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Reproductive physiology

Androgens

Learning objectives: 85

Adrenal cortex (Zona reticularis) AndrogensDehydroepiandrosterone sulfate DehydroepiandrosteroneAndrostenedione

Testis (Leydig cells) AndrogensTestosterone

(Ovaries) (Androgens)

Male reproductive system

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Vas deferens

Epididymis

Testis

Seminiferous tubule

Leydig cell

Sertoli cell

Cholesterol

Pregnenolone

Progesterone

11-deoxycorticosterone

Corticosterone

18-OH-costicosterone

Aldosterone

Desmolase

3-HSDH

11-OH-ase

21-OH-ase

18-OH-ase

18-HSDH

17-OH-ase17,20-lyase

aromatase

17-HSDH

17-OH-pregnenolone

17-OH-progesterone

11-deoxycortisol

Cortisol

Androstenedione

Estrone

Androstanediol

Testosterone

Estradiol

Biosynthesis of androgens in the testes

DHEA = Dehydroepiandrosterone

DHEAS = Dehydroepiandrosterone sulfate

Free: 2 %

Bound to protein:

-Albumin 54 %

- Gonadal steroid-binding globulin 44 %

Transport of testosterone in plasma

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Metabolism of testosterone in some target tissues

Testosterone

5α-reductase aromatase

SKIN

ADIPOSE TISSUE

(brain, liver, Sertoli cells)

TESTIS

Dihydrotestosterone 17β-Estradiol

Androgenic potencies of androgens

Dihydrotestosterone : Testosterone : Dehydroepiandrosterone = 60 : 20 : 1

100x more

Testosterone

TestosteroneTestosterone

aromatase

Estradiol

Mechanism of action

Testosterone

5α-reductase

Dihydrotestosterone

Effects

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Y-chromosome

Sertoli cells

Leydig cells Testosterone

Dihydrotestosterone

Penis

Scrotum

Wolffian duct

Embryology of the reproductive system

Sex determining Y-gene

Embryonic

(indifferent)

Gonad

Embryonic

Testis

Müllerian duct

regression

factor

Müllerian duct

regression

Vas deferens

Seminal vesicle

Epididymis

Human chorionic gonadotropin (hCG)

of the mother

32oC

Countercurrent exchanger mechanism for conservation of local

temperature and testosterone concentration in the testis

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Testosterone

TestosteroneTestosterone

aromatase

Estradiol

Mechanism of action

Testosterone

5α-reductase

Dihydrotestosterone

Differentiation of

male

external genitalia

Differentiation of

male

internal genital ducts

Differentiation of

male

hypothalamus

Plasma testosteron levels at various ages in human males

Pla

sma

tes

tost

ero

ne

(nm

ol/

l)

Fetal Neonatal

Prepubertal

Pubertal Adult Scenescence

birth

Age (years)

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Biological effects of testicular androgens in male

PREPUBERTAL

Accessory sex organs (differentiation of the Wolffian duct)

External genitalia (differentiation and growth of the penis and scrotum)

PUBERTAL

Testis (hormonal support of spermatogenesis)

Accessory sex glands (growth and secretion of the prostate gland, seminal vesicle)

External genitalia (growth of the penis and scrotum)

Bone (Ca2+, PO43- retention, epiphysial closure)

Vocal cords (voice changes)

Skin (hair growth and loss, stimulation of sebaceous glands)

Skeletal muscle (anabolic action: protein synthesis) Doping!

Erythropoiesis (red bone marrow, production of erythropoietin)

CNS (libido)

Regulation of hormone secretion

GnRH

FSH

LH

Inhibin (from Sertoli cells)

Testosterone

GnRH: Gonadotropin-releasing hormone

FSH: Follicle-stimulating hormone

LH: Luteinizing hormone

limbic system

visual-, olfactory system

hours

feedback inhibition:

+ weak androgens, estrogens

fetus:

LH ≈ human chorionic gonadotropin (hCG)FSH

LHLeptin

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Blood-testis barrier

Testosterone

Blood-testis

barrier

Sperms develop 65-70 days long

Sperm production: 45-200 millions/day

NO androgen

receptors

Carlo Maria Michelangelo Nicola Broschi

„Farinelli”

(1705 – 1782)

Vasectomy:It is a surgical procedure for male sterilization and permanent birth control. During the

procedure, the vasa deferentia of a man are severed and tied.

