PCOS-like syndrome in the young woman with cortisone reductase deficiency type 1

Katarina Krstic; Sanja Ognjanovic; Bojana Popovic; Dusan Ilic; Kovacevic Valentina Elezovic; Macut Jelica Bjekić; Palibrk Milica Opalic; Lena Radic; Olivera Stanojlović; Markovic Aleksandra Rasic; Milutinovic Danijela Vojnovic; Djuro Macut

doi:10.1530/endoabs.99.EP437

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Endocrine Abstracts (2024) 99 EP437 | DOI: 10.1530/endoabs.99.EP437

ECE2024 Eposter Presentations Reproductive and Developmental Endocrinology (78 abstracts)

PCOS-like syndrome in the young woman with cortisone reductase deficiency type 1

Katarina Krstic ¹ , Sanja Ognjanovic ¹ , Bojana Popovic ¹ , Dusan Ilic ¹ , Valentina Elezovic Kovacevic ¹ , Jelica Bjekić Macut ^1,2 , Milica Opalic Palibrk ¹ , Lena Radic ¹ , Olivera Stanojlović ³ , Aleksandra Rasic Markovic ³ , Danijela Vojnovic Milutinovic ⁴ & Djuro Macut ¹

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¹Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Department for Endocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia; ²University Medical Centre Bezanijska Kosa, Belgrade, Serbia; ³Institute of Physiology, Faculty of Medicine, Belgrade, Serbia; ⁴IBISS, University of Belgrade, Belgrade, Serbia

Introduction: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency type 1 (CRD). Only mutations in H6PD gene, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Biochemical features of CRD are increased cortisol clearance and ACTH-mediated androgen excess. There are close phenotypic similarities between CRD and polycystic ovary syndrome (PCOS): hirsutism, oligo-amenorrhea, central fat distribution, infertility. We present the case of a 21-year old woman with mutations in H6PD gene who presented with secondary amenorrhea, hirsutism and obesity.

Case: After menarche at the age of 12, there were no spontaneous periods. A pediatric endocrinologist diagnosed PCOS (Rotterdam phenotype A). Menstrual cycles (MC) were established with a combined oral contraceptive pill with antiandrogen properties. The breaks in taking the medicine was followed by absence of MC. The patient’s dominant complaints are hirsutism (mFG score - 10), obesity (BMI 33 kg/m²) and secondary amenorrhea.

Results: Investigations showed elevated basal values of androgens (testosterone 6.8 and 8.0 nmol/l [1.2-3.8 nmol/l], androstenedione 6.2 and 6.0 ng/ml [0.24-3.44 ng/ml] and 17-OH progesterone 7.2 and 7.1 nmol/l [0.4-5.0nml/l]), FAI 29.8, AMH 9.45 ng/ml; DHEAS, serum cortisol, IGF-1, prolactin and thyroid function were normal. The results obtained in 2h-OGTT indicate insulin resistance (HOMA-IR 10.5). In low-dose dexamethasone tests, including prolonged DEX I, androgen suppression was absent. Androgen suppression was occurred after administration of GnRH agonist (Diphereline 3.75 mg). Congenital adrenal hyperplasia (CAH) was biochemically excluded by the Synachten test (maximal 17-OHP 7.0 nmol/l and cortisol 685.4 nmol/l). Selective ovarian and adrenal venous sampling were inconclusive indicating abnormal androgen production from the left adrenal gland and right ovary. Genetic analyzes confirmed mutations in H6PD gene: c.455A>G (p. Tyr152Cys) and c.1123G>A (p. Glu375Lys). The result of cortisol clearance is pending. The enlarged ovaries (diameter 5 cm, volume 28 ml) with polycystic morphology were confirmed by ultrasound. Adrenal glands are described as normal (MRI).

Conclusion: The genetic analysis on H6PD gene should be done if there are inexplicably high levels of androgens in a woman with PCO-like phenotype. Peculiar functional testing is needed including specific genetic testing for rare adrenal enzymatic deficiencies.