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>> okay. we'll get started. we have a somewhat smaller but highly selective audience this afternoon but i'm sure normally there are somewhere around two to three hundred people online watching, and then when this is put on the nih video archive it
goes around the world so also exciting, a lot of people are with us for this. for those who want to take the final exam i keep telling you about, it's going to be post in two or three weeks.
the first question is to identify the structures, i'm not going to give you the answer again. today we're very fortunate to have two folks here who are knowledgeable, fertility and infertility. i
was intrigued with the quote, no society will survive are a shortage of women. disease and affliction, that's restrictive to the female. so the thoughts that run through my head when planning this, to summarize here, maybe we hope they will provoke your questions
and we'll be discussed today. so what are the facts about male and female infertility? should we really believe what we read in newspapers, a columnist who sees my way of thinking? is the rising incidence of infertility due to an aging population?
that appears in this discussion of fertility. what are the causes of infertility and how do we diagnose it, what can we do about it, sort of linked in with this is those of you who follow "science" and "nature" too, some commentaries this year, how good
is in vitro fertilization, good meaning the outcome, how successful. are there differences, does it matter? maybe this will come up today. we had talk about personalized medicine, are there thoughts as to how this is going to
influence the fertility problem? one of the more contemporary things, are we entering an era of embryo engineering, which bears on fertility issues, these are thoughts that came to my mind, we encourage you to ask questions. our first speaker today received
her ph.d. in epidemiology at the state university of new york at buffalo, she was trained as a nurse and also in sociology, has been here at nih since 2000 and she is the director and senior investigator in the division of epidemiology, statistics and preventive research in child
health and development. and as you'll see from the website where we condensed a bit her cv and put it up there so you have some references, you see the wide range of activities and studies that she's been involved and primarily from epidemiologic point of view, but
looking at some of the major issues which don't necessarily appear test tube. the second speaker received his medical degree at temple university, he's been the professor and chairman of obstetrics and gynecology at yale and tufts in boston, and
then in california, at ucla. and then came here -- when did you come here? pardon? seven years ago. amongst many accomplishments is the editor and chief of the journal on fertility and sterility, member of the
institute of medicine at the national academy, and has worked and written and discussed extensively problems related to fertility and all aspects of conception. so it's a pleasure. oh, his current title at nichd,
we're very grateful to both of you for being here and i guess you're going to lead off. >> right. good afternoon. i know it's late in the day. i thank you for coming out, infertility and fertility in general tends to attract a
sparse crowd for reasons i don't know because it's so important, and without it none of us would be here so thank you for coming. in thinking about this talk today alan thought it might be great to hear about infertility from the population perspective, and so that's what i'm going to
do is give you an overview, what we think we know to put into context a lot of the myths about what we think we know about infertility as a population level, to give you a framework to think about it clinically, one of the most disturbing figures is about half of couples
experience a problem actually come in and seek clinical care. so if you're only seeing half of the affected individuals, our clinical perspective might not be accurate. so why don't people come in and why is it hard to get a handle on infertility at the population
level? so i'm going to talk about the population perspectives, general incidence figures, risk factors, and i want to leave you with a sense infertility is more about -- more than just having a hard time getting pregnant. we're now appreciating it might
be an early signal about your health across the lifespan. and then alan is going to talk about infertility from the clinical perspective that might be of more interest to most of you and hopefully give you an overall sense of what we think we do know.
i want to start by saying that fecundity, could you impregnate a woman if you wanted to or had the opportunity, and could you get pregnant if you were a woman, so everybody thinks about fertility only pregnancy but it's so much more. there are very good population
data for most of the developed world, including the united states, to suggest that puberty, the onset for girls is earlier and faster and not so much for boys. it hasn't had such a steep decline in terms of the age of onset, and this is concerning to
a number of people, considerable controversy whether semen quality is declining across the globe with a flurry of lay articles published in the 1990s and early 2000s talking about how today's men are only half the man their father was because of current
semen quality. really quite alarming data suggesting that danish member have probably some of the poorest semen quality in the world which now means that they encourage all military con scripts as part of their baseline physical exam to donate
a semen sample so the country can monitor the quality. men in new york city look pretty good compared to the rest of the world so there you have it. but from a clinical perspective we're concerned the reproduce interval for women increased over two years over time, this
study, the first bullet suggests that for women born in 1915 through 1919, they had about 36 years of being reproductive age, for later born cohorts two years later. in part we think because of their earlier age at menarche, also the slightly increasing age
at menopause, natural, not medically or surgically induced meaning women are reproductively aged for a longer period of time. what does that mean? isn't that good? because people are starting so i have a whole collection of
cartoons about how the media portrays concerns, the potomac river, this is clearly a congress person drinking water, reading probably the washington post, spitting out his water because of what is found in the water, fish eggs found to be male and female with endocrine
disrupting chemicals. also lifestyle, this is how our study looking at bmi and semen quality that we recently completed was portrayed in the "new york times," and by the way, increasing bmi is not good for semen quality. of course, my pet peeve, i have
to be careful, this is part of the archive, is that we constantly blame women for starting later, and why, you know, wouldn't you expect maybe to experience more infertility because we're starting our families much later. and this is very true, the
average age as first pregnancy in most developed countries is now approaching 29 to 31 years depending on the country. talking about infertility which one of these men, this is about the right estimate, is likely to have infertility? they don't seem thick.
