Aromatase deficiency caused by mutation of CYP19A1 gene: A case report. / CYP19A1åŸºå› çªå˜è‡´èŠ³é¦™åŒ–é ¶ç¼ºä¹ç—‡1例.

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.

Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature.

BACKGROUND: Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. OBJECTIVE: To investigate the clinical characteristics and accurate management of aromatase-deficient children. PATIENTS AND METHODS: We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. RESULTS: Two girls and one boy (3.4-9.2 years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32 years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). CONCLUSIONS: 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.

Of Oestrogens and Sperm: A Review of the Roles of Oestrogens and Oestrogen Receptors in Male Reproduction.

The crucial role that oestrogens play in male reproduction has been generally accepted; however, the exact mechanism of their action is not entirely clear and there is still much more to be clarified. The oestrogen response is mediated through oestrogen receptors, as well as classical oestrogen receptors' variants, and their specific co-expression plays a critical role. The importance of oestrogen signalling in male fertility is indicated by the adverse effects of selected oestrogen-like compounds, and their interaction with oestrogen receptors was proven to cause pathologies. The aims of this review are to summarise the current knowledge on oestrogen signalling during spermatogenesis and sperm maturation and discuss the available information on oestrogen receptors and their splice variants. An overview is given of species-specific differences including in humans, along with a detailed summary of the methodology outcome, including all the genetically manipulated models available to date. This review provides coherent information on the recently discovered mechanisms of oestrogens' and oestrogen receptors' effects and action in both testicular somatic and germ cells, as well as in mature sperm, available for mammals, including humans.

Aromatase is required for female abdominal aortic aneurysm protection.

OBJECTIVE: The protective effects of female gender on the development of abdominal aortic aneurysms (AAAs) have been attributed to anti-inflammatory effects of estrogen. Estrogen synthesis is dependent on the enzyme aromatase, which is located both centrally in the ovaries and peripherally in adipose tissue, bone, and vascular smooth muscle cells. It is hypothesized that deletion of aromatase in both ovarian and peripheral tissues would diminish the protective effect of female gender and would be associated with increased aortic diameter in female mice. METHODS: Male and female 8- to 10-week-old mice with aromatase (wild type: WT) and without aromatase (ArKO) underwent elastase aortic perfusion with aortic harvest 14 days following. For the contribution of central and peripheral estrogen conversion to be evaluated, female WT mice were compared with female WT and ArKO mice that had undergone ovariectomy (ovx) at 6 weeks followed by elastase perfusion at 8 to 10 weeks. At aortic harvest, maximal aortic dilation was measured and samples were collected for immunohistochemistry and protein analysis. Serum was collected for serum estradiol concentrations. Groups were compared with analysis of variance. Human and mouse AAA cross sections were analyzed with confocal immunohistochemistry for aromatase, smooth muscle markers, and macrophage markers. RESULTS: Female WT mice had significant reduction in aortic dilation compared with male WT mice (F WT, 51.5% ± 15.1% vs M WT, 78.7% ± 14.9%; P < .005). The protective effects of female gender were completely eliminated with deletion of aromatase (F ArKO, 82.6% ± 13.8%; P < .05 vs F WT). Ovariectomy increased aortic dilation in WT mice (F WT ovx, 70.6% ± 11.7%; P < .05 vs F WT). Aromatase deletion with ovariectomy further increased aortic dilation compared with WT ovx mice (F ArKO ovx, 87.3% ± 14.7%, P < .001 vs F WT and P < .05 vs F WT ovx). Accordingly, female ArKO ovx mice had significantly higher levels of the proinflammatory cytokines monocyte chemoattractant protein 1 and interleukin-1ß and were associated with increased macrophage staining and decreased elastin staining. Regarding serum hormone levels, decreasing estradiol levels correlated with increasing aortic diameter (R = -0.565; P < .01). By confocal immunohistochemistry, both human and mouse AAA smooth muscle cells (smooth muscle α-actin positive) and macrophages (CD68 positive or Mac-2 positive) expressed aromatase. CONCLUSIONS: The protective effect of female gender on AAAs is due to estrogen synthesis and requires the presence of both ovarian and extragonadal/peripheral aromatase. Peripheral estrogen synthesis accounts for roughly half of the protective effect of female gender. If peripheral aromatase could be targeted, high levels of local estrogen could be produced and may avoid the side effects of systemic estrogen.

Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement.

BACKGROUND: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. OBJECTIVE AND METHODS: We studied the impact of oral 17ß-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. RESULTS: In early childhood, low doses of oral 17ß-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. CONCLUSION: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

Role of aromatase in sex-specific cerebrovascular endothelial function in mice.

