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Management of Poor Ovarian Reserve
Dr Parul Katiyar
Senior Consultant, Infertility and Reproductive Medicine
Max Hospitals, New Delhi and Gurgaon
Infertility around the world
Complex disorder, estimated to affect as many as 186 million
people worldwide, with significant influence on medical,
psychosocial & economic aspects
At any point in time ≈ 9% couples are expected to be facing some
kind of fertility related issues
Though frequency & origin of different forms of infertility differs,
approximately 40%-50% of all cases involved female factors
Inhorn MC, et al. Hum Reprod Update. 2015 Mar 22/ Connolly MP, et al. Human Reproduction Update. 2010; 16(6): 603–613.
Bhattacharya S, et al. Clinical Evidence. 2010; 11: 819-871.
Increasing incidence of Female Infertility
Crawford NM, et al. Obstet Gynecol Clin North Am. 2015; 42(1): 15-25.
%
Between years 1970 & 2002, the incidence of first child birth in
women over 30 years of age increased by six folds
Folliculogenesis
No Theca
No ability
to produce
steroids
No Theca
No ability
to produce
steroids
PrimodialPrimodial
Signals
from follicle
to recruit
Theca cells
Signals
from follicle
to recruit
Theca cells
PrimaryPrimary
Thecal cells
recruited &
differentiate;
produce LH
receptors,
steroidogenic
enzymes &
small amounts
of androgens
Thecal cells
recruited &
differentiate;
produce LH
receptors,
steroidogenic
enzymes &
small amounts
of androgens
PreantralPreantral
Thecal cells
mature &
become
steroidogenic
under LH control
↑ amounts of
androgens
produced
converted to
estradiol
Thecal cells
mature &
become
steroidogenic
under LH control
↑ amounts of
androgens
produced
converted to
estradiol
AntralAntral
Thecal cells
luteinize
Transient
endocrine
gland
Change
function to
produce
progesterone
Thecal cells
luteinize
Transient
endocrine
gland
Change
function to
produce
progesterone
Corpus
luteum
Corpus
luteum
Young JM, et al. Reproduction. 2010; 140(4): 489-504.
Formation of Thecal cell layer:
Most susceptible to follicular atresia
Formation of Thecal cell layer:
Most susceptible to follicular atresia
Androgens
affect follicle
maturation at
very early
stages
Androgens
affect follicle
maturation at
very early
stages
Gleicher N, et al. Reproductive Biology and Endocrinology 2011, 9:116.
Role of androgens in follicular maturation
 A term often used to describe a woman’s
reproductive capacity
 An inadequately defined term
 What we measure reflects only a small
component of total ovarian reserve (TOR)
What is Ovarian Reserve?
 No accurate tools available
 The best available test gives an estimation of
already recruited pool of follicles – It does not
measure the primordial follicular pool
 The commonly available measures of Ovarian
Reserve include-
 S FSH
 S AMH
 USG – Antral Follicular Count (AFC)
How to measure Ovarian Reserve
 Also referred to as Premature Ovarian Aging
 ~ 10% women, who deviate from age specific
standard
Measure Normal POR
S FSH ≤ 12 IU/ml > 12 IU/ ml
S AMH 2-4 ng/ ml < 1 ng/ml
AFC ≥ 10 < 5
What is Poor Ovarian Reserve (POR)
%
Broekmans et al: Endocrine Reviews, August 2009, 30(5):465–493
Quantity and Quality of follicles
Faddy MJ. Mol Cell Endocrinol. 2000; 163(1-2): 43-8/ Oudendijk JF, et al. Hum Reprod Update. 2012; 18(1): 1-11/ Gliecher N, et al.
Reproductive Biology and Endocrinology. 2011, 9:23.
POR leads to poor outcome of pregnancy mainly because of
two factors-
•Decreased level of intra-ovarian androgens
•Oxidative stress due to Reactive Oxidative Species (ROS)
Correlation between POR and outcome of pregnancy
Free Radicals function in microenvironments of oocytes & in follicular fluid
Changes in these microenvironments directly impact → follicular
development, ovulation, quality of oocytes, sperm–oocyte interaction,
implantation & early embryonic development
Tamura H, et al. Fertil Steril. 2009; 92: 328–343.
Oxidative Stress affect fertility!