they all seem different. and if these six men came into your office and you had a bet which one would you bet? how about these women? there's nothing unique, nothing physically presenting that would allow you to be able to pick somebody out.
i love this cartoon, if only couples came dressed neatly to their physician to discuss plans for getting pregnant. the cdc has guidance for pre-conception care and most physicians surveyed underscore how important it is yet very little pre-conception guidance
is offered, mostly because people sort of decide i think they are going to start their families or try for their families maybe after a raise, a paper published, you made "science," "cell," "nature." i've done two cohorts and they decide when the mood is right
and go for it. we only have a handful of pre-conception studies across the globe, i want to remind you this is 2015. how do you tell your couples it should take? i have never gotten an empirical
answer. you can't generalize people, it depends on the woman, blah, blah, blah. i don't blame the clinical community, truth is we have very few data to get informed answer to this question, so on average maybe about a 20 to 30%
probability of getting pregnant in an exposed menstrual cycle to intercourse, and keep in mind humans are the most inefficient reproducers of all species on the planet. we don't get it right very often. and when we trying to work in
the population level we have all kind of families, all kinds of partnerships so the traditional model is null and void. so i just wanted to emphasize again when we're talking about fecundity, we're talking about biological capacity for reproduction in men and women.
fertility is a live birth, whether you fathered it or delivered it, the best biomarker we have. so this is why it's so hard to understand infertility at the population level, if only we could categorize you and you and you, into being fecund, capable
of doing it, infecund, incapable, because you were sterile for medical or contraceptive reasons or impaired fecundity. when you're trying to plan a study, population based, how do you think you know? we can't look at people across
the room, aha, and if i see you're pregnant we can plug you in, but even among couples who have impaired fecundity, they can be clinically helped to be fecund and fertile. this emphasizes the point. three couples, all had a birth, this one came through the
traditional way, fecund, became pregnant, they had their baby, their delivery, right next to this couple that had a previous loss, they became pregnant with or without treatment, clinical care, had their baby, this with treatment, this without, they resolved infertility somehow
without medical care. the outcome is the same. nowadays when we're thinking about a lot of different outcomes, child health or even couples health, just asking how many children they have probably no longer tells the picture. so infertility, when we try to
define it, it can be further broken down by primary or secondary with primary being never able to conceive, never been pregnant, whereas the secondary had a previous pregnancy, regardless of outcome, but trying to attempt, they can't get pregnant.
you probably all know individuals who have fallen into those categories, ones who -- oops, sorry. couples trying for years finally gave up, and they had a baby, right? they resolved their infertility. we know very little about
couples who resolve their infertility in a population level. however, scandinavian countries with linkages, we can look at couples who resolve infertility in months 13 through 24 because of the receipt of free infertility treatment requires
two years of trying. so we can look at who gets pregnant between month 13 and 24 and a sizeable percentage of couples do, they sort of outgrow their infertility, if you will. now, this slide really irritates me because it says here are the clinical diagnostic subtypes of
infertility, and in general they say half is attributed to male, half to female, half to the couple, 10% to the couple, 10% to unknown. did you have a question? oh, sorry. i have yet to actually see any empirical evidence from a cohort
study of triers who are clinically diagnosed, so this is our best guess, in fact there are some very good data that show the more you undergo investigation, the more factors pop up. i'm thinking about a study done in the mid-1990s at the
university of rochester where they subjected normal fertile couples who had a baby to standard infertility diagnosis and found a high percentage of both males and females of the couple with so-called indications of infertility. really what this underscores is
we still don't understand physiologic variations very well when it comes to human fecundity but it gives us something we can tell couples, and what's most important is that we now recognize that infertility is couple-based, it is not just her.
i mean, i can think about how my two aunts couldn't have babies but i never heard about my uncle not being able to father a pregnancy. so we certainly have come a long way in this regard. so population level, we try to ask people about whether we're
directly observing them or asking them to recall how long did it take, time to pregnancy, and so usually there's some prompts given and six months, most couples that are trying get pregnant within six months, of these few pre-conception studies they say the same thing, that
about the vast majority get pregnant by six months, and by 12 months of try in pre-conception studies 15 to 20% of couples will not be pregnant at 12 months. so the cut-points of six months and twelve months for conception delayed infertility do have some
empirical basis. this slide shows the cumulative probability of pregnancy, this is from a study where we recruited couples and the point is after 12 months of infertile it flattens out, we didn't go through 24 months. just because you're not pregnant
at 12 months doesn't mean you won't get pregnant even on your own. but you can see starting from about six months what the rapid increase is, and then it does slow. and so this has led to a clinical guidance for older
women, in particular, 35 and above, if you're not pregnant within six months, it's probably quite plausible and empirically supported to seek care for diagnostic evaluation. i'm not going to go over all these but looking at what accounts for how long it takes
you, but my point here is when we do study males, we usually see the same associations that we see in females but most of them are still focusing on female. i want to point out this study because there's all kinds of guidance, if you're going to get
pregnant, don't, don't, don't do all these things. we practice precautionary principle, right? and in sweden where they take birth cohorts for several years and link women with other pregnancy cohorts and data that they have, of a whole host of
lifestyle factors that were assessed, at best they could only explain 14% of the variation in couples time to pregnancy and the only factors were whether or not she used oral contraceptive before attempting per menstrual cycling, age and parity.
