Infertility Treatment

This presentation was made in the year 2014 so might not have very recent advances.

1. Pharmacotherapy of
INFERTILITY
Nidhi Maheshwari
07/23/171

2. Humans are actually one of the least fertile species on the earth
Most fertile couple only has about a 20% chance of conception taking
place in any given month.
Fertility status begins to decline with age.
10% of the population suffers from fertility problems and this
number is increasing every year.
IntroductionIntroduction
07/23/172

3. Definitions
Infertility is defined as the inability to conceive after regularly
having unprotected sex for at least one year
Sterility whereas defined as absolute failure to conceive.
Impotence means failure to perform a sexual act.
07/23/173

4. Management of infertility
Drugs
Surgical treatment
Assisted reproduction techniques
Counseling
Adoption
07/23/174

5. 07/23/175
Female
Infertility

6. A. Hormonal –
1. Hypothalamic – pituitary hormone deficiency
2. PCOD
3. Corpus luteal phase defect
4.Decreased progesterone
5. Increased prolactin
6. Hypothyroidism
B. Infection
T.B., Gonorrhea, Chlamydia

Aetiology
07/23/176

7. C.Immunological: Cervical or serum sperm antibodies
D.Pelvic inflammatory diseases
E.Endometriosis, Retroversion, Fibroid
F.Congenital: Hypoplasia or malformation of genital tract, tubal
blockage
C.Others: poor or lack of cervical mucus
Risk factors: age, smoking, alcohol, overweight, too much
exercise, caffeine

07/23/177

8. Treatment
Correct CAUSE; Corrective Surgery, Hypothyroidism or TB
Antibiotics
Consider IUI, Low-dose Estrogen: Cervical mucus factor
Anti-sperm Antibodies
In Vitro Fertilization

Anovulation- Ovulation Inducers
07/23/178

9. FSH
Secreted by gonadotrophs in anterior pituitary gland
Maturation of germ cells in males and females
In females: causes follicular growth especially affect granulosa
cells
In males: induce sertoli cells to secrete androgen binding
proteins or spermatogenesis
LH
Secreted by gonadotrophs in anterior pituitary gland
Causes ovulation and development of corpus luteum
In males: known as ICSH (interstitial cells secreting hormone);
stimulates leydig cells to secrete testosterone
07/23/179

10. hCG
Secreted from syncytiotrophoblasts of fetus-> forms placenta
LH analogue
Maintains corpus luteum (secrets progesterone)
Can be used to induce ovulation and testosterone production (as
similar to LH)
07/23/1710

11. 07/23/17
Rate of Ovulation (%)Pregnancy (%)
Clomiphene 80 40
HMG 90 70-80
Bromocriptine 90 70-80
GnRH 80 50-80
Ovarian drilling 70-80 45-60
11

12. Clomiphene citrate
Pure estrogen antagonist at ERα & Erβ
Induces Gn secretion-> ovaries enlarge and
ovulation occurs
T1/2: 6 days (deposit in adipose tissues)
Metabolism & excretion: bile
Ix: anovulation, PCOD, oligospermia
Starting dose: 50 mg/day oral (doubled after
2 months for 2-3cycles)
From day 5 to day 9
07/23/1712

13. 07/23/1713

14. Adverse effects
polycystic ovaries, hot flushes, osteoporosis ( if treated for
more than 8 months), Multiple pregnancy
Interferes with functioning of corpus luteum: prolong luteal
phase
Regression of estrogen induced proliferative endometrium and
antiestrogenic effect on vaginal epithelium
Could be associated with epithelial ovarian cancer
Gastric upset, vertigo, allergic dermatitis
07/23/1714

15. Clomiphene-> block estrogen action at receptor on hypothalamus-
>release FSH during day 3 to day 7-> follicles get stimulated
more-> corpus luteum->ovulation
If fertilized then HCG is released from embryo-> acts on corpus
leuteum-> estrogen and progesterone is secreted-> pregnancy
maintained
If unfertilized-> no support from HCG->corpus leuteum
degenerate-> reduction in estrogen and progesterone->
menstruation and raised FSH nd LH
07/23/1715

