Gonadal Hormones
Œstrogens
Three primary œstrogens are synthesised in vivo, œstradiol, œstrone, and
œstriol, with œstradiol being the most important physiologically.
Once released into the blood stream, they are bound to alpha2-globulin
(sex hormone binding globulin, SHBG). In addition to the naturally
occurring hormones, analogues of œstrogen that are used medically include
chlorotrianisene, conjugated œstrogens, dienœstrol, diethylstilbœstrol,
mœstranol, œstropipate, and quinœstrol.
Mechanism of Action -- œstrogens act via steroid receptors. Recall
that, in general, these receptors are typically cytoplasmic or are found
on nuclear membranes. The receptor is a protein composed of three
distinct units. One portion of the receptor is specific for the hormone
for which it is the receptor. The second portion is specific for
a portion of DNA which codes for the synthesis of specific proteins.
(The function of the third portion is not known.) The hormone, upon
entering the cell, combines with the receptor to form a hormone-receptor
complex. This complex then enters the nucleus and binds with DNA
at the specific site for which the receptor is coded. This causes
the transcription of the DNA and ultimate translation of RNA to result
in the synthesis of the protein that is specific for that portion of the
DNA. Œstrogen receptors are nuclear and the hormone enters the nucleus
to cause the synthesis of specific proteins as described above.
Pharmacodynamic Response (Physiologic Effects) of Œstrogen
Œstrogen are responsible for normal events of maturation in females,
including
structural development of mammary glands
growth at puberty and closure of epiphyses at the end of growth
changes in fat distribution causes changes in body shape
axillary hair growth
increased skin pigmentation
uterine growth and development of the endometrial lining
Other effects of œstrogen include
Metabolic effects
decrease rate of bone resorption (decrease osteoclastic loss of bone,
an anti-parathyroid effect) -- œstrogens do NOT stimulate bone formation,
simply reduce its loss.
maintain structure and function of skin and blood vessels -- the mechanism
of this action is not known.
Hepatic effects
increased synthesis and release of SHBG (note -- this does NOT increase
the amount of active œstrogen, but DOES increase the amount of circulating
œstrogen available for action) and binding proteins for cortisol (cortisol
binding globulin, CBG, transcortin), thyroxine (thyroxine binding globulin,
TBG), transferrin, and fibrinogen
increased synthesis of clotting factors
altered hepatic lipid metabolism to increase circulating levels of HDLs
and VLDLs (TG) and decrease circulating levels of LDLs.
Other effects -- œstrogen will increase the movement of water and sodium
from the vasculature to interstitial spaces (increasing extracellular fluid
volume, causing œdema). In response to this shift, aldosterone activity
will increase sodium reabsorption and additional water and sodium will
be retained which also will contribute to the œdema.
Uses -- Œstrogens are used primarily as replacement therapy and as oral
contraceptives (discussed later).
Primary hypogonadism in delayed puberty -- to hasten the onset of puberty
Post-menopausal hormone replacement therapy --
the beneficial effects include
decreased cardiovascular risk (by decreasing circulating LDL)
decreased hot flashes (elimination of vascular effects of œstrogen
removal)
decreased osteoporosis (by preventing bone loss)
relief of vaginitis (vaginal atrophy and dryness induced by œstrogen
loss)
detrimental effects include
increased risk of œstrogen-dependent cancers (NOTE, the addition of
progesterone will lower the risk of endometrial cancer and the risk of
breast cancer will be no greater than pre-menopausal risk)
water weight gain
hypertension
The minimum dose of œstrogen to relieve the symptoms of menopause should
be used to minimise the detrimental effects. If atrophic vaginitis
is the primary symptom, it should be treated with topical (vaginal) œstrogen
in a cyclic manner (not continuously) to limit systemic absorption.
Similarly, if osteoporosis is the primary result of menopause, alternate
direct therapy could be more appropriate and eliminate the risks associated
with œstrogen therapy.