all this guidance we're telling people don't smoke, don't drink, don't have coffee, don't exercise too much could not be retained in the model. we don't know why it takes some couples longer than others, usually. now, retrospectively reporting
time to pregnancy, how long it took, there are only two studies that tried to assess the validity, these are two pre-conception studies, whether or not the cycle was at risk, did they have interviews in the fertile window, they interviewed the women a few years later and
asked how long. what was disturbing to us, only 17% of women could say the right number of times. this is amazing because they were doing daily reporting for a year in journals and online and they still couldn't remember, but the good muse -- news is by
three months a high percent more or less agrees. i think if we're basing it on conception delay or infertility, whether they come and tell th physician it's 13 months or 33 months, it doesn't matter, it's still getting them in the right category of whether they are
fecund or experiencing what about incidence? it's unknown. we really have very poor data except for the handful of pre-conception studies that have been able to get couples to do daily reporting on menses, on sexual intercourse and to have a
biomarker so we can identify when peak ovulation occurs. in those very couple of studies the incidence ranged from 12 to 18% with pre-conception enrollment. across the globe my point -- i think the percent that's usually talked about is about 15%, and
these numbers that are shown here is really to emphasize this is not just a developed world problem. we tend to think about the developing world or social, economically, the least resourceful countries having no problem at all.
they have too many kids in fact. how often do you hear that bias? in fact, infertility is a real problem in many parts of the globe and it has incredible economic and social stigma and implication particularly for the female partner. so the w.h.o. is very interested
in infertility across the globe. i want to tell you about the delight in finally having one of my lifelong pet peeves resolved by a great doctoral student, postdoc. so one of the surveys we do in this country, the national survey for family growth done
periodically and they report not much of an infertility problem in the u.s., that it's about 7%. and all my colleagues across the globe say how can infertility be so low in the united states when it's twice that in canada, and given how high your rates of ivf are?
that must mean your physicians are doing ivf with fertile people because the numbers don't jive. and from the time i was on faculty teaching, we looked at data, students, trying to figure out why our values are so low. along came a great danish team
led by a statistician who developed this method. what it does is removes the biases and assumption about your behavior, your behavior, your behavior when it comes to intercourse and who is at risk for intercourse and asked couples if they are on any
contraception and how long they have been without contraception and if they are sexually active. we applied this method to this same data, 7%, we applied this method based on females reporting of time, we found that the preference of infertility was more like 15% and then
believe it or not we replicated the method with a pre-doc, based on male report and find that even based on male reports, not couples, it was 12%. the point on this slide is that these are confidence intervals around the estimate and you'll notice the figure is not even in
the confidence interval. we found the 7% figure is a construct. individuals are never asked if they had infertility. they are asked about do they have a partner, do they have a regular partner, do they live together, do they have
intercourse, and so on the basis of all these answers you derive this construct, and we actually felt it was not in keeping with contemporary populations and behaviors of contemporary populations. my colleagues across the globe think okay, u.s. has outgrown
infertility problems, you have a problem just like us. we think this is probably a more realistic prevalence estimate for the u.s. now, most of the literature focuses on the female. there's lots of concerns who is going to pay for the old people,
if we don't keep this birthrate up. what this slide shows is just looking -- these are couple-based, women age 35, if her male partner is the same age prevalence of infertility is 18. for the same 35-year-old female, with a guy five years older,
prevalence nearly doubles. his age matters. just shook the world, oh my gosh, how could that be? so in the same data set, they ask a simple question is there a low tech solution to infertility? we looked at what's the one
thing you need to do to get pregnant in the traditional venue, that's to have intercourse, there's a lot of myths you can't have too much because it waters down semen quality and a host of other things. we tell people not to do some
things that is unnecessary but not sufficient condition for so in the same large database, what you saw for the couples that were having intercourse at least twice weekly, by the female's age, yes, prevalence did go up with female's age, but relative to the couples that
were only having intercourse understand once, it was much lower. so these two slides suggest a very low tech, that's going to be a joke, public health solution. have more sex with a younger male partner to reduce
there you have it. [ laughter ] you have guidance. both of these points underscore, you can't look at a couple's intended outcome from only one partner perspective. especially at the population and this is just the same slide
as the so-called determinants of time to pregnancy for infertility and i'm purposely stressing what we see in females, when we look at males. this delights me, the male biologic clock. most of my research is chemicals, lifestyle, human
fecundity and fertility, they have been all over this for a long time. yes, there are lots of movie star legend who fathered babies into their eighth and ninth decades of life, i remember hearing about them and seeing the big pictures in the
magazines. but the truth of the matter is there seems to be a male andropause like a female menopause. however, it doesn't result in quote/unquote sterility but a few longitudal studies show androgen production and
spermatogenesis does decline over the lifespan, not with the same rate as females. aging of testes and accessory glands major longitudal study, 1% reduction in blood testosterone level starting at age 30. but what is really interesting
and concerning is that advancing paternal age has been associated with a few of these pregnancy and child outcomes, all of the outcomes that we think about as being older maternal age, and in general at the population level, he is two years older than she. so the question is whether or
not we're thinking about maybe a combined parental age effect more so than just older mothers or fathers. so dads matter. so just briefly why fecundity is more than just ability to get pregnant, a lot of this is is coming from the environmental