Physical & Chemical
stimulation by aging
Ovulation process
ROSROS
ROSROS
Oxidative
Stress ↑
Oxidative
Stress ↑
OvaryOvary
Mitochondrial activity ↓
ATP synthesis ↓
Antioxidant enzyme activity
↓
Chromosomal damage ↑
Accelerate Oocyte
Aging & Oocyte
quality ↓
Accelerate Oocyte
Aging & Oocyte
quality ↓
Follicle atresia
(apoptosis)
Number of follicles ↓
Ovarian Reserve ↓
Infertility
Abortion
DNA abnormality
Jinno M, et al. Anti-Aging Medicine. 2012; 9 (1) : 6-13.
Oxidative Species - Damage Oocyte
 Lifestyle Modification
 Quit smoking
 Stop alcohol intake
 Manage weight
 Antioxidants
 Melatonin
 Vitamin C & E supplements
 Coenzyme Q10
 DHEA
Management of Oxidative Stress
Tamura H, et al. Endocrine Journal. 2013; 60 (1): 1-13.
Protects granulosa cells undergoing
luteinization from ROS in follicle
SOD: superoxide dismutase, GPx: glutathione peroxidase, CAT: catalase, GSH: glutathione , H2O2: hydrogen
peroxide, HOCL: hypochlorous acid
Role of Melatonin in ROS induced Infertility
Tamura H, et al. Journal of Ovarian Research. 2012; 5:5.
• Broad spectrum antioxidant,
synthesized in pineal gland
• Most important antioxidant in
ovarian follicle
• Does not promote oxidation under
any circumstances
• Its metabolites are also capable
anti-oxidants
• Enhances activity of other
endogenous antioxidants like
glutathione peroxidase &
superoxide dismutase
• Synergy with other antioxidants
such as Vitamins C & S
Fernando S, et al. J Ovarian Res. 2014 Oct 21;7(1):98/
http://www.anti-aging.gr.jp/english/pdf/2012/9(1)0613.pdf
Melatonin and Ooycte Maturation
How does Melatonin help in Oxidative Stress?
Stimulates
maturation-
inducing
hormone
↓ intrafollicular
oxidative damage
during
maturation
Influences sex steroid
production at
different stages of
ovarian follicular
maturation
Chattoraj A, et al. Gen Comp Endocrinol. 2005; 140: 145–55/ Reiter RJ, et al. Biol Reprod. 2009; 81(3): 445-56.
Melatonin: Enhances oocyte maturation
Fernando S, et al. Journal of Ovarian Research. 2014; 7: 98.
What does the evidence say?
Fernando S, et al. Journal of Ovarian Research. 2014; 7: 98.
What does the evidence say?
 A meta analysis of RCT’s studying role of
Melatonin supplementation during COS for
women undergoing ART found that
 Melatonin supplementation doesn’t reduce the chance
of clinical pregnancy
 Melatonin supplementation doesn’t reduce the no of
Oocytes retrieved
 There was no conclusive evidence that Melatonin
supplementation improves outcome of pregnancy
 Further RCT’s and meta analyses are required for
clear evidence
Ludimila et al. Fertil Steril. 2014; 101: 154-61.
What does the evidence say?
Bentov Y, et al. Fertil Steril. 2013; 99: 18-22/ Bentov Y, et al. Clinical Medicine Insights: Reproductive Heath. 2014; 8: 31-36.
Coenzyme Q10: Effects
CoQ10: Other Effects
Ben-Meir A, et al. Fertil Steril. 2011; 96 (3): Supp. 106.
Improved ORImproved OR Delayed ovarian follicle loss
due to aging
Delayed ovarian follicle loss
due to aging
Improves oocyte
quality
Improves oocyte
quality
Improves ovarian
response
Improves ovarian
response
Significantly ↑ no. of
ovulated oocytes
Significantly ↑ no. of
ovulated oocytes
Reduces chromosomal
abnormalities
Reduces chromosomal
abnormalities ↑ number of cumulus cells↑ number of cumulus cells
Improved ovulation rateImproved ovulation rate
DHEA represents the first compound in a new category of pharmacologic
agents with potential to “rejuvenate” ovarian environments
• DHEA = Dihydroepiandrosterone
• Most abundant circulating steroid in
humans
• Secreted by adrenal glands, testes &
ovaries
• Synthesized from cholesterol
• Can be converted into other
hormones- Estrogen & testosterone
• Levels of DHEA in women decline
with age
DHEA - Adjunctive therapy in treatment of Infertility
Poor oocyte
quality
IGF-1
Stimulation of
•Mitosis
•Steroid production by granulosa
and theca cells
Normal oocyte
maturation
DHEA
Role of DHEA in follicular maturation
Sonmezer M, et al. Reprod Biomed Online. 2009; 19(4): 508-13.
