dhea

DHEA &

FEMALE INFERTILITY

DR. JYOTI BHASKARMD MRCOG

Director LifeCareIVF

The Story of the Index Patient

• 43 year old infertile women DESPERATELY searches the literature for remedies to

avoid using an egg donor

Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series

P.R. Casson1, M.S. Lindsay,M.D. Pisarska, S.A. Carson and J.E. Buster

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine,6550 Fannin, Suite 801, Houston, Texas 77030, USA

Received February 8, 1999.Accepted June 7, 2000.

OVERVIEW

• How Does Age affect Fertility?

• How can the Ovarian reserve be Assessed?

• How does DHEA improve Ovarian reserve?

YES!!

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

Is Infertility Affected by Age?

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.

Pregnancy Rates Related to A Woman’s Age

Adapted from Hendershot GE, et.al., Infertility and age: an unresolved issue. Family Planning Perspectives. Vol,14;5 (Sept./Oct 1982), p. 288 The Alan Guttmacher Institute.

Woman’s Age (y) % Conceiving in 12 Mo 20-24 86 25-29 78 30-34 63 35-39 52

• 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

Aging & Fertility

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

Age: Miscarriage

• Recognized– Age 30: 7-15%– Age 31-34: 17-21%– Age 35-39: 17-28%– Age 40: 40-52%

• Unrecognized: 60%

Chromosomal Abnormality: Aneuploidy

• Young women 10% eggs are aneuploidic• Age 40: 30% abnormal• Age 43: 50 % abnormal• Age 45: 100% abnormal

How to asses ovarian reserve?

OVARIAN RESERVE TESTS

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

AGE SPECIFIC FSH and AMH LEVELS

Age FSH AMH < 33 Years < 7.0 mIU/mL 2.1 ng/mL

33-37 Years < 7.9 mIU/mL 1.7 ng/mL 38-40 Years < 8.4 mIU/mL 1.1 ng/mL = 41 Years < 8.5 mIU/mL 0.5 ng/mL

Antral Follicle Count (AFC)

• Follicles 2 to 5mm on Day 1 or 2

• Inter-observer variation

• If AFC < 5- significantly worse outcome

Antral Follicle Count

Interpretation Expected Response to FSH

Anticipated Cancellation with IVF

Anticipated Pregnancy Rate with IVF

<4 Very low Very poor Very high Very low

4-6 Low Poor High Low

7-10 Reduced Reduced Increased Decreased

11-30 Normal Good Low Excellent

>30 Above Normal(PCOS)

Increased risk of hyperstimulation

Low Good

Antral Follicle Count (AFC)

How to Improve Ovarian Reserve??

THE FOUNTAIN OF YOUTH

Decline of DHEA with aging

Acetyl-CoA Cholesterol Pregnenolone DHEA DHEA-S

DHEA conversions in adrenals, ovaries, testes, skin, bone, brain

Studies on DHEAFertil Steril 2005;84(3):756.

This was the first case report on the effects of DHEA on oocyte production. Describing the stunning increase in oocyte production after supplementation with DHEA in a 42-year-old patient with severe DOR, the report (correctly, as it turned out,) speculated that "ovarian function may be salvaged, even in women of advanced reproductive age."

Hum Reprod 2006;21(11):2845-9.

In this case-control study, 25 patients underwent IVF cycles both before and after supplementation with DHEA. After DHEA treatment, patients had more oocytes that fertilized and more normal embryos on day-3. More embryos were transferred, and average embryo grade were significantly higher (better), confirming the earlier hypothesis that DHEA supplementation may have beneficial effects on the ovarian functions of women with DOR.

J Assist Reprod Genet 2007;24(12):629-34.

In this case-control study, 190 women with DOR were divided into DHEA-supplemented group and control group. Women who received DHEA supplementation had more than double the pregnancy rates of women without DHEA (28.4%, compared to 11.9%).

CHR's Published Research on DHEA and Ovarian Reserve

Reprod Biol Endocrinol 2011;17(9):67.An extensive and detailed review of current best available evidence in this study confirmed that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. Based on the improvement of oocyte/embryo quality after DHEA, this study introduced a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. The study also suggested that DHEA may be the first pharmacological agent that beneficially affects aging ovarian environments.