side, i have to say, but we're now appreciating that your fecundity and fertility status is quite informative about your own health across the lifespan. for example, men that are born with genitourinary malformations across the globe are reported to have poor semen quality, so
there's been several more or let's "hits" if you will, also we know men with gu malformation are more at risk of testes cancer, and semen quality is shown to be highly associated with mortality. in denmark, in california, texas, i don't know if you self
identify with those places, and what is really interesting in the u.s. data where they are evaluating thousands of men coming from semen analysis which means at least half of them look perfectly fine, starting 7 years following that analysis they have a much higher rate of
mortality of all causes compared to the guys who are fine. and this collaborated a major study, even larger, of thousands of men in denmark suggesting semen quality may give you a sense about what's coming next. so on female there's actually people have been looking at it
longer than in males, probably because they give birth, but cohorts of girls who were born growth restricted, so less than three or fifth percentile of birth weight for gestational age enter puberty earlier, complete it faster, earlier menopause and more likelihood with metabolic
syndrome, after the reproductive years. and we know that earlier menarche or increasing length of reproductive window for women, nolo parity, poly ovarian syndrome, pre-eclampsia are associated with higher risk of cancer, and diabetes associated
with coronary heart disease, metabolic syndrome, stroke, you name it. endometriosis is associated with not only autoimmune disorders but high risk of some types of ovarian cancer as well as other reproductive site cancers, in some scandinavian countries, a
marker for tumorigenesis is something of interest. so i'm going to just end on these last two slides. has anybody ever heard of tds? denmark, neil skakebak,-a clinic at one of the major hospitals in denmark and he's been very concerned about the declining
male fecundity in the country and proposed a hypothesis called testicular dysgenesis syndrome. everybody pooh-poohed and no everybody embracing it. genes and environment come together and affect testicular development and the cells will give you a hint of what endpoint
you can see, from those results from androgen inefficiencily like genitourinary malformation, and it changed the toxicology paradigm, the dose makes the poison, you look a and oneoutcome and so now people are looking at a spectrum of reproductive outcomes. so i was trying to figure out
why the androgenrology world was so far ahead of the gynecology world because there was nobody talking about could the same sort of thing be happening with the female gonad, and quite frankly the male and female go mads aren't that different. i had another post dock, we were
kind of frustrated we tried to see if there was an ods, ovarian disgenesis syndrome and we had enough to do to think about cds and basically the same thing, that depending on mode of action, you could have a whole spectrum of end points in females, too.
and basically all anybody's trying to say, is in reproductive health, it might give us signals about what's down stream, upstream, depending on your perspective. what are you likely to encounter in your life. on that note, there's a great
deal of concern across the globe on the part of them but not all. i share the concern, i will just say, that are historically, record low fertility rates may not just simply be coupled, so you know from the pregnancy tmay be that our basic underlying biology as snps.
and this is a critical tipping point, the whole hypothesis gateway to this. so it's propose thad male reproductive health can be the canary in the case for the population, if we know what's happening to him, we might have a sense of what's happening at
the health population level and because of the rapid rate of onset of the decline of course, the couple of decades, people feel that it's more than just genes. it has to be changes in the environment instead. on that note, i will talk about
the clinical per oh, okay. >> --especially in the united states and different [indiscernible] yes, people are loking at time to pregnancy, how long it takes to geeing pregnant in relation to the length of guestation and
carry the pregnancy and birth, size, even some data on birth defects. and in general the evidence suggest thad longer it takes, the higher the odds of having earlier baby, a lighter baby, birth defects, certain ones, not all seem to be associated as
well so people are definitely think being it. haven't had it directly linked to infant mortality, only in preterm delivery. >> good talk. >> you mentioned the fertility problems are related to a couple factors what could that entail?
with one or the other? >> both of them have something onboard, that might make it difficult for them to be conceived, it could be quality and she has endometriosis and one of the things that is very interesting o me is that we really have very poor data on
the odds of getting pregnant. if she's a little off, the odds if he's a lile off and the odds if they're both a little off. we just don't have those data right now and i don't think--alan's going about this but even with semen quality, we
do the fancy analysis, nothing prediblghts whether the cole can get pregnant or not. and there are authors right now arguing why are we dog this either to look at spermia or other updates because we haven't been able to get prediction out of the semen analysis.
so it would be a couple come nothing for evaluation, whether he found one or more things in each of them. >> were there any sort of large scale perspective studies going on that are designed to look at both the biological and perhaps functional aspects of fertility.
well we finished some a couple years ago where we followed 500 through the population, and then we could only follow them for a few years and from preginance tow delivery and we've been looking at chemicals, the lifestyle because i like to have a hopefulness, at least on some
of the environmental chemicals, you can't do much about them. they near your body, they have long half life so it doesn't sound very hopeful so we're looking at the role of strelsz andoxidative stress to look get a better sense. but i think it's exciting
because the new science, new statistical models are called joint models and so if we see like the bmi effect, the semen quality in our study, the next question is does it impact time of pregnancy or pregnancy loss. so he has poor quality semen, so it doesn't mean the couple will
take longer and are they at higher risk for pregnancy loss, so the new models, can you canmodel more than one end point. you can model your cancer diagnosis and hypertension and something else. this is really exciting. this is how people come to us.
