Transcript Estrogen

The Gonadal Hormones &
Inhibitors
Control of
Sex Hormones
neural inputs
Indirect
Loop
Hypothalamus
Short
Loop
GnRH
Adenohypophysis
Direct
Loop
LH, FSH
Testes or Ovaries
Testosterone
or Estrogen &
Progesterone
Target tissues
Sex hormon
Sex hormones produced by the gonads are
necessary for
Conception
embryonic maturation
development of primary and secondary sexual
characteristics at puberty.
Their activity in target cells is modulated by
receptors.
Sex hormon
The gonadal hormones are used therapeutically in
replacement therapy, for contraception,
Management of menopausal symptoms.
Several antagonists are effective in cancer
chemotherapy.
All gonadal hormones are synthesized from the
precursor, cholesterol, in a series of steps
Estrogen
The gonadal hormones are used therapeutically in
replacement therapy, for contraception,
Management of menopausal symptoms.
Several antagonists are effective in cancer
chemotherapy.
All gonadal hormones are synthesized from the
precursor, cholesterol, in a series of steps
Estrogens
Natural estrogens
The major estrogens produced by women are
Estradiol is the most potent estrogen produced and
secreted by the ovary. It is the principle estrogen in the
premenopausal woman.
Estrone is a metabolite of estradiol. Estrone is the
primary circulating estrogen after menopause.
Estriol another metabolite of estradiol, is significantly
less potent than estradiol. It is present in significant
amounts during pregnancy, because it is the principal
estrogen produced by the placenta.
Estrogens
Natural estrogens
• during the first part of the menstrual cycle estrogens are
produced in the ovarian follicle by the theca and granulosa
cells.
• After ovulation, the estrogens as well as progesterone are
synthesized by the luteinized granulosa and theca cells of
the corpus luteum.
• During pregnancy, a large amount of estrogen is
synthesized by the fetoplacental unit
Estrogens
Synthetic estrogens
variety of chemical alterations have been applied to the
natural estrogens. The most important effect of these
alterations has been to increase their oral effectiveness.
Estrogens
Synthetic estrogens
In addition to the steroidal estrogens, a variety of
nonsteroidal compounds with estrogenic activity have
been synthesized and used clinically. These include
dienestrol, diethylstilbestrol, benzestrol, hexestrol,
methestrol, and methallenestril.
Estrogens
Pharmacokinetics
These agents and their esterified or conjugated derivatives
are readily absorbed through the gastrointestinal tract, skin,
and mucous membranes.
bioavailability of estrogen taken orally is low due to firstpass
metabolism. To reduce first-pass metabolism, the drugs
may be administered via the transdermal route (patch,
topical gel, topical emulsion, or spray), intravaginally (tablet,
cream, or ring), or by injection.
When released into the circulation, estradiol binds strongly
to an α2 globulin (sex hormone-binding globulin [SHBG])
and with lower affinity to albumin
Estradiol is converted by the liver and other tissues to
estrone and estriol
Estrogens
Pharmacokinetics
They are hydroxylated in the liver to derivatives thatare
subsequently glucuronidated or sulfated. The parent drugs
and their metabolites undergo excretion into bile and are
then reabsorbed through the enterohepatic circulation.
Inactive products are excreted in urine.
Estrogens
MECHANISM
Plasma estrogens in the blood and interstitial fluid are bound to
SHBG, from which they dissociate to enter the cell and bind to
their receptor. Two estrogen-receptor subtypes hormone a and b
mediate the effects of the hormone. The estrogen receptors
bound to heat shock proteins that stabilize them. Binding of the
hormone to its receptor alters its conformation and releases it
from the stabilizing proteins (predominantly Hsp90). The
receptor-hormone complex forms homodimers. The steroidreceptor complex is able to enter the nucleus and bind to a
specific sequence of nucleotides called estrogen response
elements (EREs) in the promoters of various genes and
regulate their transcription. This results in the synthesis of
specific proteins that mediate a number of physiologic functions
Estrogens
Physiologic Effects
FEMALE MATURATION
Estrogens are required for the normal sexual maturation and
growth of the female. They stimulate the development of the
vagina, uterus, and uterine tubes as well as the secondary
sex characteristics.
ENDOMETRIAL EFFECTS
In addition to its growth effects on uterine muscle, estrogen
also plays an important role in the development of the
endometrial lining.
EstrogensPhysiologic Effects
METABOLIC AND CARDIOVASCULAR EFFECTS
 Estrogens seem to be partially responsible for maintenance of the normal
structure and function of the skin and blood vessels in women. Estrogens
also decrease the rate of resorption of bone.
 Metabolic alterations in the liver are especially important, so that there is a
higher circulating level of proteins such as transcortin
(corticosteroidbinding globulin [CBG]), thyroxine-binding globulin (TBG),
SHBG, transferrin, renin substrate, and fibrinogen. This leads to increased
circulating levels of thyroxine, estrogen, testosterone, iron, copper, and
other substances
 Estrogens effect on plasma lipids characterized by an increase in the
highdensity lipoproteins (HDL), a slight reduction in the low-density
lipoproteins (LDL), and a reduction in total plasmacholesterol levels
EstrogensPhysiologic Effects
EFFECTS ON BLOOD COAGULATION
Estrogens enhance the coagulability of blood. Many changes
in factors influencing coagulation have been reported,
including increased circulating levels of factors II, VII, IX, and
X and decreased antithrombin III.
