Disorders of Pubertal Onset.

Evaluation of the child with abnormal pubertal development can be challenging for the primary care provider. Understanding the factors associated with timing of pubertal onset and the normal sequence of pubertal changes is useful in evaluation of children with puberty disorders. A thorough workup includes assessment of growth rate, Tanner staging, and rate of pubertal progression, in addition to an extensive history and physical examination to identify signs and symptoms of disorders associated with abnormal pubertal timing. Initial diagnostic studies will most often include a bone age, levels of gonadotropins, and levels of estradiol (for girls) or testosterone (for boys).

Anti-Müllerian hormone in dogs and cats reproduction.

The anti-Müllerian hormone (AMH) is a glycoprotein secreted by Sertoli cells in males and granulosa cells in females. It has first been determined in blood serum of dogs and cats by Place et al. in 2011 with the use of a human-based ELISA test. Meanwhile, different immunoassays have been validated for AMH determination in animals and a variety of studies have demonstrated the clinical significance of AMH. This review summarizes the current knowledge about AMH in dogs and cats and describes future opportunities for its diagnostic use.

Salivary Testosterone during the Minipuberty of Infancy
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BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 ± 78 ng/dL) while salivary T was low (7.7 ± 4 pg/mL or 0.45 ± 0.20%). In contrast, salivary T in the adolescents was much higher (41 ± 18 pg/mL or 1.3 ± 0.36%) in relation to their total serum T (323 ± 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance.
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Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure.

BACKGROUND: Primary gonadal failure is characterised by primary amenorrhoea or early menopause in females, and oligospermia or azoospermia in males. Variants of the minichromosome maintenance complex component 8 gene (MCM8) have recently been shown to be significantly associated with women's menopausal age in genome-wide association studies. Furthermore, MCM8-knockout mice are sterile. The objective of this study was to elucidate the genetic aetiology of gonadal failure in two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male. METHODS AND RESULTS: Using whole exome sequencing, we identified two novel homozygous mutations in the MCM8 gene: a splice (c.1954-1G>A) and a frameshift (c.1469-1470insTA). In each consanguineous family the mutation segregated with the disease and both mutations were absent in 100 ethnically matched controls. The splice mutation led to lack of the wild-type transcript and three different aberrant transcripts predicted to result in either truncated or significantly shorter proteins. Quantitative analysis of the aberrantly spliced transcripts showed a significant decrease in total MCM8 message in affected homozygotes for the mutation, and an intermediate decrease in heterozygous family members. Chromosomal breakage following exposure to mitomcyin C was significantly increased in cells from homozygous individuals for c.1954-1G>A, as well as c.1469-1470insTA. CONCLUSIONS: MCM8, a component of the pre-replication complex, is crucial for gonadal development and maintenance in humans-both males and females. These findings provide new insights into the genetic disorders of infertility and premature menopause in women.

Menstrual and Gonadal Function Alterations in Women with Systemic Lupus Erythematosus.

PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disorder and may affect the reproductive health status of the women. Objective is to analyze the types, incidence of various menstrual disturbances in these women, to identify risk factors and to assess the gonadal function. METHODS: The prospective cohort study was conducted in the SLE clinic of the Rheumatology Department of IPGMEandR, Kolkata from April 2010 to April 2011. Out of 152 females attending clinic, 110 patients fulfilling criteria were included in the study. RESULTS: Mean age of the study population was 27.25±3.4 years. Sixty six cases had menstrual abnormalities (12.72% amenorrhea, 44.45% oligomenorrhea, 2.7% premature ovarian failure, 10.9% menorrhogia). When comparative analysis of demographic, hormonal, ovarian Doppler and therapeutic variables of normal and abnormal cycles was carried out, following parameters were significantly more related to patients with abnormal cycle ; SLEDAI score (12.48±5.53 vs 8.69±4.9; p=0.00), disease duration (6.46±3.08 vs 4.3±1.36; p< 0.05), TSH (7.73±8.64 vs 3.07±2.06; p=0.00.), LH (6.55±4.38 vs 4.56±3.29; p=0.02), a high normal prolactin (12.57±7.75 vs 8.73±3.07; p=0.02), peak systolic velocity (6.53±2.17 vs 9.12±2.1; p=0.00), end-diastolic volume (4.21±2.9 vs 9.35±2.32; p=0.00) and cumulative dose of steroid (24.02±41.44 vs 9.32±9.96; p=0.01).Cyclophosphamide with cumulative dose ≥10 gm was related to amenorrhea and affected gonadal function. Gonadal insufficiency was evident in 33.63% and 2.72% had ovarian failure. CONCLUSIONS: Reduced menstruation is a major health concern in women with SLE as it is frequent and can result in depressed and failed gonadal function later. Doppler study of ovaries is a novel way of depiction of gonadal status in these women. Certain risk factors and revolving treatment part can be preventable.

Increased risk of gonadal malignancy and prophylactic gonadectomy: a study of 102 phenotypic female patients with Y chromosome or Y-derived sequences.

