July 2017
The Center for Human Reproduction
CHR VOICE
Clinical Care • Research • Education
the monthly CHR UPDATE
In addition, we also have to again note the issue of
nuclear transfer (i.e., 3-parent IVF), this time in
attempts to treat infertility in older women, since
colleagues here in New York City have gone public
by announcing the utilization of this technique (without
prior approval by the Food and Drug Administration)
through a newly-formed start-up company at the
startling average price of $100,000 per in vitro
fertilization (IVF) cycle. With so much truly challenging
news to comment on, we, simply, could not stay quiet
in the month of July!
Since there is important new information for infertility
patients to be disseminated, we decided to shorten the
summer hiatus for the VOICE by, after all, publishing
a July issue. This issue will, therefore, among other
subjects, address the seemingly never-ending saga
of preimplantation genetic screening (PGS), now
suddenly given the new name preimplantation
genetic testing for aneuploidy (PGT-A) by the
American Society for Reproductive Medicine (ASRM),
and by us, simply, given the acronym PGS 3.0. We will
also address a previously only marginally discussed
subject in the VOICE, which in recent months in chatrooms, however, received increasing attention: the socalled “ovarian rejuvenation.”
3-parent IVF, previously in VOICE: http://kaywa.me/x6lNY
The ultimate evidence from leading
proponents of PGS that flipping a coin
is as good as PGS 3.0 in determining
embryo ploidy
professional organizations in improving pregnancy
and reducing miscarriage rates in association with
IVF. Effectiveness of PGS 2.0 was then touted with
even bigger fanfares by the PGS industry, resulting in
even wider utilization (and even more rapid growth of
PGS laboratories and the industry as a whole).
Yes, we know that, over many months now, almost
every issue of the VOICE contained an article about
PGS. Yet, here we go again, because the audacity of
the PGS industry, simply, leaves us no other choice.
The industry’s misrepresentations, simply, cannot be
made up, and just continue giving fodder for further
commentary. Trying not to be repetitive, we already in
last month’s issue outlined why the name change for
PGS to PGT-A, recently parenthetically announced in
Fertility & Sterility (the official organ of the ASRM),
in our opinion just represented yet another marketing
tactic, which (hopefully unsuccessfully) attempts to
divert attention away from the increasingly obvious
failure of PGS 2.0, as practiced over the last half a
dozen years (see also on page 9, "PGS is no more...").
The loudest proponents of PGS 2.0, with few
exceptions, were, of course, the same “experts” who
had previously argued in favor of PGS 1.0. None of
them, however, appeared bothered in the least about
having sold to the IVF community PGS 1.0 without
prior clinical validation over many years. As we all
finally learned, PGS was not only clinically useless
Continue reading on page 2
In this issue, we cover:
Watch out for "ovarian rejuvenation" claims
PCOS and future fertility: Monthly case report
PGS no more; long live PGT-A
In Focus
Readers of these pages, of course, know that PGS
2.0 replaced PGS 1.0 once (much too late), the
latter finally declared ineffective by ASRM and other
1
..... 3
..... 4
..... 9
..... 12
Flipping a coin: Continued from Page 1
but, at least in poor prognosis patients, actually
reduced IVF pregnancy chances [Mastenbroek et al.,
N Engl J Med 207;357(1):9-17].
It all started with an oral presentation by Norbert
Gleicher, MD, CHR’s Medical Director and Chief
Scientist, at the October 2015 Annual ASRM Meeting
in Baltimore, reporting the first three live births after
transfer of “aneuploid’ embryos. His presentation,
likely, was the most talked about of that meeting.
It, unquestionably, became the starting point for
changes in PGS practice, which ultimately led to
the announcement of new practice guidelines
for PGS by the Preimplantation Genetic Diagnosis
International Society (PGDIS) barely a year later in
2016 and, therefore, to a switch from PGS 2.0 to PGS
3.0 (now also called PGT-A).
Those supposed experts’ certainty that PGS 2.0 would
succeed where PGS 1.0 had miserably failed before
was so profound that, amazingly, they, again, brought
the new PGS to market without proper prior validation
studies. A small group of PGS skeptics on both sides
of the Atlantic (including CHR) called for caution, and
warned that the IVF community may be repeating
the mistakes made in association with PGS 1.0, but
were “out-marketed” by proponents of PGS, some of
whom are undoubtedly honest and true believers in
the procedure, but others, unquestionably, primarily
driven by more profit-focused commercial interests.
PGDIS fiasco: http://kaywa.me/x6lNY
CHR’s initial ASRM report was followed shortly
thereafter by a confirmatory report from Italian
colleagues in a research letter in the New England
Journal of Medicine, which further shook up the PGS
establishment and by a report of the Bernabeu group
in Alicante, Spain, at the ESHRE meeting in 2016.
Inexplicably, as noted in the last month’s issue of this
newsletter, the PGS industry received a surprising
degree of support from a number of medical journals
in the specialty, which clearly favored articles in
support of PGS over those that attempted to critically
examine its use. No team of editors in the field,
indeed, acted in a more biased manner than the
editors at Fertility & Sterility (F&S), the official journal
of the ASRM, where proponents of PGS 2.0 were
practically given free reign (the same had happened
earlier for PGS 1.0 under a different team of editors),
and ended up deciding which PGS papers would be
accepted for publication and which would be rejected.