Castration:Before puberty: (eunuchoidism) tall body, narrow shoulders, less muscle, the genitalia

are small, the voice is high pitched, pubic and axillary hair is sparse

After puberty: secondary sex characteristics regress slowly, the voice remains deep,

some loss of libido

In the baroque music era

the „castrati” singers were

highly appreciated by

opera composers.

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Fertilisation, Pregnancy, Parturition, Lactation

Learning objectives: 87, 88

Sperm passage through the rete testis: sperms are concentrated

due to the reabsorption of Na+ and water under the influence of

estrogen.

Sperms take 2-10 days to pass through the epididymis:

maturation, storage, decapacitation and protection of sperms from

immunological damage.

During ejaculation the accessory glands sequentially contribute

their secretion to the seminal fluid.

Volume of the ejaculate: 3 ml, contains 150 million sperms

Semen: seminal fluid containing spermatozoa.

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Sexual actCoitus allows the transfer of sperms from the male to the female reproductive tract

Male sexual act:

-Erection: relaxation of the smooth muscles allows increased inflow of blood to

increase volume and rigidity.

- Emission: movement of the ejaculate into the proximal part of the urethra. It is the

result of the peristaltic contraction of the vas deferens.

- Ejaculation: It is the forceful expulsion of the semen from the urethra. Constriction

of the internal sphincter of the bladder prevents retrograde ejaculation.

Vasodilatation

Stimuli inducing erection:

Stimuli affecting the central nervous system

Mechanical stimulation of the skin

REM-sleep

Parasympathetic endings Ach/NO

Inhibition of

phosphodiesterase

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+ OxytocinReflexes

striated

muscle

striated

muscle

erogenous zone erogenous zone

higher centers

motor nerve

sympathetic nerve

parasympathetic nerve

sensory nerve

„ejaculation

center”Th10-L2

„erection

center”S2-4

Spinal cord

Stages:

Orgasm is the sudden discharge of accumulated sexual tension during the sexual

response cycle characterized by sexual pleasure.

1

2

3

4

Additional signs:

Tachycardia

Increase in blood pressure

Hyperventilation

Increased muscle tone

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Number of sperms: in the ejaculate - 150 million

in the uterus - 100 000

in the Fallopian tube - 200

fertilization - 1

Semen first coagulates and then liquefies, allowing sperms to escape.

Sperms stay alive max. 48 hours long.

Egg stays alive max. 24 hours long.

Fertilization and Implantation

Fertilization

Sperms have to reach the uterine tube to fertilize the ovum

Capacitation: sperms gain the ability to fertilize the eggs („decapacitating” factors

have to be removed) Removal of proteins around the acrosomal region of the

sperm.

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1. Sperm head binding to the zona pellucida (species specific interaction between the

sperm membrane and glycoproteins (ZP) that make up the zona pellucida)

2. Sperm head undergoes acrosomal reaction (hydrolytic enzymes and the protease

acrosin are released from the acrosome)

3. Sperm penetrates the zona pellucida

4. Sperm head enters the perivitelline space5.-6. Sperm head binds to the membrane and penetrates

Ovum completes meiosis II.7.-8. Sperm tail disappears and the nucleus decondensesFusion of the haploid chromatin of the male and female gametes.

Blocking of polyspermy (cortical degranulation) enzymes contained in the cortical granules are released into the perivitelline space. This renders the zona pellucida refractory to sperm penetration, which,along with the destruction of ZP proteins, blocks the entrance of any other sperm.

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Implantation of the blastocyste

7

Immune tolerance in pregnancy

Extrauterine pregnancy

In a fully formed placenta, maternal blood circulates through the

intervillous spaces while the fetal blood flows through the chorionic villi.

Maternal and fetal blood do not mix together.

Diffusion: O2, CO2, Steroid hormones

Facilitated diffusion: Glucose

Active transport: Na+-Symportcarrier for amino acids

Endozytosis: IgG (Rh-incompatibility!)

