Here we report the normative data of SUV and size of the adult pituitary gland with [68Ga]-DOTATATE PET/MR from a heterogenous cohort of 95 patients, stratified by age and sex. In our cohort, SUV/SUVR of the pituitary gland did not differ significantly between males and females and between younger and older groups. However, older females at age cutoffs of 55 and 60 had significantly higher pituitary SUV than younger females, which was not observed in males. When stratified by age and sex, both older and younger females had significantly higher pituitary SUV than older males. SUVR did not differ significantly when stratified by age, sex, or both. Finally, MSH of the pituitary gland in younger females was significantly greater than in younger males at both age cutoffs. The mean SUV and SUVR from the cohort may serve as reference values for the physiologic pituitary gland tissue avidity for [68Ga]-DOTATATE PET (Table 2).
The differences in SUV observed between groups stratified by age and sex generate hypotheses regarding the relationship between somatostatin receptor expression in the pituitary gland and demographic factors. The higher SUV observed in older females compared to younger females may reflect effects of menopause-related hormonal changes on somatostatin signaling. Pituitary size may increase in women during the fifth to sixth decades of life, potentially due to increased gonadotroph activity from loss of negative feedback by estrogen [17, 22, 23]. FSH upregulates SSTR2 expression in ovarian granulosa cells, suggesting a link between menopausal status and cellular SSTR2 expression [25]. The direct effect of estrogen on SSTR expression in pituitary cells is less clear, with in vitro studies showing both upregulation and downregulation [26–29]. The exact mechanisms of hormonal regulation of SSTR expression in pituitary cells are likely to be complex and receptor subtype specific [1].
When the cohort was stratified by both age and sex, both younger females and older females had significantly greater pituitary SUV than older males, suggesting that older males may express the lowest pituitary SUV. While pituitary SUV did not differ significantly between older males and younger males in our cohort, age-related pituitary atrophy may partially provide an explanation for such findings. Although andropause in males is less established than menopause in females, animal studies have shown minimal direct influence of androgens on SSTR expression on pituitary cells [30–32]. In general, pituitary gland reaches its maximum size in second to third decade of life in the setting of physiologic hypertrophy during puberty, followed by a gradual decline with age in both sexes [17, 21, 22]. While SUV or SUVR did not directly correlate with pituitary size in our cohort, one hypothesis is that age related pituitary atrophy may partially explain the lower pituitary SUV observed in older males, an effect that older females may be shielded from secondary to hormonal changes during menopause.
In pituitary adenomas, SSTR expression is highly variable within and between tumor subtypes. For instance, SSTR2 is downregulated in NFPA but not in somatotropinomas [33]. SSTR3 is expressed in most pituitary adenomas including NFPA, while SSTR5 and SSTR2 are more specific to somatotroph, thyrotroph, corticotroph, lactotroph, and gonadotroph adenomas and are likely involved in the regulation of hormonal secretion [34]. The normal pituitary gland expresses high levels of SSTR5, lower levels of SSTR2, and very low levels of SSTR3 and SSTR1 [2]. The somatostatin analogs octreotide and lanreotide bind preferentially to SSTR2 and are used in the treatment of acromegaly, while they have shown a lack of efficacy in NFPA where SSTR2 is downregulated [5, 33].
Hence, [68Ga]-DOTATATE PET, with its specificity towards SSTR2, is equipped to utilize the differential expression of SSTR by pituitary cells and tumors and offer clinically valuable information that complements anatomic imaging. While dynamic T1 weighted contrast enhanced MR sequence is the standard imaging for pituitary adenomas, it lacks assessment of intrinsic permeability properties of the gland. In large adenomas, the normal pituitary gland can be structurally displaced which impairs visualization on anatomic imaging [14]. The novel functional imaging has potential to aid in differentiating between different types of pituitary adenomas and other non-pituitary sellar malignancies. Postoperative surveillance of residual pituitary adenomas and preoperative delineation of tumors from normal tissue may be enhanced to prevent often incomplete transsphenoidal resection or to preserve normal tissue and prevent surgical complications such as hypopituitarism, which affects up to 5% of patients post-surgery [14].