16. Cumulative Pregnancy Rate continues to rise untill 10 cycles of
treatment. RCOG recommends that up to 12 cycles of
treatment should be considered
Ovulation induction with Clomiphene should be performed in
circumstances which allow access to ovarian ultrasound
monitoring
Most evidence point towards less pregnancy rate above 100 mgs
(with 100 mg or less, pregnancy rate:70%)
07/23/1716

17. Addition of menotropins or hCG on last 2 days of the course
improves success rate

No improvement in 6-8 cycles-> then start FSH + hCG
Tamoxifen can be alternative or combined with clomiphene
07/23/1717

18. Gonadotropins
 next choice, very expensive, high complication, need close
supervision and monitoring
more effective than clomiphene
Multiple pregnancy rate is less with clomiphene (6%), Gns: 20 %
Pregnancy wastage is same with both the therapies
07/23/1718

19. Tamoxifen
SERM, an anticancer; evaluated for infertility
Improve folliculogenesis: due to direct action on ovary
Beneficial effect on cervical mucus and endometrium
No hypo-pitutary intervention
Does not appear to be associated with cancer
V less hyperstimulation or side effects
07/23/1720

20. 76-81 %ovulation rate, 35% pregnancy rate in lpd, 14% in 40 mg
dose, 40% in 80 mg, higher dose required for higher pregnancy
rate in PCOD
Cc+ tamoxifen better than only cc
Hepatic metabolism
T1/2:7-14 hrs
Excretion: GI tract
Use in male infertility (?)
07/23/1721

21. CC + hMG
07/23/17
dose: 50- 100mg/day ( increased)
From day 2 to day 6
hMG : 75 u i.m on day 3,5, 7 and more
24

22. Gonadotropins
Glycoproteins
T1/2: variable
Capable of eliciting antibodies
hCG & hMG
07/23/1725

23. secreted by the fetal placental
syncytiotrophoblast cells
Can be detected in the maternal plasma several
days before the first missed period. Appear in urine
8-9 days after ovulation while disappear from urine
2 days after delivery
Sustains luteal function until the placenta starts
secreting estrogen & progesterone by the 3rd
month of pregnancy.
Human Chorionic Gonadotropin (hCG)
07/23/1726

24. Headache, edema, gynaecomastia, precocious puberty, occasional
depression, pseudopregnancy
1000-10000 IU: as dry powder with 10 ml diluent
07/23/1727

25. Human Menopausal Gonadotropins (HMG)
FSH + LH (PREGNORM): 75 IU +75IU/ampoule
Indications:
 a) Deficient production of Gonadotropins by pituitary
 b) Clomiphene failed or PCOD
 1 injection i.m./day for 10 days followed by 10,000 IU of HCG
Pure FSH (FOLGEST 75 IU): preferred in PCOD patients and in IVF
also
75% chance of ovulation within 48 hrs
High rate of multiple pregnancy and abortion: No teratogenesis
07/23/1728

26. Adverse effects
Ovarian Hyperstimulation: polycystic ovary, pain in abdomen,
ovarian bleeding, shock
Precocious puberty (if given in children)
Allergic reactions (s.c. route avoided)
Exclude prostate, breast cancer etc..
Edema, headache, mood changes
07/23/1729

27. hMG+hCG
07/23/17
1)Perform baseline oestradiol assay and ultrasound scanning
2)Administer hMG, 2 ampoules (75 IU each) per day for 3
days
3)Repeat oestradiol. If doubled, monitor hMG dosage; if not,
increase hmg dosage by 50 % for 3 days
4)Repeat step 3 until oestradiol doubles.
5)Perform ultrasound scan every 2-3 days till size of follicle
becomes 14-20 mm
6)24 hours later, administer hCG 5000 IU. Recommend IUI or
natural intercourse
7)Administer injection of hCG 3000 IU 7 days later
8)Await onset of menses or perform urine pregnancy test.
30 Shaw’s book of gynaec

28. RECOMBINANTS
Follitropin α and follitropin β (rFSH): injected I.M. or S.C.
Lutroin (rLH)
Luveris (lutropin α: rhLH)
Choriogonadotropin α (rHCG)
More purified, more expensive, replaced urine preparations in
developed countries
07/23/1731

