Good afternoon, everybody. We are here to talk about the evaluation and congenital evaluation management of congenital adrenal hyperplasia. I am Dr. Shaishav Dhage from Christie Hospital in Manchester, UK. And we are also being joined by one of my colleagues, Dr. Swag Ganava, who is a consultant endocrinologist at Manchester Royal Infirmary in the United Kingdom. Both of us do not have any conflicts of interest in relation to this particular presentation. For the purpose of being easy, I will keep the abbreviation SCH throughout the presentation. Both of us will use the abbreviation SCH instead of the long word congenital adrenal hyperplasia. So what's on the agenda today? We will discuss about the exact pathophysiology, classification and inheritance pattern. We will discuss about various types of congenital adrenal hyperplasias and how they present, what are the clinical manifestations. We will also discuss about the investigations usually carried out for the diagnostic purpose as well as for follow-up. We will discuss about various management options and what are the different challenges. And we will also dedicate some time towards the newer treatments. And we will also talk about some cases which are relevant to the CH presentation. So as all of you know, the adrenal gland has two parts, cortex and medulla. Medulla secretes catecholamines and cortex, the different layers secrete different hormones. So glucocorticoids are secreted by zona fasciculata while zona glomerulosa secretes mineralocorticoids. And the innermost layer of cortex, zona reticularis is involved in secretion of adrenal androgens. So this is the most important diagram in the pathway of steroid synthesis. As we can see, cholesterol is the basic ingredient at the baseline and there are two, three vertical pathways. The first one is for mineralocorticoid secretion, which ends up with secretion of aldosterone. The second one is for cortisol secretion and the third one is for sex steroid secretions. Now these pathways have some important enzymes involved like 3-beta-HSD, 21-alpha-hydroxylase, 11-beta-HSD in the vertical pathway and in the horizontal pathway, 17-alpha-hydroxylase and 17-20-lyase. And there is a lot of interaction. These are not compartmentalized pathways and the major abnormality in congenital adrenal hyperplasia is deficiency in the glucocorticoids and or mineralocorticoid secretions. The whole pathway gets diverted for the secretion of excess adrenal androgens and we will be discussing the pathophysiology further as we go along. So normally what happens from hypothalamus CRH is secreted, which acts on the pituitary gland. Pituitary gland makes ACTH and ACTH goes and acts on the adrenal glands, which secretes mineralocorticoids, glucocorticoids and androgens. So cortisol has negative feedback towards the pituitary and hypothalamus, which controls secretion of CRH and ACTH. And normally this works in a good harmony. However, in untreated CH, because of the enzyme deficiency, there is deficiency in secretion of cortisol, which affects the negative feedback mechanism and body increases the ACTH secretion to try and stimulate the adrenal glands. And that is the reason for adrenal hyperplasia, hence the name of the condition. However, functionally the adrenal gland is not active or less active depending on the type of enzyme deficiency. And there is excess androgen secretion, which has different manifestations depending on the type. In the treatment of CH, our aim is to replace glucocorticoids and mineralocorticoids and try and increase the negative feedback by reducing the ACTH secretion and reducing the adrenal androgens, which have different kinds of bad effects for the patient. So this diagram in short summarizes various biochemical abnormalities. As we have already discussed, reduced cortisol, increased androgens, electrolyte disturbances because of reduced aldosterone. So high potassium, low sodium, the problems with the blood pressure, blood volume and adrenal hyperplasia as mentioned. And this is accompanied by increased ACTH secretion and increased CRF. So congenital adrenal hyperplasia, the commonest type is 21 alpha-hydroxylase deficiency. More than 95% of the patients have the genetic defects in these and 5% is by the rare enzyme deficiencies. So mutation in these genes cause problem in the synthesis of cortisol and lack of negative feedback, lack of aldosterone results in chronic excess ACTH. There is accumulation of various steroid precursors and adrenal androgens and we will be discussing in each type in detail as we go along. So I will hand over to my colleague to present a couple of cases and then we'll get back to further discussion. Over to you, Dr. Ghanamar. Hi everyone. So I'll be presenting the first patient who is 28 years old lady, attended to our antenatal endocrine clinic for genetic counseling as preconception advice. Her husband is a carrier for congenital adrenal hyperplasia and she has a daughter who is two years old. They diagnosed two weeks after her birth with CEH. She's now worried about having CEH in the second child and would like us to advise before conceiving for her second pregnancy. So to summarize that her husband is a carrier and her daughter is a CEH, she has the condition. What is the chances of her next child having the condition? Okay, so I think there is one answer. Is that it? Okay, so basically having a daughter with the condition and her husband is a carrier, knowing that the CEH is autosomal recessive disorder, then there is 25% chance for her kids to have the condition and 25% chance that they will not have the condition and 50% chance of them being a carrier as any other autosomal recessive condition. So the chances will be one in four, 25%. Okay, so in summary, like classification of CEH, the