Sex and Gender Differences in Health & Disease

Stanford University well good evening everyone great to see you here again tonight just one apology unfortunately as much for me I will miss next week’s presentation because I’m on my way to Brazil so I couldn’t quite figure it sounds like it’s gonna be fun but I’m just gonna be there for a day and a half so there you go and it won’t I doubt all the outdoors even for two minutes at that time but anyhow tonight we’re gonna move away from some of the themes that we focused on in the past have a interesting tour of a topic that doesn’t get enough attention and that’s the issues of sex and gender and how they influence health and disease now we talked a lot about aging last week which was interesting in its own right and we haven’t talked about the impact the gender plays on aging but you know and on Aging and you put you know that there is an impact because those of you who Harbor the Y chromosome which parenthetically is shrinking over time not to frighten you but forget about your testosterone in the long run is a factor that that actually doesn’t subscribe to longevity as much does having two X chromosomes so there are differences in many features of life in health that are important and a champion investigator for this over literally decades of time as our speaker tonight Marcia Stefanik who I have had the privilege of both listening to and learning from during the time that I’ve been here and she has been the kind of investigator whose work has literally made headlines for some time now she has been a lead investigator in the Women’s Health Initiative and for those of you who’ve followed the press and paid attention to the changing recommendations that have occurred with regard to things like hormones diet exercise impact on one gender or another she has been the lead person for these contributions second reason why I was very eager to have her present tonight is because we’ve talked a lot about individual areas of health initiative and research that is sometimes at the laboratory level but we haven’t sprung up to the area of population-based research so the kind of work that she’s going to be contributing to in the discussion tonight is the area that we’re paying increased amounts of attention to and that’s the realm of population science now Marsha has a long legacy that led her to this place which started like almost everybody else that seems to me on the East Coast she was north of Boston in Pennsylvania at the University of Pennsylvania and south see when you’re from Boston you don’t think but it’s true she was south of Boston I guess south of the Charles River as they say and did our undergraduate work at Penn and then came to Stanford where she did her doctoral work and she has been on the faculty in the Stanford center for prevention which has been a lead organization in the Department of Medicine leading to many of the initiatives that I’ve already described so I’m really pleased to have a real icon Marcia Stefanik speak for us tonight Marcia thank you I don’t know about the icon part so I’ll say that I come from a large family with four brothers and two sisters and so sex differences is something that always interested me like why are they different from me and my sisters so I would like to start with audio sex differences I think most of us would immediately know a man from a woman but you may not realize that when we talk about the most sexually dimorphic bone in the body it’s the pelvis and this interests me a lot I do work in bone research to try and understand what it is about the genes that will turn a bone into a male pelvis so that you actually have the maximal locomotion skills versus a female pelvis so you can get a head out through that that opening and lots of women have died because they couldn’t get a head out through that opening and lots of women are still dying so these are very important pressures these two forces acting on

this one bone and it interests me a lot to try and understand why do sex differences affect all of these genes and all of the the traits that we’re going to be talking about tonight once you’ve got a different pelvis you’ve got a different leg structure basically you’re going to have a very different angle coming down from that pelvis if you have wide hips and you’re not going to run quite as fast and you’re not going to be quite as capable in certain kinds of things as someone who’s got really narrow hips and doesn’t have to come down that way and if you start to look at the elite running female runners they have narrow hips relative to wider hit women so we have a lot of dimorphism even within each of the sexes the other thing that’s going to happen then is once you’ve got a different kind of angle coming on to the knee you have a different knee structure and we do have the case that we have certain kinds of injuries that women experience much more than men do because of our biomechanics so we could do a whole talk on biomechanics but we don’t have time on the other side of the coin is the ribcage if you’ve ever noticed men have barrel shaped ribs if you do yoga you know that they breathe with their diaphragm women actually have kind of bucket handle hit ribs we we breathe differently until we get into our eighth or ninth month of pregnancy when life gets really hard you can’t get that diaphragm pushed down anymore and you start to really appreciate why you would end up with a different kind of rib structure and women will start to complain that their ribs really hurt in that eighth or ninth month but this is another case where to some extent it’s our reproductive function that has really created these different kinds of bone structures once you’ve got that kind of a rib and actually to some extent it relates to the collarbone you’re gonna have a really different shoulder girdle as well once we start to put the muscle on to this we’re going to have a different way of throwing but there are so many reasons that men and women are different when we talk about sports and when you look within each sport you’re going to see that the women who are excelling in things that normally would be a male skeleton have skeletons that are a little bit more in that direction these are distributions that vary dramatically across each sport each ethnic group we have lots of variety but we end up with a male and a female prototype so we have very well known differences in bone mass men have thicker bones we’re going to talk about that a bit a greater muscle mass lower percent body fat these are very much affected by the sex hormones and this has been my interest for a long time there’s also I think last week you probably would have heard more intra-abdominal fat you should know that the intra-abdominal fat is actually physiologically very different from subcutaneous fat those of you women who hate your thighs and your hips that fat is not easily released but lipolysis factors for that fat is very different physiologically from the intra-abdominal fat the good news for women is that that fat is also fairly safe you’re not going to release it just with stress whereas if you have a lot of intra-abdominal fat that goes right into the portal circulation right into the liver and starts to wreak all kinds of havoc on proteins that relate to your cholesterol profile and your your blood clotting factors so there’s lots of interesting issues about that and we’ll come back to that as well now what’s less appreciated is how different all the other organs are other than size so it’s true that a smaller person will have a smaller heart and so on and so forth but there’s actually structural differences in the brain there the brains are really quite different there’s some great research going on here at Stanford on those issues but each of the other systems do have sex differences that are not fully appreciated certainly not brought into a lot of the medical education and so you’re lucky in your mini medical course that you’re going to get a little bit of it what I’m going to do is I’m going to start with your sex determination recognize that the chromosomes is kind of the key we all think about the X X as a female and the X Y as a male on the on the Y chromosome there is a special region called the sexual sex determining region of the short arm of the Y chromosome and about six to eight weeks of gestation it starts as a director protein that’s going to bind the DNA and then it’s going to change the cells that are in the genital Ridge and eventually turn an indifferent going out into a testes I’m going to show you that in a moment but what’s really interesting is that we’ve been following this story long enough now that we’re aware that there are other places and some of the autosomes which are not the sex chromosomes there are genes that can actually play a role in how the testes differentiates and also in the short arm of the X there’s a particular gene and so we keep learning about these new genes and I’ll tell you their way that we’ve learned about it is in through it is by infertility clinics it turns out that in Sweden any case of infertility gets worked up genetically and they

start to really try and understand what is it about this particular person that maybe why they ended up being a different sex from what we expect so if we have an xx male we don’t expect that or an XY female and they’ve actually done all of these studies to try and sort this out now when we talk about the X chromosome the one thing to realize is that it has nearly 1,100 genes compared to the Y chromosome which has less than 80 genes so they’re very different in terms of these genes most of the X chromosome if you have tube X’s most of the second one gets inactivated or it’s actually kind of a random way that this happens but some of them actually escaped inactivation and that plays a role in some of the sex differences that we’ll be talking about when we talk about recombination you actually can have recombination so I think you probably had some genetics and you know how the strands pair up well on the short arm of the X and the y they do have some of this recombination and also genes on the Y chromosome well the other point to make is that the genes on the Y chromosome have about twice the mutation rate as those on the x question when we look at the X chromosome if there were two x’s you’d really see this but there’s a short arm and a long arm of this chromosome so the short arm is analogous to essentially the short arm and here’s a sexually dimorphic this is a schematic so it’s not very true to life but there’s also housekeeping genes that are on these chromosomes that take care of the whole chromosome just to keep it intact okay so as I mentioned there’s an inactivation that occurs so we don’t actually have two active X’s there is an inactivation of one of the x’s and this is happens really early on it’s thought to happen at the xx cells stage of the blastocyst but not all of the second acts isn’t activated about 15% of the genes on the inactive x escape and not all these escaped genes are on the Y not all escaped genes are on the Y so we have escaped genes that are sexes 10% are partially inactivated so we basically have a lot of places that we can get sex differences because of how these particular chromosomes function and in fact there’s a really interesting book called females or mosaics and to just give you some sense identical twin girls are not as identical as identical twin boys and that’s because in the case of the girls they could have this random inactivation and so they may have very different sets of what was in activated and activated whereas for the boys they just have one X and that doesn’t get inactivated the other issue to notice about sex differences x-linked recessive mutations and actually an infertility technology they have the means to examine the embryos to see is there X is there an x-linked problem on one of them and they can basically decide that that’s not one that we’re going to implant so this is a strategy that some people actually use to be sure that they don’t end up with these x-linked genes most of us just go along with what we’re going to get this is going to call us cuz of colorblindness and males in a much higher rate and a number of other issues that are again sex differences arising from these chromosomes now I’ll just mention that the female the fetal testes doesn’t actually start to secrete testosterone until about eight to ten weeks but what’s important about that is that the fetal testes does tikrit testosterone and that’s going to become important as we proceed what I’d like to do is say just a little bit of embryology and to recognize that in the beginning we are indifferent we’re not male and female we have an X and an XY those chromosomes may or may not act like XY z– as we just said depending on what’s going on with the other genes in the whole chromosome set but we can start with a buy more do a buy potential gonad and a really interesting issue is that the germ cells come from a totally different place they migrate through the embryo and they find where that gonad is going to be and depending on what happens by the time they get there either going to become sperm or eggs and so we basically have a very interesting potential to be male or female if we then take the next and this is at the five-week stage that these that the germ cells start their migration when we move on into the indifferent stage for the internal genitalia about seven weeks we have two complete sets of ducks we can be we basically could become hermaphrodites if both of these systems would completely Perdue develop but we basically have a Meza net freak duct system that becomes the wolffian ducts those will evolve into the epididymis