Stroke risk and outcome are strongly modified by estrogen. In addition to ovaries, estrogen is produced locally in peripheral tissue by the enzyme aromatase, and extragonadal synthesis becomes the major source of estrogen after menopause. Aromatase gene deletion in female mice exacerbates ischemic brain damage after stroke. However, it is not clear which cell type is responsible for this effect, since aromatase is expressed in multiple cell types, including cerebrovascular endothelium. We tested the hypothesis that cerebrovascular aromatase contributes to sex differences in cerebrovascular endothelial function. Cerebrocortical microvascular responses to the endothelium-dependent vasodilator ACh were compared between male and female wild-type (WT) and aromatase knockout (ArKO) mice by measuring laser-Doppler perfusion in vivo through a closed cranial window. Additional studies were performed in WT mice treated with the aromatase inhibitor fadrozole or vehicle. WT female mice had significantly greater responses to ACh compared with WT males (P < 0.001), which was associated with higher aromatase expression in female compared with male cerebral vessels (P < 0.05). ACh responses were significantly lower in ArKO compared with WT females (P < 0.05) and in WT females treated with fadrozole versus vehicle (P < 0.001). Conversely, ACh responses were significantly higher in ArKO versus WT males (P < 0.05). Levels of phosphorylated endothelial nitric oxide synthase (eNOS) were lower in ArKO versus WT female brains, but were not altered by aromatase deletion in males. We conclude that cerebrovascular endothelial aromatase plays an important and sexually dimorphic role in cerebrovascular function and that aromatase inhibitors in clinical use may have cardiovascular consequences in both males and females.

Aromatase-null mice expressing enhanced green fluorescent protein in germ cells provide a model system to assess estrogen-dependent ovulatory responses.

Enhanced green fluorescent protein (EGFP) has provided us with valuable approaches for tracking living cells. We established a novel line of transgenic mice, which express EGFP in the testis and ovary. Histological analysis demonstrated that spermatids in the testis and oocytes in ovarian follicles beyond preantral stages were positive for EGFP. By exploiting these features, we evaluated ovulatory responses of aromatase-gene (Cyp19a) knockout mouse expressing the EGFP transgene, which is totally anovulatory due to 17ß-estradiol (E2) deficiency. Ovulation in the knockout mice was induced by sequential injections of E2 on days 1, 4 and 5, pregnant mare serum gonadotropin on day 4 and human chorionic gonadotropin on day 6. Fluorescent oocytes were readily detectable at 15 h after the last gonadotropin injection in the oviduct under a fluorescence stereomicroscope, even when only one oocyte was present. However, when E2 supplementation on day 4 or day 5 in the regimen was omitted, no ovulated oocytes were detected, indicating that exogenous E2 supplementation at the time of gonadotropin stimulation is necessary to induce ovulation in aromatase-gene knockout mice. Our results further demonstrated that the current mouse line can provide an alternative tool to study germ cell biology, including oogenesis, ovulation and senescence.

Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia.

Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.

46,XX aromatase deficiency: A single-center experience with the varied spectrum and recurrent variants, and a systematic review of hormonal parameters.

BACKGROUND: Aromatase deficiency is a rare disorder, with only a few cases reported in India. We describe a single-center experience in western India, with a systematic review of genetically proven 46,XX aromatase deficiency patients to evaluate hormonal parameters. METHODS: Retrospective review of case records, collating phenotypic and genotypic data and molecular modeling. Systematic review of 46,XX aromatase deficiency, analyzing data on gonadotropins, estrogen and androgens. RESULTS: In the seven patients from our center, presentation was frequent in childhood or adolescence (4/7: delayed puberty or hyperandrogenism), with maternal virilization (4/7), predominance of Prader III/IV (5/7), and initial rearing as females (6/7). Three patients had hypoplastic ovaries. One patient had spontaneous regular menses. We report three novel (p.Arg115Pro, p.Arg192Pro, and c.145+1_145+4delins) and two recurrent variants (p.Val370Met, and c.145+1_145+4delins) in western and northern India, respectively. On systematic review (n=43), gonadotropins were elevated (FSH>LH) across ages (except preterm infants), androgens were elevated in about one-third of cases during childhood and puberty, and estradiol was lower than in controls in mini-puberty and puberty. Spontaneous thelarche and streak ovaries were significantly more frequent in patients with non-truncating and truncating variants, respectively. CONCLUSION: We report uncommon presentations with possible founder variants, and highlight hormonal parameters across ages. Serum FSH levels were elevated except in preterms, and can be used as a diagnostic marker.

Aromatase deficiency: an unusual cause for primary amenorrhea with virilization.