DHEA – Mechanism of Action
• DHEA supplementation - 75mg/ d for at least 4 months - should be
given to women with poor ovarian reserve or premature ovarian
failure
• Improved chances of natural conception
• Considerably improves outcome of IUI and IVF
• Better pregnancy rate and outcome
• Generally Well tolerated
• Safer than other androgens - High levels of other androgens known
to negatively affect oocyte development
Narkwichean A, et al. Reprod Biol Endocrinol. 2013; 11: 44.
DHEA – Evidence for role in clinical practice
Take home points
 Maintenance of female fertility  proper functioning of ovary is important
 Ovarian function depends on maintenance & normal development of ovarian follicles
 Oxidative stress (OS) affects both natural and assisted fertility
 Body weight maintenance, smoking cessation and stopping alcohol abuse help restore
some ovarian functions
 Melatonin, CoQ, DHEA and Vit C & E supplements help preserve/ regain lost ovarian
functions
Thank You
Dr Parul Katiyar
drparulk@gmail.com

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Management of poor ovarian reserve- Dr Parul Katiyar

  • 1. 1 Management of Poor Ovarian Reserve Dr Parul Katiyar Senior Consultant, Infertility and Reproductive Medicine Max Hospitals, New Delhi and Gurgaon
  • 2. Infertility around the world Complex disorder, estimated to affect as many as 186 million people worldwide, with significant influence on medical, psychosocial & economic aspects At any point in time ≈ 9% couples are expected to be facing some kind of fertility related issues Though frequency & origin of different forms of infertility differs, approximately 40%-50% of all cases involved female factors Inhorn MC, et al. Hum Reprod Update. 2015 Mar 22/ Connolly MP, et al. Human Reproduction Update. 2010; 16(6): 603–613. Bhattacharya S, et al. Clinical Evidence. 2010; 11: 819-871.
  • 3. Increasing incidence of Female Infertility Crawford NM, et al. Obstet Gynecol Clin North Am. 2015; 42(1): 15-25. % Between years 1970 & 2002, the incidence of first child birth in women over 30 years of age increased by six folds
  • 4. Folliculogenesis No Theca No ability to produce steroids No Theca No ability to produce steroids PrimodialPrimodial Signals from follicle to recruit Theca cells Signals from follicle to recruit Theca cells PrimaryPrimary Thecal cells recruited & differentiate; produce LH receptors, steroidogenic enzymes & small amounts of androgens Thecal cells recruited & differentiate; produce LH receptors, steroidogenic enzymes & small amounts of androgens PreantralPreantral Thecal cells mature & become steroidogenic under LH control ↑ amounts of androgens produced converted to estradiol Thecal cells mature & become steroidogenic under LH control ↑ amounts of androgens produced converted to estradiol AntralAntral Thecal cells luteinize Transient endocrine gland Change function to produce progesterone Thecal cells luteinize Transient endocrine gland Change function to produce progesterone Corpus luteum Corpus luteum Young JM, et al. Reproduction. 2010; 140(4): 489-504. Formation of Thecal cell layer: Most susceptible to follicular atresia Formation of Thecal cell layer: Most susceptible to follicular atresia
  • 5. Androgens affect follicle maturation at very early stages Androgens affect follicle maturation at very early stages Gleicher N, et al. Reproductive Biology and Endocrinology 2011, 9:116. Role of androgens in follicular maturation
  • 6.  A term often used to describe a woman’s reproductive capacity  An inadequately defined term  What we measure reflects only a small component of total ovarian reserve (TOR) What is Ovarian Reserve?
  • 7.  No accurate tools available  The best available test gives an estimation of already recruited pool of follicles – It does not measure the primordial follicular pool  The commonly available measures of Ovarian Reserve include-  S FSH  S AMH  USG – Antral Follicular Count (AFC) How to measure Ovarian Reserve
  • 8.  Also referred to as Premature Ovarian Aging  ~ 10% women, who deviate from age specific standard Measure Normal POR S FSH ≤ 12 IU/ml > 12 IU/ ml S AMH 2-4 ng/ ml < 1 ng/ml AFC ≥ 10 < 5 What is Poor Ovarian Reserve (POR)
  • 9. % Broekmans et al: Endocrine Reviews, August 2009, 30(5):465–493 Quantity and Quality of follicles
  • 10. Faddy MJ. Mol Cell Endocrinol. 2000; 163(1-2): 43-8/ Oudendijk JF, et al. Hum Reprod Update. 2012; 18(1): 1-11/ Gliecher N, et al. Reproductive Biology and Endocrinology. 2011, 9:23. POR leads to poor outcome of pregnancy mainly because of two factors- •Decreased level of intra-ovarian androgens •Oxidative stress due to Reactive Oxidative Species (ROS) Correlation between POR and outcome of pregnancy
  • 11. Free Radicals function in microenvironments of oocytes & in follicular fluid Changes in these microenvironments directly impact → follicular development, ovulation, quality of oocytes, sperm–oocyte interaction, implantation & early embryonic development Tamura H, et al. Fertil Steril. 2009; 92: 328–343. Oxidative Stress affect fertility!
