Gonadal Steroids Jan..

Synthesis, Metabolism, Mechanism of Action, Clinical Use
Rich Minshall, PhD
Associate Professor; Anesthesiology, Pharmacology
[email protected]
Chapter 40. The Gonadal Hormones & Inhibitors
Learning Objectives:
Understand the metabolic pathway of testosterone, estrogen and progesterone
synthesis and know the drugs that stimulate and inhibit their synthesis
Be familiar with the use and mechanism of action of androgen synthesis and receptor
Be aware of the treatment options for benign prostate hyperplasia and prostate
cancer: Finasteride vs Flutamide
Know the symptoms of the menopause period and which symptoms have been
shown through clinical trials to benefit from hormone replacement therapy (HRT)
Know the various estrogenic agents that may be used to treat menopausal symptoms:
Premarin, Provera; PremPro
Be aware of the protocols and routes of administration of HRT. Understand the
rationale for choosing one protocol or route over another.
Explain how a selective estrogen receptor modulator can act as an estrogen agonist in
one tissue or cell type while acting as an estrogen antagonist in another tissue or cell
type: Tamoxifen vs. Anastrazole
Steroid synthesis
The biosynthetic pathway
of the androgens and estrogens
19-carbon precursors are synthesized primarily in the ovaries, testes, and adrenals
Androgen Receptor Signaling
Control of androgen
secretion in males
(1) competitive inhibition of LHRH receptors
(2) stimulation (+, pulsatile administration) or
inhibition via desensitization of GnRH receptors
(–, continuous administration)
Lupron: synthetic analog of GnRH,
(3) decreased synthesis of testosterone in the testis;
e.g., Ketocanazole, Anastrazole
(4) decreased synthesis of dihydrotestosterone by
inhibition of 5a-reductase; e.g., Finesteride
(5) competition for binding to cytosol androgen
receptors; e.g., Flutamide
Endogenous Mechanism of Feedback Inhibition
Sertoli cells in the testis synthesize and secrete a variety of active
proteins, including müllerian duct inhibitory factor, inhibin, and
Leydig cells, upon LH stimulation, produce testosterone in the
spaces between the seminiferous tubules.
As in the ovary, inhibin and activin appear to be the product of
three genes that produce a common a subunit and two
b subunits, A and B.
Activin, composed of the two b subunits, stimulates pituitary FSH
Inhibins (A and B), which contain the a subunit and one of the b
subunits, in conjunction with testosterone and
dihydrotestosterone , are responsible for the feedback inhibition
of pituitary FSH secretion
Pharmacologic Uses of Androgens
Androgen production falls with age in men and may contribute to
the decline in muscle mass, strength, and libido. Hypo-pituitarism.
benign prostatic hyperplasia; prostatic carcinoma
treatment of hirsutism
Androgen Replacement Therapy
To replace or augment endogenous androgen secretion in hypogonadal
Used rather than gonadotropin except when normal spermatogenesis is
For hypo-pituitarism, androgens are not added to the treatment regimen
until puberty
 Start with long-acting agents such as testosterone enanthate or cypionate,
50 mg IM, initially every 4, then every 3, and finally every 2 weeks, with
each change taking place at 3-month intervals
 The dose is then doubled to 100 mg every 2 weeks until maturation is
 Finally, the adult replacement dose is 200 mg at 2-week intervals.
Table 40–6 Androgen
Preparations for
Replacement Therapy.
Route of
Sublingual (buccal)
5–10 mg/d
Testosterone enanthate
2–10 mg/d
See text
Testosterone cypionate
See text
Topical gel (1%)
2.5–10 mg/d
5–10 g/d
25–50 mg/d
Androgen Suppression Therapy
Inhibition of Steroid Precursor Conversion to Androgens
Ketoconazole-an inhibitor of adrenal and gonadal steroid synthesis
Abiraterone- inhibits the 17-hydroxylation of progesterone or pregnenolone to androgens
Finasteride- steroid-like orally active inhibitor of 5a-reductase that causes a reduction in
dihydrotestosterone levels. Moderately effective in reducing prostate size in men with benign
prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d.
Dutasteride- a similar orally active steroid derivative with a slow onset of action and a much
longer half-life than finasteride. The dose is 0.5 mg daily.
