In this talk, pediatric endocrinologist Jennifer Olson, MD, describes how the hormonal processes that lead to sexual maturity are currently understood; provides usable definitions of precocious puberty as well as delayed puberty; and lays out evaluation processes, including how to answer the key question of whether a patient with premature changes is experiencing true early puberty or simply adrenarche. She explains who should get a workup, offers tips to optimize testing accuracy and meaningful results, and clarifies when referral to a specialist is warranted.
And thank you everyone for coming, making time during lunch. Uh, let's see. Uh, that looks, looks great. OK, good to go. Thank you. Yeah, so, um, So I adjusted the title slightly to diagnosis diagnosis and Management of puberty that is too early or too late. All right. OK. Uh, I have nothing to disclose. Um, so today I'll try to cover, uh, these topics, the physiology of puberty, the timing of puberty. The difference between adrenarchy and what we call true puberty, causes of early and late puberty, how to evaluate early and late puberty, and who to refer to an endocrinologist. So first I'll just talk a little bit about um the hormonal regulation of puberty, and this is um a schematic of how um we used to uh um Think about, uh, puberty, um, uh, we still do, but, um, there's more to it. Um, so there's a pulsatile generation of GNRH from the hypothalamus that stimulates the pituitary gland to produce LH and FSH which then stimulate the testes or the ovaries, um, uh, to produce, um, Uh, testosterone, uh, or estradiol in the ovary and, um, Um, and then there's negative feedback, uh, to regulate the system. We now know that um There are additional higher regulators of puberty, um, including, um, GABA, neuropeptide Y, glutamate, um, leptin, ghrelin, um. And, uh, ultimately cispectin, which is what um regulates GNRH and then more recently, there's um this new McCorin ring finger protein 3 which inhibits cispectin, um, so it's also a regulator of puberty. So I'll just talk a little bit about um the terms that we'll use. Gonadarki is central puberty. This refers to GNRH stimulation of LH and FSH. Adrenarchy is the onset of androgen dependent changes including pubic hair, axillary hair, acne, and body odor. In females, this is due to the adrenal glands, and in males it can be either adrenal or Um, hormones from the testes. Tarche is female breast development, gynecomastia refers to male breast development, and menarche is the onset of menstruation. Um, so the hormones that regulate puberty as, um, as I just, uh, showed you include the hypothalamic pituitary gonadal axis. And this axis is active at 3 different time points, um, in the mid-fetal, um, time, the neonatal period, and then, um, in early infancy. Um, it then is quiet, uh, during the prepubertal years, generally between ages, um, 2 and 8. And then there's an increase in both the frequency and the amplitude of the GNRH pulse generate pulse generator, which occurs at the onset of puberty. The adrenal glands start to make DHEAS in particular, between 6 and 8 years in both boys and girls, but we usually don't see any evidence of this until a few years later. Um, it's important, uh, when evaluating for early, um, signs of adrenal activity to have a normal morning 17 hydroxyprogesterone in order to exclude, um, non-classic CIH. Growth hormone increases uh during puberty, and this creates a period of insulin resistance, and then, uh, disorders that uh the thyroid can cause um both precocious and delayed puberty, so it's important to evaluate thyroid function. All right, so the timing of puberty in girls. Um, so, uh, I have on the right side of the screen just, uh, the, uh, sexual maturity ratings or Tanner stages that everyone's familiar with, um, stage one being no, uh, pubertal development and, uh, stage 5 being mature female, um, development. So puberty begins in girls when the breast buds reach Tanner stage 2. And this happens at the same time as growth acceleration, and the, um, the, what we consider to be the normal timing is between ages 8 and 13 for the onset of breast buds. Um, there's a little bit of a difference in eth uh ethnic groups, um, so, um, African-American girls, um, almost a year earlier on average. Um, then, uh, white or Asian girls. Typically, pubic and axillary hair occur 11 to 1.5 years later, and then peak growth velocity, uh, is occurring between tanner, uh, breast tanner stage 2 and 3. Menarche typically occurs between breast tanner stage 3 and 4. Which is typically 2.5 years