2018. 03. 13.

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Female reproductive system (LO 66).

Neuroendocrine control of pregnancy

(LO 67).

Gabriella Kékesi

Female reproductive system

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• Fetal life:

• Oogonium (praemeiotic germ cell)

• Primary oocyte: embrionic life 20. w 6-7 million; at birth

400 000; at puberty 200 000; 400 during fertile period

• 2. trimester: Primary oocyte (20 µm, 2n DNS) + granulosa

cells + basal membrane = primordial follicle

• Meiotic division – 4n DNS

• Prepubertal development: recruitment and apoptosis

• At puberty – cyclic recruitment; cohors, FSH, dominant

follicle 1/10

• Primary follicle (>60 µm): oocyte, zona pellucida (gp)

and z. granulosa

• Secundary follicle (120 µm): stroma cells – theca interna

(hormone secretion) and externa

• Terciary follicle: antral fluid between granulosa cells

containing hormones

• Graaf-follicle (10-20 mm) – 1. meiotic division (2nDNS)

• Ovulation – beginning of the 2. meiosis

• Fertilization – 2. meiotic division (1n DNS)

Ooogenesis

14 days

190 days

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Two-cell hypothesis of estradiol synthesis and

secretion

• estradiol (E2), estriol, estron

• 2-3% free, 97-98 % binded: TBG, albumin

• ERα and β

Granulosa cell Theca interna cell

Late phase

LH receptorLH receptorFSH receptor

Cholesterol → progesteron Cholesterol → progesteron

androstenedioneestradiol

Secreted into the follicular fluid

Estrogen synthesis during lifetime• Low level after birth

• Between puberty and menopausa – cyclic

• GnRH

• FSH: developing follicles, steroid secretion, peptide hormone secretion in

ovary

• LH: hormone secretion

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Gonadotropin secretion throughout life

Target organ/cell Estrogen effect

Sexual organs

Endometrium

Uterus smooth musle

cervix

Vagina

Proliferation

Hypertrophy during pregnancy

excitability ↑

Prostaglandin synthesis ↑ at the end of pregnancy

Fluid secretion

Epithelial secretion

acidic pH

Breast Proliferation

Inhibit secretion during pregnancy

Adenohypophysis low cc – FSH-, LH-secretion inhibition

high cc for 48-50 hs – LH-surge

PRL secretion during pregnancy

Other TBG synthesis ↑

LDL synthesis ↑

Retain bone matrix – inhibits osteoclast differentiation

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Progesterone

• Production:

– steroid

– Place of production: corpus luteum; adrenal cortex; placenta

– Stored in adipose tissue

• Involved in the menstrual cycle, pregnancy, and embryogenesis of humans

– converts the endometrium to its secretory stage to prepare the uterus for

implantation

– affects the vaginal epithelium and cervical mucus, making it thick and

impenetrable to sperm

– appears to decrease the maternal immune response to allow for the

acceptance of the pregnancy

– decreases contractility of the uterine smooth muscle

– inhibits lactation during pregnancy

– a drop in progesterone levels is possibly one step that facilitates the

onset of labor

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Regulation of hormone secretion

GnRH

FSH, LH

early follicular

phase

late follicular

phase

Estradiol (E2) Progesteron

inhibition

stimulation

intermittent!!!

Luteal phase

Estradiol (E2)

Concentration-dependent feedback!!!

Ovarian cycle

• established during puberty, when GnRH secretion by the hypothalamus

stimulates the anterior pituitary gland to secrete FSH and LH.

• Follicular phase in which the follicle is growing and developing

• Ovulation in midtime

• Luteal phase, which occurs when the egg has been ovulated and the corpus

luteum is secreting estrogen and progesterone.

