Gonadal

Hormones &
Inhibitors
April Dawn R. Lucero, MD,
DipIBLM
High-Yield Terms
 5`-Reductase

The enzyme that converts

testosterone to
dihydrotestosterone (DHT)

Anabolic steroid

Androgen receptor agonists used

for anabolic effects (eg, weight
gain, increased muscle mass)
 High-Yield Terms

Breakthrough bleeding
Vaginal bleeding that occurs outside of the
period of regular menstrual bleeding
Combined oral contraceptive (COC or just
OC)
Hormonal contraceptive administered
orally that contains an estrogen and a
progestin
Hirsutism

• A male pattern of body hair growth (face, chest, abdomen)

in females that results from hyperandrogenism

HRT

• Hormone replacement therapy; refers to estrogen

replacement for women who have lost ovarian function and
nearly always involves combination therapy with estrogen
and a progestin

High-Yield Terms
SERM

Selective estrogen receptor

modulator such as tamoxifen

High-Yield Terms
Overview

• The gonadal hormones include the steroids of the ovary (estrogens

and progestins) and testis (chiefly testosterone)

• Synthetic estrogens & progestins:

a. Synthesis inhibitors

b. Receptor antagonists

c. Mixed effects
Overview
• Mixed agonists with estrogenic effects are called selective estrogen
receptor modulators (SERMs).

• Synthetic androgens, including those with anabolic activity, are also

available for clinical use.

• A diverse group of drugs with antiandrogenic effects is used in the

treatment of prostate cancer and benign prostatic hyperplasia in men and
hyperandrogenism in women.
 Ovarian
Hormones
• The ovary is the primary source of gonadal hormones in women
during the childbearing years (ie, between puberty and menopause).

• When properly regulated by follicle-stimulating hormone (FSH) and

luteinizing hormone (LH) from the pituitary, each menstrual cycle
consists of the following events:
➢A follicle in the ovary matures → secretes increasing amounts of estrogen →
releases an ovum → transformed into a progesterone-secreting corpus
luteum
• If the ovum is not fertilized and implanted, the corpus luteum
degenerates →the uterine endometrium, which has proliferated
under the stimulation of estrogen and progesterone, is shed as part of
the menstrual flow, and the cycle repeats.

MOA of both estrogen and progesterone:

• entry into cells → binding to cytosolic receptors → translocation of

the receptor–hormone complex into the nucleus → modulates gene
expression
 • The major ovarian
estrogen in women is
estradiol.
• Estradiol has low oral
bioavailability but is
available in a
micronized form for oral
use.
• It can also be
administered via
transdermal patch,
vaginal cream, or
intramuscular injection.
A. Estrogens
A. Estrogens
• Mixtures of conjugated estrogens
from biologic sources (eg, Premarin)
are used orally for hormone
replacement therapy (HRT).
• Synthetic estrogens with high
bioavailability (eg, ethinyl estradiol,
mestranol) are used in hormonal
contraceptives.
A. Effects of Estrogens
• Estrogen is essential for normal female reproductive development

• Growth of the genital structures (vagina, uterus, and uterine tubes) during
childhood

• Appearance of secondary sexual characteristics and the growth spurt

associated with puberty

• Metabolic effects: modifies serum protein levels and reduces bone

resorption
A. Effects of Estrogens
• Enhances the coagulability of blood
• Increases plasma triglyceride levels
• Reduces low-density lipoprotein (LDL) cholesterol
• Increases high-density lipoprotein (HDL) cholesterol
• Continuous administration of estrogen, especially in combination with a
progestin, inhibits the secretion of gonadotropins from the anterior
pituitary.
Clinical Use

• Hypogonadism in young females

• HRT in women with estrogen deficiency

resulting from premature ovarian failure,
menopause, or surgical removal of the
ovaries.
➢ HRT ameliorates hot flushes and atrophic changes in
the urogenital tract

• Effective also in preventing bone loss and

osteoporosis

• Components of hormonal contraceptives

A. Estrogens: Toxicity
• In hypogonadal girls, the dosage of estrogen
must be adjusted carefully to prevent
premature closure of the epiphyses of the
long bones and short stature.

