Lactotroph Cells Research Articles

Prolactin: structure, receptors, and functions.

Prolactin (PRL) is a 23-kDa protein synthesized and secreted by lactotroph cells of the anterior pituitary gland but also by other peripheral tissues. PRL binds directly to a unique transmembrane receptor (PRLR), and the JAK2/signal transducer and activator of transcription 5 (Stat5) pathway is considered the major downstream pathway for PRLR signaling. To a lesser extent, PRL may be cleaved into the shorter 16-kDa PRL, also called vasoinhibin, whose signaling is not fully known. According to rodent models of PRL signaling inactivation and the identification of human genetic alterations in PRL signaling, a growing number of biological processes are partly mediated by PRL or its downstream effectors. In this review, we focused on PRL structure and signaling and its canonical function in reproduction. In addition to regulating reproductive functions, PRL also plays a role in behavior, notably in initiating nurturing and maternal behavior. We also included recent insights into PRL function in several fields, including migraines, metabolic homeostasis, inflammatory and autoimmune disease, and cancer. Despite the complexity of understanding the many functions of PRL, new research in this field offers interesting perspectives on physiological and pathophysiological processes.

8138 Pituitary Stalk Interruption Syndrome (PSIS) in a patient with Isolated Hypogonadotropic Hypogonadism

Abstract Disclosure: A. Thomson: None. R. Osman: None. Pituitary Stalk Interruption Syndrome in a Patient with Isolated Hypogonadotropic Hypogonadism Pituitary Stalk Interruption syndrome (PSIS) is a rare cause of hypopituitarism, characterized by a radiologic constellation of thin or interrupted pituitary stalk, hypoplasia, or aplasia of the anterior lobe and with the presence of an ectopic posterior pituitary (EPP). It is most commonly associated with isolated growth hormone deficiency (IGHD) and is often diagnosed in childhood. We present one case of a patient with isolated hypogonadotropic hypogonadism in adulthood, subsequently found to have an PSIS on MRI. A 45 year old male patient presented to our clinic with hypogonadism. He gradually started developing decreasing libido, fatigue, and loss of erections. He had normal puberty and childhood growth, and has fathered one child. He denied history of anosmia or visual symptoms. Subsequent hormonal testing showed: morning Total Testosterone: 145 ng/dl (normal 264-916 ng/dl), Free testosterone 1.5 pg/ml (normal 6.8-21.5 pg/ml), LH 1.1 mIU/ml (normal 1.7-8.6 mIU/ml) and FSH of 3.6 mIU/ml (normal 1.5-12.4 mIU/ml). Prolactin was minimally elevated at 21 ng/ml (normal 4.0 - 15.2 ng/ml). Thyroid, IGF-1, cortisol, and ferritin levels were within normal limits. Repeat levels showed similar findings. He denied ever taking any form of exogenous testosterone. His pituitary MRI revealed a small volume of anterior pituitary tissue, measuring 0.2cm x 0.7cm x 0.7cm, without discrete pituitary adenoma, a hypoplastic midline stalk measuring 1.3 mm in AP diameter (nl 2-3 mm), with a T1 hyperintense nodularity measuring 0.6cm x 0.4cm along the posterior aspect of the sella turcica consistent with EPP. No additional structural abnormality or any mass lesions were identified. He was subsequently started on replacement testosterone therapy and his symptoms resolved. PSIS usually presents in childhood with IGHD. Patients may have other pituitary hormone deficiencies and congenital central nervous system defects, although panhypopituitarism is rare. There have been reports in children with delayed puberty and isolated hypogonadotropic hypogonadism who have been found to have PSIS. Only one othercase of an adult female patient exhibiting hypogonadotropic hypogonadism as the only manifestation of PSIS has been documented in the literature. Our case highlights the potential for an adult male to present later in life with hypogonadotropic hypogonadism as a manifestation of PSIS. The marginally elevated prolactin level may be due to lack of inhibition of hypothalamic dopamine on lactotroph cells within the pituitary caused by the EPP, although it is doubtful that this has clinical significance. This is a rare presentation of PSIS, clinicians should be mindful ofthis radiological constellation and the potential for isolated hypogonadotropic hypogonadism presenting unusually in the adulthood. Presentation: 6/3/2024

