Aromatase deficiency

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Aromatase deficiency
Other namesCongenital estrogen deficiency [1]
Aromatase 3EQM.png
AES results when the function of aromatase is impaired. The aromatase protein (pictured) is required for the biosynthesis of oestrogens like oestradiol in the human body.
Specialty Endocrinology
Complications Virilisation, tall stature, primary amenorrhea, multicystic ovaries,
Usual onsetAdulthood
DurationLifetime
TypesEndocrine Disruptive Disorder
CausesGenetic mutations of CYP19
Diagnostic method Extremely low level of oestrogen and elevated level of androgens
TreatmentTransdermal oestradiol replacement, hormone replacement therapy

Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. [2] It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals [3] and at least 30 cases in genetically female individuals. [4]

Contents

Signs and symptoms

The deficiency causes the virilization of XX fetuses. The onset of symptoms usually occurs in adolescence or early adulthood. The lack of estrogen results in the presentation of primary amenorrhea and tall stature. The taller than expected height occurs because estrogen normally causes fusion of the epiphyseal growth plates in the bones, and in its absence, the patient will keep growing longer. The gonadotropins LH and FSH will both be elevated and patients present with polycystic ovaries. Furthermore, the low oestrogen will predispose those with the condition to osteoporosis. [2]

Female

Male

Symptoms are generally manifested in adulthood:

During pregnancy

During gestation, a baby with Aromatase Deficiency can cause a mother to become virilized by causing the deepening of the voice, cystic acne, more hair growth than normal, cliteromegaly, and hirsutism. [7] The mother also has an increased level of circulating testosterone. [8] However, the symptoms normally regress post-partum. [2]

Complications

Pregnant mother

Aromatase is an estrogen synthase that synthesize estrone (E1) and estradiol (E2) from Androstenedione and Testosterone respectively. [9] During pregnancy, the placenta, which is fetal tissue, synthesizes large amounts of the intermediates in the biosynthesis of the estrogens, androstenedione and testosterone, but cannot convert them to estrogens due to the absence of aromatase. [9] The levels of accumulated androgens in the mother can elevate 100-fold higher than normal cycling levels which subsequently virilise both the mother and the fetus. The mother will experience cystic acne, deepening of the voice and hirsutism. [2] However, these symptoms are normally resolved following parturition. [2]

If the fetus is a male, it will develop a normal male genitalia and will proceed to grow normally and exhibit secondary male sex characteristics. [10] If the fetus is a female, it will be born with ambiguous genitalia including labioscrotal fusion and a greatly enlarged phallus. [9]

Female

Aromatase deficient female cannot synthesize estrone or estradiol in the absence of aromatase. The amount of androgen will accumulate at a very high rate in the blood, disrupting the LHRH-LH/FSH axis that can potentially lead to polycystic ovaries in adulthood. [5] In the absence of estrogen, high level of circulating LH and FSH can results in Hypergonadotropic hypogonadism. [11]

While females begin to virilise and grow hair in various places during adolescent, they are unable to menstruate without the presence of estradiol, subsequently causing primary amenorrhea, clitormegaly, and absence of breast development. [2] As puberty fails, the growth spurt is absence and bone age is delayed. [5] Without treatment, the collection of excessive androgen in the blood can lead to development of polycystic ovaries. [2]

Male

Aromatase deficient males experience a normal growth into adulthood. With a very low level of circulating estrogen (<7pg/mL), resulting in a higher level of FSH and LH in the blood. [2] Elevated level of androgens do not contribute to harmonic skeletal muscle growth like estrogen, thus, patients exhibits eunuchoid body habitus. [5]

Patients are generally tall in stature and have a pattern of persistent linear bone growth into adulthood. [2] [9] Without estrogen, the epiphyseal plates cannot fuse together properly, resulting in continuous height growth. As a necessary steroid to maintain bone homeostasis, low level of estrogen also result osteopenia and osteoporosis of the lumbar spine and cortical bone. [2] [5] Estrogen is also thought to be linked to the abnormal lipid profile and hyperinsulinemia in men, however, the detail mechanism is unknown. [2]