Suppression of ovulation in patients with intractable (persistent) amenorrhœa
Side Effects -- post-menopausal bleeding, nausea, breast tenderness, hyperpigmentation,
migraine headaches, cholestasis, water weight gain, hypertension, increased
risk of œstrogen dependent cancer
Progestins
The predominant progestin is progesterone. Medroxyprogesterone, desogestrel,
ethynodiol, hydroxyprogesterone, levonorgestrel, megestrol, norethindrone,
norethynodrel, norgestimate, and norgestrel are progestin analogues that
are used medically.
Mechanism of Action -- the progestins act via typical steroid receptor
mechanisms, discussed above.
Physiologic Effects/Pharmacodynamic Response --
In general, progestins exert catabolic rather than anabolic effects.
Specifically these effects are
Increased lipoprotein lipase activity, fat deposition
Increased release of insulin, increased response of the pancreas to
glucose (glucose-induced insulin release, and increased insulin efficacy.
Increased protein breakdown and subsequent increase in urinary loss
of nitrogen (negative nitrogen balance)
Other effects of progestins include
weak activity at glucocorticoid receptors
antagonism of mineralocorticoid (aldosterone) receptors
hyperthermia -- hypothalamic-mediated increases in body temperature
of 1-1.5 degrees, cyclical in nature and responsible for the basal temperature
increases required for successful ovulation.
Uses -- Progestins are used primarily in replacement therapy and contraception.
They may also be used in the treatment of dysmenorrhœa, endometriosis,
and hirsutism. Progestin only contraceptives (by either the oral
or depot routes) suppress ovulation for up to 18 months following discontinuation
of therapy. Therefore, they should not be used if the patient wishes
to become pregnant in the near future. Formulations of progestin
in the "mini-pill" may not prevent ovulation, but the contraceptive effect
is roughly equal to that of intrauterine devices and similar forms of birth
control. The advantage of progestin-only contraception is the lack
of risks associated with œstrogen therapy. The primary disadvantage
is a relatively high incidence of irregular cycles and spotty bleeding.
Progestins have been used to prevent spontaneous abortion, but their efficacy
is questionable. If progestins are unsuccessful in contraception,
the implant should be removed. Continued progestin administration
during pregnancy can cause birth defects such as hypospadia in males and
masculination in females.
Other Ovarian Hormones
Androgens are produced in small quantities by the ovaries.
Inhibin acts to decrease FSH and LH release from the pituitary gland
Activin acts to increase FSH and LH release from the pituitary gland
Relaxin has numerous effects, but its primary effect appears to be
relaxation of the uterine muscle during labour, permitting the cyclic contractions/relaxation
in normal delivery.
Oral Contraceptive Therapy
Oral contraceptives may be mono-, bi-, or tri-phasic in their approach
to contraception. The distinguishing characteristic of one form over
another is the dose and time of progestin administration during the monthly
therapy. Oral contraceptives may also be differentiated by their
œstrogen dose (either high dose or low dose).
Mechanism of Action -- Oral contraception is effective through the negative
feedback loop of the hypothalamic-pituitary-gonadal axis. The administration
of exogenous œstrogen/progestin causes the decreased release of FSH and
LH from the pituitary to decrease ovulation. The differing doses
of œstrogen/progestin within specific contraceptives represents the attempt
to match the monthly cycle as closely as possible, without ovulation occurring.
Pharmacodynamic Response
The pharmacodynamic responses to oral contraceptive therapy that contribute
to the prevention of pregnancy include
changes in the endometrium, so that the fertilised egg cannot be implanted
increase mucus viscosity, that prevents the entry of sperm
changes in fallopian tube structure and function altering the transit
times of egg and sperm, thus decreasing the likelihood of contact and subsequent
fertilisation
Oral contraceptives also decrease overall ovarian function. This
function usually returns to normal following cessation of therapy, but
the time to return is a function of the œstrogen dose. Typical time
to complete ovarian recovery is within 1 month of discontinuing the drugs.
