Extrapituitary Origin Research Articles

Ectopic ACTH Syndrome: Possibilities of Modern Diagnostics

The ectopic ACTH syndrome (EAS) is a constellation of clinical signs and symptoms caused by chronic excess production of cortisol by the adrenal glands due to stimulation by adrenocorticotropic hormone (ACTH) of extrapituitary origin. EAS is a rare pathology, it accounts for approximately 20% of all cases of ACTH-dependent hypercortisolism and up to 10% of all causes of endogenous autonomic cortisol production, however, it is often associated with severe hypercortisolism and is a life-threatening condition. The sources of ectopic secretion of ACTH are neuroendocrine tumors (NET), which differ in histological type, malignant potential, clinical course, and also have different, often difficult to detect localization. Early identification of ACTH -producing NET reduces the risk of death of the patient both from severe hypercortisolism and the tumor itself. The paper describes the features of the course of EAS, the possibilities of its diagnosis, and presents an algorithm for EAS diagnosis, created on the basis of the latest achievements of Russian and world medicine.

SAT612 Granulomatous Mastitis: An Unusual Presentation Of Prolactinoma

Abstract Disclosure: H.R. Alkaissi: None. E. Kim: None. S. McFarlane: None. Background: Granulomatous mastitis (GM) is a rare, benign inflammatory breast disease of unclear etiology with clinical presentation that is similar to inflammatory breast cancer and periductal lobular mastitis. It occurs mainly in younger females and during the postpartum period. Prolactin (PRL) is an essential hormone of pituitary and extrapituitary origin that promotes lactation and the development of mammary glands within breast tissues. In addition to its lactogenic effect, it has over 300 other effects, several of which are immunomodulatory, including the expression and secretion of proinflammatory cytokines from macrophages. Clinical Case: A 37-year-old African American woman presented with right breast pain and swelling for a few weeks. Her medical history includes amenorrhea for five years. She is gravida 1, para 1 with normal spontaneous vaginal delivery at the age of 20. Physical exam showed non-bloody, non-purulent nipple discharge bilaterally, otherwise unremarkable. A breast ultrasound showed a 1 cm complex cystic mass. Biopsy showed benign breast tissue, with noncaseating granulomas formed by macrophages (CD68 positive on immunohistochemistry). Ziehl-Neelsen staining for acid-fast bacilli was negative. Staining for fungi was also negative. Prolactin level was 237 ng/mL. TSH, IGF-1, and ACTH were within normal. Pituitary MRI showed a focus of abnormal signal and diminished enhancement measuring 2.8x3.2x4.2 mm within the left side of the pituitary gland is compatible with a microadenoma. The patient was started on bromocriptine 2.5mg daily. Discussion: Our patient represents a rare case of granulomatous mastitis in the setting of microprolactinoma, likely long-standing, given the five years history of amenorrhea. The immunomodulatory effect of PRL on several immune system cells, including B-cells, T-cells, and macrophages, might be an underlying mechanism. In a recent study of 25 samples of GM, metagenomics studies identified unusual organisms in 68% of the samples. Of these, Corynebacterium kroppenstedtii was the most common (60%), followed by Pseudomonas oleovorans (16%), Epstein-Barr virus (4%), Acinetobacter baumannii (4%), and Tepidiphilus thermophilus (4%). In addition, 50% of the patients had elevated PRL, and elevated immunological markers, such as C3 and IgA [1]. This suggests that GM results from an interaction between the presence of certain pathogens in a host with elevated PRL that mediates proinflammatory response.

PROLACTIN AND HYPERPROLACTINAEMIA IN FEMALE REPRODUCTIVE ENDOCRINOLOGY – AN UPDATE

Hyperprolactinaemia is one of the most frequent causes of anovulation, resulting in infertility and hypoestrogenic state with consequences on overall women’s health. Recent investigations on biological actions of prolactin, especially prolactin of extrapituitary origin, expand our knowledge on prolactin role in the human organism and open new questions connected with female reproductive function and treatment of female infertility. This article represents the review of current knowledge on prolactin physiology, etiopathogenesis, clinical features, assessment , differential diagnosis ,and teatment of hyperprolactinaemia in the female patient.

Prevalence and reproductive manifestations of macroprolactinemia.

