dhea jdr

DHEA &

FEMALE INFERTILITY

Dr.Sanjay MakwanaVasundhara Hospital & Fertility Centre

Jodhpur 342003www.vasundharafertility.com

OVERVIEW

• How Does Age affect Fertility?

• How can the Ovarian reserve be Assessed?

• How does DHEA improve Ovarian reserve?

Is Infertility Affected by Age?

YES!!

15 - 20% of all couples will experience difficulties with conception, but this increases up to 50% at age 35 – 40.

Current trends of marriage and pregnancy

1Maria et al. Ann. N.Y. Acad. Sci. 2008; 1127: 27–30. 2Gianaroli et al. Hum Reprod. 2010;25: 2374–2386. 3Schoolcraft et al. Fertil Steril. 2011 Sep; 96(3):638-40.

Infertile ↑

The Age Factor• A woman's fertility naturally

starts to decline in her late 20's.

• After age 35 a woman's fertility decreases rapidly.

• A woman is born with all the eggs she'll have, and with time, the supply diminishes.

Aging & Fertility• Decline in AFC• Reduced cohort size• Decreased oocyte quality &

potential fertility• Altered feedback

– Reduced inhibin B– Steady rise in FSH– Gradually declining AMH

Miscarriages due to AneuploidyF. J. Broekmans et al., 2009

Outcome of IVF in Women 45Years Older

• 30% Cancellation Rate • Overall PR 21.1% Per Retrieval• 85.3% Experienced a Pregnancy Loss• Overall Delivery Rate Was 3.1%

Steven D. Spandorfer, Zev Rosenwaks, Jan 2007

Ovarian reserve

What is ovarian reserve?

Describe a woman’s reproductive potential with respect to ovarian follicle number and oocyte quality

1Gianaroli et al. Hum Reprod. 2010;25: 2374–2386.

Non growing follicles (NGF) Growing follicles (GF)

Total Ovarian ReserveThis is so called

Ovarian Reserve (or FOR)

TOR decreases with time : continuous follicle recruitment

%

Quantity and quality of follicles

Broekmans et al: Endocrine Reviews, August 2009, 30(5):465–493

Reproductive period:Around 400

ovulate

Decreasing ovarian pool with age

Decreased ovarian reserve

Definition: if the follicle pool, at any given age, is smaller than

expected

In 2009: DOR was the second most common diagnosis among

infertility patients undergoing IVF in the USA (15%; SART-CORS, 2009).

One of the least well characterised etiologies of infertility

Also encountered in young women

Factors affecting ovarian reserve

How to asses ovarian reserve?

Prediction:

Baseline hormonesAntimüllerian hormoneFSHEstradiolInhibin B

Ultrasound parametersAntral follicle countOvarian volume

Dynamic testsClomiphene citrate challenge test (CCCT)

Baseline hormonesAntimüllerian hormoneFSHEstradiolInhibin B

Ultrasound parametersAntral follicle countOvarian volume

Dynamic testsClomiphene citrate challenge test (CCCT)

•Any day of the cycle•No inter-cycle variation•Low fertility: <2.2 ng/ml

•Measured using trans vaginal Us on day 3•Normal: 15-30 follicles•DOR: <6follicles

Day 3 FSH level FSH interpretation

<10 Normal FSH level. Expect a good response to ovarian stimulation.

10 - 12 Borderline FSH. Response to stimulation is somewhat reduced.

13- 15 Elevated FSH. Reduced ovarian reserve. Reduced response to stimulation.

16 - 20 Markedly elevated FSH. Marked reduction in response to stimulation

> 20 Very poor (or no) response to stimulation.

Follicle Stimulating Hormone (FSH)

Anti-Mullerian Hormone (AMH)• AMH is a glycoprotein • Appears in females at puberty• Produced by granulosa cells of pre-antral and small antral follicles• Not cycle dependant-can be measured any day• Less cycle to cycle variation than FSH• Nor effected by GnRH agonists- can

measure during downregulation• BUT expensive

AMH Level ng/ml Interpretation Expected Response to FSH

Anticipated Cancellation Rate with IVF

Anticipated Pregnancy Rate with IVF

>3.0 High, often PCOS

Very High Low Normal

1.0-3.0 Normal Good Low Normal

0.4-0.9 Low Reduced Increased Reduced

<0.4 Very Low Very Poor Very High Very Low

AMH and Ovarian Aging

Antral Follicle Count (AFC)

• Follicles 2 to 5mm on Day 1 or 2

• Inter-observer variation

• If AFC < 5- significantly worse outcome

P O R Definition

In general Failure to respond adequately to standard protocols and to

recruitadequate follicles is called ‘poor ovarian response’

Criteria by ESHRE working group (at least 2 should be present)

(i) Advanced maternal age or any other risk factor for poor ovarian response (POR)

(ii) A previous POR

(iii) An abnormal ovarian reserve test (ORT)

ESHRE: European Society of Human Reproduction and Embryology

Prevalence and outcomes

Varies between 9 and 24%

Successful pregnancy rate in these patients is as low as 2-4%

Keay SD et al. Br. J Obstet. Gynecol., 104, 521-527

↓ oocyte production

Cycle cancellation

A significantly diminished probability of pregnancy

Classification of low responders

Poor responders

Infections

DOR

Premature ovarian failure

Can be seen in reproductive age

Characterized by amenorrhea or oligomenorrhia with hyper gonadotropic and hypo estrogenic hormonal changes

Affects 1%–5% of women

Causes: genetic, iatrogenic, viral and autoimmune disease

Success rate- only 6%

How to Improve Ovarian Reserve??

