Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics.

BACKGROUND: Survival rates among childhood cancer survivors (CCS) have enormously increased in the last 40 years. However, this improvement has been achieved at the expense of serious late effects that frequently involve the endocrine system. AIM: To evaluate the cumulative incidence of endocrine diseases in a cohort of long-term CCS. MATERIALS AND METHODS: We analyzed the clinical data of 310 adults, followed for a median time of 16.0 years after the first cancer diagnosis. The monitoring protocols applied to each patient were personalized on the basis of cancer diagnosis and previous treatments, according to the Children's Oncology Group guidelines. RESULTS: The cumulative incidence of endocrine late effects steadily increased over time. At the last follow-up visit available, 48.46% of females and 62.78% of males were affected by at least one endocrine disease. The most common disorders were gonadal dysfunction, primary hypothyroidism, and GH deficiency (GHD). The main risk factors for endocrine disease were male sex (hazard ratio (HR)=1.45, 95% confidence interval (95% CI) 1.05-1.99), radiotherapy (HR=1.91, 95% CI 1.28-2.84), hematopoietic stem cells transplantation (HR=3.11, 95% CI 2.23-4.34), and older age at cancer diagnosis (HR=1.89, 95% CI 1.25-2.85). Male sex was associated with a higher risk of gonadal disorders, whereas radiotherapy specifically increased the risk of GHD and thyroid dysfunction. CONCLUSIONS: Endocrine disorders among CCS have a high prevalence and increase over time. Thus, endocrinologists need to cope with an increasing demand for health care in a field that is still little developed and that, in perspective, could also be extended to some selected types of adult cancer survivors.

Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I.

BACKGROUND: GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. SUBJECTS: We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19-32). METHODS: All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2-14.2) up to the final height. RESULTS: Final height was very disappointing (≤ -5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow- up was 8.3 yr with the longest span of 17.2 yr. CONCLUSION: We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

Premature thelarche and environmental pollutants.

Premature thelarche is usually considered a benign condition that disappears without influencing statural growth nor the timing of puberty. It is generally held a phenomenon of endogenous origin but exposure to oestrogenic pollutants must also be taken into consideration since environmental and epidemiological studies have shown that humans and some animal species are adversely affected by environmental chemical substances that interfere with the endocrine system and are known as endocrine disrupters. Environmental pollutants acting as endocrine disrupters include oestrogens and oestrogen-like products that are universally present in the form of hormones used in stockbreeding, chemicals employed in industry and agriculture, and substances naturally contained in plants and cereals. So far few studies have examined the influence of exogenous oestrogenic or oestrogen-like substances in premature thelarche, and there have been equally few reports of the occurrence of many cases in a circumscribed environment and a limited period of time. Since many agents are in a position to make a contribution to the biological mechanisms underlying thelarche, there is no easy way of determining the role of a given substance in the onset of the clinical picture. Furthermore, it must not be forgotten that both the metabolic clearance rate and the serum levels of oestradiol in healthy prepubertal children are still uncertain and even very low doses of exogenous steroid hormones might thus have significant biological effects. Aim of the work is to underline the importance of the exposure to oestrogenic environmental pollutants as possible cause of premature thelarche.

Reduction of the pituitary GH releasable pool in short children with GH neurosecretory dysfunction.

OBJECTIVES: The classical 'GH neurosecretory dysfunction' (GHNSD) refers to slowly growing children with normal GH responses to classical provocative tests but impaired spontaneous GH secretion over 24 h frequently leading to low IGF-I levels. Thus it has been assumed that these subjects have insufficiency of spontaneous GH secretion due to neuroendocrine abnormalities in spite of a normal releasable pool of GH. However, classical provocative tests do not reliably assess the maximal somatotroph capacity; thus it is still unclear if the GH pool is really preserved or not. GHRH + arginine test is more potent than the classical tests and evaluates the maximal secretory capacity of somatotroph cells. The GH response to this stimulus is reproducible and also independent of age and puberty. DESIGN AND PATIENTS: We studied the GH response to GHRH (1 microgram/kg iv) + arginine (ARG, 0.5 g/kg iv) in 19 short children with GHNSD (14 boys and 5 girls, age: 12.1 +/- 0.7 years, pubertal stages I-III, HV-SDS between -1.6 and -4.9; GH peak > 10 micrograms/l after classical stimuli but mean GH concentration (mGHc) < 3 micrograms/l). The results in GHNSD were compared with those in 38 short children with idiopathic or organic severe GHD (GHD, 29 boys and 9 girls, age: 11.2 +/- 0.6 years, pubertal stages I-III, HV-SDS between -1.8 and -4.4; GH peak < 10 micrograms/l after 2 classical provocative tests) and in 83 children with normal or familial short stature (NC, 59 boys and 24 girls, age: 11.5 +/- 0.3 years., pubertal stages I-III; HV-SDS > 25th centile, normal IGF-I levels). RESULTS: Mean IGF-I levels in GHNSD (121.9 +/- 20.3 micrograms/l) were lower (P < 0.001) than those in NC (270.3 +/- 13.8 micrograms/l) but higher (P < 0.001) than those in GHD (72.0 +/- 4.0 micrograms/l). The mean GH concentration (mGHc) in GHNSD (2.1 +/- 0.1 micrograms/l) was lower (P < 0.01) than that in NC (4.9 +/- 0.5 micrograms/l) but higher (P < 0.01) than that in GHD (1.5 +/- 0.2 micrograms/l). On the other hand, the mean peak GH response to GHRH + ARG in GHNSD (43.7 +/- 3.7 micrograms/l) was markedly higher (P < 0.001) than that in GHD (8.2 +/- 0.9 micrograms/l) but significantly lower (P < 0.01) than that in NC (60. 4 +/- 2.7 micrograms/l). All GHD patients had peak GH responses to GHRH + ARG below the 3rd centile limit of normality (20 micrograms/l), while all GHNSD patients had peak GH responses within the normal range. No significant correlation was found between GH peak after GHRH + ARG, mGHc and IGF-I levels in each group. CONCLUSION: Our study demonstrates that short children with 'GH neurosecretory dysfunction' show reduction in the GH releasable pool evaluated by the provocative and potent GHRH + arginine test. However, the peak GH response to a single GHRH + arginine test in GH neurosecretory dysfunction is always within the normal range indicating that this test as well as classical stimuli does not distinguish normal subjects from GH neurosecretory dysfunction.

