21-hydroxylase deficiency medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{Congenital adrenal hyperplasia due to 21-hydroxylase deficiency}}
{{21-hydroxylase deficiency}}
 
{{CMG}}; {{AE}}{{MJ}}
{{CMG}};


==Overview==
==Overview==
Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of [[dexamethasone]] for [[genetically]] diagnosed intranatal patients. [[Hydrocortisone]] and [[fludrocortisone]] is given in children and [[Adult|adults]]. Treatment for non-classic type of 21 hydroxylase deficiency in children includes [[hydrocortisone]] up to [[puberty]] and in women in reproductive age, [[oral contraceptive pills]] are given for regulation of [[menstrual cycle]]. Men with non-classic type of 21 hydroxylase deficiency are [[asymptomatic]] and do not need any treatment.


==Medical Therapy==
==Medical Therapy for classic type of 21 hydroxylase deficiency==
 
Medical therapy for 21-hydroxylase deficiency in [[prenatal]] period, [[neonates]], children and [[Adult|adults]], is as below:<ref name="pmid15964450">{{cite journal |vauthors=Merke DP, Bornstein SR |title=Congenital adrenal hyperplasia |journal=Lancet |volume=365 |issue=9477 |pages=2125–36 |year=2005 |pmid=15964450 |doi=10.1016/S0140-6736(05)66736-0 |url=}}</ref><ref name="pmid12213842">{{cite journal |vauthors= |title=Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=9 |pages=4048–53 |year=2002 |pmid=12213842 |doi=10.1210/jc.2002-020611 |url=}}</ref><ref name="pmid11344938">{{cite journal |vauthors=Speiser PW |title=Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency |journal=Endocrinol. Metab. Clin. North Am. |volume=30 |issue=1 |pages=31–59, vi |year=2001 |pmid=11344938 |doi= |url=}}</ref><ref name="pmid20823466">{{cite journal| author=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP et al.| title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2010 | volume= 95 | issue= 9 | pages= 4133-60 | pmid=20823466 | doi=10.1210/jc.2009-2631 | pmc=2936060 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20823466  }}</ref><ref name="pmid2 22237438">{{cite journal| author=Bose KS, Sarma RH| title=Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution. | journal=Biochem Biophys Res Commun | year= 1975 | volume= 66 | issue= 4 | pages= 1173-9 | pmid=2 22237438 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2  }}</ref>
===Early-onset: Severe 21-hydroxylase deficient CAH===
====Salt-wasting crises in infancy====
As ill as these infants can be, they respond rapidly to treatment with hydrocortisone and intravenous saline and dextrose quickly restores blood volume, blood pressure, and body sodium content, and reverses the hyperkalemia. With appropriate treatment, most infants are out of danger within 24 hours.
 
====Long-term management of CAH====
Management of infants and children with CAH is complex and warrants long term care in a [[pediatric endocrinology|pediatric endocrine clinic]]. After the diagnosis is confirmed, and any salt-wasting crisis averted or reversed, major management issues include
#Initiating and monitoring hormone replacement
#Stress coverage, crisis prevention, parental education
#Reconstructive surgery
#Optimizing growth
#Optimizing androgen suppression and fertility in women with CAH
 
=====Hormone replacement=====
The primary goals of hormone replacement are to protect from [[adrenal insufficiency]] and to suppress the excessive adrenal [[androgen]] production.
 
[[Glucocorticoid]]s are provided to all children and adults with all but the mildest and latest-onset forms of CAH. The glucocorticoids provide a reliable substitute for [[cortisol]], thereby reducing [[ACTH]] levels. Reducing ACTH also reduces the stimulus for continued hyperplasia and overproduction of androgens. In other words, glucocorticoid replacement is the primary method of reducing the excessive adrenal androgen production in both sexes. A number of glucocorticoids are available for therapeutic use. [[Hydrocortisone]] or liquid [[prednisolone]] is preferred in infancy and childhood, and [[prednisone]] or [[dexamethasone]] are often more convenient for adults.
 
