Sex differentiation to puberty. Introduction

Transcription

1 ex to puberty exual in general: chromosomal, gonadal and phenotypic sex, endocrine control of phenotypic, role of testicular hormones in male development, disorders of sexual 30 Hypothalamic sexual : sexual dimorphic areas, androgenized female model, olfactory placode and GnRH migration, development and maturation of female HPG axis as intro to puberty and to adult cyclicity Puberty: definition, hypothesis, role of GnRH and other systems, diseases Introduction repro and its story lines & Page 1

2 Introduction ex Neuroendo control egg sperm genetic sex external features gonadal sex phenotypic sex internal urogenital system external secondary genitalia sex charachteristics FH-LH secretion CN genetic sex established at conception governs development of gonadal sex sex behavior Introduction ex Neuroendo control The undifferentiated state has a bipotential gonad and both Mullerian and Wolffian systems Page 2

3 Introduction ex Neuroendo control The bipotential gonad can give origin to an ovary (cortex, default) or to a testis (medulla) Introduction ex Neuroendo control The bipotential gonad can give origin to an ovary (cortex, default) or to a testis (medulla) Page 3

4 ex and Gonadal Differentiation ex Neuroendo control undifferent gonad cortex --> ovary medulla --> testis female pattern is default unless testis-determining factor (TDF), a transcription factor of the RY gene (sex-determining region of Y gene), is present The bipotential gonad can give origin to an ovary (cortex, default) or to a testis (medulla) ex and Gonadal Differentiation ex Neuroendo control Development of the testes and ovaries from common precursors in the genital ridges. RY, (the sex-determining region of the Y chromosome), is the gene expressed only in cells that develop into ertoli cells. In the absence of RY these cells develop into follicle cells. ertoli cells express OX 9 and other transcription factors and the autocrine factor FGF9 (fibroblast growth factor 9) that lead to and multiplication of ertoli cells. nclosure of the primordial germ cells by ertoli cells to form the primitive spermatic cords and unequivocal recognition of the primitive gonads as testes occurs as early as the seventh week. ubsequent recruitment of mesenchymal cells and their into Leydig cells takes place in response to the secreted factors DHH (desert hedgehog) and PDGF (platelet-derived growth factor). Newly differentiated ertoli cells also secrete AMH (antimüllerian hormone) and inhibin. The first primordial follicles do not appear in the primitive ovary until the eleventh week. The bipotential gonad can give origin to an ovary (cortex, default) or to a testis (medulla) Page 4

5 Phenotypic Differentiation ex Neuroendo control Development of the male and female internal genitalia. Normal development of the male and female reproductive tracts. Tissues destined to form male tract are in blue; tissues that develop into female tract are in pink. Bilateral castration of either male or female embryos results in development of the female pattern. arly unilateral castration of male embryos results in development of the normal male duct system on the side with the remaining gonad, but female development on the contralateral side. This pattern develops because both testosterone and antimüllerian hormone act as paracrine factors. Phenotypic Differentiation ex Neuroendo control female pattern is default unless TDF, a transcription factor of the RY gene, is present Page 5

6 Phenotypic Differentiation ex Neuroendo control TDF of RY gene as master switch for downstream genes embryo without Y develops as female embryo with multiple X + 1Y = male XX injected with RY gene ---> male RY turns indifferent genital ridge into medullary development of testis, testosterone production, male phenotype RY gene is normally present in males but its locus was deduced from XX individuals with testis development that inherited 40kb Y chromosome (n=4) gain of function mutations in genes downstream might explain testis in XX female pattern is default unless TDF, a transcription factor of the RY gene, is present Phenotypic Differentiation ex Neuroendo control steroid receptors, ligand- dependent transcription factors, bind unique HR in the promoter of specific target genes orphan receptors, which have been cloned by homology, have no known ligands but appear to be mediators of adult endocrine function and organogenesis F-1 = Ad4BP is one of these receptors. It resembles the Drosophila Ftz-F1, which regulates the developmental homobox gene fushi tarazu (for paired body components) F-1 transcripts are found in steroid-producing organs, in ertoli cells, in pituitary gonadotrope, and in the VMN during formation of bipotential gonad, sexual (sexually dimorphic pattern), and in the adult gonad expressed in developing gonadotropes prior to expression of alpha and ß subunits of LH & FH, but not in GnRH neurons F-1 knockout mice die of corticoid insufficiency (volume depletion, low corticosterone, high ACTH), have female external & internal genitalia regardless of chromosomal sex, do not express LH & FH, and do not have the VMN a proposed homeostatic relay center involved in metabolic and reproductive control female pattern is default unless TDF, a transcription factor of the RY gene, is present Page 6