Increasing numbers of healthy births from all over
the world following transfers of allegedly “aneuploid”
embryos are finally leaving the PGS industry with no
other choice but to acknowledge that their manyyears-long policy of defining embryos via PGS
2.0 as either euploid or aneuploid was no longer
sustainable.
When CHR as the first center in the world (in
association with some colleagues at other New York
centers) in 2014/2015 announced a new program of
transferring so-called “aneuploid” embryos in certain
situations, the PGS establishment quite viciously
attacked the program as unethical. By late 2016, the
same PGS “experts” were no longer able to maintain
the position of defining any level of aneuploidy as
“abnormal,” and recommending the disposal of any
embryo with even minute alleged chromosomal
abnormalities.
Read the OPINION about hijacking: http://kaywa.me/x6lNY
F&S, therefore, has been almost exclusively
publishing manuscripts in support of PGS 2.0,
while, almost universally, rejecting manuscripts
critical of the procedure, including (without sour
grapes) a good number of manuscripts from CHR
investigators, which, fortunately, had no problems
being accepted elsewhere. Some of these rejected
manuscripts offered important new information. One,
indeed, reported the first group of healthy live births
in the world after transfer of allegedly “aneuploid”
embryos. These data have since been confirmed by
other investigators and, as will be discussed further,
created the impetus for the major restructuring
of PGS reporting by the PGS laboratory industry.
Recitation of this background information is important
because this CHR research became a crucial turning
point in the recently observed demise of PGS 2.0 with
publication of new reporting guidelines for PGS (i.e.,
creation of PGS 3.0).
Abnormal transfer policy: http://kaywa.me/x6lNY
Surprisingly high pregnancy and live birth rates,
reported by CHR and other centers from transfers
of allegedly “aneuploid” embryos only too obviously
demonstrated that old PGS testing methods and
reporting procedures were no longer sustainable. Like
PGS 1.0 before, PGS 2.0 also had failed in improving
IVF outcomes. Even more disturbingly, however,
these new transfer data of allegedly “aneuploid”
Continue reading on page 7
2
You must have heard recently about
"OVARIAN REJUVENATION"
hypothesis, primordial follicles, which contain the
most primitive and immature eggs prior to recruitment
into maturation cycles, sit in the outermost layer
of ovaries, the so-called ovarian capsule. Their
extremely immature state and minuscule size mean
that those follicles have almost no metabolic needs
and, practically, live in total isolation, and mostly
without nutritional needs. In a way, they, therefore,
can be considered “frozen in time,” like frozen eggs,
sperm or embryos are, once they are cryopreserved.
Consequently, these very immature eggs are well
protected from environmental influences.
Having a significant presence on the Internet (www.
centerforhumanreprod.com), CHR receives a large
number of inquiries daily about all kinds of fertilityrelated subjects. One such subject has been floating
toward increasing prominence over the recent
months. The subject can be summarized under the
term “ovarian rejuvenation.”
The idea of “rejuvenating ovaries” is nothing new.
This concept has been under consideration since
modern infertility treatments started in the late
50s and early 60s with initiation of gonadotropin
therapy. It is based on the recognition that ovaries
“age” as women advance in age. “Rejuvenation” of
ovaries, therefore, implies the ability to reverse this
ovarian aging process. To better understand whether
such rejuvenation is really possible, it is essential
to understand the physiological basics of ovarian
aging.
Stages of oocyte maturation
What is ovarian aging?
The ovarian age is determined by the ovaries’
principal product, their oocytes (eggs). Since
women are, likely, born with all of their eggs in
ovaries, and since these eggs are constantly lost in
large numbers, the total number of eggs (i.e., the
ovarian reserve) declines with advancing female
age. Concomitantly, egg quality also declines. As
woman grow older, they, therefore, experience in
parallel two independent declines, in egg quantity
and quality.
Resting follicles are recruited into the maturation process, which
takes place over a few months in the ovarian micro-environment.
This changes immediately, however, once such
primordial follicles are “recruited,” and start their
weeks- to months-long journeys of maturation, during
which they literally travel from the outer capsule
toward the innermost parts of the ovary (the medulla),
while rapidly growing in size. During that journey of
maturation, follicles become extremely dependent
on nutrition from their environment (stroma) and,
therefore, do become exposed to influences from the
ovarian micro-environment in which they mature.
The decline in egg quality is still widely attributed
to the fact that eggs are in ovaries from birth and,
therefore, age. In contrast, males constantly produce
fresh sperm into advanced ages, which, therefore,
remains “fresh.”
