NONHORMONAL DRUGS FOR MALE INFERTILITY BY DR SHASHWAT JANI

1. Dr. Shashwat Jani.
M. S. ( Obs – Gyn ), F.I.A.O.G.
Diploma in Advance Laparoscopy,
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : +91 99099 44160.
E-mail : drshashwatjani@gmail.com

2. Why Non Hormonal ???
The nonhormonal medical treatment
has a relevant role in male infertility since
it may solve the cause of infertility,
whereas in some other times it may
ameliorate sperm parameters by improving
the environment where spermatozoa are
produced and mature.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
2

3. Aside from endocrine causes, three
often coexisting conditions interfering with
the reproductive function may require
nonhormonal treatment:
1. Infection
2. Inflammation
3. Increased Oxidative Stress
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
3

4. Infection
• A nonempirical treatment for infertility due
to urogenital tract infections has been based
on the use of specific antibiotics, following
identification of the microorganisms by
appropriate microbiological investigation and
the relative antibiogram.
• We can distinguish the presence of
microorganisms, therefore, as microbial or
inflammatory forms.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
4

5. Causative Organisms
• Gram-negative bacteria (Enterobacteriaceae such as Escherichia
coli, Klebsiella species, Proteus, Serratia, and Pseudomonas species)
and etiological agents of sexually transmitted diseases (Chlamydia
trachomatis, Ureaplasma urealyticum, Treponema pallidum, Neisseria
gonorrhoeae, etc.) are recognized as “certain pathogens” of the
prostate.
• On the other hand, some microorganisms of the prostate, which
are occasionally detectable in the urogenital tract, are considered by
some authors to be “nonpathogenic,” “likely pathogens,” “occasional
pathogens” (Gram-positive germs, such as Enterococcus spp.,
Staphylococcus aureus, and obligate anaerobes), or “possible
pathogens” (coagulasenegative germs, such as Staphylococcus
haemolyticus, Staphylococcus epidermidis, and mycoplasmas).
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
5

6. Quinolones are considered a first-line therapy.
Cipro & Levo are common.
Trimethoprim is active against many relevant
pathogens ( 2nd Line Therapy ).
Tetracyclines have good activity against
Chlamydia trachomatis and Mycoplasma .
Doxycycline is administered at the dose of
100mg once or twice/day for 28 days.
Recently, an elevated frequency of HPV infection
in patients with infertility , as a viral form,
cannot rely on antibiotic treatment.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
6

7.  The most frequently used families of
antimicrobial drugs for the treatment of the
microbial forms are fluoroquinolones, macrolides,
and tetracyclines.
 Higher eradication rates (>90%) have been
reported with azithromycin and levofloxacin either
alone, in combination, or sequentially, depending
upon the infection site (urethral, prostatic, or both)
in patients with chronic bacterial prostatitis by
Chlamydia trachomatis infection.
 Cephalosporins, monobactams, and
carbapenems have a limited use in male infertility.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
7

8. Many studies and researches have
proved that there is a strong positive
relationship between Micronutrients &
Male fertility.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
8

9. In order to examine the association
between micronutrients and infertility,
articles with case-control, descriptive,
cohort, and interventional (clinical trials)
design, published between 1984 and 2014,
were accessed through PubMed and
Embase databases, using keywords such as
“micronutrients “ , "oxidative stress",
"antioxidant", "vitamins", "minerals", and
"infertility“….
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
9

10. Anti-inflammatory Drugs
 NSAIDs should be considered for the
treatment of the acute forms of male
accessory gland inflammation for symptoms
relief and they should be avoided for chronic
usage (if possible) in patients with infertility.
 Glucocorticoids are employed for the
treatment of infertility when antisperm
antibodies (ASA) are demonstrated.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
10

11. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
11

12.  Infertility affects about 15 – 20 % of
married couples half of which attributed to
male infertility.
 Defective sperm function considered to be
most common cause of male infertility.
 Apart from all the conventional causes of
male infertility , a new & important cause has
been identified as being responsible for
Idiopathic male infertility :
Reactive Oxygen Species ( ROS ).
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
12

13. Causes for Male Infertility
31.7
16.6
9
8.9
8.5
5.8
5
4.2
2.3
1.5
6.5
0 5 10 15 20 25 30 35
Idiopathic
Varicocele
Infection
Hypogonadism
Cryptorchidism
Malformation
Systemic
Immunologic
Tumor
Obstruction
Other
Hum Reprod Update 1999;5(2):120Percent (%)
1330-Jul-18
Dr Shashwat Jani
+91 99099 44160.

14. Idiopathic male Subfertility
 40-75% of cases.
 Most common pathological cause of
Idiopathic Subfertility is –
‘ free radical induced damage to the sperm. ‘
Free radical is defined as…
‘ Oxygen molecule containing one or more
unpaired electrons in atomic or molecular
orbitals.’
1430-Jul-18
Dr Shashwat Jani
+91 99099 44160.

15. R.O.S.
• In a healthy man, a delicate balance
exists between physiological ROS &
Antioxidants in the male reproductive
tract.
• High level of seminal ROS have been
found in 30 – 80 % of infertile men.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
15

16. Biology of ROS
Pathology stems from imbalance between
production and scavenging
Production Degradation
1630-Jul-18
Dr Shashwat Jani
+91 99099 44160.

17. ROS and Male Infertility
Urology. 1996;48(6):835–850.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
17

18. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
18

19. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
19

20. 1) Poor sperm motility
2) Teratozoospermia
3) High number of round cells in semen
4) Increased semen viscosity
5) Poor sperm membrane integrity on hypo osmoler
swelling test
6) Poor fertilization on routine IVF.
7) Poor sperm motility after overnight oocyte
incubation
8) Poor blastocyst development in absence of a clear
female factor.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
20

21. Nutritional Considerations
• Various micronutrients are
associated with male fertility.
• Deficiency of these
micronutrients may result in
infertility.
Nutritional
Factors
Free radical
scavengers
L-Carnitine Lycopene
Coenzyme
Q10
Vitamin C
Zinc Vitamin E
Arginine Glutathione
Vitamin
B12
Selenium
Altern Med Rev. 2000;5(1):28-38.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
21

22. 2230-Jul-18
Dr Shashwat Jani
+91 99099 44160.

23. Nutrition plays vital role in maintaining male fertility:
Involved in the successful maturation of sperm
Provides nutrition for motility of sperm
Improvement in sperm count and motility
Helps in production of sex hormones
Prevents sperm damage
Reduction in sperm DNA fragmentation
Suppression of ROS production
Altern Med Rev. 2000;5(1):28-38.30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
23

24. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
24

25. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
25

26. L - Carnitine
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
26

27. Three compartments of the male genital
tract :
• Epididymal tissue,
• Seminal plasma, and
• Spermatozoa
Maintain the highest free L-carnitine
concentrations in the body.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
27

28.  The main function of L-Carnitine in the
epididymis is to provide an energetic
substrate for spermatozoa.
 May be involved in the successful
maturation of sperm.
 L-Carnitine is necessary for transport of
fatty acids into the mitochondria to produce
energy.
 Low levels of L-Carnitine reduces fatty
acid concentrations within the mitochondria,
leading to decreased sperm motility
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
28

29. L-Carnitine: Clinical Trials
According to a study conducted by Costa et al. L-carnitine
increased the sperm parameters drastically
10.8
28.4
3.73.1
142.4
18
32.5
4.1
20.3
163.3
0
20
40
60
80
100
120
140
160
180
Baseline At 4 months
Motile spermatozoa (%)
Mean velocity (microns)
Linearity index
Spermatozoa with rapid
linear progression (%)
Number of ejaculated
spermatozoa
Andrologia.1994;26:155-159.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
29