29. GnRH
07/23/17
DECAPEPTIDE
Isolated by SCHALLY in 1971 by extracting and processing one
million pig hypothalami
GnRH of pigs, sheep, cows, humans are identical in structure
Synthesized in hypothalamus and also in villous stroma of placenta
T1/2: 2-8 mins; Not orally
Alternative to hMG

adjuvant in IVF. Less risk of hyperstimulation than hMG
 very expensive
32

30. Name Half life (min) Dose & method of
admin
Leuprolide acetate 180 – 220 1 mg SC daily
Buserelin acetate 75 – 85 40 mcg/kg/d, in
divided doses or 1 mg
SC daily
Nafarelin 120- 160 200 – 400mcg
intranasally, BD
Triptorelin
microspheres
4 mg IM monthly
Goserelin acetate
polymer
Deslorelin
Histarelin
3.6 mg SC monthly in
ant abdo. wall
07/23/1733
GnRH agonists

31. Pulsatile fashion: promotes synthesis and release of FSH and LH
10-20 mcg I.V. over one min; repeated every 90 min
15-20 µg S.C.
Intranasal 200 µg every 2 hr
Uses
Hypothalamic Hypogonadism (Kallman syndrome, Amenorrhoea,
Infertility)
No response to Clomiphene or/and FSH-LH
Infertility in PCOD and Endometriosis (low success rate)
07/23/1734

32. GnRH agonists: initial stimulation of release of FSH and LH
followed by desensitization or down-reglation of pituitary
gonadotropes-> loss of release of FSH and LH
Uses
Controlled ovarian hyperstimulation: Continuous pretreatment
with superactive GnRH agonist (to suppress endogenous FSH/LH
secretion); sometimes with GnRH antagonists
IVF regimens: inhibit untimely release of LH from pituitary
07/23/1735

33. Other USES: endometriosis, large uterine fibroid, central
precocious puberty, hormone dependent cancers like prostate
and breast etc..
Adverse effects: Hyperstimulation, multiple pregnacy, slight rise
in abortion rate
Prolonged use (more than 6 months): Hot flushes, loss of libido,
vaginal dryness, osteoporosis, emotional lability
ADD BACK THERAPY

07/23/1736

34. GnRH Antagonists
Act by competitive inhibition of binding of endogenous GnRH to the receptors and suppress
release of LH and FSH from onset of administration
without initial stimulation.
less ovarian hyperstimulation, more complete endogenous suppression
 quick Gn suppression. But, pregnancy rate is same or low
 very expensive and causes release of histamine
GANIRELIX: less histamine release.
CETRORELIX
ABARELIX
DEGARELIX
Given in IVF regimen to prevent LH surge during ovarian stimulation
Upregulation (?)
07/23/1737

35. D2 Agonists
07/23/17
Bromocriptine (Parlodel)
Selective D2 agonists
In hyperprolactinemia: inhibits prolactin release and restore
normal cyclic release of gonadotropins
1.25 mg at bed time every day for 7 days. Dose increased by
1.25 mg/week till hyperprolactinemia gets corrected
Cabergoline (Dostinex)
long acting oral tab
0.25 - 1mg twice weekly
38

36. Pergolide (Parlodel-LR)
Available as vaginal tab & injectables
I.M. monthly
50-100mg
Acute reduction in tumor size and prolactin levels
Minimal side effects
Quinagolide
25-150 µg daily foll by maintenance dose
Side effects: Nausea, vomiting (prefer tab at night), hypotension-
dizziness, nasal congestion, headache, constipation
07/23/1739

37. Prednisolone
07/23/17
In anovulation with high androstenedione
5 mg at night and 2.5 mg in morning until spontonaeous ovulation
occurs
40

38. PCOD
07/23/17
For infertility in PCOD females: Clomiphene Citrate: first line of
treatment
25-40% abortion rate due to CL phase defect (?)
10% hyperstimulation
With dexamethasone: improves fertility
in CC resistant patients
Tamoxifen 20-40 mg OD x 5 days
Letrozole 2.5 mg OD x 5 days OR 20 mg single dose on day 3
41