While environmental aging over time may play
some role in oocyte aging, CHR investigators have
questioned this concept of ovarian aging. They
proposed a number of years ago the hypothesis (the
“CHR hypothesis of ovarian aging”) that increasingly
poor oocyte quality with advancing female age may
not be due to aging of oocytes but actually due to
aging of the ovarian micro-environment, in which
follicles and eggs after recruitment mature. Under this
The modified ovarian aging hypothesis developed
by CHR investigators, therefore, suggests that the
age of this ovarian-microenvironment, likely, greatly
affects oocyte quality. In other words, while sitting in
ovaries, often for decades, at very primitive primordial
stages may have some negative impact, it, likely, is
relatively small. A much larger impact can be expected
Continue reading on page 10
3
Monthly Case Report: Consultation with Polycystic
Ovary Syndrome (PCOS)
In this section, we report brief case summaries we believe may be educational for patients and colleagues. We invite colleagues to
participate in this monthly feature by contributing interesting cases. Submitted cases should be described in not more than 500 words, and
suggested treatment and outcome should not exceed 250 words. If accepted for publication in the VOICE, CHR will add a commentary.
If you think that you may have an interesting case to report, please contact this newsletter’s editor, Yu Kizawa, at [email protected].
testosterone levels and relatively low sex hormone
binding globulin (SHBG). Her DHEAS level was in
mid-range. Her AMH level was high for her age at 7.4
ng/mL. In addition, the patient demonstrated FSH/LH
inversion, a fairly typical finding with the “classical”
PCOS phenotype. Her vaginal ultrasound examination
demonstrated multi-cystic ovaries but not a typical
“pearl-string” PCO-ovarian phenotype.
Case: A 27-year-old childless, single woman
presented to CHR. Though concerned about her
future fertility, she was not interested in conceiving at
the time. She was of Middle-Eastern Mediterranean
background, mildly obese with mostly truncal obesity
(BMI 33). She also demonstrated moderate acne
scars in her face and appeared mildly hirsute, with
some dark facial hair and significant amounts of black
hair on her arms.
Her fasting glucose levels were in normal range,
though her insulin levels were marginally elevated,
suggesting early insulin resistance. The patient
also demonstrated evidence of immune system
activation with elevated total IgM and IgE levels
and of inflammation, with abnormally high IL-6
and CRP. Her TSH was in clearly hypothyroid
range and she demonstrated low level TPO as well
as TG antibodies, leading to a diagnosis of likely
Hashimoto’s thyroiditis.
She reported irregular menses since menarche at
age 14, characterized by oligo-amenorrhea. Over
the year prior to presentation to CHR, she claimed
weight gain of ca. 15-20 lbs, without noticeable
changes in exercise and/or eating habits. As a
teenager, she was placed on OCPs to “regulate her
period,” more for heavy menorrhagia episodes than
menstrual irregularity. Her bleeding episodes were so
severe that, twice as a teenager, she was admitted to
a hospital and was treated for anemia.
Analysis: This patient’s work-up led to two distinct,
yet often interwoven, diagnoses: She very clearly
reflected the typical “classical” PCOS phenotype,
characterized by truncal obesity, hyper-androgenism,
a history of oligo-amenorrhea, hirsutism, elevated AMH
levels, FSH/LH inversion and early insulin resistance.
She, however, did not demonstrate a typical ovarian
PCO-phenotype. In addition, she suffered from
overt hypothyroidism and, based on evidence of
thyroid autoimmunity, from Hashimoto’s thyroiditis. A
hyperactive immune system was also confirmed by
IgM and IgE gammopathies and elevated inflammatory
markers in IL-6 and CRP.
With OCPs, her menstrual pattern regulated itself,
and she stayed on birth control till age 24. Once she
discontinued OCPs, she experienced six months of
post-pill amenorrhea but then fell into a semi-regular
menstrual pattern of 32-34 days, with a occasional
amenorrheic months.
Her past medical history was otherwise insignificant
except for an appendectomy at age 14, apparently
without overt rupture. She had periodic visits with
gynecologists and nurse midwifes over the years,
though in irregular intervals. She was never advised of
a diagnosis of polycystic ovary syndrome (PCOS).
Her family history was also insignificant, except for
the fact that her mother suffered from systemic
lupus erythematosus (SLE).
PCOS is a widely misunderstood condition; it is
perceived by many as "a disease,” which it is not.
PCOS really is a group of separate conditions, which
for reasons we will address below in more detail,
have historically been thrown together in the medical
literature in one “syndrome” named PCOS. Over the
years, it has become apparent that this syndrome
consists of very different patient groups, and groups
of experts have tried to divide PCOS into distinct
“phenotypes.”
She presented to CHR with a request for advice about
her future fertility.
Diagnostic work-up: A limited diagnostic work-
up was ordered, which resulted in the following
relevant results: The patient demonstrated hyperandrogenism, characterized by relatively high
Continue reading on page 5
4
Case report: Continued from Page 4
This has, however, been only partially successful,
as “experts” have not been able to agree on how
this PCOS pie should be divided into individual
phenotypes. Therefore, no consensus exists and
different classifications of PCOS phenotypes are used
in the medical literature, resulting in confusion and
limited ability to compare results reported in various
studies because investigated patient populations do
not match.
Resolution: The patient was advised of her diagnoses,
and was started on thyroid supplementation. She was
also advised of her risks of developing the metabolic
syndrome and of benefits of proper diet, exercise and
weight control.
