Shinshu Med J, 70⑵：101～106, 2022

Adolescent Physiological Pituitary Gland Hypertrophy Transformed
into a Prolactin-secreting Macroadenoma in Early Adulthood
Moses Osaodion Inojie1）2）, Toshihiro Ogiwara1）＊, Satoshi Kitamura1）
Takuya Nakamura1）, Maki Miyata 1）, Yoshiki Hanaoka1）, Ridzky Firmansyah Hardian1）
Samuel Chukwunoyerem Ohaegbulam2） and Tetsuyoshi Horiuchi1）1） Department of Neurosurgery, Shinshu University School of Medicine
2） Unit of Neurosurgery, Memfys Hospital for Neurosurgery, Enugu, Nigeria

The concept of physiological pituitary gland hypertrophy is well recognized in settings of increased physiological needs, such as pregnancy and puberty. However, it is very uncommon for it to transform into a neoplastic
pituitary lesion in the form of a functioning or non-functioning pituitary adenoma. In this case report, we present
a 24-year-old woman with an initial diagnosis in adolescence of physiological pituitary hypertrophy following
neuroradiological evaluation of her persistent headache, who developed a neoplastic symptomatic prolactinoma 9
years later. She underwent endoscopic endonasal tumor excision, which was uneventful with no intraoperativecomplications. The present case study revealed the possibility that adolescent physiological pituitary gland
hypertrophy can develop into prolactinoma. Hence, patients with symptomatic physiological pituitary gland enlargement should have long-term follow-up using clinical, laboratory, and neuroradiology evaluations. Shinshu
Med J 70 : 101―106, 2022
(Received for publication September 28, 2021 ; accepted in revised form November 11, 2021)
Key words : adolescent, physiologic pituitary hypertrophy, prolactinoma, pituitary adenoma,
endoscopic endonasal approach
Abbreviations : MRI, Magnetic Resonance Imaging ; CT, Computed Tomography ; PHPG, Physiologic Hypertrophyof Pituitary GlandⅠ

Although PHPG is common, its transformation into

Introduction

neoplastic pituitary lesions in the form of functioning

The concept of physiological hypertrophy of theor non-functioning pituitary adenoma is uncommon

pituitary gland (PHPG) is well recognized, and is de-based on a review of the relevant literature. Most

fined as an absolute increase in the number of one orprevious observational studies on pituitary tumori-more adenohypophysis cell subtypes, manifesting ra-

genesis could not link PHPG to the eventual develop-

diologically as pituitary enlargement beyond thement of pituitary adenoma2）4）5）. Hence, most physi-

normal range1）-3）. This is a common finding in preg-

cians reassure patients with PHPG without proper

nancy and in adolescent girls during puberty due tolong-term follow-up.

the increased physiological needs of pituitary hor-

Here, we report a female adolescent with PHPG

4）

that transformed into a prolactin-secreting macroad-mones during these periods of human development .

enoma in early adulthood.
＊

Corresponding author : Toshihiro Ogiwara
Department of Neurosurgery, Shinshu University
School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano
390-8621, Japan
E-mail : togiwara@shinshu-u.ac.jp

No. 2, 2022

Ⅱ

Case Presentation

Here, we report a 24-year-old woman who initiallypresented 9 years previously as an adolescent with101

Inojie・Ogiwara・Kitamura et al.

Fig. 1 MRI showing homogenous pituitary gland enhancement which is in keeping with physiologic
enlargement with 11 mm in pituitary hight (A and B). Current MRI images after nine years
from the initial scan, which revealed a less enhanced sellar mass that is consistent with
pituitary adenoma compressing the pituitary gland upward (C, D).

persistent bilateral dull headache and underwent

with good response and complete disappearance ofbrain magnetic resonance imaging (MRI) and hor­

symptoms. About 9 years later, she developed men­monal evaluations (Fig. 1A, B). Anterior pituitarystrual disturbance and worsening of disabling head­

hormone levels including prolactin (7.5 ng/ml) andache pain. Laboratory evaluation revealed hyperpro­

thyroid stimulating hormone (0.977μIU/ml) were alllactinemia (111.0 ng/ml) and MRI identified a de novo

within the normal limits, and primary hypothyroid­

less-enhanced pituitary tumor with optic nerve andism was clinically excluded (fT4 : 1.32 ng/dl) (Table.

pituitary stalk compression (Fig. 1C, D). However,1). Thus, the neuroimaging and hormonal assess­

she was neurologically intact on clinical examination.

ments revealed features consistent with PHPG, andApart from the increase in prolactin level, other

she was then managed as a case of benign headache

pituitary hormones were within the normal limits.