• When used as HRT, estrogen increases the risk

of endometrial cancer; this effect is prevented
by combining the estrogen with a progestin.
A. Estrogens: Toxicity

• Estrogen use by postmenopausal women is associated with

a small increase in the risk of breast cancer and
cardiovascular events (myocardial infarction, stroke).

• Dose-dependent toxicity includes nausea, breast

tenderness, increased risk of migraine headache,
thromboembolic events (eg, deep vein thrombosis),
gallbladder disease, hypertriglyceridemia, and
hypertension.
B. Progestins
• Progesterone is the major progestin in humans

• A micronized form is used orally for HRT, and progesterone-containing vaginal creams
are also available.

• Synthetic progestins (eg,medroxyprogesterone) have improved oral bioavailability.

• The 19-nortestosterone compounds differ primarily in their degree of androgenic effects.

• Older drugs (eg, L-norgestrel and norethindrone) are more androgenic than the newer
progestins (eg, norgestimate, desogestrel).
B. Effects of Progestins
• Progesterone induces secretory changes in the endometrium and is required
for the maintenance of pregnancy.

• The other progestins also stabilize the endometrium but do not support
pregnancy.

• Progestins do not significantly affect plasma proteins, but they do affect

carbohydrate metabolism and stimulate the deposition of fat.

• High doses suppress gonadotropin secretion and often cause anovulation in

women.
B. Clinical Use of Progestins

• Used as contraceptives, either alone or in combination with an

estrogen

• Used in combination with an estrogen in HRT to prevent estrogen-

induced endometrial cancer

• Progesterone is used in assisted reproductive technology methods to

promote and maintain pregnancy
 • The toxicity of progestins
is low. However, they may
increase blood pressure
and decrease HDL
• Long-term use of high
doses in premenopausal
women is associated with
a reversible decrease in
bone density (a
secondary effect of
ovarian suppression and
decreased ovarian
production of estrogen)
and delayed resumption
of ovulation after
B. Toxicity of Progestins termination of therapy.
C. Hormonal Contraceptives
• Hormonal contraceptives contain either
a combination of an estrogen and a
progestin or a progestin alone.

• Available in a variety of preparations,

including oral pills, long-acting
injections, transdermal patches, vaginal
rings, and intrauterine devices (IUDs).
 C. 3 Types of Oral Contraceptives

1. Monophasic Preparations
Combination estrogen-progestin tablets taken in
constant dosage throughout the menstrual cycle

2. Biphasic & Triphasic Preparations

Combination preparations in which the progestin or
estrogen dosage, or both, changes during the month
(to more closely mimic hormonal changes in a
menstrual cycle)

3. Progestin-only preparations
C. Hormonal Contraceptives
• The postcoital contraceptives (also known as “emergency contraception”)
prevent pregnancy if administered within 72 h after unprotected
intercourse.

• Oral preparations containing a progestin (L-norgestrel) alone, estrogen

alone, or the combination of an estrogen and a progestin are effective.

• The progestin-only preparation causes fewer side effects than the

estrogen-containing preparations.
MOA: Combination Oral Contraceptives
• Primary action: inhibition of
ovulation

• Effects on the cervical mucus

glands, uterine tubes, and
endometrium that decrease the
likelihood of fertilization and
implantation
MOA: Progestin-Only Agents
• Do not always inhibit ovulation

• MOA not well understood

• When administered before the LH

surge, they inhibit ovulation.