Because at least the “classical” PCOS phenotype is
increasingly viewed as an inflammatory condition and
because the patient demonstrated early signs of insulin
resistance, she was also advised of anti-inflammatory
and hypo-glycemic effects of Metformin but chose
not to initiate treatment at the time. She, however, did
start with a baby aspirin daily. PCOS has also been
associated with increased risk toward autoimmunity,
and especially thyroid autoimmunity. Here observed
combination of diagnoses is, therefore, not unusual.
Polycystic ovary on ultrasound
Regarding her future fertility, she was advised that
her current ovarian reserve was normal, with her
functional ovarian reserve, based on her high AMH,
even being abnormally high. Any infertility treatment
would, therefore, likely place her at some risks for
ovarian hyper-stimulation as well as multiple
pregnancy.
Here discussed case represents the “classical” PCOS
phenotype, except for the lack of the typical ovarian
PCO phenotype on ultrasound. Many erroneously
consider the "classical" PCOS to be the most frequent
and most “typical” PCOS phenotype. That is not really
the case. The literature suggests that the “classical”
PCOS phenotype represents only ca. 40% of all PCOS
patients. Indeed, an approximately equal number
of PCOS patients (under most current international
criteria) are lean women, without evidence of obesity,
hirsutism, acne and the metabolic syndrome, which
is so frequently found later in life in women with the
“classical” phenotype.
She also was advised that autoimmune thyroid disease
(and other autoimmune conditions) statistically denote
increased risk of premature ovarian aging (POA),
which would be reflected in relatively quick declines in
AMH values. She, therefore, was advised to undergo
repeat AMH evaluations every 1-2 years. Finally, she
was advised that, as a “classical” PCOS patient, she
likely, was oligo-ovulatory, which meant that she may
require help to conceive. Consequently, she should
seek out help from a fertility expert if she did not
conceive within 6 months with regular intercourse, and,
if possible, should accelerate her pregnancy attempts.
Hypoandrogenic PCOS: http://kaywa.me/ZCR7a
Recent research at CHR that concentrated exclusively
on this lean PCOS phenotype strongly suggests that
etiologies and pathophysiologies of these two most
frequent PCOS phenotypes, likely, are very different.
Whether it makes sense to keep them within one
syndrome and under one diagnostic parapet, therefore,
has to be questioned.
The patient has not returned since that consultation.
Mitochondria Study
DO YOU CARRY A MITOCHONDRIAL DISEASE
OR KNOW SOMEBODY WHO DOES?
If you do, please call us at 212-994-4400 for a free
consultation in person, by phone or via Skype. CHR
is searching for a way to prevent inheritance of these
awful diseases in collaboration with colleagues at
the famous Salk Institute for Biological Studies in La
Jolla, CA. You may be able to help us find a way to
prevent mitochondrial diseases in children!
Also widely underappreciated is the fact that PCOS
is not necessarily a static condition. It, in principle,
is a condition of young women and lightens in its
reproductive clinical expression as women grow older.
This, however, is not the case in the “classical” PCOS
phenotype when it comes to the expression of signs
and symptoms of the metabolic syndrome, which
actually increase with advancing age.
Contact us to learn more about the study: http://kaywa.me/43Mdn
5
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Abstract submission deadline is August 1st!
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Ovarian physiology | Quick updates on the "most
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6
Flipping a coin: Continued from Page 2
embryos offered strong supportive evidence that
embryos, declared unsuitable for transfer by PGS
2.0, could lead to healthy live births in surprisingly
high rates. Especially for poorer prognosis patients,
this meant that they apparently had discarded their
last pregnancy chances when their IVF centers
disposed of their allegedly “aneuploid” embryos.
But let’s not get ahead of ourselves, and start from the
beginning: Though a good number of authors on this
paper were among the most outspoken opponents
of transfers of allegedly “aneuploid” embryos when
it was first announced by CHR investigators and
colleagues, this group of PGS proponents from all
over the world now, quite remarkably, reported on
cycle outcomes of 143 allegedly “aneuploid”
embryos (now under new PGDIS criteria called
“mosaic”) that were, nevertheless, transferred, in
their paper. Though our colleagues did not give us the
professional courtesy of referencing our preceding
published work in their manuscript, we do want to
congratulate them on this combined effort, which
represents the, so far, largest number of reported
IVF cycles using aneuploid/mosaic embryos. We
are, however, especially grateful for this publication
because, contrary to the authors’ obvious intent, the
data in their publication allowed us to reach very
obvious conclusions, further demonstrating the futility
of all PGS as a diagnostic procedure. Like in the two
prior PGS marketing rounds for PGS 1.0 and PGS
2.0, claims for PGS 3.0 are, once again, false.
History, thus, repeated itself like CHR and a small
group of other colleagues had warned about for
a good number of years: Like PGS 1.0 before,
only after years of clinical use had been exposed
as clinically ineffective and even harmful to poor
prognosis patients, PGS 2.0 now had met more or
less the same fate, and the PGS industry found itself,
once again, faced with immediate need to rescue its
testing business.
“
Many of the same “experts,”
who so smoothly had
managed their laboratories’
transition from PGS 1.0 to
PGS 2.0, now, again, jumped
on the bandwagon of the
inevitable, suddenly claiming
to be leading a perfectly
natural switch from PGS 2.0 to PGS 3.0. They are
not to be believed and, indeed, are to be held
responsible for fooling the IVF community twice
before. Shame on us, if we allow them to fool us
a third time!
