Gonadal hormones & Inhibitors

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 Introduction
• Sex hormones produced by the gonads are necessary for :

• Conception

• Embryonic maturation

• Development of primary and secondary sexual characteristics at puberty

• Sex hormones are used therapeutically in:

• Replacement therapy

• Contraception

• Management of menopausal symptoms

• Several gonadal hormones antagonists are effective in cancer chemotherapy

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 Introduction
• Natural sex hormones are made by:

– the gonads (ovaries or testes),

– by adrenal gland,

– or by conversion from other sex hormones in other tissue such as liver or fat

• Hormonal control of the reproductive systems in men and women involves:

– sex steroids from the gonads,

– hypothalamic peptides (GnRH),

– and glycoprotein gonadotrophins from the anterior pituitary (FSH and LH)
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Estrogens

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 Estrogens
1. Natural Estrogens

• There are three main endogenous estrogens in humans:

– estradiol (17 β estradiol, E2), (major secretory product of the ovary)

– estrone (E1),

– estriol (E3)

• The most potent endogenous estrogen is estradiol, followed by estrone &

estriol
• Animal source: Commercially (premarin): Preparations of conjugated estrogens

containing:
– sulfate esters of estrone and equilin
• obtained from pregnant mares’ urine 8
 Estrogens
2. Synthetic estrogens:

a. Steroidal: e.g. ethinyl estradiol & mestranol

• Undergo less first-pass metabolism than naturally occurring estrogens

• thus, are more effective when administered orally at lower doses

b. Nonsteroidal compounds: e.g diethylstilbestrol

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Estrogen preparations
• For many uses, preparations are available:
– as an estrogen alone

– or in combination with a progestin

• All of the estrogens produce almost have the same hormonal effects,
– their potencies vary both:
• between agents
• and depending on the route of administration

• Estrogens are available for:

– oral,

– parenteral,

– transdermal, or topical administration 11

 Estrogen preparations
• Oral administration is common and may utilize:
– estradiol,

– conjugated estrogens,

– esters of estrone and other estrogens,

– and ethinyl estradiol

• The oral route of administration allows greater concentrations of hormone to reach the liver,
thus increasing the estrogen effects on hepatic:
• protein synthesis,

• lipoprotein profiles,
• and triglyceride levels

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 Estrogen preparations

• Transdermal preparations of estrogens:

– does not lead to the high level of the drug that enters the liver via the portal circulation

after oral administration

• Estradiol and conjugated estrogen creams also are

available for :

– topical administration to the vagina

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Estrogen pharmacokinetics
• Estradiol is extensively bound to sex hormone-binding globulin (SHBG)
• Estradiol is converted by the liver and other tissues to:
– estrone

– and estriol

– and their 2-hydroxylated derivatives

– and conjugated metabolites

– (which are too insoluble in lipid to cross the cell membrane readily) and excreted in the bile.

• Estradiol undergo enterohepatic recirculation via:

– sulfate and glucuronide conjugation in the liver,

– biliary secretion of the conjugates into the intestine,

– And hydrolysis in the gut (largely by bacterial enzymes) followed by reabsorption

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 Mechanism of action
• Estrogens exert their effects by interaction with receptors that are members of

the superfamily of nuclear receptors

• Two estrogen receptor subtypes, α and β, mediate the effect of hormone

• Both ERs are estrogen-dependent nuclear transcription factors that have:

• different tissue distributions

• transcriptionally regulate effects on a wide number of target genes

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 Mechanism of action
• In the nucleus, the ER is present as:
– an inactive

– monomer

– bound to heat-shock protein 90 (HSP90)

• Upon binding estrogen,:

– a change in ER conformation dissociates the HSP90

– and causes receptor dimerization,

– which increases the affinity and the rate of receptor binding to DNA at specific sequence of
nucleotides called estrogen response elements (EREs) in the promoters of various genes and regulate
their transcription.

– The ER/DNA complex recruits a cascade of co-activator and other proteins to the promoter region of
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target genes
 Mechanism of action
• Interaction of ERs with antagonists

– also promotes dimerization and DNA binding

• The antagonist-induced conformation facilitates:

– binding of co-repressors.