30. L- Carnitine for asthenospermia with
varicocele
Carnitine
Placebo
Zhonghua Nan Ke Xue. 2004;10(9):671–672.
There was significant improvement in sperm count,motility
and pregnancy rates in infertility due to varicocele. 30

31. L- Carnitine in idiopathic asthenozoospermia:
a multicenter study.
Italian Study Group on Carnitine and Male
Infertility.
Andrologia 1994;26:155-159
 N = 100 patients
 L-carnitine - 3 g/day
 Duration - 4 months.
 Percentage of motile spermatozoa increased from 26.9
± 1.1 to 37.7 ± 1.1 %.
 Total number of spermatozoa per ejaculate also
increased
Conclusion - Oral administration of L-Carnitine
improves sperm quality
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
31

32. • Mazzilli et al, established strict correlation
between intrasperm L-carnitine content and sperm
motility survival in bovine cervical mucus. This is
possibly due to the fact that lipids are an important
energy source for sperm in cervical mucus and to
metabolize these lipids intrasperm Lcarnitine is
essential.
• L-carnitine not only helps in lipid metabolism
but also it modulates the reserves of free CoA,
essential for tricarboxylic acid ( TCA ) cycle regulation.
• Therefore, L carnitine content can be considered as an
indicator of sperm motility life span in cervical mucus.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
32

33. Anti Oxidant Property
It is also proposed that carnitine
exerts antioxidant properties as a
result of repairing mechanism by
which elevated intracellular toxic
acetyl-CoA is removed and fatty acids
in membrane phospholipids are
replaced.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
33

34. Co Enzyme Q 10
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
34

35. • In sperm cells, coenzyme Q10 (CoQ10) is concentrated in
the mitochondria.
• Coenzyme Q10 is responsible for energy for
movement and all other energy-dependent processes in the
sperm cell.
• Reduction in levels of CoQ10 is observed in sperm cells
and seminal plasma of idiopathic (IDA) and varicocele-
associated (VARA) asthenozoospermic patients.
• It is observed that sperm cells, characterized by low
motility and abnormal morphology, have low levels of CoQ10.
*Andrologia 34 (2002), 107–111.
Co enzyme Q10 - Mechanism
3530-Jul-18
Dr Shashwat Jani
+91 99099 44160.

36. • Administration of CoQ10
increased the pregnancy rate
by 36% and with
improvement of sperm count
and functional sperm
concentration in 70% and
60% individuals, respectively.
• Sperm motility and sperm
motility index improved in
54% and 46 % while 38 %
showed improvement in
sperm morphology.
Folia Med (Plovdiv).2005;47(1):26–30.
Coenzyme Q10: Clinical Trials
Improvement in sperm motility,
motility Index and
sperm morphology
Sperm
Morphology
Motility
index
Sperm
Motility
3630-Jul-18
Dr Shashwat Jani
+91 99099 44160.

37. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
37

38. Lycopene
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
38

39.  Lycopene is a bright red pigment
and phytochemical found in tomatoes
and other red fruits, water melon &
guava.
 Belongs to a class referred to as
carotenoids which are yellow, orange,
and red pigments synthesized by
plants .
Lycopene
3930-Jul-18
Dr Shashwat Jani
+91 99099 44160.

40. The general mechanism by which
Lycopene works is by preventing
oxidative damage to sperms, which
includes
• Damage to the cell membrane
• DNA molecules
• Lipids
• Proteins
Lycopene has been demonstrated to be the most
potent antioxidant with the ranking: lycopene > α-
tocopherol > α -carotene > β- carotene > lutein.
Lycopene – Biological activity
4030-Jul-18
Dr Shashwat Jani
+91 99099 44160.

