Pituitary Secretion Research Articles

The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway. Therefore, the interactions of estrogens with GH actions in liver are biologically and clinically relevant because disruption of GH signaling may cause alterations of its endocrine, metabolic, and gender differentiated functions and it could be linked to dramatic impact in liver physiology during development as well as in adulthood. Finally, the interplay of estrogens with GH is relevant because physiological roles these hormones have in human, and the widespread exposition of estrogen or estrogen-related compounds in human. This review highlights the importance of these hormones in liver physiology as well as how estrogens modulate GH actions in liver which will help to improve the clinical use of these hormones.

Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms

Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

Management of hyperprolactinemic infertility

Abstract Pathological hyperprolactinemia may cause defective ovulation and reduced fecundability. Abnormal prolactin (PRL) secretion is usually related to an idiopathic hypothalamic dysfunction or to the presence of a pituitary adenoma. The use of medication is the most common cause of functional hyperprolactinemia. Pituitary prolactin secreting adenoma is classified according to size: micro (the vast majority) being smaller than 10 mm in diameter or macroprolactinoma (very few) of larger size. An excessive PRL secretion decreases the pulsatile release of GnRH impairing the pituitary production of FSH and LH. Furthermore it may directly impair the endocrine activity of ovarian follicles. As a consequence: defective luteal phase, inconstant ovulation and chronic anovulation are conditions frequently observed in young hyperprolactinemic patients. In addition 5% of unselected, asymptomatic infertile women show hyperprolactinemia. In such patients fertility may be promoted with long-term use of dopaminergic drugs. The normalized PRL level induced by the treatment allows the occurrence of spontaneous ovulatory cycles or the normalization of the defective luteal phase. Treatment should be continued for at least one year since half of the pregnancies occurring during dopaminergic therapy start after the first 6 months of drug assumption. An ovarian stimulation with gonadotropin and the pulsatile administration of GnRH may also induce ovulatory cycles and fertility in the infertile hyperprolactinemic patients. Hyperprolactinemia either, due to hypothalamic dysfunction, as well as the presence of PRL secreting adenoma usually improves after delivery.

First ladies in laying the foundation of neuroendocrinology

Although women were welcomed into medical practice in increasing numbers by the close of the nineteenth century, it was not until the second quarter of the twentieth century that they were recognised as valuable collaborators and contributors in the nascent field of neuroendocrinology, wherein they soon made advances that have stood the test of time. Mary Pickford at Edinburgh measured the action of acetyl choline in the supraoptic nucleus of the hypothalamus and helped to establish that vasopressin and oxytocin are formed in separate and distinct neurons. Berta Scharrer, like her future husband Ernest Scharrer, was born in Munich. Their great contribution was the proof that the posterior pituitary is not a gland, but the location of the release into the circulation of vasopressin and oxytocin from fibres in the hypothalamico-hypophysial tract. Their work succeeded in establishing against high-powered, vehement opposition the value of histological evidence in elucidating synthesis, storage and release of secretion from neuro-endocrine cells. A Rockefeller travelling fellowship allowed Marthe Vogt to move from Berlin in 1932 to London and then to Cambridge. The relations between the cortex and medulla of the suprarenal gland and the control of adrenocorticotropin were her main concerns. Dora Jacobsohn emigrated to Sweden after graduating in Berlin in 1934. She investigated control of the anterior pituitary gland by the hypothalamus, and co-operated with Geoffrey Harris in establishing the role of the hypothalamico-hypophysial portal venous system that conveys the releasing factors that preside over anterior pituitary cells. Laboratory discoveries do not constitute the whole of science, for the interpretation of evidence and recognition of general principles deserve attention. Dorothy Price, from Aurora, Illinois, received her BS in 1922 at the University of Chicago, and was glad to find employment as a histology technician in the zoology laboratory, where she was quietly appropriated by Carl Moore (1892-1955), an investigator seeking the key to hormonal control of gonadal function. The burning question was the part played by what was (then) called hormone antagonism in the biology of the testis. Price recognised that the common factor in explaining the deleterious effects of oestrin and testosterone on the testes could be traced to the anterior pituitary: the pituitary controlled testicular secretion, and the male hormone in turn controlled gonadotropin release in the pituitary. This seesaw balance explained the problem, and was the first of many regulatory systems to be recognised as ensuring stability--and later became known as negative feedback. The contributions of these five women helped place neuro-endocrinology on a firm foundation for its later expansion.