The glucocorticoid dose is typically started at the low end of physiologic replacement (6-12 mg/m<sup>2</sup> but is adjusted throughout childhood to prevent both growth suppression from too much glucocorticoid and androgen escape from too little. Serum levels of [[17-hydroxyprogesterone|17OHP]], [[testosterone]], [[androstenedione]], and other adrenal steroids are followed for additional information, but may not be entirely normalized even with optimal treatment. (''See [[Glucocorticoid]] for more on this topic.'')
 
[[Mineralocorticoid]]s are replaced in all infants with salt-wasting and in most patients with elevated [[renin]] levels. [[Fludrocortisone]] is the only pharmaceutically available mineralocorticoid and is usually used in doses of 0.05 to 2 mg daily. [[Electrolyte]]s, renin, and [[blood pressure]] levels are followed to optimize the dose.
 
=====Stress coverage, crisis prevention, parental education=====
Even after diagnosis and initiation of treatment, a small percentage of children and adults with infancy or childhood onset CAH die of adrenal crisis. Deaths from this are entirely avoidable if the child and his family understand that the daily glucocorticoids cannot be allowed to be interrupted by an illness. When a person is well, missing a dose, or even several doses, may produce little in the way of immediate symptoms. However, our glucocorticoid needs are increased during illness and stress, and missed doses during an illness such as the "flu" (or viral gastroenteritis) can lead within hours to reduced blood pressure, [[Shock (medical)|shock]], and death.
 
To prevent this, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of hydrocortisone (e.g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.
 
As an additional precaution, persons with [[adrenal insufficiency]] are advised to wear a [[medical identification tag]] or carry a wallet card to alert those who may be providing emergency medical care of the urgent need for glucocorticoids.
 
For an excellent example of parent education materials for CAH, see the [http://www.hopkinsmedicine.org/pediatricendocrinology/cah/index.html booklet] prepared by the [[Johns Hopkins Hospital|Johns Hopkins]] Pediatric Endocrine Service.
 
=====Optimizing growth in CAH=====
One of the challenging aspects of long-term management is optimizing growth so that a child with CAH achieves his or her height potential because both undertreatment and overtreatment can reduce growth or the remaining time for growth. While glucocorticoids are essential for health, dosing is always a matter of approximation. In even mildly excessive amounts, glucocorticoids slow growth. On the other hand, adrenal androgens are readily converted to [[estradiol]], which accelerates [[bone age|bone maturation]] and can lead to early epiphyseal closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone. As a consequence, average height losses of about 4 inches (10 cm) have been reported with traditional management.
 
Traditionally, pediatric endocrinologists have tried to optimize growth by measuring a child every few months to assess current rate of growth, by checking the [[bone age]] every year or two, by periodically measuring [[17OHP]] and [[testosterone]] levels as indicators of adrenal suppression, and by using hydrocortisone for glucocorticoid replacement rather than longer-acting [[prednisone]] or [[dexamethasone]].
 
The growth problem is even worse in the simple virilizing forms of CAH which are detected when premature [[pubic hair]] appears in childhood, because the [[bone age]] is often several years advanced at the age of diagnosis. While a boy (or girl) with simple virilizing CAH is taller than peers at that point, he will have far fewer years remaining to grow, and may go from being a very tall 7-year-old to a 62-inch 13-year-old who has completed growth. Even with adrenal suppression, many of these children will have already had central [[precocious puberty]] triggered by the prolonged exposure of the [[hypothalamus]] to the adrenal androgens and estrogens. If this has begun, it may be advantageous to suppress puberty with a [[gonadotropin-releasing hormone]] agonist such as [[leuprolide]] to slow continuing bone maturation.
 
In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as [[flutamide]] and by reducing the conversion of testosterone to estradiol. This conversion is mediated by [[aromatase]] and can be inhibited by aromatase blockers such as testolactone. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or [[growth hormone treatment]] to enhance growth.
 
For a more extensive review of the difficulties of optimizing growth, see Migeon CJ, Wisneiewski AB. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency: growth, development, and therapeutic considerations. Endocrinol Metab Clin N Am 30:193-206, 2001.
 