  • 12. Physical & Chemical stimulation by aging Ovulation process ROSROS ROSROS Oxidative Stress ↑ Oxidative Stress ↑ OvaryOvary Mitochondrial activity ↓ ATP synthesis ↓ Antioxidant enzyme activity ↓ Chromosomal damage ↑ Accelerate Oocyte Aging & Oocyte quality ↓ Accelerate Oocyte Aging & Oocyte quality ↓ Follicle atresia (apoptosis) Number of follicles ↓ Ovarian Reserve ↓ Infertility Abortion DNA abnormality Jinno M, et al. Anti-Aging Medicine. 2012; 9 (1) : 6-13. Oxidative Species - Damage Oocyte
  • 13.  Lifestyle Modification  Quit smoking  Stop alcohol intake  Manage weight  Antioxidants  Melatonin  Vitamin C & E supplements  Coenzyme Q10  DHEA Management of Oxidative Stress
  • 14. Tamura H, et al. Endocrine Journal. 2013; 60 (1): 1-13. Protects granulosa cells undergoing luteinization from ROS in follicle SOD: superoxide dismutase, GPx: glutathione peroxidase, CAT: catalase, GSH: glutathione , H2O2: hydrogen peroxide, HOCL: hypochlorous acid Role of Melatonin in ROS induced Infertility
  • 15. Tamura H, et al. Journal of Ovarian Research. 2012; 5:5. • Broad spectrum antioxidant, synthesized in pineal gland • Most important antioxidant in ovarian follicle • Does not promote oxidation under any circumstances • Its metabolites are also capable anti-oxidants • Enhances activity of other endogenous antioxidants like glutathione peroxidase & superoxide dismutase • Synergy with other antioxidants such as Vitamins C & S Fernando S, et al. J Ovarian Res. 2014 Oct 21;7(1):98/ http://www.anti-aging.gr.jp/english/pdf/2012/9(1)0613.pdf Melatonin and Ooycte Maturation
  • 16. How does Melatonin help in Oxidative Stress?
  • 17. Stimulates maturation- inducing hormone ↓ intrafollicular oxidative damage during maturation Influences sex steroid production at different stages of ovarian follicular maturation Chattoraj A, et al. Gen Comp Endocrinol. 2005; 140: 145–55/ Reiter RJ, et al. Biol Reprod. 2009; 81(3): 445-56. Melatonin: Enhances oocyte maturation
  • 18. Fernando S, et al. Journal of Ovarian Research. 2014; 7: 98. What does the evidence say?
  • 19. Fernando S, et al. Journal of Ovarian Research. 2014; 7: 98. What does the evidence say?
  • 20.  A meta analysis of RCT’s studying role of Melatonin supplementation during COS for women undergoing ART found that  Melatonin supplementation doesn’t reduce the chance of clinical pregnancy  Melatonin supplementation doesn’t reduce the no of Oocytes retrieved  There was no conclusive evidence that Melatonin supplementation improves outcome of pregnancy  Further RCT’s and meta analyses are required for clear evidence Ludimila et al. Fertil Steril. 2014; 101: 154-61. What does the evidence say?
