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games. My name's Caroline Delahunty, Um, a consultant, pediatrician. I gave a lecture on Tuesday on Growth, and I wanted to sort of in pediatrics, and I wanted to sort of follow on from that today. Sorry, I'm going to turn my phone off, which I didn't actually think was in my room. So I'm very sorry about this. I gave a lecture on Tuesday on Growth, and I wanted to follow on today to talk about childhood, precocious puberty, which I appreciate. You may think you never see, but it's becoming very common actually. So the textbook reported instances one in 5000. But when we go through the talk and review the literature, we will evidence that it is actually now thought to be much higher than that. So just summarizing what drives Prue puberty Tree puberty. This is obviously a male slide with the test is at the bottom, but puberty come starts in the hypothalamus of the brain with gonadotroph in releasing hormone. This stimulates the the anterior pituitary to produce luteinizing hormone and follicular stimulating hormone in both male and females in the mail, the luteinizing hormone goes down to the testes, do and stimulates the testes to through the Leydig cells to produce testosterone, which Virilize is and causes the development of the pubertal body changes and then all the sexual development libido, etcetera as you go into adulthood. Follicle stimulating hormone is responsible for the gamut gamut productions the Mata genesis in the mail and obviously, um, follicles. Ovarian follicles in the female FSH actually also causes a protein called inhibin, which inhibits the hypothalamus and the pituitary and regulates. So there is a negative feedback system on the anterior pituitary and the hypothalamus and testosterone also causes a negative inhibitory feedback on the anterior pituitary and the hypothalamus. So there's auto regulation taking place. Summarizing this in words and I will repeat is I think it's sometimes a little bit complicated. Salutin izing hormone from the anterior pituitary kicks up in puberty, stimulating the Leydig cells to reduce testosterone. Testosterone modulates LH secretions, so it provides negative feedback to modulate it to keep the levels where they want them to be. Follicle stimulating hormone stimulates the totally cells to produce sperm and spermatogenesis, but also a protein called inhibin B, which negatively feeds back on follicle stimulating hormone via the anterior pituitary I think what we've also got to remember is actually the circulating sex hormones in our body are bound to a global in called sex woman binding globulin that falls in puberty, allowing free testosterone and androgens to rise to cause the virilization. So even a child has a certain amount of testosterone circulating a certain amount of estrogen circulating. It's important for bone growth. Um, and but we have a higher. They have a higher level as well. As the levels been lower. They have a high level of sex hormone binding globulin. Don't couldn't find a very good slide of the female axes. So again, if we go back to the other slide but put ovaries and the uterus at the bottom, it is the same process. So the luteinizing hormone, coming from the anterior pituitary stimulates ovarian stromal cells to produce androgens. Remember, females have testosterone and androstenedione in particular, so they are not purely estrogen driven. They are. There is a degree. If you take hormone levels of female, you find testosterone. They're they have both okay. And then in menopause, obviously balance changes. Estrogen falls, so they have a little bit more testosterone around and equally, males have a certain amount of estrogen present as well. It's not just testosterone, LH and FSH act on the granna, loser of the ovaries and the thicker cells to develop the follicles to produce the follicles from the ovary for fertilization. And the follicles produce estradiol that produce an estrogen based compound. LH and FSH promotes follicle, maturation and ovulation and then are responsible for the embedding in the uterus. If there's fertilization and the eventual progesterone development, keep that fertilized egg embedded. But I'm not going to talk about re production. The granulosa cells produce this inhibitory negative feedback through Inhibit A and B, which inhibits for little a stimulating hormone. This is I'm just trying to demonstrate that the levels fluctuate us. But the female goes through her menstrual cycle, Um, to what the ovary is actually doing if it's embedded where it is and progesterone comes in in the luteal phase, I want to focus very much on clinical coaches puberty, not by chemical precocious puberty today. So the clinical aspects of normal puberty. We define it when the volume of the testes in the boy and I will show you a test is volume measuring tool is greater than four mills. Once they hit six mils, they're actually into starting to go into puberty. So if you see a child, a boy who is concerned, he's not entering puberty, part of your assessment is to measure his testis because as his testis grow, he's starting to go into puberty. And it's the first subtle sign he may not be so aware of, so you can give him reassurance. We stage the penile development, the penile growth, and we stage pubic and auxiliary hair growth in girls. We look at the breasts, and once they're a breast stage two, I will talk about