vas deferens and seminal vesicles if there’s testosterone present now you don’t need estrogen because you’re in a pregnant woman who’s just bathed in estrogen so what you need is you need another hormone to get in there and basically say hey there’s something else going on here and that testosterone is going to come from the fetal gonad the Parham has an effort dots become the mullerian ducts these left on their own would become a uterus fallopian tubes in the vagina but the fetal testes secretes not only testosterone but a protein called anti-mullerian hormone that suppresses the mullerian ducts and so as long as you’re secreting that protein you’ll get rid of the mullerian ducts so you’ll you won’t be a female in terms of those organs and as long as you have testosterone you’re going to end up with the the male ducts and so again without testosterone the wolffian ducts disappear without the anti-mullerian hormone the mullerian ducts disappear so we’re going to end up with one set of ducts depending on whether we have testosterone and the AMH will be a male well we’ll have male genitalia it’s a little hard to say what we will actually be for other reasons and if we don’t have testosterone or AMH we’ll have the female organs now that said another thing that I think is really interesting about all of this and just to kind of think through the fact that if all of this is programmed in to end up with these very dimorphic organs genitalia what else is going on in the whole body and we haven’t we haven’t even begun to touch into all of the other things that we should be studying and I will just do a quick sales job and let you know June 11th we’re having a very special symposium here at Stanford on beyond X&Y it’s it’s a it’s a basic science clinical science grouping where we’re going to really go through and it’s all the Institutes of Medicine are involved in this so that we’re going to be looking at all of these issues from a very basic scientific perspective to see what are the clinical relevance but one that I can just quickly mention is not only do we have to make a testes but the testes starts out the indifferent going it starts up in the abdominal cavity just like the ovaries where they’re going to end up but the testes has to migrate out from that spot make it through the abdominal wall and you all know about England all hernias which is because you have basically major way out of the abdominal organ down underneath the skin into the scrotal what will become the scrotal sack and that’s where you’re going to end up if all goes well now if all doesn’t go well and you end up with an undescended testes you have a clinical problem potentially infertility and this is something that sometimes this can be reversed with hormonal treatment at the time of puberty but this is one of the clinical issues that could happen and then the other one that I just mentioned is the inguinal hernia where you essentially have a place that you could have a little opening and some of the intestines could come out into that opening and cause a lot of pain when they can actually have umbilical hernias there are other places you can have hernias but the one that we hear the most about is this ability is this inguinal hernia so the point on this one is you can see where this is emerging and making its way through as it as it migrates down into where it’s going to take up residence as an adult so again these indifferent internal genitalia will turn into a male set and a fee set of the genitalia we don’t have time to go into more detail the other thing that we have to change is the external genitalia so again we have an indifferent stage about eight weeks you really can’t tell the difference between a male and a female at eight weeks and if you have enough androgen on board and this can be coming from the fetal testes but it could come from other things if a female is exposed to testosterone in utero or in in pregnancy this can happen there are also hormones that can be released from the adrenal gland that will be androgens androgenic can be converted to more energetic components so you can actually end up with a masculinization of what would have otherwise been a female the most potent androgen is dihydrotestosterone this is coming from testosterone in the skin in general a tissue there’s a special enzyme and I can tell you if you don’t have that enzyme you’re not going to be able to look as as male and I’ll quickly tell you that one of the interesting things that occurred during why I guess I’ll give away my age if I say this but when I was studying as a graduate student there was the finding that there’s this whole group of people that

have a genetic there’s a lot of in this community that have particular genetic mutation that they they basically do not make 5 alpha reductase and so they are born looking like girls and when they go through puberty because testosterone is so high at puberty they actually then have enough testosterone to change the situation and they essentially start to develop a penis and they start to look much more like males and in these cultures they actually have words for this penis at 12:00 and known locally as machi hem bras I don’t know if I said it right anyone who knows Spanish could say which is first woman than male and the whole community celebrates these people they recognize that we have three kinds of sexes we have a male that will stay on male a female that will stay a female and then we have a female that’s going to become a male and so we have some very interesting issues there as I pointed out or differentiation will occur at the time of puberty and this is basically from directly from testosterone that will induce the growth of the penis and then DHT will cause more changes in the prostate this is really just kind of showing you the differences between becoming a male and becoming a female and another important issue is the labia will actually fuse in the mail so that we end up with a scrotum and they’ll stay open in the female and I won’t go through all the other details there another area that changes before you’re born so all of that’s before you’re born is the hypothalamic pituitary gonadal trip and banana axis essentially we’re going to be regulating how these hormones are produced from a signal from the brain that’s going to go to the pituitary that’s eventually going to release a hormone that’s going to go to the the gonads and either stimulate testosterone or estrogen as the case may be now it actually turns out that all of that happens in utero there is a huge surge of testosterone somewhere about the eight weeks period in utero and so a lot of changes happen in the brain in eight weeks of gestation and some of those changes will continue on through but an interesting issue is that in early infancy within a few minutes of birth there’s an out there LH has this big surge about a tenfold increase in males that doesn’t happen in females it’s a short-lived surge but for about the first three hours after birth of a boy there is this big surge which then means there’s a testosterone peak and this goes on for about 12 hours so these are things that people aren’t aware of because you’re paying attention to lots of other issues but something to just realize is how much is happening before we’re even paying attention to being a girl and a boy so again the first few days after birth follicle stimulating hormone which is going to eventually stimulate the ovary to produce follicles that will eventually ovulate with luteinizing hormone signal and luteinizing hormone which is the main regulation of the testes axis exhibit a pulsatile pattern that have wide perturbations for several months so there’s a lot going on that we haven’t studied very well and these are areas that I think are fascinating and certainly deserve a lot more attention these LH pulses are much higher in males and in females so all this is happening in your infant baby now this heigen had a tropen that happens in infancy is associated with a transient second wave of differentiation of the lytic cells in the testes so that we end up with this increased testosterone for about six months in males and we do get some increased estradiol for about two years in females so all that’s going on and you’re not even paying attention you’re all saying oh my boy looks different from my girl and then we’re going through our feminist phase no they’re all the same but in fact they’re different and that doesn’t mean that means they’re equal but different if you would like to say that or maybe you don’t want to say equal whatever you want to say at any rate when we start to talk about this fundamental differences in the reproductive system in the case of men they’re they’re always reproductively capable I should say always been from puberty until somewhere in old age and maybe on for women it actually turns out that we’re really only fertile for 12 hours of a month so you can imagine how do you get all those pregnancies with only 12 hours per month but nonetheless when we talk about germ cells in the case of the male’s they actually have the ability to continue to make new sperm over there the course of their reproductive life whereas for females were born with a certain number of eggs and we basically use up every month that you ovulate you’re not just ovulating

