in vitro fertilization and longevity kostas pantos · 2017. 9. 8. · •oocyte donation was early...
TRANSCRIPT
KOSTAS PANTOS Obstetrician-Gynecologist, PhD
Head of IVF UNIT, Genesis-Athens Clinic, Greece
IN VITRO FERTILIZATION
AND LONGEVITY
In the sacrament of marriage, the absolute union in body and soul,
in Christ’s love, between man and woman, the childbearing arises
as the great purpose and splendid, according to the Divine Law.
1st Rel. Annex Sec. 11th , pg. 702, V.Moustakis et al.
The God most pure, Author of all creation, Who through Your
manbefriending love transformed a rib of Adam the forefather
into a woman, and blessed them and said, "Increase and
multiply, and have dominion over the earth”, and, by the
conjoining … and the two shall be one flesh-and whom God …
Who did also bless Your servant Abraham, and opened the
womb of Sara, and made him the father of many nations;
Wishes of Church for childbearing: Wedding Wish
Holy Matrimony - The Service of Betrothal
Among God's promise to Abraham one was that of having a
child, though he had reached the age of 100 years old and
Sarah the age of 90.
Having child at old age in the Old Testament
Old Testament, Genesis 18: 11,12, 14, 15, 18,19
As Adam the first progenitor of mankind was blessed by God, (Gen. Ch. 1:28-30) to the
same way God blessed Noah as the new progenitor of mankind.
The blessing is threefold:
The first part concerns the proliferation of people, the domination over the animals
and the food.
Next the Testament of God follows (Gen. Ch.1: 8-17), that He will not Bring about
cataclysm again and the Rainbow will be the symbol and sign of God’s promise.
The third part of the Testament (Ch. 9: 18-29) is the rest of Noah's life, which lasted
here on Earth 350 years and promises in relation to his sons Shem, Ham, and Japheth.
Correlation of Longevity in the Old Testament
Old Testament, Genesis 1
Reproduction later in life is a marker for longevity in womenBoston University Medical Center, ScienceDaily, 25 June 2014
• Women who are able to naturally have children later in life tend to live longer and the
genetic variants that allow them to do so might also facilitate exceptionally long life spans.
• A Boston University School of Medicine (BUSM) study published in Menopause: The Journal
of the North American Menopause Society, says women who are able to have children after
the age of 33 have a greater chance of living longer than women who had their last child
before the age of 30.
• "Of course this does not mean women should wait to have children at older ages in order to
improve their own chances of living longer. The age at last childbirth can be a rate of aging
indicator. The natural ability to have a child at an older age likely indicates that a woman's
reproductive system is aging slowly, and therefore so is the rest of her body."
Thomas Perls, MD, MPH, Director of the New England Centenarian Study (NECS)
Reproduction later in life is a marker for longevity in women
• The study was based on analysis of data from the Long Life Family Study (LLFS)-a biopsychosocial and
genetic study of 551 families with many members living to exceptionally old ages.
• The study investigators determined the ages at which 462 women had their last child and how old those
women lived to be.
• The research found that women who had their last child after the age of 33 years had twice the odds of
living to 95 years or older compared with women who had their last child by age 30.
• The NECS found that women who gave birth to a child after the age of 40 were four times more likely to
live to 100 than women who had their last child at a younger age.
Boston Medical Center - LLFS
Boston University School of Medicine (BUSM), Menopause: The Journal of the North American Menopause Society
AGING
Older Moms May Live LongerAlice Park Nov 17, 2016 TIME Health
http://time.com/4574770/older-moms-may-live-longer/
TIME Health
• Α multi-year study οf the nearly 28,000 post-menopausal women in the U.S., found that around half survived to reach age 90, and researchers showed that delaying childbirth is associated with longer life.
• Compared to women who weren't yet 25 when they first gave birth, women who were older than 25 were 11% more likely to live to 90.
American Journal of Public Health: “Our study is the first to look at age at first childbirth and parity [number of children] in relation to survival to very advanced age.”
• Τhe women who had two to four children were generally healthier overall than women who had one child.
• WHI studies suggest that women who have children later and live longer are also healthier as they age.
