dhea
TRANSCRIPT
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
ADDRESS 35 , Defence Enclave, Opp. Preet Vihar Petrol Pump,
Metro pillar no. 88, Vikas Marg , Delhi – 110092
CONTACT US 011-22414049, 42401339
WEBSITE : www.lifecarecentre.in
www.drshardajain.com www.lifecareivf.com
E-MAIL ID
[email protected]@gmail.com
&