Transcriptional silencing of the inhibin-α gene in human gastric carcinoma cells

Although inhibin was first identified as a hormone regulating pituitary FSH secretion, it was later recognized to act as a tumor suppressor in the gonad and adrenal glands. Recently, the alpha subunit of this dimeric hormone (inhibin‑α) was reported to be involved in prostate tumorigenesis. To identify additional roles outside the reproductive axis, we investigated inhibin‑α gene activity and subsequent cell fate in human gastric cancer cells. The results were as follows: all the gastric cancer cells had at least one of a set of abnormalities including hypermethylation of the promoter, mutation of the 5'‑UTR or allelic imbalance including LOH in the inhibin‑α gene. Hypermethylation of the promoter and mutation of the 5'‑UTR in inhibin‑α were observed in SNU‑1, SNU‑5 and SNU‑484 cells. LOH was observed in AGS, KATO III, SNU‑5, SNU‑484 and SNU‑668 cells. Treatment with 5‑AzaC, a demethylating agent, induced demethylation of the inhibin‑α promoter in the SNU‑1, SNU‑5 and SNU‑484 cell lines, with the CpG5 site being strongly influenced by 5‑AzaC. In addition, inhibin‑α mRNA and protein were maintained at low levels in most of the gastric cancer cell lines. These low levels of mRNA and protein expression could be increased in most lines by treatment with 5‑AzaC. These increased inhibin‑α expression levels seemed to be closely associated with apoptosis and suppression of cell growth. Taken together, our results reveal that the inhibin‑α gene is transcriptionally silenced in human gastric cancer cells, and that reactivation of the gene suppresses their growth characteristics. This suggests that inhibin‑α may have a more general tumor suppressor activity outside the reproductive axis.

59P Mammary Duct Endoscopy with Saline Lavage for Breast Cancer Prevention and Homeostasis Maintenance in Middle Aged Women

ABSTRACT Background Our previous report has demonstrated that mammary duct endoscopy plays important role for breast cancer screening in patients with spontaneous nipple discharge (SND). From our large quantity of mammary duct endoscopy data pool and regular follow up, we found that patients underwent mammary duct endoscopy plus saline lavage not only had decreased breast cancer incidence rate, but also greatly improved symptoms of hypothyroidism which subsequently improved their life quality. Objectives The objective of current study was to compare mammary duct endoscopy with or without saline lavage in the context of decreasing breast cancer incidence rate and improving clinical presentations of hypothyroidism. Material and methods 1000 of patients with normal initial mammary duct endoscopy were randomly divided into two groups. Group L patients underwent mammary duct lavage during the procedure; group C patients without any further intervention. For both groups of patients, questionnaires to screen symptoms of hypothyroidism were given; and a baseline TSH was recorded. Patients were followed up for physical examination and TSH level. The second time mammary duct endoscopy was performed 3 years after the initial exam. Results 2% of patients in group L had ductal hyperplasia compared to 25% in the group C; breast cancer was found in 3% in group C and none in group L. 28% of patients previously with more than two hypothyroidism symptoms became asymptomatic in group L; while in group C, 3% of patients without hypothyroidism symptoms during the initial screening became symptomatic three years later. Blood TSH level changed from 0.3 µIU/ml to 1.8 µIU/ml for group L patients and decreased from 0.4 µIU/ml to 0.3 µIU/ml for group C patients. Conclusion From this study we find that mammary duct lavage through endoscopy played significant role on prevention of breast cancer by removing mechanical blockage and subsequently decreased PRL secretion. This indirectly recovered the pituitary TSH secretion through inhibition of thyrotroph transdifferentiation into lactotroph and improved patients' life quality by homeostasis rebalance. Disclosure All authors have declared no conflicts of interest.

