Transcript Estrogen and Progesterone

Estrogen and Progesterone
부산백병원 산부인과
박영미
Natural human steroid hormones
Glucocorticoids
 cortisol
Mineralocorticoids
 aldosterone
Sex steroids
 Androgens
 Estrogens
 Progestagens
Androgens
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testosterone
dehydroepiandrosterone (DHEA)
dehydroepiandrosterone sulfate (DHEAS)
androstenedione
dihydrotestosterone (DHT)
Estrogens
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estradiol
estrone
estriol
Progestagens
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progesterone
Estrogen
Estrogens are a group of steroid compounds,
functioning as the primary female sex hormone.
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oral contraceptives
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estrogen replacement therapy in post
menopausal women
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hormone therapy for transsexual women
Like all steroid hormones, estrogens readily
diffuse across the cell membrane; inside the cell,
they interact with estrogen receptors.
Functions
: Significantly higher levels in women of
reproductive age
The development of female secondary sex
characteristics, such as breasts
The thickening of the endometrium
Regulating the menstrual cycle.
In males
 maturation of sperm
 healthy libido
Structural
 promote formation of female secondary sex
characteristics
 stimulate endometrial growth
 increase uterine growth
 maintenance of vessel and skin
 reduce bone resorption, increase bone formation
Protein synthesis
 increase hepatic production of binding proteins
Coagulation
 increase circulating level of factors 2,7,9,10,
antithrombin III, plasminogen
 increase platelet adhesiveness
Lipid
 increase HDL, triglyceride, fat deposition
 decrease LDL
Fluid balance
 salt and water retention
Gastrointestinal tract
 reduce bowel motility
 increase cholesterol in bile
Cancer
 About 80% of breast cancers rely on supplies of the
estrogen to grow.
 Increased risk of developing endometrial cancer has
been noted with increased levels of natural estrogen
 Suppression of production of estrogen is a treatment
for these cancers.
Types of estrogen
The three major naturally occurring estrogens
: estradiol, estriol, estrone
From menarche to menopause
: the primary estrogen is 17β-estradiol
In postmenopausal women
: more estrone is present than estradiol.
Estradiol is produced from testosterone and estrone
from androstenedione.
Estrone is weaker than estradiol.
Estradiol
Production
During the reproductive years, most estradiol is
produced by the granulosa cells of the ovaries
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by the aromatization of androstenedione to estrone
by conversion of estrone to estradiol by 17βhydroxysteroid reductase
Smaller amounts of estradiol are also produced by
the adrenal cortex, and (in men), by the testes.
Also produced in the brain and in arterial walls.
In particular, fat cells are active to convert
precursors to estradiol, and will continue to do so
even after menopause.
Effects
Female reproduction
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Growth hormone for tissue of the reproductive organs,
supporting the lining of the vagina, the cervical glands, the
endometrium and the fallopian tubes
 enhances growth of the myometrium
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Maintain oocytes in the ovary
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During the menstrual cycle,
luteinizing hormone surge, inducing ovulation
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In the luteal phase estradiol,
prepares the endometrium for implantation
Sexual development
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The development of secondary sex characteristics in
women is driven by estrogens, specifically estradiol
 breast development
 changes in the body shape affecting bones, joints, fat
deposition, fat structure and skin composition
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These changes are
 initiated at the time of puberty
 most enhanced during the reproductive years
 less pronounced with declining estradiol support after
the menopause.
Bone
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Individuals without estradiol (or other estrogens)
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tall and eunuchoid as epiphysieal closure is delayed or
may not take place.
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bone structure is affected resulting in early osteopenia
and osteoporosis.
Women past menopause
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accelerated loss of bone mass due to a relative estrogen
deficiency.
Brain
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Estrogens can be produced in the brain from steroid
precursors.
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As an antioxidant, they have been found to have
neuroprotective function.
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The positive and negative feedback loop of the
menstrual cycle involve ovarian estradiol as the link to
the hypothalamic-pituitary system to regulate
gonadotropins.
Blood vessels
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Improvement in arterial blood flow has been
demonstrated in coronary arteries.
Oncogene
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Estradiol supports certain cancers,
notably breast cancer and cancer of the uterine lining.