PGS laboratories in
the US and elsewhere
are apparently quite
desperate to establish yet
another indication for
use of PGS 3.0 in IVF..."
Here is why: In compliance with 2016 PGDIS
recommendations, chromosomal analyses were
performed with Next Generation Sequencing (NGS)
in the study. Also in compliance, normal-euploidy was
defined as below 20% aneuploidy (i.e., mosaicism)
in a single embryo biopsy, aneuploid-mosaic as
20-80% mosaic, and outright aneuploidy as above
80% mosaic. We refer readers to the June issue of
the VOICE for explanation why this classification
biologically makes absolutely no sense. Aside from
that fact, only normal-euploid and aneuploid-mosaic
embryos by this classification were transferred.
Embryos with over 80% mosaicism were still disposed
of as “aneuploid” - a point we will return to later.
Which, finally, brings us to the main reason for this
lengthy introduction. That reason is a paper, so far
published only in electronic format by (of course)
F&S, with two of the world’s most prominent PGS
proponents as senior authors (Munné and Fragoulis
et al., Detailed investigation into the cytogenetic
constitution and pregnancy outcome of replacing
mosaic blastocysts detected with the use of highresolution next-generation sequencing. Fertil Steril).
Not surprisingly, some of the strongest proponents
over three generations of PGS (and, concomitantly,
representatives of some of the largest PGS
laboratories in the U.S. and elsewhere), are apparently
quite desperate to establish yet another indication for
use of PGS 3.0. They, now fully accepting that many
mosaic embryos can and should be transferred, in
this paper are attempting to claim that, PGS 3.0 may
be just the right tool to differentiate which mosaic
embryos should receive priority for transfer. Like so
many others before from the PGS industry, careful
analysis of their manuscript, however, resolutely
debunks this claim.
Lack of biologicla basis: http://kaywa.me/x6lNY
Overall a remarkable 41% of mosaic embryos
(i.e., embryos, which, under the old classification
of PGS 2.0, would have been discarded)
produced an ongoing implantation (pregnancy).
Single aneuploid mosaics had as high as 50%
implantation rates. Monosomies did equally well
as trisomies. Complex chromosomally abnormal
embryos did more poorly but still resulted in ongoing
pregnancies of ca. 10%.
Though this study does not report on live birth rates,
Continue reading on page 8
7
Flipping a coin: Continued from Page 7
reported IVF outcome numbers are, nevertheless,
remarkable, not only because they fully confirm CHR’s
earlier reported pregnancy and live birth rates after
transfer of allegedly “aneuploid” embryos, but also
because they demonstrate once more how many
potentially good embryos have been disposed of
over many years by PGS laboratories during the
PGS 2.0 period.
What further shames this manuscript is, of course,
that the authors, still, recommended discarding
all embryos with over 80% of mosaicism. As
PGDIS guidelines refer to this cut off without any
supportive underlying data, so does the materials
and methods section of this manuscript. There really
is no published evidence whatsoever in the literature
that embryos with over 80% aneuploidy in a single
biopsy sample are really abnormal and incapable
of developing into normal offspring. As we noted in
the last month’s article on PGS in these pages, to
presume that an embryo with 79% aneuploidy can be
transferred safely but one with 81% cannot, makes
absolutely no biological sense. It also demonstrates a
lack of statistical knowledge!
Yet, instead of acknowledging that despite quickly
expanding utilization, PGS has remained a
diagnostic test in search of a clinical purpose,
the PGS industry is trying again to develop yet
another rationale why PGS should be continued
as the new PGS 3.0 (or PGT-A). Why anybody
should or would order a test that, as this study
by PGS proponents again demonstrates, cannot
differentiate between embryos that can safely be
transferred or should be discarded, is unclear.
Here at CHR, where we are used to "fighting for
every egg and embryo,” we assume that patients
do not want to discard by mistake even a single
healthy embryo that may still have pregnancy
potential! Why, then, utilize a test in the first
place that cannot reliably differentiate between
embryos that do and those that don't?
Further undermining the validity of this cut off,
CHR investigators, collaborating with investigators
from Rockefeller University, have demonstrated
that a single 6-cell trophectoderm biopsy,
mathematically, simply cannot determine whether
a trophectoderm is normal, mosaic or aneuploid,
even at 100% aneuploidy if all 6 cells are
aneuploid [Gleicher et al., Reprod Biol Endocrinol
2017;15(1)33].
“
By confirming unexpectedly Is an additional
high pregnancy rates from $4,000 tacked onto an
transfer
of
aneuploid- already expensive IVF
mosaic embryos in the so cycle really worth it?"
far largest published patient
cohort, the authors of the
above noted paper, despite their very obvious
intent, actually bear witness to the clinical futility
of PGS. The procedure cannot differentiate reliably
enough whether an embryo is normal-euploid,
mosaic or aneuploid and, therefore, whether
an embryo can be transferred with reasonable
expectation of pregnancy or should be discarded.
The PGS-test has no clinical purpose!