after the onset of puberty, but there's a big range. It can be half a year to up to 3 years on average, and the average age of menarche uh remains at about 12.5 years. So, we are seeing, as I, I don't need to tell you, uh, we are all seeing this earlier timing of puberty in girls. And, um, This study from 2010 just compares the percentage of seven year olds with early uh breast development, um, the number in, uh, or the percentage in 1997 compared with the percentage in 2010. So for white girls, the percentage of uh seven year old girls, uh, doubled, um, from 5% to 10%. During this time period, um, it increased in, um, African-American girls from 15% to 23%, and then there wasn't any data in 1997 for, um, Hispanic girls, but 15% in 2010, 15% of 7 year old, uh, Hispanic girls had breast development. Um, so we know that we're seeing breast development earlier. Um, we know that there is, um, uh, some variation based on ethnicity with African American girls, the earliest at an average of 8.8 years, Hispanic girls 9.3 years average, white girls 9.7, and, uh, similarly Asian girls 9.7. Um, however, um, it appears that the age of monarchy has remained relatively stable over about the last 25 years, um, about 4 months earlier in African American girls, so 12.2 years on average, and then 12.6 years in Caucasian or white girls. Um, the age of the Larky, therefore, um, and the age of monarchy appear to be less linked, uh, than they were in the past, and then we also know that, um, We see more signs of early puberty in um in uh girls who have higher BMIs over eighty-fifth percentile. Um, so I'll switch and talk a little bit about boys. Um, so for boys, um, they reach puberty when their testes are, uh, 10 or stage 2. So this is either a testicular volume of 4 mL, if you're using an, uh, uh, an orchidometer, or it's measuring, using a tape measure. Uh, if the long axis of the testes is, um, more than 2.5 centimeters, so 2.5 to 3.2 centimeters. This, um, occurs normally between the ages of 9 and 14 years. Um, that's the normal timing of puberty, um, pubertal onset for boys. Um, boys, uh, reach their peak height velocity later in puberty than girls do, so. Um, girls start to accelerate their growth at the same time, um, as, uh, breast buds, but for boys, they don't reach peak height velocity until they reach tanner stage 3, and then, um, the more, uh, obvious signs of puberty, voice change, um, uh, gynecomastia, those, those occur even later in puberty towards tanner stage 4. Um, so there's also been Uh, a decrease in the age of onset of, of puberty in boys. Um, in 1969, the average age of pubertal onset was about 11.5 years, and then, um, in the early 2000s, um, the, uh, age was about a year earlier for white males and almost 2 years earlier in African American males. Um, so why are we seeing earlier puberty in girls and boys? Well, there's a whole long list of, um, of things that are being studied and, um, Uh, considered, um, possibilities, uh, definitely BMI, um, intrauterine conditions and exposures, high meat diets, dairy products, low fiber, um, um, high stress, acti uh decreased activity levels, uh, absent fathers, endocrine disrupting chemicals, the microbiome, light exposure. Certain hair products, um, insulin resistance, geographical location, and then, um, adoption, um, from developed developing countries to more developed countries. OK, so what is the definition of early puberty? So even though we know that puberty is starting earlier in girls and boys, the recommendations for, um, at least considering evaluation haven't really changed. So if girls are showing signs of puberty before the age of 8 or boys are showing signs of puberty before the age of 9, we still consider this um to be early. We understand that there's racial differences, um. But we don't want to um miss pathology, so, uh, that's one reason for um using these age cutoffs. There are different types of early puberty. Central puberty refers to gonadotropin dependent, um, puberty. Which is uh LH and FSH stimulation, and peripheral uh puberty is gonadotropin independent. Um, and McCune Albright is a, is probably the most well-known example of this, um, and testotoxicosis in boys. Um, we also know that examination, um, and Tanner staging can be difficult, um, particularly determining when a girl has reached Tanner 2 breast stage, um. And differentiating between um glandular breast tissue and uh fatty uh or lipomastia. So when um when you go to evaluate um early puberty, what, what I think is really helpful to do is to kind of in your own mind