Anastrazole- blocks aromatase and inhibits conversion of androgens to estrogen
Receptor Inhibitors
Flutamide- potent anti-androgen that has been used in the treatment of prostatic carcinoma.
Although not a steroid, it behaves like a competitive antagonist at the androgen receptor.
Cyproterone and cyproterone acetate are effective anti-androgens that inhibit the action of
androgens at the target organ
Bicalutamide and nilutamide- potent orally active anti-androgens that can be administered as a
single daily dose and are used in patients with metastatic carcinoma of the prostate.
Spironolactone- a competitive inhibitor of aldosterone that also competes with
dihydrotestosterone for the androgen receptor in target tissues. It also reduces 17-hydroxylase
activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50–
200 mg/d in the treatment of hirsutism in women and appears to be as effective
as finasteride, flutamide, or cyproterone in this condition.
GOSSYPOL- cottonseed extract, abandoned as a candidate male contraceptive
Use of Anti-Androgen Therapy to treat BPH and Prostate Cancer
The glandular cells of the Prostate produce a milky fluid, and during sex the smooth muscles
contract and squeeze this fluid into the urethra. Here, it mixes with sperm and other fluids to make
Finasteride (Proscar, generic) and dutasteride (Avodart) are drugs used to treat benign prostatic
hypertrophy (BPH). They block 5 alpha-reductase, which is the enzyme that converts testosterone
to dehydroepiandrosterone (DHEA) that is known to stimulate growth of the prostate.
Treatment of
Prostate Cancer
Orchiectomy-surgical removal of the testicles (surgical
castration) is the single most effective method of reducing
androgens. When combinded with radical prostatectomy,
this will delay progression in patients with cancers that
have spread only to the pelvic lymph nodes.
Orchiectomy increases the risk for osteoporosis
LHRH Agonists
The primary drugs used for suppressing androgens are
LHRH agonists which block the pituitary gland from
producing LH that stimulates testosterone production.
Leuprolide (Lupron, Leuprogel), goserelin (Zoladex),
and buserelin.
Side effects: hot flashes and nipple and breast tenderness.
Anti-androgens are drugs used to block the effects of
testosterone at the receptor.
Flutamide (Eulexin, Drogenil), nilutamide (Nilandron),
and bicalutamide (Casodex). Side effect: diarrhea
Control of ovarian
secretion and the actions of
its hormones
In the follicular phase, the ovary
produces mainly estrogens;
In the luteal phase, it produces estrogens
and progesterone.
SERMs, selective estrogen receptor
Estrogen and
production and
Consider the normal menstrual cycle:
1) Estrogen released from the ovary - increases the expression
of estrogen receptors.
2) Estrogen increases the expression of progesterone receptors.
3) Progesterone down regulates the expression of estrogen
4) With the progesterone-elicited decrease in estrogen receptor
numbers - there will be a decrease in the ability of estrogen to
stimulate the production of progesterone receptors - in this
way - progesterone turns itself off.
Estrogen production from
progesterone and testosterone
via Aromatase:
Treatment of estrogendependent Breast Cancer with
Aromatase inhibitors,
Ketocanazole, Anastrazole
Estrogen and synthetic analogs
Progesterone and synthetic analogs
Structural Formulas of Selected Estrogens
Estrogen Receptor Isoforms
Estrogen Receptor Signaling
Elimination of Estrogens
17b-estradiol is primarily converted by 17b-hydroxysteroid dehydrogenase to estrone,
and converted by 16a-hydroxylation and 17-keto reduction to estriol, which is the
major urinary metabolite; sulfate and glucuronide conjugates also are excreted in the
urine. Estrone also is converted to the catechol estrogen, or 2-hydroxyestrone which is
methylated to 2-methoxyestrone
Therapeutic Use and Dose of E2:
• pharmacological considerations for E use in OC and
HRT are different because of the dose
• conjugated estrogens for HRT (0.625 mg/day for most
women; 1.25 mg in some patients)
• combination oral contraceptives in current use employ
20 to 35 mg/day of ethinyl estradiol
• Conjugated estrogens and ethinyl estradiol differ widely
in their oral potencies; for example, a dose of 0.625 mg of
conjugated estrogens generally is considered equivalent
to 5 to 10 mg of ethinyl estradiol
Physiological Effects of Estrogen
Alters liver metabolism
Affects on clotting and fibrinolysis
-  fibrinogen levels
-  synthesis of clotting factors (VII, IX, X, XIII)
-  plasminogen levels
-  plasminogen activator inhibitor
Alters metabolism of lipoproteins
-  HDL
-  TG
-  LDL
-  total cholesterol
- increases angiotensinogen and transport proteins
Physiological Effects of Estrogen
Alters vascular reactivity (endothelial mediators of contraction and
-  endothelin-1
-  TXA2 receptors
-  angiotensin II receptors
-  superoxide free radicals
-  nitric oxide synthase expression and activity
therefore  nitric oxide
• tamoxifen and clomiphene used primarily for treatment
of breast cancer and female infertility, respectively
• can produce estrogenic as well as anti-estrogenic effects
• competitively block estradiol binding to its receptor; act as
antagonists, agonists, or partial agonists depending upon
the context in which they are used
Pharmacological Effects:
• enlargement of the ovaries
• ovulation in many patients with amenorrhea, Stein-Leventhal
syndrome, and dysfunctional bleeding.