most common enzyme deficiency, as Dr. Daghi mentioned, is 21-hydroxylase deficiency. So for the classic one, one in 14,000 to 18,000, mostly like in zero enzyme activity, they will have salt wasting based on the previous slide that Dr. Daghi mentioned and simple virilizing when less than 5% enzyme activity. Non-classic CEH, they will have 20 to 50% enzyme activity. So being the most common enzyme is 21-hydroxylase deficiency. The other enzymes are less common, which is like 11-beta-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase deficiency and 17-hydroxylase deficiency and the rarest one is pleboid CEH, which is dysmolase deficiency. So the second case is a man this time and he's 26 years old, referred by his GB as he's newly attended the clinic for evaluation of loss of libido, erectile dysfunction and infertility. He was diagnosed with a problem at birth with adrenal insufficiency. However, there is no old records available as his surgery is new. His GB is treating him with hydrocortisone and fludrocortisone for the last year. Vitally, he was almost stable. He's averagely built without any obvious features of Cushing syndrome or hypoadrenalism. His testicular volume was 7 ml bilaterally and he has an average size phallus. So what could be the diagnosis at this time? Yeah, so baseline investigations for 9-AM fasting bloods without taking his hydrocortisone and fludrocortisone showed normal thyroid function test, normal IGF-1, normal urea and electrolytes, liver function test and full blood count. His 9-AM cortisol was low, 25 nanomoles per liter, ACTH is raised 256, DHAs are slightly low, testosterone is low and SHBD is 86. He has abnormally normal LH and FSH to that low testosterone, so it's hypogonatrophic hypogonadism with low cortisol and raised ACTH with normal bituitary image. So at this stage, we will be thinking of hypogonatrophic hypogonadism with adrenal insufficiency. Then we have to go for more dedicated test, which is like the synaxin test with 17-OHB measurement. So his short synaxin test showed flat response to the synaxin at 60 minutes. His initial 17-OHB was low, which is again classical CEH and he had a flat response after the synaxin. His aldosterone was 10 picomole per liter and renin was normal and ACTH remained high. So this is a bit confusing, but still, he has hypogonatrophic hypogonadism with adrenal insufficiency and markedly elevated ACTH. What would be the diagnosis at this stage? So it's congenital adrenal hypoplasia, not congenital adrenal hyperplasia, and the main thing to differentiate between the two would only be the low 17-OHB. Because the initial 17-OHB should have been high if this is a classical CEH and there is no response or flat response to the synaxin test. Next slide, please. So adrenal congenital hypoplasia, it's a very rare condition. X-linked, that's why mostly presented in male. DAX mutation, it is similar in presentation to salt-wasting 2N-2N-hydroxylase deficiency. That's why his initial presentation was straight after birth and mainly it's because of failure of development of the adrenal cortex and failure to thrive, there'll be hypotensive, low sodium and high potassium. So he has a low cortisol and aldosterone and high ACTH and renin that will all go with classical CEH. However, having 17-OHB not high, then this is agonist and having the diagnosis straight after birth makes it more likely congenital adrenal hypoplasia. And also, there is no response to the synaxin stimulation and it's in combination with hybogonatrophic hybogonades in picture at puberty. They can proceed to normal fertility if it's diagnosed early and with giving gonadotrophins or clomiphene as for induction. I will hand over to Dr. Daldy for the rest. Thank you. So we were coming back to the pathway now and we will discuss various clinical manifestations in different types of enzyme deficiency. So 21-alpha-hydroxylase is the most common enzyme deficiency and it has three different types. Classic salt wasting if the enzyme is completely absent, simple virilizing if the enzyme secretion is below 5% and non-classic when the enzyme deficiency is about 20 to 50%. So classic salt wasting is more severe in female children and they have ambiguous genitalia and earlier presentation within days to weeks from birth. So they will have low cortisol, low aldosterone and 17-OHP will be significantly high. In simple virilizing type because there is some enzyme activity the presentation is not so severe but it is in early age of life up to two to four years or a little bit earlier in female child. Ambiguous genitalia will be there in female child. In male child the genitals are normal and the aldosterone levels are usually normal hence the presentation is later cortisol levels are low. While in non-classic type in men it almost 99% goes completely undetectable as the aldosterone and cortisol levels are normal while female they will have presentation in puberty onwards at variable times based on the enzyme activity. Some of them they may have abnormalities like chlyteromegaly and you may have to do the ACT stimulated test of 17-OHP to make sure the diagnosis is right. Coming to the next enzyme deficiency that is 17-alpha-hydroxylase deficiency. Now as the pathway shows the mineralocorticoid secretion is okay however the glucocorticoid and sexteroid pathway is completely blocked. So the patients will have impaired cortisol and androgen synthesis. They will have excess mineralocorticoids because of the excess mineralocorticoids they will have hypertension, low potassium and there will be abnormal pubertal development in girls because of the sexteroid deficiency. The next type is CYP11-beta1 gene defect which will result in 11-hydroxylase deficiency. This results in the impaired secretion of mineralocorticoids