This document discusses the use of various drugs and supplements to improve blood flow and endometrial thickness in patients undergoing intrauterine insemination (IUI). It summarizes several studies that found low-dose aspirin improved endometrial pattern and pregnancy rates in IUI patients with thin endometrium. It also discusses the use of sildenafil, L-arginine, myo-inositol, D-chiro-inositol, metformin, glucocorticoids, and coenzyme Q10 to enhance IUI outcomes in patients with conditions like polycystic ovarian syndrome (PCOS) or decreased ovarian reserve.

1. Adjuncts in IUI
Dr. Saumya Prasad
M.S (Obst & Gynae)

2. Drugs that improve blood flow
Aspirin
Recently, it has been shown that high blood
flow impedance of uterine radial arteries
remains the pathophysiology behind a thin
endometrial growth.

3. Aspirin (acetylsalicylic acid ) is a prototype non steroidal anti-
inflammatory drug( NSAID) which inhibits prostaglandin
synthesis by inhibition of the enzyme cyclo-oxygenase in the
arachidonic acid cascade.
Drugs that improve blood flowAspirin

4. Low dose aspirin
Low dose aspirin inhibits the synthesis of thromboxane A2 without affecting the
synthesis of prostacyclin, thus explaining the increase blood flow velocity in
uterine and ovarian arteries

5. Low-dose aspirin for infertile women with thin endometrium receiving
intrauterine insemination: a prospective, randomized study
• Patients who had thin endometrium (< or = 8 mm) and intrauterine insemination
were divided into the aspirin and nonaspirin groups. Endometrial pattern (trilaminar
and nontrilaminar) and thickness, the pulsatility index (PI) and resistance index (RI)
of the uterine artery, spiral artery, and ovarian dominant follicles, and pregnancy
rates of both groups were measured.
• RESULTS: A total of 114 and 122 women were included in the aspirin and
nonaspirin groups, respectively. There were significantly higher percentages of
trilaminar endometrium (46.5% vs. 26.2%) and pregnancy rate (18.4% vs. 9.0%)
after aspirin therapy. There was nonsignificant difference in the endometrial
thickness, and PI/RI values of the uterine artery, spiral artery, and ovarian dominant
follicle between both groups.
• CONCLUSIONS: Higher pregnancy rate and better endometrial pattern were
achieved in patients with thin endometrium after aspirin administration.
• Aspirin therapy could not significantly increase the endometrial thickness and the
resistance of uterine and ovarian flow.
J Assist Reprod Genet. 2000 Mar;17(3):174-7.

6. It is a type five specific
phosphodiesterase inhibitor.
It improved endometrial
receptivity.
Uterine perfusion improved and
pulsatality index decreased from
3 to 2.1.
Sildenafil
Hm Reprod 2000;15:806-9
When given in a dose of
25 mg four times a day
intravaginally for 3 to 10
days.

7. Sildenafil

8. L-arginine treatment improved the RI in radial artery
to <0.81 in 89% patients.
Sixty –seven percent patients developed an
endometrium of > 8 mm .
L-Arginine
Fertil Steril 2008;89:832-9

9. Clomiphene resistant PCOS patients with enlarged highly
polycystic ovaries are more prone to both hyperstimulation and
poor response.
In majority the underlying disease is polycystic ovary syndrome
(PCOS).
Target should be to improve the internal ovarian milieu by
reducing circulating and intraovarian androgen levels.

10. Glucocorticoids given in a right time and dose reduce the
ovarian androgen levels without disrupting ovulation.
Prednisolone, a short acting and dexamethasone, a long
acting compound with no mineralocorticoid effects are
used to suppress adrenal steroid production.
The objective for adjuctive glucocorticoid use in
ovulation induction is to normalize without suppressing
adrenal steroid production.
Glucocorticoids

11. Typical dosages are dexamethasone 0.25 to 0.5 mg or 5 to 10
mg of prednisone.
A consideration may be given to 0.125 mg as a starting dose of
dexamethasone and titrating therapy to
dehydroepiandrosterone sulfate (DHEAS) levels.

12. Cyproterone Acetate
Fertil Steril 1982;37:161-7
Cyproterone Acetate is a potent progestational agent that both
inhibits gonadotropin secretion and blocks androgen action by
binding to the androgen receptors.
Besides the clomiphene and gonadotropin administration on the
basis of antiandrogenic effects cyproterone acetate has been used
as an adjuvant in ovulation induction for hyperandrogenic
anovulatory patients.
The common side effects include fatigue, edema, loss of libido,
weight gain and mastalgia.

