Ovarian insufficiency and secondary amenorrhea in a patient with a novel variant within GDF9 gene.

OBJECTIVE: Premature ovarian insufficiency is a heterogeneous condition that can be caused by several factors, such as genetic, environmental, etc. and represents one of the main causes of female infertility. One of the genes implicated is GDF9, which encodes a member of the transforming growth factor-beta superfamily that participates in the coordination of somatic cell activity, female fertility, including folliculogenesis, and oocyte maturation. Damaging variants in GDF9-encoded growth factors can cause the production of inhibin, perturb oocyte granulosa cell microenvironments, and obstruct follicle development. A novel GDF9 variant is herein reported to consolidate the role of GDF9 in ovarian function and female fertility. METHODS: A 38-year-old female was referred for the investigation of secondary amenorrhea. Eventually, she was referred for genetic evaluation whereby conventional karyotyping and Fragile-X molecular testing were normal. Whole Exome Sequencing was performed, followed by targeted Sanger sequencing in all family members for variant confirmation and evaluation. RESULTS: In this study we report a patient presenting with secondary amenorrhea due to premature ovarian failure and a pituitary lesion with radiological characteristics compatible with a Rathke cyst or a macroadenoma, residing between the adenohypophysis and neurohypophysis. Whole Exome Sequencing revealed a novel heterozygous stoploss variant c.1364A>C, p.(*455Serext*8) in the GDF9 gene. CONCLUSIONS: Should the predicted elongated GDF9 protein and differentially configurated GDF9 mature protein molecule form unstable dimers, rapid proteolytic degradation may take place and inhibit homo/heterodimer formation.

Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice.

Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring.

Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH?

BACKGROUND: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD). AIM: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma. PATIENTS AND METHODS: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors. CONCLUSION: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.

Identification of functional CCAAT/enhancer-binding protein and Ets protein binding sites in the human chorionic somatomammotropin enhancer sequences.

The human chorionic somatomammotropin (CS) A and B genes (listed as CSH1 and CSH2 in the HUGO database) are highly expressed in placenta. A 241 bp potent enhancer, nucleotides (nts) 1-241, located at the 3' end of the CS-B gene (CS-Benh) stimulates promoter activity specifically in placental trophoblast cells in vitro. Strong activity is exerted by a 23 bp element within the CS-Benh (nts 117-139), shown to interact with transcription enhancer factor (TEF) members of the transcription enhancer activator (TEA) DNA-binding domain-containing family. An identical TEF element is present in the homologous (97.5%) CS-Aenh; however, a few nucleotide differences suppress its activity. Previously, we identified regulatory sequences distinct from the TEF element within an 80 bp modulatory domain (nts 1-80) in the CS-Benh. Using structural and functional assays we now show that CCAAT/enhancer-binding protein (C/EBP) binding sites exist in the 80 bp modulatory domains of both enhancers, and an Elk-1 binding site exists in the modulatory domain of the CS-Aenh. C/EBPα or C/EBPß strongly repressed CSp.CAT activity but stimulated CSp.CAT.CS-Benh activity. In contrast, the equivalent CS-A enhancer sequences were unable to relieve promoter repression. Elk-1 overexpression also resulted in differential effects on the CS-Aenh versus CS-Benh. Finally, we provide evidence for the association of C/EBPß with the CS-A and CS-B genes in human placental chromatin, including differential involvement of C/EBPß with the CS-Aenh versus the CS-Benh, and therefore consistent with the notion that these are regions of regulatory significance in vivo. We conclude that members of the C/EBP and Ets families can differentially modulate CS-Benh and CS-Aenh activity.

Reproductive disturbances in multiple neuroendocrine tumor syndromes.

In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz-Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple-areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel-Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.

Assessment of endocrine and nutritional status in age-related catabolic states of muscle and bone.

PURPOSE OF REVIEW: Bone loss and muscle wasting are associated with increased morbidity and mortality in the elderly, most frequently as a result of fractures associated with poor neuromuscular conditioning leading to accidental falls. This paper reviews data that link pathways of the immune and endocrine systems with bone and muscle pathophysiology, as well as data on the impact of nutrition and physical activity on these systems. RECENT FINDINGS: The growth hormone-insulin-like growth factor I axis and deficiencies in sex steroid hormones in aging appear linked with changes in the hypothalamic-pituitary-adrenal axis and immune function, accompanied by increased activity of the tumour necrosis factor-alpha axis. This is associated with activation of the RANK/RANKL/osteoprotegerin pathway and insulin resistance, affecting muscle and bone physiology. Vitamin D deficiency contributes to bone loss and muscle wasting, whereas other nutritional defects such as zinc or magnesium deficiencies may further complicate these catabolic states. SUMMARY: As nutritional deficiencies responsible for bone and muscle derangement are correctable factors, careful nutritional assessment, in addition to evaluation of endocrine and immune status, may provide clinically important information allowing successful management of elderly patients in danger of neuromuscular dysfunction, accidental falls and bone fractures.