one egg you’ve got the whole set set of follicles that are delivering that are basically giving off eggs and at some point the average age is about 50 you essentially have depleted most of your eggs that said I can tell you back when I used to do rat rodent research we were aware of the fact that if you put an old ovary in a young female rat that that would start to be able to you late again and if you put a young ovary in an old rat it would become an estrus so it isn’t just the ovary there’s definitely brain aging that’s part of this whole system in terms of the endocrine pattern for males it’s pretty much well regulated so as LH goes up testosterone goes down as testosterone goes up LH goes down and they just go back and forth trying to keep it pretty equal whereas for females we have this very cyclic pattern all of you have the women have known about your menstrual cycles the control for males is completely hypothalamic in the case of females we also have the corpus luteum that is essentially the byproduct of the once the ovary sheds this are ovulating there are cells that actually start to give off progesterone and will facilitate the way this whole cycle works and we have a positive and a negative feedback in females and that I’m not going to go into the detail of that but the point I want to make is they’re very different and this is something that again differentiates men and women now as I mentioned in most animals we have this exposure to fetal or infant brain to the sex hormones and in most animals these cause irreversible changes now most of this work I can be honest with you has been done in zebra finches so we know they sing very differently if it’s a male versus a female and some other animals and we start to look at the adult reproductive behavior animal sex behavior is very very different and most of the time when people talk about differences in sex and behavior they start to talk about sex behavior as opposed to a much broader definition of what might be a behavioral difference between men and women so the sex hormone levers differ as we mentioned we have specific sex specific genes that aren’t dependent on sex hormones that may in fact affect human brains there is as I mentioned work going on here at Stanford looking at this you can actually start to see differences between the brains by age 2 and when we start to talk about a doll brains they really are different there there there’s a different size I’m not going to say who’s larger but I guess I will it is the case that male brains are larger and it’s not just because they’re larger but that doesn’t mean anything you could have a lot of you know who knows what that means we know the size and the shape of the corpus callosum are different certain of the hypothalamic nuclei are different including nuclei that relate to temperature control which is something that’s also quite different between men and women especially when we get into menopause and things like that and the good Matich open feedback response to estradiol as I mentioned is different whoops I didn’t mean to go absolutely sorry I have to get back question yes the volume is larger and there’s actually differences between gray matter and white matter and I’m going to get it really messed up if I try remember which is which but one sex has more gray matter one sex has more white matter and we don’t really have good functional distinctions about what that means some of that work is being done by Alan Reece here in the psychiatry department he’s got some really interesting fMRI data to where you can actually look at the functional changes humor is an area that he’s done a lot of work on so I won’t go into that because it’s a small enough study that I think we didn’t get enough kinds of humor to know what just do with it at any rate when we talk about this I’m going to just tell you a few anomalies to this whole system to realize that you can have chromosome disorders I’m using that word disorder if any of you have these I don’t mean to be offensive basically it’s because we have an idea of what the norm is and it doesn’t mean that anybody’s really disordered but at any rate – that really are not uncommon is Turner syndrome and Klinefelter’s syndrome the Turner syndrome is one x and the other X isn’t there this happens in about one in 2,000 female births which is why I think it’s not that uncommon these girls will have normal female genitalia their internal anatomy isn’t developed so this is a proof that we do need to exes we don’t get a functional ovary without having that second X so they have no breast development no menstruation and they’re

not fertile they also have a lot of other health problems that come on down the road and I won’t take you through all of those but well heart kidney thyroid they have other problems the other one is the male X X Y so two x’s plus a Y as long as you have a Y unless you have one of these bizarre genes on one of the autosomes that can override it and it’s very very rare that that happens as long as you have a Y you could X X X X X Y as long as you have that short that sex sex determining region of the short arm of the Y you will become a male this happens in one in five hundred births again not uncommon these males will have an undersized penis and testes they’re typically sterile they have a low interest in sex there’s somewhat feminized in their female characteristics so you can see on this example they’re showing some breast development some wider hips if desired you can actually do testosterone treatment to get some more masculine traits with this particular individual another set of disorders that can affect the prenatal hormone process are androgen insensitivity fetal e Andrew noise female and DHT deficient male the DHT to fish at males the one I already talked about this is really a 5 alpha reductase problem so that’s the guado chase or the watching I forget how you say but to show you the androgen insensitive syndrome this is a really interesting situation in which it’s a none normal the chromosomes are normal XY the males are insensitive to testosterone so they have an androgen receptor that just doesn’t respond to testosterone this can be complete or partial but essentially they develop a female external genitalia but with a shallow vagina and they often just are raised like normal girls but they never start their menstrual cycles and that’s when the guy Nicole gible examination will occur I think it is so he so what Phil says wasn’t that the reason that the person had it in Middlesex but I didn’t actually read it so I can’t say for sure okay it’s a great book won the Pulitzer Prize I thought it was I thought it was the adrenal androgens story but I’m not sure we’ll talk about that one in a minute at any rate it is a good book so we’ll we’ve we’ve got the book review now okay so this may not be discovered and essentially this person because they have a normal testes a normal fetal testes with that produce that testosterone but also the anti-mullerian inhibiting factor or the anti-mullerian hormone have none of those those the female ducks they don’t have any of those organs so they have no ovaries or uterus because they never had the mullerian factor and so they really have it’s a shallow vagina but there’s nothing else there and actually there are some famous people who have the syndrome that you think are beautiful women I’m not going to say who they are because that was released unfortunately without before we had HIPAA but there is a very famous actress who everyone thinks is a female but is actually well it is a female this is gender so we’ll get to what gender is relative to sex so the fetal the androgynous female is what I thought was in the Middlesex case but maybe Phil’s looking it up now oh it’s this one okay so the feely androgynous female is a chromosome lean normal female xx but for some reason she’s been exposed to too much androgen and this can happen because the adrenal gland may give off a lot of an androgenic or testosterone like hormone and so this is the most common case but there also were certain drugs that women were exposed to that we’re preventing miscarriages that also caused this particular problem so what happens because of the testosterone the female has external genitalia that looked very much like males so they come out with an enlarged clitoris that might look like a penis the labia are fused that resemble a scrotum now I can tell you I put this in yellow because there actually was a secretary of health who opposed this practice of immediately doing surgery on these females and this is called intersex we talk about an intersex group there’s actually a very active group now in Holland or the in the Netherlands and in certain areas in the u.s. that are basically saying let me just figure it out myself don’t do this surgery and

turn me into another sex so it’s a very controversial topic and one that I want you to think about if if you were the parent and the doctor says it’s a– and you don’t know and then you find out that XX is this and these this is like that but this purse is not going to have to have surgery the day they’re born so that they will look a certain way but will that surgery really be good will they be able to hold up and grow so these are very controversial issues that I think bears some ethical discussion but in any rate it has been reported that these girls may in fact have some Andreea androgen and drogyn ization of their brain but then that’s also a big debate do we really have such a thing so there’s a lot of debates in this and I know somebody was eager to hear what about emotions and I’m not going there I do want to know about crying though I keep trying to figure out what’s the physiology of crying and and it’s my experience that older men start to cry too is that your experience I could be wrong I didn’t mean to look at you I met everybody so it’s it’s it’s an area of Aging I think we should study I think it’d be really fascinating at any rate something is very interesting to me also is the fact that we’re born we have all this stuff going on and then we just kind of go into quiescence and we go into what’s called the juvenile pause and the hypothalamic pituitary gonadal access just kind of shuts down it’s was active as we said six to eight months from boys two to three years and girls and then it just kind of waits until puberty and what signals that onset of puberty is another very interesting topic that I don’t have time to go into but in any rate two major differences between males and females is the age at which it begins so for girls it’s about usually two years earlier than boys it’s horrible if you’re a twin and you’re the boy because there’s your sister sprouting up and I had twin brothers and sisters so I’ve got to watch that but in any rate for girls we are dealing with the fact that it seems to be getting earlier younger our puberty now this may be because girls are obese and it may be an obesity related phenomenon that you’ve probably heard about last week but at any rate because there was a longer period of time of exposure to estrogen girls bones have been a little bit more mature than boys bones and they start to take off a little bit sooner and they actually sprout up and I’ll show you this in the next slide they sprout up and they basically reach their their reproductive maturity about four years earlier so most girls are as taller they’re going to be about age 12 there’s a lot of variation on that if you haven’t started your menstrual cycle and you keep growing you actually will be taller if you have a late menses so we’ll talk about that in a minute boys are growing slowly over that period before they have their big surge and then of course the other big difference is the [ __ ] it’s not the case that girls have estrogen and boys have testosterone we both have both hormones but there’s a lot more estrogen in the girls and there’s a lot more testosterone in the boys and I won’t show you all of that but we talk about the growth spurt here you see girls taking off their this this doesn’t mean they’re still growing but they really accelerate and then and then then they start to slow off boys are about two years later and then they they go up even higher and go off now what I stuck up here was just to show you that the estrogen is affecting and it’s actually estrogen for both boys and girls that affects the bone we used to think it was testosterone but now we know that it’s really estrogen testosterone is converted to estrogens so it will affect the the cartilage which is kind of the fetal bone and then eventually you develop real bone cells but where the growth is occurring is at these ends between the shaft that called the diaphysis and the ends of the bone called the epiphysis there’s this growth plate this cartilaginous growth plate and the the shaft grows tall starts to just get taller longer and longer but as soon as you fuse that those growth plates that’s as tall as you’re going to be and when they actually do the radiographic measurements to see if your daughter your son is at their adult height they’re looking to see are those bone plates fused so that’s the place where the growth is occurring if you’re growing longer later if you don’t have your puberty yes soon you’re going to be able to get more growth before those things views and so that’s an important difference there’s lots of other secondary sex characteristics that we talk about so we’ve already talked about stature wider hips we’ve already talked about we haven’t talked really about the heavier skull and the bone structure broader shoulders in boys chest wider

