Download Estrogen

Estrogen:

A female steroid hormone that is produced by
the ovaries and, in lesser amounts, by the
adrenal cortex, placenta, and male testes.
Estrogen helps control and guide sexual
development, including the physical changes
associated with puberty. It also influences the
course of ovulation in the monthly menstrual
cycle, lactation after pregnancy, aspects of
mood, and the aging process.
Major estrogens
(1) Estradiol-17β
- most potent natural estrogen and major
secretory product of ovary.
(2) Estrone
- also of ovarian/adrenal origin; exists in
equilibrium with estradiol.
(3) Estriol
- not a product of the ovary, estriol is the
predominant urinary end product of estrogen
metabolism. In the pregnant woman, estriol, as
estradiol and estrone, are secreted by the
placenta. Displays minimal estrogenic activity.

Estradiol (E2) is the predominant estrogen
during reproductive years both in terms of
absolute serum levels as well as in terms of
estrogenic activity. During menopause, estrone
(E1) is the predominant circulating estrogen and
during pregnancy estriol (E3) is the predominant
circulating estrogen in terms of serum levels.
Biosynthesis

Estrogens, in females, are produced primarily by
the ovaries, and during pregnancy, the placenta.
Follicle-stimulating hormone (FSH) stimulates
the ovarian production of estrogens by the
granulosa cells of the ovarian follicles and
corpora lutea. Some estrogens are also produced
in smaller amounts by other tissues such as the
liver, adrenal glands, and the breasts. These
secondary sources of estrogens are especially
important in postmenopausal women. Fat cells
produce estrogen as well.
Function


The actions of estrogen are mediated by the
estrogen receptor (ER), a dimeric nuclear protein
that binds to DNA and controls gene expression.
Like other steroid hormones, estrogen enters
passively into the cell where it binds to and
activates the estrogen receptor. Since estrogen
enters all cells, its actions are dependent on the
presence of the ER in the cell. The ER is expressed
in specific tissues including the ovary, uterus and
breast.
They also act by activating G protein-coupled
receptor, GPR30.
Physiological effects of estrogens
(1) Promotion of tissue growth associated with
puberty--vagina, uterus, Fallopian tubes,
mammary glands (stromal and ductal growth).
(2) Proliferation of uterine endometrium.
(3) Increase in myometrial and Fallopian tube
peristalsis to promote ovum transport.
(4) Decrease in viscosity of cervical mucus.
(5) Biphasic inhibition on pituitary
gonadotropin secretion.
(6) Promotion of epiphyseal closure.
(7) Ovum implantation facilitated via
endometrial "conditioning".
(8) Promotion of salt and water retention via
decrease in plasma volume.
(9) Lipid metabolism (↑HDL, ↓LDL;
↓LDL/HDL ratio).
(10) Enhancement of blood coagulability.
(11) Inhibition of PTH-induced bone
resorption.
(12) Reduction of intestinal motility.
Pharmacology
Oestradiol is broken down in the stomach, but
an ethinyl group at the 17 position confers
oral activity. Ethinyloestradiol is the most
widely used oestrogen in oral contraceptives.
The other estrogen sometimes used is the 3methyl ester of ethinyloestradiol, mestranol,
which has half the potency of
ethinyloestradiol.
Other orally active oestrogens are sometimes
used therapeutically (e.g. for menaupausal
symptoms):
 Premarin: conjucated oestrone from the
urine of pregnant mares
 Oestradiol valerate: converted to oestrone
during absorption.
 Oestradiol: on a micronized solid phase,
also converted to oestrone during
absorption.
Therapeutic uses of estrogens:
(1) Oral contraceptives.
(2) Relief of menopausal symptoms.
(3) Dysmenorrhea.
(4) Failure of pituitary function/ovarian
development- estrogens will not result in normal
reproductive functioning but will promote growth
of reproductive organs and appearance of
secondary sexual characteristics.
(5) Osteoporosis.
Hormone replacement therapy

Estrogen and other hormones are given to
postmenopausal women in order to prevent
osteoporosis as well as treat the symptoms of
menopause such as hot flushes, vaginal dryness,
urinary stress incontinence, chilly sensations,
dizziness, fatigue, irritability, and sweating.

For many years, estrogen therapy and estrogenprogestin therapy were prescribed to treat
menopausal symptoms, to prevent osteoporosis
and to improve women's overall health.
However, after publication of results from the
Women's Health Initiative (WHI) in 2002 and
March 2004, the U.S. Food and Drug
Administration (FDA) now advises health care
professionals to prescribe menopausal
hormone therapies at the lowest possible dose
and for the shortest possible length of time to
achieve treatment goals. Treatment is generally
reserved for management of menopausal
symptoms rather than prevention of chronic
disease.
Premarin:


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Premarin is the commercial name for a
medication consisting primarily of conjugated
estrogens.
Isolated from mares' urine (pregnant mares'
urine).
It is available in oral
(0.3/0.45/0.625/0.9/1.25 mg), IV, and topical
(vaginal) form.