Trying to invent yet another reason for continued
use of PGS, the authors of above cited manuscript
came up with only one conclusion: PGS 3.0 should
be performed to determine which embryos should be
given priority for transfer. They could not even muscle
enough data, however, to make a logical argument in
support of that conclusion because the PGS industry,
still, has not learned from past failures: The study still
generalizes outcomes obtained in favorable prognosis
patients, while the utility of PGS, of course, varies
at different ages and with different degrees of
ovarian reserve.
Even putting this very obvious criticism aside, the
authors’ conclusions are nonsensical: Let’s for a
moment assume a patient’s embryo does have a
single chromosomal abnormality, either a monosomy
or trisomy (the most frequent abnormal findings in
human embryos on PGS). Such an embryo, according
to the study, has a 50/50 chance of implantation. In
other words, a coin flip would give us an equal
chance of assessing this embryo correctly! And,
even assuming an embryo has a slightly higher or
lower chance of implantation, would that really affect
clinical IVF practice to significant degrees, worth an
additional $4,000, tacked on to an already exorbitantly
expensive IVF cycle? We do not think so!
The authors of the paper are, nevertheless, to be
congratulated on this publication, though for obviously
different reasons than they, likely, had hoped for.
Offering in their manuscript considerable amounts
of raw data, allowing detailed reassessments of
their statistical evaluations, they provided additional
opportunities. As these words are written, CHR
investigators and statisticians are, indeed, already
hard at work in reanalyzing their raw data in more
detail. We are sure results will be interesting and will,
of course, be shared in these pages in the future!
8
PGS is no more; Long live PGT-A!
the point that the renaming of the procedure gives
the impression of a typical rebranding marketing
effort, which under the name PGS has failed twice
and, in the process, has not only wasted incredible
resources, added significant undue financial burden
to IVF and, in many cases, has actually reduced
patients’ pregnancy and live birth chances, while
leading to the mistaken discarding of large numbers
of perfectly normal human embryos.
Nothing happens by accident, not even changes in
how procedures in IVF are referred to. It now appears
time to say good-bye to a term we have been using
since the late 1990s, when European colleagues
first coined it: Preimplantation genetic screening
(PGS), then considered a small sub-category of
preimplantation genetic diagnosis (PGD) that
described chromosomal testing of human embryos
prior to transfers. At least, American Society for
Reproductive Medicine (ASRM) and Fertility & Sterility
(F&S), the official journal of the ASRM, no longer
considers PGS the appropriate term to describe a
chromosomal analysis of human embryos.
We are hesitant about being so cynical but, despite
maximal efforts by everybody here at CHR, we,
simply, could not come up with another explanation
for the sudden name change which, of course, follows
just a few short months the equally sudden radical
revamp of how the procedure is viewed by “experts,”
analyzed and reported by the industry, in more detail
discussed in this month’s lead article.
Instead, the May issue of F&S, largely dedicated
to the procedure, suddenly, and without further
explanation, was instead referring to the procedure
as preimplantation genetic testing for aneuploidy
(PGT-A). And for those who considered that a
coincidence, the recent preliminary draft of a Practice
Committee Opinion of ASRM and Society for Assisted
Reproduction (SART) had as its short tile, PGT-A for
“aneuploidy.”
While we truly hope that our cynicism will be refuted
by another, better explanation, should the name
change really be primarily only a marketing ploy, then
shame is, of course, on the PGS/PGT-A industry. But
even bigger condemnation would have to be directed
at the ASRM and its primary medical journal, F&S, for
supporting such a charade.
Since such drafts of Practice Committee Opinions
are preliminary, and ASRM members are requested
to keep them confidential until official publication, we
will not further comment on the opinion itself here.
The sudden name change is, however, peculiar
enough to comment on because it surprises not only
in its suddenness but also in its obvious coordination
by the ASRM.
The most important take-home lesson from this
column is, however, that should anybody try in the
future to promote something, either called PGS or
PGT-A to improve your IVF experience, run, just run!
We then suggest you use a tiny fraction of the money
you saved from avoiding the procedure to buy a
celebratory drink for having avoided to fall for version
3.0 of the same old ruse.
In this month’s lead article of the VOICE, we make
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9
Ovarian rejuvenation: Continued from Page 3
during weeks and months of follicle maturation after
recruitment, when the ovarian micro-environment
really can negatively affect follicles and eggs and,
therefore, produce poorer egg quality.
levels would be able to reverse existing long-term
damage to oocytes. The only remaining alternative
explanation for outcome improvements observed in
older women and younger women with premature
ovarian aging (POA) after DHEA supplementation
was, therefore, that improvements in the ovarian
micro-environment had led to better egg quality.
Differences between these two theories of ovarian
aging are of great theoretical and practical importance
because, under the traditional theory of long-term
damage, follicles and eggs recruited into maturation
are already damaged. Their ultimate fate, therefore,
is already determined and no medical treatment will,
likely, be able to improve already damaged eggs.