– The co-repressor/ER complex then further recruits other proteins

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Physiological effects

1. Growth and Development (female maturation)

• Estrogens are largely responsible for :

– pubertal changes in girls

– and secondary sexual characteristics

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Physiological effects
2. Endometrial Effects

• Estrogen plays an important role in the development of the endometrial lining.

• When estrogen production is properly coordinated with the production of
progesterone during the normal human menstrual cycle,

– Regular periodic bleeding and shedding of the endometrial lining occur.

• Continuous exposure to estrogens for prolonged periods

– leads to hyperplasia of the endometrium and abnormal bleeding patterns

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Physiological effects
3. Metabolic Effects:

a) Decrease bone resorption rate,

– largely by promoting the apoptosis of osteoclasts

– by antagonizing the osteoclastogenic and pro-osteoclastic effects of PTH & IL-6

b) Increase HDL levels and a slight decrease in LDL ,

– a reduction in total plasma cholesterol,

– and an increase in hepatic TG synthesis

c) Increase plasma levels of CBG, TBG, & SHBG

4. Enhance the coagulability of blood:
– increase circulating levels of factors II, VII, IX, and X
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– and decrease antithrombin III
Therapeutic uses of estrogens
1. Primary Hypogonadism
• estrogen-deficiency, Due to:
• primary failure of development of the ovaries,
• premature menopause,
• castration,
• or menopause

• Treatment of hypogonadism is usually begun at 11–13 years of age and

continue until the age of menopause in order to :
1) Stimulate the development of secondary sex characteristics & menses
2) Stimulation of optimal growth
3) Prevent osteoporosis

4) Avoid psychological effects of the delayed puberty and estreogen deficiency 22

Therapeutic uses of estrogens
2. Postmenopausal Hormone therapy
• Benefits of estrogen therapy include:
– amelioration of vasomotor symptoms

– and the prevention of bone fractures

– and prevention of urogenital atrophy

• Estrogen replacement therapy (ERT) in postmenopausal women is associated with:

– an increased incidence of endometrial carcinoma;

– this led to the use of HRT (with progestin) to reduces the risk of this cancer

• ERT with estrogens should use the lowest dose and shortest duration necessary to achieve an
appropriate therapeutic goal
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 Adverse Effects
1) Nausea and vomiting:
– disappear with time

– and may be minimized by taking:

• estrogens with food

• or just prior to sleeping

2) Breast tenderness:
– minimized by using the smallest effective dose

3) Postmenopausal uterine bleeding

4) Increased risk of myocardial infraction and thromboembolism events

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Adverse Effects
5) Cancer

a. Increase risk of endometrial cancer

• The risk seems to vary with the dose and duration of treatment (5 or more years)

• The concomitant use of a progestin:

– prevents this increased risk

– and may in fact reduce the incidence of endometrial cancer

b. Increased risk of breast cancer:

– No effect of short term estrogen therapy

– but a small increase in incidence may occur with prolonged treatment (the addition of
progestin does not protect)
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 Selective Estrogen Receptor Modulators (SERMs)

• Class of estrogen-related compounds:

– with tissue-selective actions

• Their pharmacological goal is:

– to produce beneficial estrogenic actions in certain tissues (e.g., bone)

– but antagonist activity in others (e.g., breast and endometrium)

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Tamoxifen
• It is a partial estrogen agonist in breast
– is used as a chemopreventive for breast cancer in high-risk women

• It is a full agonist in bone and endometrium,

– prolonged use of tamoxifen leads to 4-5 fold increase in the incidence of endometrial cancer

• ADEs:
– nausea, vomiting, hot flushes,
– & increases the risk of venous thrombosis

• Toremifene is structurally related to tamoxifen

– and has similar properties, indications, and toxicity

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 Raloxifene
• It is an estrogen agonist in bone and is approved for:
– the prevention of osteoporosis in postmenopausal women

• 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
• ADEs:
– hot flushes, leg cramps, & increased risk of DVT

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Clomiphene: ovulation-inducing agent
• Partial estrogen agonist
• Interfere with the negative feedback of estrogen on the hypothalamus:
– GnRH secretion becomes more pulsatile,

– which results in increased pituitary gonadotropin (FSH, LH) release

• Uses: Infertility associated with anovulatory cycles

• ADEs:
– headache, nausea,

– hot flushes,

– visual disturbances,

– & ovarian enlargement

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 Estrogen receptor antagonist: Fulvestrant

• It is a competitive inhibitor of estrogen action that blocks estrogen by binding to ER

• Approved for the treatment of:

– hormone receptor–positive metastatic breast cancer in postmenopausal women

with disease progression following anti-estrogen therapy (resistant to tamoxifen.)

