Gonads and hormones
of the reproductive system
Bi1100en Hormones – Cellular and Molecular Mechanisms
▪ derived from cholesterol
▪ differences in ring structure
and side chains
(17-hydroxylase)
▪ usually not stored (regulation
at the level of synthesis)
▪ lipid soluble
▪ produced in the ovary,
testes, placenta
and adrenal glands
Steroid hormones
Dorland's, 2000
Steroid hormones
pregnenolone (21 C)
↓
progesterone
(progestogens, 21 C)
↓
androgens (19 C)
estrogens (18 C)
estron (E1), estradiol
(E2), DHEA,
testosterone,
dihydrotestosterone
and other effective
hormones
Regulation of sex hormones
▪ precursors for synthesis are present in all relevant glands
▪ presence of synthetic enzymes (hydroxylation of C17 > 17-ketosteroids)
▪ signal via receptors for superior regulatory hormones (hypothalamicpituitary-gonads
axis; eg FSH or LH)
▪ degraded in the liver (conjugation with OH groups to sulphates and
glucuronic acid) and excreted in the bile or urine
Testicles (testes)
▪ parenchyma composed of seminiferous tubules, walls formed by germinal
epithelium > spermatogenesis
▪ spermatogonia protected and sustained by Sertoli cells (produce androgen
transporter, inhibin and anti-Müllerian hormone)
▪ interstitial cells located adjacent to the seminiferous tubules called Leydig
cells (testosterone production)
▪ steroid male sex hormones (19 C
in the structure)
▪ testosterone (T),
5α-dihydrotestosterone (DHT),
17-ketosteroids
(dehydroepiandrosterone/DHEA
and other molecules with weaker
androgenic effects)
▪ DHT and estradiol (E2) are
formed from T in target cells
and then released to plasma >
DHT binds to T receptors; E2
affects eg hypothalamus,
pituitary gland or production of
ejaculate)
▪ regulation via the hypothalamus
(GnRH) and pituitary gland
(FSH, LH)
▪ negative feedback (T, DHT, E2)
▪ inhibin
Androgens
Androgens - testosterone (T)
▪ men: 95 % testosterone produced in testes + 5 % produced in adrenal cortex
▪ women: ovaries and adrenal cortex
▪ Leydig cells stimulated by FSH (increases expression of LH receptor) and
LH (induces the synthesis of T)
▪ Sertoli cells stimulated by FSH > synthesis of androgen binding protein (T
transport) and inhibin (regulation of endocrine production)
▪ plasma concentrations 15 times higher in men than in women (decreases
with age)
▪ protein-bound transport (98 % albumin and sex hormone binding globulin)
▪ the testicles are target organ for T > the seminiferous tubules are protected
by hematotesticular barrier > T must be bound to the androgen-binding
protein to get across the barrier!
Androgens - function
▪ spermatogenesis (paracrine)
▪ male gender differentiation in the
prenatal period
▪ development of male secondary
sex characteristics
▪ growth and function of the
genitals, prostate and seminal
vesicles
▪ stimulating effect on
hematopoiesis
▪ anabolic effects
▪ libido, potency, ability to have sex
▪ influencing behaviour by affecting
CNS (e.g. aggression)
Androgens - mechanism of action
▪ binding to nuclear androgen receptors (directly T or after converting to DHT)
▪ conversion to estradiol (aromatase) and estrogen receptor activation
▪ dimer formation and translocation to the nucleus > influencing gene expression
Ovaries
▪ epithelium covering the
surface
▪ ligament tunica albuginea
▪ cortex (contains follicles)
▪ medulla (connective tissue
with blood vessels and
nerves)
▪ follicles (oocyte + follicular
cells)
▪ layer of follicular cells and
ligaments theca folliculi
(steroids, inhibin)
▪ humans about 400 thousand
of follicles; 400–450 ruptures
▪ primordial > primary >
secondary > Graafian f.