13. • Ovulation induction with adjuvant antiandrogen treatment was
carried out in 50 cycles of 24 hyperandrogenic anovulatory patients.
• 3 treatment groups (dexamethasone, sprinolactone & cyproterone
acetate) were established.
• In 40 cases of 50 cycles ovulation were detected & 11 pregnancies
occurred.
Orv Hetil. 1996 Nov 17;137(46):2569-71
Highest ovulation & pregnancy rate was observed in group
treated with cyproterone acetate

14. Glucocorticoids: Cochrane review
Cochrane Database Syst Rev. 2009;)
Cochrane review supports use of
dexamethasone plus clomiphene in
clomiphene-resistant women.

15. ALTERNATIVES TO CC IN PATIENTS OF PCOS
Use of insulin sensitizers
PCOS are often associated with insulin resistance as well as
defects in insulin secretion.
Metformin is a biguanide which acts in PCOS by lowering the
blood insulin level.
It is used in dose of 1500mg/day is divided doses.
It does not decrease blood glucose in nondiabetics.

16. Metformin
(Ann Transl Med. Jun 2014; 2(6): 56)
Metformin is an effective ovulation induction agent for non-
obese women with PCOS
Metformin Offers some advantages over other 1ST line
treatments for anovulatory infertility
For clomiphene-resistant women, metformin alone or in
combination with CC is an effective next step.

17. Pretreatment and co-administration of oral anti-diabetic agent
with clomiphene citrate or rFSH for ovulation induction in
clomiphene-citrate-resistant polycystic ovary syndrome.
A total of 165 infertile patients with CC-resistant PCOS who attended for treatment
were the target population for this study.
Patients were divided into three groups: groups A and B were given metformin and group C
was the control. Along with metformin, group A received CC and group B received rFSH.
Group C was treated with only rFSH. Metformin was given 1500 mg daily for 4 weeks.
Ovulation (89.09%) and pregnancy (54.55%) rates were higher in group B. Ovulation
(74.55%) and pregnancy (29.09%) rates were also satisfactory in group C but a dose of
rFSH requirement was significantly higher (P = 0.000).
In group A, both ovulation and pregnancy rate were much lower than the other two groups
(27.27% and 12.73%, respectively).
Use of metformin increases the response of ovulation-
inducing agents and can be used safely in PCOS.
J Obstet Gynaecol Res. 2013 May;39(5):966-73.

18. Metformin during ovulation induction with gonadotrophins
followed by timed intercourse or intrauterine insemination for
subfertility associated with polycystic ovary syndrome.
Preliminary evidence suggests that metformin may increase the live birth
rate among women undergoing ovulation induction with gonadotrophins.
Cochrane Database Syst Rev. 2017 Jan 24;1:CD009090
Included five RCTs (with 264 women) comparing gonadotrophins plus metformin
versus gonadotrophins. The gonadotrophin used was recombinant FSH in four
studies and highly purified FSH in one study.
Live birth Metformin plus FSH was associated with a higher cumulative live birth rate when
compared with FSH (odds ratio (OR) 2.31, 95% confidence interval (CI) 1.23 to 4.34; two
RCTs, n = 180; I2 = 0%; low-quality evidence).
This suggests that if the chance of live birth after FSH is assumed to be 27%, then the
chance after addition of metformin would be between 32% and 60%.

19. Metformin + gonadotropins
A recent systemic review & metanalyis has
shown that metformin administration
increases live-birth & pregnancy rate in
PCOS patients who receive gonadotropins
for ovulation induction.
(Reproductive Biology and Endocrinology 2014, 12:3 )

20. • Lipid oversupply
• Chronic low-grade inflammation
• Oxidative stress as root causes in the
development and exacerbation of insulin
resistance
Antioxidants - Emerging data
implicating

21. Nutraceutical
1. Improve insulin sensitivity
2. Decrease serum testosterone
3. Reduce plasma triglycerides
4. Reduce insulin resistance
5. Reduce oxidative stress, lowers TNF-alpha
6. Protective effect within the follicle
7. Reduce Homocysteine level
8. Improves lipid profile
9. Ovulation status
10.Long-term health of women with PCOS
11.Help weight loss
12.Reduce the risk of miscarriage
13.Hyperandrogenism (excess androgens, especially testosterone)
14.Oligomenorrhea , anovulation

23. Role of myo-Inositol (MI) in pathogenesis and
insulin resistance in PCOS
• A defect in tissue availability or use of DCI contribute to
insulin resistance & compensatory hyperinsulinemia.
• Hyperinsulinemia with LH results in hyperandrogenism.
• MI deficiency occurs at ovarian level in PCOS
• Myo-inositol : improve insulin sensitivity, counteract the
increased D-chiro-inositol levels in ovary, and hence
reestablishing FSH sensitivity.

