Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency
Encyclopedia
3β-Hydroxysteroid dehydrogenase II deficient congenital adrenal hyperplasia (3βHSD CAH) is an uncommon form of CAH
resulting from a mutation in the gene
for one of the key enzyme
s in cortisol
synthesis by the adrenal gland
, 3β-hydroxysteroid dehydrogenase (3βHSD) type II (HSD3B2
). As a result, higher levels of 17OH-pregnenolone appear in the blood with ACTH challenge, which stimulates adrenal corticosteroid
synthesis.
There is a wide spectrum of clinical presentations of 3βHSD CAH, from mild to severe forms. The uncommon severe form results from a complete loss of enzymatic activity and manifests itself in infancy as salt wasting due to the loss of mineralocorticoids. Milder forms resulting from incomplete loss of 3βHSD type II function do not present with adrenal crisis, but can still produce virilization
of genetically female infants and undervirilization of genetically male infants. As a result, this form of primary hypoadrenalism is the only form of CAH that can cause ambiguous genitalia in both genetic sexes.
to progesterone
, 17-Hydroxypregnenolone
to 17-Hydroxyprogesterone
, and DHEA
to androstenedione
. 3β-HSD II also mediates an alternate route of testosterone
synthesis from androstenediol in the testes. 3β-HSD deficiency results in large elevations of pregnenolone, 17-hydroxypregnenolone, and DHEA.
However, complexity arises from the presence of a second 3β-HSD (3β-HSD I) coded by a different gene, expressed in the liver and placenta, and unaffected in 3β-HSD deficient CAH. The presence of this second enzyme has two clinical consequences. First, 3β-HSD II can convert enough of the excess 17-hydroxypregnenolone to 17OHP to produce 17OHP levels suggestive of common 21-hydroxylase deficient CAH. Measurement of the other affected steroids distinguishes the two. Second, 3β-HSD I can convert enough DHEA to testosterone to moderately virilize a genetically female fetus.
aspect of severe 3β-HSD CAH is similar to those of 21-hydroxylase deficiency. Like other enzymes involved in early stages of both aldosterone and cortisol synthesis, the severe form of 3β-HSD deficiency can result in life-threatening salt-wasting in early infancy. Salt-wasting is managed acutely with saline and high-dose hydrocortisone, and long-term fludrocortisone
.
consequences of severe 3β-HSD CAH are unique among the congenital adrenal hyperplasias: it is the only form of CAH that can produce ambiguity in both sexes. As with 21-hydroxylase deficient CAH, the degree of severity can determine the magnitude of over- or undervirilization.
In an XX (genetically female) fetus, elevated amounts of DHEA can produce moderate virilization
by conversion in the liver to testosterone. Virilization of genetic females is partial, often mild, and rarely raises assignment questions. The issues surrounding corrective surgery of the virilized female genitalia are the same as for moderate 21-hydroxylase deficiency but surgery is rarely considered desirable.
The extent to which mild 3β-HSD CAH can cause early appearance of pubic hair and other aspects of hyperandrogenism in later childhood or adolescence is unsettled. Early reports about 20 years ago suggesting that mild forms of 3β-HSD CAH comprised significant proportions of girls with premature pubic hair or older women with hirsutism have not been confirmed and it now appears that premature pubarche in childhood and hirsutism
after adolescence are not common manifestations of 3β-HSD CAH.
Undervirilization of genetic males with 3β-HSD CAH occurs because synthesis of testosterone is impaired in both adrenals and testes. Although DHEA is elevated, it is a weak androgen and too little testosterone is produced in the liver to offset the deficiency of testicular testosterone. The degree of undervirilization is more variable, from mild to severe. Management issues are those of an undervirilized male with normal sensitivity to testosterone.
If the infant boy is only mildly undervirilized, the hypospadias can be surgically repaired, testes brought into the scrotum, and testosterone supplied at puberty.
Management decisions are more difficult for a moderately or severely undervirilized genetic male whose testes are in the abdomen and whose genitalia look at least as much female as male. Male sex can assigned and major reconstructive surgery done to close the midline of the perineum and move the testes into a constructed scrotum. Female sex can be assigned and the testes removed and vagina enlarged surgically. A recently advocated third choice would be to assign either sex and defer surgery to adolescence. Each approach carries its own disadvantages and risks. Children and their families are different enough that none of the courses is appropriate for all.
However, unlike 21-hydroxylase CAH, children with 3β-HSD CAH may be unable to produce adequate amounts of testosterone (boys) or estradiol (girls) to effect normal pubertal
changes. Replacement testosterone or estrogen
and progesterone
can be initiated at adolescence and continued throughout adult life. Fertility
may be impaired by the difficulty of providing appropriate sex hormone levels in the gonads even though the basic anatomy is present.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
resulting from a mutation in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for one of the key enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
synthesis by the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
, 3β-hydroxysteroid dehydrogenase (3βHSD) type II (HSD3B2
HSD3B2
HSD3B2 is a human gene that encodes for 3beta-hydroxysteroid dehydrogenase/delta-deltaisomerase type II or hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2. It is principally expressed in steroidogenic tissues and is essential for steroid hormone production...
). As a result, higher levels of 17OH-pregnenolone appear in the blood with ACTH challenge, which stimulates adrenal corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
synthesis.
There is a wide spectrum of clinical presentations of 3βHSD CAH, from mild to severe forms. The uncommon severe form results from a complete loss of enzymatic activity and manifests itself in infancy as salt wasting due to the loss of mineralocorticoids. Milder forms resulting from incomplete loss of 3βHSD type II function do not present with adrenal crisis, but can still produce virilization
Virilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
of genetically female infants and undervirilization of genetically male infants. As a result, this form of primary hypoadrenalism is the only form of CAH that can cause ambiguous genitalia in both genetic sexes.
