A look into the management of female infertility due to thin endometrium and the role of sildenafil

1. SILDENAFIL IN
FEMALE INFERTILITY

2. Contents
o Overview of female reproductive system
o Infertility
o Thin endometrium
o Sildenafil
o Indications, dose and dosage
o Clinical studies
o Summary and conclusion

3. Female reproductive
system
▪The female reproductive system is made up
of the internal and external sex organs that
function in human reproduction.
▪The internal sex organs are the uterus and
Fallopian tubes, and the ovaries.
▪The external sex organs are also known as
the genitals and these are the organs of the
vulva including the labia, clitoris and vaginal
opening.

4. Female internal sex
organs
Uterus
o The uterus is a hollow, muscular, pear-shaped
organ.
o Connected to the two fallopian tubes on its
superior end and to the vagina (via the cervix) on
its inferior end.
o The inner lining of the uterus, known as the
endometrium, provides support to the embryo
during early development.
o The visceral muscles of the uterus contract during
childbirth to push the fetus through the birth canal.

5. Female internal sex
organs
Fallopian tubes
o The fallopian tubes are a pair of muscular tubes
that extend from the left and right superior corners
of the uterus to the edge of the ovaries.
o The fallopian tubes end in a funnel-shaped
structure called the infundibulum, which is covered
with small finger-like projections called fimbriae.
o The fimbriae pick up released ova from ovary and
carry them into the infundibulum for transport to
the uterus.
o The inside of each fallopian tube is covered in cilia
that work with the smooth muscle of the tube to
carry the ovum to the uterus.

6. Female internal sex
organs
Ovaries
o The ovaries are small, paired organs located near
the lateral walls of the pelvic cavity.
o These organs are responsible for the production of
the egg cells (ova) and the secretion of hormones.
o The process by which the egg cell (ovum) is
released is called ovulation.
o The speed of ovulation is periodic and impacts
directly to the length of a menstrual cycle.

7. Ovulation, conception &
implantation
o Ovulation is the release of egg from the
ovaries.
o Conception/ Fertilization is the union of a
human egg and sperm, usually occurring
in the ampulla of the fallopian tube.
o Implantation is the very early stage of
pregnancy at which the conceptus
(fertilized embryo) adheres to the wall of
the uterus.

8. Ovulation, conception &
implantation

9. Implantation
o At this stage of prenatal development, the conceptus is a
blastocyst.
o It is by this adhesion that the fetus receives oxygen and nutrients
from the mother to be able to grow.
o Implantation of a fertilized ovum is most likely to occur about 9
days after ovulation, ranging between 6 and 12 days.

10. “ Infertility
a disease of the reproductive
system defined by the failure to
achieve a clinical pregnancy after
12 months or more of regular
unprotected sexual intercourse

11. Infertility
o Global incidence of infertility is about 13-
18%
o The incidence of infertility steadily
increases in women after age 30.
o In India, although population growth is a
major concern, there are a substantial
number of infertile couples.

12. Causes of female
factor infertility
o Ovulation disorders (40%)
o Aging
o Diminished ovarian reserve (DOR)
o Polycystic ovary syndrome (PCOS)
o Premature ovarian failure
o Others

13. Thin endometrium

14. Thin endometrium
o Adequate thickness of the endometrium is
essential to accomplish a successful
pregnancy in ART cycles
o ‘‘Thin endometrium” defined as an
endometrium thickness that can’t reach
the threshold for embryo implantation.
Fertil Steril 2008; 89: 832–9.

15. Thin endometrium
o Studies suggest minimal endometrial thickness of
7 mm, (and preferably > 9 mm) to maximize
pregnancy rates
o Several reports have shown correlation between a
‘‘thin endometrium’’ and low implantation rates
o Clinical pregnancy rates increased gradually from
53% among patients with a lining <9 mm, to 77%
among patients with a lining of >16 mm.
o Furthermore, thin endometrium causes higher risk
of miscarriage
Human Fertility 2009;12:198–203.
J Assist Reprod Genet 1993;10: 215–19.
Hum Reprod 1994;9: 363–5.
Fertil Steril 2007;87:53–9.

16. Understanding the
endometrium
Endometrium has two layers:
o a basalis layer that is adherent to the myometrium
o and a functional layer which undergoes different
phases during a menstrual cycle
o This lining is under the control of estrogen
hormone and passes through different phases
during the monthly menstrual cycle of female.

17. Understanding the
endometrium
o The average thickness of endometrium is 8 mm
which increases further in pregnancy. Less than 8
mm is considered inadequate
o During pregnancy, at least 9 mm of thickness is
required to provide a site for proper implantation of
fetus.
o This thickness not only plays a vital role in the
implantation of fetus to the walls of the uterus but
also supports the growing baby in the later stages
of pregnancy.