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Several benign gynecologic conditions that are
dependent on estrogen such as
endometriosis, leiomyoma, and uterine bleeding
Liver
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It can lead to cholestasis
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It affects the production of multiple proteins including
lipoproteins, binding proteins, and proteins responsible
for blood clotting
Pregnancy
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The effect of estradiol, together with estrone and estriol,
in pregnancy is less clear.
Promote uterine blood flow, myometrial growth,
 Sitmulate breast growth and
 At term, promote cervical softening and expression of
myometrial oxytocin receptors
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Therapy
Hormone replacement therapy
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Severe side effects of low levels of estradiol in a
woman's blood
: Often such therapy is combined with a progestin
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Treatment of infertility in women when there is a need to
develop sperm-friendly cervical mucus or an appropriate
uterine lining.
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Maintain female hormone levels in male-to-female
transsexuals.
Hormonal contraception
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A synthetic form of estradiol, called ethinylestradiol is a
major component of hormonal contraceptive devices
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Combined forms of hormonal contraception contain
ethinylestradiol and a progestin
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the inhibition of GnRH, LH, and FSH.
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prevent ovulation and thus prevent pregnancy
Other types of hormonal birth control contain only
progestins and no ethinylestradiol.
List of estradiol medications
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Oral versions : Estrace®, Activella®,
Progynova®, estrofem®
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Transdermal preparation : Alora®, Climara®, Vivelle®,
Menostar®, Estraderm TTS®
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Ointments : Estrasorb Topical®, Estrogel®
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Injection : Lunelle® monthly injection
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Vaginal ointment : Estrace Vaginal Cream®,
Premarin Cream®
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Vaginal ring : Estring®
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Conjugated estrogen preparations : Premarin®.
Contraindications
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women who are pregnant or are breastfeeding
women with unexplained uterine bleeding
certain forms of cancer
prone to blood clotting disorders
Side effects
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uterine bleeding
breast tenderness
nausea and vomiting
chloasma
cholestasis
migraine headaches
Estrone
Estrone is produced primarily from androstenedione
originating from the gonads or the adrenal cortex
In premenopausal women
: more than 50% of the estrone is secreted by the ovaries
In prepubertal children, men and non-supplemented
postmenopausal women
: the major portion of estrone is derived from peripheral
tissue conversion of androstenedione
Interconversion of estrone and estradiol
: occurs in peripheral tissue
Bioassay data
: the estrogenic action of estrone is much less than estradiol
Estrone is primary estrogenic component of several
pharmaceutical preparations, including those containing
conjugated and esterified estrogens
In premenopausal women
: estrone levels generally parallel those of estradiol
After menopause
: estrone levels increase, possibly due to increased
conversion of androstenedione to estrone
Estriol
Estriol is produced almost exclusively during
pregnancy
Estriol is the major estrogen produced in the
normal human fetus
During pregnancy the production of estriol
depends on an intact maternal-placental-fetal
unit
Fetal-placental production of estriol leads to a
progressive rise in maternal circulating levels
reaching a late-gestational peak several orders
of magnitude greater than non-pregnant levels
Estriol has been suggested to be less
carcinogenic than estradiol and estrone in
animal studies.
At doses effective for the relief of
postmenopausal symptoms, estriol does not
induce endometrial proliferation to the extent of
the other estrogens.
Topical estriol
: postmenopausal genital atrophic changes
: urinary incontinence.
Estrogen receptor
Distribution
All the ERs are widely distributed.
The ERα is found in
endometrium, breast cancer cells,
ovarian stroma cells, the hypothalamus.
The ERβ has been documented in
kidney, brain, bone, heart, lungs,
intestinal mucosa, prostate, endothelial cells.
Binding affinity
Different estrogenic compounds have different
binding affinities for alpha and beta ERs:
17-beta-estradiol binds equally well to both
receptors.
estrone and raloxifene bind preferentially to the
alpha receptor.
estriol to the beta receptor.
Selective estrogen receptor modulators (SERM)
: the concept is based on the ability to selectively
activate or block one type of ER
Tamoxifen
: ER agonist in bone and uterus
: ER antagonist in breast tissue
-> used as a breast cancer treatment
Disease : Cancer
Estrogen receptors are overexpressed in around 70% of
breast cancer cases, referred to as "ER positive".