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Ovarial cycle

• Early follicular phase

• Late follicular phase

• Ovulation

• Luteal phase

Follicular phase

• Early follicular phase

– Destruction of corpus luteum –

progesterone ↓ and estradiol is low

– FSH is still high – granulosa cells

count ↑ - estradiol and inhibin B ↑ -

FSH ↓ - cohort selection – dominant

follicle

• Late follicular phase

– LH – progesterone and estradiol ↑

from granulosa cells

– Preovulatory phase: estrogen ↑↑ - LH

surge and FSH ↑ 24 h before

ovulation

– Estradiol ↓↓ - positive feedback

decline

– LH-surge – luteinization of granulosa

cells – progesterone ↑ - basal body

temperature ↑

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Ovulation

• Progesterone – matrix

metalloproteases - egg is ovulated

from Graaf follicle

• Prostaglandines ↑ –

„inflammation”

• Egg is ready for fertilization

Luteal phase

• 14 days

• Corpus haemorrhagicum

• Luteinization of granulosa and

theca cells (reprogramming, new

enzymes) – corpus luteum

(temporary endocrine organ)

• Progesterone, estradiol, inhibin A

• Progesteron: preparation for

implantation (uterine cycle)

• Without fertilization – luteolysis –

corpus albicans – steroid level ↓ -

menses

• Fertilization – corpus luteum

graviditatis (6 weeks)

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• 1) The proliferative phase occurs between days 5-14

and coincides with the development of the follicle in

the ovarian cycle. The estrogen secreted from the

developing follicle stimulates the endometrial lining

to be rebuilt in preparation for receipt of a fertilized

egg. It takes place in the stratum functionalis of the

endometrium. Estrogenes →

• Stroma cells – growth factors

• Spiral arteries, angiogenesis, tubular glands

• 2) The secretory phase coincides with the luteal

phase of the ovarian cycle. The endometrial lining

continues to grow and prepare for a fertilized egg.

Progesterone →

• Differentiation, secretion of glans

• Stroma cells – decidual cells

• Lymphocta, mast cells, granulocyta appear

• 3) The menstrual phase marks the start of the

menstrual cycle. It occurs between days 1-5, it begins

with the beginning of the follicular phase of the

ovarian cycle. Progesterone decline →

• Stroma cells – inflammatory mediators – uterus

contraction, arterial spasm

• Protelytic enzymes – arterial decay – bleeding

(30-50 ml).

Uterine/endometrial cycle

physiological changes to the uterine lining in

response to the hormonal events of the

ovarian cycle

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Cervical cycle

• Follicular phase - estrogen – cervical mucus: thin, more, more

elastic secretion

• Luteal phase – progesterone – cervical mucus: thick, viscous

and less secretion

Neuroendocrine control of pregnancy

I. Sexual intercourse

II. Fertilization

III. Pregnancy

IV.Placenta

V. Child birth (delivery)

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Sexual intercourse

• Mechanical stimuli

• Clitoris (~glans penis), labium minora (~corpus cavernosum) filled with

blood

• Blood flow of the vagina increases, mucosal transsudation

• Vagina, uterus and pelvic stripe muscle contraction - rhytmic

• Autonomic reactions

• No refracter period ↔ male

• Oxytocin secretion

Fertilization

Sperm:

5 min

200/200 million

1/200

48 hs

acidic pH

capacitation

ovum:

cumulus oophorus

1-2 day

24 hs

• zona pellucida transition

• protection against polyspermia

• last step of meiotic phase (1n)

• praeembryo

• implantation day 7

• high progesterone level

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Pregnancy

• Time of gestation

• Uterus during pregnancy is in rest

– Relaxin, PGI2, NO, (β2-agonists), progesteron

– the tight junction between smooth muscle cells are undeveloped

• Maternal hormones: LH and progesterone from corpus luteum

• Placental hormones:

– Estrogenes

– Progesterone

– hCG (human chorional gonadotropin)

– hPL (h. placental lactogen)

– chorional corticotropin

– placental GnRH

– h. chorional TSH

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Placenta

Nourishment of the fetus and elimination of its waste products, hormone prodution

• Steroid synthesis from week 8

– progesterone, estriol from maternal cholesterol

– Foetoplacentar unit: foetal adrenal gland cortex & placenta

– No uterus contraction, breast tissue proliferation, inhibition of milk production