Old Order Amish Community in Lancaster, Pennsylvania, “Homogeneous Lifestyle”
Does the act of having a child make people live longer?
• Lifestyle has the avoiding of riskier habits.
• Offspring responsibility by taking care of their children.
• It is quite likely childless couples engage in riskier activities than women who
do not participate in these activities at all.
• Men and women with children tend to take better care of themselves.
• Breastfeeding an infant has been repeatedly found to reduce the risk of
certain cancers. This is probably due to the temporary suppression of
production of estrogen.
• Fetus can release stem cells into their mother's blood circulation that act as
generic healing agents.
• Pregnant women tend to heal faster than non-pregnant ones. Maybe each
pregnancy "heals" the mother to some extent, conferring longer lifespan.
Legitimate health benefits associated with the actual process of bearing children
• A study published in 2013 suggests that women who can't have children have a
shorter life expectancy than women who do not bear children, but the author
admits that this could partially be due to those childless women having other
health problems that caused their infertility: Though correlation found is not
necessarily a cause-and-effect relationship.(Agerbo, E. J Epidemiol Community Health 2013;67:374-376)
• There are also studies that show that women with more children live longer than
women with few children.(Simons et al. Age Ageing 2012;41:523-528)
Is there a difference in life expectancy between women who have children and infertile women?
The relationship between fertility and lifespan in humansMaris Kuningas, Signe Altmäe. André G. Uitterlinden, Albert Hofman, Cornelia M. van Duijn, Henning Tiemeier, AGE (2011) 33:615–622
Fertility has also been associated with mortality. Women with
two to three children had significantly lower mortality (hazard
ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97)
compared to women with no children.
True association of mortality vs fertility ?
• Women with children tended to have their menopause at later ages
than women without children.
• Women who have their menopause at later ages have decreased
risk of having a heart attack, stroke, or other cardiovascular
disease event, but increased risk of having breast or endometrial
cancer.
Hu et al. 1999; Sowers and La Pietra 1995
Or observational phenomenon ?
Birth rates USA 1990-2012
Birth rates by selected age of the mother: United States, 1990–2012
Source: CDC/Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Vital Statistics System.
Sauer. Reproduction at advanced maternal age. Fertil Steril 2015
Birth rates by selected age of the mother
LANDMARK PAPERS:
Sauer et al., A preliminary report on oocyte donation extending reproductive potential to women over 40. N Engl
J Med 1990;323: 1157–60.
Sauer et al., Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet
1993;341: 321–3
Pantos et al., Oocyte donation in menopausal women aged over 40 years. Hum Reprod. 1993 Mar;8(3):488-91
Birth rates by selected age of the mother: United States, 1990–2012
Source: CDC/Eunice Kennedy Shriver National Institute of Child Health and Human Development,
National Vital Statistics System Sauer. Reproduction at advanced maternal age. Fertil Steril 2015
NATURAL FERTILITY DECLINE WITH AGE
THE RELATIVE EFFECT
OF AGE ON FECUNDITY
THROUGH IVF
2011 SART data, 6/2/2013
CURRENT FEMALE REPRODUCTIVE ATTITUDES
BIOLOGICAL REALITY:
•Menopause, the loss of ovarian function,
occurs between ages of 45-55 and lasts
>9-12 months and is considered inevitable
TODAY’s CHALLENGE
•Identify perimenopausal period
•Offer realistic options in child bearing
SOCIETAL ACCEPTANCE IN DELAYED PARENTHOOD:
•Personal autonomy in decision making
•Educational goals, career pathways, ambitions
•Finding the ‘proper’ life partner
•Successful women and denial of biological reality
•Role of Reproductive Technologies in resolving reproduction issues
•Favorable reporting bias of the mass media of ‘menopausal mothers’
Pre-Conceptional counseling for AMA
Identify peri-menopausal period
•Age
Determine ovarian reserve with Known potential markers:
•AMH (Anti-Müllerian hormone) levels
•AFC (antral follicle count) as measured
by transvaginal ultrasound1-4.