The success of DHEA supplementation can,
therefore, be viewed as the first and, unfortunately,
so far the only successful clinical attempt at
ovarian rejuvenation. It is, however, reasonable
to assume that, like androgens, other important
ingredients of the ovarian micro-environment also
change with advancing female age. It now would
behoove us to learn what those are. The better we
reconstitute the micro-environment in older women,
the better will our fertility treatments fare.
“
Under the CHR hypothesis of
Differences between aging, however, the assumption
the two theories of is that eggs enter maturation
after
recruitment
mostly
ovarian aging are
of great theoretical undamaged. Consequently, if
the ovarian micro-environment,
and practical
in which they will mature, can be
importance..."
therapeutically improved, their
maturation will take place under
improved environmental conditions, and oocyte
quality at the end of folliculogenesis will be better. In
other words, under the CHR hypothesis of ovarian
aging, ovaries, indeed, can be medically rejuvenated
by reconstituting the ovarian micro-environment as
close as possible to where those micro-environments
used to be at younger ages.
Legitimate trials
This is, however, not the kind of “rejuvenation” the
Internet has been buzzing about in recent months.
There were, of course, some legitimate reports of other
potential approaches. For example, investigators in
Japan and San Francisco reported a few years ago a
form of ovarian rejuvenation, in which they removed
ovarian tissue from women who had entered
menopause prematurely (premature ovarian failure,
POF, also called primary ovarian insufficiency,
POI), treated that tissue in the laboratory with
biologically active ingredients known to activate a
certain pathway (i.e. the Hippo signaling pathway)
in primordial follicles, and then surgically re-implanted
the treated tissue into the patient. Primordial follicles
activated by this treatment, in some cases, started
growing and a very small number of so-treated
women ended up conceiving, because even women
in menopause still have follicles and eggs in their
ovaries. The problem with those follicles is, however,
that they no longer grow in response to fertility drugs
(gonadotropins). The in vitro treatment of these
women’s ovarian tissue, thus, in a way “rejuvenated”
the ovarian tissues removed and reinserted.
Rejuvenating the ovarian
micro-environment
That the ovarian micro-environment changes
with advancing female age is well documented.
Surprisingly, however, only very little is known about
what changes and at what ages. What actually
lead CHR investigators to the CHR hypothesis of
ovarian aging was the recognition that androgen
levels (i.e., male hormone levels) rapidly decline
in the ovarian micro-environment after age 40.
Since small growing follicles need good androgen
levels in these very early stages of follicle and egg
maturation, CHR investigators started reconstituting
older women with androgens (in that case with
dehydroepiandrosterone, DHEA, from which
our bodied make testosterone). With improving
testosterone levels, ovaries started producing better
eggs; better eggs led to better embryos and higher
pregnancy rates.
Requiring surgery twice, this treatment did not prove
very practical and does not appear destined for
wide clinical application. It, nevertheless, generated
considerable interest because it, of course, raised the
potential of learning how to activate these dormant
follicles in vivo (i.e., in the body). Because the Hippo
pathway can be mechanically induced, investigators
at CHR have started to investigate such an approach
It was this observation that then led CHR investigators
to develop their hypothesis of ovarian aging because it
did not appear probable to them that better androgen
Continue reading on page 11
10
Ovarian rejuvenation: Continued from Page 10
in a preliminary fashion. Unfortunately, others have
not been as measured in their approach (see below).
Though this approach was first reported over two
years ago, the claim has, still, not been formally
reported in the medical literature. It, therefore, cannot
be verified and/or duplicated. Nevertheless, at least
one center in NYC picked up on the report and has
been offering this treatment to patients (of course,
with full charges). We advise utmost caution!
Watch out for snake oil
OvaScience, Inc. (NASDAQ:OVAS) is a biotechnology
company, which presents itself as a “global fertility
company, dedicated to improving treatment
options for women around the world.” Its motto is
“improving fertility through science.” After reaching an
extravagant market cap in the hundreds of millions
of dollars based on alleged treatments that could
“rejuvenate” ovaries through “proprietary technology
that leverages the breakthrough discovery of egg
precursors cells,” OvaScience returned to a much
lower market reality even more quickly, and now
operates under new management. Its first treatment,
called AUGMENT™, initially got wide publicity, but
was never offered in the U.S. for regulatory reasons.
Now, after years of being sold in Canada and the
Middle East, the treatment still has no evidence of
efficacy.
Even more attention has been given on the Internet
and in some articles on the Web to injection of
platelet-enriched plasma into ovaries. This
approach was first reported by a center in Athens,
Greece, and was picked up by at least two centers in
NYC and others on the West Coast, who have started
offering these treatments, of course, for appropriate
fees. Once again, we advise great caution because
no validation studies on any of these products have
so far been offered.
Platelet-enriched human plasma has gained notoriety
in sports medicine, where well known athletes have
been allegedly cured from joint and other skeletal
problems by such injections. The hypothesis behind
these treatments is that platelet-enriched plasma
contains many immunologically active substances
(which is true), which exert anti-inflammatory and
other beneficial effects (which, at least as of this time,
is unproven).
