Dissociation of Pubertal Development Abnormality and Gonadal Dysfunction in Childhood Cancer Survivors.

Purpose: To determine the relationship between pubertal development and postpubertal gonadal function in childhood cancer survivors. Methods: Childhood cancer survivors (≥10 years of age) who received follow-up care in a pediatric oncology group in an academic medical center during the period from January 1, 1985, to July 1, 2010 were included in this case series. Their pubertal development and gonadal function were evaluated. Results: The cohort consists of 39 males (age 10-21 years) and 35 females (age 10-29 years) with a variety of cancer diagnosis and treatments. The average age at diagnosis was ∼7.5 years. The average age at the time of the study was 16 and 16.7 years in males and females, respectively, representing a mean follow-up interval of ∼9 years. Despite the fact that 60% of survivors received cyclophosphamide equivalents and 16.2% received cranial radiation or brain tumor resection, the majority of survivors (68%) presented with both normal puberty and normal gonadal functions at the time of follow-up. In 27% of survivors, puberty development did not predict gonadal function in early adulthood: 20% of survivors had normal puberty, but abnormal gonadal function; 7% of survivors had abnormal puberty, but gonadal function remained normal as young adults. Conclusions: Most childhood cancer survivors had normal puberty and gonadal function despite a variety of cancer treatment modalities. However, normal puberty did not predict normal gonadal function later in life in many survivors. Therefore, close follow-up with gonadal function in adolescent and early adulthood years is essential.

Protección gonadal de pacientes con malignidades hematológicas durante la quimioterapia: uso del acetato de leuprolide / Gonadal protection in patients with hematological malignancies during chemotherapy: use of leuprolide acetate

Demostrar el papel de los análogos agonistas de hormona liberadora de gonadotropinas en la reserva ovárica de pacientes hemato-oncológicas del Servicio de Hematología del Hospital Universitario de Caracas durante el año 2010, en tratamiento con regímenes de quimioterapia. Estudio de la variable reserva ovárica, mediante la cuantificación periódica de: ritmo menstrual, concentraciones de FSH, volumen ovárico, número de folículos antrales e incidencia de embarazo. Se administró acetato de leuprolide (11,25 mg) cada 3 meses vía intramuscular; se realizaron mediciones trimestrales de las concentraciones de FSH y se practicaron ecosonogramas pélvico o transvaginal cada 6 meses. Posterior al cumplimiento de los análogos de la hormona liberadora de gonadotropinas, se observó la aparición de amenorrea en las pacientes. Las concentraciones de FSH se mantuvieron estables, y siguieron la misma distribución (prueba de Levene p 0,2466) los volúmenes ováricos y el número de folículos antrales se mantienen estables, se rechaza la hipótesis de normalidad del grupo de diferencias al 5 por ciento de significancia. No se registraron embarazos. La reserva ovárica se preserva durante el tratamiento continuo con análogos

To demonstrate the role gonadotropin releasing hormone analogues in ovarian reserve in hematology patients in the hematology service at the Hospital Universitario de Caracas in 2010, treated with chemotherapy regimens. Study of ovarian reserve variable by periodic quantification of: menstrual rhythm, concentrations of FSH, ovarian volume, antral follicle number and incidence of pregnancy. Leuprolide acetate was administered (11.25 mg) intramuscularly every 3 months, were measured quarterly and FSH concentrations were performed pelvic or transvaginal ecosonograms every 6 months. After aGnRH administration, we observed the occurrence of amenorrhea in patients. FSH concentrations were stable, and followed the same distribution (Levene test p 0.2466) ovarian volume and antral follicle numbers were stable, we reject the hypothesis of normality of group differences at 5 percent significance. There were no pregnancies. Ovarian reserve is preserved during continuous treatment with analogs

Distribution of causes of infertility in patients attending primary fertility clinics in Israel.

