed for anatomical meta-analyses, was used to minimize the potential bias of the included studies [16]. The data collection process is shown in Figure 1. The characteristics of the studies included in this meta-analysis are gathered in Table 1. = 38) or because they did not have relevant or sufficient data regarding the morphometric parameters of the PG (n = 210). Finally, a total of 72 studies were included in this metaanalysis. The AQUA Tool, which was specifically designed for anatomical meta-analyses, was used to minimize the potential bias of the included studies [16]. The data collection process is shown in Figure 1. The characteristics of the studies included in this meta-analysis are gathered in Table 1.

Data Extraction
Two independent reviewers performed the extraction. Qualitative data, such as the year of publication, country, and continent, were gathered. Quantitative data, such as the sample size and numerical data regarding the morphological aspects of the PG in specific groups, were gathered. Any discrepancies between the studies identified by the two reviewers were resolved by contacting the authors of the original studies wherever possible or by consensus with a third reviewer.

Statistical Analysis
To perform this meta-analysis, STATISTICA version 13.1 software (StatSoft Inc., Tulsa, OK, USA), MetaXL version 5.3 software (EpiGear International Pty Ltd, Wilston, Queensland, Australia), and Comprehensive Meta-analysis version 3.0 software (Biostat Inc., Englewood, NJ, USA) were applied. A random effects model was used. The Chi-square test and the I-squared statistic were chosen to assess the heterogeneity among the studies [15]. P-values and confidence intervals were used to determine the statistical significance between the studies. A p-value lower than 0.05 was considered statistically significant. In the event of overlapping confidence intervals, the differences were considered statistically insignificant. I-squared statistics were interpreted as follows: values of 0-40% were considered as "might not be important", values of 30-60% were considered as "might indicate moderate heterogeneity", values of 50-90% were considered as "may indicate substantial heterogeneity", and values of 75-100% were considered as "may indicate substantial heterogeneity." The results obtained on the cadavers did not differ statistically significantly from those obtained using magnetic resonance imaging (p > 0.05). Therefore, an overall analysis could be performed.

Morphometric Parameters of the PG in Adults
The mean overall volume of the PG was 597.23 mm 3 (SE = 28.81). The mean overall height of the PG was 5.64 mm (SE = 0.11). The mean overall length of the PG was 9.98 mm (SE = 0.26). The mean overall width of the PG was determined at 13.08 mm (SE = 1.76). The Brain Sci. 2023, 13, 89 6 of 16 mean overall pituitary area was 38.06 mm 3 (SE = 2.32). The width of the infundibulum was determined at 2.10 mm (SE = 0.07). The most common shape of the PG was convex with a prevalence of 58.38% (CI: 22.21%-90.65%), followed by concave 17.72% (CI: 5.63%-34.00%) and flat 16.67% (CI: 0.00%-47.07%). Partially empty sella turcica occurred with a prevalence of 2.20% (CI: 0.00%-7.16%). The p-value in every category equaled < 0.001. All the results mentioned above, and more detailed results, including sexual dimorphisms and intercontinental differences, are gathered in Table 2.

Morphometric Parameters of the PG in Children (under 18 Years Old)
The mean overall volume of the PG was 511.53 mm 3 (SE = 112.45). The mean overall height of the PG was 4.81 mm (SE = 0.55). The mean width of the PG was determined at 10.80 mm (SE = 0.07) in Asian children. The mean pituitary area was 29.98 mm 3 (SE = 1.10) in Asian children. The most frequent shape of the PG was convex, with a prevalence of 54.03% (CI: 22.55%-84.05%), followed by flat 33.10% (CI: 7.87%-64.05%). The prevalence of the concave shape was determined to be 12.16% (CI: 6.92%-18.58%). The p-value in every category was < 0.001. All the results mentioned above, and more detailed results, including sexual dimorphisms and intercontinental differences, are gathered in Table 3.

PG Height concerning the Age Groups of the Patients
The results concerning the height of the PG in different age groups were also collected. The detailed statistical data are gathered in Table 4. A graphical representation of the differences in the heights of the PG between male and female patients and between different age groups is displayed in Figure 2.