Prior studies have demonstrated efficacy of [68Ga]-DOTATATE PET in differentiating primary and recurrent pituitary adenomas from normal pituitary tissue with significantly lower [68Ga]-DOTATATE SUV than the normal pituitary gland, in agreement with the high SUV of the normal pituitary gland observed in our cohort [18, 19]. Notably, [F18]-FDG PET avidity is higher in adenomas than normal pituitary tissue, and prior studies showed that the ratio of [F18]-FDG to [68Ga]-DOTATATE may be the more accurate metric, suggesting the utility of dual tracer PET in the evaluation of pituitary adenomas [18, 19]. Furthermore, [68Ga]-DOTATATE PET has therapeutic potential to optimize patient selection for molecular targeted therapies using somatostatin analogs and peptide receptor radionuclide therapies (PRRT) such as Lu-177 DOTATATE, already approved for therapeutic use in SSTR positive neuroendocrine tumors (NETs). In demonstrating the baseline distribution of SSTR expression, our study benefits future diagnostic and therapeutic approaches targeting SSTR in pitNET by laying a basis for the expected range of normal pituitary DOTATATE avidity in the context of demographic characteristics.
Our analysis of MSH revealed a significantly larger pituitary gland in younger females compared to younger males. This finding, while only exclusive to the younger groups in our cohort, is in concordance with prior studies that found a significant sex difference in pituitary gland size, with females having a larger size on average than males [15–17, 23]. In contrast, previous studies on the relationship between pituitary size and age have shown mixed results. One study with a cohort of less than 35 years of age demonstrated a positive correlation between pituitary size and age that was more robust in females [20]. On the other hand, another study with a cohort aged 21 to 82 showed age was inversely correlated with pituitary height, which was most pronounced in females [22]. In general, the pituitary gland reaches its maximum size in the second to third decade of life during puberty, followed by a gradual decline in both sexes with age [17, 21]. Additionally, hormonal changes throughout one’s life may also confound the observed relationship between MSH and age. For example, the pituitary gland transiently increases in size during pregnancy [35]. Nulliparous females were reported to have significantly larger pituitary glands than their multiparous counterparts [36]. Females using oral contraceptive pills experience significant reduction in pituitary volume than those who do not [37]. Menopausal females receiving estrogen replacement therapy had greater mean pituitary heights than those who did not [38].
There are several limitations to the study that must be acknowledged. While our cohort contained a non-homogenous sample, it was skewed towards females (73%) and towards older individuals (mean age = 58.9). Our cohort was also a subset from a larger pool of patients who underwent [68Ga]-DOTATATE PET examinations for evaluation of their CNS SSTR2 positive tumors. No PET imaging was dedicated solely for the assessment of the pituitary gland. As a result, every patient in the cohort had a history of intracranial pathology, most predominantly meningioma. Additionally, to reflect the pituitary gland’s vast regulatory role in the body, we initially sought to investigate relationships between pituitary [68Ga]-DOTATATE uptake and clinical variables such as FSH, menopause, TSH, oral contraception (OCP) use, BMI, and other forms of exogenous hormones, where were not included in the final analysis due to difficulties accessing the data, inconsistent documentation, and general scarcity of such information in the electronic medical record. Pituitary gland volume may change with oral contraceptive use, pregnancy, nulliparity, hormone replacement therapy, obesity, and primary hypothyroidism [35–41]. Future studies in relation to the aforementioned variables will further enhance our understanding of [68Ga]-DOTATATE PET in various clinical settings.
Lastly, in our intention to capture sex differences in pituitary gland, sex was collected as a binary variable: male and female, and chart review presumed that documented sex is unchanged from sex assigned at birth. Given sex is a multidimensional construct, our presumption of binary variable does not account for the entirety of the gender spectrum. It is also worth noting that our cohort had no transgender-identifying or gender diverse patients.
Conclusion
We present normative data of the SUV and size of the pituitary gland with [68Ga]-DOTATATE PET/MR from a heterogenous cohort of 95 patients, stratified by age and sex. Our study provides a starting point for utilizing [68Ga]-DOTATATE PET in clinical and research settings, potentially enhancing diagnosis and management of pathologies in the sella turcica and offering personalized approaches with molecular theragnostic agents. Our results generate interesting hypotheses relating pituitary biology to demographic factors, which require further corroboration with future studies both in vitro and in vivo. Future studies with larger, heterogenous populations, accounting for relevant clinical and demographic variables, and with dedicated pituitary imaging will further enhance our understanding of [68Ga]-DOTATATE PET of the pituitary gland in clinical settings.