39. If unresponsive
+ hMG or GnRH analoges
GnRh: may cause hyperstimulation
Laproscopic ovarican drilling with either diathermy or laser
Progestrone + Hcg: pregnancy support
N-acetyl cysteine 1.2 gm (PCOD patients have raised level of
homocysteine). It’s a mucolytic and insulin senstizer
Metformin in insulin resistant patients
07/23/1742

40. CORPUS-LUTEAL PHASE DEFECT
07/23/17
Either duration of luteal phase is less or less production of
progesterone: interferes with implantation

Treatment: progesterone (100 mg IM or 300-600 mg
micronized vaginal tablets)

High dose HCG (in unruptured follicular syndrome)
43

41. Endometriosis
Surgical ablation
Ovarian stimulation with IUI
Danazol: first fda approved drug for endometriosis. Its a progesterone,
has hypoestrogenic and hyperandrogenic effect causing atrohy of
endometrium in endometriosis.
Also prevents ovulation by suppressing increase of LH
Side effects: masculinizing effect
GnRH agonists are preferred
07/23/1744

42. IVF
 CC + Gn: synchronous maturation of several ova: improves
harvesting
Menotropins: induces simultaneous maturation of ova and to
precisely time ovulation: to facilitate their harvesting for IVF
07/23/1745

43. MALE
INFERTILIT
Y

44. Impaired
production or
function of sperm
Impaired shape or
movement
Low sperm concentration
Varicocele
Undescended testis
Testosterone deficiency
(male hypogonadism)
Genetic defects
Infections
07/23/1747
Impaired
delivery of
sperm
Sexual issues
retrograde
ejaculation
 blockage of
epididymis or
ejaculatory ducts
 No semen
(ejaculate)
Hypospadia
Anti-sperm
antibodies
Cystic fibrosis
General Health
and Lifestyle
 stress
Malnutrition
Cancer and its
treatment
Alcohol and drugs
Age
DM
Pesticides
Overheating of
testicles

45. Hypogonadotropic hypogonadism
Clomiphene Citrate
25 mg/day for 24 days & gap of 6 days. Duration: 6 months
Gonadotropins
Hcg: 1000-2500 IU twice/thrice a week I.M.or S.C. Add Hmg
75-150 u thrice a week
90% spermatogenesis
FSH
Higher specific activity
MOA: similar to hmg
Can be given with hcg
07/23/1748

46. GnRH
Alternative to hcg or hmg
Pulsatile administration of 50ug/kg 2 hrly S.C
In kallman syndrome.
Not effective in defective spermatogenesis and raised FSH (?)
07/23/1749

47. Androgens
Correct testosterone deficiency in patients with hypogonadism
Testosterone enanthate 250mg every 3 – 4 wk IM
Testosterone undeconate 120 – 160 mg/d orally

cutaneous applications are also available in scrotal patches or gel form.
07/23/1750
Androgens + HCG;1000-4000 IU I.M. 2-3
times/week and FSH +LH after 3-4 months;
Treatment for 6-12 months

48. Idiopathic Male Infertility
Antiestrogens: Clomiphene and Tamoxifen
stimulate the secretion of FSH & LH by blocking estrogen &
testosterone receptors in the hypothalamus
Tamoxiphene act directly on spermatogenesis by interfering with
the testicular estrogen receptor
Tamoxiphene + Testosterone Undecanoate, 40 mg TDS: helps in
spermatid differentiation & increase sperm number & improve
sperm functions.

07/23/1751

49. Anastrozole
Blocks conversion of testo->estrogen & Androstenedione-
>estrone
Males with severe infertility + low testo/estrogen ratio: increase
sperm count & motility and correct hormonal abnormality
FSH
Severe male infertility
Improve sperm structure and functions
 75-150 IU for 2 months
07/23/1752

50. Mast cell stabilizers: Ketotifen
Inhibit release of histamine and vasoactive substances from
mast cells
Prevent progressive intratesticular fibrosis and block harmful
effects of mast cell products like IL6 or trypatse on
spermatazoa
Improve sperm count and motility
07/23/1753
Pentoxifylline
Methylxanthine derivative: inhibit PDE-> increase sperm cAMP
Increase sperm count and motility
400-600 mg TDS Orally x3-6 months