Pathophysiology
3β-HSD II mediates three parallel dehydrogenase/isomerase reactions in the adrenals that convert Δ4 to Δ5 steroids: pregnenolonePregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
to progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, 17-Hydroxypregnenolone
17-Hydroxypregnenolone
17-Hydroxypregnenolone , is a C21 steroid that is obtained by hydroxylation of pregnenolone at the C17α position. This step is performed by the mitochondrial cytochrome P450 enzyme 17α-hydroxylase that is present in the adrenal and gonads. Peak levels are reached in humans at the end of puberty...
to 17-Hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
, and DHEA
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
to androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
. 3β-HSD II also mediates an alternate route of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
synthesis from androstenediol in the testes. 3β-HSD deficiency results in large elevations of pregnenolone, 17-hydroxypregnenolone, and DHEA.
However, complexity arises from the presence of a second 3β-HSD (3β-HSD I) coded by a different gene, expressed in the liver and placenta, and unaffected in 3β-HSD deficient CAH. The presence of this second enzyme has two clinical consequences. First, 3β-HSD II can convert enough of the excess 17-hydroxypregnenolone to 17OHP to produce 17OHP levels suggestive of common 21-hydroxylase deficient CAH. Measurement of the other affected steroids distinguishes the two. Second, 3β-HSD I can convert enough DHEA to testosterone to moderately virilize a genetically female fetus.
Mineralocorticoid aspects of 3β-HSD CAH
The mineralocorticoidMineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
aspect of severe 3β-HSD CAH is similar to those of 21-hydroxylase deficiency. Like other enzymes involved in early stages of both aldosterone and cortisol synthesis, the severe form of 3β-HSD deficiency can result in life-threatening salt-wasting in early infancy. Salt-wasting is managed acutely with saline and high-dose hydrocortisone, and long-term fludrocortisone
Fludrocortisone
Fludrocortisone is a synthetic corticosteroid with moderate glucocorticoid potency and much greater mineralocorticoid potency. The brand name in the U.S. and Canada is Florinef.-Uses:...
.
Sex steroid aspects of 3β-HSD CAH
The sex steroidSex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
consequences of severe 3β-HSD CAH are unique among the congenital adrenal hyperplasias: it is the only form of CAH that can produce ambiguity in both sexes. As with 21-hydroxylase deficient CAH, the degree of severity can determine the magnitude of over- or undervirilization.
In an XX (genetically female) fetus, elevated amounts of DHEA can produce moderate virilization
Virilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
by conversion in the liver to testosterone. Virilization of genetic females is partial, often mild, and rarely raises assignment questions. The issues surrounding corrective surgery of the virilized female genitalia are the same as for moderate 21-hydroxylase deficiency but surgery is rarely considered desirable.
The extent to which mild 3β-HSD CAH can cause early appearance of pubic hair and other aspects of hyperandrogenism in later childhood or adolescence is unsettled. Early reports about 20 years ago suggesting that mild forms of 3β-HSD CAH comprised significant proportions of girls with premature pubic hair or older women with hirsutism have not been confirmed and it now appears that premature pubarche in childhood and hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
after adolescence are not common manifestations of 3β-HSD CAH.
Undervirilization of genetic males with 3β-HSD CAH occurs because synthesis of testosterone is impaired in both adrenals and testes. Although DHEA is elevated, it is a weak androgen and too little testosterone is produced in the liver to offset the deficiency of testicular testosterone. The degree of undervirilization is more variable, from mild to severe. Management issues are those of an undervirilized male with normal sensitivity to testosterone.
If the infant boy is only mildly undervirilized, the hypospadias can be surgically repaired, testes brought into the scrotum, and testosterone supplied at puberty.
Management decisions are more difficult for a moderately or severely undervirilized genetic male whose testes are in the abdomen and whose genitalia look at least as much female as male. Male sex can assigned and major reconstructive surgery done to close the midline of the perineum and move the testes into a constructed scrotum. Female sex can be assigned and the testes removed and vagina enlarged surgically. A recently advocated third choice would be to assign either sex and defer surgery to adolescence. Each approach carries its own disadvantages and risks. Children and their families are different enough that none of the courses is appropriate for all.
Diagnosis
Like the other forms of CAH, suspicion of severe 3β-HSD CAH is usually raised by the appearance of the genitalia at birth or by development of a salt-wasting crisis in the first month of life. The diagnosis is usually confirmed by the distinctive pattern of adrenal steroids: elevated pregnenolone, 17-hydroxypregnenolone, DHEA, and renin. In clinical circumstances this form of CAH has sometimes been difficult to distinguish from the more common 21-hydroxylase deficient CAH because of the 17OHP elevation, or from simple premature adrenarche because of the DHEA elevation.Management of 3β-HSD II deficient CAH after infancy
Some of the childhood management issues are similar those of 21-hydroxylase deficiency:- replacing mineralocorticoid with fludrocortisone;
- suppressing DHEA and replacing cortisol with glucocorticoid;
- providing extra glucocorticoid for stress;
- close monitoring and perhaps other adjunctive measures to optimize growth.
- deciding whether surgical repair of virilized female genitalia is warranted
However, unlike 21-hydroxylase CAH, children with 3β-HSD CAH may be unable to produce adequate amounts of testosterone (boys) or estradiol (girls) to effect normal pubertal
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
changes. Replacement testosterone or estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
can be initiated at adolescence and continued throughout adult life. Fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
may be impaired by the difficulty of providing appropriate sex hormone levels in the gonads even though the basic anatomy is present.