2019, Reproduction, Marie Nováková1 PHYSIOLOGY OF REPRODUCTION 2 Life is a dynamic system with focused behavior, with autoreproduction, characterized by flow of substrates, energies and information. 3 Reproduction in mammals (humans) 1) Sexual reproduction 2) Selection of partners 3) Internal fertilization 4) Viviparity 5) Eggs, resp. embryos – smaller, less, slow development, placenta 6) Low number of offspring, intensive parental care High investment, low-volume reproduction strategy ! Pregnancy (days) Mouse 20 Rat 23 Rabbit 31 Dog 63 Cat 65 Lion 107 Pig 114 Sheep 149 Human 260 - 275 Cow 285 Rorqual 360 Elephant (Indian) 609 4 Reproduction in humans – gender comparison 1) Both male and female are born immature (physically and sexually) 2) Sex hormones are produced in men also during prenatal and perinatal periods, not in women! 3) Reproduction period significantly differs – puberty, climacterical 4) Character of hormonal changes significantly differs – cyclic vs. non-cyclic 5 Men vs. Women • Prenatal differentiation of reproductive organs • Prenatal and perinatal T production • Onset of puberty • After puberty: „stable“ T production • The end of fertile age is not definitively determined • Prenatal differentiation of reproductive organs • Final number of oocytes • Onset of puberty • After puberty: cyclic changes • Fertile age is clearly determined hypothalamus-hypophysis-gonads 6 Puberty • Adrenarche • Pubarche • Telarche • Menarche Pubertas praecox (central) Pseudopubertas praecox (peripheral) CRITICAL DEVELOPMENTAL PERIODS 1) Birth 2) Weaning 3) Puberty (adolescence) 4) Climacterical (menopause) Late puberty Critical body mass (critical amount of adipose tissue/nutritional state) 7 • Meiosis occurs only in germ cells and gives rise to male and female GAMETES • Fertilization of an oocyte by an X- or Y-bearing sperm establishes the zygote´s GENOTYPIC SEX • Genotypic sex determines differentiation of the indifferent gonad into either an OVARY or a TESTIS • The testis-determining gene is located on the Y chromosome (testis-determining factor, sex-determining region Y) • Genotypic sex determines the GONADAL SEX, which in turn determines PHENOTYPIC SEX (fully established at puberty) • Phenotypic differentiation is modified by endocrine and paracrine signals (testosteron, DHT, AMH) 8 BIOSYNTHESIS OF STEROID HORMONES CHOLESTEROL PREGNENOLON DEHYDROEPIANDROSTERON PROGESTERON ANDROSTERON CORTIKOSTERON TESTOSTERON CORTIZOL ALDOSTERON ESTRADIOL ACTH LH LH AT II. FSH chol.desmolase 17-a-hydroxylase 3-b-dehydrogenase 21-b,11-b-hydroxylase ald.synthase aromatase cortex of suprarenal glands gonads PUBERTY DHT (5a-reductase) 9 CONTROL OF SEX HORMONES SECRETION – simplified scheme HYPOTHALAMUS ADENOHYPOPHYSIS GONADS GnRH dopamine (PIF) endorphins noradrenalin FSH LH Activin Inhibin B n.arcuatus gonadoliberine (decapeptid) E P T PROLACTIN Pre-pubertal nervous block of GnRH ??? Blocking the effects of gonadotrophins Down-regulation of LH receptors in testes and ovaria Fight or flight Exercise GABA, kisspeptin 10 GONADOLIBERIN (GnRH, GONADOTROPIN-RELEASING HORMONE) - Specific origin of GnRH neurons - GnRH-I, GnRH-II, (GnRH-III) - Important up and down regulation (steroidal hormones, gonadotrophs) - Down regulation – malnutrition, lactation, seasonal effects, aging, continual GnRH - Up-regulation – effect of GnRH on gonadotrophs (menstrual cycle) Hypothalamo-hypophyseal axis - FSH, LH - Significance of GnRH pulse frequency (glycosylation) - Menstrual cycle, puberty and its onset 11 ACTIVINS and INHIBINS Inhibins – dimeric peptides – circulating hormones produced by gonads – inhibin A – dominant follicle, corpus luteum – inhibin B – testes, luteal and early follicular