By continuing to use this site, you agree to our use of cookies as described in our Cookie Policy.

What the CAH logo
This website is intended for US healthcare professionals only.

I treat CAH the same way

My Attending’s attending did— What the C@H?!

Congenital adrenal hyperplasia (CAH) has been treated the same way for over 70 years. But exciting new investigational pathways are being researched.1-3

What aspects of managing CAH do you find frustrating?

When it comes to managing CAH, what frustrations make you say WHAT THE C@H?!

Select your answers and see how your experience compares to your peers.

ACTH=adrenocorticotropic hormone; CRF=corticotropin-releasing factor; CRF1=corticotropin-releasing factor type 1; GC=glucocorticoid.

ACTH=adrenocorticotropic hormone;
CRF=corticotropin-releasing factor;
CRF1=corticotropin-releasing factor type 1;
GC=glucocorticoid.

Percentage of responders who selected these answers

Adjusting GCs to Meet Patient Goals

Managing ACTH & adrenal androgen symptoms

Mitigating high-dose GC side effects & comorbidities

Adrenal Crisis

Lab monitoring

Mental health

ACTH=adrenocorticotropic hormone; CRF=corticotropin-releasing factor; CRF1=corticotropin-releasing factor type 1; GC=glucocorticoid.

CAH: A complex disease with multiple hormonal imbalances

CAH is a group of disorders that affect the adrenal glands.1 Approximately 95% of cases are caused by 21-hydroxylase (21‑OH) deficiency, but the amount of residual enzyme activity varies.1,4 As a result, the hormonal imbalances and phenotypes vary too.4 Regardless of the degree of 21‑OH deficiency, all types of CAH patients experience overproduction of adrenal androgens.4

EFFECTS OF 21-OH DEFICIENCY4

21-OH activity Cortisol  Aldosterone  Androgens
0%
downdowndown
downdowndown
downdowndown
1%-10%
down
Unaffected
downdown
20%-30% Unaffected Unaffected
down
21-OH activity: 0%
Cortisol
downdowndown
Aldosterone
downdowndown
Androgens
upupup
21-OH activity: 1%-10%
Cortisol
down
Aldosterone Unaffected
Androgens
upup
21-OH activity: 20%-30%
Cortisol Unaffected
Aldosterone Unaffected
Androgens up

The common denominator in CAH is excess adrenal androgens.4

diagnosing cah

Endocrine Society newborn screening recommendations

To diagnose CAH and improve the positive predictive value of newborn screening, the Endocrine Society recommends 2 screenings1:

  1. A first-tier screening that measures 17‑OHP levels from dried blood spots.1
  2. A second-tier screening using either liquid chromatography–mass spectrometry (MS)/MS or cosyntropin stimulation if 17‑OHP levels are >1000 ng/dL in the first screening (usually patients with CAH have levels >5000 ng/dL).1,5

The limitations of newborn screening

false positives

While newborn screening correctly identifies most newborns with classic CAH, solely relying on first-tier screening can lead to false positives. This is particularly true for premature, sick, or stressed infants who have higher levels of 17-OHP than full-term infants.6

A second-tier screen could result in a significant reduction in false-positive rates.6

>95%

reduction in false-positive cases was observed when using first- and second-tier screening vs first-tier screening alone in a recent study.6

In this prospective study, false-positive rates (false positives/total screened) decreased from 0.75% with first-tier screening to 0.04% after second-tier screening.6

Minimizing false positives is important because it can help families avoid unnecessary testing, clinical evaluations, and associated stress and anxiety.6

false negatives

Conversely, a negative newborn screening does not necessarily rule out classic CAH.7

22%

of classic CAH cases were missed with newborn screening in a large, 12-year study (N=838,241; age range: newborn to 6 years).7*

In this study, the clinical signs of excess androgens in patients with CAH who were missed by newborn screening included atypical genitalia, accelerated growth, and advanced bone age.7 Similar rates of false negatives were observed in 2 independent studies of first-tier screening.8,9

*Combined results from first-tier only screening or first- and second-tier screening.7

The journey from cortisol deficiency to adrenal androgen excess

A closer look at the loss of negative feedback in the hypothalamic-pituitary-adrenal (HPA) axis reveals how cortisol deficiency in people with classic CAH leads to excess adrenal androgens.3,5

negative feedback3,10

loss of negative feedback3,10

CRF1R=corticotropin-releasing factor type 1 receptor.