7 Phenotypic Differentiation ex Neuroendo control female pattern is default unless TDF, a transcription factor of the RY gene, is present Phenotypic Differentiation ex Neuroendo control AMH Antimüllerian hormone (AMH) signaling pathway. AMH binds to its specific primary receptor (II), which then forms a heterodimer with and phosphorylates the secondary signal transducing subunit (I). The activated receptor complex then catalyzes phosphorylation of mad proteins on serine and threonine residues causing them to bind mad 4, which carries them into the nucleus where transcription of specific genes results in expression of an apoptotic program and resorption of the müllerian duct cells. Mullerian system regress in males (AMH) through apoptotic mechanisms (suicide) Page 7

8 Phenotypic Differentiation ex Neuroendo control Anomalies in male development due to single gene mutations. A.- Normal production of AMH, T and 5-DHT results in regression of female internal organs and the development of internal and external male organs. B.- Absence or defect in RY leads to ovarian agenesis and normal development of female internal and external genitalia and absence of male characteristics. C.- AMH absence leads to develop-ment of both male and female internal genitalia and normal male external genitalia except that in some cases the presence of the female organs interferes with normal testicular descent into the scrotum. D.- Absence of 17-hydroxylase or the androgen receptor results in an individual without an internal male or female reproductive tract, and with female external genitalia..- Absence of 5-dehydrogenase II results in normal development of male internal organs, except prostate, and normal regression of female internal sex organs. The external organs may be overtly female or ambiguous. Mullerian system regress in males (AMH) through apoptotic mechanisms (suicide) Phenotypic Differentiation ex Neuroendo control gonocytes from yolk sac move to gut and seed undifferentiated gonad: male / medulla, female / cortex gonadal anlagen is visible at 4 weeks gestation, testis at 7 weeks (if the Y gene is present) and the ovary at weeks in females apoptosis of Wolffian system in males anti-mullerian hormone (AMH), a member of the TGFß family of peptides female genitalia in the absence of Y male genitalia is dependent of androgen production by the testis. Timing, effect of congenital adrenal hyperplasia in XX testosterone, critical period, hypothalamic sexual and reproductive cycles In the absence of testis development the genetic program stimulates development of an ovary Page 8

9 Phenotypic Differentiation ex Neuroendo control T DHT 5a-reductase nucleus diff. male ext. genitalia (penis & scrotum) T nucleus diff. male int. genitals & 2nd sex charact. T 2 aromatase nucleus diff. male hypoth. (tonic vs phasic LH) chromosomal sex: and the role of RY, such as in the Klinefelter s (XXY) and in Turner s (XO) syndromes gonadal sex: when chromosomal sex is normal but gonadal is abnormal (pure gonadal disgenesis) genital fold & tubercle genital swelling phenotypic sex: can be ambiguous or in disagreement with chromosomal and with gonadal sex (pseudohermaphroditism) T induces of the internal genitalia and DHT that of the external genitalia Phenotypic Differentiation ex Neuroendo control Metabolism of testosterone. Most of the testosterone (T) secreted each day is degraded in the liver and other tissues by reduction of the A ring, oxidation of the 17 hydroxyl group, and conjugation with polar substituents. Conversion to 5- DHT takes place in target cells catalyzed mainly by the type II dehydrogenase and in nontarget cells mainly but not exclusively by the type I dehydrogenase. Aromatization of T to 2 may occur directly or after conversion to androstenedione. Note that 5- DHT cannot be aromatized or reconverted to T. T in presence of 5a-reductase generates DHT and in presence of aromatase generates 2 Page 9

10 Phenotypic Differentiation ex Neuroendo control Action of testosterone. Testosterone (T) enters target cell and binds to its nuclear androgen receptor (AR) either directly or after it is converted to 5-dihydrotestosterone (DHT). The thickness of the arrows reflects the quantitative importance of each reaction. The hormone receptor complex binds DNA along with a variety of cell-specific nuclear regulatory proteins to induce formation of the RNA that encodes the proteins that express effects of the hormone. Not shown: T may also bind to membrane receptors & initiate rapid ionic changes that may reinforce its genomic effects. T may also produce rapid changes in camp production through binding of the sex hormone binding globulin (HBG) to surface receptors. T and DHT are steroids and their mechanism of action involve intracellular receptors Phenotypic Differentiation ex Neuroendo control Action of testosterone. Testosterone (T) enters target cell and binds to its nuclear androgen receptor (AR) either directly or after it is converted to 5-dihydrotestosterone (DHT). The thickness of the arrows reflects the quantitative importance of each reaction. The hormone receptor complex binds DNA along with a variety of cell-specific nuclear regulatory proteins to induce formation of the RNA that encodes the proteins that express effects of the hormone. Not shown: T may also bind to membrane receptors & initiate rapid ionic changes that may reinforce its genomic effects. T may also produce rapid changes in camp production through binding of the sex hormone binding globulin (HBG) to surface receptors. T and DHT are steroids and their mechanism of action involve intracellular receptors Page 10