STUDY QUESTION: What is the optimal protocol of management for phenotypic female patients with Y chromosome or Y-derived sequences, in particular for adult patients? SUMMARY ANSWER: Immediate gonadectomy, long-term hormone therapy and psychological care are suggested to be the optimal management for older phenotypic female patients with Y chromosome or Y-derived sequences. WHAT IS KNOWN ALREADY: Phenotypic female patients with Y chromosome or Y-derived sequences are at increasing risk of developing gonadal tumors with age. Early diagnosis and safe guidelines of management for these patients are needed. STUDY DESIGN, SIZE, DURATION: One hundred and two phenotypic women with Y chromosome or Y-derived sequences were included in a straightforward, retrospective-observational study conducted over a period of 26 years from January 1985 to November 2010. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Patients aged 16-34 years presenting to our Academic Department of Gynecology with symptoms of disorders of sex development were subjected to history taking, hormonal evaluation, conventional cytogenetic analysis, PCR, histopathology and immunohistochemistry. Features of the gonads were examined and the outcome of prophylactic gonadectomy evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Among the patients recruited in our study, 48 patients (47.1%) were diagnosed with complete/partial androgen insensitivity syndrome (CAIS/PAIS) (46XY), 33 cases (32.4%) with gonadal dysgenesis (46XY) and the remaining subjects (20.1%) with mixed gonadal dysgenesis (with sex chromosome structural abnormalities). The total incidence of malignancy was 17.6%. Seventeen patients (16.7%) had gonadoblastoma, while one patient (1.0%) with gonadal dysgenesis had dysgerminoma. Gonadoblastoma were observed in 2/21 patients with sex chromosome structural abnormalities (9.5%), 3/33 patients with gonadal dysgenesis (9.1%), 9/30 patients with CAIS (30.0%) and 3/18 patients with PAIS (16.7%). LIMITATIONS, REASONS FOR CAUTION: Selection bias in this cohort study may affect data interpretation due to the low incidence of disorders of sex development in the general population. WIDER IMPLICATIONS OF THE FINDINGS: The risk for malignant transformation may occur in early life and highly increase with age in patients with Y chromosome or Y-derived sequences. Optimal timing of gonadectomy should be decided by multiple factors including the subgroup of disorder, age and degree of patient's maturity. In addition, gonadal biopsy is suggested when the disease is diagnosed and any evidence of premalignancy warranties gonadectomy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Scientific Research Project (2013CB967404), Natural Science Funds of Zhejiang Province (Y13H04005), Zhejiang Qianjiang talent plan (2013R10027), the Fundamental Research Funds for the Central Universities and Key Projects in the National Science & Technology Pillar Program during the Eleventh Five-Year Plan Period (2012BAI32B04). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER None.

High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: a single center retrospective study.

PURPOSE: Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. METHODS: Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. RESULTS: 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0-19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P=0.047). CONCLUSIONS: Based upon the patient's risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance gonadique et fertilité

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.

Update on adolescent gynecology.

Adolescent gynecology is an important part of clinical care of adolescent females. This discussion provides a basic review of current issues in adolescent gynecology, including consideration of current pubertal concepts with attention also given to delayed and precocious puberty. Causes of breast masses are reviewed, including discussion of the ANDI classification. It is recommended that physicians provide sexuality education to their adolescent patients, in addition to the community, to reduce the high rates of unintended adolescent pregnancy and STIs in teens that continue in the United States. Finally, attention is provided to ovarian masses and their management. Adolescent medicine physicians may have to work with a variety of specialists in their care of adolescents and the many gynecologic conditions that may arise.

Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications.

PURPOSE: As more young female patients with cancer survive their primary disease, concerns about reproductive health related to primary therapy gain relevance. Cancer therapy can often affect reproductive organs, leading to impaired pubertal development, hormonal regulation, fertility, and sexual function, affecting quality of life. METHODS: The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) are evidence-based recommendations for screening and management of late effects of therapeutic exposures. The guidelines are updated every 2 years by a multidisciplinary panel based on current literature review and expert consensus. RESULTS: This review summarizes the current task force recommendations for the assessment and management of female reproductive complications after treatment for childhood, adolescent, and young adult cancers. Experimental pretreatment as well as post-treatment fertility preservation strategies, including barriers and ethical considerations, which are not included in the COG-LTFU Guidelines, are also discussed. CONCLUSION: Ongoing research will continue to inform COG-LTFU Guideline recommendations for follow-up care of female survivors of childhood cancer to improve their health and quality of life.

The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models.

