drugs for infertility and erectile dysfunction

1. PH1.40
DESCRIBE MECHANISM OF
ACTION, TYPES, DOSES, SIDE
EFFECTS, INDICATIONS AND
CONTRAINDICATIONS OF 1. DRUGS
USED IN THE TREATMENT OF
INFERTILITY, AND 2. DRUGS USED
IN ERECTILE DYSFUNCTION
ADD TITLE
Dr. Mani Bharti
Assistant professor
Pharmacology
North DMC Medical College,
Delhi

2. LEARNING OBJECTIVES
• Describe the causes of infertility
• Enumerate drugs used in the treatment of infertility
• Describe the mechanism of action of drugs used in the treatment of infertility
• Describe the therapeutic uses, contraindication, adverse effects, and drug interactions of
drugs used in the treatment of infertility
• Describe the causes of erectile dysfunction
• Enumerate drugs used in erectile dysfunction
• Describe the mechanism of action of drugs used in erectile dysfunction
• Describe the therapeutic uses of drugs used in erectile dysfunction
At the end of the session phase 2 MBBS students shall be able to
2

3. INFERTILITY
Inability to conceive after 12 months of having sexual
intercourse with average frequency (2 to 3 times per
week), without the use of any form of birth control
Types of Infertility
• Primary infertility
• The couple has never produced a pregnancy
• Secondary infertility
• woman has previously been pregnant, regardless of the outcome,
and now is unable to conceive
3

4. CONCEPTION AND
FERTILITY
THE CHANCES OF
CONCEIVING IN ANY
GIVEN MENSTRUAL
CYCLE IS LESS THAN
20%
The main events
necessary for pregnancy
to occur are:
• ovulation
• fertilization
• implantation
Any condition that
interferes with these
events may result in
infertility
4

7. FACTORS AFFECTING FERTILITY
7
STIs and Other Infections
Gonorrhea and chlamydia can cause:
in women: pelvic inflammatory disease (a major cause of tubal infertility) and cervicitis
in men: urethritis, epididymitis, accessory gland infection Mumps, leading to orchitis, may cause
secondary testicular atrophy and leprosy
Age of the woman
after 40 the fertility rate decreases by 50% while the risk of miscarriage increases
Age of the man
increased age affects the coital frequency and sexual function
Nutrition for women,
weight 10% to15% below normal or obesity may lead to less frequent ovulation and reduced fertility
toxic agents, such as lead, toxic fumes and pesticides smoking, and alcohol
All these factors may cause:
in women: reduced conceptions and increased risk of fetal wastage
in men: reduced sex drive and sperm count

8. 8
Infertility

9. 9

10. COMPANY TEAM SLIDE
10
FIRSTNAME
LASTNAME
Designation | Description
Firstname
Lastname
Firstname
Lastname
Firstname
Lastname
Firstname
Lastname
Firstname
Lastname
Firstname
Lastname

11. “FEMALE
INFERTILITY-
”
Hypothalamic infertility
Gonadotrophin-releasing hormone (GnRH): Stimulates the release of luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary.
Luteinizing hormone (LH): Stimulates steroidogenesis in the gonads, and maintains
the secretory function of the corpus luteum.- Follicle-stimulating hormone (FSH):
Stimulates gamete production in the gonads.
Prolactin (PRL): Initiates and maintains milk production in the mammary glands
postpartum.
Human chorionic gonadotropin (HCG) is a placental hormone identical to LH.
Hypothalamic amenorrhea (stress-stopping GnRH).

12. HYPOGONADISM IN FEMALES:
• In several conditions, such as Turner syndrome(ovarian dysgenesis and dwarfism).*
A- The ovaries do not develop (or have no primordial follicles and may be represented only by a brous
streak)-
B- Puberty does not occur
Other characteristics include
• A- Short stature
• B- Primary amenorrhea
• C- Sexual infantilism
• D-High gonadotropin levels
• E-Multiple congenital abnormalities
Conception is impossible.