However, with high dose œstrogen, ovarian function may be suppressed for
up to 1 year (low dose œstrogen contraceptives show a much shorter recovery
time).
Other effects of oral contraceptives that involve the female anatomy
include uterine hypertrophy, breast enlargement, and decreased lactation
(this is not enough to interfere with breast feeding post-partum -- however,
œstrogens do appear in the milk and contraceptive therapy should probably
not be initiated until after the child is weaned).
CNS and behavioural responses to oral contraceptive therapy include
thermogenesis (progestin effect), a feeling of security (due to the decreased
risk of pregnancy), and possibly either increased neuronal activity (œstrogen
effect) or decreased neuronal activity (progestin effect).
Other endocrine effects include the aldosterone-like effect of œstrogens,
that may be at least in part off-set by the aldosterone antagonism of progestin.
(NOTE that the progestin effects will not block the œdema that results
from œstrogen, although it may lessen it by preventing additional water
retention).
Hæmatological effects are primarily thromboembolic in nature.
The risk of thromboembolism occurs with the first month of therapy and
continues throughout contraception. (Risk decreases upon discontinuation
of therapy and the return of normal ovulation.) The risk is increased
with concurrent hypertension, smoking, and in patients who are over 35
years old. The thromboembolic risk is associated with changes in
the endothelium (endothelial proliferation) which reduces venous flow and
increased risk of coagulation (due to increased platelet activity and the
increased hepatic synthesis of clotting factors).
Other hepatic effects include reduced bile flow which can cause cholestatic
jaundice, increased levels of cholesterol in bile which can cause gall
stones, and hepatotoxicity (increases in ALT and AST).
Other effects of oral contraceptive therapy include skin pigmentation
(chloasma), acne, hirsutism, and increased incidence of vaginal infections.
Severe consequences of the use of oral contraceptives include thrombo-embolism,
which may result in myocardial infarction and/or stroke and the increased
risk of development of œstrogen-dependent cancers (the risk is lessened
with the presence of progestins, as noted above).
Post-coital contraception -- "Morning After" dosing -- The use of œstrogens
to prevent pregnancy following intercourse is 99% effective if administered
within 72 hr. The therapy is characterised by a relatively high incidence
of side effects, since high doses of œstrogen are required for post-coital
contraception, including nausea, vomiting, headache, dizziness, breast
tenderness, and abdominal and leg cramps.
The beneficial effects of oral contraceptive therapy (other that prevention
of pregnancy) include
decreased risk of ovarian cysts
decreased risk of ovarian/endometrial cancer and benign breast disease
decreased incidence of pelvic inflammatory disease
decreased risk of ectopic pregnancy
decreased incidence of iron deficiency, duodenal ulcers, and decreased
incidence/severity of rheumatoid arthritis.
Anti-Œstrogen and Progestin Agents
Clomiphene
Clomiphene -- is a partial agonist at œstrogen receptors. When
œstrogens are present, it acts as an antagonist at œstrogen receptors.
In cases of gonadal insufficiency, these agents act as œstrogen agonists.
Uses -- Clomiphene is used primarily to induce ovulation in infertile
women (it has also been used to treat male infertility). It is used
to induce ovulation in patients who are anovulatory and/or amenorrhœic.
Mechanism of Action -- It is thought that the beneficial effects of
clomiphene in inducing ovulation is through an antagonistic effect on the
negative feedback loop of the hypothalamic-pituitary-gonadal axis.
In theory, clomiphene blocks the negative feedback of œstrogen, allowing
an increase in the release of FSH and LH which may result in ovulation.
Pharmacodynamic Response -- A single course of therapy results in one
ovulation of the patient. If pregnancy does not occur during this
course of therapy, it may be repeated twice at higher doses (if pregnancy
does not occur after the third attempt, the chances of pregnancy with additional
courses of therapy are very small). In patients treated with clomiphene,
there is an 80% ovulatory response rate, of which approximately ½
of the patients become pregnant.