7405 A Case of Pituitary Apoplexy in Pregnancy

Abstract Disclosure: Y. Esaki: None. G.E. Vates: None. I. Shafiq: None. Pituitary apoplexy is a rare cause of headache during pregnancy. The prevalence of pituitary apoplexy during gestation and the peripartum period is estimated to be 1 in 10,000 term pregnancies. Approximately 42-47% of these patients were known to have a pituitary lesion especially history of prolactinoma. Here we report a pregnant female developing pituitary apoplexy after discontinuation of dopamine agonist. A 27-year-old female was initially diagnosed with prolactinoma with elevated prolactin of 158.1 ng/ml (3.0-300 ng/ml). MRI revealed a 1.3 cm x 1.5 cm x 1.4 cm pituitary mass with solid and cystic components. Treatment with cabergoline 0.25 mg twice weekly was started. After 2 years of treatment, prolactin was 74.2 ng/ml and the size of the adenoma decreased to 1.0 cm x 1.2 cm x 1.3 cm. One year later, she became pregnant at age 30 and discontinued cabergoline after 7 weeks of gestation. At 12 weeks of gestation, she presented to the Emergency Department for 3 days of severe headaches associated with emesis. The ED work up includes prolactin > 2,000 ng/ml. MRI head without contrast demonstrated an interval increase in size to 1.5 cm x 1.7 cm with hemorrhagic component. Urgent evaluation by a Neuro-ophthalmologist revealed no clinical evidence of optic neuropathy. Blood work showed AM cortisol 2.3 mcg/dl (4.0-22.0 mcg/dl), TSH 0.5 mIU/L (0.4-0.5 mIU/L), FT4 0.6 ng/dl (0.8-1.8 ng/dl). Cabergoline 0.25 mg twice weekly was restarted to control the size of the tumor as well as hydrocortisone and levothyroxine for central adrenal insufficiency and hypothyroidism respectively. Four weeks later, she was 17 weeks pregnant. MRI showed a further increase in the size of the adenoma, now measuring 1.8 cm x 2.0 cm x 1.3 cm. The lesion now extended into the suprasellar cistern, affecting the optic chiasm. She underwent the transsphenoidal resection of the pituitary adenoma at 18 weeks of gestation due to the increase in size of the tumor. The final pathology was consistent with pituitary adenoma, lactotroph cell type, WHO grade 1. MRI obtained 3 months post-operation showed no residual T1 hyperintense tumor signal. There was a cyst-like expansion of the sella turcica with a decreased mass effect on the optic chiasm. She delivered her healthy baby at 40 weeks and 5 days via vaginal delivery. She received stress dose steroid during labor, then was discharged home with hydrocortisone 10 mg twice daily. She is doing well following the delivery and breastfeeding the baby. This case illustrates a rare case of pituitary apoplexy during pregnancy in a patient with prolactinoma. Pituitary apoplexy should be considered as a differential diagnosis when pregnant patients develop an acute, severe headache, especially those with an underlying pituitary adenoma. It is critical to assess and treat the hormonal deficiencies. For prolactinoma, pharmacological therapy can be initiated. Surgery is considered if the medical therapy fails. Presentation: 6/3/2024

Could low prolactin levels after radiotherapy predict the onset of hypopituitarism?

Both local and external cranial radiotherapy (RT) can induce neurotoxicity and vascular damage of the hypothalamic-pituitary area, which can promote neuroendocrine alterations. While anterior pituitary insufficiency after RT has been extensively characterized, data on the effect of RT on prolactin (PRL) secretion are limited and heterogeneous, with different patterns of PRL behavior described in the literature. A progressive decline in PRL levels, reflecting a time-dependent, slowly evolving radiation-induced damage to the pituitary lactotroph cells has been reported. To date, the association between hypopituitarism and hypoprolactinemia in patients undergoing RT has not yet been fully investigated. The few available data suggest that lower PRL levels can predict an extent damage of the pituitary tissue and a higher degree of hypothalamic dysfunction. However, most studies on the effect of RT on pituitary function do not properly assess PRL secretion, as PRL deficiency is usually detected as part of hypopituitarism and not systematically investigated as an isolated disorder, which may lead to an underestimation of hypoprolactinemia after RT. In addition, the often-inadequate follow-up over a long period of time may contribute to the non-recognition of PRL deficiency after RT. Considering that hypoprolactinemia is associated with various metabolic complications, there is a need to define appropriate diagnostic and management criteria. Therefore, hypoprolactinemia should enter in the clinical investigation of patients at risk for hypopituitarism, mainly in those patients who underwent RT.

Neuregulin 1 mitigated prolactin deficiency through enhancing TRPM8 signaling under the influence of melatonin in senescent pituitary lactotrophs

The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.

Neuropsychological complications of hypoprolactinemia.