•Basal FSH levels
•Basal E2 levels
•Inhibin B
1. Broekmans et al. Menopause. 2004;11:607-14
2. Dólleman et al. Hum Reprod. 2015;30:1974-81
3. Broer et al. J Clin End Metab. 2011;96:2532-9
4. Wellons et al. Menopause. 2013;20:825-30
PERIMENOPAUSAL CONCEPTION
“TIME IS OF THE ESSENCE”
•Natural conception
•IVF treatment
•Oocyte donation
•Oocyte or ovarian tissue cryopreservation
•OVARIAN REJUVENATION (RECENT)
•True preventive approach (best)
IVF TREATMENT OF PERIMENOPAUSAL WOMEN
• Perimenopausal women often characterized by poor response to controlled ovarian
stimulation1 and increased probability of IVF cycle cancellation due to the
retrieval of inferior quality oocytes4
• Embryo transfer after prolonged embryo culture to blastocyst stage4
• Double same cycle follicular and luteal phase mild stimulation protocols,
cryopreservation, ET in thaw had increased pregnancy rates2
• AMH-tailored stimulation protocols claim to improve pregnancy rates for women
in advanced maternal age3
• Live birth rates in perimenopausal women decline as maternal age increases4
1. Marcus et al. Hum Reprod Update. 1996;2:459-68 3.Chi-Chun et al. Taiwan Journal of OB/GYN 55(2016)239-243
2. Yanping et al. Reprod BioMed Online 2014;684-691 4. Gleicher et al. Journal of Endocrinology 2016;230,F1-F2
PERIMENOPAUSAL WOMEN & NATURAL IVF
• Studies show live birth rates significantly higher in modified natural cycles
compared to high-dose FSH & GnRH antagonist cycles1
• Other studies show natural cycle IVF only indicated for normal responders, while
poor ovarian responders do not appear to experience substantial benefits2
• As peri-menopausal women are usually characterized by poor ovarian response to
standard gonadotrophin stimulation, natural cycle IVF +/- embryo banking from
consecutive cycles +/- PGS could be a promising therapeutic option 4,5
• Reports of premature luteinization in older women suggest giving hCG trigger
earlier at lead follicle 16mm3
• Androgen supplementation(DHEA) still controversial3
1. Lainas et al. Hum Reprod. 2015; 30:2321-30–1547 2
2. Polyzos et al. Hum Reprod. 2012;27:3481–86
3. Gleicher et al. Journal of Endocrinology (2016) 230,F1-F6
3. Lawson et al. Hum Reprod. 2003;18:527-33
4. de Boer et al. Fertil Steril. 2002;77:978-85
PERIMENOPAUSAL WOMEN & OOCYTE DONATION
• Oocyte donation was early stratified in the IVF treatment of peri-menopausal1 and
post-menopausal2 women with successful results even in advanced maternal ages
(63 years)2,3
• The success of oocyte donation/recipient cycles depends on donor's age4. Namely,
if oocytes are donated by young women to older women, both embryo implantation
and pregnancy rates are restored to normal levels in the recipients, regardless of
their age 4
• Given that the cumulative birth rates after four donation/recipient cycles is >80%,
oocyte donation seems to be the most reliable option for perimenopausal woman3,5
1. Sauer et al. Am J Obstet Gynecol. 1990;163:1421–4 4. Pantos K et al. Hum Reprod. 1993;3:488-91
2. Antinori et al. Hum Reprod. 1993;8:1487–90 5. Sauer et al. J Assist Reprod Genet. 1994:11:92–96
3. Paulson et al. Hum Reprod. 1997;12:835–839
What is already known:
• Platelet-rich plasma (PRP) emerges amongst the most innovative autologous
blood products used to enhance tissue healing and regeneration
• Platelets carry more than 800 proteins, such as cytokines, hormones and
chemo-attractants of stem cells, macrophages and neutrophils, responsible
for various post-translational modifications of nearly 1,500 bioactive factors
• Platelets carry various growth factors, which are released after alpha granule
activation
• Secreted active proteins are then bound to transmembrane receptors of target
cells, causing expression of a gene sequence that directs various events, e.g.
