Management of poor ovarian reserve- Dr Parul Katiyar

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Management of Poor Ovarian Reserve

Dr Parul Katiyar Senior Consultant, Infertility and Reproductive MedicineMax 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 ThecaNo ability to produce steroids

Primodial

Signals from follicle to recruit Theca cells

Primary

Thecal cells recruited & differentiate; produce LH receptors, steroidogenic enzymes & small amounts of androgens

Preantral

Thecal cells mature & become steroidogenic under LH control amounts of androgens produced converted to estradiol

Antral

Thecal cells luteinizeTransient endocrine glandChange function to produce progesterone

Corpus luteum

Young JM, et al. Reproduction. 2010; 140(4): 489-504.

Formation of Thecal cell layer:Most susceptible to follicular atresia

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 PORS FSH ≤ 12 IU/ml > 12 IU/ ml

S AMH 2-4 ng/ ml < 1 ng/mlAFC ≥ 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

ROS

ROS

Oxidative Stress

Ovary

Mitochondrial activity ATP synthesis

Antioxidant enzyme activity

Chromosomal damage

Accelerate Oocyte Aging & Oocyte

quality

Follicle atresia (apoptosis)

Number of follicles Ovarian Reserve

InfertilityAbortion

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 OR Delayed ovarian follicle loss due to aging

Improves oocyte quality

Improves ovarian response

Significantly no. of ovulated oocytes

Reduces chromosomal abnormalities number of cumulus cells

Improved 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 YouDr Parul Katiyar

[email protected]