  • 21. Bentov Y, et al. Fertil Steril. 2013; 99: 18-22/ Bentov Y, et al. Clinical Medicine Insights: Reproductive Heath. 2014; 8: 31-36. Coenzyme Q10: Effects
  • 22. CoQ10: Other Effects Ben-Meir A, et al. Fertil Steril. 2011; 96 (3): Supp. 106. Improved ORImproved OR Delayed ovarian follicle loss due to aging Delayed ovarian follicle loss due to aging Improves oocyte quality Improves oocyte quality Improves ovarian response Improves ovarian response Significantly ↑ no. of ovulated oocytes Significantly ↑ no. of ovulated oocytes Reduces chromosomal abnormalities Reduces chromosomal abnormalities ↑ number of cumulus cells↑ number of cumulus cells Improved ovulation rateImproved ovulation rate
  • 23. DHEA represents the first compound in a new category of pharmacologic agents with potential to “rejuvenate” ovarian environments • DHEA = Dihydroepiandrosterone • Most abundant circulating steroid in humans • Secreted by adrenal glands, testes & ovaries • Synthesized from cholesterol • Can be converted into other hormones- Estrogen & testosterone • Levels of DHEA in women decline with age DHEA - Adjunctive therapy in treatment of Infertility
  • 24. Poor oocyte quality IGF-1 Stimulation of •Mitosis •Steroid production by granulosa and theca cells Normal oocyte maturation DHEA Role of DHEA in follicular maturation
  • 25. Sonmezer M, et al. Reprod Biomed Online. 2009; 19(4): 508-13. DHEA – Mechanism of Action
  • 26. • DHEA supplementation - 75mg/ d for at least 4 months - should be given to women with poor ovarian reserve or premature ovarian failure • Improved chances of natural conception • Considerably improves outcome of IUI and IVF • Better pregnancy rate and outcome • Generally Well tolerated • Safer than other androgens - High levels of other androgens known to negatively affect oocyte development Narkwichean A, et al. Reprod Biol Endocrinol. 2013; 11: 44. DHEA – Evidence for role in clinical practice
  • 27. Take home points  Maintenance of female fertility  proper functioning of ovary is important  Ovarian function depends on maintenance & normal development of ovarian follicles  Oxidative stress (OS) affects both natural and assisted fertility  Body weight maintenance, smoking cessation and stopping alcohol abuse help restore some ovarian functions  Melatonin, CoQ, DHEA and Vit C & E supplements help preserve/ regain lost ovarian functions
  • 28. Thank You Dr Parul Katiyar drparulk@gmail.com

Notas do Editor

  1. Fecundability  with  age
  2. The LH surge is a signal from the brain to the ovary that an egg is mature. The brain senses the elevated estrogen levels produced by the maturing egg and releases a burst of luteinizing hormone (LH). When the ovary is bombarded with this burst of LH, the sac-like covering (called the follicle) surrounding the egg thins, allowing the egg to escape.
  3. Androgen on ovary: Quite a paradox?? Role of androgen: Synergism with FSH Acts at early stages of maturation Instead of directly affecting the oocyte, it improves the environment. Get deeper into it later Let us look at the functions of the ovary once.
  4. Dotted line: proportion of poor quality oocyte rising constantly This is the normal decline. Cases of accelerated decline are a major concern. These patients have DOR wiz essentially lower ovarian reserve wrt the age normal at any stage.
  5. Changes in these microenvironments directly impact  follicular development, ovulation, quality of oocytes, sperm–oocyte interaction, implantation &amp; early embryonic development
  6. ROS are produced within follicle, especially during ovulatory process ROS play physiological role in process of ovulation, e.g. follicle rupture. However, excessive amount of ROS cause OS &amp; may damage oocyte and granulosa cells ROS accelerate oocyte aging &amp; deteriorate oocyte quality
  7. Melatonin produced at oocyte &amp; ovarian follicular cells In ovarian follicle: melatonin impacts function of numerous cells, especially granulosa cells &amp; oocyte
  8. ROS produced within follicles, especially during ovulation process, were scavenged by melatonin Reduced OS may be involved in oocyte maturation &amp; embryo development
  9. A woman is born with primordial follicles arrested in prophase 1- FSH- primary follicle – FSH androgen – antral follicle– matured follicle– LH – ruptured follicle– CL- progesterone. In our current strategies of management, we give GnRH, exogenous FSH, HCG for LH and progesterone for endometrial support. What we miss out on is androgens for antral follicle maturation. 1 point before getting deeper into this– Androgen does not give immediate relief. Pre treatment is necessary. Let me take u deeper into the maturing follicle now
  10. To summarize the actions of DHEA:
  11. 2 major actions: steroidogenesis and follicular maturation. Now poor quality oocytes with age is basically because of decreasing oocyte environment and decreasing androgen levels. Supplementing the patient with androgen in the form of DHEA will improve the ovarian environment dramatically. This will act on whatever remaining androgen receptors are present. The action on the granulosa cells is interesting. It acts via its action increasing the level of Insulin like growth factor-1. This in turn stimulates mitosis– proliferation of the granulosa cells and also steroid production by the granulosa cells. This gives normal oocyte maturation and hormonal feedback to optimize the quantity of pituitary FSH. Eventually DHEA helps antagonize the adverse effects age has on the oocyte.
  12. Failure of developmental process of ovarian follicle  destruction of follicle through atresia &amp; oocyte degeneration