Macroprolactinemia is characterized by predominance of macroprolactin molecules in circulation and generally has extra-pituitary origin. Macroprolactin is viewed as biologically inactive, therefore asymptomatic, and thus may not require any treatment or prolonged follow-up. In addition, data on prevalence of macroprolactinemia and its clinical manifestation are also rare. Therefore, the present study was aimed to find out prevalence of macroprolactinemia and its association, if any, with reproductive manifestations. Macroprolactin was measured in 102 hyperprolactinemia cases (>100 ng/ml prolactin level), 135 physiological hyperprolactinemia cases (50 pregnant and 85 lactating females; >100 ng/ml prolactin level) and 24 controls. Poly ethylene glycol (PEG) precipitation method was carried out to screen macroprolactin. Prolactin recovery of <25% was considered overt macroprolactinemia. Detailed clinical data was recorded which included complete medical history, physical examination and hormone measurements besides CT/MRI for pituitary abnormalities. Prevalence of macroprolactinemia was 21.57% (22/102) in hyperprolactinemia (prolactin >100 ng/ml). There was no case of macroprolactinemia in physiological hyperprolactinemia, or healthy control females. Reproductive manifestations were present in 72.73% (16/22) macroprolactinemia cases, out of which macroprolactinemia was the sole cause of associated reproductive manifestations in 68.7% (11/16) cases. Reversal of reproductive dysfunction/s was observed in five cases with appropriate treatment for high macroprolactin. Macroprolactinemia prevalence was found to be 21.5%, out of which 72.73% cases had associated reproductive dysfunctions.

Assessment of macroprolactinemia inpatients with prolactinoma

Abstract Purpose Macroprolactin, the high-molecular mass prolactin isoform, is considered to be an inactive product with extrapituitary origin. Although macroprolactinemia is considered a benign condition, there is evidence of overlapping clinical features among patients with hyperprolactinemia. Data on the prevalence of macroprolactinemia in prolactinomas is also quite limited. The aim of this study was to assess the prevalence of macroprolactinemia in our patients with prolactinoma. Methods The study included patients with macroprolactinoma (n=50) and microprolactinoma (n=16). Prolactin level was measured with an electrochemiluminescent immunoassay, and macroprolactinemia was defined as the percentage of prolactin recovery &lt;40% after the polyethylene glycol precipitation. Results Macroprolactinemia was not detected in our patients with prolactinoma (the percentage of PRL recovery range; 55%–96%). The mean percentage of prolactin recovery was similar in patients with macroprolactinoma and microprolactinoma (67.7%±8.0% and 70%±9.4%, respectively, p=0.96). Conclusion Macroprolactinemia is generally associated with negative findings on pituitary imaging. Although the monomeric prolactin is dominant, rarely macroprolactin may also be present in prolactinomas. We did not detect presence of macroprolactin in any of the patients and there was no statistically significant difference between micro- and macroprolactinomas in terms of prolactin recovery.

S100β-Positive Cells of Mesenchymal Origin Reside in the Anterior Lobe of the Embryonic Pituitary Gland.

The anterior and intermediate lobes of the pituitary gland develop through invagination of the oral ectoderm and as they are endocrine tissues, they participate in the maintenance of vital functions via the synthesis and secretion of numerous hormones. We recently observed that several extrapituitary cells invade the anterior lobe of the developing pituitary gland. This raised the question of the origin(s) of these S100β-positive cells, which are not classic endocrine cells but instead comprise a heterogeneous cell population with plural roles, especially as stem/progenitor cells. To better understand the roles of these S100β-positive cells, we performed immunohistochemical analysis using several markers in S100β/GFP-TG rats, which express GFP in S100β-expressing cells under control of the S100β promoter. GFP-positive cells were present as mesenchymal cells surrounding the developing pituitary gland and at Atwell's recess but were not present in the anterior lobe on embryonic day 15.5. These cells were negative for SOX2, a pituitary stem/progenitor marker, and PRRX1, a mesenchyme and pituitary stem/progenitor marker. However, three days later, GFP-positive and PRRX1-positive (but SOX2-negative) cells were observed in the parenchyma of the anterior lobe. Furthermore, some GFP-positive cells were positive for vimentin, p75, isolectin B4, DESMIN, and Ki67. These data suggest that S100β-positive cells of extrapituitary origin invade the anterior lobe, undergoing proliferation and diverse transformation during pituitary organogenesis.

Macroprolactinemia in a Patient with Invasive Macroprolactinoma: A Case Report and Minireview

