1. Clomiphene Update :
In Infertility
Dr. Sharda Jain
Dr Jyoti Agarwal

2. What is new in clomiphene
The TRUTH about Infertility... IT HURTS!

3. Major Causes of female infertility
Failure to
ovulate
••Hormonal
Hormonal
problems
problems
••Scarredovaries
Scarred ovaries
••Premature
Premature
menopause
menopause
••PCOS
PCOS
20-40%
Dysfunctional
fallopian tubes
••Infection
Infection
••Abdominal
Abdominal
diseases
diseases
••Previoussurgeries
Previous surgeries
••Ectopicsurgeries
Ectopic surgeries
Endometriosis
••Excessivegrowth of
Excessive growth of
the lining of the
the lining of the
uterus
uterus

4. DRUGS USED FOR
OVULATION INDUCTION
•
•
•
•
CLOMIPHENE CITRATE
GONADOTROPHINS
TAMOXIPHENE
AROMATASE INHIBITORS
Most commonly used is CC

5. WHO Classification of Anovulation &
Oligo-ovulation…
• Grp I - hypothalamic pituitary failure or hypogonadotrophic
hypogonadism, accounting for around 10% of ovulatory
disorders;
• Grp II - hypothalamic pituitary dysfunction or
eugonadotrophic, 85% of ovulatory disorders;
• Grp III - ovarian failure or hypergonadotropic hypogonadism,
4-5% of ovulatory disorders.
Cochrane Reviews 2009, Issue 4. Art. No.: CD002249.

6. For Ovulation induction an
anti-estrogen is required
Anti-estrogens are the first line treatment strategy
for WHO class 2 anovulatory infertility.

7. Clomiphene citrate
Synthetic, nonsteroidal
antiestrogen (SERM)
First anti-estrogen, approved by the
U.S. FDA in 1967
Widely used for past 45 years for
induction ovulation
Selective Estrogen Receptor Modulator

8. The uniqueness of SERMs
The SERMs bind to estrogen receptors and have
tissue-specific effects that allow them to function
as estrogen agonists in some tissues and estrogen
antagonists in other tissues

10. Clomiphene Citrate: Indications
Practice Committee of the American Society for Reproductive Medicine. FERTILITY AND STERILITY.2003; 80(5): 1302-1308.

11. Clomiphene citrate…..
Certainly
an Old
favorite in
the world
of
ovulation
induction..
But, it has negative effects…
Fertil Steril 2009;92:860-3

13. Clomiphene citrate – A racemic mixture
Cis- Zuclomiphene
Cis- Zuclomiphene
Trans- Enclomiphene
Trans- Enclomiphene
Isomer Ratio
38% Zuclomiphene & 62% Enclomiphene
Pharmac. Ther. Vol. 15, pp. 467 to 519,
1982

14. CC: Mixed estrogen agonist-antagonist

15. Enclomiphene
Anti-estrogenic
centrally
Property of ovulation
induction
Estrogenic peripherally
Increased
cervical
mucus
Short half-life of 24 hrs
Less Resistance in
patients
Endometrial
thickening
Reproductive Biomedicine Online; vol. 15;No.2. 2007, 134-148
Usadi, R, Fritz, M, Glob. libr. women's med., (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10337
Endocrinology. 1983 Feb;112(2):442-8
Middle East Fertility Society Journal; Vol. 13, No. 1, 2008;52-56

16. Zuclomiphene peripheral disadvantages
Peripheral antiestrogenic
Endometrium
Cervix
Endometrial thinning
Poor cervical
mucus
Decreased
implantation
J. Biosci., Vol. 7, Number 2, March 1985, pp. 161–
173.
Middle East Fertility Society Journal; Vol. 13, No. 1, 2008;52-56

17. Drawbacks of ZC : Benefits of EC
Enclomiphene scores over the cisisomer in terms of:
Good follicular growth
 Induces ovulation
Endometrial thickness
 Builds up endometrial lining
 No abnormal luteal phase
morphology
Zu Clomiphene
(Cis-Isomer)
Good quality of cervical
mucus (thin) which is
desirable for better
sperm transport
Short T1/2 (24 hrs): Gets
eliminated from the body
faster
Teramoto S, Kato O. Reproductive BioMedicine Online. 2007; 15(2): 134-148.
.

18. What literature has to say…
Zuclomiphene gets accumulated for a longer time in the body
Is detectable in the circulation even after 1 month of treatment
and may actually accumulate over consecutive cycles of treatment
Human Reproduction Vol.20, 2005
Enclomiphene disappears rapidly from
the circulation (less than 24 hrs)
CURRENT SCIENCE, VOL. 80, 2001
Zuclomiphene is unable to induce
ovulation due to its estrogenic nature
Hum Reprod.1989 Apr;4(3):252-6.