• Fulvestrant is administered monthly by IM depot injections

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Estrogen-Synthesis Inhibitors: Aromatase inhibitors

• Aromatase is the enzyme required for estrogen synthesis

• Agents:

1) Irreversible steroidal inhibitors: Exemestane

2) Reversible Non-steroidal inhibitors: anastrozole & letrozole

• These agents may be used as:

• first-line treatment of breast cancer

• or as second-line drugs after tamoxifen (resistant to tamoxifen) 32

Estrogen-Synthesis Inhibitors: Aromatase inhibitors

• Unlike tamoxifen, they do not increase the risk of:

– uterine cancer

– or venous thromboembolism (VTE)

• ADEs: related to reduce circulating and local levels of estrogens

– hot flushes

– and significant bone loss

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ganirelix, cetrorelix, aberelix, degarelix
gonadorelin (acetate salt of the human GnRh), goserelin,
histrelin, leuprolide, nafarelin, triptorelin

Partial estrogen agonist

Interfere with the negative feedback of estrogen..larger amounts of
GnRH per pulse…increased (FSH, LH) release…ovulation- inducing
agent

LETROZOLE, EXEMESTANE

Tamoxifen, Raloxifene, Toremifene

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Progestins

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 Progestins
• Natural progestins: Progesterone

• It is secreted by:

• the corpus luteum in the second part of the menstrual cycle, and

by the placenta during pregnancy

• Small amounts are also secreted by:

– testis

– and adrenal cortex

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Progestins pharmacokinetics
• Progesterone is rapidly absorbed

– following administration by any route

• It undergoes rapid first-pass metabolism,

– with a t1/2 of 5 minutes….. orally inactive

• Progesterone is metabolized primarily in the liver to

– pregnanediol and its sulfate and glucuronide conjugates are eliminated in the urine

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Preparations
1) Naturally occurring hormone and its synthetic derivatives, Examples:
• progesterone, hydroxyprogesterone, megestrol acetate, medroxyprogesterone, dihydrogesterone

• They display limited binding to:

• glucocorticoid,
• androgen, and
• mineralocorticoid receptors,
• >>>>>>.a property that probably accounts for some of their non-progestational activities

• Other preparations of progesterone are available for:

• oral administration (high dose of micronized progesterone),
• IM injection,
• or administration via the vagina or rectum

• Hydroxyprogesterone caproate and medroxyprogesterone acetate

• are available for IM administration 38
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 Preparations
2. Testosterone derivatives “19-nortestosterones”
• Can be given orally
• These compounds have:
• progestational activity
• and retain some androgenic activity
• Norethisterone and norgestrel
• have androgenic activity
• Newer progestins (claimed to be) without androgenic activity include: (3rd generation)
• desogestrel,
• norgestimate,
• and gestodene 40
 Effects of Progesterone
1. Neuroendocrine action:

• Progesterone produced in the luteal phase of the cycle decreases the frequency of
GnRH pulses
– ....oral contraceptives!!

2. Reproductive tract:
– Decrease estrogen-driven endometrial proliferation
– and induces a secretory endometrium

• Influences the endocervical glands,:

– changing the abundant watery secretion of the estrogen- stimulated structures
– to a scant, viscid material (progeterone effect)

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Effects of Progesterone

3) CNS:

• Increases basal body temperature (thermoregulatory center)

• Increases the ventilatory response of the respiratory centers to CO2

• and leads to reduced arterial and alveolar PCO2

• in the luteal phase of the menstrual cycle

• and during pregnancy

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Effects of Progesterone

4) Progesterone modulates lipoprotein lipase activity and favor fat deposition

5) Increases basal insulin levels and the insulin response to glucose

6) In the liver, it promotes glycogen storage by facilitating the effect of insulin

