As many of you know, about 95% of congenital adrenal hyperplasia is caused by 21-hydroxylase deficiency in the adrenal gland. And my particular interest has been in patients with classic congenital adrenal hyperplasia.

So these are patients who presented at birth or soon after birth, in the couple of weeks after birth, with symptoms of either ambiguous genitalia in a female infant or failure to thrive and episodes of vomiting and dehydration that brought them back to the emergency room, often in the male infants.

So a lot of the focus I learned about in pediatrics was, first of all, how to basically keep patients alive who had classic congenital adrenal hyperplasia. Because of the 21-hydroxylase block in the pathway to cortisol and aldosterone synthesis, adequate amounts of cortisol and aldosterone are not produced or are produced barely at all, depending on the genetic defect, and as an-- at the expense of elevated adrenal androgens being produced in an attempt to raise the cortisol levels.

So the majority of patients I see are classic, and they have the inability to produce sufficient amounts of both cortisol and aldosterone. A minority of the patients that I see are women who are also classic in that they were diagnosed at birth, so they're early onset, but the deficiency is primarily presenting as a deficiency in cortisol production with still the compensatory increase in androgens as a compensation tool, but they may not need fludrocortisone for the aldosterone replacement.

Now, in childhood, a lot of the emphasis is on keeping the child healthy and alive. These children used to die often, especially if they were male and they were not diagnosed. And getting them to adulthood-- and that was the goal for many decades and trying to optimize optimal growth because in the excess of androgens, there's premature fusion of the epiphyseal plates, and there can be short stature.

So when I started seeing the adults, a lot of other issues came to be manifest that had to do with other stages of their life that they were reaching, so one big stage being childbearing. And I followed a number of women who, as children, grew up thinking they would never be able to have children because of their congenital adrenal hyperplasia, which we know that with regulation of the glucocorticoid, unless there's something else coincident wrong, the majority of women with congenital adrenal hyperplasia due to 21-hydroxylase, which is what I'm focusing on, can have children.

And I followed these women through conception, managed them through pregnancy and delivery and breastfeeding, and managed them through future pregnancies.

So in the pediatric, there's obviously pregnancies that occur in the pediatric age range. But as an adult endocrinologist, I see, a lot of women trying to get pregnant.

The other phase that I've seen, because these individuals do have a long life expectancy now, is the accumulation of metabolic side effects. And those were not typically seen when the focus was just getting the child into early adulthood.

So because of the way we replace the hormones, which I'll refer to in a minute, there's often an excess of cortisol at various times of the day. So if one were to look at how ACTH-- CRH and then ACTH lead to cortisol production, there's a pulsatility to the CRH and ACTH release such that cortisol levels are rising about every 20 minutes. And the amplitude of the rise is greater during the day and a lower amplitude rise at night.

We can't have someone taking a pill every 20 minutes and a different dose pill every 20 minutes. It's not feasible. And the alternative is to give some kind of pump that would pulse them at certain frequencies, which would be cumbersome.

So part of our goal is to mimic the normal diurnal rhythm with higher amplitude pulses during the day, lower amplitude at night, and there being times during the day, and especially during the nighttime, where cortisol levels are extremely low and close to the lower limit of detection.

And so what that person's body is seeing over a 24-hour period may add up to a certain hydrocortisone equivalency that you could replace them with, but it's not going to end up with the rhythm and pulse amplitude that a patient with intact enzyme in the adrenal would be experiencing.

In order to make sure that the CRH and ACTH do not rise too high, and-- well, let me rephrase that. So the goal is to give them enough cortisol so they don't have symptoms of adrenal insufficiency, but as we mentioned, since 21-hydroxylase enzyme is in the pathway to both aldosterone and cortisol production but not in the pathway to androgen production by the adrenal gland, whenever cortisol levels fall and CRH and ACTH levels rise, it's at the expense of restoring cortisol but increasing androgen levels from the adrenal gland, which have more of a manifestation in women than they do in men, but affect both men and women.