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PHPG transformed into a prolactinoma

The pituitary tumor might have been a de-novo

Intraoperative findings revealed a cystic tumor with

non-functioning pituitary adenoma as well as prolac­

clear serous liquid and a thin solid component, whichtinoma, because the prolactin level was not so highwas whitish, soft, and hemorrhagic (Fig. 2A, B). Gross

as prolactinoma, and there was a possibility of hyper­

total tumor removal was accomplished. Surgery was

prolactinemia due to the stalk effect associated with

uneventful with no intraoperative complications.

a non-functioning pituitary. With sufficient informed

Postoperative neuroimaging revealed satisfactory

consent, she preferred to undergoing endoscopic en­

findings, without any signs of ischemia, hemorrhage,

donasal tumor resection for decompression of theor residual tumor (Fig. 3A, B). The patient showed

optic nerve and making a definitive diagnosis, rather

good clinical recovery with no postoperative neuro­

than medical treatment including dopamine agonists.

logical deficit. Prolactin level normalized immediately

Fig. 2 Intraoperative endoscopic view : (A) A tumor with a thin solid component, which was whitish, soft, andhemorrhagic (thin arrow). (B) Normal pituitary grand and excision cavity (thick arrow) after gross total
resection of the tumor. asterisk, dura materFig. 3
No. 2, 2022

Postoperative MRI showing complete tumor extirpation (A, B).
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Inojie・Ogiwara・Kitamura et al.

after surgery and other pituitary hormones wereTable 1 Preoperative and postoperative day 7
endocrinological data

within the normal limits (Table. 1). A tissue sample
obtained during the surgical procedure was subjected

Hormone level (normal range)

preope.

postope.

to histological analysis. Histological examination showedfT3 (2.3-4.0 pg/ml)

3.05

2.76

diffusely growing adenoma cells with eosinophilic cy­

fT4 (0.9-1.7 ng/dl)

1.52

1.49

TSH (0.50-5.00 μIU/ml)

1.51

1.09

GH (0.13-9.88 ng/ml)

0.1

0.3

FSH (1.47-16.60 mIU/ml)

6.5

4.6

LH (1.3-88.33 mIU/ml)

19.6

15.1

PRL (4.0-30.0 ng/ml)

111

14.8

Cortisol (1.0-15.0 μg/dl)

13.2

8.1

ACTH (7.2-63.3 pg/ml)

26.3

32.7

fT3, free T3 ; fT4, free T4 ; TSH, thyroid stimulating hor­mone ; GH, growth hormone ; FSH, follicle stimulating hor­mone ; LH, luteinizing hormone ; PRL, prolactin ; ACTH,
adrenocorticotropic hormone

toplasm (Fig. 4A). Immunohistochemical studies forhormones showed that the tumor was positive forprolactin (Fig. 4B), and negative for growth hormone(Fig. 4C). This tumor was composed of uniform
medium-sized cells with pale eosinophilic cytoplasm,
which was positive with Cytokeratin CAM5.2, andcentral nuclei (Fig. 4D). These pathological findings
suggested that it was a sparsely granulated lactotroph
adenoma. There were no indications for further on­
cological treatment and the patient is currently on
regular neuroradiological follow-up.

Fig. 4 An H&E-stained section revealing the typical diffuse pattern of a pituitary adenoma,
which consisted of uniform medium-sized cells with pale eosinophilic cytoplasm andcentral nuclei (A). Immunohistochemistry showing positive staining for prolactin (B),negative staining for growth hormone (C) and positive with Cytokeratin CAM5.2 (D).
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PHPG transformed into a prolactinoma

Ⅲpituitary gland, and factors involved in the physio­

Discussion

logical regulation of the pituitary gland, such as so­

Adolescents, particularly girls, tend to have pitu­

matostatin analogs and dopamine agonists, areitary gland enlargement, which can be explained by hy­

utilized therapeutically as analogs of inhibitory hypo­pertrophy secondary to physiological-endocrinologicalthalamic factors in the treatment of functioning pitu­

events associated with increased need for sex hor­

itary adenomas, including prolactinomas and non-mones, such as follicle stimulating hormone, luteiniz­

functioning pituitary adenomas5）9）-11）. A literature

ing hormone, estradiol, and estrone, around puberty1）.