18. Consequence of thin
endometrium
o If, due to any cause, this lining becomes
thin, it becomes impossible for the
fertilized egg to get implanted to the wall.
o This can lead to infertility of a female
uterus and pregnancy cannot take place
because a fertilized egg needs a strong
support for implantation and support for
growing into an embryo.

19. Causes of thin
endometrial lining
Thinning of endometrial lining is a serious
problem from gynecological point of view.
Certain causes are described below.
1. Low estrogen
2. Inadequate blood flow
3. Poor health of endometrial tissue (Any injury,
surgery, trauma or infection can cause damage to
the endometrial lining)
4. Long term use of birth control pills
5. Excessive use of clomefine citrate

20. Signs and symptoms
of thin endometrial
lining
There are no specific signs and symptoms
related to the thin endometrial lining.
However females suffering from thin
endometrial lining may present with:
1. Infertility problems
2. Abnormal menstrual cycle
3. Menses accompanied by pain
4. Irregular menses timing
5. Shorter menstrual bleeding

21. Treatment of thin
endometrium

22. Sildenafil
▪Sildenafil is a selective inhibitor of
Phosphodiesterase -5 (PDE-5), which is cGMP-
specific and responsible for the degradation of cGMP
▪Sildenafil protects cyclic guanosine monophosphate
(cGMP) from degradation by cGMP-specific
phosphodiesterase type 5 (PDE5)

23. Background
The endometrium is the special epithelial lining of
the uterine cavity
It has two layers: A superficial functional layer and a
deeper basal layer
The endometrial growth is reliant on the uterine
blood flow
Uterine blood flow is closely related with the
vascular development of endometrium
plays a significant role in the development of a
dominant follicle, formation of a corpus luteum, and
growth of endometrium
This is essential to support endometrial growth after menstruation and
to provide a vascularized receptive endometrium for implantation

24. “ In cases where ‘‘thin’’ endometrium results
from reduced endometrial blood flow,
the use of vasoactive substances may
increase endometrial perfusion with a
consequent improvement in endometrial
growth.
Improving endometrial perfusion

25. Rationale for use
▪Endothelial and inducible NO synthase isoforms have
been identified in both the vascular endothelium of
human endometrium and in the myometrium
▪Vaginally administered sildenafil suppositories could
lead to an improvement in uterine blood flow and, in
conjunction with controlled ovarian hyperstimulation,
lead to estrogen-induced proliferation of the
endometrial lining
Telfer JF, Irvine GA, Kohnen G, Cambell S, Cameron IT. Expression of endothelial and inducible nitric oxide synthase in non-pregnant
and decidualized human endometrium. Mol Hum Reprod 1997;3:69–75.
Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial
development in patients undergoing IVF. Hum Reprod 2000;15:806–9.

26. Sildenafil: potential role in female infertility
due to thin endometrium
▪Sildenafil enhances the effect of NO by inhibiting
PDE5 which is responsible for degradation of cGMP.
▪Sildenafil is a selective inhibitor of the type-V cGMP-
specific phosphodiesterase.
▪With the use of sildenafil, cGMP levels remain
elevated, which leads to vascular relaxation and
increased blood flow to improved the endometrial
thickness
Sher G and Fisch JD. Vaginal sildenafil (Viagra): A preliminary report of a novel method to improve uterine artery blood flow and
endometrial development in patients undergoing IVF. Hum . Reprod. 2000; 15: P806-809.

27. Indications
▪To improve endometrial thickness in female
infertility due to thin endometrium

28. Dose and dosage
▪Thin endometrium:
Sildenafil citrate 25 mg vaginally every 6 hours from
day 8th of the cycle for 5 days (3-10 days)
▪In ART:
Vaginal sildenafil citrate suppositories (25 mg) four
times per day from the third day of the stimulation
protocol to the evening before oocyte retrieval.

29. Clinical studies

30. Study 01

31. Study 01
▪Objective
 to study and compare the effect of vaginal sildenafil
citrate and estradiol valerate on endometrial thickness,
blood flow and pregnancy rates in infertile women
undergoing intrauterine insemination
▪Methodology
 Comparative prospective study including 100 women
with primary or secondary infertility with stimulated
cycles undergoing IUI
 In group A, 50 patients were included and given sildenafil
citrate 25 mg vaginally every 6 hours from day 8th of the
cycle.
 In group B, 50 patients were given tablet estradiol
valerate 2 mg 6-8 hourly.

32. Study 01
▪Results
 64% patients given sildenafil vaginally had vascularity up
to zone 3 whereas 48% patients given estradiol valerate
orally had zone 3 endometrial vascularity (p value =
0.038)
 The clinical pregnancy rates were 10 (20%) in group 1 and
7 (14%) in group 2 after 3 cycles of IUI. (p value = 0.042)
▪Conclusion
 Sildenafil when compared to estradiol valerate has better
results as far as endometrial vascularity is concerned
 and marginally increased pregnancy outcome in patients
undergoing IUI

33. Study 02

34. Study 02
▪Objective:
 To evaluate the effects of vaginally administered
sildenafil on endometrial thickness and IVF outcome in a
large cohort of infertile women with poor endometrial
development.
▪Intervention:
 Patients underwent IVF using a long GnRH-a protocol
with the addition of sildenafil vaginal suppositories (25
mg, 4 times per day) for 3–10 days.
▪Main Outcome Measures:
 Peak endometrial development, pregnancy, and
implantation rates.