Cause

Gene Mutation

Autosomal recessive Autosomal recessive - en.svg
Autosomal recessive

Aromatase deficiency is an autosomal recessive disease with most of the mutations occur along the highly conservative regions of the gene. Both homozygous and heterozygous mutations have been identified along various location of the exon on the P450 arom (CYP19) gene localized on chromosome15p21.1. [10] In addition, mutations in cytochrome P450 oxidoreductase (POR), which is required for enzymatic activity of aromatase, can also cause aromatase deficiency. [12]

Table 1. Summary of known homozygous mutations in P450 arom (CPY19) gene [2] [5] [11]
GenderMutation Transcription ResultsAromatase Activity (%)
FemaleGT to GC at the 5' Terminus of intron VIAn extra 87 bp insertion, between exon VI and intron VI0.3%
Female/MaleSingle base change at bp 1123: C to T in exon X Cysteine being transcribed instead of Arginine at position 375 (R375C)0.2%
Female Point mutation (R457X) in exon XNo Transcription-
FemaleMutation Valine 370 to Methionine in exon IX--
Female1600 bp deletion in exon VAromatase lacking 59 Amino Acids -
FemalePoint mutation in exon X (R435C) Missense mutation that causes loss of function-
FemaleDeletion of a single Phenylalanine residue at codon 234 in exon VI--
Female568C insertion in CYP19A1 190 Leucine was changed to Proline -
FemaleSingle base change at bp 1094 (G to A) in exon IX Glutamine instead of Arginine being transcribed at position 365 (R365Q)0.4
MaleC-base deletion in exon VResulting in a stop codon after 21 codons0.0
MaleC to A substitution in intron V, at 3' splicing acceptor site before exon VIPremature stop codon-
MaleInsertion of 21 bp at the codon 353 in exon IX--
MaleSingle base change at bp 628 (G to A) in the last nucleotide of exon V Glutamic acid instead of a Lysine being transcribed at position 210 (E210K)1.0
Table 2. Summary of known heterozygous mutations in P450 arom (CPY19) gene [5]
GenderMutationTranscription ResultsAromatase Activity (%)
FemaleSingle base changes in exon X at bp 1303: C to TCysteine was transcribed instead of Arginine at position 435 (R435C)1.1
Single base changes in exon X at bp 1310: G to A Tyrosine was transcribed instead of Cysteine at position 437 (C437Y)0.0
FemalePoint mutation (G to A) at the splicing point between exon and intron IIINo transcription0.0
Base pair deletion occurring at P408 (CCC) in exon IXNonsense codon 111 bp were transcribed down in the CYP190.0
FemalePoint mutation (GAA to AAA) at bp 628 in exon VGlutamic acid transcribed instead of lysine at position 210 (E210K)0.0
A Base pair deletion occurring at E412 in exon IXTranscribed a stop codon 98 bp downstream0.0
MalePoint mutation (ATG to AGG) at bp 380 in exon IVMethionine was transcribed instead of arginine at position 127 (M127R)-
Point mutation (CGC to CAC) at bp 1123 in exon IX2. Arginine was transcribed instead of histidine at position 375 (R375H)-
Male23 bp deletion in exon IVPremature stop codon in exon IV-
Point mutation (G to T) at first bp in intron IXAlternative splicing?-

Diagnosis

A fetus can be predicted to be suffering from aromatase deficiency when its pregnant mother is displaying virilization. A female infant can be physically diagnosed due to the abnormal genitalia along with hormonal blood test. [5] The diagnosis can be considered for any virilized 46,XX child when congenital adrenal hyperplasia is excluded. [4] The condition can be suspected for males in their late teenage years or twenties who have continued linear growth and bone pain. [3] Excessively low level of estrogen and elevated level of androgens are diagnostic markers for aromatase deficiency in both males and females. [11] Testosterone level in the urine may be normal or elevated. [5]

Treatment

In males, transdermal estradiol replacement enable epiphyseal plates closure, increases bone density, promote skeletal maturation, lower FSH and LH level to normal and decrease insulin blood concentration. [5]

In females, hormonal replacement therapy such as cyclic oral therapy of conjugated estrogen leads to breast development, menses, pubertal growth spurt, resolution of ovarian cysts, suppression of elevated FSH and LH levels in the blood, and proper bone growth. [5] Ambiguous genitalia, clitoromegaly, and ovarian cysts can be removed surgically [2] (forasmuch as not illegal).