Side effects of therapy are primarily those effects similar to menopause,
namely hot flashes. There is also a 7-10% incidence of multiple births.
Tamoxifen
Tamoxifen is also a partial agonist/antagonist at œstrogen receptors.
Its primary use is for the anti-œstrogenic (antagonistic) actions.
Mechanism of Action and Pharmacodynamic Response
Tamoxifen competitively blocks œstrogen from binding with its endogenous
receptor. This results in a decrease in œstrogenic responses.
It also may produce œstrogenic-like effects in the absence of œstrogen
(agonistic action). Some effects of tamoxifen (decreased risk of
osteoporosis, decreased risk of lipid-related myocardial infarction both
post-menopausally) reflect this agonistic action.
Uses -- Tamoxifen is primarily used in the treatment of œstrogen-dependent
breast cancer. It is also used in the prevention of breast cancer
in patients who are at high-risk (family history) of developing breast
cancer. It has also been used in the treatment of mastalgia, gynecomastia,
and pancreatic carcinoma (all of which benefit from the anti-œstrogenic
activity of tamoxifen).
Tamoxifen has also been considered for the prevention of osteoporosis
and myocardial disease in post-menopausal women. However, the risk
of endometrial cancer may preclude its use in this respect. RALOXIFENE
(Evista®) is an agent currently being investigated for the prevention
of these conditions in post-menopausal women. It is a selective œstrogen
receptor modulator (SERM) that possesses the beneficial agonist activity
on bone and lipids, but lacks the endometrial and breast effects that could
increase the risk of cancer.
Side Effects of tamoxifen therapy include hot flashes, nausea, and vomiting
(25% incidence for these effects).
Danazol
Mechanism of Action and Pharmacodynamic Response -- Danazol also acts
as a partial agonist/antagonist. It reduces the pituitary release
of FSH and LH. It also shows weak progestin, androgen, and glucocorticoid
activity. It also interacts with several steroid binding globulins
and inhibits numerous enzymes in the steroid hormone synthetic pathway.
These effects probably do not contribute to its efficacy.
Uses -- Danazol is used primarily for its antagonistic effects in the
treatment of endometriosis. It may also be used in fibrocystic breast
disease, hæmophilia, and thrombocytopænic purpura.
Side Effects of danazol include masculinisation, hot flashes, and liver
toxicity.
Mifepristone
Mechanism of Action and Pharmacodynamic Response -- mifepristone is
an antagonist at the progestin receptors, inhibiting the actions of endogenous
progestin. It also interacts with the glucocorticoid receptor.
It will prevent conception and may also induce abortion (weakly).
Uses -- mifepristone is used primarily as a post-coital contraceptive.
It is also used as an abortifacient to terminate early pregnancies (co-administration
vaginally of a prostaglandin is required to ensure full abortion) during
the first 7 weeks.
Adverse Effects -- vomiting, diarrhœa, pain, and bleeding.
Anastrozole, Letrozole, Fadrozole -- These agents act as inhibitors of
the enzyme aromatase. This enzyme is required for the synthesis of
œstrogen. Therefore, they reduce the endogenous synthesis of œstrogenic
hormones. They are currently either used or being investigated for
use in œstrogenic breast cancer that does not respond to tamoxifen treatment.
Androgens
Androgenic hormones are produced primarily by the testes (95%) and adrenal
glands (5%). They are 97-98% plasma protein bound (65% bound to SHBG,
the remainder primarily to albumin) with 2-3% remaining free for action
at cytosolic receptors.
The primary androgen that is biosynthesised is testosterone (primarily
in the testes) with smaller amounts of adrenal androgens dihydrotestosterone
(DHT), androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone
sulphate (DHEAS). Androgens (especially androstenedione) may be converted
in
vivo by the enzyme aromatase to œstrone. Testosterone is active
in most parts of the body. However, in the skin, prostate, epididymis,
and seminal vesicles, testosterone is converted (via 5-alpha reductase)
to DHT, which acts as the primary androgen in these organs.