than the hips larger hands and feet here I’m going to talk a bit about hair as we move on so we’ll get back to that I think most of these you know voice skin texture breast fat where we put the fat and a waist-hip ratio which plays a role in your risk for heart disease and we’ll get to that in a moment too now we talked about tanner stage and boys the first thing where you really say that they’ve gone through there the first sign of male puberty is testicular volume and they actually measure this volume by different stages so we talked about fumarole hair and we talked about the this the length of the penis and axillary hair underarm hair and girls when we get to breasts two buds then we start to say this is the first sign of puberty and girls but we go through these Tanner stages that’s important for pediatricians and there’s actually some very interesting work done on how Tanner stage relates to age and it’s really Tanner stage has a lot of a psychologic is associated with a lot of the psychological issues much more stronger than ages in young children now I’ve talked about fat this is actually a tissue I love fat I just think it’s the most interesting family now I need to I need to preface that by saying that I’m also very much in belief that people should exercise and I think that the human animal was made to was built and evolved to exercise so fat was what you needed between meals so that you had a reserve and I think that it was it’s a wonderful tissue it’s just that if you sit all day it works against you so the thing that’s interesting about fat as I mentioned male has put their fat in this intra abdominal area which is a great the very first thing when you want to exercise is you release fat from that intra abdominal area that’s the first light lipolytic action and so you’ve got your ready source for kind of slow moderate activity if you’re going to really sprint then you’re going to use a different kind of metabolism you’re going to use carbohydrates but for most of our activity we burn fat for females we really need to have some reserve especially if we’re starving and we need to reserve something if we’re going to have a baby and nurse that baby and it actually turns out that sex hormones play a huge role in putting that fat down and as we nurse that fat is then released so they’re very different stimuli on how this particular fat works and when people tell me that they were there studying fat tissue I want to know where did it come from because every kind of fat we have is very different and they are hormonal e effective now if I start to give this male estrogen he may very well start to put some fat on his hips and his thighs that’s something that’s we know the hormones will do that so hormones do put more subcutaneous fat on a person male or female but generally females are the ones that have it and this lipase I used to study it so you just have to know adipose tissue lipoprotein lipase it’s very interesting but you don’t have to know anything more than that it’s not on in the contrast testosterone actually decreases body fat and increases muscle mass so these things work one is anabolic the testosterone the other is catabolic the estrogens so they’re very different in terms of what kind of tissue we’re going to actually be depositing as we get excess calories now this is the this is gone awry here this is actually anabolic steroids but the point I want to make is males do put on muscle much more easily and given testosterone challenge or anabolic steroids they’re going to put on a lot more muscle than a female who might be using those hormones as well so we definitely have very different a propensity to put on muscle depending on our sex now I’ve gone a long way and I haven’t even told you about sex and gender so the time has come the reason that I insisted that we add sex to the title is that this really is the biology so sex is used as a classification generally male or female that release a your reproductive organs and the functions that derive from the chromosomes so most of what I’ve told you so far would be sex gender are is really something that’s in studies of humans now you can see lots of articles where they talk about gender differences and they’re talking about a rat but the rat the deal with gender is that this is really your self representation so when we talk about the intersex where we talked about the androgen insensitivity where you’ve got you look like a female but you might not really be have all the normal female organs that person thinks that she’s a female and we do some work with transgender I actually teach a class on sex differences and we usually bring some transgender individuals in to hear why they think they really were a man but they look like a woman or the other way around and this is really gender you basically can decide this now another use of gender that I’m just going to mention briefly

is gendered medicine which is a concept that lawn deceiving her who’s the director of the Clayman Institute on research has really been bringing to my attention that something about gendered medicine is that because a physician believes women have certain diseases and Men has certain diseases they may treat them differently and this is something that causes us a lot of problems and heart disease many physicians don’t realize that women have different symptoms and science for heart disease we’ll talk about it again as we go on and they basically just blow off the fact that this woman is having a heart attack now we actually are pretty good here at Stanford we have Jennifer Tremmel who’s got a whole clinic on women’s cardiovascular health and I think that Stanford has been well educated but it’s not true across the board and I can tell you it’s not true across the emergency system if a woman calls 911 good data the ambulance takes longer to get there than if a man calls 911 if she arrives in the emergency room it takes longer to get her in and get her calf than if it’s a man so we have a lot of things that happen differently to women and men not because of biological differences but because we have a different idea of what they may have so this is gendered medicine and I’m going to give you another example as we proceed now as we move on what I’d like to do is just quickly mention that I’m going to do sex differences in health and disease in the USA because it’s a very different story when we start to look globally and to just give you a quick sense when we talk about the USA and we talk about Australia and Europe we’re talking about countries that have a life expectancy of 75 and over regardless of their their sex whereas we can have countries where we’re really talking about a life expectancy that’s less than 50 this is largely because when we talk about life expectancy we do include those first five years and if you don’t make it out of year five which those very same countries that have low life expectancy also have a huge more cow infant mortality and so we’re not going to talk about that I will make the point that when we look at these countries we can talk about different kinds of diseases so group one is communicable maternal and nutritional conditions we really have done a great job in this country of reducing infectious diseases and communicable diseases and reducing maternal death but you can see some countries this is really a big problem and of course there would be a sex difference in that group too is a group that we spent a lot more of our time on here at Stanford which are the non communicable diseases or the chronic diseases and then Group three is injuries and I will point out that with injuries it doesn’t seem to matter what area of the world we’re coming from males have a much higher percent of deaths from injuries that do females and I don’t know if that’s a biological problem or what it is but it’s a major issue the other one that I think is obvious is maternal death I’ve already made the point that if you can’t get the baby out of the pelvis in some countries you’re in trouble now in this country we may be a little bit too quick to go to c-section and then we have a lot of controversies about what do you do with a second birth but it is the case that when we look at the deaths of mothers per 100,000 bird a hundred thousand births you can see huge death rates in these African countries and when we get to the United States in this particular data set it was 10 it’s actually climbed to 13 and I can just show you that our mortality rate in the US was really quite high in the 1900s very nice drop we actually are going up a little bit right now and there’s a big mystery so that’s another area that we don’t have time to talk about Norway actually has a very low maternal death rate they also have a really high home birth rate which is quite interesting because that’s another one of our many controversies about hospitals which 99 percent of US births are in a hospital at any rate to jump the gun I’m just going to focus on developed countries and I’ll make the point that if we match up these developed countries with fee on one side the males on the other you’re gonna see in every single one of these countries much longer life expectancy for the female relative to the male now the u.s. is not leading the life expectancy here you can see Japan is actually doing better now these data are actually 1995 I did stick in the 2004 data for the u.s. so that you can see that we’ve improved in our life expectancy oh that goes up there 72 we’ve improved in our life expectancy but that’s true in both sexes and we still have this sex difference in life expectancy and there’s a lot of interest in that issue I will make the point that when I start showing data like this so population data suffer the fact that everybody is in the pot and there it’s not all the same if we look in different ethnic groups so for instance in the u.s. when we look at black men I’m sorry

this didn’t quite come out right yet black men you see that they have a much lower life expectancy than do white men and white men have a lower expectancy than white women so there are differences in the ethnic groups that we don’t have time to go into now this is at birth in 1987 and at birth in 2004 so you can see that we’ve all improved all ethnic groups all eight all sexes this is if you are any of these ages what is your life what how many more years do you have do you expect so if you can make it to that age the whole start the game starts over again so you get some places if you can make it to 100 then people are a lot more similar than if you don’t in terms of only having two or three years left okay so when we talk about these causes of death again this is everybody thrown in together not by age and I’ll try and get you through all of these age groups in a moment but I want to make the point this is percent of deaths and here’s the total number of deaths so the first thing that you’ll notice is that when we talk about heart disease I’m going to show you that at any given age men are more likely to have a heart attack and die of heart disease and Men but when all is said and done because we do women do live longer we basically match them in the end so the leading cause of death and women is heart disease and it basically takes out as many women as it does men percentage-wise so the percent is quite similar the next category is all cancer put together which is actually less than heart disease that said I did break out the top three cancers so in men we’ll use the bottom panel first lung cancer prostate cancer colorectal cancer females lung cancers the first cause of death for cancer breast cancer colorectal cancer now men actually have accidents more accidents and they have prostate cancer and what women actually have more deaths from Alzheimer’s disease and they do breast cancer so there’s a lot of misconceptions about what our leading causes of cancer are a cause of death but this is again when you put it all together if you live long enough you’re probably going to end up dying from heart disease question probably because they live longer so that’s the one reason but we actually do have evidence now that Alzheimer’s disease seems to be female predominant anyway even if you age match them so there does seem to be a predisposition relative to men in women for Alzheimer’s disease but the fact that they live longer if we live long enough our risk of Alzheimer’s disease goes up quite a bit so the life expectancy issue does come with age-related problems okay so let’s go through the life stages now rather quickly we’ve already talked about prenatal development and sexual differentiation I’m going to give you a few pediatric examples there’s clearly not enough time to do every disease you have you’ve had three quarters to do that so we’re going to look at a little bit we’ve already talked a bit about puberty and the fact that some of these diseases I’ll just point out vary with a menstrual cycle some of the immune issues really go up and down with a menstrual cycle so we know they are hormonal II influenced when we get to young adult sexual activities a big issue we’ll talk about that I teach Stanford students so that’s what they’re mostly interested in middle age pregnancy and postpartum it actually can happen in younger ages to will touch on menopause and we’ll do a few geriatrics so this is really examples of sex differences it can’t be comprehensive but what I like to do when I pull that out and put you through this is kind of just loosely fit it two decades so that we can look at the data a bit and so when we talk about puberty will be about 12 years of age for girls about 14 for boys when we get into the twenty to thirty nine we’re in the act of reproductive phase so we’ve got menstrual cycle changes we have pregnancy we have postpartum issues men we have reproductive years for women we start to go through changes that eventually result in menopause and then we have reproductive years sixty-two 79 we are postmenopausal and then there’s a question is there an Andrew pause so I’m going to try and look at that question just a touch on that and then we get into I really should change this the older age but because as I get closer over there I feel like that has to be like another phase right they can’t be but at any rate when we look at this a point that I want to make is men are disappearing from the population at a much higher rate in each of these categories so although the numbers aren’t great one percent of girls don’t make it to age