Reprod Biol Endocrinol 2011;9(1):116.Broadening the scope beyond human fertility and into published animal data, this extensive review of literature theorized that androgens, including DHEA, may play an essential role in the maturation of oocyte-containing follicles. At certain therapeutic concentrations, DHEA and other androgens may be capable of improving the early stages of folliculogenesis. The study presented the possibility that androgens like DHEA may be forerunners of a completely new class of ovulation-inducing medications that affect much earlier stages of follicle maturation than gonadotropins.

Hum Reprod 2011;26(7):1905-9.

This study, published with Dr. Weghofer, CHR's affiliate in Austria, as lead author, showed that DHEA-supplemented women can conceive at reasonable rates even with the most severe forms of DOR, including undetectable levels of anti-Müllerian hormone (AMH). Similarly, moderate but still reasonable live birth rates were possible with DHEA supplementation.

Studies on DHEA

Tel Aviv Study 2010

• A study conducted by Adrian Shulman, MD and co-workers of Tel Aviv University in Tel Aviv, Israel

• 33 women, 17 on DHEA and 16 controls• Represents the first prospectively randomized study

of DHEA in infertility. • "In the DHEA group, there was a 23% live birth rate as

opposed to a 4% rate in the control group

Beneficial Effects of DHEA

• increased egg and embryo counts and quality

• increased chromosomally normal embryos

• Increased number of embryos for transfer in IVF treatments

• Accelerated time to pregnancy in fertility treatment

• Increased spontaneously conceived pregnancies

How DHEA Acts?

Growth Phase

Gonadotrophin dependent phase of

growth

• Act before , during or after the recruitment phase

Increases AMH Levels

Increases Ovarian Reserve

Increases Pregnancy Rates

DHEA prevents Granulosa cells apoptosis

DHEA increases FSH receptors

Increases recruitable oocyte pool

How DHEA acts??

EVIDENCE BASED STUDIES

• Improve oocytes yields via IGF-1• They promote preantral follicle growth by Granulosa

cell - specific androgen receptors • Preventing follicular atresia• Synergistic effect between DHEA and gonadotropins

“Rejuvenate” Ovarian Environment

Ovarian environments, but not resting oocytes, that age as women grow older

DHEA, and other pharmaceuticals rejuvenate ovarian environments, in normally fertile, older women

Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)Norbert Gleicher and David H Barad Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67

• Like supplementation with folic acid to prevent neural tube defects

• Supplementation with DHEA may achieve favourable public health consequences by potentially reducing aneuploidy and spontaneous pregnancy losses in a general population.

Pregnancy loss after DHEA supplementation was reduced by 50 to 80 percent

Indications – Since Jan 2007

• All women above age 40 have been offered routine supplementation

• Younger women, under age 40, are continuing to be only selectively supplemented

1. if demonstrating elevated age-specific baseline follicle stimulating hormone (FSH) levels2. Inappropriately low oocyte yield in at least one IVF

cycle

CENTER OF HUMAN REPRODUCTION

Clinical Application

• DHEA effects occur relatively quickly (apparently within 2 months) • Peak only after 4-5 months of DHEA supplementation• The beneficial effects of DHEA increased with length of

DHEA supplementation

Dosage

• Oral, pharmaceutical grade micronized medication at a dosage of 25 mg, three times daily (TID)

• Patients receive at least two months of DHEA supplementation prior to oocyte retrieval

• DHEA is maintained until pregnancy, and is discontinued with second positive pregnancy test.

Safety and Toxicity

• Despite being a steroid hormone, DHEA appears to be relatively safe if given at normal physiological doses

• Few side effects noted - breast tenderness, - reversible hirsutism in women

- mild to moderate acne due to sebaceous secretion

Side Benefits

• Improved overall feeling• Feeling of being physically stronger• Improved sex drive• Feeling of being mentally sharper• Feeling of better memory

OUR EXPERIENCE• 2012

• Selected patients – DOR and POA

• Minimum of 2 months before IUI or IVF

• One patient conceived spontaneously while being worked up or IVF

• AMH has improved in 2 patients

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

• One third of all IVF centre around the world are using DHEA in their IVF protocols

• It should be used discriminately in carefully selected patients --- DOR AND POA

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