1. An Update of
CLOMIPHENE (Enclomiphene)
in Male Infertility :Evidence Based
DR. ABHISHEK SINGH PARIHAR
DR. SHARDA JAIN

2. Causes

3. Causes
of
Male
Infertility

4. 5%
Psycological
15%
Disorders of
Sperm
motility
50%
due to
disorders of
30%
due to
obstruction of
ductus
deferens.
Causes
spermatogenesis
eg ↑ scortal tem

5. Early decline in testosterone………..
Male infertility
Major link
Testosterone deficiency

6. Testosterone deficiency
Prevalence:
26.1% males in India are suffering from
hypogonadism
Causes:
Andropause, Testosterone deficiency
syndrome (TDS) and Ageing
Indian J Urol. 2009 Apr;25(2):190-4.

7. Clomophene
citrate is used left
& right by
infertility experts
all over the
country in India
without much
support by
Cochrane review

8. 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

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

10. 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

11. Mechanism of action
Enclomiphene

12. Hypothalamic-pituitary-testicular axis
Enclomiphene
Zuclomiphene
ER antagonist
ER agonist
Induces hypothalamic
GnRH release
Opposes the action of
Enclomiphene
Increases LH & FSH levels
Increases serum
testosterone levels
IDrugs 2009 Feb;12(2):109-19
Reduces testosterone levels

13. Enclomiphene in Male Hypogonadotropic Hypogonadism
Associated with Infertility and Metabolic Syndrome
EC has a theoretical advantage over testosterone
replacement because gonadotropin levels, fertility, and
testicular size are preserved, while testosterone secretion
has a physiological, temporal pattern
•
In baboons who received 12 days of CC, EC, or ZC; EC:
–
–
•
In a phase IIb/III, double-blind trial in males with secondary hypogonadism, EC:
–
–
•
Increased serum testosterone > than CC (1144 ng/dL vs. 559 ng/dL; P=0.03)
Decreased total cholesterol level
Increased serum testosterone, LH, FSH, estrogen, FPG and cholesterol
Levels were unchanged for placebo and testosterone gel
SAFETY and TOLERABILITY: Similar to placebo; low frequency; mild-to-moderate
(hot flashes, headache, nausea, vomiting)
Hill S, et al. Idrugs. 2009. 12(2):109-119.

14. Animal study…
contd.
Study in baboons examined the effects of
12 days of treatment with clomiphene
citrate, enclomiphene or zuclomiphene
(all administered at 1.5 mg/kg/day)
Zuclomiphene failed to increase
testosterone levels
8-fold increase in testosterone levels
with enclomiphene
5-fold increase in testosterone levels with
clomiphene citrate
Hill S, et al. Idrugs. 2009. 12(2):109-119.

15. LH & FSH level after 3 & 6 months
Baseline
Androxal
Testosterone gel Androxal Testosterone gel
After 3 months
After 6 months

16. Comparing with Published data for
Clomiphene citrate….

17. Enclomiphene 25 mg shows 2.5 times more LH
rise than clomiphene 50 mg
458%
170%
*
European Journal of Endocrinology (2009) 161 163–169
Androxal® Data on File. (http://www.reprosrx.com/pr_20091006_repros_androxal_normal_sperm.php)
#

18. Enclomiphene 25 mg shows more than 4 times
FSH rise than clomiphene 50 mg
83%
354%
*European Journal of Endocrinology (2009) 161 163–169
Androxal® Data on File. (http://www.reprosrx.com/pr_20091006_repros_androxal_normal_sperm.php)
#

19. Enclomiphene shows significant
improvement in LH & FSH levels than
clomiphene citrate
Increase in testosterone levels
Increase in spermatogenesis
Elevated sperm count

20. Significant improvement in testosterone levels
218% increased
testosterone
Androxal® Data on File.
(http://www.reprosrx.com/pr_20091006_repros_androxal_normal_sperm.php)

21. Enclomiphene
Enclomiphene VS Current T Gels/ Cream
Enclomiphene

22. Enclomiphene
Indications & Dosage
Treatment of Male Hypogonadism
• Dosage: 1 capsule of Enclomiphene
25mg OD for 3-6 months

23. Lets Update ourselves on
Medical treatment with
clomiphene in male infertility

24. EC Stimulates Endogenous Production of Testosterone and
Sperm Counts in Men with Low Testosterone
•
EC was compared as an alternative to topical testosterone in a
proof-of-principle, randomized, open-label, phase IIB study in
12 men with secondary hypogonadism treated previously with
topical testosterone.
•
After discontinuation of topical testosterone, morning total
testosterone (TT) values averaged 165 ± 66 pg/dL.
– After 3 months, there was a significant rise in TT that was sustained for 3
months.
•
•
At 6 months, TT levels were 545 ± 268 and 525 ± 256 pg/dL for gel and EC groups,
respectively.
EC elevated sperm counts in all men at 3 and 6 months with
sperm concentrations in the 75–334 × 106/mL range.
– At follow-up, only EC therapy was associated with elevated sperm counts.
Kaminetsky L, et al. J Sexual Med. 2013; 10(6): 1628–1635.

25. Effect of clomiphene citrate on sperm
density in male partners of infertile couples.
Patankar et al 2007
Clomiphene citrate exerts its effect on
spermatogenesis by raising the endogenous
serum FSH, LH and testosterone levels to
initiate and maintain gametogenesis .
Researchers opined that this increase in
endogenous gonadotrophins manifests itself in
improving the sperm count, sperm motility
and to certain extent morphology of the
sperms, when there is no end-organ
pathology.

26. COCHRANE Database
syst Rev
2007 Jul 18;(4)
Anti-oestrogens appear to have a
beneficial effect on endocrinal outcomes,
but there is not enough evidence to
evaluate the use of anti-oestrogens for
increasing the fertility of males with
idiopathic oligo-asthenospermia.
WITHDRAWN: Clomiphene or tamoxifen for
idiopathic oligo/asthenospermia.

27. It is up to you to
use The hidden
facts of
Enclomiphene
In male infertility
Shared in this
presentation

28. CONCLUSION
• Clomiphene is popular for treatment of
unexplained idiopathic male infertility because it
is inexpensive and safe
• Management of secondary hypogonadism
associated with obesity, metabolic syndrome .
• Because efficacy of clomiphene is in DOUBT,
prolonged courses of empirical antiestrogen
therapy should not be used as a substitute for
more effective modes of management.

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