History

Aromatase deficiency was first recorded in literature in 1991 by Shouz and colleagues. The pregnant mother had low estrogen serum level and high androgens level in the third trimester along with signs of progressive virilisation. Upon delivery, the female infant exhibited ambiguous genitalia. Aromatase activity of the placenta was approximately ten times less than the normal range. [13]

See also

Related Research Articles

Amenorrhea or amenorrhoea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Congenital adrenal hyperplasia</span> Genetic disorders of the adrenal gland

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans.

<span class="mw-page-title-main">Virilization</span> Biological development of male sex characteristics

Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is a form of congenital adrenal hyperplasia (CAH) which produces a higher than normal amount of androgen, resulting from a defect in the gene encoding the enzyme steroid 11β-hydroxylase (11β-OH) which mediates the final step of cortisol synthesis in the adrenal. 11β-OH CAH results in hypertension due to excessive mineralocorticoid effects. It also causes excessive androgen production both before and after birth and can virilize a genetically female fetus or a child of either sex.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, 3β-hydroxysteroid dehydrogenase (3β-HSD) type II (HSD3B2). As a result, higher levels of 17α-hydroxypregnenolone appear in the blood with adrenocorticotropic hormone (ACTH) challenge, which stimulates adrenal corticosteroid synthesis.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 21-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.

Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiovascular disease, and has been linked to diseases like urinary tract infections and osteoporosis.

<span class="mw-page-title-main">Estrogen insensitivity syndrome</span> Medical condition

Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that results in an inability of estrogen to mediate its biological effects in the body. Congenital estrogen deficiency can alternatively be caused by a defect in aromatase, the enzyme responsible for the biosynthesis of estrogens, a condition which is referred to as aromatase deficiency and is similar in symptomatology to EIS.

Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles in a male. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when an adult body has been developed. Before puberty, the external sex organs, known as primary sexual characteristics, are sex characteristics that distinguish males and females. Puberty leads to sexual dimorphism through the development of the secondary sex characteristics, which further distinguish the sexes.

<span class="mw-page-title-main">Aromatase excess syndrome</span> Medical condition

Aromatase excess syndrome is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization and in females as hyperfeminization.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

<span class="mw-page-title-main">Isolated 17,20-lyase deficiency</span> Medical condition

Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impaired production of the androgen and estrogen sex steroids. The condition manifests itself as pseudohermaphroditism in males, in whom it is considered to be a form of intersex, and, in both sexes, as a reduced or absent puberty/lack of development of secondary sexual characteristics, resulting in a somewhat childlike appearance in adulthood.

<span class="mw-page-title-main">Inborn errors of steroid metabolism</span> Medical condition

An inborn error of steroid metabolism is an inborn error of metabolism due to defects in steroid metabolism.

<span class="mw-page-title-main">Leydig cell hypoplasia</span> Medical condition

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism, reduced or absent puberty, amenorrhea, and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease and inborn error of metabolism caused by deficiency of cytochrome P450 oxidoreductase (POR). POR is a 2-flavin protein that is responsible for the transfer of electrons from NADPH to all 50 microsomal cytochrome P450 (CYP450) enzymes. This includes the steroidogenic enzymes CYP17A1 (17α-hydroxylase/17,20-lyase), CYP19A1 (aromatase), and CYP21A2 (21-hydroxylase); CYP26B1 ; and the hepatic drug-metabolizing CYP450 enzymes, among many other CYP450 enzymes. Virilization of female infants in PORD may also be caused by alternative biosynthesis of 5α-dihydrotestosterone via the so-called "androgen backdoor pathway". The ABS component of severe forms of PORD is probably caused by CYP26B1 deficiency, which results in retinoic acid excess and defects during skeletal embryogenesis. All forms of PORD in humans are likely partial, as POR knockout in mice results in death during prenatal development.