▪ corpus luteum (estrogens,
progesterone)
antrum
folliculi
Ovaries - structure of follicles
Ovaries - regulation of hormonal activity
▪ hypothalamic-pituitary-ovarian axis
▪ negative feedback
▪ sex hormones belonging to steroids (18 C in the structure)
▪ synthesized from 17-ketosteroid androstenedione and partly from testosterone
▪ granulosa and theca (produces androgens > granulosa) cells in the ovaries,
placenta, adrenal cortex, Leydig cells, some target cells of testosterone
▪ estradiol (E2),estron (E1) and estriol (E3)
▪ relative efficiency E2 : E1 : E3 is 10 : 5 : 1
▪ transported by the blood mainly in complex with sex hormone binding globulin
▪ degraded mainly in the form of estriol
Estrogens
Estrogens - function
▪ typical sexual behavior of females (estrus)
▪ stimulate the formation of secondary sex characteristics during puberty
(breast growth, vaginal changes, subcutaneous fat distribution, hip growth) +
cooperation with androgens (pubic hair grow)
▪ stimulate uterine mucosa proliferation and uterine muscle contractions
(increased sensitivity to oxytocin)
▪ thickening of vaginal mucosa and increased losses of epithelial cells
(glycogen from them is processed by bacteria to produce lactic acid >
decreased pH and lower risk of infections)
▪ during the menstrual cycle stimulate the maturation of follicles in the
ovaries
▪ regulate oocyte progression through the fallopian tube and prepare it for
sperm penetration (regulation of fertilization)
▪ changes the consistency of the cervical mucus plug (support of sperm
movement and survival during ovulation)
▪ increase blood clotting
▪ affect water management (local and renal retention > edema)
▪ inhibits bone growth in length, speed up closure of epiphyseal crevices,
stimulate osteoblasts; reduce LDL levels and increase VLDL and HDL
▪ affect the CNS (sexual and social behavior etc.)
Estrogens - mechanism of action
ERα
▪ uterus
▪ vagina
▪ blood vessels
▪ breasts
ERβ
▪ ovaries
▪ prostate
▪ synthesis from pregnenolone; 21 C in structure
▪ corpus luteum, ovarian follicles, placenta, adrenal cortex (also in men)
▪ transported in plasma bound to albumin and globulin transcortin
▪ the major degradation product of progesterone is pregnanediol (liver)
▪ often antagonistic action with estrogens (necessary previous or current effect
of estrogens)
Function:
▪ preparing a woman's genitals for receiving and maturing a fertilized
oocyte and maintaining pregnancy
▪ after exposure to E, stimulates growth myometrial and endometrial
growth and remodeling (gland remodeling, change in vascularity and
glycogen content) = transition from proliferative to secretory phase
▪ support nidation of fertilized oocyte, reduces activity of myometry
▪ reduces the external uterine cervix and changes the consistency of the
mucus plug (impermeability to sperm)
▪ in luteal phase inhibits the release of LH
▪ increase of basal temperature (thermogenic effect)
Progestogens / progestins - progesterone
Progesterone - mechanism of action
▪ nuclear (nPR) and membrane (mPR) progesterone receptors
▪ isoforms A and B
Menstrual
cycle
▪ approx. 28-day secretion:
Gonadotropin-releasing
hormone (GnRH)
Dopamine (PIT)
Follicle-stimulating (FSH)
Luteinizing (LH)
Prolactin (PRL)
Progesterone (P)
Estrogens (E)
Inhibin
▪ preparing one egg for
fertilization, the female
genitals for receiving
sperm and nidating oocyte
▪ follicular / proliferative
phase, ovulation, luteal /
secretory phase
Menstrual
cycle
▪ bleeding (1st day of the
cycle)
Proliferation / follicular
phase:
▪ endometrial growth and
renewal
▪ under the influence of FSH
matures about 20 follicles
> one becomes dominant
and increases production
of estrogens > E2 has a
positive feedback effect
on adenohypophysis and
the production of FSH and
LH > stimulation of LH
synthesis and release >
ovulation
Menstrual
cycle
Secretory / luteal phase:
▪ increased mucosal
secretion and lower