>> alan are you going to discuss something about the impact of industry, agriculture, pharmaceutical, industry in terms of paths o genesis of fertility and those things related, is there any concerted movement, organizationally, professionally, from wherever to
deal with this, it's a general public aware. >> how many of you use is sunscreen in this room? only one? >> so we're not going to talk about that but it is an emerging compound of uv filters. anybody use colored dish soap?
okay. so these are compounds that are being--they're the spf factors in our sunscreen, they're being added to all personal care products, bug repellants you make it but also these uv filters are add because where do women keep their dish soap, near
the window, right? and you wouldn't want the dish soap to fade and these are highly effective at absorbing uv radiation but we're recently discovering they're so prevalent in the population on basis of biomonitorring data that cdc does for nhanes and it's
concerning and the basic researchers are finding that some of these are very highly estro genic among other biological properties and so in our study, we decided to look at them, some of the first data and we're seeing on time to pregnancy, this level, really is
what's driving the couple's kind of pregnancy, not hers at all. so we thought, well, what about semen quality, so we just submitted this paper and we're seeing very strong signals of semen quality all focus on alterations in the head. so at the joint modeling, the
next thing we're working on, we can say, males, expose tower uv filter, semen quality and does it translate actually to a longer time to pregnancy so we could begin to get those answered. so we're not going to be talking about it but the e. u. just has
a series of papers where they're attribute male factor infertility, neural developmental diseases in children. i know there's a cancer one, i can't remember which one. attributing the cause to environmental chemicals and then
they cost it out what it costs the union, so they just come out, i encourage to you take a look. i think they're at jcem, so i know this is going to be a hot one for the u.s. to follow through with. >> a few years ago when shaving
creams all had--what was it? >> i don't know. >> what was it alan, the stuff that closed the ozone, they were concerned with its release in the atmoshphere. >> aerosol. >> well that disappeared industrially within a couple of
right. because of good, really public reaction. i don't think there were any companies out there. >> same thing either way, the bpa which makes plastic stuff-- >> the point we're getting at is how do you convey this
information to the general public, not just to people who go to a doctor, but you don't read about anything like this that you're talking about where your read is the more hysterical stuff. >> a lot of the lay magazines do a nice job.
new york times writes a lot on a question of environmental chemicals and i think they do, i have to say a fabulous job. there are lots of web sites, coalitions, american colleges of gynecology, endocrine society, there's another one i can't remember, it's afrm, all the
presidents have come together to say that we need to get finite answers because, you know there isn't a lot of research, still. so i mean, but i think, people have--we can certainly answer this question, but we just need to be able to do the studies. >> you.
don't go away. [ applause ] >> i'm not. >> okay, and great. okay, good. >> okay, so i will skip over a lot of slides because i don't have a lot of time but i will hit the highlights.
>> no, no, these people want to get out of here. come on. it's the end of a long day. so number one, the only reason that we're here, biologically is to reproduce, so when you're done reproducing biologically, you fill filled your obligation
as to being born. now, is infertility a disease or not? most people think that it is a disease, but the government does not think it's a disease and for that reason, it's not been very well covered as far as insurance is concerned.
