Puberty from Bench to Clinic

J. -P. Bourguignon, A. -S. Parent

• Éditeur: S. Karger
• Année: 2015
• ISBN:
  9783318027891
• Sujet: Medicine
• Sous-sujet: Gynecology, Obstetrics & Midwifery

Puberty is a unique paradigm for the understanding of gene-environment interaction and developmental programming. Therefore, normal and abnormal pubertal development can be divided and examined in three sections: the role of genetic factors, the role of environmental factors (including nutrition) and therapeutic issues in disorders of puberty. Dealing with all of these sections and framed along current key concepts in pediatric endocrinology, experts share their view on critical issues such as weighting of genetic versus environmental factors or the impact of environmental factors in relation to critical periods in development. Not only showing the consensus and controversial issues in the various areas, each chapter presents lessons for clinical management in an attempt to link basic research, physiology and pathophysiology with the clinical management of pubertal disorders. Puberty from Bench to Clinic bridges up-to-date concepts from animal and human physiology and pathology towards a better understanding and management of pubertal disorders, making it a unique resource for researchers in the field of development and reproduction, clinical scientists and practitioners in neuro-, pediatric and adolescent endocrinology as well as gynecology.

Environmental Issues

Bourguignon J-P, Parent A-S (eds): Puberty from Bench to Clinic. Lessons for Clinical Management of Pubertal Disorders. Endocr Dev. Basel, Karger, 2016, vol 29, pp 87-121 (DOI: 10.1159/000438877)

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Animal Modeling of Early Programming and Disruption of Pubertal Maturation

Juan M. Castellano · Manuel Tena-Sempere

Department of Cell Biology, Physiology and Immunology, University of Córdoba, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, and Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Córdoba, Spain

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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.

© 2016 S. Karger AG, Basel

Maturation of the Hypothalamic-Pituitary-Gonadal Axis and Puberty: A Developmental Continuum

Puberty is a fascinating developmental period when sexual and somatic maturation is achieved and reproductive capacity attained [1]. Indeed, rather than a specific time point in postnatal development, puberty can be considered as the culmination of a maturational continuum that starts in utero and progresses throughout early postnatal, infantile, and juvenile ages [2].

The success of this developmental process relies on the proper functional organization of the so-called hypothalamic-pituitary-gonadal (HPG) or gonadotropic axis, which is responsible for the completion of gonadal development and the attainment of sexual phenotypic maturity. The function of this neurohormonal system requires the dynamic interaction of three major groups of signals arising from (i) the hypothalamus, where a subset of neurons synthesize and release the decapeptide gonadotropin-releasing hormone (GnRH), (ii) the adenohypophysis, where gonadotropes secrete the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone, and (iii) the gonads, which, in addition to producing fertilizable gametes from puberty onwards, are responsible for the release of sex steroids (i.e. estrogen and testosterone) and peptides [3]. These major components of the HPG axis are connected via feed-forward and feedback loops, thus facilitating its homeostatic regulation. In this system, GnRH neurons are considered to have a major hierarchical role and operate as the final output pathway for different regulatory signals, including central neuropeptides/neurotransmitters and peripheral hormones [4].