and glucocorticoids and the pathway is diverted towards sexteroid secretions. So there is excess steroid precursors like deoxycortisone and 11-deoxycortisol and there will be hypertension, low potassium and ambiguous genitalia in children in female children. Now coming to the next common enzyme deficiency which is the which is the 17 which is the 3-beta-HSD gene defect which is rare. It causes impaired cortisol and aldosterone synthesis, excess DHEA synthesis and because of the blockage at all three levels they will have salt wasting type, low blood pressure, low sodium, low potassium and ambiguous genitalia. Clinical manifestations of CH. Now in salt wasting time there is severe deficiency of mineralocorticoids and glucocorticoids. The patient presents within few days of birth. There is a high rate of sodium loss in urine which may exceed 50 which may exceed 50 millimoles in a day. They will lead to hyponatremia and dehydration. The patients will have hyperkalemia, metabolic acidosis and shock. Important point to understand that in children hypoglycemia could be one of the important presentations of adrenal insufficiency. They will have poor weight gain, vomiting and obviously hyperandrogenism will result in ambiguous genitalia in female children. Now coming to the virilizing form, it mainly affects the female child. Mineralocorticoid deficiency is less significant. These are more prominent during childhood. Now because of excess androgen secretion which is being diverted through the pathway and estrogen formation early in the age they may have early puberty and the bone age may be higher than actual age. So overall height may be 10% less than the general population. Again there will be ambiguous genitalia in female child however internal organs are normal. Now coming to non-classic form. So this is the most common form of CH and 90% of the people go completely undetectable. 1 in 200 is usual incidence. Mineralocorticoid and glucocorticoid activity is normal and signs of androgen excess may start appearing only in late teens or even later in the life. The genitalia are usually normal at the birth. However, some patients may have precocious puberty and early development of pubic and axillary hair. As all of us know that the development of pubic and axillary hair depends on the adrenal androgens hence people precocious puberty may happen. They will have other manifestations like hirsutism, acne, menstrual disorders and infertility later in life in female patients and some of them they are confused with PCOS the polycystic ovarian syndrome. However, men are completely asymptomatic. Now what are the different investigations done in CH for supporting the diagnosis? So salt wasting form is easily detectable at and around birth because of significant electrolyte abnormalities, abnormalities with the blood sugars. 9M fasting, 17 alpha hydroxylase enzyme levels if 17 alpha hydroxylase levels if they are more than 45 nanomoles, then it is usually diagnostic. Sometimes you may have to do shots and act in test with 17 OHP 0 minute and 60 minutes after and see what sort of response you get. They will have problems with cortisol, high ACTH levels will be there and renin and aldosterone levels will be abnormal based on the type. Androstenedione, testosterone and other adrenaline androgens will be high. Nowadays steroid biomarkers from serum and saliva are becoming available, especially the 11 oxygenated androgens, 17 urinary, 17 ketosteroids will also help in diagnosis. There might be family history in doubtful cases, you may have to do the genetic screening, which will give you the answer. So now coming to the management of CAH, so what are the primary goals? It is very important to remember in the salt wasting and virilizing type, lifelong glucocorticoids and or mineralocorticoid replacement is important. We want to restore the negative feedback mechanism so that the ACTH secretion is reduced and we also want to lower the excess adrenal androgens. What are the long-term goals? So management of long-term complications is important because we have to balance the glucocorticoid deficiency versus excess. We have to make sure the child develops normally and gonadal dysfunction is managed. Some patients will have infertility because of the issues related to excess progesterone and things like start in male patients because of excess steroids. Sometimes they will have cardiovascular problems, metabolic abnormality, obesity, blood sugar related problems, and all these things have psychological impact on their life. It affects quality of life. CAH patients are at higher risk of mental health related problems and higher risk of suicide as well. So what do we do in childhood? It is very important that we take care of the deficiency of the cortisol and mineralocorticoids. We make sure that they have got proper education, the parents and carers about prevention of adrenal crisis, explaining sick day rules and providing them with the emergency hydrocortisone injection packs as and when needed. We need to make sure that they're growing normally, they're achieving good final target height, they're achieving normal timing of their puberty, prevention of precocious puberty is important. Now in children, hydrocortisone is preferred because of short half-life and it is given in three divided doses. Long-acting potent steroids can cause growth suppression and hypercortisolism. So that should be avoided. Now what happens in adolescence? In adolescence, your main goals are achieving the normal final height and normal gonadal function. So to achieve normal height, if you could keep the hydrocortisone dose around or less than 17 milligram per meter square per 24 hours, that usually helps to achieve normal height preventing excess steroids. Prevention of