The most common cause for menstrual abnormality and virilization in children and adolescents would be congenital adrenal hyperplasia. An elevated 17(OH) progesterone is invariably seen in this condition. Aromatase deficiency can also lead to a similar presentation but differs in several aspects. The age of onset of the clinical manifestations, the phenotype, biochemical abnormalities and karyotype help us to arrive at a definitive diagnosis. However sometimes the history is atypical, biochemical abnormalities may overlap between the different conditions and prior treatment may modify the clinical features. We report here a young adult with a late presentation of aromatase deficiency to highlight the differences between the two conditions. A 27 year old lady presented to us with history of primary amenorrhea and masculine voice. She lacked feminine secondary sexual characters, had eunuchoid body habitus and prominent clitoromegaly. Consanguinity in the parents, a neonatal sibling death and elevated basal 17(OH) progesterone in the patient suggested a possibility of congenital adrenal hyperplasia. But the eunuchoid body habitus raised FSH and lack of response to dexamethasone led to a diagnosis of aromatase deficiency. Variability in the degree of aromatase deficiency is known such that maternal virilization may not occur in pregnancy. Aromatase deficiency should be suspected when a patient presents with primary amenorrhea, absence of female secondary sexual characters, virilization and tall stature with eunuchoid body proportions, and biochemical features of ovarian failure. In our country one should be aware that late presentation and prior treatment may modify disease expression and contribute to the diagnostic challenge.

Growth and hormonal profile from birth to adolescence of a girl with aromatase deficiency.

BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder caused by mutations in the CYP19A1 gene and characterized by lack of conversion of androgens to estrogens. It presents with virilization of pregnant mothers during the antenatal period, and virilization of female fetuses at birth. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess. PATIENT AND METHODS: We describe the clinical course of an Indian girl with aromatase deficiency from birth to 16 years of age. Estrogen replacement was begun at age 13.5 years. The child's growth, hormonal, radiological, and metabolic parameters were monitored throughout the course of treatment. RESULTS: The child presented with obesity, tall stature, delayed bone age, osteoporosis, hyperinsulinemia with acanthosis nigricans, and hypergonadotropic hypogonadism with cystic ovaries. Estrogen replacement resulted in a plateauing of height, improvement of bone maturation, and pubertal progression with the disappearance of ovarian cysts. However, hyperinsulinemia and acanthosis nigricans persisted despite estrogen replacement and metformin. Genetic analysis revealed a homozygous arginine to cysteine substitution at codon 435 in exon 10 of CYP19A1. CONCLUSIONS: This is the first case of aromatase deficiency reported from India. This case highlights the role of estrogen in skeletal maturation and mineralization and the effect of estrogen deficiency and androgen excess over glucose metabolism in adolescent females.

Kennedy's disease: clinical significance of tandem repeats in the androgen receptor.

Kennedy's disease (KD) or spinobulbar muscular atrophy is a hereditary X-linked, progressive neurodegenerative condition caused by an expansion of the CAG triplet repeat in the first exon of the androgen receptor gene. The phenotype in its full form is only expressed in males and presents as weakness and wasting of the upper and lower limbs and bulbar muscles associated with absent reflexes. Sensory disturbances are present. Various endocrine abnormalities including decreased fertility and gynecomastia are common and amongst the first features of KD. Animal models of KD have demonstrated improvement on withdrawal of testosterone, indicating that this agonist of the androgen receptor is required for the toxic effect. Potential therapies based on testosterone withdrawal in humans have shown some promise, but efficacy remains to be proven. Potential clinical factors, pathogenesis and future approaches to therapy are reviewed in this chapter.

Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.

As brain testosterone plays both androgenic and estrogenic actions due to its conversion into estrogen via aromatase naturally, it is unclear that the age-related reduction of testosterone increased risk of Alzheimer's disease (AD) in men is mediated through androgen alone or both androgen and estrogen mechanisms. Our previous studies using a gene-based approach in mouse model to block the conversion of testosterone into estrogen (aromatase gene knock-out, ArKO), found a depletion of estrogen and increase in testosterone endogenously in males. Here, we use crossing the ArKO mice with APP23 transgenic mice, a mouse model of AD, to produce APP23/Ar(+/-) mice to study the estrogen-independent effect of testosterone on AD. We found a significant reduction in brain plaque formation, improved cognitive function and increase NEP activity in male APP23/Ar(+/-) mice compared with age-matched male APP23 controls. In addition, we found, for the first time, a reduction of beta-secretase (BACE1) enzyme activity, mRNA level and protein expression in the male APP23/Ar(+/-) mice, suggesting that endogenous testosterone, independent from estrogen, may protect against AD in males via two major mechanisms, downregulation of BACE1 activities at transcriptional level to reduce beta amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.

Estrogen, efferent ductules, and the epididymis.

