Are there country-specific differences in the use of pegvisomant for acromegaly in clinical practice? An analysis from ACROSTUDY.

OBJECTIVE: A comprehensive picture of pegvisomant use for treating acromegaly in routine clinical practice in different countries is lacking. We aimed, therefore, to document country-specific behaviors in real-life pegvisomant use, and the main safety and effectiveness outcomes in the ACROSTUDY. DESIGN: ACROSTUDY is an open-label, non-interventional, post-marketing safety surveillance study. METHODS: A descriptive analysis was performed using data from the six top-recruiter ACROSTUDY countries, i.e., Germany (n = 548 patients), Italy (n = 466), France (n = 312), USA (n = 207), Spain (n = 200) and the Netherlands (n = 175). These nations accounted for > 85% of the ACROSTUDY cases. RESULTS: The mean pegvisomant dose at treatment start was lowest in the Netherlands (9.4 mg/day), whereas it ranged between 10.9 and 12.6 mg/day in the other countries. At year 5, the mean pegvisomant dose was around 15 mg/day in all countries, except France (18.1 mg/day). At starting pegvisomant, patients treated with monotherapy ranged between 15% in the Netherlands and 72% in Spain. Monotherapy remained lowest over time in the Netherlands. In all countries, the percentage of patients with normal IGF-1 increased steeply from < 20% at baseline to 43-58% at month 6 and 51-67% at year 1. After that, we observed minor changes in the rate of acromegaly control in all countries. The Netherlands peaked in disease control at year 2 (72%). The proportion of patients reporting changes in pituitary tumor size was generally low. Serious treatment-related adverse events were < 5% in all countries. CONCLUSIONS: Our study provided a detailed summary of real-life use of pegvisomant in the six top-recruiter ACROSTUDY nations.

Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes.

INTRODUCTION: Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potential fatal emergency. A synchronous bilateral adrenalectomy (SBA) is effective in recovering hypercortisolism. However, specific indications for an SBA are not available. We aimed to evaluate the outcome of patients who underwent an SBA and to identify biomarkers able to predict the requirements of an SBA. PATIENTS AND METHODS: A mono-centric and longitudinal study was conducted on 19 consecutive patients who underwent SBA for ACTH-dependent hypercortisolism between December 2003 and December 2017. This study population was compared to two control groups composed of patients cured after the resection of the ACTH secreting pituitary adenoma (Group A: 44 patients) and of the ACTH-secreting neuroendocrine tumours (Group B: 8 patients). RESULTS: Short- or long-term SBA complications or the recurrence of hypercortisolism did not occur. A single patient experienced Nelson syndrome. Clinical features after SBA showed improvement in the glico-metabolic assessment, hypertension, bone metabolism and the occurrence of hypokalaemia and infections. The younger the age at the time of Cushing's disease diagnosis, the longer the duration of active hypercortisolism, higher values of plasmatic ACTH and Cortisol (1 month after pituitary neurosurgery) and higher values of Ki67 in pituitary adenomas were detected in this study population as compared to Group A. CONCLUSIONS: SBA is an effective and safe treatment for patients with unmanageable ACTH-dependent hypercortisolism. A multidisciplinary team in a referral centre with a high volume of patients is strongly recommended for the management of these patients and the identification of patients, for better surgical timing.

Arthropathy in acromegaly: a questionnaire-based estimation of motor disability and its relation with quality of life and work productivity.