Bone density and metabolism in thalassaemia.

Twenty-seven thalassaemic patients (13 F, 14 M, aged 8.1-14.9 yr), regularly transfused and chelated with desferrioxamine (30-40 mg/kg/day) were studied. Every patient was submitted to auxological evaluations, dual X-ray absorptiometry to measure bone mineral density (BMD), and to the determination of bone metabolic markers of osteoclastic activity (total urinary hydroxylysylpyridinoline crosslinks, carboxyterminal pyridinoline crosslinked telopeptide of type I collagen [ICTP]) and of osteoblastic activity (bone Gla protein [BGP] and carboxyterminal propeptide of type I procollagen [PIPC]). The evaluations were repeated after 1 year, during which 13 patients continued desferrioxamine chelation while 14 underwent deferiprone chelation (75 mg/kg/day in 3 doses). The data demonstrate widespread bone alterations consisting of osteoporosis, growth failure and bone age delay. Lumber spine (L2-L4) BMD areal values (Z score) inversely correlated with age, as did height SDS of both male and female patients, indicating osteoporosis progressing with age in parallel with growth insufficiency. No clear-cut alterations in bone mineral metabolism were found in basal state and after 1 year. Extensive MR imaging studies are needed to define the contribution of residual bone marrow hyperplasia to thalassaemic osteopathy suggested by subtle radiological signs as enlargement of bone marrow cavities with thinning of the cortical bone and abnormalities of the trabecules of spongy bone.

Early hormonal and surgical treatment of cryptorchidism.

PURPOSE: We investigated the efficacy of early gonadotropin treatment of cryptorchidism for promoting testicular descent and ameliorating testicular histology. MATERIALS AND METHODS: We treated 319 cryptorchid testes in 281 boys 4 months to 3 years old with luteinizing hormone-releasing hormone and human chorionic gonadotropin sequential therapy. Surgery was done on the 207 testes that did not respond to medical treatment. Microscopic biopsies were performed in 134 of these 207 testes. Histological findings were compared to those of 30 cryptorchid testes in boys younger than 1 year who underwent surgery without previous hormonal treatment. RESULTS: Combined luteinizing hormone-releasing hormone and human chorionic gonadotropin treatment induced scrotal descent of a percentage of cryptorchid testes depending on clinical position. Therapeutic success was greater when testes were in a lower position and results were not age dependent. Hormonal treatment of cryptorchidism during the first year of life stimulated spermatogonia maturation. CONCLUSIONS: When administered at the end of age 6 months, hormonal treatment can be considered an effective and timely substitution for gonadotropin and testosterone insufficiency in cryptorchid infants. Therefore, we recommend this therapeutic procedure combined with surgery in the first year of life.

Lower lip pits and complete idiopathic precocious puberty in a patient with Kabuki make-up (Niikawa-Kuroki) syndrome.

We report on a 13 1/2-year-old patient with Kabuki make-up syndrome and complete idiopathic precocious puberty manifested at 7 1/2 years. In addition to the other specific clinical signs, she showed hypodontia and lower lip pits, as typically seen in the Van der Woude syndrome. The significance of lower lip pits in the Kabuki make-up syndrome is discussed.

Combined therapy with LHRH and HCG in cryptorchid infants.