So in order to prevent the androgen levels from getting too high, we are, by intent, giving individuals a slightly higher than physiologic dose of the glucocorticoid that they get replacement with because if we gave them anything, even a small amount below their physiologic need, during those moments, minutes, or hours, their CRH and ACTH would rise, and they'd make excess androgens.

So there's this very difficult balance that we try to reach of giving them as little glucocorticoid as possible to spare them the adverse metabolic effects of glucocorticoids, which include, as many of you know, increased risk of diabetes, increased risk of hyperlipidemia, increase in central body obesity and metabolic syndrome, which themselves are linked with increased risk for coronary heart disease and cardiovascular disease.

So we want to live-- we want to limit the dose of glucocorticoid we give so that as little-- they have as little exposure to excess glucocorticoid as possible, but specifically in women, we run the risk that if the dose is too low, their androgen levels will get too high. And the androgens are an important source of male sex hormone in women. It's where women usually get their pubic and underarm hair from that stimulation of the receptors from adrenal androgen production.

If there's too much stimulation of CRH and ACTH, the adrenal androgens will increase, and women experience the problems of acne and hirsutism, which can be very plaguing problems for a lot of women that bring them to medical attention.

So it's the difficulty of hitting the exact right balance of the amount of glucocorticoid we need to give so the patient feels well, has enough energy to make it through their day, and that it's enough that their male sex hormone production from the adrenal gland is not accelerated.

And as I mentioned, that usually ends up being, at least to some degree, in some part of the 24-hour day, supraphysiological dosing of glucocorticoid so that there are times during the day where there's not sufficient dosing of glucocorticoid, where particularly women are making more androgens, and then during the day where the dose of glucocorticoid is supraphysiologic, and then the individual risks the side effects of cortisol levels that are too high and all the negative side effects, including diabetes, that would go with cortisol levels being too high.

And on the present regimens that are available, the shortest-acting glucocorticoid we usually give patients is hydrocortisone. And the idea of that is that-- because the half life is shorter, some of the effect would dissipate before the next dose is given, so there would be periods where there was not glucocorticoid on board.

In practice, it's very hard to achieve that balance, and it's achieving that balance that there's been a real search for, is there a better regimen to achieve the balance that we need in congenital adrenal hyperplasia of enough glucocorticoid but not too much glucocorticoid?

The fludrocortisone is a mineral corticoid which is replacing aldosterone. That does not feed back on CRH and ACTH in the same way, so if aldosterone levels are low, increased male sex hormone is not produced. And the fludrocortisone, being a mineralocorticoid, doesn't have, at the doses we give, the adverse metabolic effects of the glucocorticoid.

But when we give fludrocortisone, we're giving a drug that increases sodium and water reabsorption in the kidney and increase intravascular volume. And that's what maintains the blood pressure in individuals with congenital adrenal hyperplasia with 21-hydroxylase deficiency. And there's still a balance that needs to be achieved. Too much fludrocortisone, patient might develop edema and fluid retention, and too little fludrocortisone, they may have low blood pressure, orthostatic hypotension, and feel wiped out.

So I think I've described to you the overall balance. What I'd want to say is that we know that as people age, metabolic function deteriorates on a whole. And the function I'm talking about is cardiometabolic function. So, for example, diabetes risk increases with age. Hyperlipidemia increases with age. Cardiovascular disease increases with age.

So as we have that happening in the background in the general population, in individuals who are aging, who are receiving glucocorticoid, what we want to be doing is not giving them something that's going to accelerate the already deteriorating metabolic control that aging itself brings with it.

And there's very little information available about how to treat individuals in their 60s and 70s with congenital adrenal hyperplasia because we didn't have a lot of individuals surviving to adulthood with congenital adrenal hyperplasia to even look at the natural history of what happens in the individual's 60s and 70s.