Estrogen's presence in the male reproductive system has been known for over 60 years, but its potential function in the epididymis remains an important area of investigation. Estrogen is synthesized by germ cells, producing a relatively high concentration in rete testis fluid. There are two estrogen receptors (ESR), the presence of which in the head of the epididymis is well documented and consistent between species; however, in other regions of the epididymis, their expression appears to be isotype, species, and cell specific. ESR1 is expressed constitutively in the epididymis; however, its presence is downregulated by high doses of estrogen, making the design of experiments complicated, as the phenotype of the Cyp19a1(-/-) mouse does not resemble that of the Esr1(-/-) mouse. Ligand-independent and DNA-binding Esr1 mutant models further demonstrate the complexity and importance of both signaling pathways in maintenance of efferent ductules and epididymis. Data now reveal the presence of not only classical nuclear receptors, but also cytoplasmic ESR and rapid responding membrane receptors; however, their importance in the epididymis remains undetermined. ESR1 regulates ion transport and water reabsorption in the efferent ducts and epididymis, and its regulation of other associated genes is continually being uncovered. In the male, some genes, such as Aqp9 and Slc9a3, contain both androgen and estrogen response elements and are dually regulated by these hormones. While estrogen pathways are a necessity for fertility in the male, future studies are needed to understand the interplay between androgens and estrogens in epididymal tissues, particularly in cell types that contain both receptors and their cofactors.

Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.

CONTEXT: Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens. OBJECTIVE: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences. DESIGN AND PATIENT: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy. MAIN OUTCOME MEASUREMENT: A genotype-phenotype correlation was found. RESULTS: By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type. CONCLUSION: Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.

Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor alpha.

OBJECTIVE: A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ERalpha and ERbeta agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation. METHODS: Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ERalpha (16alpha-LE2) and ERbeta (8beta-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA). RESULTS: Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-gamma levels, which were significantly abrogated by administration of 16alpha-LE2, but not 8beta-VE2. In contrast, both 16alpha-LE2 and 8beta-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16alpha-LE2 or 8beta-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16alpha-LE2, but not 8beta-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII-specific IgG. CONCLUSION: These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ERalpha is the dominant receptor that mediates these effects.

Aromatase deficiency in an Ontario Old Order Mennonite family.

OBJECTIVES: Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents. Herein, we report the first Old Order Mennonite family with that diagnosis. CASE PRESENTATION: Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His). Her older brother was later confirmed with the same genetic diagnosis. CONCLUSIONS: Recognizing the cultural sensitivity, unrecognized affected cases, and late presentation of males affected with aromatase deficiency, this condition may be more prevalent than believed in that population.

Steroid profiling in preeclamptic women: evidence for aromatase deficiency.

OBJECTIVE: Experimental data have revealed the critical role played by 2-methoxy-estradiol, a metabolite of 17ß-estradiol, in the pathophysiology of preeclampsia. We used gas chromatography/mass spectrometry to measure a whole panel of hormonal steroids in the plasma from women during the third trimester of their pregnancy. STUDY DESIGN: The population study consists of 24 pregnant patients with different outcomes: normal, or complicated by isolated preeclampsia or by severe preeclampsia with Hemolysis Enzyme Liver Low Platelets (HELLP) syndrome. RESULTS: 17ß-estradiol was reduced by 50% in isolated preeclampsia, and by 70% in severe preeclampsia with HELLP syndrome (normal: 8.54 ± 0.9 ng/mL; isolated preeclampsia: 4.65 ± 1.0 ng/mL; severe preeclampsia with HELLP syndrome: 2.64 ± 0.4 ng/mL), as is estrone. Downstream, 2-methoxy-estradiol was decreased only in severe preeclampsia with HELLP syndrome. The concentrations of estrone and 17ß-estradiol precursors were comparable between groups, suggesting that placental aromatase is deficient in preeclampsia. CONCLUSION: The gradual decrease of estrogen levels with increasing severity of preeclampsia suggests an impairment of placental steroidogenesis.

A novel compound heterozygous variant in CYP19A1 resulting in aromatase deficiency with normal ovarian tissue.

BACKGROUND: Aromatase deficiency leading to virilization in mother and female fetuses during pregnancy is a rare disease. It is characterized by impaired estrogen production, increased gonadotropins, and ovarian cysts. CASE: Herein, we report a clinical phenotype of the virilized female due to a novel compound heterozygous variant in CYP19A1 [IVS10 + 1 G > A; c.344 G > A (p.R115Q)], with normal gonadotropin levels at the time of admission and histologically normal ovarian tissues. CONCLUSION: Aromatase deficiency should also be considered even if the initial follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are normal, and ovarian cysts are lacking.