Download Gonadal Medications

Pharmacology: Reproductive Pharmacology (Wu)
ESTROGENS:

Structure and Function:
Naturally Occurring Estrogens:
o 18 carbon steroids with:

Phenolic A ring (principle requirement for selective high affinity binding at estrogen receptor)

Hydroxy at carbon 3

Beta hydroxyl or ketone at position 17 on D ring
o Most potent naturally occurring estrogen is 17β-estradiol
Administration:
o Estradiol is metabolized in the liver and therefore ineffective when given orally
o Modified derivatives have been produced that avoid hepatic inactivation and can be given orally

Example: ethinyl estradiol
Non-Steroidal Estrogens:
o Synthetic estrogens that have increased oral bioavailability following oral dose

Diethystilbestrol: one of the first synthesized non-steroidal estrogen and is still one of the
most potent

Biosynthesis:
Formation: formed from androstenedione or testosterone using aromatase enzyme
o CYP enzyme that generates the phenolic A ring of the chemical structure
Sources of Estrogen:
o Pre-Menopausal Women: granulosa cells of the ovary are the principal source (estradiol)
o Men and Post-Menopausal Women: adipose tissue is the principal source
o Pregnancy: large quantities produced by the placenta

Mechanism of Action:
Regulate the transcription of a limited number of genes (between 50 and 100):
o Enters the cell by passive diffusion, distributes through the cell and binds nuclear estrogen R
o Once R activated, binds specific DNA sequences (hormone responsive elements) that modulate
transcription of adjacent genes
Estrogen receptor:
o Found in estrogen responsive tissue
o Member of super gene family of steroid receptors

Physiological and Pharmacological Actions:
Puberty:
o Hypothalamus releases GnRH in a pulsatile fashion  release of FSH and LH

Initially FSH and LH in small amounts with limited estrogen synthesis

This is what is responsible for physical changes associated with puberty
o After ~2 years, sufficient estrogen is produced to induce endometrial changes and bleeding
o Increased estrogen also feedsback on hypothalamus to decrease release of GnRH

Suppress pituitary FSH

Biphasic effect on pituitary LH (midcycle surge critical for ovulation)
Menstruation:
o Estrogen can induce menstrual bleeding in patients with non-functional/absent ovaries (single large
dose or treatment for several weeks with smaller dose)
o Threshold dose is a dosage in which menstruation will result in the absence of estrogen withdrawal
o Menstruation can be induced in patients taking uninterrupted estrogen by briefly giving progesterone

Metabolic Actions:
Anabolism: much weaker anabolic agents than androgens
Salt and Water Retention: can occur at high doses causing edema
o This is the cause of water retention in the latter half of the menstrual cycle
Decrease in LDL cholesterol and increase in HDL cholesterol: would appear to be beneficial to the CV system,
but they also have several unwanted effects (effect on lowering/elevating CAD risk and MI is controversial)
o
Increase several coagulation factors
o Sodium and water retention can lead to HTN

Bioavailability:
Therapeutic Estrogens: readily absorbed through the skin, mucous membranes and GI tract
Natural Estrogens: limited effectiveness because of metabolic inactivation in the liver (first pass effect)



Therapeutic Use:
Oral Contraception
Postmenopausal Hormone Replacement Therapy (HRT):
o Treatment of hot flashes, sweating, atrophic vaginitis and high risk of osteoporosis
o Osteoporosis risk (smokers, thin, Caucasian, inactive, low Ca++ intake, family history)

Prophylactic tx with estrogen is best if started before significant bone loss occurs

However, use of estrogen often not justified because of other effective treatments and
potential side effects

Women who have undergone oophorectomy and hysterectomy are more suited for
treatment with estrogen, since the risk of endometrial cancer is no longer an issue
o Generally administered in cyclic fashion (ie. 3 weeks on, 1 week off) and in lowest dose required for
symptom relief
o Often given in combination with progesterone
Primary Hypogonadism:
o Basics: replacement therapy in estrogen-deficient patients; Tx usually begins at age 11-13 to stimulate
development of secondary sex characteristics
o Causes:

Ovarian dysgenesis

Dwarfism or hypopituitarism

Castration
Other:
o Dysmenorrhea: can inhibit ovulation with estrogen to relieve this disorder, however, it is not the
treatment of choice

NSAIDs: believed that the cause is uterine production of PGs (therefore, NSAIDs are DOC)
o Prostate Cancer:

Diethylstilbestrol: used in palliative treatment of prostate cancer (action on hypothalamus
can inhibit androgen secretion)
 Leuprolide: GnRH analog that has generally replaced diethylstilbestrol due to
similar efficacy and less side effects (used with an antiandrogen)
Adverse Effects:
Postmenopausal bleeding: estrogen therapy is the most common cause (may be confused with endometrial
cancer)
o To avoid confusion, use minimum effective dose in a cyclic fashion (so bleeding will be during
withdrawal, if it occurs)
o Endometrial hyperplasia can be prevented by co-administration of a progestational agent
Other issues: all can be minimized by using the minimum effective doses
o Nausea
o Breast tenderness
o Hyperpigmentation
o Migraine headaches
o Cholestasia
o HTN
Cancers:
o Endometrial Cancer:

Associated with use of estrogen in postmenopausal women
 Lower with low dose treatment and when administered in a cyclic fashion
 Also lowered if co-administered with progestational agent

In pre-menopausal women, risk is decreased with the combination of estrogen and progestin
as administered in oral contraceptives
o Other Cancers:

Increased risk of breast cancer with the use of oral contraceptives (?)

Increased risk of other cancers due to post menopausal hormone use
Cardiovascular Risk:
o Increased risk of heart disease, stroke, and blood clots
Contraindications:
Do not use in patients with estrogen-dependent neoplasms (ie. uterine or breast cancer)
Do not use in patients with undiagnosed genital bleeding, liver disease or a history of thromboembolic disorders
Avoid estrogen treatment during pregnancy (esp. during the first trimester)


Drug Prototypes:
Natural Estrogens:
o Estradiol (estrace)
o Estradiol salts (estradiol benzoate, valerate, cypionate)

Prepared in oil for slow release after IM injection
o Estrone
o Equilin (Δ7-estrone)
o Conjugated estrogens (premarin, estrone, equilin)

Sodium sulfate derivatives for injection
Synthetic Estrogens:
o Diethylstilbestrol
o Ethinyl Estradiol
o Mestranol
Alternative Therapies for Managing Menopausal Symptoms:
Botanical Products: those containing or acting like estrogens may provide some relief of menopausal symptoms
o Soy Food: has been suggested to benefit women with mild hot flashes
o Other Products: all being looked at to see effects on promoting bone, heart and brain health as well as
potential risks (ie. of cancers)

Black cohosh, red clover, hops, dong quai, flax seed and dietary soy
ANTIESTROGENS:

Introduction:
Variety of compounds that inhibit or modulate estrogenic activity
o Competitive antagonists for estrogen receptor (most specific and widely used)*
o Inhibitors of estrogen synthesis (ie. aromatase inhibitors)
o Agents that exert opposite physiological effects (ie. progestins and androgens)

Estrogen Receptor Competitive Antagonists:
Agents:
o Tamoxifen
o Clomiphene
Chemistry:
o Both are metabolically activated by hydroxylation of the C4 position on the A ring
o Depending on the orientation of the alkylaminoethy side chain, agonist or antagonist activity is
observed

Trans: antiestrogens

Cis: estrogen agonists
o Isomerization can occur after metabolic activation (in vitro effects do not always predict in vivo
activity)
Pharmacological Effects:
o Clomiphene: effective in the treatment of infertility

Inhibits gonadotropic effects of the pituitary (potent contraceptive) in animals, but in
humans, its principal effect was enlargement of the ovaries