35. Study 02
▪Results:
 Of 105 patients, 73 (70%; Group A), attained an
endometrial thickness of 9 mm
 whereas 32 (30%; Group B) did not.
 Implantation and ongoing pregnancy rates were
significantly higher for Group A (29% and 45%) than for
Group B (2% and 0).
▪Conclusion:
 Vaginal administration of sildenafil enhanced
endometrial development in 70% of patients studied.
 High implantation and ongoing pregnancy rates were
achieved in a cohort with a poor prognosis for success.

36. Study 03
▪Study details:
 In a prospective study, 10 patients in our fertility center
gave their informed consent to be treated with vaginal
sildenafil citrate suppositories (25 mg) four times per day
from the third day of the stimulation protocol to the
evening before oocyte retrieval.

37. Study 03

38. Summary of key
findings of other
supporting studies
 Sildenafil improved endometrial vascularity and
marginally increased pregnancy outcome. The clinical
pregnancy rates were 20% in SC group and 14% in
estrogen group after 3 cycles of IUI (P=0.042)
 The endometrial vascularity was significantly higher after
sildenafil treatment in 21 patients (P<0.01). Embryo
transfer was done in 19 women, out of which 9 (47.36%)
women conceived
Mangal S, Mehirishi S. To study and compare the effect of vaginal sildenafil and estradiol valerate on endometrial thickness, blood flow
and pregnancy rates in infertile women undergoing intrauterine insemination. Int J Reprod Contracept Obstet Gynecol 2016;5:2274-7.
Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K. Vaginal sildenafil: Role in improving endometrial blood flow in
women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Int J Sci Res 2015;4:292-4.
Study04Study05

39. Summary of key
findings of other
supporting studies
 The clinical pregnancy rate was two-fold higher in the
study group (Sildenafil), compared to control group but
not statistically significant (47.6% vs. 25.9%, P=0.209)
 All three (A: Vit E, B: L-arginine, C: Sildenafil)
interventions improved uterine RA-RI and EM in the
patients with a thin endometrium
 Pregnancy rates: 50% in sildenafil group, 11% in
L-arginine, 20% in Vitamin E, and nil in control group
Kim KR, Sun Lee H, Ryu HE, Park CY, Min SH, Park C, et al. Efficacy of luteal supplementation of vaginal sildenafil and oral estrogen on
pregnancy rate following IVF-ET in women with a history of thin endometria: A pilot study. J Womens Med 2010;3:155-8.
Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K. Vaginal sildenafil: Role in improving endometrial blood flow in
women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Int J Sci Res 2015;4:292-4.
Study06Study07

40. Summary of key
findings of other
supporting studies
 Long GnRH-Lupron was used for ovarian stimulation
 Sildenafil vaginal suppositories 25 mg, 4 times/day for
3–10 days
 Sildenafil enhanced endometrial development >9 mm in
70% of patients studied.
 It increased the implantation rate and ongoing pregnancy
rate in above patients compared to patients with <9 mm
endometrial lining
Sher G, Fisch JD. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor
endometrial development. Fertil Steril 2002;78:1073-6.
Study08

41. Summary of key
findings of other
supporting studies
 The NK-cell activity was significantly decreased after
vaginal sildenafil therapy endometrial thickness was
significantly increased
 Sildenafil decreases pulsatility index indicating increase
in uterine blood flow and increased endometrial
thickness.
Jerzak M, Kniotek M, Mrozek J, Górski A, Baranowski W. Sildenafil citrate decreased natural killer cell activity and enhanced chance of
successful pregnancy in women with a history of recurrent miscarriage. Fertil Steril 2008;90:1848-53.
Sher G, Fisch JD. Vaginal sildenafil (Viagra): A preliminary report of a novel method to improve uterine artery blood flow and endometrial
development in patients undergoing IVF. Hum Reprod 2000;15:806-9.
Study09Study10

42. Summary &
conclusion
▪Luteal supplementation of sildenafil citrate can be used for
improving the endometrial thickness, therefore can be used
as an adjuvant therapy in patients with thin endometrium.
▪Sildenafil has good outcome in terms of uterine receptivity,
endometrial vascularity, and marginally increased
pregnancy outcome in patients undergoing IUI or IVF-ET.
▪Vaginal sildenafil is generally well tolerated with minimal
adverse effects (vaginal sildenafil suppositories are free
from side effects related to oral sildenafil)