Prolactin (PRL) is primarily produced by the pituitary lactotrophic cells and while initially named for its role in lactation, PRL has several other biological roles including immunomodulation, osmotic balance, angiogenesis, calcium metabolism, and appetite regulation. Most of the PRL-related literature has traditionally focused on hyperprolactinemia, whereas hypoprolactinemia has received little attention. There is evidence to suggest that PRL receptors are widely distributed within the central nervous system including the limbic system. Furthermore, PRL has been shown to play key role in the stress regulation pathway. Recent data also suggest that hypoprolactinemia may be associated with increased sexual dysfunction, anxiety, and depression. In this paper we discuss the current understanding regarding the neuropsychological impact of hypoprolactinemia and highlight the need for adequately defining hypoprolactinemia as an entity and consideration for future replacement therapies.

Serum Prolactin Levels and Mortality in Adults Without Prolactinoma: A Meta-Analysis.

Prolactin (PRL) is a highly versatile, multifunctional hormone synthesized and secreted by lactotroph cells of the anterior pituitary. Its metabolic role has been extensively studied even in normoprolactinemic populations. Recently, a wealth of observational data have outlined the potential prognostic value of PRL in various clinical settings. This systematic review aims to systematically evaluate and quantitatively synthesize the association between serum PRL levels and risk of mortality in adults without prolactinoma. A systematic literature search was conducted up to June 10, 2023, to identify studies reporting the association of serum PRL levels with clinical outcomes of adults without prolactinoma. A random-effects meta-analysis was conducted to quantify the adjusted hazard ratios [(a)HRs] for all-cause and cardiovascular death (CVD) during follow-up. Twenty-eight studies were deemed eligible reporting the outcomes of adults without prolactinoma, in whom serum PRL levels were measured for risk-stratification. Fourteen studies reported appropriate data for meta-analysis encompassing a total of 23 596 individuals. Each unit of PRL increase was independently associated with increased risk of all-cause (pooled aHR = 1.17 [1.08-1.27]; I2 = 48%) and CV mortality (pooled aHR = 1.54 [1.14-2.09]; I2 = 89%). Individuals belonging to the highest PRL category had significantly higher risk for all-cause (pooled aHR = 1.81 [1.43-2.30]; I2 = 65%) and CV (pooled aHR = 1.59 [1.04-2.42]; I2 = 82%) mortality compared to their lowest-PRL category counterparts. The association between PRL levels and in-hospital death did not reach statistical significance. PRL levels seem to be an independent predictor for mortality. Further validation is warranted before its role as a risk-stratification tool can be delineated in clinical practice.

Current Insights in Prolactin Signaling and Ovulatory Function.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

Effect of Hyperprolactinemia on Bone Metabolism: Focusing on Osteopenia/Osteoporosis.

Prolactin is a hormone secreted from lactotroph cells in the anterior pituitary gland to induce lactation after birth. Hyperprolactinemia unrelated to lactation is a common cause of amenorrhea in women of a childbearing age, and a consequent decrease in the gonadotropin-releasing hormone (GnRH) by a high prolactin level can result in decreased bone mineral density. Osteoporosis is a common skeletal disorder characterized by decreased bone mineral density (BMD) and quality, which results in decreased bone strength. In patients with hyperprolactinemia, changes in BMD can be induced indirectly by the inhibition of the GnRH-gonadal axis due to increased prolactin levels or by the direct action of prolactin on osteoblasts and, possibly, osteoclast cells. This review highlights the recent work on bone remodeling and discusses our knowledge of how prolactin modulates these interactions, with a brief literature review on the relationship between prolactin and bone metabolism and suggestions for new possibilities.

Hypoprolactinemia. Does it matter? Redefining the hypopituitarism and return from a mumpsimus : "Absence of proof is not the proof of absence".

Prolactin (PRL) is secreted by the lactotroph cells in the anterior pituitary gland which is under inhibitory control of dopamine. The mature human PRL has more than 300 physiological actions including lactation, reproduction, homeostasis, neuroprotection, behavior, water and electrolyte balance, immunoregulation and embryonic and fetal development. PRL is involved in the growth and development of mammary gland, preparation of the breast for lactation in the postpartum period, synthesis of milk, and maintenance of milk secretion. Abnormalities in the synthesis and secretion of PRL may result in hyperprolactinemia or hypoprolactinemia. Although hyperprolactinemia has been extensively investigated in the literature, because of the subtle or unclearly defined symptoms, hypoprolactinemia is a less-known and neglected disorder. Failure of lactation is a well-known clinical manifestation of hypoprolactinemia. Recent studies reveal that hypoprolactinemia may have some effects beyond lactation such as increased risk for metabolic abnormalities including insulin resistance, abnormal lipid profile, obesity and sexual dysfunction. Very low level of PRL is suggested to be avoided in patients receiving dopamin agonist treatment to prevent unwanted effects of hypoprolactinemia. Another important point is that hypoprolactinemia is not included in the classification of hypopituitarism. Anterior pituitary failure is traditionally classified as isolated, partial and complete (panhypopituitarism) hypopituitarism regardless of prolactin level. Therefore, there are two kinds of panhypopituitarism: panhypopituitarism with normal or high PRL level and panhypopituitarism with low PRL level. In this review, we present two personal cases, discuss the diagnosis of hypoprolactinemia, hypoprolactinemia associated clinical picture and suggest to redefine the classification of hypopituitarism.