11 Phenotypic Differentiation ex Neuroendo control Action of testosterone. Testosterone (T) enters target cell and binds to its nuclear androgen receptor (AR) either directly or after it is converted to 5-dihydrotestosterone (DHT). The thickness of the arrows reflects the quantitative importance of each reaction. The hormone receptor complex binds DNA along with a variety of cell-specific nuclear regulatory proteins to induce formation of the RNA that encodes the proteins that express effects of the hormone. Not shown: T may also bind to membrane receptors & initiate rapid ionic changes that may reinforce its genomic effects. T may also produce rapid changes in camp production through binding of the sex hormone binding globulin (HBG) to surface receptors. T and DHT are steroids and their mechanism of action involve intracellular receptors Phenotypic Differentiation ex Neuroendo control ndocrine pathologies include hypofunction and hyperfunction of primary or secondary origin Page 11

12 ex Differentiation and Development Disorders ex Neuroendo control Turner syndrome patients (XO) usually have short stature and delay puberty ex Differentiation and Development Disorders ex Neuroendo control beware of single bars Complete testicular feminization (XY, AR mutation)) and an undervirilized male Page 12

13 ex Differentiation and Development Disorders ex Virilization fetal adrenal steroidogenesis defects Neuroendo control 3ßH-steroid dehydrogenase partial (top) and complete deficiency in male (top) and (below) virilization in genetic in female (below) females with 21 H deficiency Hypogonadotropic hypogonadism before and after treatment with T cypionate ex Differentiation and Development Disorders ex Neuroendo control Page 13

14 Hypothalamic Differentiation ex Neuroendo control Male hypothalamic is caused by T to 2 aromatization in sexual dimorphic areas Hypothalamic Differentiation ex GnRH neurons GnRH GnRH Neuroendo control Female hypothalamic, the default program, includes 2 s ability to induce ovulation Page 14

15 Hypothalamic Differentiation ex Neuroendo control Female hypothalamic, the default program, includes 2 s ability to induce ovulation Hypothalamic Differentiation ex Neuroendo control embriology, neonatal androgenization, POA, 2 positive feedback, 2 vs in androgenized rats, pituitary deafferentation, transplant, HHA, M, glia and portal vessels, maturation of the HPG axis GnRH neuroanatomy, migration, Kallman syndrome, hypogonadal mouse, sex behavior, H. burtoni, GnRH agonist / antagonists olfactory placode sexual dimorphic areas tonic vs phasic LH control the preovulatory surge of GnRH & LH Female hypothalamic, the default program, includes 2 s ability to induce ovulation Page 15

16 Neuroendocrinology of Puberty ex Neuroendo control Puberty as a process and its relationship to the theoretical control the onset of puberty as an example of the hypothalamic maturation of the theoretical neural components of a feedback system controlling pulsatile GnRH release and reproduction "ability to carry a fetus to terminus" and "temporal maturational process" as components in the definition of female puberty and in their relationship with the black boxes of the control system Female hypothalamic, the default program, includes 2 s ability to induce ovulation Phenotypic changes at puberty ex Neuroendo control Female hypothalamic, the default program, includes 2 s ability to induce ovulation Page 16

17 Functional changes at puberty ex Neuroendo control infantile uterus responds to steroids well before the onset of puberty (assays and ideopathic precocious puberty) neonatal ovary has autonomous follicular growth and responds to gonadotrophins during infantile period (has steroid output) neonatal anterior pituitary responds as an adult pituitary when transplanted to adult hypox rats (neonatal AP to their mothers) the CN negative and positive feedbacks of 2 on LH and FH are not present in the infantile period, but they become progresively active during the prepubertal period ( - and + FB approaches) Female hypothalamic, the default program, includes 2 s ability to induce ovulation Hormonal change at puberty ex Neuroendo control LH GH Female hypothalamic, the default program, includes 2 s ability to induce ovulation Page 17

18 Theories on puberty onset ex Neuroendo control while dynamic AP-ovarian relationship are operative before puberty, its onset results from the elaboration of sufficient hormones it is brought about by removal of inhibitory inputs to gonadotropins (reseting of the gonadostat) it is caused by stimulation of facilitatory inputs on gonadotropin secretion (increase in central drive), rather than by gonadostat resetting puberty onset is the climax of a cascade of developmental changes occurring harmoniously during reproductive immaturity the cascade of events preceding puberty is elicited by hypothalamic "timekeeping" genes (homeotic genes), which activate a central drive neurogenic mechanism Female hypothalamic, the default program, includes 2 s ability to induce ovulation Theories on puberty onset ex GnRH Neuroendo control GnRH GnRH GnRH GnRH Female hypothalamic, the default program, includes 2 s ability to induce ovulation Page 18

19 Puberty-related Pathologies ex Neuroendo control 7 year old boy, central precocious puberty 2ary to neurofibromatosis, unaffected twin Puberty-related Pathologies ex Neuroendo control 5 year old 2 year old Precocious puberty central ideopathic (girl) & 2nd to congenital adrenal hyperplasia (boy) Page 19