sort out, is this um patient showing signs of just adrenarchy, which would be pubic hair, axillary hair, body odor, acne, or are you really, um, do you really have to worry about um true central, um, Or peripheral, uh, precocious puberty. And in those cases, you, you can palpate breast tissue, you have or you have testicular enlargement, um, for boys, and then, um, you determine whether it's central or peripheral. Um, but this is, um, important because then you're going to tailor your evaluation, um, to the signs, um, and symptoms that you're seeing. Um, so, on history, um, you'll ask the parent usually, when, uh, when did you first notice the changes? What changes did you see? Um, has there been progression since you first noticed, um, uh, signs of puberty? When was maternal monarchy? Um, does dad remember how old he was when his voice changed? Um, did father, um, did the dad grow after high school? Was he a late bloomer? Um, and then on exam, You're looking for pubic hair, axillary hair, you're looking to see um if uh the testes are enlarged, you may be um measuring them. You're looking at the growth curve to see if there's been growth acceleration and then um you're trying to determine in girls especially, um, you know, is that breast tissue um that's glandular or is it fatty tissue. And then you can use a tape measure um to measure testes. So we see a lot of kids with um isolated premature adrenarchy. And again, this is due to the production of adrenal androgens and DHEA uh or the sulfated um version of DHEA DHEAS, um, is in the TANR 2 to TANR 3 range in, uh, generally in kids who are, um, uh, under the age of 8. Um, we see this more often in kids who were born small for gestational age, and then we also know that it is, um, can be the first sign of, um, PCOS, um, that may develop later in girls. So, for these kids, um, it's important to exclude non-classic, um, CAH. And, uh, or an adrenal tumor. So the evaluation for isolated premature adrenarchy is um generally uh looking at a DHEAS level, um, and then a morning 17 hydroxyprogesterone and a bone age X-ray. OK. So, um, now we're gonna talk about true precocious puberty, which can again be either central or peripheral, and, um, so this means that you're either palpating breast tissue in girls or you're seeing testicular enlargement in boys. And if it's central, then it's a gonadotropin dependent process. So you have GNRH activation of LH and of the LH and FSH receptors. And um then also keep in mind that um HCG uh acts on the LH receptor as well, and so, um, Males, um, it's important, especially in boys with central precocious puberty or signs of early puberty to measure an HCG level, um, uh, as they can, um, uh, uh, tumors producing HCG can, um, mimic precocious puberty or cause precocious puberty. Um. And then in peripheral precocious puberty, you actually have um suppression of LH and FSH uh with elevations in either testosterone or estrogen. And again, this is seen in the McCune-Albright syndrome where you have an activating mutation of the GNAS gene um or in test toxicosis, which is an activating mutation of the LH receptor. So, um, the, uh, hypothalamic pituitary gonadal axis is active in infancy. And, um, on this, Um, oh, I think this, sorry, the little, um, picture got cut off, sorry. Um, but LH and FSH, um, decline immediately after birth, and then they start to rise in the first, um, after about a month, so in 30 to 60 days after birth, they were, they rise to pubertal levels, um, and this results in stimulation of the ovaries or the testes to, um, produce. Uh, pubertal levels of testosterone or estradiol. They then return to prepubertal levels. In girls, it takes about 1 year, although FSH can be elevated for up to 3 to 4 years, and then in boys, they're usually to prepubertal levels by the age of about 6 months. Um, the FSH levels in girls are, uh, typically much higher than they are in boys. Um, but this, it's important, um, this window of, uh, looking into the, um, hypothalamic pituitary gonadal axis is, um, helpful if you're evaluating, um, uh, babies with either, um, Um, optic nerve hypoplasia or, um, uh, different types of ambiguous genitalia, um, at birth because you can, um, have this little, um, temporary, uh, period of time where you can evaluate their, um, their hypothalamic pituitary gonadal axis and, and then that gives you, tells you, um, what to expect later on, um, when it's time for them to go into puberty. So we, um, see, um, this commonly, um, isolated premature filarkey. So this is just, uh, breast development that