PHYSIOLOGY OF REPRODUCTION
Life is a dynamic system with focused behavior, with
autoreproduction, characterized by flow of substrates,
energies and information.
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 !
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
INDIFFERENT GONAD week
XY XX 6.
medulla cortex
SERTOLI CELLS CELOM GRANULOSIS 7.
LEYDIG CELLS MESENCHYME THECA 8.
SPERMATOGONIA GERM.EPITH. OOGONIA 9.
AMH
m W M w 10.
T
Shift of programme
SEX DIFFERENTIATION
Non-disjunction, mosaic. Examination (amniocenthesis, biopsy of chorioid.tissue).
Genetic male Genetic female
testes-determining gene (SRY)
wolffian duct
(epidydimis, vas deferens)
mullerian duct (tuba uterina, uterus
AMH!!!
RATIO A/E
T a AMH affects internal genitalia in unilateral way (inner gene)
• 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)
AMH (MIH, MIF, MIS, MRF) – ANTIMŰLLERIAN HORMONE
1940, TGF-b, receptor with internal TK activity
Source: Sertoli cells (5th prenatal week) or embryonal ovary (36th prenatal
week)
In adult women – granulosa cells of small follicles (NO in antral – under
influence of FSH - and atretic follicles)
Role in men:
• Regression of müllerian duct
• Marker of central hypogonadism
Role in women:
• Lower plasmatic levels (by one order), till climacterical
• Estimation of ovarian reserve (AMH level corresponds to pool of pre-antral
follicles)
• Marker of ovarian functions loss (premature climacterical)
• Diagnosing of polycystic ovaria syndrome
TUMOUR MARKER
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)(inhibition-treatment of alopecia)
(lack in hermaphrodites; inhibition-treatment of endometriosis)
Impact of androgens on CNS.
GONADOLIBERIN (GnRH, GONADOTROPIN-RELEASING HORMONE)
Characteristics
- Specific origin of GnRH neurons out of CNS
- GnRH-I, GnRH-II, (GnRH-III) – Gq/11 (PKC, MAPK)
- 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)
- GNRH1 – hypothalamus; GNRH2 – other CNS areas
Hypothalamo-hypophyseal axis
- FSH, LH
- Significance of GnRH pulse frequency (glycosylation)
- Menstrual cycle, puberty and its onset
Other functions and places of production
- CNS – neurotransmitter (area preoptica)
- Placenta
- Gonads
- Tumours (prostate, endometrium)
Clinical consequences
Continuously administered GnRH
analogues – treatment of oestrogen/steroiddependent
tumours of reproduction system
- Treatment of premature puberty
(leuprorelin – agonist!)
- Unknown function
- Inputs from various CNS areas (pons, limbic
system)
- Dominating inhibitory effect of sex hormones
with exception of estradiol (negative-positive
feedback)
- Kisspeptin in women
- Inhibitory effect of PRL
- Effect of circulating substrates (FA, Glu)
- Leptin (NPY, kisspeptin)
- Stress of various origin
- Acute – MC impairment without effect on
fertility
- Chronic – impairment of fertility, decreased
levels of circulating sex hormones
GONADOLIBERIN – REGULATION OF SECRETION
Pinilla et al., Phys Rev 92: 1235- 1316, 2012
CONTROL OF SEX
HORMONES SECRETION
CONTROL OF SEX HORMONES SECRETION
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
LEPTIN A REPRODUCTION
Activation of reproductive system does not depend on age, but on nutritional state of organism.
LEPTIN: ob-protein, ob-gen, 7.chromosome
„leptos“ = thin, slim
polypeptide, 176 AA
Bound in hypothalamus: n.paraventricularis, suprachiasmaticus, arcuatus a
dorsomedialis
Produced in: adipocytes, placenta, stomach, mammal epithelium (???)
Leptin plasmatic levels are sex-dependent (less in males) and do not depend on
nutritional state
Leptin receptor: gene on 4.chromosome, 5 types of receptor, A-E
Receptor B – effect in gonads and hypophysis
Leptin is not only a factor of body fat amount, but affects also the regulation of
neuroendocrine functions including hypothalamo-hypophyseo-gonadal axis.
ncl. arcuatus
area preoptica - reproduction
???Critical amount of adipose tissue – leptin – hypothalamus – LHRH - puberty
Effects of leptin on testes are not fully elucidated yet.
Testosterone and dihydrotestosterone suppress production of leptin in adipocytes!
REGULATION OF PUBERTY ONSET BY LEPTIN
Critical body mass.
Leptin plasmatic levels in pre-pubertal children are sex-independent.
Pre-pubertal „leptin resistance“ (relative).
In puberty, girls produce 2x more leptin per 1kg of adipose tissue than boys.
