Etiology and Treatment of Growth Delay in Noonan Syndrome

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

Pituitary gland and growth hormone

The pituitary gland (PG) is said to be a “master” endocrine gland and through its tropic hormones influences other endocrine glands to secrete hormones that have a variety of effects on body systems. Growth hormone (GH) is a pituitary gland hormone that has direct and indirect effects produced by somatotrophs in early fetal life. It is essential for normal postnatal growth and has diverse effects across multiple physiological systems. The somatotrophic axis is made predominantly of GH, insulin-like growth factor 1 (IGF-1) and other factors regulating growth. This review summarises the relevant anatomical relationships of the PG, the basic aspect of GH physiology which includes mechanism of action (MOA), regulation and secretion and a direct and indirect action of GH through IGF-1, an important mediator of most of the peripheral action of GH.

MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and pregnancy: a contemporary review

Although fertility is frequently impaired in women with acromegaly, pregnancy is apparently becoming more common due to improvement in acromegaly treatment as well as in fertility therapy. As a result, several studies on pregnancy in patients with acromegaly have been published in recent years adding new and relevant information to the preexisting literature. Also, new GH assays with selective specificities and the knowledge of the expression of the various GH genes have allowed a better understanding of somatotrophic axis function during pregnancy. In this review, we show that pregnancy in women with acromegaly is generally safe, usually with tumoral and hormonal stability. Although the paucity of data limits evidence-based recommendations for preconception counseling and pregnancy surveillance, controlling tumor size and hormonal activity before pregnancy is highly recommended to ensure better outcomes, and surgical control should be attempted when feasible. Treatment interruption at pregnancy confirmation has also proven to be safe, as drugs are not formally allowed to be used during pregnancy. Drug exposure (somatostatin analogs) during early or whole pregnancy might increase the chance of a lower birth weight. Aggressive disease is uncommon and may urge individual decisions such as surgery or drug treatment during pregnancy or lactation.

Hyperandrogenism in adolescent girls: relationship with the somatotrophic axis

Background:During puberty there is a physiologic increase in adrenal and ovarian androgens. It has been suggested that the somatotrophic axis may be related to the development of hyperandrogenism and anovulation in non-obese adult women with polycystic ovarian syndrome (PCOS). The objective of the study was to investigate whether ovarian androgen secretion in young postmenarchal girls is related to the function of their somatotropic axis.Methods:This was a cross-sectional study of adolescent girls. We studied non-obese adolescent girls with hyperandrogenism (HA; n = 21) matched with control girls (C; n = 25) for chronological age, age at menarche and body mass index. We obtained a fasting blood sample for measurement of serum glucose, insulin, 17-hydroxyprogesterone (17OH-Prog), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, sex hormone-binding globulin (SHBG), total testosterone, IGF-I, IGF-II, IGFBP-1, IGFBP-3, ghrelin, leptin, AMH (antiMüllerian hormone), luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the follicular phase of the menstrual period. We performed an oral glucose tolerance test to determine blood glucose, insulin and ghrelin levels and urine samples to measure urinary GH (growth hormone) levels.Results:As expected, the hyperandrogenic girls had significantly higher Ferriman scores, basal total testosterone, free androgen index (FAI), androstenedione, AMH, and basal LH levels compared with the girls in controls. Serum IGF-I, IGF-II, IGFBP-3 and urinary GH did not differ between HA and C. There was a correlation between urinary GH and FAI in all girls (r 0.29, p < 0.05). In addition, in HA girls FAI correlated with insulin, homeostasis model assessment (HOMA) and ghrelin.Conclusions:We observed a correlation between urinary GH and FAI in the hyperandrogenic and control girls, suggesting that the function of the somatotrophic axis may influence the secretion of androgens in adolescent girls.

Cysteamine: a human health dietary additive with potential to improve livestock growth rate and efficiency

Cysteamine is a biological compound produced in the gastrointestinal tract and hypothalamus of all animals that acts on the somatotrophic axis. Cysteamine is finding increasing application in human medicine and also as a natural, in-feed growth promotant for monogastric and ruminant livestock that increases feed conversion efficiency, growth rate and leanness. It improves nutrient digestion and absorption by increasing portal-drained viscera blood flow and net portal absorption, while also reducing gastroenteropancreatic, plasma and hypothalamus concentrations of the inhibitory hormone, somatostatin (SRIF). Dietary inclusion rates required to achieve growth responses are typically about 10 times higher in ruminants than those required for pigs, but it is unclear whether ruminal breakdown of cysteamine is contributing to this difference. While short-term stimulation of growth, milk production and improved feed use efficiency are apparent, studies over longer periods are required, especially in breeding animals, due to the process of SRIF depletion being reversible. This review provides an overview of cysteamine’s mode of action in improving nutrient utilisation and its application in human nutrition and health, as well as its potential use as a growth promotant in the livestock industries.