usually occurs between the ages of 6 and 24 months, and it is due to this mini puberty of infancy. Um, at this age, it's not, um, due to, um, maternal hormones. Um, it is important though to, to at least ask about exposures in the home to Uh, hormone containing medications or creams, um, Lavender and tea tree oils. Um, but this type of, um, breast development, usually parents will say sometimes the breasts look bigger, sometimes they look smaller, it seems to wax and wane. Um, and then, um, if there aren't any other signs of puberty, um, then usually you can just, um, provide close follow-up. Um, but if the breasts seem to be getting larger, if you see other signs of puberty like pubic hair, then, um, then you have to, uh, evaluate further for, for, um, central precocious puberty. Or if, um, the breast, uh, tissue, um, persists beyond two years, which sometimes it does, and it's, it's still usually this condition, but, um, at that point, you probably wanna get some labs. So what are the causes of um precocious puberty and what is um the epidemiology? So, precocious puberty is much more common in girls and boys, 4 to 10, uh, ratio to 1, females to males. It's thought to be, um, more genetic than environmental. Um, we know it's more common if you have a child who was, um, adopted from a developing country to a developed country. Again, more common in girls. And it's more common if there's a history of any type of CNS injury. Um, there is some interesting, um, recent studies on the genetics of early puberty, and there is a, um, has been found, um, in 9%, um, of central precocious puberty and up to 19% in familial central precocious puberty, this loss of function mutation in this McCorin ring, um, finger, um, 3, Protein. Um, so this is inherited, uh, from the father, um, in an autosomal dominant transmission and, um, right now, testing for this is only um in research, um, uh, conditions since the treatment's gonna be the same either way. OK, so once you've uh decided whether what type of uh early signs of puberty um this patient has, then you're going to uh pursue your laboratory um evaluation. So is it adrenarchy only, um, again, isolated pubic hair, axillary hair, body odor, or are you worried about true central precocious puberty because there's palpable breast tissue or there's testicular? Um, enlargement, um, and then you're gonna go from there. There's, um, this is a helpful article. It's, it's from a year ago. Um, it's in the um Journal of Clinical Endocrinology and Metabolism, and it's March 2023, and it's, um, uh, it's uh the approach to the patient with central precocious puberty, and it's pretty good, a good review article if you're interested. OK. So if you are going to, um, we've already talked about how to evaluate early uh isolated adrenarchy. So now, um, we're gonna talk more about evaluating um your patient who has signs of uh true precocious puberty. So LH is always the most sensitive biomarker um for central precocious puberty. And if you, if you can get a um baseline LH level that is at least 0.3 units per liter, then you have confirmation on a baseline sample that this is central precocious puberty. Um, the important things, however, are that it has to be done on an ultrasensitive assay. So, um, and it's best if it's an early morning sample. Um, and if your level is less than 0.3, it does not exclude central precocious puberty. And this is why We do the um GNRH stimulation testing. So in early puberty, because of the pulsatile um nature of the um GNRH um pulse generator, you may or may not capture a pubertal LH level on a baseline sample. Um, and, uh, if you don't, it doesn't mean that that your patient doesn't have precocious puberty, it just means that you didn't capture it. The, uh, again, the test has to be done at a Quest Diagnostics or a LabCorp or Esoteric, um, uh, our lab, uh, uh, sends all the samples out to Esoteric where they're run on an ultra sensitive assay. Um, but unfortunately, if your patient goes to Sutter or some of the other, um, commercial, you know, uh, hospitals or labs, um, it, you, you may get a result that just says less than 0.2, and that's not sensitive enough to, to really help you. Um, and then depending on if you're evaluating a girl or a boy, you'll want an estradiol or testosterone level. And then, um, again, you wanna make sure it's done on an ultrasensitive assay. Uh, early morning samples are still the best, and then you wanna be, um, really mindful of your units. Um, so, an estradiol level of greater than 15 picograms per mL is, um, pubertal at