Monica Gola

Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH--an update.

CONTEXT GH deficiency (GHD) of the adult is a clinical condition characterized by the presence of several traditional and emerging cardiovascular risk factors that can significantly increase cardiovascular morbidity and mortality. It is still an open issue whether GH replacement is able not only to improve cardiovascular risk factors but also to decrease cardiovascular morbidity and mortality. EVIDENCE ACQUISITION The major source of data acquisition included PubMed research strategies. Original articles, systematic reviews and meta-analyses, and included relevant citations were screened. EVIDENCE SYNTHESIS In untreated GHD, cardiovascular risk is increased due to abnormal lipid profile (increased total and low-density lipoprotein cholesterol, increased triglycerides, and reduced high-density lipoprotein cholesterol) and impaired glucose metabolism. Emerging cardiovascular risk factors/markers such as proinflammatory cytokines, C-reactive protein, and adipokines are also increased in GHD patients. Increased cardiovascular morbidity and mortality have also been reported in GHD. GH treatment has been shown to improve both traditional and emerging cardiovascular risk factors and markers. However, evidence on the effects of GH replacement on cardiovascular events and mortality is limited. CONCLUSION The GHD population may be considered at high cardiovascular risk, and GH substitution may be expected to bring an added value to patients with hypopituitarism in terms of cardiovascular protection. However, there is too limited evidence (rarely coming from randomized and controlled studies) to recommend GH treatment based on the cardiovascular status of the patients.

Resistance to somatostatin analogs in acromegaly: An evolving concept?

The aim of acromegaly treatment is to control the disease by suppressing GH hyperactivity and reducing the size or impeding the growth of the pituitary GH secreting mass. Over recent years, many studies have emphasized the role of SS analogs in the treatment of acromegaly. In fact, SS analogs have been demonstrated to be an effective tool not only in the control of GH hyper-secretion but also more recently in the control of tumor growth, in a relevant number of acromegalic patients both as primary or adjunctive treatment. In this context, the therapeutic failure of medical treatment with SS analogs needs to be accurately defined particularly when they are used as primary treatment but also when they are given to patients previously operated upon, since other effective therapeutic options are nowadays available. Current definition of resistance to SS analogs is based on their efficacy to control GH and IGF-I. However, due to the emerging significance of the shrinkage effect of SS analogs on pituitary adenomas as well as to the apparent dissociation between this effect and the biochemical effects of treatment with these analogs, an evolution in the concept of SS resistance is likely to be occurring. In this review, we will discuss the biological basis of the discordance between biochemical and volumetric effects of SS analogs, and we will address the intriguing clinical and therapeutic aspects related to a possible redefinition of the resistance to SS analogs.

Growth hormone deficiency in the adult

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.

Current guidelines for adult GH replacement.

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD usually results from damage to the pituitary gland or hypothalamus. Such damage may be caused by a tumor in the area or by treatment for a tumor (surgery or radiotherapy). Childhood–onset GHD presents with low growth velocity, is often idiopathic, and may continue in adult life in up to 50% of cases. GHD may also develop in some children and adult survivors of childhood malignancy following cranial irradiation or chemotherapy. Adult GHD commonly presents with the following problems:

Growth hormone deficiency and cardiovascular risk: do we need additional markers?

Atherosclerosis, a chronic inflammatory disease of large and medium size arteries, continues to be the leading cause of cardiovascular events and one of the most common causes of mortality and cardiovascular disease [1]. Atherosclerotic lesion progression depends on chronic inflammation in the artery wall, and the innate and adaptive immune responses are involved in these processes [2]. In recent years, several new circulating markers, including C-reactive protein (CRP), fibrinogen, lipoprotein(a) (Lp(a)), and homocysteine [3–5] have been proposed as potential risk factors for atherothrombotic vascular disease. It is known that alteration of the GH/IGF-1 axis contributes to determining cardiovascular disease as suggested by clinical studies reporting increased risk for cardiovascular morbidity and mortality in adults with GH deficiency (GHD) [6, 7]. Epidemiological studies in the general population have also shown that IGF-1 levels in the low-normal range are associated with an increased risk of ischemic heart disease and stroke outcome [8, 9]. Moreover, activity of GH/ IGF-1 axis decreases with aging [10] and hypothyroidism [11] both conditions of increased cardiovascular risk. Hypopituitary GHD adults have been shown to have an increased number of atheromatous plaques in carotid and femoral arteries, as compared with control individuals. Other signs of atheromatosis found in GHD patients include an increased intima-media thickness, more pronounced stiffness of carotid arteries, and less aortic distensibility [12]. GHD is also associated with abnormalities in body composition that may have an impact on cardiovascular risk. In fact, a clustering of cardiovascular clinical risk factors has been reported in GHD patients, including truncal adiposity and increased visceral fat, changes in body composition and insulin resistance, negative changes in lipid profiles and abnormal hemostatic factors [13]. Echocardiographic studies have demonstrated that adult patients with GHD have reduced left ventricular (LV) mass and impaired cardiac performance as shown by decreased ejection fraction and abnormal LV diastolic filling [14]. Other studies have reported decreased LV posterior wall thickness, without any difference in internal diameter or ejection fraction in patients with GHD versus those without GHD [15]. Despite many studies, although limited in follow-up time and in the number of patients, showing an improvement in GH-mediated both systolic and diastolic function by echocardiography or radionuclide angiography [14, 15], it remains unclear if there may be a direct favorable effects on cardiac function by physiological GH replacement therapy [16]. In fact, recently, Andreassen et al. [17] evaluated cardiac function before and during GH treatment using cardiac magnetic resonance imaging and measurement of circulating levels of B-type natriureticpeptides. They showed that patients with untreated GHD had unchanged ejection and LV mass as compared with control subject. One year of adequate GH replacement therapy was not associated with significant increases in LV volume, ejection fraction, or LV mass. No changes in brain M. Gola (&) A. Giustina Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy e-mail: monica.gola10@tiscali.it