The pituitary gonadotropin follicle-stimulating hormone (FSH) interacts with its membrane-bound receptor to produce biologic effects. Traditional functions of FSH include follicular development and estradiol production in females, and the regulation of Sertoli cell action and spermatogenesis in males. Knockout mice for both the ligand (Fshb) and the receptor (Fshr) serve as models for FSH deficiency, while Fshb and Fshr transgenic mice manifest FSH excess. In addition, inactivating mutations of both human orthologs (FSHB and FSHR) have been characterized in a small number of patients, with phenotypic effects of the ligand disruption being more profound than those of its receptor. Activating human FSHR mutants have also been described in both sexes, leading to a phenotype of normal testis function (male) or spontaneous ovarian hyperstimulation syndrome (females). As determined from human and mouse models, FSH is essential for normal puberty and fertility in females, particularly for ovarian follicular development beyond the antral stage. In males, FSH is necessary for normal spermatogenesis, but there are differences in human and mouse models. The FSHB mutations in humans result in azoospermia; while FSHR mutations in humans and knockouts of both the ligand and the receptor in mice affect testicular function but do not result in absolute infertility. Available evidence also indicates that FSH may also be necessary for normal androgen synthesis in males and females.

Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children's Oncology Group.

The majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors. Although cancer therapy is associated with many adverse effects, one of the primary concerns of young male cancer survivors is reproductive health. Future fertility is often the focus of concern; however, it must be recognized that all aspects of male health, including pubertal development, testosterone production, and sexual function, can be impaired by cancer therapy. Although pretreatment strategies to preserve reproductive health have been beneficial to some male patients, many survivors remain at risk for long-term reproductive complications. Understanding risk factors and monitoring the reproductive health of young male survivors are important aspects of follow-up care. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) were created by the COG to provide recommendations for follow-up care of survivors at risk for long-term complications. The male health task force of the COG-LTFU Guidelines, composed of pediatric oncologists, endocrinologists, nurse practitioners, a urologist, and a radiation oncologist, is responsible for updating the COG-LTFU Guidelines every 2 years based on literature review and expert consensus. This review summarizes current task force recommendations for the assessment and management of male reproductive complications after treatment for childhood, adolescent, and young adult cancers. Issues related to male health that are being investigated, but currently not included in the COG-LTFU Guidelines, are also discussed. Ongoing investigation will inform future COG-LTFU Guideline recommendations for follow-up care to improve health and quality of life for male survivors.

[Radiation induced side effects]. / Effets indésirables de la radiothérapie.

More than half of all people with cancer are treated with radiation therapy. Over the last decade the technical advances, both in therapy beam precision and imaging, have greatly improved the therapeutic ratio and accuracy of modern radiotherapy. However, damaging healthy tissues near the tumor leads to radiation induced injury that develops immediately and continue to progress long after exposure to radiation. Recently dramatic advances have been made in understanding the determinant of tissue response to radiation exposure.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood.

BACKGROUND: It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done. METHODS: We classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH). RESULTS: Ten (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function. CONCLUSION: The concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.

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.

Reproductive aging, sexuality and symptoms.

Female sexual dysfunction (FSD) affects ~50% of postmenopausal women. Unfortunately, it often goes undiagnosed because both patients and health-care providers may be reluctant to bring it up at an annual office visit. FSD encompasses both physical and emotional components, all of which are often intermingled. Exhaustion, anxiety, stress, interpersonal relationship issues, hormonal changes and their sequelae on vaginal tissue, medication side effects, and medical problems all play a potential role. This review discusses some of the common etiologies and diagnostic and management options.

Detección precoz de trastornos endocrinológicos / Early detection of endocrinological disorders

Se revisan los trastornos más comunes del sistema endocrino que se detectan en la consulta no especializada. Se hace énfasis en: a) Trastornos tiroideos tales como hipo o hipertiroidismo, nódulos de la tiroides y la importancia de la enfermedad de la tiroides durante el embarazo, b) la enfermedad adrenal en la hipertensión y el enfoque de la incidentaloma suprarrenal c) hiperparatiroidismo primario y la deficiencia de vitamina D d) Trastornos gonadal y la importancia de la detección precoz de la enfermedad hormonal, tanto en la disfunción ovárica y testicular

We review the most common disorders of the endocrine system that are detected in non-specialist consultation. Emphasis is placed on: a) thyroid disorders such as hypo-or hyperthyroidism, thyroid nodules and the importance of thyroid disease during pregnancy, b) adrenal disease in hypertension and the approach to the adrenal incidentaloma c) metabolic disorders such as primary hyperparathyroidism and vitamin Ddeficiency d) gonadal disorders and the importance of early detection of hormonal disease in both ovarian and testicular dysfunction

[Place of inhibin B investigation in clinical andrological praxis]. / Význam stanovování inhibinu B v klinické andrologické praxi.

Inhibin B is a gonadal dimeric peptide, produced in men in testicular Sertolli cells. Inhibin B blood level knowledge can be a useful tool in the management of difficult diagnostic problems, such as ambiguous genitalia, the distinction between cryptorchidism and anorchidism and the hypogonadotrophic hypogonadism/delayed puberty differential diagnosis. Inhibin B measurements can help in gonadal dysgenesis evaluation, androgen insensitivity management and also in the diagnosis of some gonadal tumors. In adult men, inhibin B evaluation is helpful in the investigation of male infertility, especially in the judgment of the prognosis of testicular biopsy in in-vitro fertilization programs. Although commercial kits for inhibin B measurement are available at present, its evaluation is accessible in the Czech Republic for the time being in only very limited number of laboratory centers.