13. 1- GONADOTROPHIN-RELEASING
HORMONE (GNRH) AGONISTS
• GnRH is used in hypothalamic infertility in women to stimulate FSH and
LH secretion and to induce ovulation. For this purpose, it is necessary to
mimic the physiologic intermittent "pulsatile" release (every 90min) by
means of a programmed infusion pump.
• Gonadorelin super agonists are GnRH analogs that bind with very high
avidity to GnRH receptors.
• As a result of the non-physiologic uninterrupted receptor stimulation,
initial augmentation of FSH and LH output is followed by a prolonged
decrease.
• Buserelin, leuprorelin, Goserelin, and triptorelin are used in patients with
prostatic carcinoma to reduce the production of testosterone, which
promotes tumor growth.
13

14. SYNTHETIC ANALOGUES OF GNRH
• MOA: Synthetic analogues of GnRH cause an initial rise, in the secretion of gonadotrophins (LH
and FSH). Chronic administration causes increased negative feedback, down-regulation of the
hypothalamic-pituitary-gonadal axis and a subsequent fall in the secretion of gonadal steroids.
• Uses
• Prostate cancer
• breast cancer (advanced disease or early oestrogen receptor-positive disease)
• Infertility.
• Endometriosis (short-term only)Induction of endometrial thinning (e.g. in anaemia due to uterine fibroids
or prior to surgery).
• SE:
• Menopausal-like symptoms, Reduced bone density, Hypersensitivity reactions, Headache, Gl
disturbance
• GnRH agonists should not be used in patients with undiagnosed vaginal bleeding due to the potential
masking of symptoms of underlying endometrial disease.
14

15. 2- GONADOTROPINS(FSH, LH & HCG)
• The gonadotropins (FSH and LH) are glycoproteins that are produced in
the anterior pituitary.
• The regulation of gonadal steroid hormones depends on these agents.
• They find use in the treatment of infertility:
• 1- Injection of hMG or FSH over a period of 5 -12 days causes ovarian follicular
growth and maturation.
• 2- Subsequent injection of hCG, ovulation occurs.
• Adverse effects:
• ovarian enlargement and possible ovarian hyperstimulation syndrome, which may be
life-threatening.
• Multiple births are not uncommon
15

16. ANOVULATORY MENSTRUAL CYCLE
INFERTILITY
• Estrogens and progestins are used to stop ovulation in patients with severe
dysmenorrhea or to stop ovarian function in patients with hirsutism or amenorrhea.
• There are reported cases of infertility, ectopic pregnancy, and premature delivery.
• Estrogen provides negative feedback on the release of LH and FSH by the pituitary
gland, thus preventing ovulation.-Progestin also thickens the cervical mucus, thus
hampering the transport of sperm.
• Withdrawal of the progestin stimulates menstrual bleeding during the placebo week.
• Treated by the use of antiestrogens (clomiphene).
• In female patients with failure of ovarian development, therapy with estrogens in
combination with progestins. It replicates most of the events of puberty.
• Genital structures grow to normal size, breasts develop, axillary and pubic hair grows,
and the body achieves a normal feminine contour.
• Estrogen may increase growth, but if used too soon, it can accelerate epiphyseal fusion
and cause a short final height (treated with androgens and growth hormone).
16

17. ANTIESTROGEN'S (CLOMIPHENE)
• Is an antioestrogen drug that acts as a pure antagonist in all tissues.
• MOA: The antioestrogen clomiphene binds competitively to estrogen receptors and
decreases the sites available to endogenous estrogen, including hypothalamic and
pituitary estrogen receptors.
This inhibition leads to a disruption in the negative feedback of estrogens on the
hypothalamus and pituitary, a subsequent increase in the secretion of GnRH and
gonadotropins, and ultimate stimulation of ovulation.
• Indications-The agent is used to treat infertility associated with anovulatory
menstrual cycles.
It is effective only in women with a functional hypothalamus and adequate endogenous
estrogen production.
Adverse effects- Are dose related.- Ovarian enlargement, vasomotor symptoms, and
visual disturbances.
17