it in a minute. And once they're developing pubic and axillary hair, they are starting into puberty. They're developing through puberty. This is a slide you've seen before. If you're with me. On Tuesday, the International Conference on Growth, the ICP concept so infant child and pubertal concept of growth that Children have three stages of significant growth in the Pubertal phase is usually from the age of 12 to final height. It's dependent on sex steroids, mainly, but not purely testosterone. In boys and estrogen and girls that cause an increase in growth hormone secretion to accelerate that height growth. The result in growth acceleration is eventually stopped by the bones, fusing their epiphany. Seal growth plates, which is due to estrogen in both sexes. And that's what stops height growth. Once you've reached your adult height, get very growth in Children. We said that the childhood centre I'll is not the most accurate predictor. The most accurate predictor is taking account of the mid parental height. In a boy you had 12.5 centimeters to mom. You add it to Dad's height. You take mom's height. You had 12.5 centimeters. You add it to Dad's height, and then you divide by two, and that should be their height and a girl you take 12.5 centimeters away from Dad's height. Added to Mom's height. Divide by two. The puberty onset is to find, so there's something called panna staging. So Tana described the stages of puberty and classified it, and this is what we use internationally. The W H O. Use it right. I'm pretty sure it's international breast budding Stage two. When you start to see some breast protrude, rinse with the glandular tissue developing. You see some Ariola widening and you see the little pillar. The nipple actually start to stick out a little bit more. The average age the textbooks tell you is 11 in boys, the first stages testicular enlargement, six mils. Average age is 11.5. Here's a pictorial assessment is it doesn't come across very well. I'm sorry about that. Um, showing for girls. The this is childhood. You can sometimes get a slight elevation. But this is when we think puberty is really starting. The areola has got bigger. If we were looking face on, you can't really see it. The areola is bigger, the pillar of the nipple ist aren't protrude and we have a little bit of a true Vince. Then as we go through the stages, that becomes more obvious. Looking at pubic hair, I'm trying to get so at stage two, you've got some course often quite fine hair. This looks quite dark, coming up up from the labia, but not going up too higher into the pubic area and certainly not going down into the legs as time goes on, this gets thicker, curlier and coarser and gets more obvious. And then when you're in your adult body, you should have pubic hair on your upper thighs. And it's very course and a large area. And boys, you see the testicular involvement first of all, and maybe some strands of pubic hair. Then the pubic hair. You get penile growth taking place, increasing testicular size, more pubic hair and again that goes on through the stages. This is what we measure the testicular volume with so puberty is nicely labeled as six. So the numbers come on. Whereas this is four to I don't know what that is, right. Okay, But soon as you hit six, you're starting into puberty and then you follow through with growth of the test IBS bills grow fast. Do purty the slide you've seen before on Tuesday, the peak height velocity is at the age of 12, unusual but associated with breast stage two and three. So that's when you're going to see that height growth spurt. They slow down with their height growth spurt and in general they stop when they are menstruating. They are close to their final height, so they grow fast at the beginning. Boys grow fast in the middle. They have slow both, Um, at the start of puberty, they accelerate their height mid puberty, which is associated with growth, the Penis. And they have a peak height velocity. When Penal and Peter Care growth is G four and they will continue to grow even though they have finished their pubertal secondary sexual developments, there is still some height going on. They may not be at their final height. This is it pictorially on. Do I access? You have some height velocity and I'm demonstrating what I just said. So, boys, you'll see that with pin our growth, they get a increase in height velocity which then, um, fails off sort of decreases their height. Velocity decreases as they come into facial hair and shaving. Well, really, I want you to take away you this slide because it becomes very important when we come into the clinical debates of when to treat effective growth on pubertal timing. So we have three stages of per pubertal time. And if we look particularly these slides, we have the early developers in the light blue average age of puberty, developers in dark blue and late developers in red and boys in both. Actually, what I want to show you is that the final height obtained If you look at these lines, the final height obtained is the same in all three groups. It just depends at what age they get there. But just by varying, when you go into puberty doesn't mean you're going to be taller. So the final height is the same. Okay, so summarizing that puberty starts the same aging girls and boys, there's not a lot of difference. It's just boys go through it much slower and don't show that height, which is what