one 1.4 percent of boys 0.7 percent of boys our girls die before 20 twice as many high twice as well twice as many half a percent when we get the 20 to 29 we see again where we basically are losing men we’re still losing more men we start to get closer in the 60s but by the time we get out to 80 we still have more than 50% of the women who were born and we’re only down to about a third of the men so when we start to talk about diseases of aging many of the things that we think of as sex differences have to take into the account that we’ve got the hardy guys out there and then we still have half of the females and so it’s really hard to say what’s a physiological difference I mean the clinical relationship is still important this person is sick whatever but we really have been slowly getting ourselves to a survivor pool of 80 plus year old men relative to women women we can start to get closer to that about 90 so to just kind of quickly go through this if we just look at causes of death in children this is kind of a too big of a lump-sum it would be better if I broke it into pre and post pubertal but the number one cause of death there’s not many deaths but the number one causes accidents and then we actually do have total cancers showing up in girls whereas for boys the next one is assault and homicide it does show up with girls suicide it does show up with girls the cancers we’ve mentioned do show up so some of these things are kind of the same and heart disease is already starting to take a few when we actually look at this accident issue it’s quite interesting this is actually deaths in numbers so this is a number of boys that are dying from accidents relative to girls and somebody asked me why is this peak at thirty to forty five and I really have to go research that I don’t actually know why all of a sudden in our middle-age crisis we start dying in accidents again but at any rate and I’ll let you guess we can actually look this up and I should have before I came here but at any rate you can see that out here it’s really just a matter of the men are there we don’t have many of them left and so it’s it’s the females and if we actually match this by rate we see that in every one of these younger age groups we have this male higher rate of men this is actually who’s coming into the emergency room relative to girls but when we get out into the 65 plus their rates are pretty similar okay so cancer deaths in this young group are pretty much the same causes so childhood cancers don’t seem to have a real strong male-female in terms of the big the big hitters I will say that testicular cancers something that hits a 20 year old male and obviously doesn’t hit a 20 year old female an issue that I have to bring up in any talk I give is childhood obesity this is something that you just have to know this is a very very serious problem and it’s serious and whites but it’s even more serious for Mexican American boys and African American girls and the reason why it’s serious is that we have all these comorbidities that you heard about last week and I just want to point this one out which is type 2 diabetes it’s now projected that 30% of boys that were born in 2040 percent of girls that were born in 2000 will develop type 2 diabetes this is the big problem coming down the pike that we have to get our hand so that’s maybe as a bit of a sex difference okay sexually transmitted diseases oh I meant to fix this slide sorry but at any rate you should just know the US has the highest rate in any industrialized country we have a 19 million about 19 million per year and girls our women are much more likely to get these as our youth and people of color now in the case of women this relates to our Anatomy it’s a lot easier to pass it from a man to a woman than the other way around and we’re we’re vulnerable to chlamydia and gonorrhea because of changes that happen during puberty in the cervix when we talk about pelvic inflammatory disease there’s about a million women per year that have this there may be no signs or symptoms it can go undetected this is true in boys and girls but there are more serious consequences for women than there are for men and this is infertility tubal pregnancies chronic pain and cervical cancer and pregnant women with STDs our greater is for miscarriage premature delivery so these are issues that have some sexual differences or sex differences I think most of you are very aware that we kind of struck a hit here with finding a

virus that actually causes cancer cervical cancer and that we know that there’s the top two types that cause this changes in the service cervical squamous cells is HPV 16 and 18 it’s very common in women that are 18 to 30 years of age now what you should know is that our normal immune system fights this and clears it for most people so most of us basically are able to take care of this ourselves but there’s a small percent of girls who that doesn’t happen for and so there is this recommendation there’s a lot of controversy about that so just to let you know this area is full of controversy but the speculation is that if we could vaccinate girls at age 11 we could eliminate 70% of the cervical cancer in the u.s. so this is a young person’s issue moving on to the next group we still have accidents as a leading cause of death in the case of men suicide homicide are the next two these are particularly taking out the black men so we talked about the life expectancy for african-american this is an SES issue heart disease is already showing up and you can see that one that I want to point out is breast cancer so we have total cancers showing up in men but we don’t have one cancer that’s popping up whereas we already have breast cancer in the 2239 group and if we actually pull that out and look at cancer a little bit more you see that the top five cancers now look different in boys and girls so now we have breast cancer and cervical cancer whereas some boys were still with leukemia brain colorectal cancer we also have the non-hodgkins lymphoma and lung and bronchus cancer so we’re getting a male cancer showing up so cancers start to look different now in this age group I’m not going to take you through the immune system obviously you had a whole lecture on that but just to make two quick points when we talk about b-cells these are going to be making the antibodies and T cells are going to activate the b-cells and they’re going to attack a pathogen that has affected you I won’t go into the rest of this but what I want you to know is that this is another sex difference it turns out that women have a more robust immune response they have higher levels of proteins and reactions that we that we basically designate as demonstrating a stronger immune system so IgM & cd4 these cell counts are considered evidence that there’s a stronger immune reaction they show a stronger humoral and cell mediated responses to vaccination with a variety of antigens and they have this mountain heightened the amount of heightened thymus one immunity to immunization from antigens and so basically some of this may really relate to autoimmune diseases and I think you had a whole lecture on autoimmune but I want to just take a little step further make the point that we talk about autoimmune disease we we kind of have two kinds of autoimmune disease we have organ specific and non organ specific you’ve probably heard of many of these and this is the whole spectrum going from the to the non Oregon so there’s a long list of autoimmune diseases but to just highlight a few in the short time I have what you can see is there’s sex differences so this is the percent of women relative to men that have Sjogren’s syndrome that has systemic lupus erythematosus tyroid disease scleroderma and actually I put a little note here about scleroderma I’m going to show you in a minute some of the hormone reasons that we may have differences in some of these immune response but there’s a very interesting phenomenon that came along that was identified called micro chimerism in a disease called scleroderma which is something where your skin gets really taut and I won’t go into all of the details but they actually in this particular lab they found that these women had a really high percent of fetal stem cells circulating in their blood that was from their male offspring now it could have been from the female offspring too but they don’t have a test to look for that they have a test to look for a why in an xx person and so what they learn from that is that it’s actually the case that when you’re when you’re pregnant there are stem cells that the embryo is making that pass out of the placenta into the mother circulation and take up residence there and they actually found that these lingered for at least 30 years and so one of the issues is in that women do have this foreign body on board we have the ability we have basically exposure to foreign DNA and we basically may be responding and developing some of our autoimmune at some of our immune system response so these are kind of hypotheses we don’t have them completely worked out but scleroderma is the one where we have