====Psychosexual development and issues====
Nearly all [[mammal]]s display [[sexual dimorphism|sex-dimorphic]] reproductive and sexual behavior (e.g., lordosis and mounting in rodents). Much research has made it clear that prenatal and early postnatal androgens play a role in the differentiation of most mammalian brains. Experimental manipulation of androgen levels in utero or shortly after birth can alter adult reproductive behavior.  
 
Girls and women with CAH constitute the majority of genetic females with normal internal reproductive hormones who have been exposed to male levels of testosterone throughout their prenatal lives. Milder degrees of continuing androgen exposure continue throughout childhood and adolescence due to the imperfections of current glucocorticoid treatment for CAH. The psychosexual development of these girls and women has been analyzed as evidence of the role of androgens in human sex-dimorphic behaviors.
 
Girls with CAH have repeatedly been reported to spend more time with "sex-atypical" toys and "rough-and-tumble" play than unaffected sisters. These differences continue into adolescent, as expressed in social behaviors, leisure activities, and career interests. Interest in babies and becoming mothers is significantly lower by most measures.
 
Cognitive effects are less clear and reports have been contradictory. Two studies reported spatial abilities above the average for sisters and for girls in general. Other evidence in males with and without androgen deficiencies suggest that androgens may play a role in these aptitudes.
 
However, gender identity of girls and women with CAH is nearly always unequivocally female. Sexual orientation is more mixed, though the majority are heterosexual. In one study, 27% of women with CAH were rated as bisexual in their orientations. Abnormalities of body image due to the effects of the disease likely play a role in the sexual development of these women, and one cannot conclude that the androgens are the major determinant of their erotic interests.
 
====Prenatal diagnosis and treatment====
Since CAH is an [[autosomal recessive]] disease, most children with CAH are born to parents unaware of the risk and with no family history. However, once a first child has CAH, it can be predicted that each successive child will have a 25% chance of being born with the disease (12.5% chance of an affected girl, 12.5% chance of an affected boy). Few families would choose not to continue with a pregnancy of a second child with CAH but all would wish to minimize the degree of [[virilization]] of a girl. There is no known prenatal harm to a male fetus from CAH, so treatment can begin at birth.
 
Adrenal glands of female fetuses with CAH begin producing excess [[testosterone]] by the 9th week of gestation. The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks. Theoretically, if enough [[glucocorticoid]] could be supplied to the fetus to reduce adrenal testosterone production by the 9th week, virilization could be prevented and the difficult decision about timing of [[history of intersex surgery|surgery]] avoided.
 
The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother.