FRI370 Hyperthyroidism And Acromegaly In A Patient With A Mature Plurihormonal PIT1 Lineage PitNET/Adenoma

Abstract Disclosure: D. Slack: None. A.C. Levine: None. Background: TSH- and GH-secreting pituitary neuroendocrine tumors (PitNETs) are both rare entities, with an incidence of 1 per million people and 1-4 per million people, respectively. Thyrotroph, somatotroph, and lactotroph cells have the same progenitor, regulated by the PIT1 transcription factor. Thus, it is not unusual for PIT1 positive tumors to exhibit immunhistochemical expression of TSH, GH, and prolactin. It is vanishingly rare, however, for these tumors to secrete multiple biologically active hormones with apparent clinical sequelae. We herein report on a case of a patient with a plurihormonal PIT1 lineage PitNET secreting prolactin with secondary amenorrhea, TSH causing central hyperthyroidism and GH resulting in acromegaly. Clinical Case: A 42-year-old woman with a 1-year history of amenorrhea presented with 3 months of progressive weight loss, fatigue, palpitations, and tremulousness. She was found to have central hyperthyroidism, with an elevated free T4 (>7.77 ng/dL, nl 0.82 – 1.77) and inappropriately normal TSH (3.25 uIU/mL, nl 0.45 – 4.5). Full endocrine workup confirmed central hyperthyroidism with elevated free T4 (5.02 ng/dL) and TSH (4.68 uIU/mL) and also demonstrated hyperprolactinemia (122 ng/mL, nl 4.8 – 23.3 ng/mL), elevated IGF-1 (795 ng/mL, nl 91 – 308 ng/mL), GH (19 ng/mL, nl 0 – 10) and free alpha subunit (28 ng/mL, nl <1.02). Over the ensuing 4 months, she noted enlargement of her lips, nose, feet, and hands. MRI demonstrated a pituitary macroadenoma measuring 2.2 cm x 2.7 cm x 2 cm with asymmetric extension into the left cavernous sinus and mild elevation of the adjacent optic chiasm. She underwent an uncomplicated transsphenoidal resection of the tumor with no residual tumor noted on post-op MRI. Discharge medications were hydrocortisone 10 mg AM and, 5 mg early afternoon and levothyroxine 50 mcg daily. One month postoperatively, labs were notable for a low TSH (0.16 mIU/L), normal free T4 (1.62 ng/dL), down-trending IGF-1 (339 ng/mL), and normal prolactin (15.1 ng/mL). Additionally, AM cortisol and ACTH levels remained normal after holding her morning dose of hydrocortisone. She reported resolution of all presenting symptoms of thyrotoxicosis as well as decreasing size of her hands, feet, and nose. Pathology revealed a mature plurihormonal PIT1-lineage PitNET, with immunoreactivity for PIT1, GH, TSH, and prolactin and MIB-1 index of 3%. Conclusion: This case demonstrates the potential for PitNETs to secrete multiple biologically active pituitary hormones, including prolactin, TSH and GH, highlighting the importance of maintaining an index of suspicion for pituitary causes in the evaluation of thyrotoxicosis and of considering the plurihormonal potential of PitNETs in patients presenting with multiple endocrinopathies. Presentation: Friday, June 16, 2023

