Georgios E Papadakis1,2, Agathe Dumont3, Jerome Bouligand4,5, Fanny Chasseloup4,5, Anna Raggi6, Sophie Catteau-Jonard3,7, Odile Boute-Benejean8, Nelly Pitteloud1,9, Jacques Young2,5,10, Didier Dewailly3,7. 1. Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, CH-1011 Lausanne, Switzerland. 2. Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, F-94275 Le Kremlin-Bicêtre, France. 3. Department of Reproductive Medicine, Université de Lille, Centre Hospitalier Universitaire (CHU) Lille, F-59000 Lille, France. 4. Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Kremlin-Bicêtre F-94275 France. 5. Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche-U1185, Fac Med Paris Saclay, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. 6. Fertisuisse, CH-4600 Olten, Switzerland. 7. University of Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, INSERM U1172, Lille, France. 8. Department of Clinical Genetics, Université de Lille, CHU Lille, F-59000 Lille, France. 9. Faculty of Biology and Medicine, University of Lausanne, CH-1011 Lausanne, Switzerland. 10. Université Paris-Saclay, F-91405 Orsay Cedex, France.
Abstract
STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Authors: C Gusmano; R Cannarella; A Crafa; F Barbagallo; S La Vignera; R A Condorelli; A E Calogero Journal: J Endocrinol Invest Date: 2022-07-17 Impact factor: 5.467