BACKGROUND: Infertility is one of the most prevalent health disorders in young adults. OBJECTIVES: To study the distribution of causes of infertility in couples referred to primary infertility clinics in Israel. METHODS: Data for a 9 year period were derived from two clinics of major women's hospitals run by the country's largest health insurance fund. All patients were treated by one physician. Laparoscopy was not performed to rule out endometriosis. RESULTS: Of the 2515 couples identified, 1991 (79.2%) had a definitive diagnosis following complete workup (including hysterosalpingography). Mean age was 29.6 +/- 6.0 years; mean duration of infertility was 1.7 +/- 1.8 years. Primary infertility accounted for 65% of cases. Causes of infertility were male factor (45%), oligo-ovulation disorders (37%), and tubal damage (18%). Infertility factors were identified in the woman alone in 30.6% of cases and the man alone in 29.2%. Two combined infertility factors were found in 18% of patients, and three combined factors in 0.5%. The rate of unexplained infertility (which probably includes non-tubal endometriosis) was 20.7%. CONCLUSIONS: As male factor accounts for almost half of all cases of infertility in couples, sperm analysis is mandatory before any treatment.

Gonadal dysfunction in male cancer patients before cytotoxic treatment.

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

[Peripheral precocious puberty]. / Przedwczesne dojrzewanie plciowe pochodzenia obwodowego.

The term precocious puberty is defined as the appearance of secondary sex characteristics before the age of 8 in girls and 9 in boys. There are two major forms of premature sexual maturation: gonadotrophin-dependent (central, or 'true' precocious puberty) and gonadotrophin- independent precocious puberty. The latter, also called peripheral precocious puberty, is characterized by increased production of sex steroids, causing the typical physical changes of puberty, in the absence of reactivation of the hypothalamic-pituitary axis. It may result from several different disorders including testotoxicosis, McCune-Albright syndrome, congenital adrenal hyperplasia, adrenal and gonadal tumours. The accumulation of knowledge regarding the pathogenesis of symptoms and the development of safe, effective treatment modalities have led to earlier intervention in patients with peripheral precocious puberty to prevent the decline in their psychosocial wellbeing, adult height and quality of life. We review the ethiopathogenesis, clinical picture, diagnosis and treatment of various disorders causing peripheral precocious puberty and provide the reader with current recommendations concerning approach to the patient with this health problem.

A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse.

Smallie (slie), a spontaneous, autosomal-recessive mutation causes dwarfing and infertility in mice. The purpose of this study was to determine and characterize the underlying molecular genetic basis for its phenotype. The slie locus was mapped to chromosome 1, and fine-structure mapping narrowed the slie allele within 2 Mb between genetic markers D1Mit36 and Mpz. To pinpoint the underlying mutation quantitative real-time PCR was used to measure the relative expression levels for the genes residing within this region. Expression of one gene, Ddr2, which encodes discoidin domain receptor 2 (DDR2), was absent in slie homozygote mice. Genomic sequencing analysis detected a 150-kb deletion that extended into the Ddr2 gene transcript. Detailed phenotype analysis revealed that gonadal dysregulation underlies infertility in slie mice because all females were anovulatory and most adult males lacked spermatogenesis. The pituitary gland of prepubertal slie mice was smaller than in wild-type mice. The basal levels and gene expression for pituitary and hypothalamic hormones, and gene expression for hypothalamic-releasing hormones, were not significantly different between slie and wild-type mice. Circulating levels of IGF-1 did not differ in slie mice despite lower Igf-1 mRNA expression in the liver. After exogenous gonadotropin administration, the levels of secreted steroid hormones in both male and female adult slie mice were blunted compared to adult wild-type, but was similar to prepubertal wild-type mice. Taken together, our results indicate that the absence of DDR2 leads to growth retardation and gonadal dysfunction due to peripheral defects in hormonal-responsive pathways in slie mice.

Involvement of Pitx2, a homeodomain transcription factor, in hypothyroidism associated reproductive disorders.