Discussion
The PG is a pea-sized gland that sits in the hypophyseal fossa of the sphenoid bone and is surrounded by the sella turcica, covered by the dural fold (diaphragma sellae) (Figure 3). In humans, it comprises two main lobes, anterior and posterior, with the interme-

Discussion
The PG is a pea-sized gland that sits in the hypophyseal fossa of the sphenoid bone and is surrounded by the sella turcica, covered by the dural fold (diaphragma sellae) (Figure 3). In humans, it comprises two main lobes, anterior and posterior, with the intermediate lobe joining them together. During the first two decades of life, the PG grows rapidly and weighs approximately 500 mg by 20 years of age [3,81]. However, with time, significant interstitial fibrosis of the pituitary tissue develops, leading to decreased proportions of the gland [81]. Furthermore, the PG goes through considerable changes in size during pregnancy. It was proven that during pregnancy, the PG becomes somewhat hyperintense on T1-weighted images (one of the basic pulse sequences in MRI that demonstrates the differences in the T1 relaxation times of tissues), similar to that described for neonates [81,82].
The morphological properties of the PG vary considerably in the general population. Singh et al. conducted a study analyzing the morphometry of the PG using MRI [24]. In the study, the authors stated that the differences in the mean pituitary height and volume between females and males were statistically significant. The mean PG height was reported to be 5.80 ± 1.32 mm and 5.37 ± 1.25 mm for females and males, respectively. Another study by Suzuki et al. presented lower results concerning the height of the PG (5.0 ± 1.7 mm in women and 4.7 ± 1.4 mm in men) [74]. Denk et al. [83], in turn, reported higher values than those in the studies mentioned above (6.1 ± 0.1 mm in women and 5.6 ± 0.2 mm in men). Although the PG height varies between the studies, on average, it is greater in females than in males. Our meta-analysis provides similar results, where females had higher PGs than males (5.40 ± 0.14 mm in women and 4.96 ± 0.12 mm in males).
In the present study, we highlight how the height of the PG changes throughout life. On average, women had taller PGs. However, in females and males, the height peaked in the age group of 20 to 29. With time, the height decreased substantially in females and males, proving that the PG decreases in size throughout life. However, some studies have reported an increase in pituitary height again during the fifth decade of life, especially in females [24,61,67]. The increased activity of gonadotrophs explained this phenomenon in During the first two decades of life, the PG grows rapidly and weighs approximately 500 mg by 20 years of age [3,81]. However, with time, significant interstitial fibrosis of the pituitary tissue develops, leading to decreased proportions of the gland [81]. Furthermore, the PG goes through considerable changes in size during pregnancy. It was proven that during pregnancy, the PG becomes somewhat hyperintense on T1-weighted images (one of the basic pulse sequences in MRI that demonstrates the differences in the T1 relaxation times of tissues), similar to that described for neonates [81,82].
The morphological properties of the PG vary considerably in the general population. Singh et al. conducted a study analyzing the morphometry of the PG using MRI [24]. In the study, the authors stated that the differences in the mean pituitary height and volume between females and males were statistically significant. The mean PG height was reported to be 5.80 ± 1.32 mm and 5.37 ± 1.25 mm for females and males, respectively. Another study by Suzuki et al. presented lower results concerning the height of the PG (5.0 ± 1.7 mm in women and 4.7 ± 1.4 mm in men) [74]. Denk et al. [83], in turn, reported higher values than those in the studies mentioned above (6.1 ± 0.1 mm in women and 5.6 ± 0.2 mm in men). Although the PG height varies between the studies, on average, it is greater in females than in males. Our meta-analysis provides similar results, where females had higher PGs than males (5.40 ± 0.14 mm in women and 4.96 ± 0.12 mm in males).
In the present study, we highlight how the height of the PG changes throughout life. On average, women had taller PGs. However, in females and males, the height peaked in the age group of 20 to 29. With time, the height decreased substantially in females and males, proving that the PG decreases in size throughout life. However, some studies have reported an increase in pituitary height again during the fifth decade of life, especially in females [24,61,67]. The increased activity of gonadotrophs explained this phenomenon in older women due to the loss of negative feedback by gonadal steroids [24]. However, Singh et al. presented an increase in the height of the PG in males [24]. Unfortunately, the mechanism behind this phenomenon is still unknown. However, it may be similar to the one in females, though the phenomenon of andropause in males is not as well understood as menopause in females. Interestingly, our meta-analysis showed that the increase in the height of the PG after the fifth decade of life happened in males only. Furthermore, the average volume of the PG was also analyzed in different populations. Interestingly, the largest PG volume was found to be present in females from Asia (706.69 mm 3 ), and the lowest was found in males from Europe (456.42 mm 3 ). These values are crucial to be aware of because they represent the typical average properties of the PG, which may be used as reference points when trying to diagnose potential pathologies of this gland.