Due to the loss of 21-OH activity, the adrenal glands cannot make cortisol or, in many cases, aldosterone. The lack of cortisol results in a loss of negative feedback in the HPA axis. The loss of negative feedback increases secretion of CRF—a primary regulator of the HPA axis—from the hypothalamus. CRF then binds to CRF1 receptors in the pituitary gland and increases ACTH release, leading to an overproduction of adrenal androgens.3,5

A deep dive into what happens in the adrenal glands3,11

17-OHP=17-hydroxyprogesterone; A4=androstenedione.

Without sufficient 21-OH activity to produce cortisol and aldosterone, excess steroid hormone precursors instead are shunted to androgen synthesis pathways, leading to excess adrenal androgens and related symptoms.3,11

The untapped potential of the CRF pathway in CAH management

An investigational pathway that separates management of androgen excess from GC treatment of cortisol deficiency could be of great interest to practitioners who treat CAH. One avenue of research among those being explored is blocking CRF1 receptors or other receptors in the HPA axis, which could potentially help reduce ACTH and adrenal androgen overproduction.3 Watch below to learn about the breakthrough of CAH treatment in the 1950s, the challenges of today—and how research is looking to the future.

Link copied to clipboard

Length: 02:54

NARRATOR VO: Back in the 1950s, the introduction of corticosteroids (glucocorticoids and mineralocorticoids) was a game changer. For the first time, physicians had tools that could begin to offer patients with congenital adrenal hyperplasia (CAH) the possibility of a longer life. Corticosteroids compensate for cortisol and aldosterone deficiency in CAH. But controlling the overproduction of adrenal androgens remains a pressing challenge. Supraphysiologic doses of glucocorticoids (doses higher than needed to replace the missing cortisol) have been shown to lower levels of adrenocorticotropic hormone (ACTH) and androgens. But they do this indirectly, and can be associated with short- and long-term steroid-related risks. Despite, and maybe because of these risks, large retrospective studies show that about 2/3 of CAH patients have poorly controlled androgens. And today’s treatment paradigm requires constant trade-offs in the attempt to reduce androgens without exposing patients to the negative effects of high-dose steroids—just as it has for the past 70 years.

PATIENT VOICES: What the C@H?!

NARRATOR VO: While hydrocortisone and other glucocorticoids are the right tools for cortisol insufficiency, they are not ideal for managing androgen excess because of the potential collateral damage caused by the high doses most patients require. But cutting-edge research could reveal a solution—by looking deeper into the role of the hypothalamic-pituitary-adrenal (HPA) axis in regulating the body’s adaptive stress response. Corticotropin-releasing factor (CRF) has been identified as a primary regulator of the HPA axis including production of adrenal cortisol, aldosterone, and androgens. CRF is secreted by the hypothalamus and binds to CRF type 1 (CRF1) receptors in the pituitary gland, to promote ACTH release, which stimulates adrenal hormone production. When cortisol levels rise, CRF secretion is switched off, creating the negative feedback loop that allows the HPA axis to maintain homeostasis. But in patients with CAH, supraphysiologic doses of glucocorticoids are often needed to engage this negative feedback loop and suppress ACTH overproduction. The CRF pathway is being investigated as an opportunity for an independent mechanism to control androgen overproduction. Blocking CRF1 receptors or other receptors in the HPA axis could act directly to lower ACTH and androgen production—and allow the reduction of glucocorticoids to doses needed to replace cortisol—for potentially fewer high-dose steroid-related side effects and risks. Glucocorticoids changed the game of managing CAH, but for 70 years that has meant juggling with one hand tied behind our backs. We’ve waited long enough. It’s time to rethink CAH.