References

  1. ↑ RESERVED IU. "Orphanet: Aromatase deficiency". www.orpha.net. Retrieved 14 April 2019.{{cite web}}: CS1 maint: numeric names: authors list (link)
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (December 1995). "Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of oestrogens". J. Clin. Endocrinol. Metab. 80 (12): 3689–98. doi:10.1210/jcem.80.12.8530621. PMID   8530621.
  3. 1 2 Lee JH, Lee NC, Tung YC (2020). "SUN-033 A Rare Case: Bone Pain and Continued Linear Growth in a Young Adult Male Due to Aromatase Deficiency". Journal of the Endocrine Society. 4 (Supplement_1): SUN-033. doi: 10.1210/jendso/bvaa046.212 . PMC   7209073 .
  4. 1 2 Fan L, Zhang B, Li L, Gong C (2020). "Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature". Clinical Endocrinology. 93 (6): 687–695. doi:10.1111/cen.14277. PMID   32623730. S2CID   220369250.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C (April 2008). "Human models of aromatase deficiency". J. Steroid Biochem. Mol. Biol. 109 (3–5): 212–8. doi:10.1016/j.jsbmb.2008.03.026. PMID   18448329. S2CID   23048215.
  6. ↑ Fan L, Zhang B, Li L, Gong C (2020). "Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature". Clinical Endocrinology. 93 (6): 687–695. doi:10.1111/cen.14277. PMID   32623730. S2CID   220369250.
  7. 1 2 Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, and Lee SJ (2016). "HA novel null mutation in P450 aromatase gene (CYP19A1) associated with development of hypoplastic ovaries in humans". J Clin Res Pediatr Endocrinol. 8 (2): 205–10. doi:10.4274/jcrpe.2761. PMC   5096477 . PMID   27086564.
  8. ↑ Jones ME, Boon WC, McInnes K, Maffei L, Carani C, Simpson ER (May 2007). "Recognizing rare disorders: aromatase deficiency". Nat Clin Pract Endocrinol Metab. 3 (5): 414–21. doi:10.1038/ncpendmet0477. PMID   17452968. S2CID   8581107.
  9. 1 2 3 4 Blakemore J, Naftolin F (July 2016). "Aromatase: Contributions to Physiology and Disease in Women and Men". Physiology. 31 (4): 258–269. doi: 10.1152/physiol.00054.2015 . PMID   27252161.
  10. 1 2 Bulun SE (2014). "Aromatase and estrogen receptor α deficiency". Fertility and Sterility. 101 (2): 323–329. doi:10.1016/j.fertnstert.2013.12.022. ISSN   0015-0282. PMC   3939057 . PMID   24485503.
  11. 1 2 3 Mazen I, Mcelreavey K, Elaidy A, Kamel AK, Abdel-Hamid MS (January 2018). "Aromatase deficiency due to homozygous CYP19A1 mutation in a 46, XX Egyptian patient with ambiguous genitalia". Sex Dev. 11 (5–6): 275–279. doi:10.1159/000485278. PMID   29324451. S2CID   3595100.
  12. ↑ Parween S, Fernández-Cancio M, Benito-Sanz S, Camats N, Velazquez MN, López-Siguero JP, Udhane SS, Kagawa N, Flück CE, Audí L, Pandey AV (2020). "Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype". The Journal of Clinical Endocrinology & Metabolism. 105 (4): e1272–e1290. doi: 10.1210/clinem/dgaa076 . PMID   32060549.
  13. ↑ Shouzu M, Akasofu K, Harada T, Kubota Y (March 1991). "A new cause of female pseudohermaphroditism: placental aromatase deficiency". J. Clin. Endocrinol. Metab. 72 (3): 560–566. doi:10.1210/jcem-72-3-560. PMID   1825497.

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