Reproductive function depends on the activity of the gonadotropic axis, which is controlled by a hypothalamic neural network whose main function is to regulate the secretion of gonadotropin-releasing hormone (GnRH). This endocrine network is not mature at birth, and several phases of activation-inactivation of the gonadotropic axis are necessary for its normal development. The postnatal maturation of the GnRH network lies under the control of a neurodevelopmental program that starts in fetal life and ends at puberty. There are many clinical situations in which this program is interrupted, leading to congenital hypogonadotropic hypogonadism (CHH) and an absence of puberty. For many years, attention has mainly been focused on the genetics of isolated CHH. More recently, the emergence of new genomics techniques has led to the description of genetic defects in very rare syndromes in which CHH is associated with complex neurological dysfunctions. Here, we review the clinical phenotype and genetic defects linked to such syndromic CHH. This analysis highlights the close link between the ubiquitin pathway, synaptic proteins and CHH, as well as unexpected mutations in genes encoding nucleolar proteins.
{"title":"Congenital Hypogonadotropic Hypogonadism: A Trait Shared by Several Complex Neurodevelopmental Disorders.","authors":"N. de Roux, J. Carel, J. Léger","doi":"10.1159/000438875","DOIUrl":"https://doi.org/10.1159/000438875","url":null,"abstract":"Reproductive function depends on the activity of the gonadotropic axis, which is controlled by a hypothalamic neural network whose main function is to regulate the secretion of gonadotropin-releasing hormone (GnRH). This endocrine network is not mature at birth, and several phases of activation-inactivation of the gonadotropic axis are necessary for its normal development. The postnatal maturation of the GnRH network lies under the control of a neurodevelopmental program that starts in fetal life and ends at puberty. There are many clinical situations in which this program is interrupted, leading to congenital hypogonadotropic hypogonadism (CHH) and an absence of puberty. For many years, attention has mainly been focused on the genetics of isolated CHH. More recently, the emergence of new genomics techniques has led to the description of genetic defects in very rare syndromes in which CHH is associated with complex neurological dysfunctions. Here, we review the clinical phenotype and genetic defects linked to such syndromic CHH. This analysis highlights the close link between the ubiquitin pathway, synaptic proteins and CHH, as well as unexpected mutations in genes encoding nucleolar proteins.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"29 1","pages":"72-86"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64898664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Khattab, T. Yuen, Li Sun, M. Yau, Ariella Barhan, M. Zaidi, Y. Lo, M. New
A major hallmark of classical congenital adrenal hyperplasia (CAH) is genital ambiguity noted at birth in affected females, which leads to psychological and psychosexual issues in adult life. Attempts to correct genital ambiguity through surgical intervention have been partially successful. Fetal hyperandrogenemia and genital ambiguity have been shown to be preventable by prenatal administration of low-dose dexamethasone initiated before the 9th week of gestation. In 7 of 8 at-risk pregnancies, the unaffected fetus is unnecessarily exposed to dexamethasone for weeks until the diagnosis of classical CAH is ruled out by invasive procedures. This therapeutic dilemma calls for early prenatal diagnosis so that dexamethasone treatment can be directed to affected female fetuses only. We describe the utilization of cell-free fetal DNA in mothers carrying at-risk fetuses as early as 6 gestational weeks by targeted massively parallel sequencing of the genomic region including and flanking the CYP21A2 gene. Our highly personalized and innovative approach should permit the diagnosis of CAH before genital development begins, therefore restricting the purposeful administration of dexamethasone to mothers carrying affected females.