so a big problem with infertility treatment is that it's all out of pocket and it's a very expensive treatment, a we will know more about that in a minute. let's see, the causes of fertility at this, but as far as female is concerned, occluded
falopennian tube system important, the factor is a result of infection, male factor was covered quite well, a large part of women that don't ovulate, have the regular cycles and they don't produce eggs and if a woman life--well a woman with polycystic ovary syndrome,
ovulating only four or five times a year, so her ability to conceive is cut in half compared to the normal woman who ovulates 13 times a year and of course there is that unexplained infertility group that germane mentioned. now this is what the biology
consists of. i can come out here, right? , yes. >> so here's the ovary, start out with primordial follicles, these are formed four months before they are produced and they are independent of generatedat o tropeins and this
is probably an area where toxins have a pretty strong input. then, the cycle starts on day one and on day 14, the egg is released into the falopennian tube, and the sperm has to be in there before the egg gets released. the average sperm count and
200 million sperm is only a thousand ever get into the falopennian tube, so it's a difficult trip for the sperm. fertilization occurs in the end of the falopennian tube, the embryo then stays in the falopennian tube for about the four days tthen comes into the
utexous and constantly dedividing and i'll show you some blastocysts in just a few minutes and then it implant and you can see implantation here. now if a hundred eggs are ovulated, only 20 of those will turn out to be pregnancies. so there's a giant loss in the
falopennian tube of fertilized eggs. now we don't know that, we don't know that of our patients but it's probably something that we'll learn in a future and giant cause of infertility, what causes those eggs to fertilize but never make it to the point
where they go on to--go on to the egg. and this goes through the paradigm of ovulation, the number of chromosomes, splitting and eventually a haplotype you see in the oocyte that's finally ovulated in the far left. now sperm, are interesting as
well. sperm penetrate through the canwall, outside wall, but th] only--only one sperm can get into the--get into the egg to fertilize the oocyte nucleus, if not you would have problems so as soon as the sperm penetrates--there's a laser here
well it doesn't matter. as soon as the sperm penetrates those cortical granules you see activate and no other sperm can get in. yes there are diseases where the cortical granules don't work but in those cases of course, those cases of polyspermia and those
embryos are not viable. so it's a very complicated system, it's amazing it works at all but obviously it works in most patients and it works most of the time and this is just an ultrasound of an oocyte, you can see the black whole and of course this is a laproscopy of
the pelvis, you can see the uterrous, can you see the flail opennian tubes and you can see the ovaries. now the eggs get into the falopennian tube by happen stance. there's no mechanism by which the tube speaks to the oocyte
and there's no way that the--that we know that the egg and sperm talk to each other, so it's just a case where the falopennian tube encases the ovary, and the egg gets into the pale opennian tube, usually only one egg maturely and made percycle and the same with the
sperm, here's the egg here and the sperm is swimming around and it's just mass action that that sperm gets in and unexplaining perfillity to give medications that that make four or five eggs and it newellerically increases the chance, if you have four or five eggs were likely that the
sperm get in and it's more likely that the falopennian tube will pick up the eggs so that's one of the treatments for patients with unexplained fertility. now male factor. this is a man with a free radicalson jock strap, one of
the reasons well, the testicles are descended in the male, in order to keep the temperature 1 degree below normal basal interior temperature, because if you, if the testicles were interior and we have cases where they're not distended then the testicles woancht make sperm so
that's why they're distended. now i will tell you this fact that you will remember forever there are two mammals that don't have descended testicles. one is the whale. and the reason that the whale--well, the whale and the dolphin, mammal, the dolphin
that's a mammal and of course that makes sense because the water was very cold and that's just as harmful for making sperm as the core basal temperature, the other is the elephant and the reason for the elephant was once an aquatic animal and the trunk was a snorkel and for that
reason, the elephant has evolved to have internal testicles even though it's a--even though it's a land mammal--land mammal now. now of course, the sperm count is critical. it's the physical examination of the fetterile male, to look at sperm count, it is
controversial, there are ways to measure sperm and i don't want to go into the details but most are done by this technique where it's a strobe light and and you can see that the moving sperm, this is just one sperm and you can see it moving and if you see a sperm like this, it's not
moving, it's a dead sperm. and most sperm counts are down this way. the least important important factor in this sperm count is the way that sperm looks. the morphology. the most important feature of the firm is the ability to swim.
it's motility obviously, it has to get to where it's involved in this action. now this is a study that was done at the university of washington; it's a one--this is one male, they studied five mails and they had them do sperm counts over 120 weeks.
they were not allowed to have any other, every time they ejaculated it had to be for the sake of the sperm count and what can you see very interestingly s&p that the sperm count changes dramatically, probably around 70 or 80 weeks. well from the day the sperm is
released it was formed 70 days ago, so that probably indicates that that male had a cold or a peb role episode that drove the sperm could you recollect down. so we get two sperm counts on that to make sure that we're getting the normal is, and the frequency of they're having
intercourse, if they're having every typh days if they're every five days, if it's every day, it's every day. of other thing is here it shows how desperate some submittal students are to get through medical school that they're willing to participate in this
study. now germane mentioned older men, this is owen o'neill, but the fact is a good one. male factor pertility does increase with age as does single gene defects. but in women, it's a little bit more interesting or maybe
interesting is the wrong word but it's a little more understandable because it's an olfactory. what happens in women as they age, the five rules break down more easily and then you get nondisjunction of the proem studies of
-chromosomes, so what an example of that is downs syndrome where in older women it's more common because the chromosomes break away in taken--they fashion. now what you see in older women is not only is fertility anda we'll talk about ha in a minute
not only does fertility decline but also the rate of miscarriage because these are very high in older women as like turner syndrome and those that break now it's interesting because it was always thought that that was the women's problem, that those break because it's in an older
egg, but the truth is 15% of the time, they're the break is due to the male, that the male contributes to those fib rules as well, because they break, this shows age and it shows the miscarriage rate as women go on to get older. now, unfortunately a lot of data
we work with, as germane mention side looking at the infertile population, there's not a lot of populationot fetterile population, this happens to be a study that's not a bad study, it does come from a general population, but most of the studies come from infertile
populations so one has to take that into consideration. next problem of course is ovulation, this sticks at the top, this is basian decoder at body temperature, after temperature, the basal body temperature, because of the production of project roan does
up 610ths of a degree and you can see--.6-10ths of a degree and you look at the surge, now when you had the l. a. surge, the patient doesn't ovulate for 36 hours, so when the stick turns color they shouldn't have intercourse for 36 hours or 24 hours and most people don't
believe that and they have intercourse as soon as the stick turns blue because they think well that has to be because that's the way the test is designed and it takes at least 24-36 hours for that surge to cause the [indiscernible] to be now tubal disease used to be
treated by tubal surgery. this is a tube that was onstructurally indeed the middle and you will do an anast mowsis, put the two together, so it open, the brace to bring it together, the tubal surgery has disappeared to a great degree and it's been replaced by
invitro fetterrizealization, so in 1978, baby brown was born in england, step ford and edwards, after reportedly a hundred hundred tries, a thousand tries for all we know, they had a pregnancy based on putting this sperm and egg in a petary dish allowing the embro o to form and
putting it back into the uterrous and you can see here, the egg, the sperm, that's where the sperm is injected into the egg, it was motility of the sperm is not good enough to get in. can you see the two nuclei here, can you see an early embryo and
you can see a blastocyst has about 150 cells, here the embryo has six-eight cells. and this is just the implantation, can you see this personal fluid where the--where the embryo was placed inside the uterine cavity. now here, this is all the
different treatments, as far as fertility is concerned. you can do iui, which means washing the sperm and putting it up in the uterrous, so instead of a thousand, 10,000 get up in the falopennian tube. it's the least successful or least helpful treatment.