• They also affect cervical mucus,

tubal function, and the endometrial
lining.
 • Combination hormonal
contraceptives are used in
young women with primary
hypogonadism to prevent
estrogen deficiency.
• Combinations of hormonal
contraceptives and
progestins are used to treat
acne, hirsutism,
C. Other Clinical Uses and
dysmenorrhea, and
Beneficial Effects
endometriosis.
of Hormonal Contraceptives
 • Benign, but usually a
progressive & aggressive
disease
• The presence & growth of
the glands & stroma of the
lining of the uterus in an
aberrant & heterotopic
location.
• In 33% of women with
chronic pelvic pain
• In 30-45% with infertility
• Typical patient: mid-30s,
nulliparous & involuntarily
infertile, & has symptoms of
Endometriosis secondary dysmenorrhea &
pelvic pain
C. Other Clinical Uses and Beneficial Effects
of Hormonal Contraceptives
• Users of combination hormonal contraceptives have reduced risks of
ovarian cysts, ovarian and endometrial cancer, benign breast
disease, and pelvic inflammatory disease

• Lower incidence of ectopic pregnancy, iron deficiency anemia, and

rheumatoid arthritis
Toxicity

a. Thromboembolism

• Major toxic effect

• Relate to the action of the estrogenic

component on blood coagulation

• Well-documented increase in the risk of thromboembolic events (myocardial infarction, stroke,

deep vein thrombosis, pulmonary embolism) in older women, smokers, women with a personal
or family history of such problems, and women with genetic defects that affect the production or
function of clotting factors.

• However, the risk of thromboembolism incurred by the use of these drugs is usually less than
that imposed by pregnancy.
Toxicity

b. Breast cancer

• Evidence suggests that the lifetime risk of breast cancer in women

who are current or past users of hormonal contraceptives is not
changed, but there may be an earlier onset of breast cancer.
Other toxicities
The low-dose combined oral and progestin only contraceptives cause significant
breakthrough bleeding, especially during the first few months of therapy. Other
toxicities of the hormonal contraceptives include nausea, breast tenderness,
headache, skin pigmentation, and depression.

• Preparations containing older, more androgenic progestins can cause weight

gain, acne, and hirsutism.

• The high dose of estrogen in estrogen-containing postcoital contraceptives is

associated with significant nausea.
Contraindications to Oral
Contraceptive Use
Absolute Contraindications:
• History of vascular disease
• Systemic disease that may affect the vascular
system

Other CI:
• Cigarette smoker older than 35 years
• Uncontrolled HPN
Contraindications to Oral
Contraceptive Use

• Breast or endometrial cancer

• Undiagnosed uterine bleeding

• Elevated triglyceride levels

• Pregnancy

• Acute liver disease

Antiestrogens & Antiprogestins
A. Selective
• Mixed estrogen agonists that have estrogen
Estrogen agonist effects in some tissues and act as partial
agonists or antagonists of estrogen in other
Receptor tissues.
Modulators
Tamoxifen
Antagonist Effects Agonist Effects

• A SERM that is effective in the treatment of • As an agonist of endometrial receptors,

hormone-responsive breast cancer, where it tamoxifen promotes endometrial hyperplasia
acts as an antagonist to prevent receptor and increases the risk of endometrial cancer
activation by endogenous estrogens.
• Increases the risk of venous thrombosis
• Prophylactic use of tamoxifen reduces the
incidence of breast cancer in women who are • Tamoxifen has more agonist than antagonist
at very high risk. action on bone and thus prevents

• Causes hot flushes osteoporosis in postmenopausal women

Raloxifene
• Prevention and treatment of osteoporosis in
postmenopausal women

• Partial agonist effect on bone

• Like tamoxifen, it has antagonist effects in breast

tissue and reduces the incidence of breast cancer in
women who are at very high risk

• Unlike tamoxifen, the drug has no estrogenic effects

on endometrial tissue.

• Adverse effects: hot flushes (an antagonist effect) and

an increased risk of venous thrombosis (an agonist
effect)
 Clomiphene

• A nonsteroidal compound with tissue-

selective actions
• Induce ovulation in anovulatory women
who wish to become pregnant
• By selectively blocking estrogen receptors in
the pituitary, clomiphene reduces negative
feedback and increases FSH and LH output.
The increase in gonadotropins stimulates
ovulation.
 B. Pure Fulvestrant
Estrogen • A pure estrogen receptor antagonist (in all
tissues)
Receptor • Treatment of women with breast cancer that
Antagonists has developed resistance to tamoxifen
C. Synthesis
Inhibitors
Danazol

• Inhibits several cytochrome P450 enzymes involved in gonadal

steroid synthesis and is a weak partial agonist of progestin,
androgen, and glucocorticoid receptors.