{"title":"Noninvasive Prenatal Diagnosis of Congenital Adrenal Hyperplasia.","authors":"A. Khattab, T. Yuen, Li Sun, M. Yau, Ariella Barhan, M. Zaidi, Y. Lo, M. New","doi":"10.1159/000439326","DOIUrl":"https://doi.org/10.1159/000439326","url":null,"abstract":"A major hallmark of classical congenital adrenal hyperplasia (CAH) is genital ambiguity noted at birth in affected females, which leads to psychological and psychosexual issues in adult life. Attempts to correct genital ambiguity through surgical intervention have been partially successful. Fetal hyperandrogenemia and genital ambiguity have been shown to be preventable by prenatal administration of low-dose dexamethasone initiated before the 9th week of gestation. In 7 of 8 at-risk pregnancies, the unaffected fetus is unnecessarily exposed to dexamethasone for weeks until the diagnosis of classical CAH is ruled out by invasive procedures. This therapeutic dilemma calls for early prenatal diagnosis so that dexamethasone treatment can be directed to affected female fetuses only. We describe the utilization of cell-free fetal DNA in mothers carrying at-risk fetuses as early as 6 gestational weeks by targeted massively parallel sequencing of the genomic region including and flanking the CYP21A2 gene. Our highly personalized and innovative approach should permit the diagnosis of CAH before genital development begins, therefore restricting the purposeful administration of dexamethasone to mothers carrying affected females.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"30 1","pages":"37-41"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000439326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64904607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The histrelin implant has emerged as a therapeutic option for the treatment of central precocious puberty that has been favorably received by patients and providers. Inserted subcutaneously, the 50-mg implant provides continuous release of the potent gonadotropin-releasing hormone analog (GnRHa) histrelin. Profound suppression of the hypothalamic-pituitary-gonadal (HPG) axis occurs within 1 month of its placement resulting in pubertal arrest, attenuation of skeletal advancement and a progressive increase in predicted adult height. Although marketed for annual use, suppression lasting 2 years from a single implant has been demonstrated. Placing and removing the device is a minor outpatient procedure easily accomplished by a pediatric surgeon using local anesthesia. The major downside to the implant is a ∼25% rate of breakage upon removal. Information about the recovery of the HPG axis following histrelin explantation is limited but suggests an average time to menarche comparable with depot GnRHa formulations albeit with wide individual variation.
{"title":"Experience with the Histrelin Implant in Pediatric Patients.","authors":"E. Eugster","doi":"10.1159/000439330","DOIUrl":"https://doi.org/10.1159/000439330","url":null,"abstract":"The histrelin implant has emerged as a therapeutic option for the treatment of central precocious puberty that has been favorably received by patients and providers. Inserted subcutaneously, the 50-mg implant provides continuous release of the potent gonadotropin-releasing hormone analog (GnRHa) histrelin. Profound suppression of the hypothalamic-pituitary-gonadal (HPG) axis occurs within 1 month of its placement resulting in pubertal arrest, attenuation of skeletal advancement and a progressive increase in predicted adult height. Although marketed for annual use, suppression lasting 2 years from a single implant has been demonstrated. Placing and removing the device is a minor outpatient procedure easily accomplished by a pediatric surgeon using local anesthesia. The major downside to the implant is a ∼25% rate of breakage upon removal. Information about the recovery of the HPG axis following histrelin explantation is limited but suggests an average time to menarche comparable with depot GnRHa formulations albeit with wide individual variation.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"30 1","pages":"54-9"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000439330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64904730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Individuals with higher-than-normal blood sugar levels used to be diagnosed as having either type 1 or type 2 diabetes. We now know that a wide range of different factors can cause diabetes, including single gene defects, which account for at least 1% of all diabetes cases and up to 4% of cases in the pediatric population. However, misdiagnosis remains common due to the considerable clinical overlap between the different diabetes forms. Monogenic diabetes onset can occur shortly after birth, as observed in neonatal diabetes mellitus, or any time later in life. The present chapter outlines the genes currently known to be involved in monogenic diabetes. Some of these genes are involved in β-cell development, with mutations often leading to a decreased β-cell number, while others play important roles in β-cell function and maintenance. Monogenic forms of autoimmune diabetes and epigenetic causes will also be discussed. A genetic diagnosis may influence treatment choice and prognosis determination and may also lead to family counseling. Genetic screening using next-generation sequencing is becoming more practical as it becomes increasingly accessible and less expensive.