the next is clough mid, and it causes you--causes the patient to make more eggs, you do clomid, and iui, and there's difference there, so hmg is injectable, so instead of four eggs you make 10 or 20. looking at the numbers it reintegrated services creases
pregnancy rate and the last is ivf where the put the embryo back in the uterterrous so it's not unknown as far as egg and sperm is concerned. now the problem of course, is the better the treatment, as far as the outcome is concerned the more expensive said.
and you can see here, ivf is $9000, hormonal treatment is a $2000, just for--just as an example. so this is an expensive process. i now want to--that's the biology, i have more biology but it's more ethics and questions than it is looking at the actual
biology. so a good problem is, having twins. most inferile patients want to have twins. there is seivet% of infertile patients that have ivf, they want to are twins. reason they want twins, they've
waited a long time and it's economically better and you go through one cycle of ivf and have you two children, the problem is for the obstetrician, twins are a problem because twins are associated, yes they look cute when you kind of walk into the grocery store or
supermarket and they're there, but twins of course have problems and mainly based on an increased prematurity rate, but most patients want--most peoplement twins. but luckily or in a responsible way, most of us through single embryo transfer now.
you put one embryo back, it's very rare that have you twins and--those are just identical twins and that's a happen so single embryo transfer is very important. it's a very important--very important concept and i guess and accept it as a reasonable
form of treatment. this is a study that we've been looking at single verses double embryo transfer and you can see that the single--eventually the single transfer has done just as well, as the--putting back to. now the other thing that's important is now that we grow
embryos, instead of putting them back on day three, we put them back on day five. so we know the healthier embryos, the stronger--stronger embryos have made it to day five, therefore putting one back is successful. now of course, this is a
technology that's gone awry. we're very highly scrutinized. one of the reasons is that kind of everybody is participate nothing reproduction in some way or another so people are interested in that, but nevertheless we had problems. this was one of them this, was a
patient that had multiple eggs, it wasn't ivf if was ovulation induction and fertilization that way but you can--you know the press show this is cute picture with everybody, everybody with milk on their upper lips but the truth is all these babies are severely damaged.
some of them are deaf, one is blind and deaf, most of them are feed by feeding tubes because they were born at just about a pound. so this is something we like to avoid but it makes it into the press quite often. so now let's talk any some of
the legal aspects of this. who owns the embryo? famous case couple of treated in norfolk, they had a frozen embryo, the couple moved to california, they wanted the people in norfolk to ship their embryo by way of fedex, to california.
the group in norfolk, can't do that, suppose the embryo sits on the tarmac and becomes hot and the embryo is destroyed, we're not going to release it, it was actually a doctor that was the owner, doctor and his wife were the owner of that embryo but the court said that the couple owns
the embryo and they can determine what happens to it. suro gasy is a giant issue where a third party is involved. embryo research is something that's very interesting to us here. --so when you do ivf, every embryo is not perfect, don't put
them back, but we don't do ivf here at the nih. cloning of course, is an intellectual discussion. no one does cloning and no one's particularly interested in it, the original when [indiscernible] was born, people said cloning would be great
because we could make a copy of you so that when you were 80 and your copy was 20 and you needed a kidney, they could take the kidney from the 20 year-old and give it to the 80 year-old. well that's ridiculous because the 20 year-old would be a person and not necessarily--not
an organ grower. and now regulation, regulation is very interesting. we're the only specialty that has a registry where every ivf cycle is registered. there are false in it, but nevertheless it is a regulated industry and we will talk one
minute about that that it will become more regulated. now some of the ethical is sex selection something we can do? it is successful, if you came in and said you wanted a male, a child, we could put only the male embryos back, we can sex
embryos but most people, it's a mute question because most people don't want to pay $12,000 to have the gender, if they can afford it, the gender they particularly want. now what about postmortem reproduction, where a man is killed in an accident and the
urology goes and collects that sperm and freezes that sperm so that they can have--so that family can have that genetic material procreated. storage, what happens to the embryos, how do you destroy them and what happens to the embryos and treating patients as far as
disease is certained, i will give you one example of that. i spoke to the little people of america a number of years okay and seeds that achond rough atom placia could be eliminate indeed one generation, it's a single gene, makes abnormal cartilage, well they went nuts because they
don't view it as a disease. they get married, they have children, they work, they have lives, and so i disease perpetuation is a question and one of them still, each after 20 years one of the most controversial things we do is single women insemester nation
where a woman goes to a sperm bank, she's not married of course now freezing egg system another issue. so the last thing i want to talk about is mitochondrial, treatment of mitochondrial disease and this is a very current issue and it ties this
all together. mitochondrial disease is a serious spectrum of deceases teffects almost every organ, some people are blind, some people have no muscle strength, some people are blind and have no muscle strength, some people have hearing defects.