Indeed, the company has mostly moved on from this
initial product line, and is now offering a successor
product, called OvaPrime™. While AUGMENT™
was designed “to improve IVF outcomes,” the
company claims that OvaPrime™ “could increase
a woman’s egg reserve.” Whether it really does so
is, of course, unknown, and a healthy degree of
skepticism appears appropriate. The company is also
developing OvaTure™, “a potential next-generation
in vitro (IVF) fertilization treatment that could help
a woman produce healthy, young, fertilized eggs
without hormone injections.” That would be a very
welcome addition to the currently available fertility
treatment offerings, but we, again, advise caution in
paying for unvalidated products.
Our friends and steady readers of the VOICE, of
course, know how interested we are here at CHR in
research that advances fertility care and allows quick
translational applications. We, therefore, would
strongly hope that all of here described attempts at
ovarian “rejuvenation” will be properly researched
and reported. Unfortunately, this is currently not the
case. Most of these “products” are introduced to the
market without any prior validation. We consider
this inappropriate, potentially dangerous and often
misleading because uninformed patients often
believe these to be established procedures.
Above, we noted the interesting work of Japanese and
West Coast colleagues regarding the Hippo pathway,
and noted that there was a scientific rationale for
exploring the possibility of trying to activate this
pathway in vivo in order to avoid the double surgery
required under our colleagues’ protocol. Though the
purpose was not activation of the Hippo pathway in
ovaries (at least they did not describe their practice
as such), the Internet has recently been flooded
by reports, where women with POF/POI have, with
allegedly favorable results, all kinds of biological
substances injected into their ovaries.
They are not! And this is why we felt we had to write
about them.
Commercializing three-parent
babies
Since we are already writing about the unethical
commercialization
of
unestablished
infertility
treatments, we cannot help but mention an Internet
article by Emily Mullin on June 13, 2017, called "The
Fertility Doctor Trying to Commercialize Three-Parent
A center in a Middle Eastern country reported
success in POF/POI patients through injections of
the patients’ own white blood cells into ovaries.
Continue reading on page 12
11
Ovarian rejuvenation: Continued from Page 11
Babies" (https:www.technologyreview.com/s/608033/
the-fertility-doctor-trying-to-commercialize-threeparent-babies/).
In Focus
This feature presents microscopic images from CHR’s laboratories,
edited by our Director of the Division of Laboratories and Senior
Scientist, David F. Albertini, PhD.
As it turns out, one of our New York City colleagues,
who a few months ago was in the news for helping a
woman conceive a “3-parent baby” by what is called
spindle-cell transfer, has again made the headlines.
Readers of these pages may recall that this case was
presented as an altruistic step in helping a mother
avoid another affected child, who had lost prior
children to a mitochondrial genetic disease which she
transmitted to her offspring.
Our previous reports on spindle transfer: http://kaywa.me/T9kCG
It now turns out that nothing is ever as altruistic as it
is presented to the public. As this article disclosed,
John Zhang, MD, PhD, quietly established a new
company, (seriously!) called Darwin Life already in
2016 (we assume the Food and Drug Administration,
FDA, will love the name), which on its website (http://
www.darwinlife.com) proclaims “introducing human
egg reconstitution in vitro fertilization,” i.e., the use of
nuclear transfer technology to treat older infertile
women by placing the woman’s (older) nucleus into
young egg donor’s cytoplasm.
Here is an image of a human blastocyst that has been
labeled to demonstrate the contact points between
cells making up the outer shell of the embryo, the
trophectoderm. Trophectoderm biopsies are used to
estimate the genetic composition of human embryos
in preimplantation genetic screening (PGS), a matter
of much debate here at CHR and around the world.
(For a detailed discussion of PGS/PGT-A, see articles
on pages 1 and 9 of this issue.)
We previously discussed in these pages that the
hypothesis behind such an approach of treating
older women is the belief that in older women the
mitochondria in the egg’s cytoplasm have run out
of steam. Replacing them with mitochondria from
a young egg donor, therefore, should improve the
eggs' overall quality, while any resulting child will,
overwhelmingly, still have all of his parents’ genes,
though the child will also have a very small amount of
genetic material from the egg donor (hence the name
"3-parent" IVF).
This image was taken by Agata Durda during her
summer research project at the CHR. Agata is a premed student at Pace University here in NYC.
IVF treatment cycle with spindle cell transfer!
Interestingly, Zhang is planning to offer this procedure
to women only between ages 42 to 47. Women
at these ages here at CHR still quite routinely
conceive with regular IVF. Maybe, we should invite
Zhang to a prospectively randomized study in women
at those ages, comparing not only how regular IVF
outcomes at CHR compare to those with spindle cell
transfers by Zhang, but also, what the cost difference
ends up being.
Three-parent IVF basics: http://kaywa.me/T9kCG
Importantly, at current knowledge levels, all of this
is still a hypothesis that needs to be proven. Once
again, we strongly encourage well-conducted
research to determine whether this hypothesis is
correct or not. That, however, does not seem to be
the goal of Darwin Life. As Emily Mullin reports, the
goal is to charge a laughable $80,000-120,000 per
Visit CHR on Facebook:
https://www.facebook.com/thechr
-The CHR
Fighting for every egg and embryo!
Follow CHR:
http://twitter.com/infertilityNY
12
Check out our video resources:
https://www.youtube.com/user/
CenterForHumanReprod
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13