Oral Octreotide Absorption in Human Subjects: Comparable Pharmacokinetics to Parenteral Octreotide and Effective Growth Hormone Suppression

Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. Four single-dose studies were conducted in 75 healthy volunteers. Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 μg octreotide were administered. We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Prolactin-releasing peptide is a potent mediator of the innate immune response in leukocytes from Salmo salar

Prolactin (PRL)-releasing peptide (PrRP) is a strong candidate stimulator of pituitary PRL transcription and secretion in teleosts. However, the role in control of extrapituitary PRL expression or its effects on innate immunity are unclear even in mammals. To study the possible presence of PrRP in peripheral organs, PrRP expression patterns and their effect on innate immunity were characterised in SHK-1 cells and head kidney (HK) leukocytes purified from the salmonid, Salmo salar. We detected immunoreactive cells in leukocytes from blood and HK of S. salar and found that PrRP mRNA was abundantly expressed in these cells. We have recently reported that physiological concentrations of native PRL, downstream of neuropeptide PrRP were able to induce expression of pro-inflammatory cytokines and the production of reactive oxygen species (ROS) in HK leukocytes and macrophages from S. salar and Sparus aurata. It is of interest to note that in this work we have revealed that synthetic PrRP was able to induce expression of pro-inflammatory cytokines (interleukins) IL-1β, IL-6, IL-8, IL-12 and PRL. We also show here that PrRP increased both (ROS) production and phagocytosis. Taken together, our results demonstrate for the first time that PrRP may be a local modulator of innate immune responses in leukocytes from S. salar.

Cospeptin, a novel reproductive peptide

Using a bioinformatics screen, our group recently discovered the novel neuropeptide cospeptin. We detected highest levels of cospeptin in the hypothalamus, including the periventricular nucleus, suggesting that cospeptin may influence pituitary hormone secretion. Cospeptin treatment alone failed to alter secretion of anterior pituitary (AP) hormones from dispersed primary rat pituitary cells; however, we found that cospeptin pre‐treatment potentiated release of luteinizing hormone in response to gonadotrophin‐releasing hormone (GnRH) stimulation. To determine if cospeptin plays a role in regulation of reproductive function, we compromised production of endogenous cospeptin by administration of siRNA directed against cospeptin into the lateral cerebroventricle of adult female rats, and used vaginal cytology to track the integrity of the estrous cycle. Treatment with cospeptin siRNA caused a delay in the appearance of the next estrus, and led to a decrease in GnRH receptor message in AP, suggesting cospeptin sensitizes gonadotrophs by upregulating the transcription of the GnRH receptor. These and other results suggest that cospeptin is an important reproductive hormone that modulates the sensitivity of pituitary gonadotrophs to GnRH through regulation of the expression of GnRH receptor.

Ovarian estradiol modulates the stimulatory effect of ovulation-inducing factor (OIF) on pituitary LH secretion in llamas

This study was designed to: 1) characterize the effect of ovulation-inducing factor (OIF) on pituitary LH secretion in ovariectomized (OVX) llamas; and 2) determine the effect of OIF on LH secretion in OVX llamas pretreated with estradiol-17β (E-17β) or estradiol benzoate (EB). In Experiment 1, intact and OVX llamas (n = 5 or 6 per group) were assigned to a two by two factorial design: 1) Intact llamas treated with 1 mL of phosphate buffered saline (PBS); 2) Intact llamas treated with 1 mg of purified OIF; 3) OVX llamas treated with 1 mL of PBS; or 4) OVX llamas treated with 1 mg of purified OIF. In Experiment 2, intact and OVX llamas (n = 5 or 6 per group) were randomly assigned to the following groups: 1) Intact llamas treated with 1 mg of purified OIF; 2) OVX llamas treated with 1.0 mL of PBS; 3) OVX llamas treated with 1.0 mg of purified OIF; 4) OVX llamas primed with E-17β, followed by 1.0 mg of purified OIF. Experiment 3 was similar as described for Experiment 2, except that priming was done with EB. In Experiment 1, animal category by treatment and animal category by treatment by time interactions tended (P = 0.08) to affect LH concentration. The effect of OIF on LH released was partly restored (P < 0.05), to the values observed for the intact OIF-treated females, when OVX llamas were primed with E-17β or BE (Experiments 2 and 3). We concluded that peripheral estradiol concentrations in llamas partially modulates the effect of OIF on pituitary LH secretion; however, other ovarian factor(s) could also participate in this modulatory action.