7) Decreases the plasma levels of many a.a’s and leads to increased urinary

nitrogen excretion

8) Decreases Na+ reabsorption in the kidney

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 Therapeutic uses of Progestins
1. Hormone replacement treatment: in combination with estrogen for

hormone therapy of postmenopausal women

2. Contraception: either alone or with an estrogen

3. Decrease the occurrence of endometrial hyperplasia and carcinoma

caused by unopposed estrogens

4. Test for estrogen secretion and for responsiveness of the endometrium

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Therapeutic uses of Progestins

5) Treatment of dysmenorrhea, endometriosis, and bleeding

disorders
 Adverse Effects
• Major effects:
– headache,
– depression, (mood changes)
– weight gain,
– & changes in libido
• Progestins with androgenic activity (19-nortestosterone derivatives):
1) Plasma lipids: increase LDL and cause either no effect or modest
reduction in serum HDL levels
2) Acne
3) Hirsutism
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Antiprogestin: Mifepristone
• It effectively competes with progesterone for binding to PR
• Mifepristone:

• decreases endogenous progesterone

• coupled with blockade of progesterone receptors

• in the uterus increases uterine prostaglandin levels

• and sensitizes the myometrium to their contractile actions

• Mifepristone also causes cervical softening, which facilitates expulsion of

the detached blastocyst

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 Antiprogestin: Mifepristone
• Clinical uses:

1) Early termination of pregnancy (abortificant):

– in combination with misoprostol or other prostaglandins (missed miscarriage)

2) Emergency postcoital contraceptive

3) Control high blood sugar levels (hyperglycemia) in adults with endogenous
Cushing’s syndrome
• ADEs:
• Prolonged vaginal bleeding (major)

• abdominal pain,

• uterine cramps,

• & N, V, D 48
 Selective Progesterone Receptor Modulators (SPRMs)

• Exert clinically relevant tissue-selective progesterone:

– agonist,
– antagonist,
– or partial (mixed) agonist/antagonist effects on various progesterone target
tissues
• Ulipristal:
– approved by FDA in June 2010
– for use as an emergency contraceptive

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Hormonal contraception

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 Types of hormonal contraceptives
1. Combined oral contraceptive

2. Progestin-only contraceptives

3. Postcoital or emergency contraceptives

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 Combined oral contraceptive

• The most frequently used agents

• containing both an estrogen and a progestin

• Their theoretical efficacy is considered to be 99.9%

• Combination oral contraceptives are generally provided in

• 21-day packs

• with an additional 7 pills containing no active hormone

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Combined oral contraceptive
• Further divided into:

I. Monophasic:

– constant dosage of both components during the cycle

II. Multiphasic (biphasic & triphasic):

– dosage of one or both components is changed once or twice during

the cycle
• The U.S. FDA approved Beyaz tablets,:

• an estrogen/progestin combined oral contraceptive

• that also contains a folate (levomefolate calcium 0.451 mg)

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Multiphasic combined oral contraceptives

Biphasic combination tablets

Ortho-Novum, Necon
Days 1–10 Ethinyl estradiol 0.035 Norethindrone 0.5
Days 11–21 Ethinyl estradiol 0.035 Norethindrone 1.0

Triphasic combination tablets

Enpresse, Triphasil, Tri-Levlen, Trivora
Days 1–6 Ethinyl estradiol 0.03 L-Norgestrel 0.05

Days 7–11 Ethinyl estradiol 0.04 L-Norgestrel 0.075

Days 12–21 Ethinyl estradiol 0.03 L-Norgestrel 0.125

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 Combined oral contraceptive
• The estrogen:

– in most combined preparation is ethinyl estradiol,

– though a few preparations contain mestranol instead

• Progestins are :

– 19-nor compounds that have varying degrees of:

• androgenic,

• estrogenic,

• and antiestrogenic activities

– that may be responsible for some side effects

• The most common progestins are :

– norethindrone, norethindrone acetate,

– norgestrel, levonorgestrel,
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– desogestrel, norgestimate, and drospirenone
Combined oral contraceptive
Additional options for combined hormonal contraceptives include:

1. Transdermal patch:
– containing ethinyl estradiol and norelgestromin:

– applied weekly for 3 weeks.