proliferation, collagen synthesis
• Active secretion within 10 min after activation, with more than 95% of the
pre-synthesized growth factors secreted within 1 h
Platelet-rich plasma (PRP)
Dhilllon et al.Arthritis Res Ther 2012;14:219, Qureshi et al. PLoS One 2009;4:e7627,
Mussano et al, Platelets,2016 Early Online: 1–5
PRP treatment in medicine
• Bone regeneration
• Osteoarthitis
• Nerve injury
• Tendinitis
• Myocardial infraction
• Alopecia
• Ocular surface disease
• Skin rejuvenation
• Wound healing and fat grafting
1.Yu et al., 2011 2. Mishra et al., 2009 3. Li et al., 2008 4. Khatu et al., 2014
5. Alio et al., 2012 6. Yuksel et al., 2013 7. Sommeling et al., 2013
• Reports of fibrosis and inflammation as hallmarks of aging ovary1
• PRP treatment reported to cause angiogenesis activation, inflammation control,
anabolism increase, cell migration, differentiation and proliferation, plus reverses
apoptosis 2,3
• The study of an ischemia/reperfusion injury rat model has shown that PRP
treatment diminishes the oxidative stress and the ovarian histopathology caused by
the bilateral adnexal torsion, while it increases the peritoneal vascular endothelial
growth factor5
•PRP treatment has improved vascularization and quality of an implant in an
autologous ovarian transplantation4
•PRP has promoted endometrial growth in women with poor endometrial quality6
PRP treatment in Gynaecology
1. Shawn M Briley et al.Reproduction 2016;0129 4. Bakacak et al. Gynecol Obstet Invest. 2016;81:225-31
2. Pietrzak and Eppley. J Craniofac Surg. 2005;16:1043-54 5. Callejo et al. J Ovarian Research. 2013;6:33
3. Borrione et al. Am J Phys Med Rehabil. 2010;89: 854–61 6. Chang et al. Int J Clin Exp Med. 2015;8:1286-90
Our experience with autologous PRP treatment
• Endometrial treatment
• Women with a history of ET failures and thin endometrium
• Women with a history of chronic endometritis
• Ovarian treatment
• Menopausal women under the age of 54 years
• Peri-menopausal women under the age of 50 years seeking IVF with own eggs
Genesis Athens Hospital Ethics Committee approved the study protocol in accordance to the Helsinki
declaration and all participants gave informed consent
Subjects Eight peri-menopausal women undergoing PRP treatment constituted the
study population. All subjects, aged 45.13±4.42 years, had absence of
menstrual cycle for 4.88±1.13 months.
The hormonal profile was determined before the PRP treatment and at
monthly intervals after the PRP treatment in order to monitor the ovarian
function. The presence of developing follicles was confirmed by ultrasound
scan.
Methods PRP was prepared using the RegenACR®-C Kit and was infused into the
ovaries using a transvaginal ultrasound-guided injection.
All patients underwent natural cycle IVF without any ovarian stimulation or
GnRH antagonist supplementation .
When a follicle of >16 mm was observed, ovulation triggering was achieved
with 5000 IU of hCG and follicle aspiration was performed 32 hours later by
the transvaginal route.
Results:
The successful ovarian rejuvenation was confirmed by the
menstrual cycle restoration 1-3 months after the ovarian PRP
treatment.
The subsequent oocyte retrievals were successful in all cases,
resulting in 2.50±0.71 follicles of 15.20±2.05 mm diameter,
1.50±0.71 oocytes and 1.50±0.71 MII oocytes.
All mature oocytes were inseminated by ICSI and the 1.50±0.71
resultant embryos were cryopreserved at 2pn stage until transfer.
No embryo transfer has been performed.
PRP treatment in menopausal women
• Scope:• To investigate whether PRP treatment could have revitalizing effects on the
dysfunctional ovaries of menopausal women.