• Clomiphene is used in conjunction with human menotropins and
CG to induce ovulation
• Tamoxifen exhibits anti-estrogenic, estrogenic, or mixed activity
depending upon the species and endpoint measured; inhibits the
proliferation of cultured human breast cancer cells, but stimulates
proliferation of endometrial cells
• estrogen-like effect to enhance bone density
• does not seem to exhibit antiestrogenic effects on lipoprotein profiles
• tamoxifen and clomiphene produce hot flashes in some women, the
expected vasomotor effect
Mechanism of Action
Clomiphene and tamoxifen bind ER and prevent binding of E
the drugs and estradiol may interact with overlapping but slightly different regions
of the ligand binding site
depending upon the specific cellular context and gene in question, anti-estrogen
binding may yield a receptor complex that has full, partial, or no intrinsic activity
best considered as functional competitive receptor antagonists in breast cancer cells
and the pituitary
Clomiphene can stimulate ovulation in women with an intact hypothalamicpituitary-ovarian axis and adequate endogenous estrogens who have failed to
ovulate; opposes the negative feedback of endogenous E resulting in increased
gonadotropin secretion and ovulation
clomiphene increases the amplitude of LH and FSH pulses, without a change in
pulse frequency, acting largely at the pituitary level to block inhibitory actions of E
on gonadotropin release from the gland and/or is somehow causing the
hypothalamus to release larger amounts of GnRH per pulse
Clomiphene also used in men to stimulate gonadotropin release and enhance
the effects of tamoxifen on proliferation of breast cancer cells appear to result largely
from estrogen receptor blockade
mammary tumors that contain ERs show a higher frequency of response to
antiestrogens than do tumors without appreciable receptor levels
Selective Estrogen Receptor
Modulators (SERMs)
Multiple Outcomes of Raloxifene
Evaluation (MORE)
Double Blind Placebo-Controlled Trial
7705 PMP women aged 31 to 80
Raloxifene 60 mg/d or 120 mg/d or placebo
Follow-up for 36 months for efficacy and 40 months for
adverse events
Increased BMD in femoral neck by 2.1% (60 mg) and by 2.4%
(120 mg)
Increased BMD in spine by 2.6% (60 mg) and by 2.7% (120 mg)
Increased risk of VTE (RR=3.1)
Conclusions: Raloxifene increases BMD in spine and femoral
neck and reduces risk of vertebral fracture – but increases risk
of venous thromboembolism
Tamoxifen vs. Anastrazole ?
Nat Rev Cancer. 2003
Aromatase inhibitors
for breast cancer:
lessons from the
Johnston SR, Dowsett
Tamoxifen vs. Anastrazole ?
Tamoxifen vs. Anastrazole ?
Tamoxifen vs. Anastrazole ?