Umbilical vein

Umbilical arteries

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Duration of pregnancy: 38 weeks „post conceptionem” or

40 weeks „post menstruationem”

Response of the mother to pregnancy:

1) Cardiac output +40%

2) Blood volume +30%

3) Blood pressure -15 mmHg

4) Dietary proteins + iron,folic acid

Recommended weight gain during pregnancy: 12 kg

3.3 kg fetus

0.7 kg placenta

1 kg amniotic fluid

0.7 kg uterus

1.3 kg blood

0.2 kg breast

5 kg fat/interstitial fluid

During pregnancy placenta is the main source of leptin. At the same time

hypothalamus becomes resistant to leptin, so appetite and food intake

increase throughout pregnancy.

Hormone levels in human maternal blood during normal pregnancy

Estradiol

Progesterone

Human chorionic gonadotropin (hCG)

Concentration

Weeks

Human placental lactogen (HPL)

Weeks

Weeks

Weeks

Weeks

Estriol

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Carbohydrates

Glycoprotein hormones

β3 ≈ β4

Hormone levels in human maternal blood during normal pregnancy

Estradiol

Progesterone

Human chorionic gonadotropin (hCG)

Concentration

Weeks

Human placental lactogen (HPL)

Weeks

Weeks

Weeks

Weeks

Estriol

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PREGNANT NON-PREGNANT

Pregnancy test

test control

antibody (free)

hCG-Antigen

antibody (fixed)

urine

Hormone levels in human maternal blood during normal pregnancy

Estradiol

Progesterone

Human chorionic gonadotropin (hCG)

Concentration

Weeks

Human placental lactogen (HPL)

Weeks

Weeks

Weeks

Weeks

Estriol

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Mother

Fetoplacental unit

Placenta

Hormone levels in human maternal blood during normal pregnancy

Estradiol

Progesterone

Human chorionic gonadotropin (hCG)

Concentration

Weeks

Human placental lactogen (HPL)

Weeks

Weeks

Weeks

Weeks

Estriol

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Myometrium

prostaglandins

depolarization

gap junctions

contractile

proteins

increased

excitability

oxytocin

stimulus

conduction

contraction

stimuli from cervix and vagina

po

sitiv

e fe

ed

ba

ck

Mother (blood)

estrogens

progesterone

increase in

oxytocin

receptors

Parturition

Development of the breast:Puberty:

Estradiol

Progesterone

Pregnancy:

Estrogens

Progesterone

Human placental lactogen

Prolactin

Glucocorticoid

Insulin

Prolactin

polypeptide (199 amino acids)

Synthesis: Hypophysis, (mammary gland, endothelium,

some neurons, T-Lympocytes)

Effect:

During pregnancy – full lobuloalveolar development of the mammary

gland, secretion of milk

Inhibits secretion of GnRH

Stimulates REM-sleep

Modulation of immune reactions

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breast

neural

impulses

estrogen

short

feedback

Sleep Regulation of prolactin

secretion

glucocorticoids

Lymphocyte

opiatesdopamine

Fetal and neonatal physiology

The endocrine regulation of growth

Learning objectives: 89, 90

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Fetal circulation

HbF (α2γ2)

HbF exhibits a low affinity

for 2,3-DPG+

Higher Hb concentration

Botalli

Arantii

vascular resistance is high in the lung

(hypoxic pulmonary vasoconstriction)

Umbilicalvein

Umbilicalarteries

upper partof the body

lower partof the body

rightventricle

gut

O2 saturation (%)

% of cardiac output

liver

Placenta

Breathing

1) increase in the surface area available for gas exchange

2) fall in pulmonary vascular resistance

ad 1) Amniotic fluid is pressed out by the birth process.

Mild hypoxia and hypercapnia, as well as cold skin trigger the first breath.

Amniotic fluid is absorbed from the respiratory system (reabsorption of Na+ and water).

+Surfactant production

Perfusing its body by breathing independently instead of utilizing placental oxygen is the first challenge of a newborn.

ad 2) Breathing increases pO2 in the lung, that dilates pulmonary blood vessels.

Local release of endothelial prostacyclin and NO.

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At birth removal of the placental circulation increases systemic vascular resistance, whereas pulmonary expansion decreases pulmonary vascular resistance.

At birth left atrial pressure beginsto exceed the right atrial pressure, causing the foramen ovale to close.

Closure of the ductus arteriosus completes the separation between pulmonary and systemic circulation (reduced prostaglandin E2 levels).

Changes in the circulation at and around birth

before birth after birth

Breathing improves blood gas parameters.

Arterial pO2 increases from approx. 25-30 to 80-100 mmHg

Arterial O2 saturation increases from approx. 60% to 95%

Switch from fetal HbF to adult HbA hemoglobin.