GCs: the only treatment option for nearly 70 years

Corticosteroids have long been the treatment paradigm for CAH.1 Physiologic GC doses are sufficient to treat the cortisol deficiency inherent to CAH, while supraphysiologic doses are required to indirectly regulate adrenal androgen production via negative feedback to the hypothalamus and pituitary.1,3,12,13 These high GC doses (relative to Addison’s disease) help lower the amount of CRF released from the hypothalamus and consequently reduce activation of CRF1 receptors and release of ACTH from the pituitary.3,12,13

The Endocrine Society recommends regular androstenedione (A4) and
17-hydroxyprogesterone (17-OHP) measurements to help monitor CAH.1

Question Question

When monitoring your patients, how frequently are you able to achieve consistently timed androstenedione (A4) and 17-OHP measurements?

GCs are not ideal for managing adrenal androgen excess

Although the treatment paradigm has remained the same for decades, it remains challenging to manage excess adrenal androgens effectively with GCs.1,13 In fact, studies show that approximately 2/3 of patients with CAH receiving GCs have poorly managed adrenal androgen levels.3,14,15* This means that patients taking high-dose GCs are at risk of side effects like weight gain, type 2 diabetes, and osteoporosis/osteopenia—but may also still be at risk of excess adrenal androgens.1,3,12 Symptoms of excess adrenal androgens can affect both males and females of varying ages, and include difficulty achieving full growth potential, acne, hirsutism, and fertility problems.1,5,16

Based on analysis of serum androstenedione (A4) measurements from 2 large studies of patients with classic CAH.3,14,15

A constant tug‑of‑war between

A constant
tug‑of‑war between

Symptoms AND Side effects — What the C@H?!

CAH patient needs are highly individual and change over time due to life circumstances. The central challenge of treating CAH is balancing patient goals, the need to suppress adrenal androgen production, and the risks of high GC doses. It is a difficult and delicate process that must be revisited often.1

symptoms related to excess ACTH and adrenal androgens1,3,5,11,16-20

Children Adolescents Young Adults Older Adults
Advanced Bone Age
(premature
epiphyseal fusion) 		apply apply
Early Puberty apply apply
Acne apply apply apply apply
Hirsutism apply apply apply apply
TARTs and OARTs apply apply apply apply
Oligomenorrhea
and Amenorrhea 		apply apply
Negative Mental
Health Impact 		apply apply apply apply

OARTs=ovarian adrenal rest tumors; TARTs=testicular adrenal rest tumors.

Question Question

Considering the symptoms above, how many of your patients with CAH may have excess ACTH and adrenal androgens?

high GC doses can
cause serious, long‑term side effects

high GC doses can cause serious, long‑term side effects

Prescribing supraphysiologic doses of GCs in order to control adrenal androgens can lead to long-term complications that affect patient health and quality of life, even if a patient seems to be handling treatment without noticeable issues.1,5 Ensuring patients are aware of the long-term side effects of high-dose GCs is an important part of CAH care.

In a multicenter study of young adults with CAH (median age of 33 years old) treated with GCs, 73 of the 244 patients had at least 1 of the assessed cardiometabolic and bone comorbidities. The comorbidities of these 73 patients included21:

Chart showing GC side effects, osteoporosis 59%, hyperlipidemia 23%, type 2 diabetes 22%, hypertension 14% Chart showing GC side effects, osteoporosis 59%, hyperlipidemia 23%, type 2 diabetes 22%, hypertension 14%

SIGN UP FOR EXPERT INSIGHTSON CAH & MORE

Join the WHAT THE C@H?! community and be among the first to receive new resources that may change the way you approach CAH, including videos from expert CAH practitioners discussing their experience with this condition.

*Indicates required field.

This field is required.
This field is required.
Please enter a valid email address.
Please make a selection.
Please enter a valid ZIP code.

By completing and submitting this form, you agree to sign up for communications from Neurocrine Biosciences, Inc. You are confirming that you understand and agree to the Privacy Policy and Terms and Conditions.