FRI314 Prolactinoma And Macroprolactin; A Diagnostic Dilemma

Abstract Disclosure: A. Farooqi: None. S. Dewan: None. J. Jun: None. Prolactin is a 199 amino acid, 23 (Kilo Dalton) kDa protein secreted by pituitary lactotroph cells. The two other major forms of prolactin present in circulation are big prolactin, the dimeric 40-60 kDa prolactin and big-big prolactin or macroprolactin, 100-150 kDa complexes of 23 kDa prolactin and IgG autoantibodies. Hypothalamic dopamine is the primary regulator of prolactin secretion through its inhibitory effect. Prolactinoma accounts for ∼40% of pituitary tumors with clinical presentations of hypogonadotropic hypogonadism and tumor-related mass effects. A 77-year-old female with a past medical history of hypertension and hyperlipidemia was admitted after a mechanical fall. She underwent a computed tomography (CT) of the brain which incidentally showed a pituitary mass. Magnetic resonance imaging (MRI) of pituitary showed a homogenously enhanced 3.0 x 3.5 x 2.8 cm mass centered in the Sella turcica, invading the supra-seller cistern, left cavernous sinus, and orbital apex abutting the optic chiasm and optic tracts. The patient did not report headache, nausea, vomiting, visual changes, or abnormal milky nipple discharge. Physical examination was unremarkable without any neurologic deficit. Formal ophthalmology evaluation showed intact extra ocular movements, visual field-testing using octopus 24-2 and Humphrey test showed few missed points, though not suggestive of pituitary related loss. Serum prolactin was measured at 1432 ng/ml (reference range, 0-25). The presence of macroprolactin was considered due to the absence of clinical features of hyperprolactinemia. The monomeric prolactin was found to be 68.7% (<40%) at 867.5 ng/ml of the total prolactin at 1259.7 ng/ml with 31.3 % of other prolactin forms are present. Evaluation for other pituitary functions was unremarkable with thyroid stimulating hormone (TSH) of 0.72 uIU/ml (0.49-4.76l), morning serum cortisol of 52.9 ug/dl (6.7-22.4), and insulin like growth factor (IGF-1) 73 ng/ml (20-214). Cabergoline 0.5 mg twice weekly was prescribed. This case illustrates a menopausal state as a probable explanation for lack of clinical features of hyperprolactinemia with macro adenoma while macroprolactin should be considered. Presentation: Friday, June 16, 2023

FRI397 An Unusual Case Of Galactorrhea- Think About Breast Implants !

Abstract Disclosure: P. rimal: None. C. Musurakis: None. J.L. Gilden: None. Introduction: Elevation of prolactin (PRL) levels can occur due to physiologic or pathologic disorders of lactotroph cells. The most common causes for hypersecretion and resulting galactorrhea (GAL), a milky breast discharge, are pregnancy, breast feeding, hypothyroidism, chronic kidney disease, medications, chest wall trauma, or even stress. Although GAL is a rare complication after breast augmentation or reconstruction surgery, it can be bilateral, ipsilateral or contralateral, and is thought to be self-limiting. GAL can be cosmetically and psychologically distressing. The treatment depends on identifying the underlying cause, severity of symptoms, and can be medical, surgical, and might even necessitate breast implant removal. Clinical case: A 34-year-old Latina female G3P2 AB1 with prediabetes (BMI=22), history of gestational diabetes, and migraine headaches, was referred to the endocrine clinic for elevated PRL levels and 2 years of persistent GAL. Although originally regular, she had 3 months of menometrorrhagia following a COVID booster. She denied recent pregnancy, breast-feeding, breast masses, hirsutism, symptoms of thyroid disorders, chest wall trauma, infection, or symptoms of pituitary dysfunction. She was not taking medications associated with PRL elevation. Upon further evaluation, she reported frequently massaging the bilateral cosmetic breast implants to avoid formation of scar tissue. Lab evaluation showed initial PRL elevation of 35.8 ng/mL (nl=2.8-29.2); with normal LH=10.9 mIU/mL(nl 1.9-12.5) and FSH =4.9 mIU/mL(nl 2.5-10.2); estradiol=200.89 pg/mL(19.5-144.2); progesterone <0.5 ng/mL(nl <0.8);urine pregnancy test negative, HCG normal <2.6 mIU/mL (nl 2.6-4.2) ; ACTH=14 pg/mL (nl 0-47); AM cortisol=13.33 mcg/dL; salivary cortisol=<0.03 and 0.05 mcg/dL(nl 0.004-0.56); free testosterone=3.2 pg/mL(nl 0.1-6.4); SHBG =83.55 nmol/L(nl 17.69-138.26) total testosterone slightly elevated 50 ng/dL (nl 2-45); DHEAS=215 mcg/dL(nl 35-430); normal thyroid tests [(TSH 1.06 uIU/mL(0.550-4.780 ), free T4=1.05 ng/dL(0.76-1.46) Thyroid peroxidase antibody 28 U/mL(0-60)], Pelvic Ultrasound-benign right ovarian cyst and left ovary with subcm. follicles. Normal MRI of pituitary. Mammogram-dense breasts with bilateral implants. A Repeat PRL was 20.4 ng/mL with monomeric PRL normal at 8.6 (3.2-25.2 ng/mL), and later 13.70 ng/mL after stopping massaging of the breasts. The etiology of GAL was attributed to the breast implants with massaging, after excluding all other potential causes. Conclusion: Although other etiologies for galactorrhea should be considered, breast implants with manipulation must always be thought of as a possibility. This case highlights the importance of taking a thorough and complete medical history when evaluating all patients with galactorrhea. Presentation: Friday, June 16, 2023