you see to the external I, whereas they accelerate their height mid puberty about two years later. But they are starting in puberty, probably only about six months later than girls. Final height is independent of the age they go in, but men are taller because the three factors their pubertal growth starts two years later than girls, so they've had more time for height. Growth in childhood is more intense, and they're slightly bigger to start off with. Anyway. Boys are bigger than girls through childhood. We're gonna talk about bone is so there's a couple of slides on bone age. We can determine where you are in growth through you, the age of your bones, which sounds rather strange. And we What we do basically is assess skeletal maturity. Because, remember, we talked about growth stopping when the bones mature when those growth plates have fused. So we assess skeletal maturity to look at the bone age. Does it correlate with the child's age? Or is it a head of the child in precocious puberty or in constitutional delayed puberty? Is it behind the child? So it's calculated by taking an X ray of the left hand and risk. So it's a standardized group of epiphany See plates that you look at that the radiologist can tell the maturity of the epiphany seal plate by doing measurements of width and depth, depth and density on them. And you can then plot that bone age to see how it correlates with the child's actual age. So that's the Ristic tray that I've been talking about. The radiologist looks at the epiphany, sees in all those small bones and then takes an average. I want to go on two cases, look forward, actually, for um uh, am I speaking to you quickly? Let's look at some cases to make this clinical. So you are seeing a two year old girl with normal growth. But Mom has noticed a symmetry of her breast development. I don't know if anyone wants to shout out or put in the chat, but you'll have to read it out for me. Heather, what do you think about this? Does this worry you? That child's breast right is greater than the left in a two year old and otherwise clinically normal child. Are you concerned? Is this a sign of early puberty? Which is what Mum's concern is? The answer is no. It's normal. It is very common for Children in growth at all stages to have a symmetry of the breast. So we would simply be a sure we would do nothing more unless there were other signs of a growth or pubertal abnormality. But in a clinically normal child with simple asymmetry of the breast, you reassure this little one is a bit more complicated. I'm sorry, there's lots of words, but I'm going to read it out. She's an eight year old girl with a six month history who comes to you because Mom is concerned that she's noticed bilateral breast enlargement, the development of pubic hair. She has no axillary hair yet. She's got no evidence of PV bleeding or mucoid discharge. She's not got a change in body odor. She's not sweating, but she has got acne developing on her forehead. Past medical history is normal, and you note that Mum achieved Meineke at age 12. There is a family predisposition to the age you go into puberty. She's not on any medicines like because in androgen ization, and she has no headaches or anything else on systemic review. So she seems to be a simple early puberty. She looks well. She does have the acne. You examine her, including C. N s examination. Don't forget to examine them neurologically and you confirm that she does, in fact, have breast stage two pubic hair. Stage two, no axillary hair. But reassuringly, her height and weight are on the 91st. Cental. She has good height. What do you want to do? I'm happy for people to shout out or say What are they going to do with an eight year old in early puberty? It's an interesting debate. Okay, in general, we do nothing believe it or not, he say it is a normal variant, and puberty is becoming younger, across certainly the West and America. So I would take into account the race of this child, actually, but the fact that she's got good height is reassuring. I'd be much more concerned if she was on the third center aisle, because if she's got good height, that's very positive. It shows that she should attain a good adult height, even if she comes back. If she refuses the epiphyseal early, she should still hit that 50th percentile, maybe not the 90th center, but will come down. I think you have to have a discussion about her emotional state, but in general we would just monitor and make sure that this is not an accelerated, aggressive puberty. Because, remember, I have said that the timing through puberty is very. Although she started at age still may not reach men icky until 11 12. So provided this is not aggressive, I would do nothing. This is a very clear case of puberty, so you've now got a 22 month old, a two year old presenting to the GP with Coryza, and then there's a coincidental finding of breast development. This is a true case and pubic hair development. Mom gave a history of instrument intermittent PV bleeding over nine months, which he had gone to the GP with. But at that point they wondered whether it was nappy rash thrush. They weren't quite sure what was going on, and they treated topically subsequent that the pubertal pubic hair has developed, and, more recently, the breast development has come in. She's a normal birth, is noted that she has dark skinned and asymmetric pigmentation, which is a sign almost