Cardiovascular risk in aging and obesity : Is there a role for GH?

GH has significant impact in adults. In fact, patients with the GH deficiency (GHD) syndrome are now recognized as having an increased cardiovascular risk. The effects of human aging on GH secretion have been evaluated by a number of researchers. Studies of 24 h secretion of GH have shown variable reductions in most 24-h GH secretory parameters in middle-aged and in older men and women, resulting in a decrease in plasma levels of its anabolic mediator IGF-I. Obesity is also associated with several endocrine and metabolic abnormalities. These include decreased serum GH concentrations, reduced GH half-life, frequency of GH secretory episodes and daily GH production rate. The mechanism of the low GH in obesity is not completely understood nor is it clear whether its relationship with visceral adiposity is causal. The aim of this article will be to review the available clinical data concerning the potential involvement of “subclinical” or perhaps better “functional” GHD, which is observed in aging and obesity, in the increase in cardiovascular risk which characterizes these two conditions.

Effects of recombinant follicle-stimulating hormone on bone turnover markers in infertile women undergoing in vitro fertilization procedure.

CONTEXT There is experimental but limited clinical evidence that FSH may have direct effects on bone. OBJECTIVE The aim of the study was to evaluate the effects of acute FSH stimulation on bone turnover in premenopausal women. DESIGN AND SETTING We conducted a prospective study at a referral center. PATIENTS Twenty-nine infertile women (age range, 30-40 yr) undergoing an in vitro fertilization procedure were included in the study. INTERVENTIONS Pharmacological suppression of endogenous gonadotropin and estradiol (E2) production by GnRH analog (leuprolide 1 mg/d s.c.) was followed by stimulation with recombinant FSH (rFSH; starting dose, 375 IU/d s.c.). MAIN OUTCOME MEASURES We measured serum osteocalcin, C-telopeptides of type-1 collagen (β-CTX), FSH, and E2 at the beginning of leuprolide administration (T0), at the beginning of rFSH administration (T1), and 3 d (T2) and 10 d (T3) after the first dose of rFSH. RESULTS At T1, the suppression of FSH and E2 secretion, as an effect of leuprolide administration, led to a significant increase in serum β-CTX values vs. T0 (P < 0.001). After the administration of rFSH, a rapid increase in serum FSH was observed, whereas serum E2 values increased more slowly. At T2, the increase in serum FSH values above our reference range for early follicular phase (with E2 in the reference range) did not induce any significant change in median serum β-CTX values as compared to T1. At T3 (when both FSH and E2 were high), serum β-CTX values decreased significantly vs. T1 (P < 0.001). Osteocalcin did not change significantly throughout the study period. CONCLUSIONS Our model suggests that FSH does not acutely exert relevant direct effects on bone metabolism in premenopausal women.

Development of acromegaly in a patient with anorexia nervosa: pathogenetic and diagnostic implications.

Anorexia nervosa (AN) is a psychosomatic disorder characterized by an alteration in body image, resulting in eating abnormalities that lead to malnutrition associated with secondary endocrinological disturbances. AN is associated with high levels of GH and low levels of IGF-I, suggestive of a nutritionally acquired lack of GH action or GH resistance and of an unbalanced hypothalamic GH neuroregulation with GHRH prevalence on SS tone. In this clinical report, we describe the development of acromegaly in a patient affected by AN and we discuss pathogenetic and diagnostic implications.