In 238 boys with cryptorchidism, between the ages of 4 and 48 months, luteinizing hormone releasing hormone (LHRH) was administered as nasal spray 1.2 mg/day for 4 weeks. The nonresponders received human chorionic gonadotropin (HCG) 500 I.U. i.m. three times a week for 3 weeks. With the combined treatment 37.8% of testes descended into the scrotum. Testicular descent occurred more often in patients whose testes were located in a lower position. Histological findings indicated a reduction in the number and maturation of germ cells. A clear improvement of germ cells trophism was observed in boys hormonally treated and operated on before the 12th month of life. Early administered combined treatment with LHRH and HCG can be considered as a substitution of the gonadotropins insufficiency manifested by most cryptorchid infants in the first months of life.

[A neonatal ovarian cyst associated with transient endocrine anomalies]. / Cisti ovarica neonatale associata ad anomalie endocrine transitorie.

The authors present a case of enormous neonatal ovarian cyst associated with ipoglicemia, ipotiroidism and ipocalcemia. This baby presents also stenosis of the pulmonary artery and congenital dysplasia of the hip. The case is interesting because this type of association is unusual and has not been described before.

[The medical treatment of cryptorchism in early childhood]. / Trattamento medico del criptorchidismo nella prima infanzia.

To evaluate the efficacy of early treatment of cryptorchidism, we studied 154 children, 133 with unilateral and 21 bilateral cryptorchidism, between the ages of 6 months and 6 years. Only fullterm newborns without other pathological signs were selected for treatment which was undertaken only after the sixth month of life, when the time of late spontaneous testicular descent has been passed. By clinical evaluation, cryptorchid testes were classified as not palpable, inguinal and prescrotal. Patients were treated by LHRH nasal spray 200 mcg in each nostril 3 times a day (total 1.2 mg/day) for 4 weeks. In the case of failure, HCG (500 I.U. im. 3 times a week for 3 weeks) was further administered. We considered as therapeutic success testicular descent into the lower half of the scrotum. By LHRH treatment 36 testes (20.5%) reached the scrotum, when HCG was added in unsuccessful cases 47 other gonads (26.8%) descended. Total descent rate by LHRH + HCG was 47.3% (table 1). Uni- and bilateral forms of cryptorchidism responded to therapy without any significant difference (table 2). Abdominal testes failed to descend into the scrotum, 28.7% of inguinal testes and 81.3% prescrotal testes descended. Scrotal descent was dependent only by position of cryptorchid testes and not by age of patients (table 3). Higher descent rates obtained at older ages were due to higher incidence of milder forms of cryptorchidism (table 3). Side effects of combined therapy were light. In our experience, medical treatment by LHRH + HCG started after the first 6 months of life causes testicular descent in about one half of testes; it can place into the scrotum gonads with better fertility prognosis.

A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: combined administration of pyridostigmine and growth hormone-releasing hormone.

The diagnosis of growth hormone (GH) deficiency (GHD) is currently based on failure to increase plasma GH levels to an arbitrary cutoff point of 7 or 10 micrograms/l in response to two provocative stimuli. False negative responses to these tests, however, frequently occur thus reducing their diagnostic reliability. The aim of this study was to assess a combination of pyridostigmine (PD) and GH-releasing hormone (GHRH) (60 mg oral PD 60 min before 1 microgram/Kg GHRH iv) as a reliable test probing pituitary somatotropic function. In fact PD, an acetylcholinesterase inhibitor, strikingly potentiates GH response to GHRH likely by inhibiting somatostatin release. The combination PD + GHRH was tested in normal children and adolescents (NS, n = 27) and in a large group of short children classified as having familial short stature (FSS, n = 24), constitutional growth delay (CGD, n = 34) and GH deficiency (organic, oGHD, n = 6; idiopathic, iGHD, n = 10). In all groups results obtained by PD + GHRH were compared with those obtained by testing with GHRH, clonidine (CLON) and PD alone and by studying spontaneous nocturnal GH secretion over 8 hours. Assuming 7 micrograms/l as minimum normal GH peak, a positive response occurred in only 18/24, 11/12 and 12/13 NS for GHRH, CLON, and PD, respectively. In contrast even assuming a minimum normal GH peak as high as 20 micrograms/l, PD + GHRH induced a positive response in 27/27 NS all having a nocturnal GH mean concentration (MC) greater than or equal to 3 micrograms/l. Therefore PD + GHRH test gave no false negative responses and this was true not only in NS but even in all FSS and CGD having a GH MC greater than or equal to 3 micrograms/l. On the other hand, PD + GHRH induced a negative GH response in all oGHD and in 8/10 iGHD patients. In the remaining two iGHD patients, PD + GHRH demonstrated a normal pituitary GH reserve in spite of a GH MC less than 3 micrograms/l and low IGF-I level, thus pointing to a hypothalamic pathogenesis for the GHD. Considering FSS and CGD children having a GH MC less than 3 micrograms/l, PD + GHRH showed a primary pituitary GH deficiency in 3/12 CGD with low plasma IGF-I levels. In conclusion, in slowly growing children PD + GHRH test is the most reliable provocative test for the diagnosis of primary pituitary GH deficiency being capable to discriminate between an unequivocally normal and impaired somatotropic function.(ABSTRACT TRUNCATED AT 400 WORDS)