• Study population:• Thirty four women in menopause (no menses >12 - 96 months), aged 45.26±6.12
years
• Primary outcome measure:• restoration of the menstrual cycle
• Secondary outcome measure:
- Improvement of hormonal levels (FSH,LH,E2,AMH)
- Folliculogenesis reactivation, oocyte retrievals with mature (MII)
oocytes and their reproductive outcome
Results: • In 16 / 34 menopausal women (47%) menstrual cycle
restored within 1 to 3 months
• In 7 women follicles were observed on the first month immediately after treatment
• 6 women underwent oocyte retrieval
• In 3 cycles MII eggs were retrieved
• 1 patient proceeded to embryo transfer
• Singleton pregnancy -> spontaneous abortion 13th week of gestation
PRP treatment in menopausal women
Abstract accepted 7th International congress IVI 2017
PRP Treatment in Menopausal women
No FSH AMH M/PAUSE(YRS)
AGE PRP Rx menses cyclesPOST-PRP
IVF (Natcycles)
Outcome
1 55,5->23 0,2 2 30 Dec 2015 16 5 2 MII VITRIFIED
2 65->43 0,01 1 46 May 2016 11 1 No egg
3 58->28 0,1 1 41 July 2016 9 1 No egg/ no menses now
4* 84->47 0,01 6 49 Sept 2016 2 0 No menses now
5 47->26 0,03 2 49 Sept 2016 2 0 No menses now
6 25->13 2,2 1 41 Sept 2016 8 2 1 MII vitrified
7 67->23 0,01 3 41 Sept 2016 2 0 No menses now
8 83->23 0,01 1 50 Sept 2016 2 0 No menses now
9 99->84 0,01 6 54 Nov 2016 2 0 Spotting every 2 months
10 118->29 0,03 1 48 Nov 2016 3 0 Menses
11* 110->59 0,01 3 49 Nov 2016 2 0 Menses
12 128->23 0,01 8 37 Dec 2016 4 1 No egg/ Still menses
13 149->… 0,02 4 39 Dec 2016 1 1 Clinical Pregnancy***
14 92->39 0,01 3 41 Dec 2016 4 0** Menses
15 88->67 0,5 2 47 Jan 2017 2 0 Menses
16 144->134 0,03 46 Jan 2017 1 0 Menses
*** Spontaneous miscarriage at 13th week of gestation ** Follicle observed but not OPU * Updated data on menstruation
PRP treatment in menopausal women
Study conclusions:
Following PRP treatment there was successful menstrual restoration in almost half of women
Some women had retrieval of mature oocytes after natural cycle IVF and embryos after ICSI
Wider application:
PRP therapy may extend the fertility potential and help menopausal women to achieve a pregnancy with own oocytes
PRP Treatment in peri-menopausal womenFSH < 15
COUPLES AGE IVF CYCLES EGG 2PN OUTCOME RESULT
1 41 1 1 1 ET Ongoing singleton pregnancy
2 47 1 2 2 ET Negative
3 46 4 5 5 ET Ongoing singleton pregnancy
4 39 1 1 1 Freeze
5 45 1 0 0
6 45 1 1 0
7 39 2 1 1 Freeze
8 43 3 0 0
9-24 33-50 NONE NATURAL COITUS OR CYCLE RESTORATION
COUPLES AGE IVF CYCLES EGG 2PN OUTCOME RESULT
1 46 2 2 0
2 39 4 5 4 Freeze
3 45 2 2 0
4 49 4 1 0
5 50 2 1 1 ET Negative
6 47 2 1 0
7 29 2 0
8 46 6 3 3 Freeze
9 47 1 1 1 ET Negative
10 47 1 0
11 45 1 2 2 Freeze
12-27 32-49 NONE NATURAL COITUS OR CYCLE RESTORATION
PRP Treatment in peri-menopausal women
FSH :15 - 30
COUPLES AGE IVF CYCLES EGG 2PN OUTCOME RESULT
1 48 1 1 0
2 46 1 0
3 47 1 0
4 44 1 1 0
5 42 1 1 0
6 44 1 1 0
7 45 2 0
8 48 2 1 0
9 38 3 3 1 Freeze
10 49 3 0
11 48 4 4 0
12 42 4 3 0
13 49 4 0
14 44 4 4 1 Freeze
15 45 6 3 2 ET Negative
16 48 8 5 3 ET Negative
17 35 1 1 0
18-19 36-49 None Presence of follicles Natural coitus
20-43 32-52 None NATURAL COITUS OR CYCLE RESTORATION
PRP Treatment in peri-menopausal womenFSH > 30
Regarding the observed folliculogenesis
Many peri-menopausal women may maintain a restricted amount
of inactive primordial follicles, that could be activated by the PRP
growth factors for subsequent ovarian tissue regeneration and
maturate into preantral and antral follicles.