of androgen secretion virilization. So it's abnormal, and there was no evidence of trauma for the PV bleeding. Her anal inspection was normal. There's no evidence of child sexual abuse here because you do need to think about it. Although you've got other signs of puberty now. The pubertal stages are confirmed. She has passed stage two with breast development, but they said you don't expect to stage one, and Stage two would worry me, and she has pubic hair. Stage two, her weight and her height under O F. See her on the 99th percentile. So she's got accelerating growth as well. So that's true precocious puberty. We're now going to go on to talk about in a little bit more detail. So we define it into whether it's central, whether we think it's kept. Basically, do we think it's coming out of the brain? Or do we think it could be coming from the adrenal glands driving Eastern androgen ization? Or do we think it's coming, for example, from a tumor of the testes or ovaries in their own right? We also define it into whether we think it's with the sex of the child or whether it's indeterminant virilization, an ice a sexual. I have never seen ice a sexual. What you usually get is true. Central, precocious puberty go in with the sex of the child. Um, you can get very rare adrenal tremors, causing peripheral androgen ization. You can also get a peripheral inborn error of metabolism with congenital adrenal hyperplasia. They tend to be problems with the metabolism of the adrenal glands, diverting production into androgens. So if we focus on central, which is by far the most common, most of it is idiopathic. It is not related to any tumor's or inborn errors, So 95% in girls. Unexplained boys were a little bit more worried. They may have a brain tumor sitting in there if we get a boy in precocious puberty, it worries just more than a girl in precocious puberty. So 95% girls, it's idiopathic, and the majority of precocious puberty is female, and it's innocent. It's not related with an intracranial. Pathology is just an overdrive of that natural cycle, which we don't understand. If you have a child who has a brain abnormality such as hyper hydrocephalus or cerebral palsy, precocious puberty is more common. It can be secondary to oncology treatments and drugs, and but we need to think in the minority. Could they have a brain lesion sitting in there? Could they have a tumor sitting in the hypothalamus or the anterior Buick pituitary? Could they have a hematoma or a neurofibromatosis? Or they could Could they even have a tumour of the pineal gland, which sits just below the pituitary? So we're going to want to neuro image when you look at sorry, this shouldn't be caused central, precocious puberty. When you look at a child when you're examine them. When a mom comes to you, there are normal variants of early puberty development. Some Children come with just breast development, and they do not progress on to the pubic hair development. So the breast development isolated breast development is called fell icky. Then you can equally get Children, and this is quite proper common, actually, that you get a drone Archy, where they come with pubic hair development. But they may go into puberty slightly earlier than the normal child, but they don't. The development isn't completely central. It is just pubic hair. They won't have the breast development etcetera, and their puberty doesn't progress very raw rapidly, and we tend to reassure those. Actually, in fact, we tend to discharge them now and say, Look, come back. If you see other changes of puberty, we don't even keep them in clinic. We reassure them that this is normal to have isolated breast development to have isolated pubic hair development, and they're often about the ages of six or seven. They're quite young. Between six and 10. You will see this, and we reassure there are various syndromes that don't present precocious puberty. I've never seen this bandwidth grown back. Apparently it's associated type of thyroidism which is why we look at thyroid function when we're looking at the anterior pituitary glands and you may get galactorrhea and multi polycystic multi ovary syndrome. McCune Albright, you do see a little bit. So when you're looking at the skin, you want to look for Cafe Ole spots those brown pigmented cafe spots that you're seeing, um, as part of your examination, because that may take you down a Syndrome wrote route. You need to think about adrenal disorders when you're looking at precocious puberty, which I appreciate is not central. It's peripheral. Um, could this child have congenital adrenal hyperplasia that is partial and not giving you the steroid losing crisis, but is causing early precocious puberty? Or could they have an adrenal tumor, which is driving the virilization we've talked about fell icky and our Janaki, So I'm going to go on. We need to investigate the child in post puberty unless you're that eight year old where you're going to reassure and watch. If you're very early, you're going to investigate. You're going to do a bone age. We tend to do a bone age across the board anyway, because it's simple. I'm going to say noninvasive. It doesn't involve hurting the child. There's no pain in having an X ray because you're looking at the anterior pituitary. My practice is always to do thyroid function. We measure the sex hormones estradiol on testosterone. We want to exclude the adrenal