A case report: successful pregnancy after controlled ovarian hyperstimulation by using short-acting gonadotropin releasing hormone agonist only

Controlled ovarian hyperstimulation (COH) is widely used in in vitro fertilization and embryo transfer (IVF-ET) to achieve multiple follicle development during one treatment cycle. COH is usually initiated by gonadotropin releasing hormone agonist (GnRHa) to down-regulate pituitary secretion of gonadotropins, suppress endogenous LH surge and synchronize multiple follicles development, which is followed by stepwise exogenous gonadotropins stimulation [1, 2]. Here we report a case of successful pregnancy after inducing multiple follicles development by using short-acting GnRHa only. A 31-year-old woman, 50 kg weight, was administrated in our unit for four-year primary infertility. Her menstrual cycle was 28 days, lasting 6–7 days. The basal serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) level was 5.1 mIU/mL, 3.56 mIU/mL, and 38.81 pg/mL, respectively. The numbers of antral follicles were eight per ovary. In the mid-luteal phase, the patient was administrated of short-acting GnRHa (Decapeptyl, Ferring, Germany) 0.1 mg/day for pituitary down-regulation] to initiate an IVF treatment cycle. After 14 days administration, the serum FSH was 4.58 mIU/mL, LH was 29.23 mIU/mL, and E2 was 26.79 pg/mL. Transvaginal ultrasound examination showed that there were five follicles with average diameter more than 10 mm, and the largest one was 14 mm. 0.1 mg Decapeptyl was continuously given for one more day and the LH level maintained 29.96 mIU/mL. Then, we decreased the dose of GnRHa to 0.05 mg/day and continuously given for four more days. Ultrasound examination showed five follicles with average diameter more than 20 mm, the largest one was 28 mm. The patients’ serum E2 increased to 1,270 pg/mL, LH was 13.51 mIU/mL. 0.05 mg Decapeptyl was continuously given in the morning and 10,000 IU human chorionic gonadotropin (hCG) was administered to trigger egg maturation in the evening. The patient was scheduled for oocyte retrieval 34 h after the hCG injection. Five oocytes were obtained and three fertilized successfully. Two grade I embryos at the 8-cell stage were transferred at d3, and a surplus grade I embryos at the 7-cell stage were frozen. Routine luteum support (UTROGESTAN 200 mg, Bid, Laboratoires Besins-Iscovesco, France) was given after embryo transfer (ET). Serum β-hCG level examined 14 days after ET was 613.9 mIU/mL, indicating a successful biochemical pregnancy. A transvaginal ultrasound examination 4 months after ET confirmed an ongoing intrauterine twin pregnancy.

GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET)

Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in “in Vitro” Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH) agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.

Antineoplastic Action of Growth Hormone-Releasing Hormone (GHRH) Antagonists

Some of the antagonists of growth hormone-releasing hormone (GHRH) are able to inhibit the growth of various experimental human cancers. The antitumor effects of first antagonists seemed to be dependent mainly on the disruption of pituitary secretion of growth hormone (GH), followed by the reduction in the levels of circulating insulin-like growth factor (IGF)-1, an important growth factor for cancer cells. It seems obvious, that growth hormone deficiency (GHD) induced by GHRH antagonists with all its complications, could limit the beneficial effects of GHRH antagonists therapy, and decrease patients' quality of life. The discovery of local autocrine/paracrine production of GHRH and other related growth factors in many tumoral tissues, in combination with the wide expression of GHRH receptors on cancer cells, directed the research to the synthesis of more potent GHRH antagonists. These compounds exert strong inhibitory effects directly on tumor growth, with scarce endocrine action. The receptor-mediated mechanisms comprise complex and still not completely understood effects on intracellular signaling pathways that are strictly related to human tumorigenesis. This review summarizes recent patents and latest observations on the antineoplastic role of GHRH antagonists in human tumors with emphasis on potential therapeutic applications in clinical oncology.