Progesterone derivatives
Progesterone Receptor
Progestins are lipophilic and diffuse freely into cells where they bind to the PR
(PR-A and PR-B)
PRs are ligand-activated nuclear transcription factors that interact with a
progesterone response element in target genes to regulate their expression
PRs are expressed in the female reproductive tract, the mammary gland, the
CNS (including the pulse generator in the hypothalamus), and the pituitary
expression of PRs is induced by estrogens; its presence is a common marker for E
A single PR gene yields two forms of the receptor, the so-called A and B forms
that arise from two translational start codons; the physiological and
pharmacological significance of the two forms is unknown, but may relate to
intracellular vs cell surface membrane PR
progestins enhance differentiation and oppose the actions of E to stimulate cell
proliferation by decreasing ER levels, increasing local metabolism of estrogens to
less active metabolites, or induction of gene products that blunt cellular
responses to estrogenic agents
Biological Activity of Progestins
Vasomotor instability (hot flashes), night sweats
Increase incidence of cardiovascular disease
Genitourinary atrophy
Metabolic changes – fat redistribution
Skin changes
Insomnia, fatigue, dysphoria, anxiety
Loss of memory? Susceptibility to dementia?
Menopause Timetable
Women may enter menopause earlier than they realize. Estrogen levels usually
drop before menopausal symptoms are seen. Below, the typical ages for various
AGE -35
Dropping estrogen levels
Menstrual irregularity
Mood swings
Loss of concentration
Hot flashes
Vaginal dryness
Last period
Heart Disease
Sources: “Perimenopause: Preparing for the Change” by Nancy Lee Teaff and Kim Wright (Prima Publishing, 1996);
“Perimenopause: Changes in Women’s Health After 35” by Drs. James E. Huston and L. Darlene Lanka
(New Harbinger, 1997).
Hormone Replacement Therapy
Menopause: cessation of menses; loss of ovarian function
leading to a state of permanent amenorrhea
Ovarian follicle no longer responds to gonadotropin, thus
estrogen is not produced
Lack of negative feedback results in increased levels of
gonadotropins (FSH and LH)
Amenorrhea lasting 1 year – average age 51.4 years
(2 yrs earlier in smokers)
Climacteric: series of physiologic, endocrinologic and
psychologic changes that signify the transition from
reproductive to non-reproductive life that spans several
years – perimenopausal
Routes and Compounds
• Oral Estrogens
Premarin, Cenestin
Esterified estrogen
Ethinyl estradiol
Estrone sulfate
Micronized estrogen
• Transdermal Estrogens
– Less effects on liver – no
first pass effect
– Patches, creams
• Vaginal Estrogens
– Vaginal creams – including
– Vaginal ring
• Parenteral Estrogens
– Estrogen esters
• Progesterones
– Medroxyprogesterone
– Norethindrone – etc.
– Micronized progesterone
Examples of HRT Preparations
• Prempro – continuous combined
Premarin and Provera
Premphase - continuous sequential Premarin
14 days then Premarin plus Provera for next 14
• FEMHRT – continuous combined ethinyl
estradiol plus norethindrone
• Ortho-Prefest – continuous combined; 6 day
cycle – day 1-3 micronized estradiol and day 4-6
micronized estradiol with norgestimate
Proposed Benefits of HRT
• Decreased incidence of cardiovascular disease
• Improved lipid profiles
• Vasodilatory effects
• Antiplatelet activity
• Decreased fibrinogen levels
• Direct myocardial effects
• Antioxidant activity
• Prevention of bone loss*
• Treatment of vasomotor symptoms (hot flashes)*
• Prevention of colon cancer
• Prevention of Alzheimer’s disease
• Prevention of urinary incontinence
• Alleviation of sleep disorders
* known effects of estrogen
Relative Risk for Estrogen Use and Coronary Heart Disease
Study Type
Hospital Case-Control
Pop Case-Control
Prospective Internal
Prospective External
All Studies Combined
Prospective Internal
Control and
Cross Sectional
Reproduced with Permission. Stampfer, M. & Colditz, G. Estrogen replacement therapy and coronary heart disease: A quantitative assessment of the
epidemiologic evidence. Preventive Medicine. 1991;20, 47-63.
