Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

Details

Serval ID
serval:BIB_B8BA5EDB19CD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.
Journal
Human reproduction
Author(s)
Papadakis G.E., Dumont A., Bouligand J., Chasseloup F., Raggi A., Catteau-Jonard S., Boute-Benejean O., Pitteloud N., Young J., Dewailly D.
ISSN
1460-2350 (Electronic)
ISSN-L
0268-1161
Publication state
Published
Issued date
28/04/2020
Peer-reviewed
Oui
Volume
35
Number
4
Pages
939-949
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility?
PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility.
PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD.
In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018.
Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients.
All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies.
The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD.
The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.
No specific funding was used for this study. There are no potential conflicts of interest.
N/A.
Keywords
P450-oxidoreductase deficiency, amenorrhea, anovulation, congenital adrenal hyperplasia, high progesterone, infertility, ovarian macrocysts
Pubmed
Web of science
Create date
25/04/2020 21:57
Last modification date
24/10/2020 5:21
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