Growth hormone regulation of follicular growth

The somatotropic axis-consisting of growth hormone (GH), the insulin-like growth factors 1 and 2 (IGF1 and IGF2), GH binding protein (GHBP), IGF binding proteins (IGFBPs) 1 to 6, and the cell-surface receptors for GH and the IGFs-has major effects on growth, lactation and reproduction. The primary target tissues for GH are involved in growth and metabolism. The functionality of the somatotropic axis depends in part on the expression of liver GH receptor (GHR), which determines the amount of IGF1 released from the liver in response to GH. The IGF1 acts as a pleiotropic growth factor and also serves as the endocrine negative feedback signal controlling pituitary GH secretion. Growth hormone and IGF1 undergo dynamic changes throughout the life cycle, particularly when animals are either growing, early post partum or lactating. Cells within the reproductive tract can respond directly to GH but to a lesser degree than the primary target tissues. The major impact that GH has on reproduction, therefore, may be secondary to its systemic effects on metabolism (including insulin sensitivity) or secondary to the capacity for GH to control IGF1 secretion. Insulin-like growth factor 1 and IGFBP are also synthesised within the ovary and this local synthesis is a component of the collective IGF1 action on the follicle. Future studies of GH should focus on its direct effects on the follicle as well as its indirect effects mediated by shifts in nutrient metabolism, insulin sensitivity, IGF1 and IGFBP.

Calcium and other signalling pathways in neuroendocrine regulation of somatotroph functions

Relative to mammals, the neuroendocrine control of pituitary growth hormone (GH) secretion and synthesis in teleost fish involves numerous stimulatory and inhibitory regulators, many of which are delivered to the somatotrophs via direct innervation. Among teleosts, how multifactorial regulation of somatotroph functions are mediated at the level of post-receptor signalling is best characterized in goldfish. Supplemented with recent findings, this review focuses on the known intracellular signal transduction mechanisms mediating the ligand- and function-specific actions in multifactorial control of GH release and synthesis, as well as basal GH secretion, in goldfish somatotrophs. These include membrane voltage-sensitive ion channels, Na+/H+ antiport, Ca2+ signalling, multiple pharmacologically distinct intracellular Ca2+ stores, cAMP/PKA, PKC, nitric oxide, cGMP, MEK/ERK and PI3K. Signalling pathways mediating the major neuroendocrine regulators of mammalian somatotrophs, as well as those in other major teleost study model systems are also briefly highlighted. Interestingly, unlike mammals, spontaneous action potential firings are not observed in goldfish somatotrophs in culture. Furthermore, three goldfish brain somatostatin forms directly affect pituitary GH secretion via ligand-specific actions on membrane ion channels and intracellular Ca2+ levels, as well as exert isoform-specific action on basal and stimulated GH mRNA expression, suggesting the importance of somatostatins other than somatostatin-14.

GnRH agonist active immunization influences gonadotropin receptor expression in pituitary gland, uterine development and secretion of peripheral reproduction hormones in female mice

Abstract Objective The present study was conducted to assess the effects of the GnRH agonist (alarelin) on the expression of GnRHR, FSHR and LHR mRNAs in the pituitary gland and uterine development in female mice. Methods Sixty pre-estrus female mice were randomly assigned to 4 groups (n = 15). The mice in experiment group 1 (EG-1), experiment group 2 (EG-2), and experiment group 3 (EG-3) were subcutaneously injected with 0.375 μg/kg, 0.75 μg/kg and 1.5 μg/kg alarelin antigen emulsion, respectively, once a day during 7 consecutive days to enhance immune response. Mice in the control group (CG) were injected with 0.l ml solvent once a day on 7 consecutive days. The samples of blood, pituitary and uterine horns were collected aseptically at day 21 from each mouse. Fluorescence quantitative RT-PCR was implemented to detect gene expression of GnRHR, FSHR and LHR in the pituitary glands. ELISA was used to measure the serum LH and FSH concentrations. The uterine slices were observed under an optical microscope;...

