After about age 32, a woman's fertility potential gradually declines. Infertility in older women may be due to a higher rate of chromosomal abnormalities that occur in the eggs as they age. Older women are also more likely to have health problems that may interfere with fertility. The risk of miscarriage also increases with a woman's age. A gradual decline in fertility is possible in men older than 35. The reason is straightforward. A woman is born with all the eggs she'll have. And with time, the supply diminishes. The remaining eggs also age along with the rest of the body.
FIG. 10. Schematic representation of the changes in average early follicular levels of endocrine and ovarian ultrasound markers for ovarian aging according to the STRAW phases of reproductive aging. Note the late decrease in estradiol and inhibin A levels, the gradual decrease in AMH across the subsequent stages, and the abrupt decrease in inhibin B in the menopausal transition. Drawing is based on several sources (46, 66, 95, 109, 122, 124, 155, 329).
DR. JYOTI BHASKAR
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,
Received February 8, 1999.
Accepted June 7, 2000.
• How Does Age affect Fertility?
• How can the Ovarian reserve be Assessed?
• How does DHEA improve Ovarian reserve?
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
• 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.
• Decline in AFC
• Reduced cohort size
• Decreased oocyte quality &
• Altered feedback
– Reduced inhibin B
– Steady rise in FSH
– Gradually declining AMH
Miscarriages due to Aneuploidy
F. 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
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
• 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
>3.0 High, often
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
Interpretation Expected Response
<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
Increased risk of
Antral Follicle Count (AFC)
Studies on DHEA
Fertil 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
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
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?
dependent phase of
• Act before , during or after the recruitment phase
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
• Supplementation with DHEA may achieve favourable
public health consequences by potentially reducing
aneuploidy and spontaneous pregnancy losses in a
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
• Younger women, under age 40, are continuing to be
only selectively supplemented
1. if demonstrating elevated age-specific baseline
follicle stimulating hormone (FSH) levels
2. Inappropriately low oocyte yield in at least one IVF
CENTER OF HUMAN REPRODUCTION
• 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
• 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
• Improved overall feeling
• Feeling of being physically stronger
• Improved sex drive
• Feeling of being mentally sharper
• Feeling of better memory
• Selected patients – DOR and POA
• Minimum of 2 months before IUI or IVF
• One patient conceived spontaneously while being worked up or
• AMH has improved in 2 patients
• Age is the main determinant of success of infertility
• AMH is the most promising method of assessing
• 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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