formation of tarts and menstrual issues and obviously lack of compliance is a challenge as in any other adolescent condition. What are the principles of management after you have reached the final height and in adults? So here the main goals are prevention of infertility or sub-fertility and optimize the quality of life of the patient. Longer acting steroids are preferred in adult population because of improving the compliance issue and it also achieves better reduction in the early morning ACTH. It does help to improve fertility to some extent, reduction in size of the tarts and improvement in the fertility and sperm count. Lowest dose to suppress adrenal androgens should be aimed to prevent metabolic complications, diabetes, cardiometabolic syndrome, etc. So what are the different forms of steroids available at the moment? Hydrocortisone tablets divided into three to four doses, hydrocortisone site unit suspension was available in the past, however, it has been withdrawn. In children to achieve the small possible doses from 0.5 to 5 milligram, hydrocortisone sprinkles are available, however, the cost is important implication in this. I have given the costs in GBP, that is the Great British Pounds and conversion into the US dollars. However, I am not sure what exactly the cost in US, it is just a conversion, the actual costs may be different. And then there are different other steroids available, which we will discuss. So hydrocortisone as I said is the most commonly used steroid in at least in children, in adult or adolescent age group onwards, other long acting or intermediate acting steroids can be used. Dexamethasone has a lot of side effects, it should be used cautiously. And it should be avoided in those who are seeking pregnancy or are pregnant because it crosses the placenta and it will affect the fetal development and adrenal glands. In the mineralocorticoid replacement, flutocortisone is the most commonly used drug. So mineralocorticoid replacement is important because it helps to reduce the requirements of glucocorticoids, it also helps to restore the intravascular volume and reduces ACTH levels as well. It is very important to monitor hypertension in children especially and adolescent age group you may have to give sodium supplements because of the resistance to mineralocorticoids. So 9-alpha flutocortisone is the most commonly available drug which is given orally. The monitoring is by plasma renin activity and direct renin levels, electrolytes and blood pressure monitoring. Also monitor for the symptoms of salt craving, postural hypotension, failure to thrive, etc. And it is important to remember that hydrocortisone has some flutocortisone like activity and flutocortisone does have some glucocorticoid activity as well. Now monitoring of the CH patients. So obviously keeping the holistic approach, monitoring for generalized well-being and quality of life, it is very important. They need psychological help and support, you should refer them accordingly. Monitoring of height, weight, BMI, blood pressure and capillary blood glucose at each visit is important. Monitor for signs and symptoms of over or under replacement. Now what sort of targets are we supposed to use? Now this is a debatable area and most of the times the treatment should be like we should not suppress the 17-OHP too much. Up to three times of the normal level is acceptable. Anything which is completely in the normal range of 17-OHP is usually probably overcorrection and it can cause steroid related side effects. It is important to monitor electrolytes, hemoglobin A1c, lipid profile and bone mineral density appropriately. Also keep an eye on ACTH levels because that gives you the idea how well the patient is treated. Monitor of monitoring of adrenal androgens and plasma renal activity as well. Also monitor for gonadal dysfunction. In female patients menstrual history is important. In men measuring the size of testicles may require monitoring by testicular ultrasounds and newer techniques like 11-oxygenated androgens are more reliable as compared to conventional androgens and as mentioned holistic approach is again very important. Now there can be some specific areas in terms of female and male patient monitoring. In female patients especially those who are seeking for fertility you should try and maintain the serum progesterone level 0.6 nanograms to achieve high fertility. Try to maintain the testosterone and androstenedione in the reasonably normal range which indicates good control. While in men androgen to testosterone ratio more than 0.5 indicates excess adrenal androgens and we try to maintain this ratio less than 0.5 in these patients. Also monitoring of TARTs as I said is important because that will affect the sperm count. Now what are the challenges in management of CH? So inadequate hormone control is one of the important issues, failure to suppress HP axis and persistently high ACTH levels. They are also at high risk of adrenal crisis as compared to other types of adrenal insufficiency patients and the death rates are higher as compared to other insufficiency patients. They are at high risk of infectious illnesses as well because of the steroid related immunosuppression. Again TARTs and ovarian adrenal rest tumors will affect fertility in these patients to some extent. Steroid growth and development. They tend to achieve about 10% or less height as compared to normal population. Hence that monitoring is equally important. Now the balance between excess steroids and side effects is very important because they will develop various complications like cardio metabolic abnormality, obesity, type 2 diabetes, high blood pressure, dyslipidemia, insulin resistance and various other problems can happen because of excess steroids. Patients may develop