A pituitary adenoma secreting follicle-stimulating hormone with ovarian hyperstimulation: treatment using a gonadotropin-releasing hormone antagonist

To describe the management of a patient with a pituitary adenoma secreting follicle-stimulating hormone (FSH) associated with ovarian hyperstimulation who was treated with a gonadotropin-releasing hormone (GnRH) antagonist. Case report. University teaching hospital. A woman of reproductive age with secondary amenorrhea and ovarian hyperstimulation due to a pituitary adenoma secreting FSH, which persisted after transsphenoidal surgery. Clinical treatment with a GnRH antagonist. A decrease in serum estradiol levels. During the treatment period, ovarian hyperstimulation decreased as shown by a reduction in estradiol levels and an improvement in the patient's clinical condition and in the ultrasonography parameters. The GnRH antagonist was found to be effective for the short-term treatment of ovarian hyperstimulation secondary to a pituitary adenoma secreting FSH, thus representing a therapeutic option that should be taken into consideration in such cases.

Hereditary Pituitary Hyperplasia with Infantile Gigantism

We report hereditary pituitary hyperplasia. The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. The study is a retrospective analysis of three cases from one family. The study was conducted at the National Institutes of Health, a tertiary referral center. A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. The condition was treated by total hypophysectomy. We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development.

Ghrelin potentiates TSH-induced expression of the thyroid tissue-specific genes thyroglobulin, thyroperoxidase and sodium-iodine symporter, in rat PC-Cl3 Cells

Ghrelin is a 28-amino-acid peptide that stimulates pituitary growth-hormone secretion and modulates food-intake and energy metabolism in mammals. It is mainly secreted by the stomach, but it is also expressed in many other tissues such as cartilage or the thyroid gland. In the present study we have analyzed by RT-PCR and using immunohistochemistry and immunofluorescence the expression and tissue distribution of ghrelin and its functional receptor (GHS-R type 1α) in thyroid cell-lines and in normal and pathological rat thyroid tissue. Additionally, by measuring the incorporation of BrdU, we have investigated if, as previously noted for FRTL-5 cells, ghrelin enhances the proliferation rate in the PC-Cl3 rat-thyrocyte cell-line. Finally, we have determined the stimulatory effect of ghrelin on TSH-induced expression of the tissue-specific key genes involved in the synthesis of thyroid hormone: thyroglobulin, thyroperoxidase and sodium–iodine symporter. Our data provide direct evidence that C-cell secreted ghrelin may be involved in the paracrine regulation of the thyroid follicular cell function.

New targeted therapies in pituitary carcinoma resistant to temozolomide

To evaluate the antitumoral efficacy of everolimus in pituitary carcinoma resistant to temozolomide, the correlation with mammalian target of rapamycin (mTOR) signaling in the tumor and to present recent advances and future treatments of pituitary carcinomas. Pituitary carcinomas are rare and largely unresponsive to current treatment options. Recent reports on the antitumoral efficacy of temozolomide in some such patients are encouraging, yet most patients appear to show resistance to its actions. As a potential alternative, the mTOR inhibitor, everolimus, has been shown to potently inhibit pituitary cell proliferation highlighting mTOR inhibition as a promising therapeutic approach for pituitary carcinomas. We described the tumoral effects of a combination therapy with everolimus (5 mg/day) and octreotide (30 mg/month) and the mTOR signalling expression in a patient with pituitary ACTH carcinoma, compared to 17 other ACTH adenomas. Clinical and biochemical evaluation were performed every month, and imaging after 3 month of treatment. mTOR signaling was assessed by microarray expression analysis of each of the 18 adenoma tissues. Combined therapy failed to control pituitary tumor growth and ACTH secretion. Slight activation of mTOR signaling was found in all ACTH tumors alongside important variations between tumors. Low antitumor efficacy shown by everolimus might be explained by the weak activation of mTOR pathway in ACTH tumors. Everolimus treatment was inefficient at controlling secretion and tumor growth of one ACTH pituitary carcinoma. More clinical cases, with mTOR signalling expression analysis of the tumor, must be published before any conclusions can be drawn.