PURPOSE: Arthropathy is a common and disabling complication of acromegaly. Since in this condition radiological findings rarely correspond to functional impairment, we elected to quantify in a large cohort of acromegalic patients: the degree of motor disability compared with data from general population, the impact of joint involvement on quality of life and work productivity, and to look for associated factors. METHODS: In 211 acromegalic patients, 131 with controlled disease and 80 with active disease, eight validated scales were used to evaluate the (i) prevalence and distribution of arthropathy, (ii) degree of motor disability and joint symptoms (VAS, AIMS symptoms and WOMAC), (iii) quality of life (AcroQoL and PASQ) and work capability (WPAI:GH) as consequences of joint complications. RESULTS: Using the WOMAC questionnaire, for which population based normative values are available, a significantly higher prevalence and severity of motor disability was detected in acromegalics compared to the general population from literature. The results provided by the different questionnaires turned out to be highly concordant. All measures of motor disability correlated both with impaired quality of life and motor disability and were worse in females and in patients with higher BMI. CONCLUSIONS: The questionnaires VAS, AIMS symptoms, and WOMAC (this latter both as a whole and with its functionality subscale), with their scores, proved to be the most adequate tools to evaluate motor disability and its consequences on both quality of life and work productivity in acromegaly. Female gender and higher BMI are associated with worse articular symptoms.

Analysis of characteristics and outcomes by growth hormone treatment duration in adult patients in the Italian cohort of the Hypopituitary Control and Complications Study (HypoCCS).

PURPOSE: To examine differences in effects according to growth hormone (GH) treatment duration in adult GH-deficient patients. METHODS: In the Italian cohort of the observational Hypopituitary Control and Complications Study, GH-treated adults with GH deficiency (GHD) were grouped by duration of treatment; ≤ 2 years (n = 451), > 2 to ≤ 6 years (n = 387) and > 6 years (n = 395). Between-group differences in demographics, medical history, physical characteristics, insulin-like growth factor-I standard deviation score (IGF-I SDS) and lipid profile at baseline, last study visit and changes from baseline to last study visit were assessed overall, for adult- and childhood-onset GHD and by gender using ANOVA for continuous variables and Chi-squared test for categorical variables. RESULTS: At baseline, treatment duration groups did not differ significantly for age, gender, body mass index, GHD onset, IGF-I SDS, lipid profile, and quality of life. Mean initial GH dose did not differ significantly according to treatment duration group in any subgroup, except female patients, with highest mean dose seen in the longest duration group. In the longest duration group for patients overall, adult-onset patients and male patients, there were significant decreases in GH dose from baseline to last visit, and in total and low-density lipoprotein (LDL)-cholesterol concentrations. IGF-I SDS increased, to a greater extent, in the longest duration group for patients overall and female patients. CONCLUSIONS: The results show that long-term GH treatment is associated with decreasing GH dose, increased IGF-I, decreased LDL-cholesterol and the presence of surrogate markers that help to give confidence in a diagnosis of GHD.

Pancreatic neuroendocrine tumors in MEN1 disease: a mono-centric longitudinal and prognostic study.

PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine neoplastic syndrome associated with a greater risk of endocrine tumor development like pancreatic neuroendocrine tumors (p-NET), with different clinical characteristics from sporadic ones. This paper aims to compare clinical, hystological and morphological aspects of p-NET in patients affected from MEN1 (MEN1+) and not-affected ones (MEN1-). METHODS: We performed a retrospective observational study. Data was collected between December 2010 and December 2015, including patients with a histological diagnosis of p-NET and radiological imaging. We compared clinical, histological, radiological, and prognostic aspects of MEN+ p-NET with MEN-1 p-NET. RESULTS: Of the 45 patients enrolled, 13 MEN1+ and 21 MEN1- cases were analyzed. Frequency of not secreting p-NETs and insulin secreting p-NETs, histopathological grades and Ki67 expression were superimposable between MEN1+ and MEN1- patients. MEN1+ pNETs are more often multicentric compared to MEN1- pNETs. Frequency of liver and nodes metastatic spread was higher in MEN1- p-NET compared to MEN1+ p-NET. Analyzing p-NET according to the disease outcome, we found that recovered and stable p-NETs in MEN1+ patients, compared to MEN1- cases, are diagnosed at lower age (p = 0.04/p = 0.002) and that are more frequently multifocal lesions (p = 0.009/p = 0.002). CONCLUSIONS: In our study pNETs in MEN1+ and pNETs in MEN1- don't significantly differ for prognosis but only for clinical features. p-NET stage disease and prognosis can be positively influenced by early diagnosis and screening in index patients' first-degree relatives.

Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment.

INTRODUCTION: Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant. SUBJECTS AND METHODS: Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. RESULTS: Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. CONCLUSION: Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism.

DIAGNOSIS OF ENDOCRINE DISEASE: Primary empty sella: a comprehensive review.

Primary empty sella (PES) is characterized by the herniation of the subarachnoid space within the sella, which is often associated with variable degrees of flattening of the pituitary gland in patients without previous pituitary pathologies. PES pathogenetic mechanisms are not well known but seem to be due to a sellar diaphragm incompetence, associated to the occurrence of upper sellar or pituitary factors, as intracranial hypertension and change of pituitary volume. As PES represents in a majority of cases, a neuroradiological findings without any clinical implication, the occurrence of endocrine, neurological and opthalmological symptoms, due to the above describes anatomical alteration, which delineates from the so called PES syndrome. Headache, irregular menses, overweight/obesity and visual disturbances compose the typical picture of PES syndrome and can be the manifestation of an intracranial hypertension, often associated with PES. Although hyperprolactinemia and growth hormone deficit represent the most common endocrine abnormalities, PES syndrome is characterized by heterogeneity both in clinical manifestation and hormonal alterations and can sometime reach severe extremes, as occurrence of papilledema, cerebrospinal fluid rhinorrhea and worsening of visual acuity. Consequently, a multidisciplinary approach, with the integration of endocrine, neurologic and ophthalmologic expertise, is strongly advocated and recommended for a properly diagnosis, management, treatment and follow-up of PES syndrome and all of the related abnormalities.

Growth hormone receptor isoforms and fracture risk in adult-onset growth hormone-deficient patients.

INTRODUCTION: Growth hormone deficiency is considered the most important factor determining skeletal fragility in hypopituitary patients. Osteoblasts and chondrocytes express growth hormone (GH) receptor. Two GH receptor isoforms (GHRi) have been identified: they differ for the presence/absence of a protein fragment encoded by exon 3 of GHR gene. Consequently, three genotypes were identified: carriers of both the full-length proteins (flfl-GHR), carriers of one full-length protein and one deleted protein (fld3-GHR) and carriers of both deleted proteins (d3d3-GHR). This polymorphism confers a higher sensitivity to endogenous GH and to recombinant human GH (rhGH); its effect on bone metabolism and skeletal fragility is unknown. The aim of this article was to investigate the role of GHRi in predicting skeletal fragility in adult-onset GHD (AO-GHD) patients. SUBJECTS AND METHODS: A cross-sectional study was conducted to investigate the association between the d3-GHR isoform and the prevalence of morphometric vertebral fractures (VFs) in AO-GHD. Ninety-three AO-GHD were enrolled. Forty-nine patients carried flfl-GHRi (52·7%), and 44 patients (47·3%) carried at least one allele of the d3-GHR isoform. Thirty-two VFs were documented. Fifty-seven patients underwent rhGH replacement therapy. RESULTS: Median age was significantly higher in fractured patients as compared to nonfractured ones; d3-carrier patients showed a lower VF risk as compared to flfl-GHRi (OR: 0·37, 95% IC: 0·24-0·55, P < 0·0001). This finding was also confirmed in AO-GHD undergoing rhGH replacement therapy. CONCLUSION: This study suggests that d3-GHR may protect AO-GHD particularly when treated with rhGH from the risk of VFs.

Clinical management of teratoma, a rare hypothalamic-pituitary neoplasia.