In mammals, the initiation of puberty requires a sustained increase in the neurosecretory activity of GnRH neurons [5, 6]. This increase is determined by coordinated changes in transsynaptic and glial inputs to the GnRH neuronal network, consisting of an increase in stimulatory signals and the loss of inhibitory influences [5, 6]. A relevant part of the excitatory control of puberty is provided by neurons that synthesize glutamate [7, 8], kisspeptins [9, 10] (for further details, see ‘Convergent Mechanisms for Pubertal Disruption: Putative Roles of the Central Kiss1 System'), and neurokinin B (NKB) [11] as neuronal transmitters. Of note, kisspeptins, the peptide products encoded by the Kiss1 gene, and NKB, a tachykinin peptide encoded by TAC3/Tac2 gene, are coexpressed in the same cell type in specific brain areas, namely the arcuate nucleus (ARC); this cell population has been termed KNDy neurons [12, 13]. Apparently, the release of NKB from KNDy neurons can activate kisspeptin secretion from the same cell type and, eventually, modulate GnRH neurosecretory activity [13-15]. The inhibitory circuitry responsible for the control of puberty is largely dependent on neurons that produce GABA, endogenous opioids, and eventually RFamide-related peptides [16, 17]. GABAergic neurons can modulate GnRH release through indirect actions on neurons connected to the GnRH neuronal network [5, 18], or direct actions mediated by the activation of GABA_A receptors on GnRH neurons [19, 20]. Opiatergic neurons inhibit GnRH release through different peptides acting on different receptors [21]. These actions may be exerted directly on GnRH neurons [22] or indirectly on neurons involved in the stimulatory control of the GnRH neuronal network, such as KNDy neurons [23]. RFRP neurons may produce one or two peptides, RFRP1 and RFRP3, acting on a single receptor expressed in GnRH neurons, NPFFR1, to directly inhibit its neurosecretory activity [24, 25]. In addition to neuronal inputs, glial cells, such as astrocytes, participate in the regulation of GnRH neurons and puberty via two mechanisms: the release of growth factors and other bioactive molecules, and plastic changes in glial-to-GnRH neuron contacts and adhesiveness [6].

The development of the above hypothalamic networks depends on the dynamic interplay between genes and environment, which is not only crucial for puberty to occur, but also for its timing. Interestingly, while genetic determination plays a relevant role in this process [26], the substantial variation in the age of puberty detected even within homogeneous populations [1] points to the environmental cues as determining factors for the tempo of puberty. In this sense, recent epidemiological studies have documented a trend for an earlier initiation of puberty in girls, as estimated by the beginning of breast development [27, 28], and boys, as estimated by the beginning of genital and pubic hair growth [29]. This phenomenon seems to be related to the higher prevalence of childhood obesity and/or the increased exposure to endocrine-disrupting compounds (EDCs) [27, 30, 31]. However, the causative association between these environmental factors and the disruption of pubertal development remains to be conclusively demonstrated. Of note, recent evidence is mounting that altered timing of puberty may derive from the impact of inappropriate exposure to nutritional factors and/or compounds with sex steroid activity on the development and/or function of the hypothalamic Kiss1 system (for further details, see ‘Convergent Mechanisms for Pubertal Disruption: Putative Roles of the Central Kiss1 System').

In this chapter, we will (i) review the impact of early sex steroids and nutritional factors on pubertal development, (ii) describe different experimental/preclinical models of pubertal disruption induced by early exposure to compounds with sex steroid activity and early nutritional manipulation, and (iii) discuss the compelling evidence pointing to the hypothalamic Kiss1 system as a potential target for the pubertal disruption induced by inappropriate exposure to nutritional factors and/or compounds with sex steroid activity.

Early Influences on Pubertal Maturation: Roles of Sex Steroids and Nutrition

Early life events do impact on the function of diverse physiological systems and can induce permanent alterations that last or even manifest in later life [32]. These contentions set the basis of the developmental programming hypothesis, which proposes that exposure of the developing tissues/organs to an adverse stimulus or insult during critical or sensitive periods of development can permanently reprogram normal physiological responses, leading to hormonal disorders later in life [33]. Of note, the timing of exposure and severity of these environmental factors will determine the resulting phenotypes. Thus, the environment faced during early development is considered of crucial importance for defining the biological fate of any organism.

Interestingly, not all organs/tissues display the same sensitivity to the environmental factors. For instance, the central nervous system has been shown to be more vulnerable to the environment than external genitalia, at least during early prenatal life [34]. This fact emphasizes the importance of early events in the proper development of all brain structures and their respective physiological functions. Among them, the hypothalamus, as a brain structure, and reproduction, as a physiological function, are paradigmatic examples: the former because it is essential for maintaining body homeostasis by ensuring adequate physiological responses against environmental demands [35, 36], and the latter because it is indispensable for the perpetuation of the species.

It is well known that attainment of reproductive capacity at puberty, and its maintenance during adulthood, depends on the proper functional organization at early stages of development of the central (hypothalamic) circuitries responsible for the control of the pulsatile secretion of GnRH [3, 4, 37]. Probably, one of the major events in the development of those hypothalamic networks is the process of sexual differentiation of the brain, which is closely related with other sex-determination phenomena, such as gonadal and gen...