Two hypotheses have been proposed to explain why this
causes tumorigenesis
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Firstly, binding of estrogen to the ER stimulates
proliferation of mammary cells, with the resulting
increase in cell division and DNA replication leading to
mutations
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Secondly, estrogen metabolism produces genotoxic
waste
The result of both processes
: disruption of cell cycle, apoptosis and DNA repair
-> tumor formation
ERα is certainly associated with more differentiated tumors,
while evidence that ERβ is involved is controversial.
Different versions of the ESR1 gene
: associated with different risks of developing breast cancer.
Estrogen and the ERs have also been implicated in
ovarian cancer, endometrial cancer, colon cancer,
prostate cancer
Progesterone
C-21 steroid hormone
: involved in the female menstrual cycle,
pregnancy and embryogenesis
Progesterone belongs to a class of hormones
called progestogens, and is the major naturally
occurring human progestogen.
Progesterone should not be confused with
progestins, which are synthetically produced
progestogens
Synthesis
Synthesized from pregnenolone, a derivative of cholesterol
The precursor of the mineralocorticoid aldosterone
Conversion to 17-hydroxyprogesterone of cortisol and
androstenedione.
Androstenedione can be converted to testosterone, estrone
and estradiol.
Sources
Progesterone is produced in the adrenal glands, the gonads
the brain, and, during pregnancy, in the placenta.
Increasing amounts are produced during pregnancy :
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Initially, the source is the corpus luteum
After the 8th week production of progesterone shifts over
to the placenta
The placenta utilizes maternal cholesterol as the initial
substrate,
most of the produced progesterone enters the maternal
circulation
some is picked up by the fetal circulation and is used as
substrate for fetal corticosteroids.
At term the placenta produces about 250 mg
progesterone per day.
Effects
Reproductive system
: "hormone of pregnancy”
: many roles relating to the development of the fetus
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Converts the endometrium to secretory stage to prepare
the uterus for implantation
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Affects the vaginal epithelium and cervical mucus
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If pregnancy does not occur, progesterone levels will
decrease, leading to menstruation
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Normal menstrual bleeding is progesterone withdrawal
bleeding.
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During implantation and gestation, progesterone appears
to decrease the maternal immune response to allow for
the acceptance of the pregnancy.
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Progesterone decreases contractility of the uterine
smooth muscle.
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In addition progesterone inhibits lactation during
pregnancy.
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The fall in progesterone levels following delivery is one
of the triggers for milk production.
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A drop in progesterone levels is possibly one step that
facilitates the onset of labor.
Nervous system
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Progesterone belongs to the group of neurosteroids that
are found in high concentrations in certain areas in the
brain and are synthesized there.
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Neurosteroids affect synaptic functioning, are
neuroprotective, and affect myelinization.
They are investigated for their potential to improve
memory and cognitive ability.
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Progesterone as a neuroprotectant affects regulation of
apoptotic genes.
Its effect as a neurosteroid works predominantly through
the GSK-3 beta pathway, as an inhibitor.
Other systems
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It raises epidermal growth factor-1 levels, a factor
often used to induce proliferation, and used to
sustain cultures, of stem cells
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It increases core temperature during ovulation.
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It reduces spasm and relaxes smooth muscle.
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It acts as an antiinflammatory agent and regulates
the immune response.
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It reduces gall-bladder activity
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It normalizes blood clotting and vascular tone,
zinc and copper levels, cell oxygen levels, and
use of fat stores for energy
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It assists in thyroid function, in bone building
by osteoblasts, in bone, teeth, gums, joint,
tendon, ligament and skin resilience by
regulating various types of collagen, and in
nerve function and healing by regulating myelin
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It appears to prevent endometrial cancer by
regulating the effects of estrogen
Medical applications
Both to address acute situations, and to address the longterm decline of natural progesterone levels
Because of the poor bioavailability of progesterone when
taken orally, many synthetic progestins have been designed
However, the roles of progesterone may not be fulfilled by
the synthetic progestins which in some cases were
designed solely to mimic progesterone's uterine effects
Progesterone is used
 to control anovulatory bleeding.
 to prepare uterine lining in infertility therapy
 recurrent pregnancy loss due to inadequate
progesterone production
Progesterone is being investigated as potentially beneficial
in treating multiple sclerosis
Progesterone receptor antagonists, SPRM (RU-486) can be
used to prevent conception or induce medical abortions
Progesterone is used in hormone therapy for transsexual
women, and some intersex women
- especially when synthetic progestins have been ineffective
or caused side-effect