This field is required.

Unlike the CAH treatment landscape for the last 70+ years, our site is constantly evolving.2
Be sure to visit us in the near future for more information.

Unlike the CAH treatment landscape for the last 70+ years, our site is constantly evolving.2 Be sure to visit us in the near future for more information.

References

  1. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865
  2. Wilkins L, Lewis RA, Klein R, et al. Treatment of congenital adrenal hyperplasia with cortisone. J Clin Endocrinol Metab. 1951;11(1):1-25. doi:10.1210/jcem-11-1-1
  3. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. doi: 10.1038/s41574-022-00655-w
  4. Auer MK, Nordenström A, Lajic S, Reisch N. Congenital adrenal hyperplasia. Lancet. 2022;401(10374): 1-18. doi:10.1016/S0140-6736(22)01330-7
  5. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383(13):1248-1261. doi:10.1056/NEJMra1909786
  6. Bialk ER, Lasarev MR, Held PK. Wisconsin’s Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia. Int J Neonatal Screen. 2019;5(3):33. doi:10.3390/ijns5030033
  7. Sarafoglou K, Banks K, Kyllo J, et al. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA. 2012;307(22):2371–2374. doi:10.1001/jama.2012.5281
  8. Chan CL, McFann K, Taylor L, Wright D, Zeitler PS, Barker JM. Congenital adrenal hyperplasia and the second newborn screen [published correction appears in J Pediatr. 2013 Jul;163(1):308]. J Pediatr. 2013;163(1):109-113.e1. doi:10.1016/j.jpeds.2013.01.002
  9. Eshragh N, Doan LV, Connelly KJ, Denniston S, Willis S, LaFranchi SH. Outcome of newborn screening for congenital adrenal hyperplasia at two time points. Horm Res Paediatr. 2020;93(2):128-136. doi:10.1159/000508075
  10. Schröder MAM, Claahsen-van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disord. 2022;23(3):631-645. doi:10.1007/s11154-022-09717-w
  11. Hindmarsh PC, Geertsma K. Congenital Adrenal Hyperplasia: A Comprehensive Guide. Elsevier/Academic Press; 2017.
  12. Auchus RJ, Witchel SF, Leight KR, et al. Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative. Int J Pediatr Endocrinol. 2010;2010:275213. doi:10.1155/2010/275213
  13. Turcu AF, Auchus RJ. Novel treatment strategies in congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2016;23(3):225-232. doi:10.1097/MED.0000000000000256
  14. Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. doi:10.1210/jc.2010-0917
  15. Finkielstain GP, Kim MS, Sinaii N, et al. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(12):4429-4438. doi:10.1210/jc.2012-2102
  16. Prete A, Auchus RJ, Ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2021;186(1):R1-R14. doi:10.1530/EJE-21-0794
  17. Koren R, Koren S, Khashper A, Benbassat C, Pekar-Zlotin M, Vaknin Z. Ovarian adrenal rest tumor in congenital adrenal hyperplasia: is medical treatment the first line option? Arch Endocrinol Metab. 2021;65(6):841-845. doi:10.20945/2359-3997000000415
  18. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab016
  19. Dessinioti C, Katsambas A. Congenital adrenal hyperplasia. Dermatoendocrinol. 2009;1(2):87-91. doi:10.4161/derm.1.2.7818
  20. Engels M, Span PN, van Herwaarden AE, Sweep FCGJ, Stikkelbroeck NMML, Claahsen-van der Grinten HL. Testicular adrenal rest tumors: current insights on prevalence, characteristics, origin, and treatment. Endocr Rev. 2019;40(4):973-987. doi:10.1210/er.2018-00258
  21. Righi B, Ali SR, Bryce J, et al. Long-term cardiometabolic morbidity in young adults with classic 21-hydroxylase deficiency congenital adrenal hyperplasia. Endocrine. 2023;80(3):630-638. doi:10.1007/s12020-023-03330-w