{"title":"Genetic Defects of the β-Cell That Cause Diabetes.","authors":"Caroline Stekelenburg, V. Schwitzgebel","doi":"10.1159/000439417","DOIUrl":"https://doi.org/10.1159/000439417","url":null,"abstract":"Individuals with higher-than-normal blood sugar levels used to be diagnosed as having either type 1 or type 2 diabetes. We now know that a wide range of different factors can cause diabetes, including single gene defects, which account for at least 1% of all diabetes cases and up to 4% of cases in the pediatric population. However, misdiagnosis remains common due to the considerable clinical overlap between the different diabetes forms. Monogenic diabetes onset can occur shortly after birth, as observed in neonatal diabetes mellitus, or any time later in life. The present chapter outlines the genes currently known to be involved in monogenic diabetes. Some of these genes are involved in β-cell development, with mutations often leading to a decreased β-cell number, while others play important roles in β-cell function and maintenance. Monogenic forms of autoimmune diabetes and epigenetic causes will also be discussed. A genetic diagnosis may influence treatment choice and prognosis determination and may also lead to family counseling. Genetic screening using next-generation sequencing is becoming more practical as it becomes increasingly accessible and less expensive.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"31 1","pages":"179-202"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000439417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64906398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Parent, D. Franssen, J. Fudvoye, A. Pinson, J. Bourguignon
The aim of this chapter is to revise some common views on changes in pubertal timing. This revision is based on recent epidemiological findings on the clinical indicators of pubertal timing and data on environmental factor effects and underlying mechanisms. A current advancement in timing of female puberty is usually emphasized. It appears, however, that timing is also changing in males. Moreover, the changes are towards earliness for initial pubertal stages and towards lateness for final stages in both sexes. Such observations indicate the complexity of environmental influences on pubertal timing. The mechanisms of changes in pubertal timing may involve both the central neuroendocrine control and peripheral effects at tissues targeted by gonadal steroids. While sufficient energy availability is a clue to the mechanism of pubertal development, changes in the control of both energy balance and reproduction may vary under the influence of common determinants such as endocrine-disrupting chemicals (EDCs). These effects can take place right before puberty as well as much earlier, during fetal and neonatal life. Finally, environmental factors can interact with genetic factors in determining changes in pubertal timing. Therefore, the variance in pubertal timing is no longer to be considered under absolutely separate control by environmental and genetic determinants. Some recommendations are provided for evaluation of EDC impact in the management of pubertal disorders and for possible reduction of EDC exposure along the precautionary principle.
{"title":"Current Changes in Pubertal Timing: Revised Vision in Relation with Environmental Factors Including Endocrine Disruptors.","authors":"A. Parent, D. Franssen, J. Fudvoye, A. Pinson, J. Bourguignon","doi":"10.1159/000438885","DOIUrl":"https://doi.org/10.1159/000438885","url":null,"abstract":"The aim of this chapter is to revise some common views on changes in pubertal timing. This revision is based on recent epidemiological findings on the clinical indicators of pubertal timing and data on environmental factor effects and underlying mechanisms. A current advancement in timing of female puberty is usually emphasized. It appears, however, that timing is also changing in males. Moreover, the changes are towards earliness for initial pubertal stages and towards lateness for final stages in both sexes. Such observations indicate the complexity of environmental influences on pubertal timing. The mechanisms of changes in pubertal timing may involve both the central neuroendocrine control and peripheral effects at tissues targeted by gonadal steroids. While sufficient energy availability is a clue to the mechanism of pubertal development, changes in the control of both energy balance and reproduction may vary under the influence of common determinants such as endocrine-disrupting chemicals (EDCs). These effects can take place right before puberty as well as much earlier, during fetal and neonatal life. Finally, environmental factors can interact with genetic factors in determining changes in pubertal timing. Therefore, the variance in pubertal timing is no longer to be considered under absolutely separate control by environmental and genetic determinants. Some recommendations are provided for evaluation of EDC impact in the management of pubertal disorders and for possible reduction of EDC exposure along the precautionary principle.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"29 1","pages":"174-84"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64898488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Puberty is a fascinating developmental transition that gates the attainment of reproductive capacity and culminates the somatic and sexual maturation of the organism. Rather than a circumscribed phenomenon, puberty is the endpoint of a long-lasting developmental continuum, which initiates in utero. Besides important genetic determinants, the tempo of puberty is influenced by numerous endogenous and exogenous factors that, acting at different levels of the developing hypothalamic-pituitary-gonadal (HPG) axis along the maturational continuum indicated above, can influence puberty onset. Among the different modifiers of puberty, in this chapter we will focus our attention on two major groups of signals, sex steroids and nutritional cues, and how these interplay mostly with the central elements of the HPG axis, and especially with gonadotropin-releasing hormone neurons and their key upstream afferents, Kiss1 neurons, to influence the timing of puberty. Special emphasis will be given to summarize information emerging from relevant preclinical (mostly rodent) animal models, and how this information might be relevant in terms of translational medicine, as it may help for a better understanding and eventually management of pubertal disorders of escalating prevalence worldwide.