baseline, um. Sometimes you see, get an estradiol that's uh given in nanograms per mL and then it would be above 1.5. So, um, Uh, the units are important. Um, usually, we look at thyroid function and then also keep in mind as, uh, for boys that HCG can stimulate that LH receptor and, um, certain germ cell tumors can, can present as precocious puberty. So we do um a lot of um GNRH stimulation testing. This is the testing we do in the day hospital. It takes about 5 hours. It's um the gold standard for confirming central precocious puberty, especially if you don't get an uh baseline LH level that is at least 0.3 or higher. Um, we draw a baseline LH, FSH, and estradiol. Um, the patient then gets 250 mcg of leuprolide as a subcutaneous injection, and then through their IV they get, um, LH, FSH, and estradiol levels drawn at 23, and 4 hours. And an LH level greater than 5, confirms central precocious puberty on a stimulation test. All right. So, additional um uh evaluation or testing um could be a pelvic ultrasound. So if your LH is suppressed, but you're seeing lots of uh estrogen, then you have to go looking at the ovaries to see if there um are uh estrogen producing ovarian cysts, um, which is seen in, um, Again, McCune Albright, which is a constellation of endocrine disorders, polyostatic fibrous dysplasia, and cafeoli macules, um, and then, um, a good, uh, radiologist can give you, uh, uterine measurements and ovarian measurements that can, um, where there are published published standards, um, for prepubertal and pubertal, um, sizes. Usually, a bone age X-ray is um 2 years advanced in true central precocious puberty, um, but we also see a lot of bone age advancement due to obesity, so that, keep that in mind. Um, when to do a brain MRI is always, um, a big question. Um, boys, um, all boys should have a brain MRI if you have confirmed central puberty, um, by your Um, lab testing, um, because pathology is found in 40 to 75% of boys who have, uh, central precocious puberty or puberty before the age of 9. the most common finding is, uh, a hypothalamic hematoma. This is, um, these are associated with, um, gelastic seizures, and then, um, germ cell tumors, um, are also Um Uh, causes. Girls, um, it depends on the age and whether or not they have any central nervous system symptoms. Um, in this recent, uh, review, um, in JCE&M a year ago, uh, they broke it down, um, and reported that, uh, 25% of girls who have precocious puberty. Before the age of presenting before the age of 6 years have intracranial pathology, whereas only 3% of girls between the ages of 6 and 8 years were found to have intracranial um pathology. So, For girls who are between the ages of 6 and 8 years, um, It's important to at least weigh the risks of, you know, uh, finding something incidental, um, potentially needing sedation, um, creating more anxiety for the parent or the child and the child and or the child. Um, and so, at least, um, there's, you know, the suggestion of not performing an MRI in girls if there's no CNS, um, symptoms. Um, so, what is the treatment? Um, so, um, excluding and treating any, any underlying cause, um, and then considering medical intervention to temporarily suppress puberty. And we do this for two reasons. One is to preserve final height, uh, in boys and girls, and then the other is to delay the onset of menses in girls. So, we Generally treat all boys to preserve their final height. And then for girls, again, um, under, under the age of 6, there's good data to support treating to um improve final height. Um, between the ages of 6 and 8, there's a, a varied response um to pubertal suppression, and then there's no evidence that height will be increased, um, if Um, treatment to suppress puberty is initiated in girls after the age of 8. Um, however, it doesn't mean we don't treat some girls after the age of 8 because, um, certainly you can delay the onset of, of menses, um, with treatment. Um, so treatment, um, is, uh, done with, um, GnRH agonists. These are, um, We think of these um as super agonists because they flood the um LH uh receptor and um That's how they turn off central puberty. Um, there's, uh, intramuscular leuprolide, which comes as a 1 month, 3 month, and 6 month preparations, and then there's the hysterellin or sepralin implant, which has been FDA approved to suppress puberty for 12 months, but there's published, um, Uh, literature, uh, now showing that it is effective for up to 2 years, um, or even, even longer. So we're using it, um, often for 2 years. Um, this, these are the preparations that are