search identified some individual case reports ofThis enlargement may cause a mass effect as patients

corticotroph adenoma in patients with Addison’s dis­predominantly present with headache and rarely

ease after treatment with corticosteroids5）9）12）. Al­with visual disturbance1）3）6）. The diagnosis of PHPG

though these observations point to the potential roles

is largely clinico-hormono-radiological. Thus, pitu­

of hormonal factors in pituitary tumorigenesis, theitary enlargement (pituitary height ≥ 9 mm, or great­correlation between PHPG and pituitary adenoma

er than that predicted by age, gender, and ethnicity)formation remains unclear.

with normal hormonal assessment and gland homo­

Another possibility is that the patient had an ade­

geneity on plain and contrast-enhanced MRI with anoma in situ misdiagnosed as PHPG at the initialconspicuous posterior pituitary bright spot is consid­

presentation in adolescence, which later increased in

3）
4）
7）

. There­size and then acquired secreting potential, because

fore, proper evaluation of patients on initial presenta­

she had no prior histological confirmation of PHPG astion is the key to differentiating PHPG from adenoma.

her initial diagnosis was largely based on clinico-

However, the duration over which peripubertal pitu­

hormono-radiological evaluations. Conversely, previ­itary gland hypertrophy persists is still unknown,

ous attempts at surgery for biopsy or decompres‑and few data are available on the epidemiology, diag­sion for PHPG resulted in therapeutic mishaps as

nosis, and treatment of PHPG. These issues must be

histopathological results did not add diagnostic value

addressed by further research on pituitary glandto the clinical diagnosis, yet the patients have to bearpathologies.

the morbidity associated with the surgery4）7）. Data

ered as PHPG to avoid therapeutic errors

In the present case study, it was especially note­available in the literature recommend only clinico-worthy that PHPG diagnosed in adolescence later

hormono-radiological evaluation for diagnosis ofdeveloped into a prolactin-secreting pituitary mac­

physiological hypertrophy of the pituitary gland3）4）.

roadenoma after a period of 9 years. The transforma­

This present case was diagnosed with symptomatiction of PHPG into a neoplastic lesion in the form of

PHPG in adolescence 9 years before this recent pre­functioning or non-functioning pituitary adenoma

sentation of functioning pituitary adenoma, but she

has not been reported previously. We believe that

had no long-term follow-up care because of thethis is a consequence of some hormonal factors

belief that physiological pituitary enlargement isinvolved in the pathogenesis of pituitary tumors,benign and has no risk of neoplastic transformation.

which has not been previously implicated. Studies in

Therefore, this case presentation suggests the needseveral animal models have shown that hormonal

for an appropriate regimen of long-term follow-up in

effects, such as hypothalamic trophic or inhibitory

patients with symptomatic physiological pituitaryhormones, or abnormal feedback regulation mecha­

hypertrophy. Finally, the significant issue of this casenism from peripheral hormones, could lead to pitu­

report was that the transformation from PHPG to5）8）

itary adenoma. However, previous studies could
5）

prolactinoma has not been clarified histologically,

not provide evidence for this in humans . Mean­

molecular biologically and clinically, and further

while, the preponderance of prolactinomas in females

studies of this issue are warranted.

may be linked to the influence of estradiol on theNo. 2, 2022

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Conclusions

Ethical Approval

This case presented is an unusual example of pitu-

All procedures performed in the studies involving

itary adenoma that revealed the possibility of adoles-

human participants were in accordance with thecent physiologic pituitary gland hypertrophy under-

ethical standards of the institutional and/or national

going transformation into a prolactinoma. Hence,research committee and with the 1964 Helsinki dec-

patients with symptomatic physiological pituitary

laration and its later amendments or comparable

gland enlargement should have long-term follow-up

ethical standards. Informed consent was obtainedwith clinical, laboratory, and neuroradiology evalua-from the participant included in the study.

Ⅳ

tions. This case report will improve knowledge on
pituitary tumorigenesis.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict ofinterest.
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（2021. 9. 28 received ; 2021. 11. 11 accepted）

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