• Sometimes used in the treatment of endometriosis and fibrocystic

disease of the breast.
D. Gonadotropin-
Releasing
Hormone
Analogs
D. GnRH Analogs

• The continuous administration of gonadotropin-releasing hormone (GnRH) agonists (eg,

leuprolide) suppresses gonadotropin secretion and thereby inhibits ovarian production
of estrogens and progesterone.

• Used in combination with other agents in controlled ovarian hyperstimulation

• Treatment of precocious puberty in children

• Short-term (<6 mo) treatment of endometriosis and uterine fibroids in women

➢Treatment beyond 6 mo in premenopausal women can result in decreased bone
density
E. Antiprogestins

Mifepristone (RU 486)

• An orally active steroid antagonist of progesterone and glucocorticoids

• Major use: abortifacient in early pregnancy (up to 49 d after the last

menstrual period)

• The combination of mifepristone and the prostaglandin E analog misoprostol

achieves a complete abortion in over 95% of early pregnancies.
Mifepristone (RU 486)

• Most common complication: failure to induce a complete abortion

• Side effects (primarily due to the misoprostol):

✓Nausea

✓Vomiting

✓Diarrhea

✓Vaginal cramping and bleeding associated with passing the pregnancy

Androgens
• Testosterone and related androgens are produced in the testis, the
adrenal, and, to a small extent, the ovary.

• Testosterone is synthesized from progesterone and

dehydroepiandrosterone (DHEA).

• In the plasma, testosterone is partly bound to sex hormone-binding

globulin (SHBG), a transport protein.
• The hormone is converted in several organs (eg, prostate) to
dihydrotestosterone (DHT), which is the active hormone in those tissues.

• Because of rapid hepatic metabolism, testosterone given orally has little

effect.

• It may be given by injection in the form of long-acting esters or

transdermal patch.

• Orally active variants are also available

Androgens

• Oxandrolone and stanozolol are examples of drugs that, in laboratory

testing, have an increased ratio of anabolic-androgenic action.

• However, all the so-called anabolic steroids have full androgenic

agonist effects when used in humans.
Mechanism of Action

• Like other steroid hormones,

androgens enter cells and bind to
cytosolic receptors.

• The hormone-receptor complex

enters the nucleus and modulates
the expression of target genes.
Effects

• Testosterone is necessary for normal development of the male fetus and

infant and is responsible for the major changes in the male at puberty
(growth of penis, larynx, and skeleton; development of facial, pubic, and
axillary hair; darkening of skin; enlargement of muscle mass).

• After puberty, testosterone acts to maintain secondary sex characteristics,

fertility, and libido.

• It also acts on hair cells to cause male-pattern baldness.

 Effects

✓ Anabolic action that involves increased

muscle size and strength
✓ Increased red blood cell production
✓ Excretion of urea nitrogen is reduced,
and nitrogen balance becomes more
positive
✓ Helps maintain normal bone density
Clinical Use

• Primary clinical use: replacement therapy in

hypogonadism

• Androgens have also been used to stimulate red blood cell

production in certain anemias and to promote weight gain
in patients with wasting syndromes (eg, AIDS patients).

• The anabolic effects have been exploited illicitly by

athletes to increase muscle bulk and strength and perhaps
enhance athletic performance.
Toxicity

Use of androgens by In women who are

females results in pregnant with a female
virilization (hirsutism, fetus, exogenous
enlarged clitoris, deepened androgens can cause
voice) and menstrual virilization of the fetus’s
irregularity. external genitalia.
Toxicity
Paradoxically, excessive doses in
men can result in feminization
(gynecomastia, testicular
shrinkage, infertility) as a result of
feedback inhibition of the pituitary
and conversion of the exogenous
androgens to estrogens.
In both sexes, high doses of
anabolic steroids can cause
cholestatic jaundice, elevation of
liver enzyme levels, and possibly
hepatocellular carcinoma.
Antiandrogens
A. Receptor Inhibitors

• Flutamide and related drugs are nonsteroidal competitive antagonists

of androgen receptors. These drugs are used to decrease the action
of endogenous androgens in patients with prostate carcinoma.