Challenges in management

Older ovaries have few antral follicles, high rates of atresia, and ↑ “resistanc

e” to OI

Despite various predictive tests - poor responder revealed definitively only

during ovarian stimulation

Need for a drug which acts in the preliminary stages of follicle development

and can avoid the first cycle failure itself

LH

PROGESTERONE

+Androgen

OogenesisGaps in treatment

FSH

HCG

Role of androgens in follicle maturation

Androgens affect follicle maturation at very early stages

DHEA

DHEA concentration wrt. age

Stimulate granulosa cells

High concentration of androgen receptors in pre-antral and antral stage

•Follicular maturation•Steroidogenesis

Role of androgens in follicular maturation

DHEA TO IMPROVE OVARIAN FUNCTIONDHEA TO IMPROVE OVARIAN FUNCTION

Reprod Biomed Online. 2009 Oct;19(4):508-13.

Who require DHEA?

• Women with

– Physiological ovarian ageing ( all above age 40 )

– Premature ovarian ageing( Below the age of 38)

DEHYDRO EPIANDROSTERONE (DHEA)

Physiological Ovarian Ageing

• All women above age of 40 with decreased fertility

• Poor ovarian reserve due to age


Premature ovarian ageing

• Function of the ovary is impaired

• FSH level above 95 % tile

• AMH below 95 %tile for her age


PREMATURE OVARIAN AGEINGTESTOSTERONE EVALUATED

• UPPER 1/3 OF NORMAL

• NO DHEA

• LOW 2/3 OF NORMAL

• DHEA GIVEN


• AMH increases in parallel with length of DHEA supplementation

• This increase is more pronounced in younger POF than older DOR patients

• Improvement in AMH levels predicts pregnancy success. Gleicher et al, rep.biomed online 2010.,

Reduces IVF cancellation ratesReduces IVF cancellation rates•DHEA supplementation shows increase in IGF1

concentrations to potentiate gonadotrophin action in women with diminished ovarian reserves

•Increase in average embryo scores per oocyte in IVF cycle outcomes and reduces IVF cancellation rates

•DHEA supplementation facilitates gonadotrophins effect, it also reduces the dose of gonadotrophins in IVF cycles

Human reproductions sep 2006

Hum Reprod. 2010 Oct;25(10):2496-500. Epub 2010 Aug 21.

Hum Reprod. 2000 Oct;15(10):2129-32.

Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF

(Ref. 1 Human Reproduction 2006; 21: 2845-2849

Reduces miscarriage ratesReduces miscarriage rates•DHEA supplementation has shown to have

progestogenic effects in women with age related poor ovarian function to support conception and prevent miscarriages

•DHEA augument gonadotrophin secretion augment HCG secretion to support corpus luteum for production of progesterone to support pregnancy

•Overall reduces miscarriages and improve cumulative pregnancy outcome

Fertility and sterility sep 2006

Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation

Ref. 1 Reproductive Biology and Endocrinology 2009, 7:108 )

Effect on pregnancy rate and speed of conception

Control gp : 101 patients selected for IVF

Study gp : 88 women with poor ovarian reserve evidenced by inadequately poor response to OI

Had IVF (microdose agonist/gn max 450-600IU

Outcome –cumulative preg rate of 11 % IVF cancellation rate 26 % Miscarriages 44%

DHEA 25mg TID for 3.7± 0.3 months

62 had IVF, 9 had atleast one prior OI, 17 missed

Fertility and sterility vol 86,suppl 2, sep 2006

Conclusion : DHEA supplementation in women with diminished ovarian reserve, independent of age, leads to increased, and more rapid, conception rates

Outcome – Cumulative preg rate of 27% IVF cancellation rate of 10% Miscarriages 24%

REPORTED REPRODUCTIVE BENEFITSImproves egg/embryo numbers & quality

Spontaneous pregnancies

High IVF pregnancy rates

Shortens time to conceive

Cumulative pregnancy rates increases Barad et al,j Assist.rep. Genet 2007


DOSAGE FOR USE IN INFERTILITY • Administration of DHEA for 2 months

80µg/day increased the level of DHEA to 544+/- 55µg

• Administration of DHEA ,four months prior to IVF cycles increases the response of the ovaries to gonadotrophin treatment and also improves the overall outcome

Fertility and sterility sep 2005


Dosage- 25 mg three times a day

- Stay with DHEA till pregnancy

- Stop after pregnancy is confirmed

Is there a role in PCOS ?• All patients with PCOS have increased senstivity to androgens upto 70% have elevated androgen levels and other 30% are in the high normal range

• Hence initial conversion of DHEA to androgens does not favour its usein treatment of PCOS

ROLE IN PCOs

Poorly responding PCOS

Where testosterone is decreased

Better response with DHEA


Conclusions

• Age is the main determinant of success of infertility treatments

• AMH is the most promising method of assessing ovarian reserve

• DHEA acts by Rejuvenating Ovarian Environment in women with DOR and POA

• It significantly improves pregnancy rates in IVF• It decreases miscarriages and pregnancy losses

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