Intracranial teratomas are rare and comprise about 0.5 % of all intracranial tumours. Actually, a total of 15 cases of sellar-suprasellar teratoma have been described in the last 24 years. Although rare, hypothalamic-pituitary teratomas should be taken into account in the differential diagnosis of hypothalamic-pituitary region tumours. The current review focuses on the clinical and therapeutic management of pituitary region teratomas. Teratomas occur more frequently in children and young adults than in the older population and in males as compared to females. Symptoms at diagnosis are usually neurological defects, diabetes insipidus and hypopituitarism. Teratoma diagnosis can be suggested though neuroimaging findings. Magnetic resonance imaging remains the preferred modality for assessment of teratoma. Neuro-radiological findings of mixed-density mass, usually with mixed cystic and solid components or inclusions of teeth, fat and calcification can be suggestive. Tumour markers as beta-HCG and alpha-FP can be useful at teratoma diagnosis for distinguishing immature teratomas, mixed GCTs and mature teratomas with immature or malignant components. Optimal treatment for mature teratoma is neurosurgical excision. Radical excision is advocated as recurrence rate for a mature teratoma is extremely low in cases of complete resection and long-term outcome is excellent. During post-treatment follow-up, in cases of healing, according to tumour marker evaluation and contrasted MRI findings, hormone replacement therapy should be considered, also for secondary hypogonadism and GH deficit, with a more intense follow-up. However, as actually few evidence are available, safety data have to be confirmed also trough a surveillance study.

Understanding the effect of acromegaly on the human skeleton.

INTRODUCTION: Acromegaly, caused in most cases by Growth Hormone (GH)-secreting pituitary adenomas, is characterized by increased skeletal growth and enlargement of the soft tissue, because GH and its effector Insulin-like Growth factor-1 are important regulators of bone homeostasis and have a central role in the longitudinal bone growth and maintenance of bone mass. Areas covered: Despite the anabolic effect of these hormones is well known, as a result of the stimulation of bone turnover and especially of bone formation, many acromegalic patients are suffering from a form of secondary osteoporosis with increased risk of fractures. Expert commentary: In this review, we summarize the pathophysiology, diagnosis, clinical picture, disease course and management of skeletal complications of acromegaly, focusing in particular on secondary osteoporosis and fracture risk in acromegaly.

Association between l-thyroxine treatment, GH deficiency, and radiological vertebral fractures in patients with adult-onset hypopituitarism.

OBJECTIVE: In this study, we aimed at evaluating the association between radiological vertebral fractures and levo-thyroxine (l-T4) replacement doses in adult patients with hypopituitarism. DESIGN: Cross-sectional study. METHODS: We studied 74 adult hypopituitary patients (males, 43; females, 31; mean age, 57 years; and range, 23-79) with central hypothyroidism treated with l-T4 (median daily dose: 1.1  µg/kg). All patients also had severe GH deficiency (GHD) and 38 of them were replaced with recombinant GH. Vertebral fractures were assessed by a quantitative morphometric analysis performed on thoracic and lumbar spine lateral X-ray. RESULTS: Radiological vertebral fractures were found in 23 patients (31.1%) in association with untreated GHD (P=0.02), higher serum free T4 levels (P=0.03), a higher daily dose of l-T4 (P=0.005), and a longer duration of hypopituitarism (P=0.05). When GHD was treated, the prevalence of vertebral fractures was more frequent (P=0.03) in patients receiving high l-T4 doses (third tertile: >1.35  µg/kg per day) as compared with patients who were treated with lower drug doses (first tertile: <0.93  µg/kg per day). Such a difference was not observed in patients with untreated GHD who showed a higher prevalence of vertebral fractures regardless of l-T4 daily doses. Multivariate analysis showed that untreated GHD (odds ratio: 4.27, 95% CI 1.27-14.33; P=0.01) and the daily dose of l-T4 (odds ratio: 4.01, 95% CI 1.16-14.39; P=0.03) maintained a significant and independent association with vertebral fractures in patients with central hypothyroidism. CONCLUSIONS: Our data suggest for the first time that a relative overtreatment with l-T4 may influence the fracture risk in some patients with hypopituitarism.

Vertebral fractures in patients with acromegaly: a 3-year prospective study.