19. • Twenty-six normoprolactinaemic women
• Women treated with 100 mg clomiphene citrate daily from
day 2 of the first cycle for 5 days
• Following a ‘washout’ cycle were then randomized to receive
50 mg either the En or the Zu isomer daily from day 2 of the
third cycle for 5 days.

20. Enclomiphene 50 mg comparable to
Clomiphene citrate 100 mg
p < 0.01
p <0.05
Hum Reprod.1989 Apr;4(3):252-6.

21. EC is the Isomer Active in Inducing Follicular Development
Parameter
CC cycles
Spontaneous
ZC
Normoprolactinemic women (N=26; mean age=32 yrs) with EC
regular menstrual cycles
(mean ± SEM) patent fallopian tubes being treated with donor insemination
cycles
and
Serum oestradiol Day 0
3388±530**
1022±141
2595±500*
1176±171
Serum oestradiol Day 1
3772±614**
1236±158
3262±638**
1232±151
Serum progesterone
95±14**
43±4
95±15**
44±8
Mean number of
follicles>16 mm
2.4±0.3**
1.2±0.3
2.1±0.3
1.2±0.2
Day of LH peak
14.9±0.4
13.9±0.6
15.2±0.3
13.3±0.4*
Spinbarkeit of the endocervical mucus was significantly
reduced in CC-treated cycles and EC-treated cycles but
there was no reduction in the ZC-treated cycles
Glasier AF, et al. Human Reproduction.1989;40(3): 252-256.

22. Lets recap the clomiphene cycle
and
Monitoring

23. 50 mgm of Enclomiphene =
100 mgm of clomiphene
Day of start of clomiphene cycle does not improve
the pregnancy rate
(day 2, 3, or 5)
Increasing the dose of clomiphene does not increase
the chances of ovulation
If ovulation has been documented with 50 mgm dose ,
continue with the same dose

24. Each cycle needs to be monitored
• Minimum monitoring
• Better monitoring
• Best monitoring
LH kit
TVS
TVS + LH kit
With positive 2 lines following 2 days should be

25. Usually started from Day 8 - 10
• If CC started from D5
• Monitoring from D12
• Ovulation expected by
D 16 – 17

26. HCG Trigger
• GT
18 – 20 mm
• CC
22 – 24 mm

27. How many inseminations
2 or 1
Male factor
Low monitoring
TWO

28. HOW MANY CYCLES
We at lifecare
6
(including of all )
Cummulative
success rate
50 %

29. Luteal phase support is needed
in all cases of cc
Method
Pregnancy Rate (%) for
unexplained infertility
Intercourse (Timed)
4
IUI
6
CC
6
CC+IUI
8
FSH / HMG
7.7
CC / FSH /IUI
9-12
3
FSH/ HMG/IUI
17 – 20 %
5
In vitro fertilization
20 to maximum 30
2
Natural Intercourse is NOT Prohibited During
Monitoring

30. For ovulatory disorders
Treatment should begin
with a low dose, 50 mg
daily for 5 days.
(1 tablet of
Enclomiphene)
• The dose should be
increased only in those
patients who do not
ovulate in response to 50
mg of Enclomiphene.

31. Enclomiphene generally is very well
tolerated
Side effects are rarely persistent or severe enough
to threaten completion of treatment.

32. Side Effects (2% -10% of women)
• Vasomotor flushes (hot flushes)
• Mood swings
• Visual disturbances: Blurred,double vision,
scotoma
• Isolated reports of optic neuropathy
• If visual disturbances identified, it is prudent to stop
treatment and consider alternative methods of
ovulation induction
• Breast tenderness
• Pelvic discomfort
• Nausea
Practice Committee of the American Society for Reproductive Medicine. FERTILITY AND STERILITY.2013; 100(2):341-348.

33. KEY TO SUCCESS
Patient selection !
Proper stimulation
Right timing to IUI
Luteal support

34. Dr ALKA KRIPLANI & Dr P. GUPTA

35. Improves
Cervical
Mucus quality
Unlike
clomiphene
Purest isomer
Of
Clomiphane
Ultra-short
Acting (24 hrs),
Unlike
Clomiphane
Enclomiphene
Improves
Endometrial
Thickening
Unlike
Clomiphene
Improves
Follicular
Development
Like
Clomiphene

36. Enclomiphene is the main player for
ovulation induction and its short half-life can
effectively cancel the positive feedback at the
hypothalamic level
Enclomiphene is the one
primarily responsible for the
ovulation-inducing actions of CC
Reproductive Biomedicine Online; vol. 15;No.2. 2007, 134-148
Usadi, R, Fritz, M, Glob. libr. women's med., (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10337

37. The need of the hour for
Ovulation Induction is…
• Take only the positive effects of Enclomiphene
• Remove the negative effects of Zuclomiphene
The end result would be…
Maximum
efficacy
Highest Safety

38. Thank
you