Background. Macroprolactin, the high-molecular prolactin isoform, is considered to be an inactive in vivo product with extrapituitary origin. Patients with macroprolactinemia are usually asymptomatic, with negative pituitary imaging. Based on these data, most authors do not recommend treatment and long-term followup in subjects with macroprolactinemia. However, there is evidence for overlapping clinical features among subjects with hyperprolactinemia due to monomeric or “big big” PRL isoform. Case Presentation. We present a 35-year-old female patient with secondary amenorrhea, mild obesity, hirsutism, headache and blurred vision. Hormonal evaluation revealed an extreme hyperprolactinemia (PRL = 10 610 mIU/L) almost exclusively due to macroprolactin isoform (MPRL = 10 107 mIU/L; recovery after PEG precipitation 4.7%) and hypogonadotropic hypogonadism. An invasive pituitary macroadenoma was visualized on MRI, and cabergoline therapy was initiated. Disappearance of clinical signs and symptoms, normalization of gonadotropin levels, and restoration of regular ovulatory menstrual cycles after 1 year of treatment are arguments in favor of preserved-macroprolactin bioactivity in this case. The significant decrease in MPRL levels and tumor volume in response to dopamine agonist therapy is suggestive for the tumoral origin of this isoform. Conclusions. Although macroprolactinemia is considered to be a benign condition, pituitary imaging, dopamine agonist treatment, and prolonged followup should be recommended in some particular cases.

Acromegaly: role of surgery in the therapeutic armamentarium.

Acromegaly is a complex disease that requires the intervention of a multidisciplinary team. The most frequent clinical manifestations are growing of distal parts of the body and some areas of the face. Patients may also present arterial hypertension, diabetes mellitus, colonic polyps, cardiomegaly, neurological and endocrine changes secondary to the presence of a GH-secreting tumor in pituitary or extrapituitary origin, or eutopic hypothalamic GHRH hypersecretion and peripheral GHRH hypersecretion. Surgery is the first treatment used for most patients, regardless of the cause. In the great majority of cases, pituitary tumor can be removed through a transsphenoidal approach. Craniotomy is reserved for those cases with giant tumors, particularly when they grow toward the middle or posterior cranial fossa. Best surgical results are obtained when the tumor is confined into the sella turcica or if it has a regular suprasellar extension. When the disease cannot be controlled with surgery, medical treatment is indicated. Somatostatin analogues are included as the first line of medication, followed by dopamine agonist and growth hormone receptors antagonists. Radiation therapy can be also indicated in two main forms for residual tumor with medically refractory patients: radiosurgery for small tumors or fractionated stereotactic radiotherapy for larger ones.

Solitary plasmacytoma of the sphenoid sinus involving the pituitary fossa: A case report and review of the literature

A rare case of solitary plasmacytoma of the sphenoid sinus involving the pituitary fossa is reported. A 50-year-old woman with a history of diplopia and a mass in the sphenoid sinus and the sellar region, documented by computed tomography, was referred to our department with a presumed diagnosis of nonfunctioning pituitary adenoma. The clinical and biochemical characteristics were unrevealing, but magnetic resonance imaging examination demonstrated the extrapituitary origin of the lesion. The patient was operated on by the transsphenoidal approach, and the lesion was histologically diagnosed as a plasmacytoma. Review of the literature disclosed II previously described cases of myelomatous disease presenting clinically as a pituitary adenoma. Our case demonstrates that magnetic resonance imaging investigation may help in distinguishing the extrapituitary origin of a mass involving the pituitary fossa.

Biochemical modifications involved in the maturation of the ovine fetal adrenal gland in late gestation: their modalities and regulation.

During the last month of intra-uterine life, the steroidogenic response of the ovine fetal adrenal glands to ACTH increases and becomes maximal at the time of birth. This development involves modifications at different steps of the adrenocorticotropic hormone (ACTH) action mechanism. It has been shown that the enhanced capacity of the cells to produce cAMP is related to at least three factors: an increased number of ACTH receptors, increased activity of the Ns subunit of adenylate cyclase, and enhancement of guanosine 5'-triphosphate (GTP) availability. The ability to produce pregnenolone and the activity of both 3 beta-hydroxy steroid dehydrogenase/isomerase and 17 alpha-hydroxylase are mainly enhanced in the steroidogenic pathway. The infusion of ACTH for 5 days into 115 to 120-day old fetuses results in the development of most of these biochemical process. Similarly, ACTH can induce maturation of cultured fetal adrenal cells and some other proopiomelamocortin (POMC)-derived peptides can potentiate its acute steroidogenic activity in vitro. However, even in the absence of ACTH, the adenylate cyclase system and the steroidogenic potency of cultured cells increase but to a lesser extent than when ACTH is present in the culture medium. It is suggested that ACTH is the main trophic hormone of the ovine fetal adrenal during the last month of gestation, even if other stimulatory factors may also be important. The in vivo maturation of ovine fetal adrenal is blocked by the presence of some unknown inhibitory factors in the fetal circulation which are of likely extrapituitary origin.

Alpha 2u-Globulin is present in the rat anterior pituitary.