Premarin is a form of hormone replacement
therapy. Premarin pills are used most commonly in
post menopausal women who have had a
hysterectomy to treat hot flashes, and burning,
itching, and dryness of the vagina and surrounding
areas. It can also be used in conjunction with a
progestin pill in women who have not had a
hysterectomy. For women already taking the drug it
can be used to treat osteoporosis, although it is not
recommended solely for this use.
The most common side effects associated with
Premarin use are vaginal yeast infections, vaginal
spotting or bleeding, painful menses, and cramping
of the legs.
PROGESTERONE
Site of synthesis: ovaries, adrenal and
placenta (testes and adrenal in male).
 Terminology:
Progestin: any of a group of steroid hormones,
including synthetic forms, that have the effect
of progesterone
Progestogen: any of a group of steroid hormones
that have the effect of progesterone
Progesterone: the naturally occurring hormone,
produced in the corpus luteum of the ovary

Physiological effects
(1) Development of secretory endometrium.
(2) Decrease in myometrial contractility
(3) Decrease in fallopian tube peristalsis
(4) Increase in viscosity of cervical mucus
(5) Mammary gland development
- promotion of development of lobules
and alveoli
(6) Feedback inhibition on pituitary
gonadotropins
- not as potent as the estrogens.
(7) Thermogenic effects-appears to be a direct effect
on thermoregulatory centers in the hypothalamus.
(8) Increase in basal insulin levels and insulin
response to glucose.
(9) Respiratory effects - increased response to CO2.
(10) Lipid metabolism (↓ HDL, ↑ LDL; ↑ LDL/HDL
ratio).
(11) ↑ Na+ and H2O elimination
(12) Weight gain
Pharmacology:
Progesterone itself is destroyed by stomach acid
but can be administered as suppository. There
are three forms of progesterone which are
absorbed after oral preparation:
 Dydrogesterone: which is a very weak
progestogen.
 17 α-hydroxyprogesterone derivatives, the best
known of which is medroxyprogesterone
acetate. Other 17-OH derivatives are megestrol
acetate and chlormadinone acetate.


19-nor-Progesterone: the commonest progestogen
in oral contraceptives. Removal of the CH3 group
from the 19 position of testosterone protect the
steroid from acid breakdown. The 19-norprogesterones are related to this compound and all
have some residual androgenic activity. It includes
norethisterone, norgestrel (is the most potent and
widely used), & levonorgestrel.
Three newer progestogens, norgestimate,
desogestrel and gestodene are all chemically related
to levonorgestrel. Cycle control is improved with
lower incidence of intermenstrual bleeding and less
adverse effect on blood lipid.
The progestogens used in currently available
combined contraceptive pills fall broadly into
three groups:
 1st generation progestins--------norethindrone.
 2nd generation --------levonorgestrel.
 3rd generation-------gestodene, desogestrel and
norgestimate.
The newest COCP (Yasmin)contains a
progestogen with both antiandrogenic and
antimineralocorticoid activity (drospirenone).
Therapeutic uses of progestins
1)
2)
3)
4)
5)
6)
7)
8)
Contraceptives (COCP, POP, injectable
progesterone, progesterone releasing IUS).
Dysmenorrhea.
Endometriosis.
Dysfunctional uterine bleeding.
Prevention of habitual abortion, premature
labor.
Amenorrhea due to unopposed estrogen.
Infertility due to shortened luteal phase.
Endometrial cancer.
SIDE EFFECTS:

Nausea, bloating, breast tenderness, headache,
change in vaginal discharge, mood swings,
blurred vision, dizziness, or drowsiness may
occur.
PRIMOLUT -N

Norethisterone 5 mg tablets
Norethisterone is a strong progestogen with
negligible androgenic effects

Indications

Dysfunctional bleeding, premenstrual syndrome,
cyclical mastopathy, timing of menstruation,
endometriosis, menorrhagia.


Dysfunctional uterine bleeding:
The administration of one tablet PRIMOLUT N
three times daily over 10 days, in the majority of
cases, leads to the arrest of uterine bleeding that is
not associated with organic lesions within 1 to 3
days. Nevertheless, to ensure treatment success,
PRIMOLUT N must be taken for the full 10 days.
About 2 to 4 days after completion of the
treatment, withdrawal bleeding will occur with the
intensity and duration of normal menstruation.


