Download Hormones

Gonad Hormones : Female
Prof.Dr.Gülden Burçak
2011-2012
Ovary : produces female sex
hormones and female germ cells
 The ovarian follicles are of two functional types;
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nongrowing ( primordial) and growing
Primordial follicles degenerate (atresia)
Mature ovarian follicle (graafian) consists three
layers of cells : theca externa, theca interna and
granulosa
The oocyte is contained within the follicular fluid
After rupture of the mature follicle and release of
the ovum, granulosa and theca cells proliferate to
form the corpus luteum.
Corpus luteum is a transient endocrine organ
Hypothalamic-Pituitary-Ovarian Axis
Constant pulsatile release of GnRH from the
hypothalamus
 Synthesis, storage and secretion of
gonadotropins (FSH and LH) from the
anterior pituitary
 (-/+)Feedback relationships between the
ovarian hormones (estradiol,progesterone) ,
GnRH, FSH and LH secretions
 Cyclical ovarian function
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(+) Feedback of gonadal steroids on pituitary
E2 > 700 pmol/L,maintenance of elevated
levels for at least 48 hours
 Progesterone, only after the pituitary has
been exposed to prolonged high levels of E2
 Chronic stress or profound weight loss can
disrupt the pattern of GnRH secretion and
lead to anovulation and amenorrhea.
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In childhood : HPA remains highly sensitive to
(-) feedback effects of gonadal steroids
In puberty : adrenarche, decreased
sensitivity of HPA to (-) feedback and
gonadarche, increased E2, onset of ovulatory
cycles
androstenedione,DHEA, DHEAS: 6-8 years
pulsatile secretion of GnRH is critical in the
initiation of puberty.
in girls FSH increases earlier than LH
Ovarian steroid hormones
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Estrogens C18 (Granulosa)
17 ß-Estradiol
Estrone : post-menopause
Estriol : in pregnancy
Progestagens C21 (Corpus Luteum)
Pregnenolone
Progesterone
17 OH Progesterone
Androgens C19 (Theca)
DHEA, androstendione, testosterone,
dihydrotestosterone
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Aromatization of androgens in granulosa cells (also
some estradiol in corpus luteum)
Three hydroxylation steps, O2 and NADPH
P450 mixed-function oxidase
Testosterone
estradiol
Androstendione
estrone
Peripheral aromatization of androgens
Adrenal androgens : DHEA (major but weak),
androstendione (potent)
Conversion : 3β-hydroxy steroid dehydrogenase,Δ5,4
isomerase
During pregnancy and post-menopausal period
In adipose cells, liver, skin and other tissues
Increased aromatase activity , estrogenization in
cirrhosis,hyperthyroidism, aging and obesity
Ovarian nonsteroidal hormones
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Cytokines, growth factors and neuropeptides
Inhibins : multifunctional glycoproteins A and B
Inhibin A(αßA) is low in early follicular phase, high in
the luteal phase ;inhibin B(αßB) parallels FSH
Inhibin B synthesized in granulosa cells and inhibin A
in corpus luteum cells.
increase theca cell androgen production
Ovarian-pituitary negative feedback relationships
Activins : disulfide-linked dimers of the ß-subunits
of inhibin.
Activin A produced in the ovary augments the
effects of FSH
Activin B produced in the gonadotropes increases
FSH secretion
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60% loosely bound to albumin (>3000mg/L)
38% bound with high affinity to SHBG
% 2-3 is free
Progesterone binds strongly to CBG and
weakly to albumin
The binding proteins provide a circulating
reservoir of hormone
The metabolic clearance rates are inversely
related to SHBG affinity
Conjugated derivatives are not bound
SHBG synthesis in
hepatocytes
Increased by thyroid hormones, estrogens (510x),decreased levels of androgens,high
carbohydrate diet, stress, aging, cirrhosis.
 Decreased by androgens (2x)
hyperprolactinemia, increased growth
hormone, obesity, menopause, progestins,
glucocorticoids.