PROLACTIN - PRL
Characteristics
- Protein
- Lactotropic cells (only PRL)
- Mammosomatotrophic cells (PRL and GH)
- Hyperplasia – pregnancy and lactation
- Expression regulated by oestrogens, dopamine, TRH and thyroid
gland hormones
- Polypeptide, circulating in 3 forms (mono-, di-, polymer)
- Monomeric PRL – highest biological activity
- Monomeric PRL further cleaved (8/16 kDA)
- 16 kDA PRL – anti-angiogenic function
- PRLR – mamma, adenohypophysis, suprarenal gland, liver,
prostate, ovary, testis, small intestine, lungs, myocardium, SNS,
lymphocytes
Regulation of secretion
- Pulsatile secretion: 4 – 14 pulses/day
- Highest levels during sleep (REM, nonREM)
- Lowest levels between 10:00 and 12:00
- Gradual decrease of secretion during aging
- TIDA cells – dopamine (-, D2R)
- Paracrine – endothelin-1, TGF-b1, calcitonin, histamine (-)
- FGF, EGF (+)
- TRH, oestrogens, VIP, serotonin, GHRH at higher concentrations
(+)
- CCK - ?
Co-hormone
Milk production during pregnancy and lactation =
„survival“ function
Other functions – metabolic, synthesis of melanin,
maternal behaviour
Breast development a lactation
- Puberty – mamma development under the effects
of GH a IGF-1
- Effect of oestrogens and progesterone
- Age of 8 – 13
- During pregnancy – proliferation of alveoli and
proteosynthesis (proteins of milk and colostrum)
- During the 3rd trimester – production of
colostrum (PRL, oestrogens, progesterone, GH,
IGF-1, placental hormones)
- Lactation – increase in PRL post-partum,
without sucking drop after approx. 7 days
- Milk accumulation prevents further PRL
secretion
- Role of oxytocin
Reproductive function of PRL
- Lactation = amenorrhea and secondary
infertility
- Inhibition of GnRH secretion
- Significance of kisspeptin neurons (PRLR)
- Putative role of metabolic factors
Immune function of PRL
- Anti-inflammatory effects ?
Clinical consequences
- Hyperprolactinemia – some antihypertensive
drugs, chronic renal failure
- Macroprolactinemia
- Galactorrhoea – role of GH (acromegaly)
- PRL deficiency
PROLACTIN - FUNCTIONS
Puberty
• Adrenarche
• Pubarche
• Menarche
• Telarche
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)
MALE REPRODUCTION SYSTEM
TESTOSTERON PRODUCTION:
•Embryonic – sex differentiation, development of generative organs
•Perinatal – descensus testis (?)
•Fertile period – LH pulsation
•After 50.year – 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
SPERMATOGENESIS
Leydig cell
Capillary
Basal membrane
Spermatogonium
Tight junction
Spermatocyte
Spermatide (haploid)
Sertoli cell (contraction)
Spermia
70 days
1-64 (6 divisions)
Temperature<35°C
Acrosom (enzymes)
Head (nucleus, DNA)
Body (mitochondria)
Flagella (microtubules, 9+2)
Lumen:
androg., estrog.
K+
glutamate, aspartate
inositol
PRODUCTION OF SPERM
SEMINIFEROUS TUBULES
SPERMATOGONIA SPERM 2 months
SERTOLI CELLS ABG temperature
LEYDIG CELLS radiation
EPIDYDIMIS maturing, motility 14-21 days
VAS DEFERENS storing months
SPERMATOCYSTS fructose
fibrinogen
prostaglandins
PROSTATE Ca2+, profibrinolysin
SPERM
T
Ejaculation:
3-4 ml
108 sp / ml (season)
pH = 7.5
motility (3mm/min)
Relaxin – improves motility of spermatogonia
Relaxin
FSH
FSH
LH
Volume 1,5 - 2,0
pH 7,2 - 8,0
Concentration of sperm 20 mil/ml
Total number of sperm 40 mil and more
Motility 50% and more in category A+B, above 25% in A
Morphology 30% and more of normal forms
Vitality 75% and more of living sperm
Leukocytes up to l mil/ml
Autoaglutination < 2 (scale 0 - 3)
SPERMIOGRAM
SEXUAL REFLEXES
CNS cortex, limb.system sexual behaviour
sexual agitation
nn.pudendales mechanoreceptors stimulation
nn.erigentes corpus cavernosum erection
gl.bulbourethralis lubrication
pl.pelvicus epidydimis, vas def.
sem.ves., prostate emission
m.bulbocavernosus ejaculation
trigonum vesicae ur. constriction
PARASYMP.
SYMP.
Sacral
spinal
cord
(glans penis)
(Ach, VIP)