seen this micro chimerism many people got excited about this was going to explain everything like all the others and it didn’t so nothing in science works that nicely but it works very nicely in other ways I guess at any rate there are a number of others you can see here male slowly we get to the point where with type 2 or type 1 diabetes which is an autoimmune disease it’s pretty similar between males and females now this could go on there are couple that are male predominant ankylosing spondylitis is one where you get this kind of fusion of your vertebral column and so you become very stiff and that starts to hit people when they’re in their late 20s and 30s but for the most part autoimmune disease is about 80 to 90 percent of them are females instead of males so that’s a big sex difference and this is just showing you a schematic of the ones that kind of hit in our reproductive years versus the one that hits in our post menopausal phase and there is some evidence that hormones are really are influencing this so that we talk about the B being much greater than the T cell immunity estrogen stimulates the B cell autoimmunity and then when estrogens fall a lot of times these regress and so there is some evidence that hormones play a role and contrast and we talk about T being more important than the B cells these actually become much more prevalent in older age so hormones may play a role it’s certainly not the whole story nothing is just one simple story rheumatoid arthritis is another one that’s much more common in women than in men and this one I want to mention just because it is the case that multiple sclerosis is more common in women and I wish this was a woman diagram sorry about that it was a case that in the early in the beginning of the century well nineteen hundred’s the ratio was one to one and then in about 50 years it was one to two and then it kept increasing and now it’s one to four so we don’t really understand why we’re getting the sex difference but what I wanted to show you this one is there’s another condition that is nine to one women to men called fibromyalgia that people haven’t been able to figure out what is this it’s something where a woman is in pain Annamayya and the one out of ten men are one out of ten people they have all of these problems and they weren’t able to find it they were basically saying it’s in your head and so that was something that women had to go through feeling like I’m suffering all the time but it’s in my head they have now actually found a cell in the brain that lissa cytokines that basically seem to be responsible and in the last three years they’ve come up with some medications but the reason I show it is that these are actually very similar in terms of their symptoms and so this is a place where the X the belief is that this might be an autoimmune disease and we just need to do more work on it speaking of pain one of the common misperceptions is that women can handle more pain than men and it turns out believe it or not not to be true and so people always think well but women have to give birth and that has to be the most painful thing that ever was but you know now we’re giving birth to maybe three or four it’s true that we used to be giving birth to 12 and you know I don’t know how many Franklin had but you know some people have lots of births but it’s still a rather short period of your life and when you actually look at the pain issue it turns out that women have lower pain thresholds they respond to stimuli and that’s true of cold he is a heat cold electrical shock chemical shock so there there’s some very interesting work going on here at Stanford in the pain clinic where and it probably relates to sex differences in opioid receptors and and how we function with opioids but just to show you that there’s a lot there’s a long list of pain related problems that females exceed males in by a long shot in addition to just these sensory things that we’ve talked about so there’s a lot of medical conditions that relate to it and there are a few for men as well I don’t have time to go through all of these one that’s very typical of women is very nadh’s disease which is a problem that probably related to peripheral artery disease but not completely that doesn’t solve the whole problem if you put your hand into a cold refrigerator you’re you can basically become frostbitten and this is rare in men and something that women have so we have a lot of sex differences and we have a lot of explaining to do to figure out why do we have all of these differences in my opinion okay so another one is baldness we have this idea that men are bald and women aren’t there’s actually a male pattern baldness and a female pattern baldness it’s called androgenic alopecia it’s an autosomal dominant trait eight thirty percent of white men by the age of 30 have some of this male pattern baldness fifty percent of white men by age 50 and whites are four times more likely than blacks so it’s kind of interesting that the current fashion is

black shave their heads and whites don’t but at any rate I guess they don’t have to at any rate so the other thing is female pattern balding is also at androgenic alopecia they’re slight different I put path though here because I don’t know that we should call it a pathophysiology it sounds like there’s something wrong with it and it’s it’s a normal it’s pretty normal if 50% of people have it so I’m a little reluctant to call it pathophysiology but we do understand the physiology of this that basically the hair follicles become minute miniaturized instead of being big ones they become small ones and I won’t go into the different phases of how hair works but to kind of just move to the next point it’s a really site-specific action of act of androgen so we know the androgens play a big role in pubic and axillary chest and beard hair and so when we talk about Axler that’s underarm hair that’s true for girls as well if you don’t have DHT you don’t end up with underarm hair so those individuals that we talked about that lack the 5-alpha reductase don’t have underarm hair as well as some of the other things and they’re not going to get a beard when we talk about scalp we’re talking about the terminal or the course here and for women we have adrenal androgens that can cause this problem 5 alpha reductase is converted from testosterone DHT so that’s kind of the real issue there and I won’t show you the different pictures but what’s really interesting is that even though both sexes can go bald the pattern is very different and that I don’t understand yet I’m trying to understand why is it that we have this male pattern and female they kind of lose their hair all over they don’t have these particular kinds of bald spots so there is still a sex difference even when we’re talking about the hormones that are are playing the role to move on when we get into our Middle Ages and this is I call this early middle age and soon get to look at late middle age but this is early middle age so again not very many of the deaths are occurring 2.4 percent of all female deaths before the age of 65 point 4 percent of males in addition to the ones that we’ve had before but we’re slowly adding to them the point here is that when we look at women can’t total cancer exceeds heart disease but no individual cancer does so here’s lung cancer already taking more lives than breast cancer it’s a deadlier cancer and here’s colorectal cancer the case of males it’s pretty even heart disease with all cancers put together accidents still there and here’s our lung cancer and so we don’t actually and suicide we don’t have another we don’t have prostate cancer showing up just yet so yeah I don’t actually know that people die of upper respiratory very often so lower respiratory is kind of a year lower lungs it’s deeper in there as opposed to up in the bronchus that okay so in terms of the probability developing cancers I’m just going to point out a couple things on this busy table and you get all the slides so you can study them at your leisure but I’ll make the point that one in two men will die of cancer eventually in the course of his lifetime now the one that’s this isn’t actually this isn’t dying I’m sorry this is getting cancer this is not dying of cancer this is the incidence so one or two men will get cancer to a large extent this is prostate cancer it’s actually the case that many men have prostate cancer that don’t know they have prostate cancer they’ve done these autopsy studies of men who have died from other reasons and they’ve done autopsies and they see that they have prostate cancer but it didn’t cause them any problems and so there’s actually part of the cancer debate you’ll probably hear more about it next week is you know do we need to be so aggressive if it’s not really going to cause symptoms and I won’t go into that at this point but to make the point that it’s very rare in young men and clearly increases as we age similarly melanoma the skin increases as we age so you can take a look age is clearly a big risk factor for everything now when we talk about cancer incidence I will point out that when we look at male/female differences what you’re gonna see oh I guess I forgot to put the females in there did I not show you a female oh yeah okay I’m sorry I jumped basses so in the case of females one in three women will get cancer in the course of her lifetime breast cancer is the one that’s going to be the most common remember prostate was one in six so this is one in eight and this is because if we live long enough this is going to eventually happen now to just jump back to where I was I want to make the case that we look at incidents it doesn’t matter what ethnic group we look at in the United States males have more cancer this is total cancers than females when we go and look at the kinds of cancers we can look at this is looking

again at cases so the most common cancer in males is the prostate cancer I did highlight urinary bladder because it’s much more common in men than and female so it’s maybe a male cancer you could it has reasons for that breast cancer is the leading female cancer so these are very different between men and women uterine and ovarian obviously some of those lung cancer is really pretty common in both men and women as is colorectal cancer now to move on to deaths the exact same story it doesn’t matter what ethnic group you look at in the United States males die from cancer at a higher rate than females do and if we look at the kinds of cancers that we’re dying from lung cancer is pretty much responsible this is the percent of cancer deaths so just to qualify that it’s pretty similar prostate cancer is actually not causing as many deaths percentage-wise as as breast here you see ovarian here you see the uterine corpus and here you see the the bladder so there are some differences between men and women and the kinds of cancers we get but then again as I mentioned more men now lung cancer is a big part of the male/female difference so her question is because this be early detection that there’s a difference between women getting screened relative to men those are you know in terms of the incidents I think that’s a possible explanation it’s not the only explanation in terms of death I guess even their treatment could be a possible explanation and this is again a case where gendered medicine is part of the story as well so you know who’s going to get screened who’s going to be encouraged to be screened but that’s an excellent question right yeah I don’t have time to go into why do all these sex differences exist okay so a few more coronary heart disease this is one as I mentioned but when we adjust this by age we see that men get heart disease at a higher rate than then females do now this is very much an age issue I can just tell you that this difference caused an entire area of my research because people were basically saying women are protected against heart disease because they have estrogen and when they go through menopause they lose their estrogen and they lose their protections so that’s the story that we used to live with and so I actually tried to figure out is that true or is it just that men start getting heart disease at earlier ages for all kinds of other reasons including where they put their fat and all kinds of other things and so this is actually a logarithmic scale of heart disease putting on top of that menopause and the data are like compiled from lots of population studies and what you see is no evidence whatsoever that menopause is changing the course of heart disease on the other hand with breast cancer even though I mentioned the fact that the older we get the more like a really good breast cancer this is a huge curve the slope of this when you have that estrogen your own estrogen on board that influence on breast cancer is remarkable go through menopause and you actually see that menopause is somewhat protective or is protective I think so I don’t have time to take you through all menopause but basically we do talk about menopause now is a very long it’s no longer the case where you jump off a cliff and you know today I’m premenopausal tomorrow and post-menopause we now recognize that this is a slow gradual change that goes along with age and this is something where it’s very different for men and women it’s something that women will remember when they went through their menopause you start to have a regular menstrual cycles you have hot flushes and night sweats now men actually do experience hot flashes and night sweats when they’re taking Antigona adil hormones for treating prostate cancer so there are men who know what hot flushes are and they don’t like them either at any rate when we talk about there’s other things that happen when you don’t have your estrogen on board there’s a transitory accelerated bone loss now when we talk about natural menopause this basically is if you still have your uterus and can check on your bleeding you’ve stopped bleeding for 12 months and that’s considered a natural menopause you take out the ovaries you can have menopause any age so that’s surgical menopause now for most women you do have some estrogen on board you make some estrogen in your dream Oh glands as do men and testosterone can be converted to estrogens in fat tissue so it actually is a case that obese men and women have higher estrogens which is one reason that obese men start to develop breasts but in any rate most women don’t report symptoms after they’ve been through they’re three to five years I have a curve that shows that some women continue having over 40 years so it’s not true that we’re all going to just be so lucky