hormones, so we do A D H A s. It's one of the adrenal tumor. Tumor is it's hydro androstenedione. But don't worry. This is all very technical. You're going to do your adrenal gland hormones. You're going to look at your luteinizing and follicle stimulating hormone. You'll do baseline tests you may want to stimulate to see what it does you're going to do an ultrasound of the pelvis, the uterus and the ovaries. You stage their development. You're going to think about an MRI of the brain to look for tumor's, and we tend to look for congenital adrenal hyperplasia. So we tend to do 17 hydroxy progesterone, and we look at the urinary steroid excretion. How much androgen testosterone and eastern are they throwing out in their urine? The important thing is always to have examined child and includes C. N s and visual fields, because the opportunity tumour may affect your visual fields do the bit biochemistry, as I've just listed and then think about. Do you want to stimulate this plan to be absolutely clear, as opposed to just a random measure of the eastern and testosterone? It depends what your results came in, as if they're extremely high. You may be happy to do it without stimulation. If you're not sure, you're going to have to go on and give luteinizing hormone releasing hormone to the child and then measure their FSH and LH and then measure the estradiol and testosterone. And again, I've talked about pelvic and pituitary imaging. I think this is where things get interesting. I really am going to speed up, actually, So does precocious puberty lead to behavioral problems? Which is why there's a debate about how much you should treat. There was a perception that they had adverse behavior, but actually the studies now are disproving that so. 33 patient's small numbers There's not much data out there showed that on the total behavior problems scale, only 27% of them only a minority fear of them were more depressed and had more aggressive, volatile moods. But post puberty once they were through it, they were fine. So you're not going to predispose the child to having more mental health or behavior problems? Does it affect final height? Remember that slide I showed you that showed even the early late and mid and late didn't affect the height. But what about Propo cious puberty? Does that change height? So 20 untreated, precocious puberty, 90% had a fetal height on the third center aisle and a mean final height of 161 centimeters, so only two centimeters less than the normal. So we looked at the age. So if you're in puberty at the age of nine, your height will be 100 and 59.5 compared to going in later on three centimeters difference at 1/6 right. Three. So we also know that puberty seems to be longer if you start earlier. So if you start at the age of nine, you're going to spend almost three years in puberty. Whereas if you start at the age of 12, you're only spending 1.5. So there's a variation in the duration, but it doesn't seem to be having a huge effect on height. just challenged what we should be doing. Historically, we've always treated the 68 year olds okay, but there's now felt to be a spectrum within that group. There may be a group that are less aggressive through puberty, and if you simply monitored them and saw them three months later, six months, nine months, 12 months you may see if they're going to be aggressive. You could do a bone age, and you can get a feel for where they're going. By how old are they on their bone? Are they a lot older than their actual age, or are they only 20% above their Chronicle age? So study looked at less than six year olds their final height when they compared treatment to no treatment. There was a 6.5 centimeter difference in final height if they were under the age of six. But when they looked at the Children that were above six, the 6 to 8 year old group there wasn't much difference. In height, there was only half a centimeter, so we're treating for half a centimeter because they're likely so in summary, there's now a thought based on evidence that 6 to 8 year olds with slower progressing puberty unless advanced a bone age. Not treating is the correct thing to do because you're not affecting height retreat. There's various ways of treating. If you go on the Web, you or your re textbooks, you're going to say there's various ways of treating in the UK at the moment. I believe we're mainly We're mainly blocking the gonadotroph in releasing hormone, stimulating the anterior pituitary. We're blocking the receptor of stimulation, so we're using a gnrh antagonist. You can equally believe it or not. Use a G N R H agonist, which feels counter productive. But remember that gnrh is pulse it tile If you flood back gnrh system. Eventually, the negative feedback inhibit inhibit release of FSH and LH. So although you may cause a slight acceleration at the beginning, you eventually inhibit the FSH and LSH. But we block the receptors, or we use the gnrh antagonist, a blocker. Well, you only do it for complete central, precocious puberty, and it's reconsider it if they've got abnormal height potential. And we have proved biochemically either in puberty. It's not just a clinical, it's a clinical and biochemical criteria for entry, and they've got abnormal height potential. But there is a discussion with the family of the psychosocial consideration. Can this child cope emotionally and it's an individualized entry into treatment? I