Mechanism of Action
Androgens exert their action via typical hormone receptors. Androgenic
receptors are primarily cytosolic and enter the nucleus following formation
of the hormone-receptor complex. As noted above, there is some selectivity
in the specific receptor (testosterone vs. DHT) and the site of action.
Physiologic Effects and Pharmacodynamic Responses
The surge of androgen synthesis and release at puberty causes the typical
events of puberty in the male: penile growth, scrotal growth and descent,
appearance of axillary and facial hair, growth of the larynx and thickening
of the vocal cords, growth of the prostate and seminal vesicles, increased
bone growth and closure of the epiphyses. Other pubertal actions
that may also appear if androgens are administered post-pubertal include
increased activity of sebaceous glands, and darkening and thickening of
the skin
Metabolic effects of androgens include decreased synthesis and release
of SHBG (recall that obesity may also decrease SHBG) and other carrier
proteins, increase the synthesis of clotting factors, increase the synthesis
of lipoprotein lipase (specifically the isozyme for triglyceride), decrease
circulating levels of HDLs and may increase the circulating levels of LDLs.
NOTE that with the exception of clotting factors, these effects are the
opposite of those observed with œstrogens.
Other effects of androgens include increased renal synthesis and release
of erythropoietin and the shifting of vascular fluids to extracellular
spaces (similar to the œstrogens).
Anabolic effects of androgens -- androgenic hormones increase lean body
mass and increase protein synthesis/decrease protein breakdown, causing
a positive nitrogen balance (decreased loss of nitrogen). The anabolic
effects of androgens are distinct and separate from the gender specific
actions of the hormone. However, all analogues of androgen possess
potent anabolic effects. The ratio of androgenic:anabolic effect
ranges from 1:1 for endogenous testosterone to as high as 1:13 for oxandrolone
(most ratios are much smaller and oxandrolone has not consistently demonstrated
this wide margin in all studies).
Uses of androgenic hormones and their analogues (methyltestosterone, fluoxymesterone,
methandrostenolone, oxymetholone, ethylestrenol, oxandrolone, nandrolone,
stanozolol, dromostanolone)
Replacement therapy in male hypogonadal hypogonadism, either in the
treatment of infertility or in delayed puberty. Preparations may
be injected in depot forms, taken orally, or applied dermally (scrotal
patch, usually requiring b.i.d. application).
Androgenic hormones have been used in females to treat breast engorgement
(through a negative feedback mechanism), endometriosis (same mechanism),
osteoporosis (less effective that œstrogens and often used in conjunction
with them), and breast cancer in pre-menopausal women.
Androgenic steroids may be used in the treatment of anæmia associated
with renal failure (decreased production of erythropoietin). This
use has essentially been supplanted by recombinant forms of erythropoietin
and is seldom employed.
Androgens have been used for their anabolic effects to prevent muscle
wasting in patients with debilitating diseases (cancer, AIDS, burns) or
in chronic corticosteroid therapy.
Abuse of androgenic hormones -- these agents may be abused by athletes
for their anabolic effects at doses from 10-200 times the normal therapeutic
doses. The anabolic effects are more prominent in females than males.
Generally the anabolic effects are greater when combined with intense exercise
and a high protein diet.
Adverse Reactions -- In the female, androgens will cause masculinisation
including clitoral enlargement, hirsutism, male pattern baldness, deepening
of the voice, irregular menstrual cycle, changes in libido, and a decrease
in breast size. In males, extensions of the androgenic effects will
occur (enhanced male pattern baldness), and negative feedback will result
in testicular atrophy. Males may also experience gynecomastia and
decreased libido. Both genders may demonstrate behavioural changes
(irritability, aggression, psychoses at higher abuse doses), cholestatic
jaundice, liver dysfunction. Androgenic use has also been associated
with hepatic carcinoma. Androgens are contraindicated in androgen-dependent
tumours and should be used with caution in patients with congestive heart
failure.