THU553 Anti-tumor Effect Of Rosiglitazone Via Upregulating 15-PDGH In Prolactin Secreting Adenoma

Abstract Disclosure: C. Kang: None. J. Oh: None. E. Wang: None. S. Lee: None. J. Nam: None. J. Hong: None. E. Lee: None. C. Ku: None. Background: Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPAR γ) ligand, are used to treat type II diabetes. Over the last few years, PPAR γ has received much attention for its ability to exert variable tumors. Objective: The aim of this study is to investigate the anti-tumor effect of rosiglitazone on prolactin secreting pituitary adenomas and its mechanism. Materials & Methods: Lactotroph cell line (GH4, MMQ) were treated with Phosphate-buffered saline (PBS) or rosiglitazone. In vitro analysis such as qPCR, immunoblot, prolactin (PRL) ELISA, Cell proliferation assay, and Fluorescence-activating cell sorting (FACS) analysis were performed to examine the effect of rosiglitazone on Lactotroph cell lines. Result: To investigate the direct effect of rosiglitazone on PRL secretion of the pituitary adenomas, GH4 and MMQ cells were treated with rosiglitazone 1, 5, 10, 50 μM for 72 hr. Both PRL mRNA and secretion levels were significantly decreased by rosiglitazone in a dose-dependent manner. In previous studies, 15-PDGH has been implicated as a tumor suppressor gene with the property that inhibits the tumor growth. Interestingly, 5 μM rosiglitazone upregulated the mRNA and protein levels of 15-PDGH in both GH4 (4.73-fold) and MMQ (4.04-fold) cells. Next, we investigated whether rosiglitazone had any effects on the proliferation of prolactinoma cells. Proliferation of the GH4 and MMQ cells were significantly decreased by rosiglitazone in a dose-dependent manner after treatment. Rosiglitazone potently induced cell cycle arrest in sub-G1inGH4 and MMQ cells. Furthermore, rosiglitazone treatment significantly increased both early (2.31-fold) and late apoptosis (1.9-fold) of GH4 and MMQ cells. Conclusion: These results collectively position 15-PDGH as a potential new therapeutic target for prolactinomas and implicate rosiglitazone as a possible alternative pharmacological approach for prolactinomas. Presentation: Thursday, June 15, 2023

The Role of Aromatase Inhibitors in Male Prolactinoma

dopamine agonists are the recommended treatment for male prolactinomas, but some patients may develop dopamine-agonist-resistant hyperprolactinemia, leading to persistent hypogonadism that requires treatment with testosterone. However, testosterone replacement therapy may be associated with a decrease in the efficacy of dopamine agonists due to the aromatization of testosterone to estradiol, which can stimulate the proliferation and hyperplasia of lactotroph cells in the pituitary, inducing resistance to dopamine agonists. this paper systematically reviewed the role of aromatase inhibitors for men with prolactinoma and dopamine-agonist-resistant or persistent hypogonadism following treatment. we performed a systematic review of all studies (according to PRISMA guidelines), assessing the role of aromatase inhibitors, including anastrozole and letrozole, for male prolactinoma. An English-language search for relevant studies was conducted on PubMed from its inception to 1 December 2022. The reference lists of the relevant studies were also reviewed. our systematic review identified six articles (nine patients), including five case reports and a single case series, on the use of aromatase inhibitors for male prolactinomas. Reducing estrogen levels with an aromatase inhibitor improved sensitivity to dopamine agonists, as the addition of anastrozole or letrozole improves the control of prolactin levels and may lead to the shrinkage of tumors. aromatase inhibitors are of potential value to patients with dopamine-agonist-resistant prolactinoma, or when hypogonadism persists while using high-dose dopamine agonists.

Pregnancy-induced pituitary apoplexy: Two lives at stake

Pituitary apoplexy in a pregnant woman is a devastating condition that develops secondary to a massive increase in the size of the pituitary gland and hyperplasia of lactotroph cells caused by high estrogen levels of pregnancy. The resultant sudden hemorrhage or infarction into the pituitary gland or a tumor leads to gland destruction with serious consequences like acute adrenal insufficiency, circulatory shock, neurological deterioration, and visual loss. Prompt handling of complications is necessary to prevent maternal and fetal mortality. Resuscitation is aimed at the early correction of hemodynamic instability, fluid-electrolyte abnormalities, hormone deficiencies, and intracranial hypertension. Urgent decompressive pituitary surgery may be required if the patient has rapidly declining vision and neurological status. Management of such patients is challenging and requires multi-disciplinary collaboration. We describe here the emergency handling of pituitary apoplexy in a pregnant woman.