The first problem has not yet been entirely solved, but it has been shown that if [[dexamethasone]] is taken by a pregnant woman enough can cross the placenta to suppress fetal adrenal function.  
=== 1. Prenatal treatment===
In the [[prenatal]] period [[virilization]] of female [[fetus]] begins early; therefore, early treatment is required as follows:
* If classic [[CYP21A2]] [[gene]] [[mutations]] exist in parents, [[maternal]] administration of [[dexamethasone]] should be prescribed.
** Preferred regimen: [[Dexamethasone]] 20 micrograms/kg q24h in 2 or 3 fractioned doses [[Orally ingested|orally]].
*** [[Dexamethasone]] crosses the [[placenta]] into the [[fetal circulation]] and prevents [[ambiguous genitalia]] in female [[fetus]]. 
*** This treatment should be started before 9 weeks of [[pregnancy]] age; if treatment cannot be started by 9 weeks, it should not be given at all.
*** If [[Cell-free system|cell-free]] [[fetal]] [[DNA testing]] reveals the gender to be male, treatment should be discontinued.
*** Approximately 85% of managed cases appear quite normal after [[delivery]].
*** [[Side effects]] of [[prenatal]] [[dexamethasone]] are:<ref name="pmid208234662">{{cite journal| author=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP et al.| title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2010 | volume= 95 | issue= 9 | pages= 4133-60 | pmid=20823466 | doi=10.1210/jc.2009-2631 | pmc=2936060 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20823466  }}</ref><ref name="pmid9814461">{{cite journal| author=Lajic S, Wedell A, Bui TH, Ritzén EM, Holst M| title=Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 11 | pages= 3872-80 | pmid=9814461 | doi=10.1210/jcem.83.11.5233 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9814461  }}</ref><ref name="pmid18060943">{{cite journal| author=Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ et al.| title=Maternal corticosteroid use and orofacial clefts. | journal=Am J Obstet Gynecol | year= 2007 | volume= 197 | issue= 6 | pages= 585.e1-7; discussion 683-4, e1-7 | pmid=18060943 | doi=10.1016/j.ajog.2007.05.046 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18060943  }}</ref><ref name="pmid27482827">{{cite journal| author=Wallensteen L, Zimmermann M, Thomsen Sandberg M, Gezelius A, Nordenström A, Hirvikoski T et al.| title=Sex-Dimorphic Effects of Prenatal Treatment With Dexamethasone. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 10 | pages= 3838-3846 | pmid=27482827 | doi=10.1210/jc.2016-1543 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27482827  }}</ref><ref name="pmid24278432">{{cite journal| author=Khalife N, Glover V, Taanila A, Ebeling H, Järvelin MR, Rodriguez A| title=Prenatal glucocorticoid treatment and later mental health in children and adolescents. | journal=PLoS One | year= 2013 | volume= 8 | issue= 11 | pages= e81394 | pmid=24278432 | doi=10.1371/journal.pone.0081394 | pmc=3838350 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24278432  }}</ref>
**** [[Postnatal]] [[failure to thrive]]
**** [[Psychomotor retardation|Psychomotor]] [[developmental delay]]
****Increased risk of [[cleft lip and palate]]
****Increased risk for [[Psychiatric disorders|psychiatric disturbances]] and [[ADHD]]


At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl.
=== 2. Neonatal treatment ===
'''2.1 Medical therapy for 21-hydroxylase deficiency in the neonates is as follows:'''<ref name="pmid20823466">{{cite journal| author=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP et al.| title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2010 | volume= 95 | issue= 9 | pages= 4133-60 | pmid=20823466 | doi=10.1210/jc.2009-2631 | pmc=2936060 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20823466  }}</ref>
* Preferred regimen: [[Hydrocortisone]] 20 to 30 mg/m<sup>2</sup>  q24h divided in three doses [[Orally ingested|PO]] '''<u>AND</u>''' [[Fludrocortisone]] 100 mcg q12h [[Orally ingested|PO]] '''<u>AND</u>''' [[sodium chloride]] one gram or 4 mEq/kg q24h divided in several doses [[Orally ingested|PO.]]
** The minimization of [[steroid]] doses should be considered to avoid [[steroid]] [[complications]] in [[infants|infants.]] 
** Growth suppression and shorter height in adulthood are the [[complications]] of using high dose [[steroids]] which occurs in [[neonates]].
'''2.2 Ambiguous genitalia:''' 
* [[Ambiguous genitalia]] should be managed immediately. 
* [[Infants]] with [[ambiguous genitalia]] and non palpable [[gonads]] should be considered to have [[congenital adrenal hyperplasia]] and [[empirical treatment]] should be start early after obtaining [[blood]] sample for [[17-hydroxyprogesterone]].
* Initial [[empiric therapy]] should contains doses of [[glucocorticoid]] and [[mineralocorticoid]] and [[sodium chloride]] supplementation.
** Preferred regimen: [[Hydrocortisone]] is 20 to 30 mg/m<sup>2</sup> q24h divided in three doses [[Orally ingested|PO]] '''<u>AND</u>''' [[Fludrocortisone]] 100 mcg q12h [[Orally ingested|PO]] '''<u>AND</u>''' [[sodium chloride]] one gram or 4 mEq/kg q24h divided in several doses [[Route of administration|PO]].
'''2.3 Adrenal crisis:'''
* Preferred regimen: [[Normal saline]] 0.9 percent, 20 mL/kg [[intravenous]] [[Bolus (medicine)|bolus]] '''<u>AND</u>''' [[dextrose]] 10 percent 2 to 4 mL/kg [[intravenous]] [[Bolus (medicine)|bolus]] (if there is significant [[hypoglycemia]]) '''<u>AND</u>''' [[hydrocortisone]] 50 to 100 mg/m<sup>2</sup> [[intravenous]] [[Bolus (medicine)|bolus]], '''<u>THEN</u>''' continue [[hydrocortisone]] alone 50 to 100 mg/m<sup>2</sup> [[Intravenous therapy|IV]] per day divided into four times per 24 hours.
** The [[blood]] sample should be obtained for [[steroid hormone]] levels before giving [[hydrocortisone]].  
** [[Hyperkalemia]] should be corrected on the base of its level and [[complications]].