Physiological and Pharmacological
Actions of Estrogen
Developmental Actions:
 Puberty and secondary sexual characteristics of females
 growth and development of the vagina, uterus, and fallopian tubes
 with other hormones cause enlargement of the breasts, promotion of ductal growth,
stromal development, and the accretion of fat; molding body contours, shaping the
skeleton, and growth spurt of the long bones
 growth of axillary and pubic hair and pigmentation of the genital region; regional
pigmentation of the nipples and areolae that occur after the first term of pregnancy
Metabolic Effects of E:
 blocks bone resorption and increases bone formation
 increases the level of the hydroxylase that converts vitamin D to 1,25dihydroxyvitamin D3 in the kidney
 slightly elevates serum triglycerides and reduces total serum cholesterol levels
 increases HDL levels and decreases LDL values
 alters bile composition by increasing cholesterol secretion and decreasing bile acid
secretion, leading to increased saturation of bile with cholesterol which may be the
basis for increased gallstone formation
 decrease slightly fasting levels of glucose and insulin,
 increase plasma levels of cortisol-binding globulin (CBG or transcortin), thyroxinebinding globulin (TBG), and sex steroid-binding globulin (SSBG), which binds both
androgens and estrogens
Physiological and Pharmacological
Neuroendocrine Actions:
P decreases the frequency of the hypothalamic pulse generator and increases the amplitude of
LH pulses
Reproductive Tract:
• P released during the luteal phase of the cycle decreases estrogen-driven endometrial
proliferation and leads to the development of a secretory endometrium
• decline in P release from the corpus luteum at the end of the cycle determines onset of
• P influences the endocervical glands; the abundant watery secretion of the estrogenstimulated structures is changed to a scant, viscis material, decreasing penetration of the
cervix by sperm
• E-induced maturation of the vaginal epithelium is modified toward the condition of
pregnancy by P
• P is very important for the maintenance of pregnancy: suppress menstruation and uterine
contractility, which led to the use of progestins to prevent threatened abortion. However, such
treatment is of questionable benefit because diminished P is rarely the cause of spontaneous
Mammary Gland:
• P, acting with E, induces proliferation of the acini of the mammary gland
• during the normal menstrual cycle, the mitotic activity in the breast epithelium is very low in
the follicular phase and then peaks in the luteal phase… P triggers a single round of mitotic
• in contrast, in the endometrium, proliferation is greatest in the follicular phase due to
increasing E and is opposed by P in the second half of the cycle
• hormonal control of proliferation is thus different in breast and endometrium; these cell52 of
specific effects should be kept in mind when interpreting therapeutic and untoward effects
E and P
Physiological and Pharmacological
Actions of Progesterone:
CNS Effects:
• an increase of about 1°F may be noted midway through the normal menstrual cycle
at the time of ovulation
• the temperature rise persists for the remainder of the cycle until the onset of the
menstrual, and thus clearly due to P. The mechanism of this effect is unknown
• P increases the ventilatory response of the respiratory centers to carbon dioxide and
leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle
and during pregnancy
• P may have depressant and hypnotic actions, perhaps inducing drowsiness after
Metabolic Effects:
• P increases basal insulin levels and the rise in insulin after carbohydrate ingestion
• long-term administration of more potent progestins, such as norgestrel, may decrease
glucose tolerance
• P stimulates lipoprotein lipase activity and seems to enhance fat deposition
• P and medroxyprogesterone acetate (MPA) cause either no effect or modest reduction
in serum HDL; 19-nor progestins may cause more pronounced decrease in HDL
levels, possibly due to androgenic activity. Thus, progestins may diminish the
beneficial effects of estrogens on serum lipoprotein profiles in situations where the
two agents are given together, such as OCs and HRT.
• P may diminish the effects of aldosterone in the renal tubule and cause a decrease in
sodium reabsorption that may increase mineralocorticoid secretion from the adrenal
Relationship Between
Estrogen and Progesterone
1) Estrogen exerts positive feedback on its own activity.
Estrogen stimulates the expression of estrogen receptors.
2) Estrogen must precede progesterone to elicit full progesterone sensitivity.
Estrogen stimulates the expression of progesterone receptors.
3) Progesterone has anti-estrogenic activity - which helps to terminate
estrogenic activity.
- Progesterone suppresses expression of estrogen receptors.
- Progesterone facilitates the metabolism of estradiol to weaker metabolites.
- Progesterone may act as a partial agonist at the estrogen receptor.

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