– Week 4 is hormone-free patch, and withdrawal bleeding occurs

2. Vaginal ring
– containing ethinyl estradiol and etonogestrel:

– is used for 3 weeks.

– Week 4 is ring-free, and withdrawal bleeding occurs

• Efficacy, contraindications, and ADEs similar to those of oral contraceptives

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Transdermal patch

Vaginal ring
 Mechanism of action
1. Estrogen:
– inhibits secretion of FSH via negative feedback on the anterior pituitary,

• and thus suppresses development of the ovarian follicle

2. Progestin:
• Inhibits secretion of LH
– and thus prevents ovulation

• Induces viscous mucus

– that reduces sperm penetration

• induces an endometrium that is not receptive to implantation

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 Adverse effects
1. Vascular Effect:
• Oral contraceptives increase the risk of various CV disorders,
• especially in women ≥35 years
• who are heavy smokers (with predisposing risk factors)

a. VTE (e.g. PE) :

• Risk is related to the estrogen but not the progestin content of oral contraceptives
b. MI: depend on the specific composition of the pill used and the patient's
susceptibility to the particular effects
c. Cerebrovascular disease

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Adverse effects
2. Cancer

• Combined oral contraceptives reduce the risk of endometrial and ovarian

cancer.

– This is due to the inclusion of progestins

– Which opposes estrogen-induced proliferation, throughout the entire 21 days

• Their ability to induce neoplasms is controversial

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 Adverse effects
2. Metabolic effects:

a. Weight gain: more common with the combination agents containing androgen-
like progestins
b. Serum lipids:

• Estrogen causes:
– an increase in HDL and a decrease in LDL

• Progestins:
– antagonize the beneficial effect of estrogen

– (particularly the 19-nortestosterone derivative)

• Estrogen-dominant preparations are best for:

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– individuals with elevated serum cholesterol
 Adverse effects
3. Miscellaneous Effects

a) Nausea, mastalgia, and edema:

– related to the amount of estrogen

b) Breakthrough bleeding:

• Occur if the estrogen-to-progestin ratio is too low to produce a stable

endometrium

• May be prevented by:

– switching to a pill with a higher ratio or

– using biphasic and triphasic oral contraceptives

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Adverse effects

c) Mild headache and migraine headaches

d) Increased skin pigmentation, acne, and hirsutism:

– mediated by the androgenic activity of the 19- nor progestins

e) Cholestatic jaundice & increase the incidence of symptomatic gallbladder disease

(e.g. cholecystitis and cholangitis)

f) Amenorrhea in some patients following cessation of administration of oral

contraceptives 64
 Contraindications
1) The presence or history of :
– thromboembolic disease,

– cerebrovascular disease,

– MI, Coronary artery diseae [CAD]

– or congenital hyperlipidemia

2) Known or suspected carcinoma of the breast

3) Carcinoma of the female reproductive tract

4) Estrogen-dependent/responsive neoplasias
5) Abnormal undiagnosed vaginal bleeding
6) Pregnancy

7) Past or present liver tumors or impaired liver function

8) Women ˃ 35 years of age who smoke heavily (e.g., >15 cigarettes/day) 65
 Drug interactions
1. CYP450 enzyme inducers e.g.:

– rifampin,

– barbiturates,

– and phenytoin

• may result in contraceptive failure

2. Antibiotics :

– reduce estrogen enterohepatic recycling

– and may decrease the effectiveness of oral contraceptives

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 ANDROGENS
• Testosterone is the main natural androgen.

• It is synthesized mainly by the interstitial cells of the testis, and in smaller amounts

by the ovaries and adrenal cortex.

• Dehydroepiandrosterone and androstenedione are important intermediates.

• They are released from the gonads and the adrenal cortex, and converted to

testosterone in the liver

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 Mechanism of action
• In most target cells, testosterone works through an active metabolite,

dihydrotestosterone, to which it is converted locally by a 5α reductase

enzyme.

