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;
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
 (+) 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.
 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
 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
 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
 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
 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 (5-
10x),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.
 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
 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
 Progestins
 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
 Menstrual cycle-Luteal phase
 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
 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 fetal-
maternal unit
 Mammary gland development
 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
 Pathological States
 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