but at any rate most women will have three years of hot flushes some will continue in Sweden that they actually have these great databases and they show that 9 percent of women aged 70 and over still have hot flashes but now we have gradual bone loss and so I want to talk about that I will tell you that even though obese women have higher estrogen levels it turns out they have worse hot flushes and we’re actually studying that now in biology with Craig Heller trying to understand is this because we’re insulating our bodies and basically we can’t dissipate the heat if we’re carrying too much fat so this is something that we’re trying to understand I’ll just quickly mention the Women’s Health Initiative because it was brought up this was really a study menopause really is very nicely treated with estrogen or just wait it out if you could wait it out that’s probably your best bet but not all women can we never say that you shouldn’t use estrogen to take care of menopause but we had this kind of epidemic if you will or a problem in the medical community where the idea was that women were protected against heart disease by estrogens so we should put them on estrogen to prevent heart disease and this was really happening at human really high rate so we really had millions of women who did not have hot flushes being put on hormones to prevent heart disease and so we actually studied this in the Women’s Health Initiative we had a huge study really two trials one of women with a uterus who are taking estrogen and progestin the progestin protects the uterus against endometrial cancer which is stimulated by estrogen and then if you had a hysterectomy just estrogen and this is really a schematic I don’t have time to take you through all the data you don’t want to see that anyway but we had stopping rules based on all the epidemiology that we had available to us so we had the strong belief that estrogen would protect you against heart disease we were worried about breast cancer we really didn’t know about stroke was kind of bouncing around it’s not so common that we had as great population data as we’d like we did expect blood clots mostly from the high dose oral contraceptive literature and from a study that they did in men back in the 70s where they gave them five times the dose of estrogen that we ever would give a woman and they had blood clots and heart attacks and they didn’t have a good time and they developed breasts and that wasn’t very good either and then we did expect benefits to bone and the deal was we would stop the trial if breast cancer happened and the overall picture was harm but we wouldn’t stop it if breast cancer happened in the overall picture was benefit and vice versa if if we had a benefit we wouldn’t stop and unless the overall picture was benefit so to just cut to the chase in the case of the estrogen and progestin trial and this is something the media still doesn’t have work these trials came up with different results the estrogen and progestin trial done in women with a uterus basically the first thing that happened was we had our preset cut point for breast cancer was hid and that would not have stopped the trial because act by that time we already had fewer hip fractures and fewer colorectal cancers that this would have basically tared it out to even but the hypothesis was wrong and our public prevention role rules were wrong we had more heart attacks not fewer more strokes and the blood clots so the overall picture was clearly one of harm and we sent out a huge alerts to everybody that the estrogen and progestin was not something we should be prescribing to prevent chronic diseases and older women now this actually was a huge story some of you might remember it at first it was about hormones and then everybody started talking about menopause and what we were trying to explain to them as well the hormone story we study was about whether you give these hormones to older women to prevent diseases of aging and it wasn’t about menopause which it turned out we didn’t know very much about because we weren’t studying it it wasn’t a life-threatening problem it was just a quality of life issue for women so this was a case where we recognized we really need to understand this physiology and I think in understanding this physiology we’re learning more about the physiology of men and especially temperature regulation and some of the other issues but one of the things that happened was women came off these hormones and doctors stopped prescribing these hormones at a huge rate and the interesting thing was two years or five years later we actually saw in the registry the seer registry is this giant surveillance system for looking at cancer we actually saw breast cancers drop in the whole population of the United States and this was the estrogen positive breast cancers and this is actually quite a remarkable drop not a thing that I’ve ever done in prevention could have done this and so this was not even what we set out to do but it was a

huge population benefit to just basically stop that particular practice now that says that’s dropping hormones across the country we had not really even published the estrogen only trial before women’s start coming off their pills and in that case we did not see increased breast cancer and we did not see increased heart disease so in the estrogen only trot cancer we did see higher strokes and we also saw the benefit to bone and so this was really a more neutral picture now I don’t know how it really applies to everybody I will tell you that in this trial we had a really high percent of women who were obese and so I don’t know how it applies to thin women we do have data on breast cancer for instance that thin women have increased risk of breast cancer when they go on estrogen and overweight women don’t so it’s a complicated story but the important thing is it’s a different story than the the estrogen and progestin trial so when we talk about how this the trials are similar and how they’re different they were similar in showing no benefit to heart disease and then actually increased harm in the one case more strokes more blood clots but benefit to bone it’s really very good for bone but we have alternatives to bone but I don’t have time to tell you about the breast cancer results were different the global index is a overall balance so the balance was in harm for one trial and balance for the other now osteoporosis is another important issue this is one that’s called a woman’s disease so back to gendered medicine very few physicians check bone density on older men one out of three hip fractures is in a man so we have this problem that we don’t focus on something that isn’t a man’s disease even though men get it so when we talk about osteoporosis this is a really strong bone here’s an osteoporotic bone you can see not only is it a lot thinner but they’re fractures there’s just no engineering integrity there there’s no structural integrity when we look at their risk factors these all comes from studies of women with the exception of the primary secondary hypogonadism and men where they just have really low testosterone and it’s really testosterone being converted to estrogen we don’t know their risk factors for men we not studied them very well I will show you that when we look at bone men are losing bone just as women are but they’re hired to start with women have this accelerated drop at menopause and then they resume so they hit a fracture threshold about ten years earlier than men so it’s the reverse of heart disease women are about ten years behind men and men are about ten years behind women yes I’m trying to get the slide to come up because I don’t have your picture here but it’s called the study of osteoporotic fractures and men mr. Ross I’m the principal investigator you’ll probably get letters from me so this is a study that this is a study that has has 6,000 men who are 65 and over one of our participants actually turned 100 and is still going strong you just came in recently in addition to this study so we are doing this we’re trying to correct this problem this is kind of one of my missions is be sure that we study men when we need to study men and we actually have a really interesting sleep study I don’t know if you’re in that one – but this is what how we put them into bed we basically go to their homes and we wire them up completely and we get all this information looking for whether we’re trying to figure out what causes heart disease and these now and I will point out we talk about sleep they’re really women complain a lot about sleep problems with menopause and I think it’s absolutely true but I think it’s also worth noting that at every age women have more sleep problems than do men and so this is another place where we have kind of a misconception and we’re coming near the end we’re going to talk a little bit about aging and men so in the case of men there is a decrease in hormone production there is some sexual problems the hair the graying is not related to the androgens by the way so it’s not part of the alopecia issue we’ve already talked about the baldness voice is actually some changes in the vocal cords so there is a slight elevation we’re not really sure about body odor and acne which are things that start at puberty what happens to them we haven’t studied it very well but an area that we’re really in interested in that we hope to study and mr. Oz is sarcopenia which is a loss of muscle mass and an increased fat where there used to be muscle you probably heard about that last week I hope you did but at any rate it seems to be that stem cells that should be replacing your muscles start to make fat instead of muscle and we’re very interested in that phenomenon hopefully in I’ll come back in a few years and tell you about that in terms of bone density we do see a