Blocking estrogen receptor in the hypothalamus and pituitary blocked normal estrogen
feedback resulting in increased gonadotropin release with increased ovarian gametogenesis
and steroidgenesis
o Tamoxifen: drug of choice for palliative treatment of estrogen receptor positive (estrange-dependent)
breast cancer

Low incidence of toxic effects

However, drawback is increased risk of endometrial and uterine cancer
Pharmacokinetics:
o Absorption: both are readily absorbed by the GI tract
o Clearance: slow (half lives of 5-7 days)

Other Antiestrogens:
Leuprolide: sometimes used as an antiestrogen (GnRH analog)
o Early in treatment (1-2 weeks), concentrations of gonadotropins remain high
o Later in treatment (continued use), GnRH receptors on pituitary gonadotrophs become desensitized,
therefore leading to significant (but reversible) suppression of gonadotropin and steroid release
-
Aromatase Inhibitors:
o Agents in this Class:

Anastrozole

Letrozole

Exemestane
o Classification:

Steroidal Agents: exemestane is a substrate analog that acts as a suicide inhibitor to
irreversibly inactivate aromatase

Nonsteroidal Agents: letrozole and anastrozole interact reversibly with the heme groups of
CYPs (aromatase is a CYP)
o Use:

Treatment of postmenopausal women with breast cancer: intratumoral aromatase results
in E2 concentrations 10x that of plasma in breast carcinoma (no increased risk of endometrial
or uterine cancer)

Induction of ovulation in pre-menopausal women with infertility: letrozole
PROGESTINS:

Structure and Function:
Binding of progestins to progesterone receptor requires KETONE moiety on the A ring (estrogens required
phenol ring)
Substituents on C17 greatly affect the biological activity of various progestins

Biosynthesis:
Synthesized and secreted from the corpus luteum in response to LH during the 2 nd half of the menstrual cycle,
just prior to ovulation
If ovum fertilized, developing trophoblast immediately begins secreting chorionic gonadotropin (sustains the
corpus luteum  continues to produce progesterone)
During the 2nd or 3rd month of pregnancy, the placenta itself begins to secrete estrogen and progesterone

Physiological and Pharmacological Actions:
During Cycle: note that estrogen is also essential for the below developments
o Release of progesterone leads to development of secretory endometrium
o Abrupt decline in progesterone is PRIMARY determinant for onset of menstruation
o Progesterone secretion is the cause of the 1°C increase in body temperature at midcycle (just prior to
ovulation)
During Pregnancy:
o Important in maintaining pregnancy, suppressing menstruation and uterine contractility
o Diminished progesterone levels can be the cause of spontaneous abortion (rare)
o Causes a proliferation of the mammary gland acini (along with estrogen; also occurs to a small degree
during the normal cycle)

Mechanism of Action:
Diffuse freely into cells (similar to estrogens) and interact with a nuclear progesterone receptor
When activated, the receptor binds specific hormone responsive elements and modulates gene transcription
Progesterone receptor has a narrow tissue distribution (primarily in female reproductive tract)

Absorption:
Progesterone: readily absorbed in GI tract but minimally effective by oral route due to extensive hepatic
metabolism (like estrogen)
Derivatives: effective orally because they are not readily metabolized in the liver (esp. derivative with ethinyl
moiety at C17)

Therapeutic Uses:
Oral Contraception
Hormone Replacement Therapy (HRT)
Other uses related to ovarian suppression:
o Dysfunctional uterine bleeding
o Dysmenorrhea
o Premenstraul syndrome (progestins have been used but efficacy has not been shown)
Endometriosis:
o Mild cases treated similarly to dysmenorrhea
o More severe cases (ie. with painful extraneous masses and intertility) require treatment aimed at
causing regression of ectopic endometrial growth (up to 6-9 months of oral progestin tx)