Hypothyroid-associated reproductive disorders have now become a striking phenomenon worldwide but the molecular mechanism behind these disorders is not fully known. Pitx2 gene encodes homeodomain transcription factor, which regulates Plod2 gene in brain tissue, transactivates gonadotropin genes in pituitary and plays a substantial role in cell growth and proliferation in different tissues. Pitx2 binds to Plod2 promoter and activates this gene in rat ovary. In this report, we show that Pitx2's expression is markedly reduced in hypothyroid ovary as well as in ovarian granulosa cells, which is recovered with T(3)-supplementation both in vitro and in vivo conditions. Reduced Pitx2 expression could decrease Plod2 expression and hence facilitate ovarian ECM degradation. We have also observed similar pattern of expression of Pitx1 and -3 in hypothyroid and T(3)-supplemented ovaries. The temporal expression of Pitx2 across the estrous cycle shows that it is expressed through all the 4 phases of the cycle and reaches its maximum in the proestrus phase suggesting its possible role in ovulation followed by luteinization. The present study reveals that the reduced Pitx2 expression in hypothyroid ovary could lead to ovarian dysfunction by modulating the Pitx2-Plod2 interaction, further study will be necessary to unravel the complete regulatory mechanism of Pitx2 in ovarian function.

Absence of mutation in the follicle-stimulating hormone receptor gene in severe primary hypothyroidism associated with gonadal hyperstimulation.

BACKGROUND: Severe hypothyroidism can cause a distinct form of precocious puberty in children, characterized by delayed skeletal maturation, predominance of FSH-mediated effects over LH-mediated function, and reversal of sexual precocity upon thyroid hormone replacement. The etiology of this unusual form of precocious puberty in children remains poorly understood. Recently, three mutations of the FSH receptor gene have been identified in women with spontaneous ovarian hyperstimulation during pregnancy. All three mutated receptors displayed abnormally high sensitivity to hCG which caused gonadal stimulation. Two of these mutations displayed concomitant increase in sensitivity of the mutated receptor to TSH. In this report, we describe four children with primary hypothyroidism and gonadal hyperstimulation. The aim of this study was to determine whether these patients' gonadal hyperstimulation is due to a mutation in their FSH receptor gene. METHODS: DNA was extracted from all four patients with primary hypothyroidism and gonadal stimulation. The entire FSH receptor gene was sequenced and analyzed. RESULTS: Direct sequencing of these patients' FSH receptor gene did not demonstrate any mutation, proving that the cause of gonadal stimulation in these patients is not due to the increased sensitivity or constitutive activation of a mutated FSH receptor. CONCLUSIONS: The elevated TSH in these patients and prior demonstration of the in vitro ability of TSH to bind to the FSH receptor lead us to hypothesize that the gonadal stimulation in these patients is TSH-mediated. The fact that gonadal stimulation is not seen in all patients with severe hypothyroidism raises the question as to whether polymorphisms of the FSH receptor gene and/or possible changes in the TSH molecular structure may contribute to the TSH-mediated activation of the FSH receptor.

Aportación del laboratorio clínico en las disfunciones gonadales / No disponible

No disponible

Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's syndrome.

Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushing's syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushing's disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing's syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14-79 years), 12 patients with ACS (4 men, 8 women, aged 32-79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm2), T-score and Z-score referred to the manufacturer's normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76+/-0.03 g/cm2; T-score, -2.78+/-0.28; Z-score, -2.25+/-0.30) while patients with CD (BMD, 0.87+/-0.02 g/cm2; T-score, -1.74+/-0.24; Z-score, -0.99+/-0.32) showed DXA values between the first group and controls (BMD, 1.02+/-0.02 g/cm2; T-score, -0.35+/-0.19; Z-score, 0.33+/-0.16). The difference in BMD at the spine remained statistically significant ( P=0.04) after adjustment for the non-significant differences in age, UFC and fat mass between CD and ACS. Conversely, femoral bone densitometric parameters were not significantly different between patients with ACS and CD, even if they were more reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S levels, expressed as standard score ( Z-score) values referred to a group of 180 healthy subjects stratified by sex and different age groups (<40 years, between 40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age on such hormone (ACS DHEA-S Z-score -0.88+/-1.4 versus CD DHEA-S Z-score 2.25+/-2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar BMD ( r=0.41, P=0.02) and femoral BMD ( r=0.43, P=0.01). DHEA-S Z-score values were also significantly correlated with osteocalcin levels ( r=0.45, P=0.01). Our data suggest that bone loss is greater in ACS than in CD. A plausible explanation comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic actions on bone. However, this hypothesis needs to be confirmed in large, prospective series of patients with Cushing's syndrome of different etiology.

Obesity and gonadal function of women.

Excessive visceral adiposity is associated with metabolic and reproductive abnormalities. Adipose tissue is an active endocrine gland and participates in multiple mechanisms in the reproductive function of women. The nature of the complex interaction of obesity with the female reproductive function remains a challenge. Several links have been implicated in the gonadal dysfunction of obese women, like insulin resistance and hyperinsulinemia, via which ovarian androgen production is stimulated resulting in hyperandrogenemia, increased peripheral aromatization of androgens to estrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased GH and IGFBPs, increased leptin levels and altered neuroregulation of the hypothalamic-pituitary-gonadal axis. The impact of obesity in these mechanisms and their influence on female reproductive function are discussed in this article.

Primary amenorrhoea: analysis of 48 cases.

The clinical analysis of 48 patients of primary amenorrhoea seen at All India Institute of Medical Sciences, New Delhi for a period of 3 years, was performed. Twenty-six patients (54.2%) had muellerian anomalies, 11 (22.9%) had hypogonadotropic hypogonadism, 8 (16.6%) had hypergonadotropic hypogonadism and 3 (6.3%) had genital tuberculosis. The study highlights the role of transabdominal sonography in the work up of these cases. It suggests the reproductive potential of these cases by visualising the genital organs and makes laparoscopy and intravenous pyelography obsolete and selects the cases who deserve to be further investigated.

Bone mineral density in young adult survivors of childhood cancer.

PURPOSE: Childhood cancer and its treatment can affect normal bone accretion. In this study, bone mineral density (BMD) in young adult survivors of childhood cancer is assessed to determine what cancer-related factors, patient characteristics, or treatment-related complications correlate with reductions in BMD. PATIENTS AND METHODS: The study population consisted of 40 (24 women) long-term survivors of childhood cancer treated at the Memorial Sloan-Kettering Cancer Center for a solid tumor (n = 16), lymphoma (n = 14), or acute leukemia (n = 10) at a mean age of 12.7 +/- 0.96 years and evaluated at a mean age of 25.8 +/- 0.7 years. Dual energy X-ray absorptiometry was used to determine BMD of the lumbar spine, femoral neck, and total body and single photon absorptiometry was used to determine BMD of the distal radius. RESULTS: The mean BMD standard deviation score (SDS) for the patients was significantly reduced compared to controls at the distal radius (-1.57 +/- 0.18, p = 0.0001), femoral neck (-0.68 +/- 0.20, p = 0.00014), and total body (-0.33 +/- 0.15, p = 0.03) but not at the lumbar spine (-0.22 +/- 0.22, p = 0.33). Univariate analysis revealed that gonadal dysfunction (i.e., estrogen or testosterone insufficiency) (p = 0.018) was the only variable that correlated with a reduced BMD. CONCLUSION: Young adult survivors of childhood cancer have reduced BMD. Because age at study coincides with the normal age of attainment of peak bone mass and peak bone mass is a major determinant of BMD later in life, many of these patients are at increased risk for osteoporosis and fractures.