decrease in bone density with time and I really I’ll just – for the sake of completeness point out that by the time we get into the 60 to 79 we still have we have cancers exceeding all other causes of death but heart disease is exceeding it in individual cancer in this particular age group there’s something not quite right on that so I’m gonna just move because I’m a little worried about I want to focus back on men so with men there is this decrease of testosterone and it’s not the case that they just stay high all their lives the older men get the lower their testosterone and there is a point where we start to talk about hypo gonna do levels when we talk about that the the medical problem is not just low testosterone it’s if you also have symptoms that suggest that your body’s not responding that it doesn’t have testosterone responses so this is decreased libido sense of vitality we’ve mentioned the erectile dysfunction reduce bone mass and bone density and anemia so this is an interesting thing testosterone actually increases blood count and that’s a big sex differences are anemic levels so you can see that about 20% of men aged 60 and over at about 30 to 40% of men’s 80 and over have this there is a big trial underway that unfortunately Stanford didn’t get we almost got it looking at testosterone very much like the Women’s Health Initiative but smaller pieces trying to understand does testosterone health aging men and this was actually something I wanted to just quickly mention oh sorry one of the concerns is prostate cancer but I’ve always made this interesting observation that testosterone levels are going down when prostate cancer is going up so we don’t really have very good cause-and-effect data on that particular phenomenon and the Institute of Medicine did a report where they really weren’t very convinced that that was a problem and so this is the areas of study now that the Institute of Medicine has felt we really need to do with men and testosterone looking at body composition and strength physical function cognitive function mood depression sexual function quality of life cardiovascular Blood prostate and other multiple outcomes the question yes so heard her allusion I think I had it up there is that the most common estrogen that we use is conjugated equine estrogen which equine is horse so it is extracted from horses there are real estrogens available for women the case of testosterone most of these are testosterone that they’re doing but the original if you study the history the history was dog testes and and cow ovaries and things like that so these studies are being done with testosterone so I think I’m at the very end now and I just want to say that by the time we’re 80 plus remember we still have more than 50% of women and we have about a third of the men that were ever born heart disease is the leading cause of death and these old people older people cancer is the next all together now stroke so the question about stroke you see that when we get into the 80 plus we have stroke appearing in men as well as women but we have Alzheimer’s in women and we don’t have it in men so there is a sex difference that we’re very interested in trying to understand and here’s lung cancer showing up in both groups and prostate cancer here you see when we actually do it this way we don’t have breast cancer any longer in this group in this age group as being hitting this it comes up very soon thereafter so I don’t want to say that it’s not it’s just not one of the top five I think it’s like two fourths of six and so that’s the end that’s just a whirlwind of sex differences but I can tell you this is a ten week course that I give and we just scratch the surface in each one of those classes there are huge sex differences in diseases there’s lots of reasons and screening detection education how the medical system works we have so many avenues to look at in this issue to try and understand the sex differences and studying sex differences in on themself is not so important as helping both men and women and many of us believe that the more that we study these differences the more we’re going to get to the real basic biology in ways that we haven’t really even tried to do yet and so this is a new field it’s been going on for about a decade there’s a lot of interest in it now and Stanford’s women’s health at Stanford is actually got sex differences as one of its primary missions that we’re trying to study and many of the Institute’s are involved in it now thank you

so much I think we have time for questions I should put a good picture on there huh well there’s a lot of controversy in that field so when you say the medical profession it depends on what part of the medical profession you’re in the FDA and I agree with them basically say that you know if you can’t tolerate so we say go for moderate to severe symptoms if you can’t tolerate the symptoms going on as low a doses is effective for you for a shorter period of time so that’s kind of nebulous but basically instead of 0.62 5 milligrams of conjugated equine estrogen or its counterpart so there’s estradiol there are patches there’s lots of different kinds and that’s another whole talk you go on a dose that’s about half what we used to be recommending and you don’t plan to stay on with the rest of your life you basically go on it for maybe two years come off see how you feel if everything is horrible again then go back on six months so basically it’s kind of there’s no discouragement for using the hormones the way they were indicated by the FDA for menopause management they still are the best game in town in terms of bioidenticals this is essentially the idea that you’re trying to get exactly the same kind of hormones in your body that are you’re trying to replace hormones in your body that are like your own I don’t think the science is very good on that so I think the hype is great but we don’t have good studies it doesn’t make a lot of sense to me that I’m going to measure my low hormones and tell me that’s what I should replace what I’d like to know is what am I missing not what do I have so I’m not real enthusiastic about it and I can tell you the American College of obstetrics and gynecology basically feels the same so again it depends when you say the medical profession there’s lots of variations on that theme so she was asked she’s trying to understand what’s happening in that first two years of life so as soon as you’re born there’s this big LH surge that occurs and so the fetal tests the young testee says fetus anymore it’s now a new baby newborn baby’s testes gives off testosterone for about six months and the females also have some pulsatile stuff going on they start just secrete some estrogen from their ovaries for about two years so the interesting thing is that and then everything quiets down until puberty so this is rather new information it’s not that new but it’s it certainly I didn’t know it when I went through graduate school so it’s it’s it’s you know at least 20 years he just came out of a pregnant woman so she says she has a friend is afraid to give her child soy and I don’t want to get into anybody’s you know what they want to do with their children but just to remind you that you know all those boys were in a pregnant woman who had really highest Ridge and lava so they were they were exposed to lots of estrogen just before that birth okay I need to look for a man now there yes so there’s a lot of questions about taking out the ovaries and there’s it’s it’s kind of a new debate going on right now whether we should or shouldn’t so the hysterectomy is taking out the uterus often there’s a good reason for taking out the uterus so there’s been excessive bleeding this is particularly true with obesity women bleed more because they have those higher estrogen levels without progesterone certain ethnic groups like African Americans have fibroids at a much higher rate so they have bleeding there are multiple reasons for hysterectomy in terms of are we doing too many I think that things have changed a lot it does vary a lot by state so I think there are some states that are doing too many and others that aren’t and I don’t want to really criticize without knowing why but in

terms of the ovaries it used to be kind of a prophylactic thing if you’re in there let’s take out the ovary so they won’t get ovarian cancer which is a very deadly cancer because it goes undetected for a long time but the question then is does that estrogen that those ovaries were producing have health value and so the answer to your question is I don’t really know and we’re trying to understand that now and there’s a person at UCSF Vanessa Jacobi who’s kind of making that her career and I’m actually mentoring her so I hope that I will learn more as she learns more but I don’t know the answer yet oh you’re a man wait let me get a woman in the back okay so her question was as a treatment for osteoporosis the same in women and men and the answer is some of the drugs have been fda-approved for men so there’s been some research done in men but compared to what we know about women it’s really lacking so we do have some things that we do with women that we don’t have those studies for men and let’s say the other part of the question and you read tests for bone density along the way I think most endocrinologist do you know I don’t actually know what the guy what the rationale would be in that you’re taking the drug and I don’t think you’re going to ever get all that bone back but I think they do some evaluation to see if you need to go into a more aggressive kind of treatment okay yeah that’s a great question so it turns out some of the autoimmune diseases actually regress when you go through pregnancy so multiple sclerosis actually tends to get better and it might be because of the estrogen the high estrogen the problem is then when you deliver and your hormones fall then it comes back so the pregnancy the hormones do benefit some of the autoimmune diseases no so I’m sorry that no it’s not but I can see where you get that okay so she asked was I saying that male babies cause more of the autoimmune problems is that for the mother okay so the problem is it’s a test that they were doing to look for these fetal stem cells and the test only is able to look at Y chromosomes separate from X chromosomes so there there’s probably just as much problem with having an xx baby but they can’t find it in the tests they have right now so it’s just a matter of getting the test where we can look for the female fetal cells as easily as we can now look at the male fetal cells and if I say anything wrong you correctly you know it’s so he asked about the b-cells where I was making the point that the antibody seemed to be something that autoimmune disease that have higher b2t are coming into this reproductive years and he wants to know about men and unfortunately I don’t know the answer I have to admit that I’ve done more women’s health and I have men but now that I’m interested in sex differences I would hope to find the answer do you know okay so they do some testosterone therapy for women mostly for libido to increase sexual libido that’s the main purpose of it actually it’s the case that testosterone is converted to estrogen to take care of the bone so it you know we used to believe that testosterone was the reason men had denser bones but it is but indirectly because they’re converting it to estrogen so there there isn’t a good reason to to use testosterone just for that purpose but it would I mean you if you can convert it as long as you have the aroma taste to in you know to convert it you can convert it okay it’s a great question I don’t know the answer and you know the problem with

there’s a few areas in this field that are really challenging one is oral contraception because they kept changing the doses so the dose is that of the people that are now old enough that they’re getting diseases of aging they either never took oral contraceptives cuz they didn’t exist or they took really high doses and now we’re finally getting the epidemiology that we need on the next group but they’ll keep changing it so with puberty we have a similar kind of problem where the age of puberty is slowly going down and girls probably because of the obesity issue but that’s kind of our best guess we don’t know for sure about that so I don’t know the answer and I think it’s going to be hard to get the we call it cohort epidemia where you’re following a cohort of people too many things change before you get to the point where you can look at the diseases of aging yeah that’s what I you know I really was negligent I I meant to look that up because you can actually look all of this up in the CDC you can actually go onto your computer and look up all the causes of accidents Motor Vehicles is the most common one drug-related is the most common one and people like to say it’s testosterone but I don’t know if it’s just awesome I think it’s all that it might be field testosterone so your brain comes out like that I don’t really know you know our society allows boys to take risks when you start I actually do teach in the human biology program and they had this great a core B core where the a core you learn all the social sociology and you start to realize there’s all these other explanations the B course the biology and so there’s a lot of things that allow boys to take risks of this culture that may relate to it as well and it might be testosterone I don’t know yeah actually there are differences and boys are good at the okay one more you know I knew that if there is it so small that it’s not going to make the difference you’d like or that we’d like right and it depends who we’d like it so for your reading pleasure I did look it up Middlesex is about the Alpha five reductase deficiency and it’s a great book if you haven’t read it because the first phase of this youngsters life was growing up as a girl and then he got to adolescence and converted to a boy and so I sent you a note recommending that you read it and I’d recommend it to you as well yes so you can this is your assignment for next week anyway thank you all see you next time for more please visit us at stanford.edu