51. Immunological Disorder
Methylprednisolone
For treatment of antisperm antibodies
40-60 mg X 4-6 weeks in decreasing doses: for low grade auto-
immune orchitis
07/23/1754

52. Emission & Ejaculatory Failure
Alpha sympathomimetic and Anticholinergics
In retrograde ejaculation & transport aspermia secondary to
emmision failure
Due to retroperitoneal lymphadectomy or Diabetes Mellitus
MIDODRINE: 5-15 mg I.V.
IMIPRAMINE: 25-75 mg oral
BROMPHENIRAMINE: 8mg TDS
07/23/1755

53. Elevated Reactive Oxygen Radicals
Tocopherol
Antioxidant and fat soluble vitamin
Protective action on lipid peroxidation in sperm membranes via
scavenging of free oxygen radicals
In asthenozoospermia and abnormal acrosome reaction
300-600 mg Daily
07/23/1756

54. Bromocriptine: effective treatment for sexual dysfunction in
men with hyperprolactinaemia
Anti-oxidants, mast cell blockers and alpha blockers need
further evaluation
The use of systemic corticosteroids for treatment of antisperm
antibodies : can only be recommendedin the context of further
research
07/23/1757

55. Erectile Dysfunction
Inability to attain & maintain erection of penis during sexual
performance.
07/23/17Also known as impotence58

56. Causes
1.Vascular – HT, Arteriosclerosis
2.Neurological – spinal cord injury
3.Hormonal – Androgen deficiency
4.Drugs – Anticholinergics (?) antipsychotic, antihypertensives
5.Psychological – Anxiety, stress, depression
6.Misc: Smoking, alcohol, obesity, chronic illness
7.Potassium deficiency or arsenic contamination of drinking water
07/23/1759

57. Treatment
Correct underlying disorder
Stop medications (if they are cause)
Aerobic exercise
Medical management
Penile prosthesis, Penis Pump
07/23/1760

58. PDE5 Inhibitors
Sildenafil (Viagra)
Inhibits PDE 5 in corpora cavernosa of penis -> prolongs cgmp
better erection
Presence of NO is essential for its action
By itself, it does not improve libido, orgasm or ejaculationnot
even erection
But, improves the quality & duration of erection in response to
sexual stimulation.
07/23/1761

59. single oral dose of 50 mg 1 hr before the intended sexual
activity.
T1/2: 2-4 hr
clinical effectiveness lasts for 4 hrs
Metabolized in the liver by CYP450
Headache, dyspepsia, nasal congestion, Potentiates
hypotensive effect of nitrates, Visual disturbances
 beneficial in patients of pulmonary hypertension
07/23/1762

60. Tadalafil (Cialis)
Chemically unrelated to sildenafil.
Similar properties & longer duration of action
Less ocular toxicity
T1/2: 17.5 hr. effect lasts for 36 hrs.
5 – 20 mg twice a week.
Vardenafil (Levitra)
07/23/1763

61. Papaverine
nonselective phosphodiesterase inhibitor -> ↑cAMP & cGMP
levels in penile erectile tissue
Higheffly effective in psychogenic & neurogenic ED but not in
vasculogenic ED.
Phentolamine
Non-selective α antagonists
Vasodilator, hypotension & reflex tachycardia
07/23/17Given in injectable form64

62. Alprostadil
PGE1
With DDAIP: as topical cream
injected directly into the cavernosa or placed inside the urethra as a
minisuppository from which it diffused into cavernosal tissue.
Useful in non respondents to sildenafil
superior to papaverine in efficacy
 low incidence of priapism & fibrosis.
Painful erection
Approved in canada and US
07/23/1765

63. Other drugs..
Antidepressants: Trazodone
Testosterone I.M
Yohimbine: 2antagonist shows some benefit in psychological than
α
organic origin
Apomorphine: D1 & D2 agonist
Sublingual orbuccal tablet
Useful in patients with coexisting BHP, CAD & HT.
Bromocriptine (?)
07/23/1766

64. Thankyou……
07/23/1767

65. 07/23/1768