Whether the fetus is an affected girl can be determined by [[chorionic villus sampling]] at 9-11 weeks of gestation, or by [[amniocentesis]] at 15-18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal [[DNA]] is analyzed to see if she carries one of the known abnormal alleles of the ''CYP21'' gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1 mg daily.
===3. Management in children===
* Preferred regimen: [[Hydrocortisone]] ([[cortisol]]) in a dose of 10 to 15 mg/m<sup>2</sup> [[body surface area]]/day [[Orally ingested|PO]] '''<u>AND</u>''' [[fludrocortisone]] in a dose of 50 to 200 mcg per day (0.05 to 0.20 mg/day) [[Orally ingested|PO]].
** [[Mineralocorticoid]] replacement should be started in all 21-hydroxylase deficient patients, and often may be tapered after six months of age.
'''3.1 Response to therapy can be monitored by checking the following parameters:'''
* Serum [[17-hydroxyprogesterone]]
* [[Androstenedione]]
* [[Plasma renin activity]] or direct [[renin]]
* Height measurements


Most mothers who have followed this treatment plan have experienced at least mild [[Cushing's syndrome|cushingoid]] effects from the glucocorticoid, but have borne daughters whose genitalia are much less virilized.
===4. Management in adults===
'''21 hydroxylase deficiency should be managed as follows:'''<ref name="pmid20823466">{{cite journal| author=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP et al.| title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2010 | volume= 95 | issue= 9 | pages= 4133-60 | pmid=20823466 | doi=10.1210/jc.2009-2631 | pmc=2936060 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20823466  }}</ref><ref name="pmid2843311">{{cite journal| author=Horrocks PM, London DR| title=Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia. | journal=Clin Endocrinol (Oxf) | year= 1987 | volume= 27 | issue= 6 | pages= 635-42 | pmid=2843311 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2843311  }}</ref><ref name="pmid27623069">{{cite journal| author=Stewart PM, Biller BM, Marelli C, Gunnarsson C, Ryan MP, Johannsson G| title=Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 12 | pages= 4843-4850 | pmid=27623069 | doi=10.1210/jc.2016-2221 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27623069  }}</ref><ref name="pmid3060026">{{cite journal| author=Hughes IA| title=Management of congenital adrenal hyperplasia. | journal=Arch Dis Child | year= 1988 | volume= 63 | issue= 11 | pages= 1399-404 | pmid=3060026 | doi= | pmc=1779155 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3060026  }}</ref><ref name="pmid11344938">{{cite journal |vauthors=Speiser PW |title=Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency |journal=Endocrinol. Metab. Clin. North Am. |volume=30 |issue=1 |pages=31–59, vi |year=2001 |pmid=11344938 |doi= |url=}}</ref><ref name="pmid9829228">{{cite journal |vauthors=Lopes LA, Dubuis JM, Vallotton MB, Sizonenko PC |title=Should we monitor more closely the dosage of 9 alpha-fluorohydrocortisone in salt-losing congenital adrenal hyperplasia? |journal=J. Pediatr. Endocrinol. Metab. |volume=11 |issue=6 |pages=733–7 |year=1998 |pmid=9829228 |doi= |url=}}</ref><ref name="pmid7015786">{{cite journal |vauthors=Jansen M, Wit JM, van den Brande JL |title=Reinstitution of mineralocorticoid therapy in congenital adrenal hyperplasia. Effects on control and growth |journal=Acta Paediatr Scand |volume=70 |issue=2 |pages=229–33 |year=1981 |pmid=7015786 |doi= |url=}}</ref>


