Secondary ovarian insufficiency (SOI) and infertility due to glucocorticosteroid-induced adrenal hypoandrogenism

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Barad, Pasquale Patrizio, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4796372/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract That ovarian insufficiency and resulting infertility can have iatrogenic causes is well known; but that never before included corticosteroid therapy. We now report two longstanding so-called “unexplained” infertility cases which, upon presentation to our center were diagnosis with secondary ovarian insufficiency (SOI) as a consequence of abnormally low adrenal androgen production following prolonged corticosteroid therapy. Androgens at small growing follicle stages act synergistically to follicle stimulating hormone (FSH) in fostering follicle growth and maturation. Hypoandrogenism, therefore, reduces numbers and quality of follicles and oocytes and, in most severe cases, can lead to complete arrest of folliculogenesis and SOI. Both women demonstrated caseation of pituitary ACTH secretion, leading to very low peripheral androgen levels. Discontinuation of exogenous corticosteroid therapies and exogenous androgen supplementation with dehydroepiandrosterone (DHEA) reversed their abnormal endocrine profiles. One patient since conceived through in vitro fertilization, while the second patient is still in treatment. Here presented observation suggests that iatrogenic-induced ovarian insufficiency - and, in most severe case SOI - may be more common than is currently appreciated and, frequently, may be misdiagnosed as “unexplained” infertility. premature ovarian aging (POA) primary ovarian insufficiency (POI) secondary ovarian insufficiency (SOI) hypoandrogenism iatrogenic ovarian insufficiency unexplained infertility female infertility Introduction The hypothalamic – pituitary - adrenal axis (HPAA) is for several reasons essential for successful reproduction. The definition of under- or over-active adrenal function currently, however, only refers to the two outer layers of the adrenal cortex, the mineralocorticoid-producing zona glomerulosa (zG), and the glucocorticoid-producing zona fasciculata (zF). Paradoxically, Insufficiency or hyperactivity in the androgen-producing zona reticularis (zR) is not considered part of the diagnosis, an omission we have previously pointed out ( 1 ). Hypoandrogenism in association with low functional ovarian reserve (LFOR) in infertile women is very common and usually the consequence of insufficiency of the zR. The condition has been reported in a range of infertility etiologies, from younger women with premature ovarian aging (POA), also called occult primary ovarian insufficiency (oPOI ( 2 ), to older women with physiological ovarian aging causing low functional ovarian reserve (LFOR) ( 2 ), in the hyper/hypo-androgenic polycystic ovary syndrome (HH-PCOS), which at younger ages is the hyper-androgenic, lean PCOS phenotype-D (by Rotterdam criteria)( 3 – 5 ), and in secondary ovarian insufficiency (SOI), a rare condition that is commonly mistaken for primary ovarian insufficiency (POI) and is caused by adrenal androgen insufficiency adversely affecting ovarian folliculogenesis ( 6 ). It is this last group of infertile women we are addressing in this communication by describing for the first time the diagnosis of SOI in two women who presented with a longstanding incorrect diagnosis of “unexplained” infertility, - a diagnosis in textbooks still alleged to represent up to 15–25% of all female infertility diagnoses. Both of these patients, moreover, were found to experience adrenal androgen insufficiency as a consequence of long-term – adrenal suppression with glucocorticoid therapy. Since adrenals by weight produce approximately half of women’s androgens and since normal androgen levels are especially at small growing follicle stages essential for normal ovarian follicle maturation ( 7 ), insufficiency of the zR can affect ovarian function, in extreme cases even leading to follicle maturation arrest and, therefore, SOI ( 6 ). This was first demonstrated in a knock-out mouse model ( 8 ), with further evidence developed in several animal models and clinical studies since ( 7 – 10 ). As insufficiencies of zG and zF uniformly have been considered autoimmune, and since other hypo-androgenic infertility diagnoses have been associated with autoimmunity ( 3 , 4 , 11 ), adrenal hypoandrogenism