18. SELECTIVE ESTROGEN RECEPTOR
MODULATORS(SERM)
• Tamoxifen has an inhibitory effect on estrogen receptors of the breast and hence is the
drug of choice for treatment of ER/PR positive breast cancer.
• However it has a stimulatory effect on estrogen receptors of bone (decreases bone
resorption), lipids (increases HDL, decreases LDL), and uterus (causes uterine
hyperplasia).
• Raloxifene has a stimulatory effect on estrogen receptors of bone and is hence used for
prophylaxis and treatment of postmenopausal osteoporosis. It also has a stimulatory
effect on lipids (increases HDL and decreases LDL) and coagulation (thrombosis), and
has an inhibitory effect on the breast and uterus.
• Its use is associated with hot flashes.
• Ospemifene is the latest SERM approved for the treatment of dyspareunia.
18

19. 19

20. 20

21. SELECTIVE ESTROGEN RECEPTOR
DOWNREGULATION (SERD)
• Fluvestrant is a pure antiestrogenic drug that has only an inhibitory effect
on estrogen receptors. It is 100 times more potent inhibitor than
tamoxifen and also causes proteasomal degradation of estrogen
receptors.
• It is the drug of choice for the treatment of tamoxifen-resistant ER/PR
positive breast cancer.
• Dose is 250 mg by subcutaneous route once in a month.
• Side effects are rare and is safer as compared to tamoxifen.
21

22. SELECTIVE TISSUE ESTROGEN ACTIVITY
REGULATOR
• Tibolone
• Agonist at – vagina, blood vessels, bone
• Designer HRT
22

23. AROMATASE INHIBITOR
• Post menopausal breast cancer
• Adrenal glands produce androgen which is converted
in estrogen by aromatase
• Drugs- Letrozole, Anastrozole, Exemastane
23

24. POLYCYSTIC OVARIAN SYNDROME
INFERTILITY
• PCOS is a heterogeneous disorder that affects approximately 6-8% of women of
reproductive age, making it the leading cause of anovulatory infertility and the most
common
• The diagnosis of PCOS is complicated by variations among women of the presenting
signs and symptoms.
• The anti-diabetic Metformin is effective in the treatment of polycystic ovary syndrome.
• It lowers insulin resistance seen in this disorder and can result in ovulation and,
therefore, possibly pregnancy
24

25. MALE STERILITY (ANDROGENS)
• Testosterone replacement therapy is used for male patients with hypogonadism."
• In males, dysfunction of Leydig cells or failure of the hypothalamic-pituitary system can
lead to inadequate secretion of androgens, and testosterone replacement therapy is
used.- Testosterone deficiency occurs:-
• A- Before puberty: it results in failure to complete puberty.-
• B- After completion of puberty: lead to loss of libido and energy, decreased muscle
mass and strength, decreased hematocrit and hemoglobin, and decreased bone
mineral density.
25

26. 26
Androgens

27. MANAGEMENT OF MALE STERILITY
• Testosterone is available in different preparations.
• For male endogenous testosterone deficiency, an oral drug is ineffective because of
liver metabolism.
• Intramuscular (Cypionate: Synthetic ester derivative with slow release and long Half-life
(8 days).
• Enanthate (heptanoate ): or transdermal testosterone overcomes 1st-pass metabolism
to reach normal serum concentrations. Absorbed into the lymph, enabling it to bypass
the liver and enter, via the thoracic duct, the general circulation.
• Upon diffusion of the ester from the depot, esterase's quickly split off the acyl residue, to
yield free Increasing lipophilicity, esters will tend to remain in the depot, and the duration
of action therefore lengthens.
27

28. • Indications
• Primary hypogonadism: testicular failure due to cryptorchidism, bilateral torsion, orchitis,
vanishing testis syndrome, or orchidectomy
• Hypogonadotropic hypogonadism: idiopathic gonadotropin, LHRH deficiency or
pituitary-hypothalamic injury from tumors, trauma or radiation.
• Stimulation of spermatogenesis.
28