Indeed, platelet-derived growth factors (PDGFs), regulating cell
growth and division, have been shown to enhance blood vessel
formation and growth.
PDGFs have been localized in human oocytes and granulosa cells,
while their receptors in granulosa cells suggest a potential
association with primordial follicle activation.
Regarding the observed folliculogenesis
The recent detection of ovarian stem cells1, germline stem cells1
and very small embryonic-like stem cells2 in human ovarian
surface epithelium as well as their ability to differentiate into
oocytes under certain conditions, create new data for the origin
of PRP-derived follicles.
Therefore, the continual flow of hormones and growth factors,
which may become temporarily available in the rejuvenated
ovary of peri-menopausal women and premature ovarian failure
(POF) patients by the PRP treatment, could give birth to 'new
primary ovarian follicles' and subsequently to antral follicles.
1. White et al. Nat Med 2012;18:413–421 2. Virant-Klun et al. Differentiation 2008;76:843–856
Patient reasoning for ovarian PRP treatment
33%
17%
42%
8%
IVF
NATURAL COITUS
MENSTRUAL CYCLE RESTORATION
YOUTH
INCREASE OF HEALTH LIMIT AND LIFE EXPECTANCYHELLENIC STATISTICAL AUTHORITY (ELSTAT) in collaboration with the European Common
Action and coordinated by the National Institute of health and Medical Research
o In the EU life expectancy at the age of 65 years old in 2011 was 18.0 years for
men and 21.4 years for women, an increase of more than one year compared
with the figures of 2005 (1.3 years for men and 1.2 years for women), touching
so highest average of 86.4 years for life expectancy of modern woman.
o On the basis of 2012 SILC evidence (Survey on income and living conditions of
Households), at the age of 65 years, women spend 7.3 years (35% of remaining
life) without limitation of day-to-day activities.
TIME
In 2013 in the US, there were 677 births in women 50 years old and
older-over 600 deaths in 2012, according to CDC's National Vital
Statistics Report.
The largest increase was 14% in women aged 45-49, whose birth rate
jumped within one year: to 7.495 in 2013 from 7,157 in 2012."
There are countries that have set an upper age limit in order to reduce
State spending on older women (State insurance agencies).
There are other countries where indirectly shift the responsibility to private
clinics that perform in-vitro fertilization and to the health care professional,
as is the case in the United Kingdom.
AGE LIMIT IN IVF AND THOUGHTFUL
In countries with strict legislation and strong limitations on assisted
reproduction issues, as Australia’s age limit of 52 years , while Israel has set
the age limit for IVF at 54 years.
In European countries such as Croatia, Czech Republic, Estonia, Finland,
Ireland, Latvia, Luxembourg, Malta, Poland, Portugal, Slovakia, Slovenia and
Spain, there seems to be no similar restriction in age of the infertile women to
have access to assisted reproductive technologies (ART).
AGE LIMIT & ART IN EUROPE
Francesco Paolo Busardò, BioMed Research International, Vol. 2014, Article ID 307160, Review Article The Evolution of Legislation in the Field of Medically Assisted Reproduction and Embryo Stem Cell Research in European Union Members
o In the USA there is great variety among the various States with
most of them not mentioning any limit (ASRM 2013).
o The advised limit by ASRM was increased to 55 years and all the
States of America tend to harmonize with it, and seems to affect
other scientific societies of infertility worldwide. (Austin J In Vitro Fertili.
2014;1(1): 3. Is There an Age Limit to Become Pregnant in the Ivf Era? Bruno Ramalho
de Carvalho, Center for Assistance in Human Reproduction, Brazil)
o Only minimal States have a limit of 45 or 50 years.
AGE LIMIT & ART IN THE U.S.
HOW OLD IS TOO OLD: NO CLEAR - CUT ANSWERCASE:Omkari Panwar form India:70 yrs old delivered twins 2008
CONSIDERATIONS:
• Age of the mother
• Associated health complications
• Remaining life expectancy
• Proper screening medical and psychological of the mother to be
• Best interests of the child to come
• Social concerns
1. MacArthur et al. Menopause. 2016;23:799-802 2. Soderstrom-Antilla Hum Reprod Update. 2001;7:28-32
1,2
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