likely is also the consequence of an autoimmune process, but this fact remains to be confirmed. Materials and methods We here for the first time report two patients in the literature in whom we, with great certainty, established insufficiency in androgen production in their adrenal zR, leading to peripheral hypoandrogenism and, consequentially, SOI. We, moreover, also were able to establish that the underlying cause of their adrenal androgen insufficiency was long-term corticosteroid treatments. Both women presented from other fertility centers with a diagnosis “unexplained” infertility, a widely accepted diagnosis in the fertility literature, though in our opinion an oxymoron, considering the fact that what remains “unexplained,” always depends on the depth of a patient’s diagnostic work-up. Patients with this diagnosis at our center, therefore, always undergo a more thorough diagnostic evaluation than they had been exposed to before, which in almost all cases leads to previously overlooked diagnoses ( 12 ). Ethics Approval Both patients consented in writing to use of their medical record for research and publication purposes, as long as their anonymity was maintained. As case reports extracted from the center’s anonymized medical record bank this condition was met and their publication was approved by our Institutional Review Board {IRB) based on expedited review. Results Case reports Case 1 After elsewhere diagnosed with secondary “unexplained” infertility, a 34-year-old gravida 1 para 1 presented for second opinion. Her BMI was 26 kg/m 2 and she reported regular menses. Her medical history was significant for irritable bowel syndrome, lumbar spinal discomfort, and eczema, treated with 0.05% clobetasol propionate ointment, a super-potent (Class I) topical steroid. Her sister had psoriatic arthritis. Before presentation to our center, she had failed two fresh in-vitro fertilization (IVF) cycles and one frozen-thawed embryo transfer (FET). Both fresh cycles produced normal oocyte yields, - but few embryos, a typical presentation of HH-PCOS ( 3 , 4 ). Hormonal testing revealed secondary adrenal androgen insufficiency and undetectable estradiol, suggestive of SOI ( 6 ) (Table 1 ): Her free testosterone (FT) was 0.4 pg/mL, total testosterone (TT) 5.0 ng/dL, DHEA 103.0 ng/dL and DHEA-S only 92.0 ug/dL. Her SHBG was 64.0 nmol/L, FSH was 6.2 mIU/mL, her estradiol was undetectable at < 25.0 pg/mL, and her AMH was at 1.8 ng/mL. Her cortisol was abnormally high at 17.7 ug/dL and her ACTH was undetectable at < 5.0 pg/mL (see Table 1 ). A repeat hormone panel two months after tapering her corticosteroids revealed resumption of normal ovarian and adrenal activity (Table 1 ). She since conceived at her initial fertility center and delivered a healthy child. Case 2 A second female presented to our center as a 40-year-old gravida 1 para 0 with three years of primary “unexplained” infertility followed by a spontaneous pregnancy loss after fetal heart at 10 weeks. Her BMI was 29.3 kg/m 2 and she reported a history of allergic asthma, treated with inhaled fluticasone/salmetero. Fittingly, her CRP of 8.0 mg/L was elevated, as was her IgE at 530.4 IU/mL, and she also demonstrated eosinophilia of 6.9%. She had failed 5 IVF cycles elsewhere, one of which resulted in above noted spontaneous miscarriage. Her AMH was 1.9 ng/mL and her baseline FSH was 6.6 mIU/mL. Her estradiol of < 25 pg/mL was at undetectable level and her androgens were extremely low (Table 1 ). Because of low DHEA-S, her hypoandrogenism apparently was of adrenal origin, likely caused by long-term chronic inhalation of corticosteroids. Her SOI was likely caused by her adrenal hypoandrogenism. Following cessation of her steroid therapy and initiation of DHEA supplementation (25mg TID), adrenal and ovarian hormones returned to normal: DHEA rose from 39.0 to 188.0 ng/dL, DHEA-S rose from 28.8 to 365.0 µg/dL, TT rose from 9.0 to 22 ng/dL and FT rose from 1.7 to 3.7 pg/mL, with SHBG rising from 17.8 to 21.4 nmol/L. At the time of this report, this patient is still in IVF treatment. Discussion As noted earlier, hypoandrogenism is a characteristic feature of several female infertility diagnoses ( 7 – 11 ). This includes the 2017 discovery that phenotype-D under Rotterdam PCOS criteria with advancing age significantly differs in ontogeny from all other PCOS phenotypes, with changing androgen levels being one of the typical characteristics. Like the other 3 PCOS phenotypes after