Growth hormone-secreting tumors: genetic aspects and data from animal models.

Hereditary cases of growth hormone (GH)-secreting tumors have been classified into three clinical entities: the multiple endocrine neoplasia type 1 (MEN1) syndrome, the Carney complex (CNC) and the isolated familial somatotropinomas (IFS). The genomic defects associated with MEN1 are all linked to various mutations of the MEN1 gene, which is located at chromosome 11q13 and codes for menin, a nuclear protein expressed in multiple tissues. Inactivation of the MEN1 gene appears to be only rarely associated with sporadic pituitary tumor development. A CNC-associated gene, the type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PRKAR1A), is located at 17q23-24. A second CNC candidate gene is located at chromosome 2p15-16, with characteristics of inheritance consistent with an oncogene; however, this gene has not been identified yet. PRKAR1A mutations are infrequently associated with sporadic GH-secreting adenomas. A candidate IFS gene is located at 11q13, in proximity to the MEN1 gene, at a locus narrowed down to a 2.21-Mb area, with approximately 50 genes, that does not appear to include the MEN1 gene. Apart from the linkage of IFS to 11q13, a possible linkage to 2p16 has also been raised, although data are still inconclusive. This manuscript reviews genetic aspects of hereditary GH-secreting tumors, data from animal models resulting from the inactivation of the MEN1 and PRKAR1A tumor suppressor genes and available in vitro data regarding possible functions of menin, the product of the MEN1 gene.

Medical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs.

Relief of symptoms can be achieved following surgery for growth hormone (GH)-secreting adenomas, as well as after pharmacological therapy with somatostatin analogs. Recently, long-acting somatostatin analog depot formulations, octreotide LAR and lanreotide SR have become available. Somatostatin analogs control GH/insulin-like growth factor (IGF)-1 excess, induce tumor shrinkage in a high proportion of patients, improve symptoms of acromegaly with relatively limited side effects and are successfully administered in patients not suitable for surgery. Furthermore, preoperative somatostatin analogs have been suggested to improve outcome for tumors with limited invasiveness, while surgical tumor debulking in cases that are, at least partially, somatostatin resistant, increases the achievement of normal IGF-1 levels by postoperative somatostatin analog treatment. Effective control of hypertension, as well as diabetes, is mandatory in order to reduce the increased vascular morbidity/mortality. Control of GH/IGF-1 excess generally improves glucose metabolism. Somatostatin analogs improve insulin sensitivity, exerting, however, a concomitant direct inhibitory effect on insulin secretion, with a net balance leaning towards a deterioration in glucose homeostasis. As a result, oral insulin secretagogues (and/or insulin) should probably be preferred to insulin sensitizers in acromegalic patients developing diabetes while on somatostatin analogs. Nevertheless, glucose tolerance remains normal in most of the nondiabetic acromegalic patients, while diabetic acromegalic patients on insulin are at risk for hypoglycemia during initiation of somatostatin analog therapy. Although successful management of acromegaly has been associated with improvement in morphological and functional parameters of cardiomyopathy, limited and conflicting information is available regarding the effect on blood pressure control. Contradictory results have also been reported regarding sleep hypopnea or apnea in treated acromegalic patients. As acromegalic skeletal abnormalities are rather irreversible, apneic episodes may persist after normalization of hormonal levels. Aggressive therapy, including surgery, pharmacological treatment and, in some cases, pituitary irradiation, aiming at normalization of IGF-1 levels, is required for arthropathy management. Some improvement in pain, crepitus and range of motion has been observed after treatment with somatostatin analogs. Information on the impact of disease control, either by surgery or somatostatin analog treatment, on gonadal function is limited. Finally, the link between the hormonal/biochemical and the psychiatric/psychological features of acromegaly, as well as a potential basis for positive effects of somatostatin analog therapy remain unclear.