 The normal level of SHBG is about 30-50%
lower in men than in women.
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Metabolism of ovarian steroids
In the liver,estradiol (E2) and estrone(E1 ) are
converted to estriol (E3) and conjugated with
glucuronic a. or sulfate; excreted by the
kidney
 Oral estrogens are effective because the
activity of conjugating enzymes are low
 Progesterone is converted to pregnanediol,
conjugated (sodium pregnanediol-20
glucuronide) and excreted by the kidney
 Some synthetic steroids have progestational
activity and avoid hepatic metabolism;used as
contraceptives
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Estrogens
Maturation of primordial germ cells
 Provision of the hormonal timing for
ovulation
 Developing the tissues that will allow
for implantation of the blastocyt
 Establishment of the milieu required for
the maintenance of pregnancy
 Provision of the hormonal influences for
parturition and lactation
 Anabolic effects on bone and cartilage
 Vasodilation and heat dissipation
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Progestins
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generally require the previous or concurrent presence
of estrogens
reduce the proliferative activity of the estrogens on
the vaginal epithelium
convert the uterine epithelium from proliferative to
secretory ; preparing it for implantation of the
fertilized ovum.
enhance the development of the acinar portions of
breast glands after estrogens have stimulated ductal
development.
decrease peripheral blood flow, decrease heat loss
Menstrual cycle-Follicular phase
A particular follicle begins to enlarge under the
influence of FSH
 E2 and LH rise, E2 reaches its max. level 24 hours
before the LH (FSH) peak and sensitizes the
pituitary to GnRH
 LH peak heralds the end of the follicular phase and
precedes ovulation by 16-18 hours.
 Follicle rupture ,releasing an ova
 Continual administration of high doses of estrogen
(oral contraceptives) supresses LH and FSH release
and inhibits the action of GnRH on the pituitary
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Menstrual cycle-Luteal phase
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The granulosa cells of the ruptured follicle luteinize
and form the corpus luteum
Corpus luteum produces progesterone and some E2
Estradiol peaks about midway through the luteal
phase and then declines to a very low level.The major
hormone is progesterone
LH is required for the early maintenance of the
corpus luteum and the pituitary supplies it for 10days.
If implantation occurs LH function is assumed by hCG
hCG stimulates progesterone synthesis by corpus
luteum until placenta begins to make in large amounts
In the absence of implantation corpus luteum
regresses causing a decrease in progesterone.
Placental hormones maintain
pregnancy
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Human chorionic gonadotropin hCG
structurally similar to LH
supports corpus luteum until placenta produces sufficient
amounts of progesterone
Progestins
6-8 weeks : corpus luteum produces progesterone
thereafter : placenta produces progesterone (30-40 times
more)
Placenta does not synthesize cholesterol and depends on
maternal supply
Estrogens
E1, E2, E3
The major hormone is E3 synthesized by feto-placental function
Placental lactogen (PL): chorionic somatomammotropin/ placental
growth hormone
Steroid metabolism by the fetalmaternal unit
Mammary gland development
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E2 (for ductal growth)
Progesterone (alveolar proliferation)
Additional actions of prolactin,
glucocorticoids, insulin
Progesterone inhibits milk production and
secretion in late pregnancy
Lactation : prolactin and oxytocin
The production of oxytocin and it’s receptors
are stimulated by estrogens and inhibited by
progesterone
Menopause
Weak estrogen ,E1, produced by
aromatization of androstenedione
 Marked increases of LH and FSH
 Estrone is not always able to prevent
the atrophy of secondary sex tissues
and osteoporosis
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Pathological States
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Hypogonadism
Gonadal dysgenesis
Polycystic ovary syndrome : overproduction of
androgens ( hirsutism, obesity,irregular
menses,impaired fertility)
Hypergonadism
Granulosa-theca cell tumors
Persistent trophoblastic tissue : benign
hydatiform mole and its malignant form ,
choriocarcinoma
Infertility
Elevated testosterone,decreased SHBG
DHEA sulphate :adrenal ;androstenedione : ovary