irregular menses and secondary polycystic ovaries. There will be altered uterine lining because of continuous exposure to high levels of progesterone. Hence taking care of those things is equally important to achieve fertility. Elevated adrenal androgens will also suppress the HPM axis causing hypogonadotrophic hypogonadism picture in both sexes. So it is important to achieve maximal control over the elevated adrenal androgens. This slide just depicts TARTs. So as all of us know that there are adrenal rest cells present in the rectal testes and they will undergo hyperplasia and hypertrophy if there is excess exposure to androgens and in the later stages it can even affect the testicular parenchyma and hamper the sperm production. So it is very important that we actually would control over the adrenal androgens which will prevent TART formation and improve fertility and sperm count. Now what are the novel therapies? Novel therapies are of different types. One is replacement of glucocorticoids. There have been some improvement in the different type of steroids and the formulations which may help achieve better control, lower doses of steroids and prevent ACTH excess. While there are some therapies which are directed towards reduction of CRH and ACTH. So the couple of new agents on the block are the CRH receptor antagonist, Tildeserfant and Kreneserfant. We will discuss about them in a little bit detail further. Then blocking ACTH by ACTH antibodies. In excess, in extreme cases, adrenalectomy or using the adrenotoxic drugs like Mitotain. In the ideal world, gene therapy and cell-based therapy will be probably the best option. However, those things are still in development, especially non-classic CH when the treatment approach is tailored treatment, anti-androgens could be used. And there have been few other drugs like Nivinimi which is the cholesterol receptor blocker and Abiratron which is the 17, CYP17A1 enzyme blocker commonly used nowadays in the CA prostate. So we will discuss about these things one by one. These are all novel therapies. Some of them, they have shown good efficacy and tolerability. So coming to various newer preparations of improved glucocorticoids. So modified release hydrocortisone, dual release hydrocortisone, Planadren, then delayed and sustained release Cronocort and then in rare cases subcutaneous pump. So Planadren is being used in adenine sufficiency because of other reasons other than CH. It has not been proven to be very useful in CH patients. The data is lacking. It does not really improve the early morning ACTH surge. So it is basically a dual release system where there is a immediate release code and inside there is a sustained release core. The dose is usually once a day and the tablets available are 5 and 20 milligrams. Then there are cost implications as compared to normal prednisolone and hydrocortisone prescriptions. Cronocort which is FMODE. So this is a modified release twice daily medication. They advertise it as a toothbrush. So that means when you brush in the morning and brush at night and take at both the times the capsules available as 5, 10 and 20 milligrams and they have been approved for the use in children more than 12 years of age and in adults. They are more effective in suppressing the early morning ACTH surge and some of the studies have shown that they reduce the adrenal arrest tumors. The specific indications could be when the patient is not well controlled and has excess steroid replacement, if the patients have typical difficulty in taking multiple doses in a day or those who are trying to achieve fertility and those who have problems with pubertal development and growth in these kinds of patients, they can be used. Again, cost is the most important implication probably. Now coming to hydrocortisone pump, it is something similar to insulin pump. The technique is similar, which kinds of replicates the physiological rhythm, reduces overall glucocorticoid dose and improves the control. It has been used in some patients when there is a supraphysiological dose requirements androgen excess or any other intolerability to normal steroids. Again, it achieves good biochemical control, however, it has failed to show improvement in the quality of life. The other issues is quite cumbersome, invasive, expensive, requires extensive monitoring and lot of patient engagement. So these are the drawbacks of the hydrocortisone pump. Now coming to next option, the targeting pituitary and ACTS secretion and CRH. So CRH1 receptor antagonist, Tildesulfon and Krenesulfon, these are the two new agents. Indications for their use, elevated androgens, those who are on supraphysiological doses of glucocorticoids to try and achieve lower doses and those who have poor biochemical control. The drawback of this therapy is we need to continue glucocorticoid replacement side by side. They do not do anything for glucocorticoid replacement. So Tildesulfon phase two trials have been conducted in a different dose varying from 100 to 1000 milligram. In one study, they use 400 milligram. It did show improved ACTH levels, androstenedione and 17 OHP levels in poorly controlled patients. However, did not show any significant improvement in the patients who had already had good control. So again, the drawback is patient needs to continue the glucocorticoid replacement. It has shown to interact with dexamethasone. So if somebody is on dexamethasone, then you will have to change it to some other steroid preparation and long term studies are still underway. They are usually safe and well tolerated and the trials have shown that they also reduce the size of TARD. Now comparing Tildesulfon and Crenesulfon, Tildesulfon is once a daily dose while Crenesulfon is twice a daily dose. Crenesulfon is first generation, highly