PSAT253 Differentiation of Pituitary Hyperplasia From Adenoma in the Setting of Severe Hypothyroidism

Abstract Introduction Pituitary hyperplasia due to long-standing or profound primary hypothyroidism is a rare finding in children. It occurs because of constant stimulation of thyrotrope cells by a thyrotropin-releasing hormone secreted from the hypothalamus due to a lack of negative feedback from thyroid hormones. The clinical presentation and imaging can mimic a pituitary mass. Patients can present with features of hypothyroidism, hyperprolactinemia, and even visual field defects if the hyperplastic pituitary gland compresses the optic chiasm. This case highlights this uncommon finding and discusses subtle clinical signs of hypothyroidism in children. Case Presentation A 10-year-old boy was incidentally found to have a pituitary lesion (15 mm×14 mm) when an MRI of the brain was performed as a healthy volunteer screening procedure. History and physical exam revealed cold intolerance, lack of height growth for 2 years (crossing down from 75th to 25th percentile), and dry skin with the barely palpable thyroid gland. There was no family history of thyroid or auto-immune disease. Evaluation of pituitary hormones showed remarkably high thyroid-stimulating hormone (>500 mcIU/ml) in the setting of undetectable free thyroxine, positive thyroid peroxidase antibody, low insulin-like growth factor-1, mildly elevated prolactin (67.4 mcg/L), and mild macrocytic anemia. Conclusions Differentiation of pituitary hyperplasia from pituitary hormone-secreting or non-secreting adenomas is crucial, as the primary modality of treatment of pituitary hyperplasia secondary to primary hypothyroidism is thyroid hormone replacement and not surgery unless the patient has visual field defects necessitating of decompression of the optic chasm to avoid permanent vision loss. In general, pituitary hyperplasia is described as homogeneously enhancing with the "nipple sign," which is when the pituitary gland has smooth contours, but a central protrusion of a pituitary mass is present. Elevated TRH can also lead to lactotroph hyperplasia, causing increased prolactin. Growth hormone secretion may be reduced by hypothyroidism and/or by damaged somatotroph cells due to space-occupying pituitary hyperplasia. Macrocytic anemia has been reported in patients with hypothyroidism and is thought to be an adaptation to a decreased basal metabolism. Early recognition and treatment of hypothyroidism during childhood is essential for normal growth and development. In children with the prolonged disease, final height may be compromised, and academic performance and psychosocial well-being may decline. Gradual replacement of thyroid hormone to therapeutic doses by slowly escalating doses of levothyroxine may be beneficial to prevent complications of therapy such as pseudotumor cerebri or empty sella due to rapid shrinkage of lactotroph and thyrotrope cells. Previous studies have shown approximately 85% of those with pituitary hyperplasia due to primary hypothyroidism demonstrate decreased pituitary gland size after starting thyroxine replacement and recommend repeating pituitary MRI after 2-4 months. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON170 Treating human primary non-functioning pituitary adenoma cells with cabergoline

Abstract Clinically non-functioning pituitary adenomas (NFPAs) represent the second most common subtype of pituitary tumours, representing 15-43% of all pituitary adenomas. NFPAs are usually benign tumours with no clinical evidence of hormonal hypersecretion. In most of the cases the tumours are arising from the gonadotroph linage, but silent corticotroph, somatotroph, thyrotroph and rarely lactotroph cell characteristics can be discovered with immunostaining. As a result of lack of hormonal hyper-secretion, the diagnosis of NFPAs is made most often when the patient presents with mass effects due to a macroadenoma. NFPAs are most common tumour types in surgical series, and their primary treatment is indeed surgery. However, complete resection is achieved only in about 66% of the cases, and 20% of gross total resected tumours recur after 10 years. Over the past few decades, remarkable progress has been achieved regarding medical treatment options for pituitary tumours. However, NFPAs remain the only subtype with no widely accepted pharmacological treatment. Dopamine receptor type 2 (DRD2) and somatostatin receptor (SST) expression have been demonstrated in NFPAs, prompting the investigation of dopamine agonists and somatostatin analogues as potential treatment strategies. The DRD2 agonist cabergoline is already used as first-line treatment of prolactinomas to induce tumour shrinkage and reduce prolactin secretion. Here we aim to investigate the efficacy of cabergoline on human NFPA tissue. We assessed DRD2 expression levels via immunohistochemistry and qPCR in a large cohort of NFPAs (n=40) and in few prolactinomas (n=10). D2DR has two different isoforms, long (D2RL) and short (D2RS), which are differently expressed and can induce different effects on cell viability. In cabergoline-sensitive prolactinomas D2RS is the predominant isoform. NFPAs shown 10-fold and 5-fold decrease expression of D2RS and D2RL compared to prolactinomas, respectively. Additionally, in NFPAs we observed a significant decrease of cAMP production after cabergoline treatment (45% ±7; p<0.0001); however, viability after one-week cabergoline treatment showed only 4% (±0.7; p<0.0002) reduction, compared to a 10% decrease in prolactinomas (p<0.05). We also observed no difference in secretion of chromogranin A release in NFPAs upon treatment with cabergoline. We have also seen in NFPAs downregulation of Ga i2 protein expression levels, highlighting the general decrease of expression levels in the dopamine pathway (50% less, p<0.004). Our data suggest that the difference in cabergoline responses between NFPAs and prolactinomas may be due to their distinct expression of D2DR isoforms, which differ by 29 amino acids in the third cytoplasmic loop, essential for G-protein binding. It has been shown that D2RL, but not D2RS, requires Gai2. The difference in D2R isoform expression could translate to distinct G-protein activation, ultimately leading to the contrasting viability results after cabergoline treatment. Taken together, these data will help inform future treatment strategies for patients with NFPAs. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON169 D2R Expression in Dopamine-Agonist Resistant Prolactinomas