{"title":"Animal Modeling of Early Programming and Disruption of Pubertal Maturation.","authors":"J. M. Castellano, M. Tena-Sempere","doi":"10.1159/000438877","DOIUrl":"https://doi.org/10.1159/000438877","url":null,"abstract":"Puberty is a fascinating developmental transition that gates the attainment of reproductive capacity and culminates the somatic and sexual maturation of the organism. Rather than a circumscribed phenomenon, puberty is the endpoint of a long-lasting developmental continuum, which initiates in utero. Besides important genetic determinants, the tempo of puberty is influenced by numerous endogenous and exogenous factors that, acting at different levels of the developing hypothalamic-pituitary-gonadal (HPG) axis along the maturational continuum indicated above, can influence puberty onset. Among the different modifiers of puberty, in this chapter we will focus our attention on two major groups of signals, sex steroids and nutritional cues, and how these interplay mostly with the central elements of the HPG axis, and especially with gonadotropin-releasing hormone neurons and their key upstream afferents, Kiss1 neurons, to influence the timing of puberty. Special emphasis will be given to summarize information emerging from relevant preclinical (mostly rodent) animal models, and how this information might be relevant in terms of translational medicine, as it may help for a better understanding and eventually management of pubertal disorders of escalating prevalence worldwide.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"29 1","pages":"87-121"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438877","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64898790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sexual maturation is closely tied to growth and body weight gain, suggesting that regulative metabolic pathways are shared between somatic and pubertal development. The pre- and postnatal environment affects both growth and pubertal development, indicating that common pathways are affected by the environment. Intrauterine and early infantile developmental phases are characterized by high plasticity and thereby susceptibility to factors that affect metabolic function as well as related reproductive function throughout life. In children born small for gestational age, poor nutritional conditions during gestation can modify metabolic systems to adapt to expectations of chronic undernutrition. These children are potentially poorly equipped to cope with energy-dense diets and are possibly programmed to store as much energy as possible, causing rapid weight gain with the risk for adult disease and premature onset of puberty. Environmental factors can cause modifications to the genome, so-called epigenetic changes, to affect gene expression and subsequently modify phenotypic expression of genomic information. Epigenetic modifications, which occur in children born small for gestational age, are thought to underlie part of the metabolic programming that subsequently effects both somatic and pubertal development.
{"title":"Consequences of Early Life Programing by Genetic and Environmental Influences: A Synthesis Regarding Pubertal Timing.","authors":"C. Roth, S. DiVall","doi":"10.1159/000438883","DOIUrl":"https://doi.org/10.1159/000438883","url":null,"abstract":"Sexual maturation is closely tied to growth and body weight gain, suggesting that regulative metabolic pathways are shared between somatic and pubertal development. The pre- and postnatal environment affects both growth and pubertal development, indicating that common pathways are affected by the environment. Intrauterine and early infantile developmental phases are characterized by high plasticity and thereby susceptibility to factors that affect metabolic function as well as related reproductive function throughout life. In children born small for gestational age, poor nutritional conditions during gestation can modify metabolic systems to adapt to expectations of chronic undernutrition. These children are potentially poorly equipped to cope with energy-dense diets and are possibly programmed to store as much energy as possible, causing rapid weight gain with the risk for adult disease and premature onset of puberty. Environmental factors can cause modifications to the genome, so-called epigenetic changes, to affect gene expression and subsequently modify phenotypic expression of genomic information. Epigenetic modifications, which occur in children born small for gestational age, are thought to underlie part of the metabolic programming that subsequently effects both somatic and pubertal development.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"29 1","pages":"134-52"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64898690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An array of oral agents is available for the treatment of hyperglycaemia in type 2 diabetes. This systematic inventory focuses on 'old' oral agents, including metformin, sulfonylureas (SUs), thiazolidinediones, alpha glucosidase inhibitors, and meglitinides. Twelve meta-analyses and six randomized controlled trials that used patient-relevant outcomes as primary endpoints were critically reviewed. Guidelines recommend the use of metformin or an SU as the first-line pharmacotherapeutic options. Beneficial effects of metformin have been demonstrated for 'any diabetes-related endpoint' and 'all-cause mortality' in small study groups of overweight and obese patients with newly manifested type 2 diabetes. Various SU agents are available, for which a class effect has clearly been disproven. Beneficial effects have only been demonstrated for glyburide in preventing microvascular complications. Thiazolidinediones have been withdrawn from the markets in some countries. Meta-analyses found an increased coronary risk for rosiglitazone. The benefit-to-risk ratios of alpha glucosidase inhibitors and meglitinides regarding hard endpoints remain uncertain. Diabetes treatment is complex and individualised. We identified several studies focusing on the efficacy of treatment policies rather than on single drug effects. However, as long as the efficacy of single agents regarding hard clinical endpoints is unclear, interpretation of study results on treatment policies remains speculative.