Knowledge of the anatomy of the PG and its morphometric properties is of immense importance when performing surgical procedures on it or in the area of the sella turcica. Pituitary adenomas account for approximately 10-15% of surgically treated central nervous system tumors [84]. The standard approach to the pituitary area is the transsphenoidal midline route, which avoids brain retraction and is known to be less traumatic. In this approach, endoscopes are commonly used as the sole visualizing tool. However, if the pituitary tumor has considerable suprasellar and parasellar extension, the transcranial approach might be more suitable [85].
The PG may be the subject of numerous incidental and benign conditions. These include cysts, which are incidentally found in approximately 10% to 20% of the population [86], rounded calcifications in the gland, or pituitary stones, that do not present as clinically significant findings [3]. A somewhat controversial pathology of the PG is the empty sella. This phenomenon was first described in the 1950s [87]. It is believed to be caused by a weakening of the diaphragma sella. This, in turn, enables the transmission of the cerebrospinal fluid pulsations in the suprasellar cistern to the intrasellar area [3]. This ultimately leads to an incomplete or complete flatting of the PG and, with that, a loss of physiological functioning of the gland.
The relation between the morphology of the PG and various degenerative pathologies, such as Alzheimer's disease (AD), has been a topic of interest in the literature. One protein that is said to play a role in the pathogenesis of AD and Creutzfeldt-Jakob disease is clusterin [88]. Clusterin, or apolipoprotein J, is a circulating glycoprotein with numerous functions, such as lipid transport and immune modulation [89]. An age-dependent increase of clusterin in the PG was studied by Ishikawa et al. [90] in an immunohistochemical study. They found a positive correlation between the age of the subjects in years and the percentage of clusterin-positive cell area in the anterior lobe of the PG. However, there was no statistical relationship between the clusterin levels and gender. These results suggest that PG clusterin is produced following degenerative changes.
However, the mechanism of this phenomenon is still unclear. The role of the hypothalamicpituitary axis in Alzheimer's disease was also discussed previously. Interestingly, there is a gender-biased predisposition towards females specific to AD [90]; therefore, the role of sex steroids regulated by the hypothalamus-pituitary-gonadal axis was investigated. Evidence has suggested that estrogen deficiency, which follows menopause, may contribute to the pathogenesis of AD [91]. Estrogen synthesis and secretion from the theca interna cells in the ovary are mainly stimulated by the luteinizing hormone produced in the anterior PG. Therefore, potential pathologies of the PG, such as hypopituitarism, may cause a decrease in the synthesis and secretion of luteinizing hormone and, subsequently, cause decreased estrogen levels. This mechanism may potentially lead to an increased risk of developing AD. Hypopituitarism is most commonly caused by pituitary adenomas, which may be diagnosed with imaging studies. Our study may be helpful for physicians diagnosing the previously mentioned neoplasms because we provide standard morphometric data of the PG, which may be used as the reference point when comparing measured values of a PG with an adenoma.
Thyroid dysfunction could be a potential risk factor for dementia development; numerous epidemiological data implicates both hyperthyroidism and hypothyroidism [92,93]. Yong-Hong et al. [93] conducted a study where the hypothalamic-pituitary-thyroid axis was assessed. The study showed that the patients with AD had significantly lower thyroidreleasing (TRH) and thyroid-stimulating (TSH) hormones, total and free triiodothyronine, and total and free tetraiodothyronine when compared to the control group. These results present how AD may be associated with the lowered function of the hypothalamic-pituitarythyroid axis.
The present study is not without limitations. It may be burdened with potential bias, as the accuracy of the data taken from various publications limits the results of this meta-analysis. Additionally, most of the evaluated studies come from Asia. The total number of PG's analyzed from Asia equaled 1203, while from Europe, there were 1186, and from North America, there were 1093. Therefore, the overall results of this study may be burdened, as they may reflect the anatomical features of Asian people rather than the global population. Variations of organs' shape and dimensions are frequently observed by medical professionals and could influence daily clinical practice, including imaging diagnostics, therapeutic decisions, and surgical procedures [4]. Although not without limitations, our meta-analysis attempts to estimate pituitary morphology based on the data from the literature that meet the requirements of evidence-based anatomy.

Conclusions
The present study analyzed the morphology and morphometric features of the PG. Our results show that, on average, females from Asia have the highest volume of PG (706.69 mm 3 ), and males from Europe have the lowest (456.42 mm 3 ). These values are crucial to be aware of because they represent the normal average properties of the PG, which may be used as reference points when trying to diagnose potential pathologies of this gland. Furthermore, the present study's results prove how the PG's size decreases with age. The results of the present study may be helpful for physicians, especially surgeons, performing procedures on the PG.

Funding:
The author(s) received no financial support for the research, authorship, and publication of this article. Dr Mateusz Koziej was supported (a scholarship) by the Foundation for Polish Science (FNP). The funders had no role in the study's design, data collection and analysis, decision to publish, or preparation of the manuscript.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available upon request from the corresponding author.