24. Physiological function of myo-inositol
• It is a precursor of D-chiroinositol. Myo-inositol (MI) is
converted to DCI in cell by an insulin-dependent
epimerase (an enzymatic reaction).
• Both MI and DCI show an insulin-like action. The inositol
phosphoglycans (IPGs) are mediators of insulin action
for glucose uptake and use. IPGs are mediators in a
nonclassic insulin signaling .
• Both MI and DCI increases the physiological insulin-
receptor activity and reduce glucose levels in serum.
Contd..

26. Inositol is a six-carbon polyol - insulin
sensitizer
Belongs to the vitamin B complex
Epimerization of the six hydroxyl-groups of inositol
Belongs to the vitamin B complex
Nine stereoisomers
Myo-inositol (MI)
D-chiro-inositol (DCI)
Myoinositol

27. • Provides a level I a evidence of MYO effectiveness.
• MYO mechanism of action mainly based on improving
insulin sensitivity of target tissues
• MYO restores ovulation & improves oocyte quality.
• MYO reduces hyperandrogenism and dyslipidemia.
Gynecological Endocrinology, 2012; 1–7
Effects of myo-inositol in women with PCOS: a
systematic review of randomized controlled
trials

28. Myo-inositol
• MI and DCI have similar role in improving insulin
sensitivity.
But MI has following action at ovarian level also:
– MI is involved in process of oocyte maturation.
– MI is responsible of glucose cell uptake, it improves
energy status in ovary
Contd..

29.  PCOS patients in group 1 (n = 98) were
given 4 g MYO and 400 μg folic acid before
and during ovulation induction. The
patients undergone controlled ovarian
hyperstimulation (COH) with recombinant
FSH and IUI.
 The patients in group 2 (n = 98), were given
recombinant FSH directly and 400 μg folic
acid.
 Total rFSH dose and cycle duration were
significantly lower and clinical pregnancy
rates were higher in group 1.The
pregnancy rate for group 1 was %18.6 and
for group 2 was %12.2.
Conclusıons: This study
shows that MYO should be
considered in the treatment
of infertile PCOS patients.
MYO administration
increases clinical pregnancy
rates, lowers total rFSH dose
and the duration of the
ovulation induction.
Gynecol Endocrinol. 2017 Jul;33(7):524-528
Myo-inositol administration positively effects ovulation induction and
intrauterine insemination in patients with polycystic ovary syndrome: a
prospective, controlled, randomized trial

30. Myo-inositol also represents an
improvement in IVF protocols for
Patients with PCOS.
Hormone Molecular Biology and Clinical Investigation. 2018; 20170067
• 70% of the women had a restored
ovulation, and 545 pregnancies
were observed.
• a pregnancy rate of 15.1% of all
the myo-inositol and folic acid
users
 In an open, prospective, non-blinded,
non-comparative observational study,
3602 infertile women used myo-inositol
and folic acid between 2 and 3 months
in a dosage of 2 × 2000 mg myo-inositol
+2 × 200 μg folic acid per day.
 In the second part of this trial it was
investigated if the combination of myo-
inositol + folic acid was able to improve
the oocyte quality, the ratio between
follicles and retrieved oocytes, the
fertilization rate and the embryo quality
in PCOS patients undergoing IVF
treatments
Management of women with PCOS using myo-inositol and folic acid. New
clinical data and review of the literature

31. D-Chiro-insitol
• An action on liver, aimed at reducing
insulinemic levels.
• Administration of D-Chiro-inositol has been
demonstrated to improve glucose tolerance,
decrease serum androgens & improve ovulation
in PCOS patients.
(J Pediatr. Endocrinol Metab.
2000;13Suppl 5:1295-8
(New Engl J Med.1999;340:1314-20)

32. • Type II diabetics show decreased DCI-IPG and
total DCI in skeletal muscle.
• Insulin sensitivity in women with PCOS may be
due in part to a defect in the conversion of myo-
inositol to d-chiro-inositol, limiting tissue
availability.
• Oral DCI administration improves insulin
sensitivity, ovulation, and serum androgen levels
in both obese and lean women with PCOS.