available in the US, um, so leuprolide or Lupron, Depo Lupron has been available since 1993 in the, the one month formulation, um, in 2007, that's when hysterellin became available, um, in 2011, the three month leuprolide became available in 2017. Uh, the six month I am, um, Uh, preparation tryptoder or tryptorellin. Uh, became available and then in 2020, um, this, um, fenolvi or the six month subcutaneous, uh, leuprolite acetate was approved. So, um, this is just from that article, um, kind of how to approach girls with, uh, breast development between the ages of 6 and 8 years, and kind of the some of the challenges. Um, we know that the age of thelarchy has decreased over time, but the age of menarche, um, hasn't decreased as much. And so it seems like there's a slower tempo of puberty, um, among girls who have early breast development. Um, and then, um, there are these additional considerations, um, which we, which we have gone through, you know, needing, um, a baseline LH on an ultrasensitive assay, um, the risk of doing an MRI since, um, there's, you know, uh, Little, um, pathology in, in girls between the ages of 6 and 8, not improving height in girls, uh, over the age of 8. so, yeah, a lot of things to consider when, um, talking to families about pubertal, um, evaluation and treatment. Although it is, um, the treatments, uh, are, are safe and the data is reassuring, um, in terms of bone health and fertility, uh, and things like that. Um, so, um, these are just some of the challenges, um, um, and I, I think you all know this, that, that you're seeing more girls with breast development, um, between ages 6 and 8. treatment, um, doesn't impact, um, height, uh, always impact height at this age. Um, Um We're, we're getting more referrals for early breast development, um, since the COVID-19 pandemic, and so this brings up questions about sedentary lifestyle, increased screen time, psych uh psychological stress, um, and then, Um, it's important to, to also recognize that environmental factors, um, that are driven by socioeconomic disparities may serve as confounders, and there is some risk, um, of missing pathology if you sort of assign a race-based guidelines in central precocious puberty. So that's why it's important. To thoroughly, you know, evaluate each individual patient, um, and their personal risk factors, signs, symptoms, um, independent of their BMI or their race. OK. So, all right. So now that we've talked about early puberty, um, we'll go the other direction and talk about delayed puberty. So, um, for girls, Uh, delayed puberty is, uh, the lack of breast buds, um, uh, by the age of 13, or the absence of menarche by age 15, or 3 years after the onset of, um, TANR 2 breast development. And for boys, it's the absence of testicular enlargement by the age of 14. We see a lot more delayed puberty in males than we do in females, and there's often a history, uh, a family history of late bloomers. So either Um, dad, uh, continued to grow after high school, um, or mom had, um, a late menarchy, and then, um, Usually the final height of late bloomers is, uh, falls within their genetic potential, but it can be on the, on the low side of the normal, normal range. OK. So this is just a typical growth curve of a boy who, who, uh, was kind of growing along, um, pretty, pretty normally and then fell off his growth curve, and, and that's, um, Uh, for 2, that's 2 reasons. Usually one is that, um, typically when other boys are, um, going into their growth spurt, late bloomers, um, not only are they not in their growth spurt, but they also at the same time have what we refer to as a prepubertal slowdown. So they really kind of fall off the curve, um, and this is when usually often we end up seeing them. And then as they kind of um go into puberty, they have this delayed type of growth spurt and then they end up kind of in the lower um lower range of their genetic um potential. Um, so what causes delayed puberty? So, um, in girls, um, it can be constitutional delay of growth in puberty, although that's less common than in boys. Um, it can be, um, Either, um, when you look at your labs, you're looking usually either at hypogonadotropic hypogonadism, meaning that you have low um gonadotropins, LH and FSH. This can be due to uh chronic illness like cystic fibrosis, celiac disease, uh, Um, inflammatory bowel disease, uh, rheumatologic conditions, um, it can be psychosocial, uh, uh, anorexia, excessive exercise, athletic triad, that type of thing. Um, if they have anosmia, then you have to consider, um, Coleman