Metastatic Endometrial Carcinoma:
o May use progestins as palliative measure in recurring, metastatic endometrial carcinoma
Drug Prototypes:
Medroxyprogesterone
Norethindrone
Norgestrel
Ethynodiol
Megestrol Acetate
ANTIPROGESTINS:

Introduction:
Currently under investigation as contraceptive agents
Similar to antiestrogens, focus is on receptive competitive antagonists

Mifepristone (RU-486):
MOA: derivative of norethindrone that is a potent competitive antagonist at both progesterone and
glucocorticoid receptors
Pharmacological Action:
o Administration during follicular phase of cycle: prevents ovulation by blocking progesterone receptors
at the level of pituitary or hypothalamus (no mid-cycle surge of gonadotropins  delayed follicular
development)
o Administration during luteal phase of cycle: blocks progesterone action in the uterus, causing release
of prostaglandins from endometrium and menstrual bleeding
o Glucocorticoid antagonist: binds receptor with 4x higher affinity than dexamethasone; inhibits
feedback to hypothalamus from adrenal cortex, resulting in increased adrenal steroidogenesis
Bioavailability:
o Bioavailability of dose by oral route ~25%
o Clearance is slow (half-life of 20 hours)
Therapeutic Uses:
o Abortifacient in early pregnancy when used in combination with prostaglandins
o Post-coital contraceptive (single 600mg dose of mifepristone)
o Possible use on progesterone-sensitive tumors

Lipopristone (ZK98734): new drug developed for this purpose
ORAL CONTRACEPTIVES:

Types of Oral Contraceptives:
Combination Preparations: contain both estrogen and progestin (most common; 99-100% effective)
Biphasic and Triphasic Preparations: low amounts of progestin combined with estrogen; amount of progestin
varies during the cycle
SubQ Implants: progestin implants containing norgestrel (extremely effective and long-lasting)
o Release 1/5th to 1/3rd as much steroid as oral agents
o Low hormone levels have little effect on lipoprotein, carbohydrate metabolism, or BP
o Disadvantages:

Need for surgical insertion and removal

Irregular bleeding typical of progestin-alone preparations
Single-Entity Preparations:
o Progestin Alone (“minipill”): introduced in order to eliminate the use of estrogen (thought to be
responsible for undesirable effects (less popular preparations)

Lower efficacy (97-98%)

More irregular cycle
o Diethystilbestrol: post-coital (morning after pill)

Effective within 72 hours of sexual intercourse

Newer preparations available due to unpleasant side effects (N/V) and potential danger (if
ineffective, abortion is recommended due to high probability of vaginal carcinoma in female
offspring)
o Newer Emergency Contraceptives:

Preven (norgestrel/ethinyl estradiol)

Plan B (norgestrel)

Mifepristone: single 600mg dose


Mechanism of Action:
Current preparations interfere with fertility by inhibiting ovulation
Combination therapy suppresses plasma concentrations of FSH and LH
o Estrogen: inhibits pituitary release of FSH
o Progesterone: inhibits estrogen- induced LH surge
Adverse Reactions:
Important Point: most studies of adverse reactions looked at older preparations (ie. estrogen alone or those
containing higher amounts of estrogen or progesterone)
o Risk to benefit ratio needs to be assessed for each patient
CV Disorders:
o Increase in risk of thrombophlebitis and thromboembolism (esp. in preparations with high estrogen)
o Increased platelet aggregation and accelerated clotting (estrogens)
o Higher incidence of cerebral and coronary thrombosis (additive with addition factors such as smoking,
age and HTN)
o Mild HTN often observed; severe HTN can also be observed (due to Na and water retention)
o Increase in mortality and morbidity

Highest in older women and those who smoke

Risk reduced with preparations containing lower hormone levels (but not eliminated)
o Important to note that prevention of pregnancy also prevents CV risks associated with the pregnancy
itself (therefore, some risk in order to use oral contraceptives is acceptable)
Cancer:
o Increased incidence of vaginal, uterine and breast carcinomas (associated with estrogen use)
o Some cases of benign and malignant hepatomas (benign tumors regress with d/c of oral contraceptive)
o Increased risk of endometrial and cervical cancer in pre-menopausal women (estrogen-only
contraceptive; greatly diminished with combination preparations)
ANDROGENS:

Introduction:
Principal Androgen: testosterone
Synthesis: in the testis (principal hormone in males); small amounts also synthesized in the ovary and adrenal
cortex of the female
Prohormone: for 2 classes of steroids
o 5α- reduced androgens (ie. dihydrotestosterone): active steroids mediating most androgenic activity;
bind androgen receptor with 10x greater affinity than testosterone itself
o Estrogens: enhance some androgenic activities and clocker others
Net Effect: results from the sum of all 3 forms of endogenous androgens in any given tissue (testosterone,
dihydrotestosterone and estrogens)

Structure and Function:
Natural Testosterone: has poor oral bioavailability because of extensive inactivation in the liver (same as
estrogen and progesterone)
Chemical Modifications: have been used to slow the rate of catabolism and enhance the androgenic potential
o Esterification of 17β-hydroxy group: with various carboxylic acids, which decreases its polarity

More soluble in lipid vesicle used for parenteral administration

Slows release and prolongs it action

Ester hydrolyzed prior to hormone action
o Alkylation of 17α position: inhibits hepatic metabolism (allows for oral administration)
o Other Modifications: may have a variety of effects

Slowing rate of catabolism

Enhancing potency

Altering the metabolic profile

Biosynthesis:
Testosterone levels are high in males at 3 points in their lives:
o Embryogenesis (when male phenotypic development takes place; ~8 weeks gestation- levels fall prior
to birth)
o Neonatal period (levels fall to prepubertal levels within a few months)
o Time of puberty
-



Puberty:
o Unknown stimulus results in secretion of GnRH by the hypothalamus, causing the pituitary to secretion
LH and FSH in a pulsatile fashion
o LH and FSH regulate testicular growth, spermatogenesis and steroidgenesis

LH: acts primarily of Leydig cells of the testes to stimulate steroidgenesis

FSH: acts primarily on the Sertoli cells of the seminiferous tubules to promote
spermatogenesis
o Complex interactions between the two also exist

FSH augments the effects of LH on Leydig cells

Testosterone needed for sperm maturation
o Testosterone feeds back to suppress LH and FSH release by inhibiting the release of GnRH
Physiological and Pharmacological Action:
Embryonic Development: androgens virilize the UG tract (critical role in development of male phenotype)
Neonatal Period: function unclear
Puberty: androgen secretions responsible for development of the male habitus (possibly contribute to aggressive
and sexual behavior of males)
Anabolic Affects (Nitrogen Retaining Activity):
o Hypogonadism: administration of androgens causes reduction in the urinary excretion of N, K, Na, Cl

Nitrogen retention observed as development of male muscle pattern (particularly in the
shoulder and girdle)
o Men without hypogonadism: androgen induced positive nitrogen balance is short lived (1-2 months)

Due to the effects in men with hypogonadism, it was assumed that pharmacological doses of
androgens would promote muscle development above that which is observed in men with
normal testicular secretion
 Tried to develop pure anabolic steroids (without androgenic actions)
 Unfortunately, anabolic and androgenic effects represent different responses to
the same hormone in different tissues (cannot be separated)
 All anabolic steroids tested to date are also androgenic
Mechanism of Action:
Action mediated through the androgen receptor (also a member of the super gene family of hormone receptors)
Activation of the receptor results in binding to specific DNA sequences (HREs) and modulation of gene
transcription
Therapeutic Uses:
Hypogonadism:
o Failure of the testes to secrete androgen

Cannot be recognized until there is a delayed onset of puberty

Age of onset of puberty varies greatly (do not treat too early)