41. Lycopene: Clinical Trials
66
53
46
0
10
20
30
40
50
60
70
Improvement
(%)
Sperm
concentration
Motility
Morphology
Lycopene in infertility
Int Urol Nephrol. 2002;34:369–372.
 A Study evaluated the
effect of oral lycopene
therapy in men with
idiopathic Subfertility.
 Lycopene - 2000 mcg,
twice a day for three
months
 N - 30 Patients
4130-Jul-18
Dr Shashwat Jani
+91 99099 44160.

42. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
42

43. Zinc
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
43

44.  Zinc is a micronutrient abundantly present in meat and
seafood and serves as a cofactor for more than 80 enzymes
involved in DNA multiplication and protein synthesis
 Zinc deficiency is associated with decreased
testosterone levels & sperm count.
 Zinc levels are generally lower in infertile men with
diminished sperm count.
 Furthermore, zinc finger proteins are implicated in the
genetic expression of steroid hormone receptors*, and zinc also
has anti-apoptotic ** and antioxidant properties.***
*Endocr Rev 1992 :13,129–145.
**Curr Drug Targets 2003:4,323–338.
***Free Radic Biol Med 31,266–274.
Rev Prat. 1993;43:146-151.
Ann Nutr Metab. 1986;30:213-218.
4430-Jul-18
Dr Shashwat Jani
+91 99099 44160.

45. Effects of zinc supplementation on
subfertility
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
45

46. Zinc – Clinical Trials
 N - 100 men with asthenozoospermia
 Two groups--250 mg twice daily zinc therapy for 3 months
and no therapy.
 Duration – 6 months
 There was significant improvement in the sperm quality;
sperm count, progressive motility, fertilizing capacity.
Conclusion: Zinc therapy has a role in improving sperm
parameters in men with asthenozoospermia
Eur J Obstet Gynecol Reprod Biol. 1998 Aug;79(2):179-84.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
46

47. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
47

48. ARGININE
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
48

49.  Arginine is essential for sperm motility, metabolism,
capacitation, acrosome reaction, and is a precursor for
producing petruscine, spermine, and spermidine.
 According to a study by Schachter et al. Arginine
significant improved sperm count and motility after
taking 4 g/day for three months.
 A recent study conducted in Itali also showed that
arginine is effective in male infertility
 The recommended daily allowance (RDA) is 20 g,
with an upper limit of 30 g.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
49

50. FOLATE
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
50

51.  Adequate folic acid intake is
associated with a decreased frequency
of sperm DNA abnormalities.
 Still its role is controversial.
 The RDA is 400 mg.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
51

52. SELENIUM
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
52

53. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
53
 Selenium and glutathione are essential to the
formation of phospholipid hydro peroxide
glutathione peroxidase.
 Deficiencies of selenium can lead to instability of the
mid-piece, resulting in defective motility
 However, it can be toxic if consumed in excess.
ArchAndrol. 1992;29:65-68. Science
1999;285:1393-1396.
Environ Mol Mutagen. 2009 [Epub ahead of
print]

54. METHYL COBALAMINE
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
54

55. • Vitamin B12 is important in cellular replication,
especially for the synthesis of RNA and DNA, and
deficiency states have been associated with
decreased sperm count and motility.
• Various studies have shown that Methylcobalamine
improves the sperm parameters
• However, studies show that Methylcobalamine is
effective in only just over 20% of infertile men.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
55

56. Vit - E
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
56

57. • Oral supplementation with vitamin E significantly
decreases the malondialdehyde concentration
and improves the sperm motility
• Although Invitro studies have prooved the
efficacy of vitamin E, human studies are lacking
• Although there are few human studies, they
recruited only few patients.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
57

58. To conclude
 Infertile couples are likely to try multiple
Micronutrients hoping to improve their
chances of conception with minimal risk and
cost before proceeding with ART.
 A recent Cochrane review in 2011 did
demonstrate improved pregnancy and live
birth rates with adequate dosages of
Micronutrients.
30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
58

59. 30-Jul-18
Dr Shashwat Jani
+91 99099 44160.
59