Anti-Androgens
The primary use of anti-androgenic agents in males is in the treatment
of prostate cancer. The treatment options of prostate cancer include
orchiectomy or high dose œstrogen therapy (neither of which is attractive
to most men due to psychological implications) and gonadotropin inhibition
by sustained GnRH administration (leuprolide) and anti-androgen drugs.
Finasteride
Mechanism of action -- finasteride inhibits the enzyme 5-alpha reductase,
thus decreasing the formation of DHT.
Pharmacodynamic response -- the decrease in DHT reduces the androgenic
effects of that hormone (RECALL that DHT is the primary androgen that affects
the prostate gland).
Uses -- In addition to prostate cancer, finasteride is also used in
the treatment of male pattern baldness (which is mediated at least in part
through androgenic hormones). It has also been used for the treatment
of hirsutism of women (see adverse reactions below).
Adverse reactions -- in males, finasteride may cause a mild and transient
impotence, decreased libido, and decreased ejaculate volume -- in females
who are pregnant or may become so, finasteride can cause birth defects
in male fœtuses
Flutamide
Mechanism of Action and pharmacodynamic response -- flutamide acts
as an androgen antagonist, directly blocking the effects of androgenic
hormones at their receptor.
Uses -- flutamide is used primarily in the treatment of prostatic cancer.
It has also been used in the treatment of female hirsutism.
Adverse reactions -- Males may experience hot flashes (60%) and decreased
libido/impotence (>30%) -- these side effects also occur when GnRH antagonists
are used in the treatment of prostate cancer. Other side effects
are primarily GI in nature (diarrhœa -- 12% and nausea/vomiting -- 11%).
In pregnant females, flutamide may cause pseudohermaphroditism of the male
fœtus. BICALUTAMIDE is a similar agent currently undergoing trials
-- it may produce less GI side effects than flutamide.
Cyproterone
Mechanism of Action and pharmacodynamic response -- androgen receptor
antagonist. The acetate salt also has agonist activity at progestin
receptors. This action may cause negative feedback to suppress FSH
and LH release, thus contributing to the overall anti-androgen effect.
Uses -- cyproterone currently has orphan drug status in the U.S.A.
It is used to treat female hirsutism. It has also been used to suppress
libido and inappropriate sexual behaviour in male sex offenders in Europe.
Adverse Reactions -- similar to flutamide.
Spironolactone -- In the presence of strong androgens, spironolactone may
exhibit androgen antagonist effects. It may also decrease the synthesis
of androgens. It also has been used in the treatment of female hirsutism.
Male Contraception
Attempts at chemical contraception in males has been tried in the past
with anti-androgen and gonadotropin suppressive therapies. In general,
these approaches are only 50% effective. Mechanistically, these approaches
either decrease androgenic effects in maturation of the spermatocytes in
the case of the former or through negative feedback suppression of androgen
release in the latter. Early studies indicate that depot administration
of testosterone with daily administration of levonorgestrel may be as much
as 94% effective as a male contraceptive.
Gossypol -- is an agent found in cottonseed that has been investigated
as an oral male contraceptive.
Mechanism of Action -- gossypol decreases spermatogenesis and also
causes destruction of the seminiferous tubules, interfering with sperm
transport.
Pharmacodynamic response -- gossypol reduces sperm count to levels that
are unlikely to result in fertilisation. Its effects are generally
reversible UNLESS high doses are used that drop sperm counts exceedingly
low or if used chronically (greater that two years), when the effects may
be at least partially irreversible.
Uses -- gossypol currently has orphan drug status in the U.S.A. only
for the treatment of cancer of the adrenal cortex.
Adverse reactions -- hypokalæmia, diarrhœa, dyspnœa, and neuritis.
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