{"title":"The 'Old' Anti-Diabetic Agents: A Systematic Inventory.","authors":"Susanne Buhse, I. Mühlhauser, M. Lenz","doi":"10.1159/000439369","DOIUrl":"https://doi.org/10.1159/000439369","url":null,"abstract":"An array of oral agents is available for the treatment of hyperglycaemia in type 2 diabetes. This systematic inventory focuses on 'old' oral agents, including metformin, sulfonylureas (SUs), thiazolidinediones, alpha glucosidase inhibitors, and meglitinides. Twelve meta-analyses and six randomized controlled trials that used patient-relevant outcomes as primary endpoints were critically reviewed. Guidelines recommend the use of metformin or an SU as the first-line pharmacotherapeutic options. Beneficial effects of metformin have been demonstrated for 'any diabetes-related endpoint' and 'all-cause mortality' in small study groups of overweight and obese patients with newly manifested type 2 diabetes. Various SU agents are available, for which a class effect has clearly been disproven. Beneficial effects have only been demonstrated for glyburide in preventing microvascular complications. Thiazolidinediones have been withdrawn from the markets in some countries. Meta-analyses found an increased coronary risk for rosiglitazone. The benefit-to-risk ratios of alpha glucosidase inhibitors and meglitinides regarding hard endpoints remain uncertain. Diabetes treatment is complex and individualised. We identified several studies focusing on the efficacy of treatment policies rather than on single drug effects. However, as long as the efficacy of single agents regarding hard clinical endpoints is unclear, interpretation of study results on treatment policies remains speculative.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"31 1","pages":"28-42"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000439369","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64905627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.
{"title":"Sex Steroid Replacement Therapy in Female Hypogonadism from Childhood to Young Adulthood.","authors":"E. Norjavaara, C. Ankarberg-Lindgren, B. Kriström","doi":"10.1159/000438892","DOIUrl":"https://doi.org/10.1159/000438892","url":null,"abstract":"The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"29 1","pages":"198-213"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438892","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64899150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There are many etiologies of peripheral precocious puberty (PPP) with diverse manifestations resulting from exposure to androgens, estrogens, or both. The clinical presentation depends on the underlying process and may be acute or gradual. The primary goals of therapy are to halt pubertal development and restore sex steroids to prepubertal values. Attenuation of linear growth velocity and rate of skeletal maturation in order to maximize height potential are additional considerations for many patients. McCune-Albright syndrome (MAS) and familial male-limited precocious puberty (FMPP) represent rare causes of PPP that arise from activating mutations in GNAS1 and the LH receptor gene, respectively. Several different therapeutic approaches have been investigated for both conditions with variable success. Experience to date suggests that the ideal therapy for precocious puberty secondary to MAS in girls remains elusive. In contrast, while the number of treated patients remains small, several successful therapeutic options for FMPP are available.
{"title":"Treatment of Peripheral Precocious Puberty.","authors":"Melissa J Schoelwer, E. Eugster","doi":"10.1159/000438895","DOIUrl":"https://doi.org/10.1159/000438895","url":null,"abstract":"There are many etiologies of peripheral precocious puberty (PPP) with diverse manifestations resulting from exposure to androgens, estrogens, or both. The clinical presentation depends on the underlying process and may be acute or gradual. The primary goals of therapy are to halt pubertal development and restore sex steroids to prepubertal values. Attenuation of linear growth velocity and rate of skeletal maturation in order to maximize height potential are additional considerations for many patients. McCune-Albright syndrome (MAS) and familial male-limited precocious puberty (FMPP) represent rare causes of PPP that arise from activating mutations in GNAS1 and the LH receptor gene, respectively. Several different therapeutic approaches have been investigated for both conditions with variable success. Experience to date suggests that the ideal therapy for precocious puberty secondary to MAS in girls remains elusive. In contrast, while the number of treated patients remains small, several successful therapeutic options for FMPP are available.","PeriodicalId":72906,"journal":{"name":"Endocrine development","volume":"49 1","pages":"230-9"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000438895","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64899162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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