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Neonatal jaundice (Icterus neonatorum)

Most infants develop visible jaundice due to elevation of unconjugated

bilirubin concentration during their first week.

Relatively low activity of the enzyme glucuronosyltransferase which normally

converts unconjugated bilirubin to conjugated bilirubin that can be excreted

into the gastrointestinal tract.

In phototherapy, blue light is typically used.

„Kernicterus” is a bilirubin-induced brain dysfunction: the blood–brain barrier

is not fully functional in neonates and therefore bilirubin is able to cross the

barrier.

Growth hormone receptor signalling pathways.Reprinted from TRENDS in Endocrinology and Metabolism 12(6), J. Herrington and C. Carter-Su, Signaling pathways activated by the growth hormone receptor, 252-257, 2001, with permission from Elsevier,

The activated JAK2 molecule

phosphorylates itself and the

cytoplasmic domain of the GH

receptor on tyrosine residues.

These phosphotyrosines form

binding sites for signaling

proteins.

Growth hormone receptor

Growth hormone (GH)

Janus

Homology between GH, prolactin and hPL

Secreted in the acidophilic cells (40 % of the anterior pituitary)

Phosphorylation

+

New protein synthesis

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Growth hormone

Polypeptide (191 amino acids)

Effects:

Metabolic effects

Protein metabolism: synthesis of proteins (anabolic effect)

Fat metabolism: mobilization of stored fat (lipolysis)

Carbohydrate metabolism:

„anti-insulin” effect:

decreased insulin sensitivity of cells

decreased glucose uptake into some tissues

increased hepatic glucose output

Growth promoting effect

Liver (muscle, kidney etc.):

secretion of somatomedins (Insulin-like growth factors)

„insulin-like” activity

increased glucose uptake

increased protein synthesis

stimulated chondrocyte proliferation

doping

Somatomedin - Insulin-like growth factor

Insulin-like growth factor-1 (IGF-1) Insulin-like growth factor-2 (IGF-2)

Polypeptide

It is secreted by the liver and other tissues in response to stimulation by growth

hormone.

IGF-2 is NOT affected by growth hormone!

It regulates growth of the fetus before birth

liver

pre-pro-IGF-1

pre-pro-IGF-2

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Growth hormone-releasing hormone

Growth hormone-

inhibiting hormone

epiphyseal

growth

Liver

Lipolysis

Glykogenolysis

Protein synthesis

glucose

amino acids

free fatty acids

GHRH

Inheritance,

exercise, sleep, stress

Estrogens

Androgens

Growth hormone

stomach

hours

GH

GHRH

Somatostatin

10 p.m. 10 a.m.Thyroid hormones

Glucocorticoids

(physiological concentration!)

Increase the number of

GHRH receptors

Overproduction of growth hormone

Childhood:

Gigantism

Adulthood:

Acromegaly

Growth hormone deficiency

Childhood:

Dwarfism

Adulthood:

metabolic symptoms

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17.09.2009.

Guinness World Record

8.2. 2011.

251 cm

Enlargement of hands and feet (increase in ring size and shoe size) Increased prominence of jaw and/or forehead Thickened skin, especially on palms of hands or soles of feet, increased sweating HyperglycemiaImpaired vision (bitemporal hemianopia)Stimulation of prolactin receptors

overuse of growth hormone

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Laron-dwarfs

Pygmy is a term used for various ethnic groups whose average height is unusually

short; adult men grow to less than 150 cm in average height.

Pygmy peoples

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Regulation of growthFertilized egg adult person

Hyperplasia: increase in number of cells

Hypertrophy: enlargement of cells

+ Differentiation

Intrauterine growth: (approx. 50 cm)

Genetic information

Maternal environment (nutrition, drugs, alcohol)

Metabolic (eg. diabetes mellitus of the mother)

Hormones

Insulin

Insulin-like growth factor-2 (IGF-2)

Human placental lactogen

(Thyroid hormones)

Extrauterine growth:Growth hormone

Insulin-like growth factor-1 (IGF-1)

Androgens, estrogens

Hormones regulating Ca++ (Parathormone, Calcitonin, Calcitriol)

Thyroid hormones (permissive effect)

Glucocorticoids (oversecretion inhibits normal growth)

Cretinism