lipophilic. Both of them they have shown effective ACTH and androgen reduction especially in poorly controlled patients. Tildesulfon has shown good effect while Crenesulfon will help in well controlled patients as well to reduce the glucocorticoid dose further. Both of them they need concomitant use of glucocorticoid therapy and need to be taken with the fatty meal. Now recently the trial, the phase three trial results for Crenesulfon have been published in New England Journal and this therapy has shown to reduce the target physiological dose of the glucocorticoids and also the androgen levels in about 60 to 75 percent patients as compared to the placebo. So these are newer and important drugs. Few other drugs in the development are ACTH antagonists. This is specific monoclonal antibody against the ACTH. The preclinical studies have shown that it has shown substantial and durable reduction in the plasma levels of glucocorticoids. The next options targeting ACTH function is the MC2R that is melanocorticotropin receptors to receptor blocker or ACTH receptor antagonist. Again phase 1 trials are ongoing. These are selective non-peptide drugs oral and they have shown dose dependent separation of corticosteroids and reversal of ACTH excess and even hypertrophy. So it will be interesting to see the human studies MC2R peptide antagonist are in preclinical development. Now targeting the steroid production itself the acetyl coenzyme cholesterol acetyltransferase inhibitor ACAT1 nevanimib. It shown reduction of cholesterol histobioavailability for steroid production and it reduces ACTH dependence steroid production. In phase 2 study it is shown decrease in 17 OHP levels within 2 weeks of treatment however further trials have been suspended because of the adverse event adverse events. Abiratron is a potent CYP17A1 inhibitor. It is being commonly used nowadays in prostate cancer patients. Phase 1 and phase 2 trials in CH patients have shown normalization of androstenedione. However because this blocks the pathway completely it will result in excess ACTH and potentially worsen the TARDS and obviously because it completely suppresses the exogenous sex hormone secretion. It is not suitable for long term use. In extreme cases drugs like mitotin which are adrenal toxic which basically completely inhibits steroidigenesis it cannot be used routinely because of the toxicity and teratogenicity. However in patients with significant TARDS it has shown to restore fertility. Adrenalectomy again results in complete loss of glucocorticoids so there will be uncontrolled ACTH and symptoms like Nelson syndrome may develop and chronic ACTH excess can cause development of TARDS. So it is the last resort in very severely resistant cases. Now targeting androgen function so various drugs have been used for drug combination therapy like aromatase inhibitor, anti androgens like flutamide in addition to routine glucocorticoids and flutocorticoids have been used. However they possibly result in excess ACTH and the trials were stopped because of side effects of flutamide. Other agents currently in development are testolactone which is an aromatase inhibitor which blocks the conversion of androgens to estrogen and they can be some of these anti androgen agents may be used in non-classic CH based on the patient's particular symptoms. Coming to gene-based and cell-based therapy so gene-based therapy is the replacement of functional CYP21H gene which causes normal 21OH production that is the aim. So intraadrenal and intramuscular single injection has been used with adenovirus vector and the study in mice showed normalized progesterone and ACTH secretion phase 1 and phase 2 studies in human being are underway. Cell-based therapy basically transplantation of adenocorticoid or adenocorticoid like cells which are isolated from animals, human donors or generated de novo and they have been programmed through stereogenic factors and result in cortisol secretion in a stimulant manner in a stimulant dependent manner and phase 1 studies have been done in the animal models. So to summarize current treatments are suboptimal and they result in various several long-term complications. Treatment goals are different in different age groups. Gene therapy would be ideal or cell therapy would be ideal but till then we have to continue using daily glucocorticoids which is indispensable in addition to mineralocorticoids as and when required depending on type of CH. Modified glucocorticoid preparations may be helpful to some extent in selected patients. CRF-1 and ACTH receptor antibodies have shown to improve biochemical control and overall reduction in the glucocorticoid doses and it is very important not to forget about the importance of mental health, fertility and quality of life. Now I will hand over back to my colleague Dr. Ganava for few selected cases and then we will also discuss about specifics in the management of non-classic CH. Over to you Dr. Ganava. Dr. Bragidze, there was a question on the chat about if you can reveal the enzymatic like the pathway again. We will answer the questions in the end. Okay. So I think we have already been touched on about pregnancy and CH however like the cases will consolidate the facts. So I'm presenting a 32-year-old lady with non-classical CH. She's obviously not on any treatment however she's trying to conceive for a year or so. She had one miscarriage before. She isn't happy with the advice given by her GB. Her partner genetic test was negative for CH. She also suffers from acne, hercitis, and menstrual irregularities which were all well controlled on oral contraceptive pills for a few years now. Her investigations showed slightly raised testosterone, androstenedione is slightly raised, DHEAs are within normal level, 17-OHB is