===Childhood onset (simple virilizing) CAH===
'''4.1 Treatment goals'''
* Provide proper dosing of [[glucocorticoid]] and [[mineralocorticoid]].
* Decrease secretion of [[cosyntropin]]; therefore decrease [[adrenal]] overstimulation and [[androgen]] production.
'''4.2 Glucocorticoids and mineralocorticoid replacement''' 
* Preferred regimen: [[Hydrocortisone]] 15-30 mg q24h divided into three doses [[Orally ingested|PO]] '''<u>AND</u>''' [[Fludrocortisone Acetate|9-alpha-fludrocortisone acetate]] 0.1 to 0.2 mg q24h [[Orally ingested|PO]].
* Alternative regimen (1): [[Dexamethasone]] 0.75 mg q24h [[Orally ingested|PO]] '''<u>AND</u>''' [[Fludrocortisone Acetate|9-alpha-fludrocortisone acetate]] 0.1 to 0.2 mg q24h [[Route of administration|PO]].
* Alternative regimen (2): [[Prednisone]] 5mg q24h [[Orally ingested|PO]] '''<u>AND</u>''' [[Fludrocortisone Acetate|9-alpha-fludrocortisone acetate]] 0.1 to 0.2 mg q24h [[Orally ingested|PO]].
'''4.3 Considerations'''
*[[Glucocorticoids]] reduce the excess production of [[adrenal]] [[androgens]] and reduce the excessive secretion of both [[corticotropin-releasing hormone]] and [[ACTH]].
* Stress dosing: In patients with 21-hydroxylase deficiency and serious [[illness]], [[glucocorticoids]] stress dosing is necessary.
* [[Dexamethasone]] is very potent and long-acting [[glucocorticoid]] that effectively suppresses [[ACTH]] secretion but almost always causes the development of [[cushingoid appearance]] with chronic use.
* The proper dose of [[Fludrocortisone Acetate|fludrocortisone acetate]] should be used to restore normal [[serum]] [[potassium]] concentrations and [[plasma renin activity]].
'''4.4 Therapy consideration in women'''
* Lowering blood [[androgen]] levels with [[glucocorticoids]], can helps women to control annoying [[Cosmetics|cosmetic]] [[symptoms]] such as [[acne]] and [[hirsutism]].
* In  21-hydroxylase deficient patients [[oral contraceptive pills]] in combination with [[glucocorticoids]] can be used to regulate the [[menstrual cycle]] and induction of [[ovulation]].


The mainstay of treatment is suppression of adrenal testosterone production by a [[glucocorticoid]] such as [[hydrocortisone]]. Mineralocorticoid is only added in cases where the plasma [[renin]] activity is high.
== Medical Therapy for non-classic type of 21 hydroxylase deficiency ==
Medical therapy for non-classic type of 21 hydroxylase deficiency is as following:<ref name="pmid2137832">{{cite journal |vauthors=Spritzer P, Billaud L, Thalabard JC, Birman P, Mowszowicz I, Raux-Demay MC, Clair F, Kuttenn F, Mauvais-Jarvis P |title=Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia |journal=J. Clin. Endocrinol. Metab. |volume=70 |issue=3 |pages=642–6 |year=1990 |pmid=2137832 |doi=10.1210/jcem-70-3-642 |url=}}</ref><ref name="pmid20823466">{{cite journal |vauthors=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC |title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=9 |pages=4133–60 |year=2010 |pmid=20823466 |pmc=2936060 |doi=10.1210/jc.2009-2631 |url=}}</ref><ref name="pmid2142968">{{cite journal |vauthors=Frank-Raue K, Junga G, Raue F, Vecsei P, Ziegler R |title=[Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate] |language=German |journal=Klin. Wochenschr. |volume=68 |issue=12 |pages=597–601 |year=1990 |pmid=2142968 |doi= |url=}}</ref><ref name="pmid24622419">{{cite journal |vauthors=Merke DP, Poppas DP |title=Management of adolescents with congenital adrenal hyperplasia |journal=Lancet Diabetes Endocrinol |volume=1 |issue=4 |pages=341–52 |year=2013 |pmid=24622419 |pmc=4163910 |doi=10.1016/S2213-8587(13)70138-4 |url=}}</ref>
=== 1. Children ===
* Preferred regimen: [[Hydrocortisone]] 10 to 15 mg/m<sup>2</sup> divided into three doses q24h.
** Treatment should be continued until [[puberty]].
**In [[symptomatic]] girls after [[puberty]], other treatment options such as [[oral contraceptive pills]] may be used in order to avoid [[glucocorticoids]].