phase of ovarian cycle Activins – dimeric peptides – FSH stimulation – autocrine/paracrine effects Folllistatin – monomeric polypeptide – FSH inhibition - „supplementary “ regulation of FSH and LH secretion - activins = regulation of transcription - follistatin and inhibins = inhibition of activins through appropriate activin-receptor binding 12 FSH and LH - functions FEMALES FSH - Growth and development of follicular cell (maturation) - Biosynthesis of estradiol - Regulation of inhibin synthesis during follicular phase - Upregulation of LH receptors (preovulatory follicles) - Selection of dominant follicle - Recruitment of follicles for next cycle LH - Stimulation of estrogen synthesis at various levels (theca) - Oocyte maturation (preovulatory follicle) - Rupture of ovulatory follicle, ovulation - Conversion of follicle wall to corpus luteum MALES FSH Spermatogenesis (Sertoli cells) LH Intratesticular synthesis of testosterone (Leydig cells) 13 MALE REPRODUCTION SYSTEM 14 TESTOSTERON PRODUCTION: •Embryonic – sex differentiation, development of generative organs •Perinatal – descensus testis (?) •Fertile period – LH pulsation •Ageing – decrease of sensitivity to LH FSH LH SERTOLI CELLS LEYDIG CELLS INHIBIN B TESTOSTERON AMH ACTIVIN DHT ABG aromatase GnRH glycoproteins HUMOURAL CONTROL OF REPRODUCTIVE FUNCTIONS IN MAN - - - PROLACTIN 5a-reductase estrogen 15 FEMALE REPRODUCTION SYSTEM 16 OOGENESIS DEVELOPMENT: 6-8 weeks GERMINAL EPITH. hormonally OOGONIA FOLLICLE independent mitotic division PRIMORDIAL 24 weeks OOCYTES I. 7 x 106 1. meiosis birth prophase 2 x 106 hormonally puberty OOCYTES II. 3 x 105 dependent haploid DOMINANT (cyclic) 2. meiosis ATRETIC metaphase GRAAF OVUM OVULATION 2. meiosis – end climacterical 0 17 CYCLIC CHANGES ovarian uterine GnRH FSH, LH estradiol basal temper. 0 4 14 28 MENS. PROLIPHER. SECRETORY PHASE + _ 0.5 – 0.75°C FOLICULLAR OV. LUTEAL PHASE 6-10x 2-3x progesteron + vagina/cervix uteri + mamma 90 30 360 18 VESICULAR FOLLICLE PRIMARY FOLLICLE - FSH Growth acceleration of primary follicle – change into vesicular follicle: 1) estrogens released into follicle stimulate granul. cells UP REGULATION of FSH receptors and intrinsic positive feedback (higher sensitivity for FSH!!!) 2) UP REGULATION of LH receptors (estrogens and FSH) – another acceleration of growth due to „higher sensitivity“ to LH (positive feedback) 3) Increased estrogens and LH secretion accelerates growth of theca cells, secretion is increased explosive growth of follicle 19 DOMINANT FOLLICLE 1. High levels of oestrogens from the fastest-growing follicle 2. Negative feedback on FSH production from adenohypophysis 3. Gradual decrease in FSH secretion 4. „Dominant follicle“ continues in growing due to intrinsic positive feedback 5. Other follicles grow slowly and subsequently become atretic 20 MECHANISMS OF OVULATION LH PROGESTERON Hyperaemia of follicle Secretion of prostaglandins Weakening of follicle wall PROTEOLYTIC ENZYMES (collagenases from theca externa) Degeneration of stigma Rupture of follicle Release of oocyte Transudation of plasma into follicle Swallowing of follicle 21 EFFECTS OF OVARIAN HORMONES E P Secondary sexual signs + Adipose tissue: store (predilection), (critical amount) Bone tissue: absorption closure of fissures development of pelvis Total water retention: + + Sexual behaviour: + Ovaries: maturation of follicles Hysterosalpinx: motility motility Uterus: proteosynthesis proteosynthesis vascularisation and proliferation of endom. secretion of endom. glands glycogen motility motility Cervix: colliquation of „plug“ creation of „plug“ Vagina: cornification of epithelium proliferation of epithelium Mamma: growth of terminals growth of acines