CONTEXT: Cross-sectional studies showed an elevated prevalence of vertebral fractures in acromegaly. However, no data are available on incident vertebral fractures in this clinical setting. OBJECTIVE: The objective of the study was to investigate the incidence and risk factors of vertebral fractures in patients with acromegaly. DESIGN: This was a 3-year prospective study. SETTING: The study was conducted at referral centers. SUBJECTS: Eighty-eight patients with acromegaly (33 females, 55 males; mean age 50 years, range 21-85 years) and 106 control subjects, matched for sex and age (43 females and 63 males, mean age 55 years, range 33-79 years), attending outpatient bone clinics participated in the study. MAIN MEASURES: Patients and control subjects were evaluated for the incidence of vertebral fractures using a quantitative morphometric approach on spine x-ray, which was performed at baseline and after 3 years of follow-up. At the same time points, patients with acromegaly were also evaluated for bone mineral density with dual-energy X-ray absorptiometry at lumbar spine and femoral neck. RESULTS: After a 3-year follow-up, 37 patients with acromegaly (42.0%) and 4 control subjects (3.8%) experienced incident vertebral fractures (P < .001). The incidence of vertebral fractures was significantly higher in patients with active disease as compared with those who had controlled/cured acromegaly at the study entry (62.5% vs 25.0%; P < .001). The risk of incident vertebral fractures was significantly associated with hypogonadism, a change in the femoral neck bone mineral density, and prevalent vertebral fractures at the study entry only in patients with controlled/cured acromegaly, whereas in patients with active disease, the fracture risk was not influenced by the above-mentioned clinical factors, but it was significantly associated with the duration of active acromegaly. CONCLUSIONS: This prospective study demonstrates a high rate of incident vertebral fractures both in patients with active and controlled acromegaly.

Double pituitary adenomas.

Double pituitary adenomas represent up to 2.6 % of pituitary adenomas in large surgical series and up to 3.3 % of patients with Cushing's disease have been found to have double or multiple pituitary adenomas. We report the case of a 60-year-old male patient whose medical history began in 2002 with erectile dysfunction; hyperprolactinemia was found and MRI showed a 6-mm area of delayed enhancement in the lateral portion of the right pituitary lobe. Treatment with cabergoline was started with normalization of prolactin levels; the following MRI, performed in 2005 and 2008, showed shrinkage of the pituitary lesion. In 2005, the patient began to manifest weight gain, hypertension, and facial plethora, but no further evaluations were done. In January 2010, the patient came to our attention and underwent multiple tests that suggested Cushing's disease. A new MRI was negative. Bilateral inferior petrosal sinus sampling showed significant pituitary-to-peripheral ratio and, in May 2010, the patient underwent exploratory pituitary surgery with evidence of a 1-2-mm white-coloured midline area compatible with pituitary adenoma that was surgically removed. Post-operatively, the patient's clinical conditions improved with onset of secondary hypoadrenalism. The histologic examination confirmed a pituitary adenoma (immunostaining was found to be positive for ACTH and negative for prolactin). We report the case of an ACTH-producing microadenoma metachronous to a prolactin secreting microadenoma although not confirmed histologically, shrunk by medical treatment. A review of data in the literature regarding double or multiple pituitary adenomas has also been done.

Male fertility and reduction in semen parameters: a single tertiary-care center experience.

Background. Infertility is both a clinical and a public problem, affecting the life of the couple, the healthcare services, and social environment. Standard semen analysis is the surrogate measure of male fertility in clinical practice. Objective. To provide information about the relationship between semen parameters and spontaneous conception. Methods. We evaluated retrospectively 453 pregnancies that occurred among 2935 infertile couples evaluated at an infertility clinic of a tertiary-care university hospital, between 2004 and 2009. Results. Normal semen analysis was present only in 158 patients; 295 subfertile patients showed alterations in at least one seminal parameter. A reduction in all seminal parameters was observed in 41 patients. Etiological causes of male infertility were identified in 314 patients. Conclusion. Our data highlights the possibility of a spontaneous conception with semen parameters below WHO reference values. Therefore, we support the importance of defining reference values on a population of fertile men. Finally, we analyzed the related ethical issues.