myometrial contractility,
preparation for nidation
▪ corpus luteum develops >
progesterone production
> P and E2 dampens
production of GnRH and
thus also LH and FSH
(negative feedback of E2)
> without fertilization and
nidation, CL decays the
22nd day of the cycle
>decrease of P and E
concentrations >
vascular constriction and
endometrial ischemia
Menstrual cycle - hormonal regulation
Follicular phase:
▪ low LH levels promote androgen production in thecal cells and FSH induces
aromatase in granulosa cells that forms estrogens from androgens
synthesized in theca
▪ estrogens increase the density of FSH receptors in the follicle (formation of a
dominant follicle)
▪ at the beginning of the follicular phase estrogens create negative feedback
and suppress FSH and LH (indirect effect on GnRH)
▪ in the late follicular phase, estrogens increase the amount of LH receptor in
granulosa cells > progesterone and its conversion to other androgens in
theca > more estrogens
▪ inhibin suppresses FSH
▪ estrogens increase LH secretion (positive feedback) > LH-peak > ovulation
Luteal phase:
▪ LH, FSH and estrogens turn follicle into corpus luteum > significant increase
in progesterone > P and E suppress secretion of GnRH, LH and FSH
(negative feedback) > decrease in P and E > resumption of FSH secretion
Hormonal regulation of pregnancy
▪ mother's ovarian hormones > placental hormones protect corpus luteum
▪ placental hormones enter the circulation of fetus and mother
▪ placenta needs steroid precursors from adrenal cortex of mother and fetus >
produce P and E > DHEA in adrenal cortex > E/T in the placenta/testes
▪ human chorionic gonadotropin (HCG), corticotropin-releasing h. (CRH),
estrogens (E), progesterone (P), human placental lactogen (HPL),
POMC and others
Hormonal regulation of pregnancy:
Human chorionic gonadotropin (HCG)
▪ produced in placenta from day 10 of pregnancy (pregnancy tests from urine)
▪ 237 AA, heterodimer (α subunit identical to LH, FSH and TSH)
▪ acts through the hHCG receptor and cAMP
▪ significant action in the first trimester
▪ replaces the action of LH and maintains the production of P and E in
corpus luteum (produced mainly by placenta from week 6), which keep the
endometrium in the secretory phase
▪ stimulates production of DHEA, DHEA-S and other steroids in adrenal cortex
▪ suppresses the maturation of follicles in the mother's ovary (instead of LH)
Hormonal regulation of pregnancy:
Human placental lactogen (HPL), corticotropin (CRH)
HPL
▪ human chorionicsomato(mammo) tropin
▪ produced by the placenta
▪ increasing concentrations during pregnancy
▪ stimulates mammary gland growth and milk production, increases the
concentration of glucose in the mother's blood
▪ affects the growth and development of the fetus
CRH
▪ produced in the placenta
▪ the key role in inducing childbirth (the length of pregnancy depends on the
rate of its cummulation)
▪ supports ACTH secretion by fetal pituitary > ↑ cortisol in fetal adrenal glands
> ↑ CRH (positive feedback)
▪ stimulates DHEA production by fetal adrenal glands > E in the placenta
▪ at the end of pregnancy E predominates over P > induced expression of
oxytocin receptors in uterine muscle cells and increasing uterine irritability
> oxytocin secretion due to irritation of baroreceptors in the uterus
Activin and inhibin
▪ belongs to TGF-β protein family (also e.g. anti-Müllerian hormone)
▪ activin is dimer of identical or very similar β subunits linked by disulfide
bridge
▪ inhibin has the identical β subunit but remotely related α subunit
▪ gonads, pituitary gland, placenta and other organs (e.g. corpus luteum)
▪ binding to transmembrane receptors with kinase activity
▪ almost opposite biological activity
▪ A supports x I suppresses FSH production and secretion
▪ they also affect cell proliferation and differentiation, metabolism, immunity or
wound healing processes