33. D-chiro-inositol supplementation showed a marked
reduction in hyperandrogenism
It also shares most of the clinical effects of Myoinositol
Combined administration of MI and DCI in physiological plasma
ratio (40:1) works better than each administered alone
Gynaecol Endocrinol. 2014; 30(3):205-208

34. The supplementation of inositol improves the oocytes
quality and increases the number of oocytes

35. The use of coenzyme Q10 and DHEA during IUI and IVF
cycles in patients with decreased ovarian reserve.
• The objective of this study is to compare the combination of
dehydroepiandrosterone (DHEA) and coenzyme Q10 (CoQ10) (D + C) with DHEA
alone (D) in intrauterine insemination (IUI) and in vitro fertilization (IVF) cycles
among patients with decreased ovarian reserve
• Three hundred and thirty IUI cycles involved D + C compared with 467 cycles of D;
78 IVF cycles involved D + C and 175 D.
• In both IUI and IVF, AFC was higher with D + C compared with D (7.4 ± 5.7 versus
5.9 ± 4.7, 8.2 ± 6.3 versus 5.2 ± 5, respectively, p < 0.05). D + C resulted in a more
follicles > 16 mm during IUI cycles (3.3 ± 2.3 versus 2.9 ± 2.2, respectively, p = 0.01),
while lower mean total gonadotropin dosage was administered after D + C
supplementation compared with D (3414 ± 1141 IUs versus 3877 ± 1143 IUs
respectively, p = 0.032) in IVF cycles.
• Pregnancy and delivery rates were similar for both IUI and IVF.
Gynecol Endocrinol. 2016 Jul;32(7):534-7
D + C significantly increases AFC and improves ovarian
responsiveness during IUI and IVF without a difference in clinical
outcome.

36. N-acetyl- cysteine
NAC maybe the treatment for the improvement of insulin circulating levels
and insulin sensitivity in hyperinsulinemic patients

37. NAC may have beneficial effect on endometrial thickness

38. Potent antioxidant
Works in conjunction with NAC as a
reducing agent to prevent glutathione from
becoming oxidized
Lowers TNF alpha and triglyceride
Increases LDL
Improves insulin sensitivity
R- lipoic acid

39. Research shows a clear link between
chromium and glucose metabolism
Significantly improved glycemia among
patients with diabetes.
Reduce insulin resistance and to help reduce
the risk of cardiovascular disease and type 2
diabetes.
Chromium

41. Vitamin D Deficiency common in PCOS patients and
low levels linked to insulin resistance
It lowers :
TNF-alpha
C-Reactive Protein
MMP-9 and MMP-2
Vitamin D

42. Vitamin D has an important role in the pathogenesis of insulin
resistance in PCOS

43. Vitamin C is a Potent antioxidant
Reduces oxidative stress
Proper ratio required to stabilize NAC
Protective effect within the follicle

44. Manganese Reduce hyperglycemia when taken
with DCI
Calcium Improves insulin sensitivity; may help
weight loss
Magnesium Strong link between Mg
deficiency and insulin resistance; improves
diabetic hyperinsulinemia; decreases systemic
inflammation
Mangenese, Biotin , Magnesium

45. Biotin May improve glucose tolerance and insulin
sensitivity; may lower triglycerides
Choline Essential nutrient; precursor to
acetylcholine; may help regulate homo-cysteine
levels

46. Bromocriptine
• Majority of the PCOS patients (17-43%) are
hyperprolactinemic
• Bromocriptine induces ovulation in these
patients by reducing serum prolactin level.
• It also induces ovulation in some anovulatory
patients with occult /transient
hyperprolactinemia.
J Clin Diagn Res. Nov 2013; 7(11): 2541–2543

47. Micronutrients
Green tea Diabetes Metab J. Jun
2013; 37(3): 173–175
Has positive effect on
glucose metabolism
Zinc Hum. Reprod. Update
2007 13 (2): 163-174
Plays an important role in
ovulation
Vitamin B12, folic acid
pyridoxine
J NTR Univ Health Sci
2012;1:139-47
Reduces homocysteine
levels ,which if raised can
lead to defective
ovulation
Chasteberry International Journal of
Toxicological and
Pharmac ological
Research 2013-14;
5(4):109-120
Used to treat hormonal
imbalances in women
because it has an
immediate effect on
pituitory gland