[Role of a mini-invasive approach in the diagnosis and treatment of tubo-peritoneal infertility as an altenative to IVF]. / Il ruolo di un approccio chirurgico mini-invasivo nello diagnosi e trattamento della sterilità tubo-peritoneale in alternativa alla FIVET.

AIM: Tubal factor infertility accounts for approximately 25-35% of cases of female infertility. Identifiable causes of tubal infertility are postinfectious tubal damage, postsurgical adhesion formation, and endometriosis-related adhesions. Aim of this study was to evaluate the results of a diagnostic/therapeutic minimally invasive approach in patients with suspect or ascertained mechanical infertility in terms of obtained pregnancies. METHODS: The study enrolled 143 patients who underwent diagnostic or operative laparoscopy, with chromopertubation, peritoneal or endometrial culture, salpingoscopy when indicated and diagnostic or operative hysteroscopy. Nine patients with submucous-intramural or multiple intramural fibroids underwent miomectomy by minilaparotomy following hysteroscopy and chromopertubation. Patients were contacted periodically by telephone to monitor the onset and outcome of pregnancy. The mean length of follow- up was 49 months (range: 11 to 118 months). RESULTS: Of the 152 patients considered in the study, 61 became pregnant (40%). Twenty-three pregnancies resulted in miscarriage, two in tubal pregnancy and one patient aborted after a diagnosis of Down syndrome. In total, 32% of the patients achieved a term pregnancy. CONCLUSION: The diagnostic/therapeutic mini-invasive approach allows women to become pregnant naturally and it is, therefore, an option for couples with ethical and religious concerns. The percentage of pregnancies is higher than after in-vitro fertilization. When efficacious, this approach allows additional spontaneous conceptions without renewed therapy and the course of pregnancy and the type of delivery will not differ from those in a normal population.

Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency.

OBJECTIVE: GH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD. DESIGN: Cross-sectional study. METHODS: Fifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23-81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach. RESULTS: Vertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 microg/24 h, range: 24-135 vs 49 microg/24 h, range: 30-96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values. CONCLUSIONS: Glucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients.

Isolated growth hormone deficiency: clinical entity?

Isolated GH deficiency (IGHD) is a distinct picture defined as a condition of GHD not associated with other pituitary hormone deficiencies, with or without an organic lesion. It can be drawn depending on the history, clinical picture, and age of onset of GHD. In childhood, 3 categories of IGHD can be identified: IGHD due to manifest organic alterations of the hypothalamo-hypophyseal system, genetically determined, and idiopathic. Adults with IGHD can also be grouped in those who had prior childhood IGHD, those who acquire IGHD secondary to structural lesions or trauma, and those with idiopathic IGHD. Diagnosis of IGHD in childhood requires clinical and auxological assessment, combined with biochemical tests, neuroradiological and genetic evaluation. In adults there is no single biological marker that offers the same diagnostic usefulness as the growth rate in children, therefore, both a clearly positive GH provocative test and an IGF-I level below the lower limit of normal should be present. Therapeutic response to GH replacement in IGHD is comparably favorable in both adult-onset and childhood-onset and is most likely to benefit those patients who have more severe GHD.

Fertility and hypopituitarism.

Fertility outcomes in hypopituitaric women are about half of those reported in isolated hypogonadotropic hypogonadism; GH deficiency (GHD) is a major contributor to poor pregnancy rate. GH seems to play a physiological role in the control of male sexual maturation and adult reproductive functions. In males, GH regulates gonadal differentiation, steroidogenesis, and gametogenesis, as well as gonadotropin secretion and responsiveness. In females, GH has a role not only as a modulator on gonadotropins, mediated by the property of IGF-I to amplify the action of both LH and FSH on granulosa, but also, through a direct GH action, on follicular maturation. GH treatment seems to play an important role in the sensibilization of ovary responsivity and uterine morpholgy in GHD patients. Since GH, directly or indirectly via IGF-I, regulates reproductive functions at all levels of the hyophyseal-pituitary-gonadal, it should always be tested as a possible cause of unexplained infertility.