slightly raised, serum cortisol is within normal, ACTH is normal. So this is likely a picture of non-classical CH. So given that she is planning for pregnancy and she's trying to conceive, and based on what Dr. Daghi mentioned, which of the following treatment options is most appropriate for her case? Is it hydrocortisone at bedtime once daily given that it's short half-life? Or is it dexamethasone 2.5 at bedtime, or breed insulin 3mg at bedtime, or spironolactone or flutamide? So as mentioned, hydrocortisone and breeding insulin, but hydrocortisone in the answer is once daily, so that will not suppress the ACTH and will not benefit the patient of reducing the breed strong. Breeding insulin 3mg at bedtime, it will have a longer half-life and it will have more effect on the steroidogenesis pathway to suppress the ACTH, hence the broad testosterone level. Okay, so a bit about CH and pregnancy. So the cortisol is normal, that's why in normal situations out of pregnancy context or conception steroid replacement is not indicated. The reason why it's affecting her fertility, obviously, because of combination of elevated ACTH and 2N2N-hydroxylase insufficiency in non-classical CH, this will result in overproduction of the adrenal broadestrone and 17-hydroxybroadestrone, and this will divert that pathway for formation of adrenal androgenes and this will go against her fertility. So the main goal in non-classical CH female who are trying to conceive is to suppress the ACTH. As we mentioned, the hydrocortisone has a short half-life, so with one daily dose will not work. Dexamethasone will affect the fetus by crossing the placenta and obviously flutamide and spironolactone are unsafe in pregnancy. Okay, so again, as we mentioned, so we know like congenital adrenal hyperplasia in pregnancy is something we have to closely monitor. Preconception in joint clinics and during pregnancy, they have to be reviewed in an MDT clinic with endocrinologists specialised in CH management and obstetrician. We should also continue the treatment with hydrocortisone in three divided doses or breathing cilone and flodrocortisone. As we mentioned, we should avoid dexamethasone as it will cross the placenta unless the fetus has been tested genetically and confirmed having the condition. As I said, we have to review in the second and third trimester because the steroid requirement will increase. We should also work closely with the obstetrician for peri-labour plans, if it is normal or if it's the cesarean section and along with the anesthetist as they will require stress doses of hydrocortisone. I will hand over to Dr. Dardy. Okay, so the last question I think for today would be again, a 26-year-old woman evaluated for oligominorheum, hirsutism and facial acne. She has no salt craving, no hyperpigmentation and there is no postural hypotension. This time the patient is not planning for pregnancy. Her condition was normal. Clinically, she has some facial hirsutism, acne, but without overt signs of cushioning or hypoadrenaline. So the differential diagnosis would be between polycystic ovary syndrome or non-classical CH and we have to keep in mind she's not planning for pregnancy. So initial investigation showed normal cortisol, 17Hb is 18, which is raised, DHAs are raised and 17Hb did not suppress. So this goes more with a non-classical CH than it being just polycystic ovary syndrome. Which of the following is the most appropriate treatment in her case, given that she's 26, she's symptomatic in terms of hirsutism and acne, but she's not planning for pregnancy. So is it spironolactone or OCP or nocturnal doxamethasone or breath insulin or hydrocortisone and clodrocortisone? I think we have already mentioned this and the treatment should be combined oral contraceptive pills. Next slide. Yeah. So as Dr. Daghi mentioned about the approach for the confirmatory testing, so in non-classical CH or CH in general in females, so the initial test is a 9am fasting cortisol and 17Hb. If it is more than 45.4 nanomoles per deciliter, then it's diagnostic. If it's in a gray area between 6.1 and 45, then it's suggestive of the diagnosis. However, this will need to go for a synaxin test with 17Hb level for confirmation. If it is more than 45.4, then that will bring them up to the diagnostic zone, so it will be confirmatory test. But if the above criteria is not met, however, the initial testing are suggestive, then you have to go for the genetic testing for the C21A2. Yeah, I will hand over to Dr. Daghi. Okay. So discussing further about, thank you, Dr. Ghanavi. So discussing further about approach to non-classic CH in females, so very important to remember clinical features are similar to PCOS, so ideally in every patient we are suspecting polycystic ovaries, you should be doing the 17Hb fasting levels, irregular menses, hyperandrogenism, hyersutism, acne, chlytomegaly. These are all common symptoms in these patients and they can present any time, like in adult age. So what are the treatment goals? So treatment goals are really individualized based on the time of the presentation of the patient and what is their main concern and what they want exactly to address. To treat adrenal insufficiency, if they have, then obviously cortisol and protocortisone is the main treatment and to treat the effects of excess ACTH or menstrual problems or virilization, adrenal arrest tumors, etc. Now focus in this particular patient is menses and hyperandrogenism. So oral contraceptive pills usually normalize estrogen, menstrual cycles help to improve SSBG levels and reduces androgen bioavailability. Spiron lactone could be second choice if the patient is not seeking for pregnancy and they should be informed that they have to use at least two different forms of contraception. The spiron lactone