don't understand. Actually, this may have come out of right. Okay, We know Children seem to be from international data, and I think slides come later that they're going into puberty earlier. Um, we're not quite sure why we think nutrition has an impact. Are there environmental estrogen's driving Children? We don't know. Are they bombarded with sex leading to a change in physiology? I think that's a bit of a hypothetical one, but it's out there in the debate, a time an American magazine did early puberty's. Why our girls growing up faster. And we do know that this subjective rise in there is data being collected, that there's a rise in referrals to enter crime clinics in the UK with girls in precocious puberty. And there has been a study done which I'm going to come to. I think I've asked about what time show in this is American study. Huge number of girls studies looked 17,077 girls massive massive database, 90% of the Children were white, 10% from Afro African American girls. The African American girls started their breast development 8.87 years and puberty hair 8.78 so slightly before their breast development. Normally I would expect it to almost go the other way. And they were menstruating by 12 white girls again menstruating by 12. And the data is there what they did show, though as as on this chart, what we're seeing is that the age of puberty is get entering into puberty is getting younger when you go back to 1948. So if you look now, we're showing puberty is becoming younger. In 1948 girls went into puberty not at the age of eight or nine, but much more so at the age of 11. So over time we are bringing these Children into puberty younger and again on that big database. He also showed evidence of puberty at the age of 34567 down the bottom more prevalent in the African Americans in comparison to the white US A. Children. I guess what I'm just trying to tell you is that puberty is becoming younger on international data and therefore to change our practice not necessarily to treat the 6 to 8 year olds is when we look at final height is appropriate. But there is still debate the current recommendations in general support of Herman Giddens work and the right. So the old recommendations used to be that we treated the 6 to 8 year olds. The new guidelines are to evaluate them if they're less than seven and African Americans less than six and boys are different if they are less than eight. But really, there's minimal benefit in general of the LHRH antagonist for the 6 to 8 year olds without significant improvement in height, I am very all right. Yeah, a hunter. We've got less than 15 minutes left. So and there's also a question in the chat. Now I'm going to caution to the international variation. I'm going to conclude this, Okay, so just as a final point, if I was working in Nepal, I would probably be thinking a bit differently to working in Europe and the US A. So there is international variation, just as a comment premature adren Arche. Although we say it is benign, it can be associated with polycystic ovary system. I don't actually screen ultrasound the ovaries, though, because it's difficult to identify polycystic ovaries at that stage. But it's something for the g P to think about. If there's infertility or many key problems later on and insulin resistance. There you go. I'm going to stop sharing my sides and okay questions in the chat, right? Does having good question actually, precocious puberty have an effect on later life, such as menopause? Know is the answer to that. Not to our knowledge. Um, I guess you're wondering. So is Eastern because it started earlier, eventually going to run out? No, they don't seem to have an earlier menopause. Any other questions? There's no other questions in the chat, but if anyone wants to Oh, there's one that's been added now. Oh, gosh, I don't know what's the correlation between sexual abuse and goes puberty? I can't answer that. I'm afraid, Um, I don't know. Scary thought that isn't it? Uh, I don't know. I think it's a bit of a scary thought that one. So just because the eight year old has is developing our adult body, it's quite a common referral Actually, I've and it. I've been a consultant for 21 years, and it's definitely becoming more common. It's quite surprising. I think the concern with the parents is often the emotional, the emotional effect of going through puberty at a young age. Uh, the discussion's always end up, but she's too young to cope with this, Uh, but we would always neuro image a boy because they probably got a tumor. Thank you for the comments. Everyone. I don't know in the chat because I'm teaching next week. Does anyone want to put in at what topics they would like covered? Because obviously, I'm not aware of what you're managing to get covered within your own medical school. So if there's anything particularly you want covered, you can type it in for me. I think if there's no further comments, um, can you hear me? Uh, sorry. I think if there's no further comments, then um, if everyone could just do the feedback now, um and then I'll give you a few minutes to do that and then post. It's a difficult, but, um, thank you very much, Doctor Delahunty. Thank you. Um, and I believe you've got a lecture next week. Next week? Yes. Okay, great. So hopefully everyone here can join again next week and hopefully we'll have more people. Okay. Thank you. Thank you very much. Bye. Thank you.