menarche hyperandrogenic, between ages 25–35 years only the D phenotype transitions from hyper- to hypo-androgenism, thereby becoming treatment-resistant, - unless low androgen levels are corrected ( 3 , 4 , 6 ), therefore, recently given the acronym hyper/hypo- androgenic PCOS (HH-PCOS) ( 6 ). A ten-year transition period between ages 25–35 through normo-androgenic range, likely explains why phenotype D in the literature is generally described as normo-androgenic. Though we remain impressed by how frequently we diagnose this PCOS phenotype in our patient population, the adrenal hypoandrogenism caused by insufficiency of the zR in most HH-PCOS and other hypo-androgenic infertile women is usually not severe enough to cause complete arrest of follicle maturation. Complete cessation of estradiol production by granulosa cells, as seen in here reported two cases, therefore, is rare. Most women with hypoandrogenism, indeed, do not present with a picture of complete SOI, though they may be already relatively treatment-resistant to standard infertility treatments because of their low androgen levels. And, like here reported two patients, they, therefore, may often have a diagnosis of “unexplained” infertility because most fertility centers do not routinely assess androgen levels in their female patients. Hypo-androgenism, however, significantly affects oocyte yields as well as oocyte quality ( 8 – 10 ), and, as recently reported, will make patients treatment resistant to IVF ( 6 ). Though still a somewhat controversial subject, androgen supplementation appears to reverse in such patients this treatment resistance ( 6 ). By first, shutting down adrenal androgen production through suppression of ACTH, in here presented cases, exogenous steroids, rather than autoimmunity, appear to have been the primary culprits in shutting down adrenal androgen production and, secondarily, ovarian folliculogenesis. Under the believe that systemic side-effects are rare, steroids are commonly prescribed for a large variety of clinical conditions. Here presented two cases, to the best of our knowledge, are the first ever reported suggesting that steroid medications are able induced female infertility as a consequence of insufficient adrenal androgen production. As previously noted, hypo-androgenism adversely affects follicular growth at small growing follicle stages, thereby reducing estradiol production by follicles ( 7 , 9 , 10 ). Here reported two cases demonstrate that long-term maternal steroid use may impair adrenal androgen production through interruption of the HPAA by suppressing ACTH secretion from the pituitary. ACTH regulates all three zonas of the adrenal corte. Through adrenal androgen production, ACTH, thus, also -secondarily - exerts influence over ovarian function. Androgen-driven interplay between adrenals and ovaries should not surprise, considering both stem from a common embryonic primordium ( 13 ). Moreover, after ovaries, adrenal glands contain the highest density of anti-Müllerian hormone (AMH) receptors of any other organ in the female human body ( 14 ), an observation that strongly suggests that AMH may play an important, still undiscovered, role in adrenal-ovarian hormone homeostasis. It may also lead to an answer why in both here presented cases AMH levels were surprisingly normal, yet estradiol production by follicles was completely absent. In summary, we here presented for the first time a new cause for SOI, likely often going undiagnosed and miscategorized as “unexplained” infertility ( 15 ). 15 By publishing these two cases, we hope to provide an impetus for further studies. Our observation also coincides with the relatively recent publication in Nature Medicine which demonstrated that adrenal suppression as a consequence of inhaled steroids is much more common than has been so-far appreciated ( 16 ), making it only that more likely that SOI as consequence of long-term steroid treatments is currently an underappreciated diagnosis. Table 1 Hormone levels of both patients before and after steroid withdrawal. Hormone Patient 1 Patient 2 Normal range Baseline Withdrawal Baseline Withdrawal FSH (mIU/mL) 6.2 -- 6.6 3.1 Age-dependent Estradiol (pg/mL) 26.0 AMH (ng/mL) 1.8 -- 1.9 1.4 Age-dependent SHBG (nmol/L) 64.0 143.0 17.8 21.4 17.0–124.0 Free testosterone (pg/mL) 0.4 1.0 1.7 3.7 0.1–6.4 (Age-dependent) Total testosterone (ng/dL) 5.0 26.0 9.0 22.0 2.0–45.0 DHEA (ng/dL) 103.0 100.0 39.0 188.0 385.0–2030.0 DHEAS (µg/dL) 