hyperandrogenism control may take up to one year. So you have to give the realistic expectations to the patients and obviously if the patients are seeking for pregnancy and you are not achieving good control of the progesterone levels, then you may use short term steroids as an option which will help to conceive. Adrenal steroids will reduce ACTH and androgen levels, however, they will have higher risk of developing Cushing's syndromes and mood disorders. Dexamethasone is most effective drug to reduce ACTH levels, however, it has got significant side effects as well. In pregnancy, hydrocortisone or prednisolone is preferred because it is metabolized by the placenta and does not affect fetus, but dexamethasone does cross the placenta and can affect the fetus and very important to realize that if you normalize or suppress the ACTH that is kind of suppress the 17-OHP that is actually over treatment. So up to three times of normal of 17-OHP three times or below less than that is your target range, but you should not try to suppress it 17-OHP completely. So with this, we end the presentation. Thank you for your patience and we'll go through some questions now. I cannot see the chart. Let me just go through. I have been answering a few questions while this was the time. So maybe see, okay, please again show steroid pathway slide with enzymatic block in patients with 11-hydroxylase deficiency and alternatives to hydrocortisone. So I will show the answer to the first question later on, let us see. So alternatives to hydrocortisone, as we have already mentioned, different types of steroids, prednisolone, different newer preparations of hydrocortisone and in some cases dexamethasone as well. The next question is how should you treat a non-classic CH postmenopausal with progressive hirsutism? So very good question. So basically you need to use adrenal androgen suppressants in these patients. So spironolactone could be one of the choice for these patients. In some cases, you may be able to use the GnRH analogs to suppress. And obviously you need to be very careful in postmenopausal patients that you have ruled out other causes of progressive hirsutism because you need to rule out adrenal malignancies and different types of ovarian tumors like subtotally cell tumors, etc. So you have to be very sure about the diagnosis first before treating these patients. And as I said, the GnRH analogs can have good results in some of these patients. 3 mg, there is no 3 mg preparation of prednisolone. Either it is usually 1 mg or 5 mg. So you will have to use it accordingly and different places may have different types of preparations available. The next question is for older patients with SWCAH on combination therapy with glucocorticoids and flutrocortisone who may start developing hypertension. If maintaining normal electrolytes and GolPRA, would you prefer to treat with antihypertensive agent primarily or to reduce flutrocortisone as the first intervention? So this is really getting the balance is important, especially when the patients are older. So if you are not able to, so we will usually say that you monitor the renin levels and see if they are being adequately controlled with your flutrocortisone. And if that is not the case, then probably reducing flutrocortisone dose is not may not be a good idea. You might have to use additional antihypertensive treatment. So it is balancing is probably right. How often is ACTH elevated in non-classic CH? Would it be elevated enough for CRF-1 antagonist to be effective? Now that that's a very good question. But we don't see that often in the ACTH levels are not really elevated in non-classic CH. In fact, non-classic CH most of the times the cortisol and mineralocorticoid levels are normal. Yeah. So now we'll go back to the first question about the 11 for hydroxylase deficiency. Let me just 11 hydroxylase. Can you see my screen again? Try it again. No. It doesn't seem to be working, I'm not sure, no, it's just the same thing we're seeing, isn't it? Is that for the pathway? Yeah, it's for the pathway. I mean, if they want, I can, the slides will be available later on, isn't it, Jessica? Yes, the slides will be available after the presentation. Sorry for that, I couldn't technically understand, okay. Any more questions, anything? I have answered a few questions while you're talking, I thought, just for the time. Okay, that's absolutely fine, yeah. So I think one of the questions was, do you screen all the patients suspected PCOS? Probably, I would say yes, because it is quite common, and as I said, 90% of the times it goes undetectable, so it's always a good idea to do 17 OHP screening, but what happens most of the times, the GPs would have already done the screening by the time they refer the patients to us. So yeah, and obviously, each country, the system is different, but most of the GPs... We have recently diagnosed a patient referred for bilateral, he's 75, who has bilateral hyperplasia incidentally on the scan, and he tends to be at the age of 75, is non-classical CH. Yeah, so the important thing to understand is that it is quite common, 1 in 200, and as I said, in females, 90% of the times they go undetectable if they don't have any specific symptoms, and in men, almost 99.9% go undetectable. So screening is always important, especially in the PCOS settings, I would say that that's my personal view. Okay. Yeah. Okay, so if there are no more questions, I think we will end the session. Thank you very much. Thank you. Have a great day. Thank you. Thank you, Jessica. Thank you, Brian. Thank you, Dr. Zaghi.

congenital adrenal hyperplasia

adrenal gland

hormone production

glucocorticoid replacement

mineralocorticoid replacement

enzyme deficiencies

newer treatments

mental health

fertility

gene therapy