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 Testosterone: Physiologic effect
• Changes in the skin (pubic, axillary, beard)
• Larynx (deepening of the voice),
• Skeletal growth
• ↑ lean body mass
• Male development
• Anabolic effect on muscle and bone mass: ↑ CHON synthesis, ↓ CHON
breakdown
• Other effects: erythrocyte production, masculinization in females

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Preparations
• Testosterone itself can be given by SC implantation or by transdermal

patches (male replacement dose approximately 2.5 mg/day.

• Various esters (e.g. enanthate and proprionate) are given by

intramuscular depot injection.

• Testosterone undecanoate and mesterolone can be given orally.

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Unwanted effects
 Unwanted effects of androgens include:

• Decrease of gonadotrophin release, with resultant infertility,

• Salt and water retention leading to edema.

• Adenocarcinoma of the liver has been reported.

• Impair growth in children (via premature fusion of epiphyses),

• Cause acne

• Masculinisation in girls

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Clinical uses
Androgens (testosterone preparations) as hormone replacement in:

- male hypogonadism due to pituitary or testicular disease (e.g. 2.5 mg/day patches)

- female hyposexuality following ovariectomy (e.g. 300 μg/day patches).

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Anabolic Steroids
• Androgens can be modified chemically to alter the balance of anabolic and other
effects.
• Such 'anabolic steroids' (e.g. nandrolone) increase protein synthesis and muscle
development
• They are used in the therapy of aplastic anaemia
• Notoriously abused by some athletes
• Unwanted effects are described above plus cholestatic jaundice, liver tumours
• Increased risk of CHD are recognized adverse effects of high-dose anabolic steroids.

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Antiandrogens
• Cyproterone is a derivative of progesterone and has weak progestational

activity.

• It is a partial agonist at androgen receptors, competing with

dihydrotestosterone for receptors in androgen-sensitive target tissues.

• Through its effect in the hypothalamus, it depresses the synthesis of

gonadotrophins.

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Clinical Uses
• It is used as an adjunct in the treatment of prostatic cancer during initiation of

treatment

• It is also used in:

 Therapy of precocious puberty in males,

Therapy of masculinisation and acne in women.

 It also has a central nervous system effect, decreasing libido,

 Treating hypersexuality in male sexual offenders

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Antiandrogens…
• Cyproterone & cyproterone acetate inhibit the action of androgens at
the target organ.

• It also has an effect that suppresses the feedback enhancement of LH

and FSH, leading to more antiandrogenic effect.

• They are used for hirsutism and in men to decrease excessive sexual
drive.

• Flutamide is a competitive antagonist and has been used in prostatic

carcinoma.
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 Antiandrogens…
• Since dihydrotestosterone (not testosterone) is the essential androgen in the
prostate, androgen effects is reduced by an inhibitor of 5a-reductase.

• Finasteride is an inhibitor of this enzyme and reduces dihydrotestosterone.

• Finasteride also reduces prostate size in BPH.

• The dosage in prostatic carcinoma is 5 mg/d.

• It is used in the treatment of hirsutism in women and early male pattern baldness in men (1
mg/d).

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Antiandrogens…
• Bicalutamide and nilutamide are antiandrogens given as a single daily dose and are
used in patients with metastatic carcinoma of the prostate.

• Spironolactone, a competitive inhibitor of aldosterone, also competes with

dihydrotestosterone for the androgen receptors.

• It also reduces 17a-hydroxylase activity, lowering plasma levels of testosterone and

androstenedione.

• It is used in the treatment of hirsutism in women and is as effective as finasteride,

flutamide, or cyproterone in this condition.

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Danazol
• Danazol is a synthetic steroid that inhibits release of GnRH and,
consequently, of gonadotrophins (FSH and LH).
• Danazol inhibits gonadotrophin secretion (especially the mid-cycle
surge), and consequently reduces estrogen synthesis in the ovary
• In men, it reduces androgen synthesis and spermatogenesis.
• It has androgenic activity.
• It is orally active and metabolised in the liver.

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Danazol…
• Danazol is used in sex hormone-dependent conditions including

endometriosis, breast dysplasia and gynaecomastia.