A third key aspect of management is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the [[testes]] are pubertal in size, or that testosterone remains elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by [[leuprolide]].
=== 2. Adults ===
* Female patients may need [[oral contraceptive pills]] for regulation of [[menstrual cycle]]; [[oral contraceptive pills]] are preferred other than [[glucocorticoids]] in this condition.
* Female patients with [[infertility]] and [[Anovulatory cycle|anovulatory cycles]] who desire [[Conceive a child|conceive]], [[glucocorticoids]] with above dosage are the initial choice for [[ovulation]] induction.


As outlined above, recent additions to treatment to preserve growth include [[aromatase]] inhibition to slow bone maturation by reducing the amount of testosterone converted to [[estradiol]], and use of blockers of estrogen for the same purpose.
* Male patient with non-classic 21-hydroxylase deficiency are [[asymptomatic]] and they do not need treatment.
 
Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness of injury.
 
===Late onset (nonclassical) CAH===
Diagnosis of late-onset CAH may be suspected from a high 17-hydroxyprogesterone level, but some cases are so mild that the elevation is only demonstrable after cosyntropin stimulation. Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation.


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
 
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Latest revision as of 15:32, 24 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Overview

Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone for genetically diagnosed intranatal patients. Hydrocortisone and fludrocortisone is given in children and adults. Treatment for non-classic type of 21 hydroxylase deficiency in children includes hydrocortisone up to puberty and in women in reproductive age, oral contraceptive pills are given for regulation of menstrual cycle. Men with non-classic type of 21 hydroxylase deficiency are asymptomatic and do not need any treatment.

Medical Therapy for classic type of 21 hydroxylase deficiency

Medical therapy for 21-hydroxylase deficiency in prenatal period, neonates, children and adults, is as below:[1][2][3][4][5]

1. Prenatal treatment

In the prenatal period virilization of female fetus begins early; therefore, early treatment is required as follows:

2. Neonatal treatment

2.1 Medical therapy for 21-hydroxylase deficiency in the neonates is as follows:[4]

2.2 Ambiguous genitalia: 

2.3 Adrenal crisis:

3. Management in children

3.1 Response to therapy can be monitored by checking the following parameters:

4. Management in adults

21 hydroxylase deficiency should be managed as follows:[4][11][12][13][3][14][15]

4.1 Treatment goals

4.2 Glucocorticoids and mineralocorticoid replacement 

4.3 Considerations

4.4 Therapy consideration in women

Medical Therapy for non-classic type of 21 hydroxylase deficiency

Medical therapy for non-classic type of 21 hydroxylase deficiency is as following:[16][4][17][18]

1. Children

2. Adults

  • Male patient with non-classic 21-hydroxylase deficiency are asymptomatic and they do not need treatment.