• hCG:

– Corpus luteum

– Testosterone production in the male fetus

• hPL:

– Maternal effect (~acromegalia)

– Diabetes of pregnancy

Placenta

• Connects the developing fetus to the uterine wall - Umbilical cord

– Two umbilical arteries

– One umbilical vein

• Components:

– Fetal: develops from the same blastocyst that forms the fetus

– maternal part: develops from the maternal uterine tissue

• Size and shape:

– 500g; discoid

• Functions:

– Nutrition

– Excretion

– Immunity (cloaking from immune system of mother)

– Barrier function

– Endocrine function

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Protective (barrier) functions … BUT …• against infectious agents (IgG)

• there are some microbes that can cross this barrier, occasionally following placental lesions

and can lead to a miscarriage or leave behind congenital abnormalities. Transmission

possibilities:

– the transplacental infection during or shortly before birth

– the passage of the child through the maternal birth canal (HIV in the cervix mucus).

• Sexually transmitted diseases:

– treponema pallidum; HIV (15-20%) ; Gonorrhea (blennorrhoea neonatorum)

• Fetotoxic infections: rubella virus; toxoplasmosis; listeriosis; cytomegalovirus

• Medications:

– antibiotics and corticoids can pass through the placental barrier.

– certain steroid hormones get through as well (depending on their size).

• medications with well-documented teratogenic effects: e.g., Thalidomide (tranquillizer,

Contergan scandal), Roaccutane

• Barbiturates, alcohol… (abuse, addiction)

Endocrine function

• Before implantation hormone production is ensured through ovarian and

hypophyseal hormones

• During the pregnancy the hormone concentration in the maternal blood is

regulated by the cooperation of the placental, hypophyseal and fetal

suprarenal hormones as well as hormones from the gonads:

– The activity of the corpus luteum decreases progressively with the beginning of the 8th

week

– Replaced by the placenta at the end of the 1st trimester

At the beginning of the pregnancy the

syncytiotrophoblast produces the HCG

that has effects at both the level of the

infantile suprarenal glands (induces

DHEA) and the maternal corpus luteum

(induced secretion of E2 and P).

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Figure 3 The placenta, in concert with the fetal adrenal glands and liver, constitutes an

interactive endocrine entity, known as fetoplacental unit

Monticone, S. et al. (2012) Adrenal disorders in pregnancy

Nat. Rev. Endocrinol. doi:10.1038/nrendo.2012.155

Adapted from Rehman, K. S., Carr, B. R. and Rainey, W. E. The human placental/fetal adrenal endocrine cascade in parturition: the

role of cortisol and corticotrophin-releasing hormone. Topical Endocrinology 25, 16–22 (2005) with kind permission of the publisher

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Labour, delivery

• physiological phases:– 1. preparatory phase:

• Tight junctions between muscle cells

• Oxytocin receptors ↑

– 2. phase:• Uterus contraction

• Dilatation of cervix

– 3. phase:• Diaphragma, thoracal and abdominal muscle contraction

• Delivery of the infant

• Delivery of the palcenta (afterbirth)

• Tonic uterus contraction – reduce bleeding (oxytocin)

• fetal glucocorticoids from adrelnal gland cortex

• estradiol production in placenta

• PGE2, PGF2α synthesis in uterus – contraction

• Oxytocin: permissive role, terminal contraction at the end of the 2. phase

Breast

• Sexual dimorphism after puberty (estrogen secretion in ovary)

• Prolactin, GH, glucocorticoids

• Amount of fat and connective tissue increases, proliferation, enlargement of mammary gland

• Pregnancy:– Secretion gland (PRL, hPL, esztrogens, progesterone)

– Proliferation, new alveoles

• Postpartum:

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Prolactin (PRL)

• proliferation, enlargement of mammary gland during pregnancy

• milk production

• Regulatory role of PIF, PrRH, TRH

• Breast feeding, estrogen, stress and hypothyreosis increases its production

• Smoking decreases its production

• High PRL – infertility