• Spironolactone, a drug used principally as a potassium-sparing

diuretic, also inhibits androgen receptors and is used in the treatment
of hirsutism in women.
B. 5α-Reductase Inhibitors
• Testosterone is converted to DHT by the enzyme 5α-reductase.

• Some tissues, most notably prostate cells and hair follicles, depend on DHT
rather than testosterone for androgenic stimulation.

• This enzyme is inhibited by finasteride, a drug used to treat benign prostatic

hyperplasia and, at a lower dose, to prevent hair loss in men.

• Because the drug does not interfere with the action of testosterone, it is less
likely than other antiandrogens to cause impotence, infertility, and loss of libido.
C. Gonadotropin-Releasing Hormone
Analogs and Antagonists
• Suppression of gonadotropin secretion, especially LH, reduces the
production of testosterone.

• This can be effectively accomplished with long-acting depot

preparations of leuprolide or similar gonadotropin-releasing hormone
(GnRH) agonists.

• These analogs are used in prostatic carcinoma.

C. Gonadotropin-Releasing Hormone
Analogs and Antagonists
• During the first week of therapy, an androgen receptor antagonist
(eg, flutamide) is added to prevent the tumor flare that can result
from the surge in testosterone synthesis caused by the initial
agonistic action of the GnRH agonist.

• Within several weeks, testosterone production falls to low levels.

• The GnRH receptor antagonists abarelix and degarelix are approved

for advanced prostate cancer.
D. Combined Hormonal Contraceptives

• Combined hormonal contraceptives are used in women with

androgen-induced hirsutism.

• The estrogen in the contraceptive acts in the liver to increase the

production of sex hormone-binding globulin, which in turn reduces
the concentration of the free androgen in the blood that is causing
the male-pattern hair growth characteristic of hirsutism.
E. Inhibitors of Steroid Synthesis

• Ketoconazole, an antifungal drug, inhibits gonadal and adrenal

steroid synthesis.

• The drug has been used to suppress adrenal steroid synthesis in

patients with steroid-responsive metastatic prostate cancer.
Questions
Which of the following is an estrogen that is
used in most combined hormonal
contraceptives?

(A) Clomiphene
(B) Estrone
(C) Ethinyl estradiol
(D) Diethylstilbestrol (DES)
(E) Norgestrel
 • Ethinyl estradiol, a synthetic estrogen
with good bioavailability, is the

Answer = C
estrogenic component of most
combined oral contraceptives, the
transdermal contraceptive, and the
vaginal ring contraceptive.
 A 23-year-old woman
desires a combined (A) Evidence of hirsutism
oral contraceptive for (B) History of gastroesophageal reflux disease and
pregnancy protection. is currently taking omeprazole
Which of the following (C) History of pelvic inflammatory disease
patient factors would (D) History of migraine headache that is well
lead a health controlled by sumatriptan
professional to (E) She plans to use this contraceptive for about 1
recommend an yr and will then attempt to become
alternative form of pregnant
contraception?
Answer = D
Estrogen-containing hormonal
contraceptives increase the risk of
episodes of migraine headache
Men who use large doses of anabolic steroids are
at increased risk of which of the following?

(A) Anemia

(B) Cholestatic jaundice and elevation of

aspartate transaminase levels in the blood

(C) Hirsutism

(D) Hyperprolactinemia

(E) Testicular enlargement

 Answer = B
In men, large doses of anabolic steroids are
associated with liver impairment, including
cholestasis and elevation of serum concentrations of
transaminases.