References

  1. ↑ Merke DP, Bornstein SR (2005). "Congenital adrenal hyperplasia". Lancet. 365 (9477): 2125–36. doi:10.1016/S0140-6736(05)66736-0. PMID 15964450.
  2. ↑ "Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology". J. Clin. Endocrinol. Metab. 87 (9): 4048–53. 2002. doi:10.1210/jc.2002-020611. PMID 12213842.
  3. ↑ 3.0 3.1 Speiser PW (2001). "Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency". Endocrinol. Metab. Clin. North Am. 30 (1): 31–59, vi. PMID 11344938.
  4. ↑ 4.0 4.1 4.2 4.3 Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP; et al. (2010). "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 95 (9): 4133–60. doi:10.1210/jc.2009-2631. PMC 2936060. PMID 20823466.
  5. ↑ Bose KS, Sarma RH (1975). "Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution". Biochem Biophys Res Commun. 66 (4): 1173–9. PMID 22237438 2 22237438 Check |pmid= value (help).
  6. ↑ Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP; et al. (2010). "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 95 (9): 4133–60. doi:10.1210/jc.2009-2631. PMC 2936060. PMID 20823466.
  7. ↑ Lajic S, Wedell A, Bui TH, Ritzén EM, Holst M (1998). "Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia". J Clin Endocrinol Metab. 83 (11): 3872–80. doi:10.1210/jcem.83.11.5233. PMID 9814461.
  8. ↑ Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ; et al. (2007). "Maternal corticosteroid use and orofacial clefts". Am J Obstet Gynecol. 197 (6): 585.e1–7, discussion 683-4, e1–7. doi:10.1016/j.ajog.2007.05.046. PMID 18060943.
  9. ↑ Wallensteen L, Zimmermann M, Thomsen Sandberg M, Gezelius A, Nordenström A, Hirvikoski T; et al. (2016). "Sex-Dimorphic Effects of Prenatal Treatment With Dexamethasone". J Clin Endocrinol Metab. 101 (10): 3838–3846. doi:10.1210/jc.2016-1543. PMID 27482827.
  10. ↑ Khalife N, Glover V, Taanila A, Ebeling H, Järvelin MR, Rodriguez A (2013). "Prenatal glucocorticoid treatment and later mental health in children and adolescents". PLoS One. 8 (11): e81394. doi:10.1371/journal.pone.0081394. PMC 3838350. PMID 24278432.
  11. ↑ Horrocks PM, London DR (1987). "Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia". Clin Endocrinol (Oxf). 27 (6): 635–42. PMID 2843311.
  12. ↑ Stewart PM, Biller BM, Marelli C, Gunnarsson C, Ryan MP, Johannsson G (2016). "Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency". J Clin Endocrinol Metab. 101 (12): 4843–4850. doi:10.1210/jc.2016-2221. PMID 27623069.
  13. ↑ Hughes IA (1988). "Management of congenital adrenal hyperplasia". Arch Dis Child. 63 (11): 1399–404. PMC 1779155. PMID 3060026.
  14. ↑ Lopes LA, Dubuis JM, Vallotton MB, Sizonenko PC (1998). "Should we monitor more closely the dosage of 9 alpha-fluorohydrocortisone in salt-losing congenital adrenal hyperplasia?". J. Pediatr. Endocrinol. Metab. 11 (6): 733–7. PMID 9829228.
  15. ↑ Jansen M, Wit JM, van den Brande JL (1981). "Reinstitution of mineralocorticoid therapy in congenital adrenal hyperplasia. Effects on control and growth". Acta Paediatr Scand. 70 (2): 229–33. PMID 7015786.
  16. ↑ Spritzer P, Billaud L, Thalabard JC, Birman P, Mowszowicz I, Raux-Demay MC, Clair F, Kuttenn F, Mauvais-Jarvis P (1990). "Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia". J. Clin. Endocrinol. Metab. 70 (3): 642–6. doi:10.1210/jcem-70-3-642. PMID 2137832.
  17. ↑ Frank-Raue K, Junga G, Raue F, Vecsei P, Ziegler R (1990). "[Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate]". Klin. Wochenschr. (in German). 68 (12): 597–601. PMID 2142968.
  18. ↑ Merke DP, Poppas DP (2013). "Management of adolescents with congenital adrenal hyperplasia". Lancet Diabetes Endocrinol. 1 (4): 341–52. doi:10.1016/S2213-8587(13)70138-4. PMC 4163910. PMID 24622419.

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