syndrome. Um, and then for hypergonadotropic hypogonadism, meaning that your LH and FSH levels are elevated, this is what we see in Turner syndrome or in primary ovarian failure, which can be autoimmune or um idiopathic. Um, for boys, um, constitutional delay of growth and puberty is much more common, and there's generally a family history, um, and again, um, you, you can have hypogonadotropic, uh, hypogonadism with low LH, FSH, and low FSH, uh, again, chronic illness. Um, I think I included sickle cell disease here, um, CF celiac. Um, boys can have anorexia or, or overexercising, um, Coleman syndrome, um, brain tumor, idiopathic. Um, and then again for um if you have elevated LH and FSH and low testosterone, this is what you see in primary testicular failure, um, and in Klinefelter syndrome. So, the evaluation, um, after you've done your history and your physical exam, um, would be to evaluate for, you know, chronic disease, so CBC, metabolic panel, a sed rate, thyroid function, um, usually growth factors, um, because usually they're presenting, um, with poor growth. In addition to delayed puberty, um, a karyotype, um, and then looking at a morning LH FSH, testosterone, or estradiol, depending on if it's a boy or a girl, uh, again, on an ultrasensitive assay, um, considering a celiac screen, uh, bone age, um, thinking about a pelvic ultrasound in a girl, um, and then looking at, um, uh, markers for, um, Um Testicular and ovarian function inhibit B and AMH. And then, um, Um, I don't, did I put, and then did I put MRI on there? I can't see on my screen. Um, it would be a bone, yeah, bone agent, and then, um, Uh, MRI depending on your, on your findings. Treatment of delayed puberty, um, so we, um, usually refer to this as a jumpstart, um, and this is again, much more common, uh, for boys and girls, but generally, it's a short course of intramuscular testosterone, about 2 50 mg, um. Uh, every month for 3 to 6 months, you should see an increase in testicular volume to about 6 to 8 mLs, um. Which, um, indicates some endogenous production of LH. Um, once you complete your course, your short course of testosterone, you wanna wait several months and then repeat the morning LHFSH and testosterone, and they should be in, um, pubertal levels. If they're not, then you have to consider that it's, um, permanent, um, hypogonadotropic hypogonadism. And you can't necessarily know that when you um embark upon um this pubertal jumpstart. For girls, you would consider treating with low-dose estradiol for 3 to 6 months and it can be either oral um or um transdermal with these um uh patches. And then again, um, you stop the treatment, wait several months to wash out, and then repeat, uh, repeat the labs. Um, so who should be referred? Well, certainly not, um, not everybody, um, needs to be referred, and, and not everybody even needs, uh, you know, a big evaluation, um, but I think at least considering and thinking about, um, you know, girls who are showing signs of puberty before the age of 8, or if they're Progressing rapidly through puberty, um, if they have monarchy before the age of 9 1/2, if they have any signs of virilization such as chloromegaly, um, Then, um, those would be good, um, reasons to refer. Um, boys, um, Again, uh, are just, uh, we see early puberty in boys less often than in girls, so I think it's more important, uh, to refer boys who are showing early puberty. Um, so it's, um, you know, they're showing, um, Pubic hair with um With small testes, you have to worry about, um, you know, an adrenal process or non-classic CAH, um, if they're showing testicular enlargement, you really have to worry about, um, Uh, CNS pathology, and uh if they're progressing rapidly through puberty, you have to worry um about pathology. If they're crossing um percentiles early, um, if their bone age. is significantly advanced, um, and if they have a morning 17 hydroxyprogesterone that suggests CIH. And then for delayed puberty, again, um, Girls who haven't started puberty by 13, haven't had menarchy by 15, or um menses within 3 years of starting um puberty, and then boys who don't have testicular enlargement by 14, um, or puberty that starts and doesn't progress. So, um, typically when we see boys, um, Adolescent boys with Klinefelter syndrome, they, you know, they, they, they do start puberty, they just, you know, their testes, uh, remain kind of in the 10 or 2 range, um. So, uh, if, you know, puberty begins but doesn't progress, that would be a reason. To uh consider Klinefelter syndrome or other pathology. Um, and yeah, that's it.