Clinical Uses
Primary Hypogonadism
Estrogens have been used extensively for replacement
therapy in estrogen-deficient patients. The estrogen
deficiency may be due to primary failure of development of
the ovaries, premature menopause, castration, or
menopause. Treatment of primary hypogonadism is usually
begun at 11–13 years of age in order to stimulate the
development of secondary sex characteristics and menses,
to stimulate optimal growth, to prevent osteoporosis, and to
avoid the psychological consequences of delayed puberty
and estrogen deficiency
Clinical Uses
Postmenopausal Hormonal Therapy
The primary indication for estrogen therapy is menopausal
symptoms such as vasomotor instability (for example, hot flashes
or hot flushes) and vaginal atrophy, therapy with the lowest dose
of estrogen required for symptomatic relief is recommended.
Treatment may be required for only a limited period of time and
the possible increased risk for breast cancer avoided. In women
who have undergone hysterectomy, estrogens alone can be
given 5 days per week or continuously, since progestins are not
required to reduce the risk for endometrial hyperplasia and
cancer. Hot flushes, sweating, insomnia, and atrophic vaginitis are
generally relieved by estrogens. For women who have not
undergone a hysterectomy, a progestin is always included with
the estrogen therapy
Estrogen
Therapeutic uses of estrogens
Osteoporosis is effectively treated with estrogen;
however, other drugs, such as alendronate, should be
considered first-line therapy over estrogen.
Use of estrogen in contraceptive will discus later
Estrogen
Adverse effects:
Postmenopausal uterine bleeding.
Breast tenderness & increased risk of breast cancer.
Endometrial hyperplasia & increased risk of endometrial cancer (if
not given with a progestin).
Thromboembolic disorders.
Hypertension.
Cholestasis.
Nausia.
Migrains.
Vaginal adenocarcinoma in young women whose mothers were
treated with diethylstilbestrol in an effort to prevent miscarriage.
Selective Estrogen Receptor Modulators
(SERM) (clomiphene, tamoxifen, raloxifene)
In the past, a number of these agents had been
categorized as antiestrogen.
SERM bind estrogen receptors, but have
different effects on different tissues i.e. they
display selective agonism or antagonism
according to the tissue type for example:
tamoxifen is an estrogen antagonist in breast
cancer, but acts as a particular agonist on the
uterus giving rise to endometrial hyperplesia
SERM
Drug
Uses
Side effects
Tamoxifen
palliative treatment of metastatic breast
cancer in postmenopausal women. It
may also be used as adjuvant therapy
following mastectomy or radiation and
to reduce the risk of breast cancer in
high-risk patients.
Hot flushes, menstrual
irregularities, Increased risk of
endometrial cancer.
Raloxifene
postmenopausal osteoporosis. reduce
the incidence of invasive breast cancer
in postmenopausal women.
Clomiphene
Male & female infertility
DVT & pulmonary embolism.
are dose related and include
headache, nausea, vasomotor
flushes, visual disturbances,
and ovarian enlargement.
Progesterone
Source
Corpus luteum under the control of luteinizing hormone.
Placenta.
Actions:
Prepares the uterus for implantation of the fertilized ovum.
Inhibit uterine contraction that would expel the fetus.
alveolobular development of the secretory apparatus in the breast..
-ve feed back effect on luteinizing hormone so, block ovulation.
Thick cervical secretion, so block sperm penetration.
Thermogenic i.e. it increases body temperature.
Compete aldosterone on mineralocorticoid receptor so induced
sodium retention.
Decreases the plasma levels of many amino acids.
Progestine
Progesterone and progestins
(progestogens):
Progesterone is the natural hormone. It is not
effective orally due to the extensive 1st pass
metabolism so, it must be given by i.m injection.
It has a short duration of action.
Progestins are synthetic derivatives of
progesterone, effective orally, and have a long
duration of action.
Some of progestins have androgenic,
estrogenic, and even glucocorticoid-like effects.
progestin
Uses of progestins:
Oral contraception.
Dysfunctional uterine bleeding.
HRT
Dysmenorrhea.
Endometriosis.
Suppression of postpartum lactation.
Infertility if due to deficiency of progesterone.
Maintenance of pregnancy.
Progestine
Adverse effects
1. Increase blood pressure in some patients.
2. The more androgenic progestins also reduce plasma
HDL levels in women.
3. Combined progestin plus estrogen replacement therapy
in postmenopausal women may increase breast cancer
risk significantly compared with the risk in women
taking estrogen alone.
Antiprogestogens
Mifepristone:
It is an orally active steroid antagonist of
progesterone & glucocorticoid receptors.
It is used for induction of abortion in the 1st trimester
(abortifaciant).
It is used as a single oral dose followed by PGE1
(gemeprost) or PGF2α (dinoprost) analogue to
produce uterine contraction.
The major adverse effects are significant uterine
bleeding and the possibility of an incomplete abortion