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To prevent recurrence of dysfunctional bleeding in
patients with anovulatory cycles, it is recommended
to administer PRIMOLUT N prophylactically. One
tablet 1 to 2 times daily from the 16th to the 25th
day of the cycle. Withdrawal bleeding occurs a few
days after administration of the last tablet.
Menorrhagia:
Treatment with PRIMOLUT N one tablet 3 times
daily from day 5 - 25 of the cycle has been shown
to be effective in reducing menstrual blood loss.
ANDROGENS
Androgens in Females
 Sites of synthesis--ovaries, adrenals,
placenta
 Physiological significance
- apparently not necessary for
normal menstrual cycling, but may be
involved in pubertal growth spurt, libido
Danazol


It is an isoxazole of testosterone with isolated
weak androgenic activity and no estrogenic or
progestagenic effects.
Danazol inhibits ovarian steroidogenesis
resulting in decreased secretion of estradiol and
may increase androgens. Pituitary hormones are
largely unaffected, although luteinizing hormone
may be slightly elevated.

It was approved by the US Food and Drug
Administration (FDA) as the first drug to
specifically treat endometriosis in the early
1970s. Although effective for endometriosis, its
use is limited by its masculinizing side-effects.
Its role as a treatment for endometriosis has
been largely replaced by the GnRH agonists.

Danazol has been used for other indications,
namely in the management of menorrhagia,
fibrocystic breast disease, immune
thrombocytopenic purpura, breast pain
(mastodynia) and hereditary angioedema.
Although not currently a standard treatment for
menorrhagia, danazol has resulted in significant
relief in young women with menorrhagia in a
study, and, because of a lack of significant
adverse effects, it was proposed as an alternative

Side effects:

Androgenic side effects are of concern, it includes
hirsutism. On rare occasion, it can deepen the voice.
Other possible side effects include acne and oily skin.
Because danazol is metabolized by the liver, it cannot
be used by patients with liver disease, and in patients
receiving long-term therapy, liver function must be
monitored on a periodic basis.
Some patients who use danazol experience weight
gain and fluid retention.
Danazol, like most other androgenic agents, has been
linked with an increased risk of liver tumors. These are
generally benign.
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Antiprogesterones:

These either inhibit progesterone formation
or block the receptor (mifepristone, RU486).
They are abortifacient and contraceptive.
Anti-androgens:
Anti-androgens include: cyproterone acetate,
spironolactone, stillbestrol, flutamide and
cimetidine.
Cyproterone acetate commonly used to treat
hirsutism in female.
Other commonly used hormons
therapy in gynecology:
gonadotrophins

Human menopausal gonadotrophin (hMG)
was used initially for ovulation induction in
anovulatory women until the introduction of
IVF led to its use to induce multiple
ovulation so that a large number of follicles
and oocytes could be obtained. E.g. of these
drugs:



Pergonal (menotrophins): human
menopausal gonadotrophin; hMG, contains
both FSH and LH.
Metrodin: purified human urinary FSH
preparation.
Gonal-F: recombinant FSH.
Gonadotrophin-releasing
hormone analogues:
GnRH [LH_RH] is naturally secreted in
intermittent pulses.
For induction of ovulation is given intravenously
or subcutaneously by special pump which
deliver the hormone in pulses.
If it is given continuously it cause pituitary
desensitization which result in inhibition of
ovarian steroidogenesis & amenorrhoea.

The administration of a GnRH agonist result in
an initial agonist effect, leading to the
production of both FSH and LH, the so-called
‘flare-up’ effect followed by a sustained decline
in both pituitary response and gonadotrophins
production, a process known as pituitary down
regulation. A number of synthetic ,long-acting
analogues of GnRH have been synthesized, they
are administered as intranasal sprays or as
subcutaneous depot preparations E.g.:
Goserelin (zoladex).
Uses:


GnRH agonists are used with controlled ovarian
stimulation (COS) to improve the outcome of
ovarian stimulation by allowing synchoronous
folliculogenesis and later to prevent premature
luteinization by supressing the endogenous LH
surge.
In the management of hormon dependent
conditions as endometriosis.
Gonadotrophin-releasing
hormone antagonists

They competitively bind (block) gonadotrophic
receptors. They are capable of immediate
inhibition of pituitary gonadotrophin secretion
and are unlikely to offer advantages over the
currently available agonists due to the absence of
flare-up effect. E.g.: Ganirelex.
Human chorionic gonadotrophin
(hCG)

Mimics LH surge to induce ovulation. E.g.:
pregnyl