• Unwanted effects are common, and include gastrointestinal disturbances,

weight gain, fluid retention, dizziness, menopausal symptoms, muscle

cramps and headache

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Male Contraceptive
• Gossypol – phenolic compound that reduces sperm density by 99% in

men and impairs sperm motility

• 20mg/D x 2 mos. or 60mg/wk

• not continued >2yrs.

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 ERECTILE DYSFUNCTION
• Erectile function depends on complex interactions between physiological and

psychological factors.

• Erection is caused by vasorelaxation in the arteries and arterioles supplying the

erectile tissue.

• This increases penile blood flow; the consequent increase in sinusoidal filling

compresses the venules, occluding venous outflow and causing erection

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 ERECTILE DYSFUNCTION ……
• Innervation of the penis includes autonomic and somatic nerves.

• Nitric oxide is probably the main mediator of erection and is released both from

nitratergic nerves and from endothelium.

• Erectile function is adversely affected by several therapeutic drugs (including many

antipsychotic, antidepressant and antihypertensive agents), and psychiatric and

vascular disease.

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Causes

There are several organic causes, including:

• hypogonadism ,

• hyperprolactinaemia,

• arterial disease

• various causes of neuropathy (most commonly diabetes)

89
 Treatment
• The generally negative picture picked up somewhat when it was found

that injecting vasodilator drugs directly into the corpora cavernosa

causes penile erection.

• Papaverine , if necessary with the addition of phentolamine, was used

in this way.
 The route of administration is not acceptable to most men, but diabetics in particular are often

not needle-shy, and this approach was a real boon to many such patients.
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 Treatment……..
• PGE1 (alprostadil) is often combined with other vasodilators when given

intracavernosally.

• It can also be given transurethrally as an alternative (albeit still a somewhat

unromantic one) to injection.

• Adverse effects of all these drugs include priapism.

 Treatment consists of aspiration of blood (using sterile technique) and intracavernosal administration of a

vasoconstrictor such as phenylephrine.

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PHOSPHODIESTERASE TYPE V INHIBITORS

• Orally active phosphodiesterase inhibitors are now generally the drugs of choice.

• Sildenafil, the first selective phosphodiesterase type V inhibitor that influence erectile

function.

• Tadalafil and vardenafil are also phosphodiesterase type V inhibitors licensed to treat

erectile dysfunction.

• Tadalafil is longer acting than sildenafil.

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PHOSPHODIESTERASE TYPE V INHIBITORS………

• In contrast to intracavernosal vasodilators, phosphodiesterase type V

inhibitors do not cause erection independent of sexual desire, but

enhance the erectile response to sexual stimulation.

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Mechanism of action…
• When sexual stimulation causes local release of NO, they inhibits

PDE-V hence causing increased levels of cGMP in the corpus

cavernosum, resulting in smooth muscle relaxation and inflow of

blood to the corpus cavernosum.

• Sildenafil at recommended doses has no effect in the absence of sexual

stimulation.

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 Pharmacokinetic aspects and drug interactions

• Peak plasma concentrations of sildenafil occur approximately 30-120 min after an oral

dose and are delayed by eating, so it is taken an hour or more before sexual activity.

• It is given as a single dose as needed.

• It is metabolised by CYP3A4, which is induced by carbamazepine, rifampicin and

barbiturates, and inhibited by cimetidine, macrolide antibiotics, antifungal

imidazolines, some antiviral drugs (such as ritonavir) and also by grapefruit juice .

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 Contraindications
• Tadalafil has a longer onset & half-life than sildenafil, so can be taken longer before

sexual activity.

• A clinically important pharmacodynamic interaction of all phosphodiesterase V

inhibitors occurs with all organic nitrates, which work through increasing cGMP and

are therefore markedly potentiated by sildenafil

• Consequently, concurrent nitrate use, including use of nicorandil, contraindicates the

use of any phosphodiesterase type V inhibitor

97
 Side effects
• Many of the unwanted effects of phosphodiesterase type V inhibitors are caused by

vasodilatation in other vascular beds; these effects include

• hypotension,

• flushing and

• headache.

• Visual disturbances: sildenafil should not be used in patients with hereditary retinal

degenerative diseases (such as retinitis pigmentosa)

98