Abstract Introduction Dopamine-agonist (DA) resistant prolactinomas are characterized by failure to achieve normal prolactin levels or reduce tumor size by at least 50% on maximal conventional DA dosages. This occurs in about 10% of patients on cabergoline and is more common in larger macroadenomas, and in men compared with women. The underlying cause of resistance may be a lack of D2 receptor (D2R) tumor expression. As high dose DA therapy may have serious cardiac side effects, it is important to determine the D2R expression. Further, the sexual dimorphism observed in resistant prolactinomas may be due to estrogen receptor alpha (ERα) expression in female tumors, as ERα signaling has been shown to enhance sensitivity to DAs. We investigated the possibility that androgen receptor (AR) signaling in males promotes resistance via induction of transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease, a known promoter of tumor progression in prostate and lung cancer. Methods This is a retrospective, single-center study conducted at an academic quaternary-care center. Immunohistochemical (IHC) analysis was performed on 16 specimens from surgically removed lactotroph cell type tumors, including D2R, growth hormone (GH), prolactin (PRL), TMPRSS2, ERα, AR, and the stem cell marker, CD133. We simultaneously conducted a chart review of the Electronic Medical Record to determine age at diagnosis, tumor size, initial PRL level, medical treatment, and reason for surgical resection. Results A total of 14 patients were included in our study. Two patients had multiple surgeries for resistant prolactinomas such that the sample size included 16 specimens- 7 resistant prolactinomas and 9 controls (resected for another reason other than treatment resistance). There were 2 men and 3 women in the resistant group, and 5 women and 4 men in the control group. Baseline prolactin level was higher in the resistant group (2413ng/mL) than the control group (676.4ng/mL) and tumor size was larger—2.05cm vs. 1.57cm in the largest diameter in the resistant vs. control groups, respectively. D2R expression was positive in 8 out of 9 controls vs. 1 out of 7 in resistant tumors. ERα positivity did not correlate with DA resistance. AR expression was negative in all specimens although the majority of tumors in both groups did express TMPRSS2. CD133 was negative in all but one of the resistant tumors. Conclusion We found that 80% of specimens from patients with DA-resistant prolactinomas had negative D2R expression. The one resistant tumor that had positive D2R and negative TMPRSS2 expression was from an 11 year old girl who also had negative ERα expression that may explain the lack of response to dopamine agonist therapy. D2R IHC can identify lack of D2R expression in DA-resistant tumors and provide a rationale for discontinuation of high dose DA therapy to avoid toxicity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Management of a prolactinoma patient with manifestations of amenorrhea and infertility

Prolactinoma is an adenoma arising from the lactotroph cells of the pituitary gland that secrete prolactin. It is considered the most commonly diagnosed pituitary tumor and accounts for about 40% of all pituitary tumors. This study discusses a female patient suffering from prolactinoma with manifestations of amenorrhea and infertility. According to an MRI examination, the patient had a tumor with signs of apoplexy measuring ± 2.7 x 1.5 x 1.9 cm in the intrasellar, extending to the suprasellar. On the other hand, an examination indicated that the prolactin serum level of the patient was > 200 ng/ml (increased). The patient had consulted a neurosurgeon for consideration of surgery due to the large size of the prolactinoma, but the patient temporarily refused surgery.