29. 29

30. 30
MOA: Two main mechanisms:
A- Activation of the androgen receptor: directly or as 5a-
dihydrotestosterone(DHT).
B-Conversionon to estradiol and activation of certain estrogen receptors.
• Free testosterone (T) is transported into the cytoplasm of target tissue cells,
where it can-
• A- Bind to the androgen receptor
• B- Reduced to 5a-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5a-
reductase.
• DHT binds to the same androgen receptor even more strongly than T (potency
2.5x) that of T.
• The T-receptor or DHT-receptor complex undergoes a structural change that
allows it to move into the cell nucleus and bind directly to specific nucleotide
sequences of the chromosomal DNA.
• The areas of binding are called hormone response elements(HREs), and
influence the transcriptional activity of certain genes, producing the androgen
effects.

31. 31
Testosterone
estradiol

32. SIDE EFFECTS
32
• In pre-pubertal children, testosterone causes acne,
hirsutism, gynecomastia, and sexual aggression as well
as growth disturbances
• Excess androgen in men can cause priapism,
impotence, reduced spermatogenesis, and
gynecomastia Androgens can also cause edema and an
increased LDL/HDL ratio, which may be harmful to those
with hyperlipidaemic or CHF.

33. ERECTILE DYSFUNCTION (IMPOTENCE)
• is the inability to get and keep an erection firm enough for sex.
• Having erection trouble from time to time isn't necessarily a cause for concern.
• If erectile dysfunction is an ongoing issue, however, it can cause stress, affect your self-
confidence and contribute to relationship problems.
• Problems getting or keeping an erection can also be a sign of an underlying health condition
that needs treatment and a risk factor for heart disease
33

34. SYMPTOMS
• Erectile dysfunction symptoms might include persistent:
• Trouble getting an erection
• Trouble keeping an erection
• Reduced sexual desire
34

35. CAUSES
• Male sexual arousal is a complex process that involves the brain, hormones, emotions, nerves,
muscles and blood vessels.
• Erectile dysfunction can result from a problem with any of these. Likewise, stress and mental
health concerns can cause or worsen erectile dysfunction.
• Sometimes a combination of physical and psychological issues causes erectile dysfunction.
• For instance, a minor physical condition that slows your sexual response might cause anxiety
about maintaining an erection.
• The resulting anxiety can lead to or worsen erectile dysfunction.
35

36. CAUSES
Physical causes Psychological causes
Heart disease
Clogged blood vessels (atherosclerosis)
High cholesterol
High blood pressure
Diabetes
Obesity
Metabolic syndrome , Parkinson's disease
Multiple sclerosis
Certain prescription medications
Tobacco use
Peyronie's disease — development of scar tissue
inside the penis
Alcoholism and other forms of substance abuse
Sleep disorders
Treatments for prostate cancer or enlarged prostate
Surgeries or injuries that affect the pelvic area or
spinal cord
Low testosterone
Depression, anxiety or other mental health
conditions
Stress
Relationship problems due to stress, poor
communication or other concerns
36

37. ERECTILE DYSFUNCTION TREATMENT
• Androgens
• PDE-5 Inhibitors – sildenafil,, vardenafil
• Papaverine/Phentolamine induced petadalafilnile erection (PIPE) therapy
• Prostaglandin E1

38. SILDENAFIL
• Absorbed orally and t1/2 4 hrs
• Inhibits PDE 5 in corpus cavernosum of penis
• 50mg 1 hour before sexual activity
• Potentiate nitrate’s hypotension activity
• Ketoconazole, erythromycin, and verapamil increases its activity – CYP3A4 inhibition
• Renal and hepatic disease increases its level

39. TADALAFIL
• More potent, longer acting
• Nitrates are contraindicated for upto 3 days after tadalfil (longer action)
• Less visual disturbances

40. PIPE THERAPY
• Papaverine (3-20mg) with or without phentolamine (0.5-1mg) injected in corpus
cavernosum
• Reversed by aspirating blood from corpus cavernosum or by injecting phenylephrine
locally
• Repeated injections – penile fibrosis
• Used rarely

41. THANK YOU
41