it can be very profound. it can be very mild. but it's usually pretty profound. it's carried in the mitochondria. so the treatment is is to take out the nucleus of the effected embryo, and put it in--take out
the nucleus of a healthy--healthy egg, that has normal mitochondria and put that in there and let that--that patient--let that child be born free of mitochondrial disease. now there's a couple quandarys here, one is once that person now--you've changed the germ
line in that patient because if it's a female, the new mitochondria and that's why it's called third parent procreation is that third--that now that mitochondrial passed on from generation to generation. because this is complicated because the mitochondria,
doesn't give you much, it's not identifiable. you don't look a special way because of the might o chond riathere is one caveat here in that it could--there are animal experiments that show that one milt o chond ria is different than a mitochondria and that
some mitochondria have more energy associated with it. so you know, if you have--you want to have an athlete, you take the mitochondria from a woman who's a mar raathon runnener the--marathon runner in the olympirks. so that's one facet of this.
the other is that the fda because it's the result of a transplant, the fda is going to weigh in on this and to regulate it. so it's also interesting because it will trickle down to the whole field. so this is--this is a
dynamically growing field. there are lots of questions. we've done great. we've done great things in the last 30 years but we've raised a number of interesting questions. now i'll give my answer to the mitochondrial question as far as ethics are concerned.
the child has three options tcan be born with severe mitochondrial disease, born free of disease, or not be here at all and as a physician, the middle one is the best one to be and on that note i'll stop. thanks. [ applause ]
[inaudible question from audience] >> those that make sperm survive and those that didn't make sperm, that brand disappeared so it's survival of the fittest essentially. >> okay, thank you. >> so what about--there's this
question of--that pops up in the newspapers and more journals of the claim when they follow kids who were born by invitro fertilization that they're shorter or not so smart or green hair or all kinds of business, is there anything to that? >> the's no evidence of any
problem, these kids that are born that way. now, there is--the only thing that's documented is that there's a slight increase in congenital anomalies in these offspring. and there are methylation problems like decaweed men or
had--i'm not trying to minimize it but these are all. now let's say congenital anomalies, the average congenital anomaly rate in a normal conception is four%. in a--well post ivf seem parallel and 7 percent, so the paper says it's twice as high,
if you go from four to seven, that's fair enough that this place is high, but to a couple when you tell them you have the 93% chance of a inarmal child, compared to a 90--96% chance that it doesn't dissuade, i mean we inform them but it doesn't dissuade patients but i'll tell
you an interesting paper, we didn't publish in the--actually it was just kind of published, i don't know if it was the same people or not, but in the bay area, faye fobbed that patients that were born from ivf had a higher incidence of autism than the general population.
but the truth is, this is a bad population study autism, number one the people that can afford it are pretty much in the computer industry in that area, they're usually in the computer area when they're older because they're slightly not socially well adept and many people in
that area, in that industry, you ow have--they're compromised. their autism spectrum patients anyway. >> so, it's hard to differentiate whether this is precluded or whether it is an effect of ivf, but other populations have--they've looked
for that and they haven't found that. so it's--by and large, this is a good outcome. this is a--it's a good outcome for patients but that doesn't mine it shouldn't be continued to be studied and once the fda gets involved, in this, then
there will be certainly better monitored. >> so we should add to the formula that it should be a young man, a young woman and somebody who's not in the computer industry. [laughter] >> well i tried to do an
experiment, have an island somewhere in the caribbean, with young women and bring older men in, have them procreate these women so we can see--we have many, many men volunteering but no women would volunteer for the >> how long have you had any other questis?
>> [laughter] >> microsoft announced today, i read it quickly in the paper this morning that they are going to be hiring folks with aspergers, because they real real have fantastic attention to the level of detail especially like for computer debugging.
>> yeah, i saw that well thatta a fact. many people in that industry are aspergers, and you know they have special talents. >> well, wait a minute we shouldn't get into that--listen, thank you. >> don't forget where you work.
>> we'll cut that out joseph. >> listen, thank you both, very, very much. that was very informative and exciting.