The possibility that the pituitary gland may contain as yet undiscovered regulatory factors is intriguing. Recent reports have suggested the presence, in the anterior pituitary, or a number of proteins of extrapituitary origin. alpha 2u-Globulin, a rat serum and urinary protein, previously shown to be synthesized in the submaxillary gland and in the liver under anterior pituitary control, has now been localized by immunocytochemistry in the cytoplasm of some cells of the anterior pituitary. No alpha 2u-globulin could be detected in either the intermediate or posterior pituitary. The presence of alpha 2u-globulin was confirmed and quantitated by radioimmunoassay. Using RNA blot analysis and cloned alpha 2u-globulin cDNA probes, we could not detect alpha 2u-globulin mRNA sequences in pituitary RNA, indicating that alpha 2u-globulin is not synthesized therein. The presence of alpha 2u-globulin, presumably of circulatory origin, in certain anterior pituitary cells suggests that it may play a role in anterior pituitary function.

The Human Chorionic Gonadotropin-Like Substance in the Plasma of Normal Nonpregnant Subjects Is Not Modulated by the Gonadotropin-Releasing Hormone*

To determine whether the hCG-like substance found in the plasma of normal nonpregnant subjects is secreted and regulated like a pituitary gonadotropic hormone or prohormone, we measured its concentration before and 60 min after the acute iv injection of 500 microgram Gonadotropin-releasing hormone (GnRH). The study was performed in 12 normal young men. The hCG-like substance was purified from the other plasma proteins by 2 successive diethylaminoethyl-Sephadex A-50 chromatographies and by gel filtration on Sephadex G-100. Its concentration was measured by a specific RIA, corrected for losses and for possible contamination with human LH (hLH). The median basal concentration in plasma was 19 pg/ml (mean, 41; range less than 5 to 169), and there was no correlation with corresponding hLH concentrations. After the injection of GnRH, the median, mean, and range of concentrations remained constant, whereas the mean hLH concentration increased over 8-fold. This indicates that no significant amounts of the hCG-like substance are acutely releasable from the pituitary gland and that its plasma concentrations are not modulated by GnRH in a fashion similar to hLH. It also constitutes an argument for an extrapituitary origin of the plasma hCG-like substances in normal men.

ACTH-Like Peptides, Pituitary-Adrenocortical Function and Avoidance Behavior

Publisher Summary ACTH and its analogues have appreciable affinity for stereo-specific opiate receptors in synaptosomal membranes of brain tissue. Interestingly, α-melanocyte stimulating hormone, vasopressin, substance P and thyroid releasing hormone proved to be inactive. These observations supported the view that ACTH-like peptides (ALP) interfere with morphine in the central nervous system. In addition to this, the findings are in accordance with observations that ALP can antagonize the analgesic effects of opiates. The discovery of behavioral effects of ALP had a profound influence upon the study of endocrine control over adaptive behavior, and greatly contributed to the development of research into neuropeptides and peptidergic transmission in the brain. Considerable evidence suggests that ALP may act upon brain protein synthesis and catecholamine turnover, and that they bind to opiate receptors. The experimental observations that ALP of extra-pituitary origin are present in the brain led to the assumption that such neuropeptides are involved in neural transmission. The biologically active and immunoreactive ACTH content of the brain remained unchanged after either hypophysectomy or dexamethasone administration. These last observations indicate that other factors are involved in regulation of pituitary ACTH synthesis than that of the brain ALP. Whether the neuropeptides are directly involved in neural transmission or rather are playing a modulatory role, is still the subject of investigations.

Immunoreactive beta-melanocyte-stimulating hormone in cerebrospinal fluid and plasma in hypopituitarism: evidence for an extrapituitary origin.

Immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) was measured in the plasma of 19 patients with hypopituitarism and in the cerebrospinal fluid (CSF) of five of these patients. In neither plasma nor CSF were the beta-MSH concentrations significantly different from those in normal controls. These observations raise the possibility that beta-MSH may be produced by and secreted from neural tissue; this is supported by the findings of beta-MSH in high concentrations in many parts of the brain.

Gonadotrophic Potency of Avian Blood Serum

MANY reports have been published concerning the gonad stimulating hormones of the pituitary gland. Considerable attention has been given, also, to the gonadotrophic hormones of extrapituitary origin. Fluhman (1932) reported that an increase in ovarian weight resulted when immature rats were injected with an extract prepared from the blood of pregnant women. Pencharz, Cole and Goss (1940) observed similar results when using an extract of serum obtained from pregnant mares. Leathern and Morrell (1938, 1939) induced estrus in the dog by treating them with extracts obtained from menopausal urine, pregnancy urine, and the urine of normal men. The blood of normal humans contains gonad stimulating substances according to the report of Freed (1935).This study was undertaken to determine the gonadotrophic potency of blood serum obtained from chickens at different ages. Since gonad stimulating substances of extra-pituitary origin have been obtained from other animals it was thought that chicken blood .