Need to be assessed for pituitary and gonadal dysfunction
o If complete testicular failure is confirmed, prolonged therapy with a long acting testosterone ester is
appropriate (dosage= 10mg IM per day)

If begun at expected time of puberty, normal development is observed (if therapy is delayed
until long after expected puberty, result may be variable and incomplete)

Testosterone can only exert its full action in a balanced hormone environment
 Example: patients with concomitant growth hormone deficiency will not respond
to androgen therapy unless GH is also included
o In patients with post-pubertal testicular failure, androgen therapy will generally result in return to
normal sexual activity
Catabolic States:
o Negative Nitrogen Balance: may be observed during minor injury or surgery

Treatment of WELL-NOURISHED patients in the first few days following injury or surgery
improves nitrogen balance (without significant therapeutic effect)

Androgens have a strong dependence on adequate nutrition and health (generally
ineffective in acute illness, severe trauma, and protein depletion with chronic illness)
Athletic Performance:
o Clear that androgens do promote muscle growth in immature boys and women of all ages
o Benefit from normal, therapeutic doses in mature men is questionable

Massive doses of some androgens may enhance development in sexually mature men



Controlled studies on the effect of these treatments on strength and performance
inconclusive

If there is a beneficial effect, MOA unknown because androgen receptor in sexually mature
men is functionally saturate
 Possible MOA is antagonism of glucocorticoid receptors, blocking catabolic effect of
these steroids
Stimulation of Erythropoiesis:
o Normally, there is a difference in hematocrit between males and females due to stimulatory effect of
testosterone on EPO
o Androgens have been used to treat refractory anemia, bone marrow failure, myelofibrosis and renal
failure
o However, recombinant EPO has largely replaced this use of androgens
Carcinoma of the Breast:
o Testosterone preparations have been used in the palliative treatment of breast cancer, especially in
premenopausal women
o MOA is unknown (most likely acting as an antiestrogen)
o Usefulness of treatment questioned due to the fact that success rates with conventional chemotherapy
are generally higher
Adverse Effects:
Virilizing Effects:
o Masculinization in women (acne, growth of facial hair, coarsening of voice, menstrual irregularities due
to suppression of FSH and LH)

Will subside slowly if stopped as soon as they are noticed

Long term treatment can result in male pattern baldness, excessive body hair, prominent
musculature and hyptertrophy of the clitoris (can be irreversible)
o Profound virilization and disturbances in growth and bone development can occur in children

Promotion of epiphyseal closure (can persist for months after tx stopped)

Need to use caution in children and are contraindicated in pregnancy (masculinization of
female fetus)
o Massive doses of anabolic steroids or prolonged treatment with androgens can also result in
azoospermia (inhibition of gonadotropin secretion and conversion of androgens to estrogen)

Low sperm count can persist for 3 or more months after treatment termination
Feminizing Effects:
o Can occur in men (primarily gynecomastia)
o Due to aromatization to estrogen
o Particularly of concern in children (have extraglandular aromatase activity relative to adults) and in
men with liver disease (decreased androgen clearance)
Toxicity:
o Edema (Na retention)
o Jaundice

Orally active androgens with 17α-alkyl grounds can cause cholestatic hepatitis

Prominent in large doses (athletes and palliative treatment of neoplasia)

Not observed with parenterally administered testosterone esters (as a result, preferred
treatment for cancer chemotherapy)
o Increased risk of hepatic adenocarcinoma (long-term treatment with orally active androgens)
Drug Prototypes:
Testosterone: aqueous suspensions for IM injection (10-50mg)
Testosterone Salts
Oxymetholone
Oxandrolone
Methyltestosterone
Fluoxymesterone
Danazol: derivative of 17α-ethinyl testosterone with weak progestin and androgen activity
o Suppresses ovarian function by inhibiting midcycle surge of LH and FSH
o Used in the treatment of endometriosis
ANTIANDROGENS:

Introduction:
Compounds that block the synthesis or action of androgens can be used for management of several conditions:
o Hyperplasia and carcinoma of the prostate
o Male-pattern baldness
o Virilization in females
o Precocious puberty in boys
o Inhibition of libido in male sex offenders
Most effective inhibitor of testosterone synthesis is continuous treatment with GnRH analog (ie. leuprolide)
o Results in decreased plasma LH and decreased testosterone secretion (desensitize GnRH receptors)
Two kinds of drugs blocking androgen action:
o Competitive antagonists of androgen R
o Synthesis inhibitors

Finasteride:
o MOA: inhibits 5α-reductase enzyme (required to convert testosterone to active form of
dihydrotestosterone)

Cytoproterone Acetate:
o MOA: competitive antagonist of dihydrotestosterone for androgen receptor
o Use: treatment of acne, male-pattern baldness, hirsutism and virilization in women, prostate hypertrophy
and cancer , precocious puberty and inhibition of libido in male sex offenders

Flutamide and Bicalumatide:
MOA: non-steroidal anti-androgens that are competitive antagonists of the androgen receptor
o Flutamide: used in the treatment of prostate cancer with leuprolide
o Bicalutamide: new drug with less hepatotoxicity than flutamide

Ketoconazole:
MOA: inhibits glucocorticoid and androgen synthesis in the adrenal gland

Spironolactone:
MOA: competitive antagonist for the androgen receptor
Use: treatment of female hirsutism
GnRH and GnRH ANTAGONISTS:

Basics:
GnRH release for hypothalamus normally governed by a hypothalamic neural pulse generator
Important for the regulation of the synthesis of gonadal steroids through pituitary gonadotropins (LH and FSH)

Clinical Uses of GnRH:
Endometriosis: growth of tissue resembling endometrium outside the uterus
o Cause: excess estrogen created each month (seen primarily during reproductive years; very rare in post
menopausal women)
o Therapy: aimed at lowering estrogen levels to control the disease

Leuprolide (GnRH Analog): tx with low doses for 6 months
 Concomitant therapy with low dose HRT has been reported to decrease bone loss
without decreasing clinical effectiveness

Nafarelin (GnRH Analog): available as nasal preparation that is started between days 2 and 4
of the menstrual cycle
 Amenorrhea occurs in many women after several months of treatment
 ~60% of women are symptom free by the end of treatment
Uterine Fibroids: benign tumors (most common neoplasm in females) that grow in the muscle layers of the
uterus; may grow as a single tumor or in clusters
o Effect of Hormones:

Have estrogen receptors that are estrogen sensitive (therefore, they may enlarge rapidly
during pregnancy due to increased estrogen and tend to regress during menopause)

Possible role of progesterone and progestins in fbroid growth has also been postulated
o Therapy:

Leuprolide: used in combination with surgery
 GnRH analogs force fibroids to shrink pre-operation and allow for a shorter, less
complicated surgery
 Treatment course is 3 months in symptomatic women

Nafarelin: nasal spray has also been used to shrink fibroids

GnRH Antagonists:
Cetrorelix Acetate: synthetic decapeptide that reversibly binds pituitary GnRH receptors without activating them
o Use: treatment of endometriosis and uterine fibroids
OXYTOCIN:

Basics:
9 amino acid peptide hormone secreted by posterior pituitary
During 2nd half of pregnancy, uterus increases the expression of oxytocin receptors (increasingly sensitive to it)
Pharmacological concentrations of oxytocin powerfully stimulate uterine contractions (useful for labor induction)

Clinical Use:
Induction of labor: administered by IV; also used to augment abnormal labor that is protracted or arrested
o MOA:

Acts through G protein coupled R and the PIP2/Ca second messenger system to contract
uterine smooth muscle

Also stimulates the release of PGs and leukotrienes that facilitate uterine contraction
Based on the above rationale, the following actions are used to suppress pre-mature labor:
o Increasing hydration to lower plasma concentrations of oxytocin
o Atosiban (oxytocin receptor competitive antagonist)