92.0 58.0 28.8 365.0 23.0–266.0 ACTH (pg/mL) < 5.0 -- 17.5 19.8 6.0–50.0 Cortisol (µg/dL) 17.7 -- 3.6 (AM) 10.5 (AM) 6.0–18.4 (AM) 2.7–10.5 (PM) Abbreviations ACTH, adrenocortical hormone; AMH, anti-Müllerian hormone; BMI, bod mass index; CRP, C-reactive protein; DHEA, dehydroepiandrosterone; FSH, follicle stimulating hormone; FT, free testosterone; HH-PCOS, hyper/hypo-androgenic polycystic ovary syndrome; HPAA, hypothalamic- pituitary-adrenal axis; IVF, in vitro fertilization, LFOR, low functional ovarian reserve; oPOI, occult primary insufficiency; PCOS, polycystic ovarian syndrome; POI, primary ovarian insufficiency; SHBG, sex hormone binding globulin; SOI, secondary ovarian insufficiency; TT, total testosterone; zF, zona fasciculata; zG, zona glomerulosa; zR, zona reticularis. Declarations Competing Interests N.G. and D.H.B. are listed as co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgen supplementation in women with low functional ovarian reserve. Others relate to diagnostic and potential therapeutic benefits of AMH. N.G. is a shareholder in Fertility Nutraceuticals, and is owner of The CHR., where much of the research reported in this manuscript was performed. N.G. and D.H.B. also receive patent royalties from Fertility Nutraceuticals, LLC. N.G. and P.P. also received research support, travel funding and lecture fees from various Pharma and medical device companies, none, however, over the last 3 years and none in any way related to this manuscript. Other authors have no conflicts to report. Author Contribution Study concept A.B. and N.G.; data collection and literature search, A.B. and L.M.; First manuscript draft, N.G.; Multiple subsequent revisions, L.M., D.H.B., P.P., N.G. All authors agreed on the final manuscript. STUDY FUNDING : Intramural funds from the Center for Human Reproduction (CHR), where the study was conducted and unrestricted funds form the Foundation for Reproductive Medicine, a not-for-profit foundation. References Gleicher N, Kushnir VA, Albertini DF, Barad DH. Including the zona reticularis in the definition of hypoadrenalism and hyperadrenalism. J Clin Endocrinol Metab 2017a;102(9):3569–3570 Gleicher N, Kim A, Weghofer A, Kush. J Endocrinol 2014;222(3)nir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH. Hypoandrogenism in association with diminished functional ovarian reserve. Hum Reprod 2013;28(4):1084–1091. Gleicher N, Kushnir VA, Darmon SK, Wang Q, Zhang L, Albertini DF, Barad DH. New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens. J Steroid Biochem Mol Biol. 2017; 167:144–152 Gleicher N, Kushnir VA, Darmon SK, Wang Q, Zhang L, Albertini DF, Barad DH. Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age. Endocrine. 2018;59(3):661–676. Gleicher N, Darmon S, Patrizio P, Barad DH. Reconsidering the polycystic ovary syndrome. Biomedicines 2022;10:1505 Gleicher N, Darmon S, Molinari E, Zhang L, Hu J, Albertini DF, Barad DH. A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as a new fertility diagnosis. Endocrine 2020; PMID: 3309651 Prizant H, Gleicher N, Sen A. Androgen actions in the ovary: balance is key. J Endocrinol 2014;2014;222(3):R141-151 Sen A, Hammes SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Edocrinol 2010;24(7):1393–1403 Sen A, Prizant H, Hammes. Understanding extranuclear (nongenomic) androgen signaling what a frog oocyte can tell us about human biology. Steroids 2011;76(9):822–828 Sen A, Prizant H, Light A, Biswas A, Hayes E, Lee HJ, Barad D, Gleicher N, Hammes SR. Androgens regulate ovarian follicle development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci USA 2014;111(8):3008–3013 Gleicher N, Weghofer A, Oktay K, Barad D. Do etiologies of premature ovarian aging (POA) mimic those of premature ovarian failure (POF). Hum Reprod 2009;24(10:2395–2400 Gleicher N, Barad D. Unexplained infertility: does it really exist. Hum Reprod 2006;21(8):1951–1955 Huang CC, Yao HH. Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs. Mol Reprod Dev 2010;77(6):489–496 NCBI Resources. https://www.ncbi.nlm.nih.gov/gene/269 , accessed March 13, 2022. Gelbaya TA, Potdar N, Jeve YB, Nardo LG. Definition and epidemiology of unexplained infertility. Obstet Gynecol Surv 2014;69(2):109–115 Kachroo P, Stewart ID, Kelly RS, Stav M, Mendez, et al. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat Med 2022;28:814–822 Additional Declarations Competing interest reported. N.G. and D.H.B. are listed as co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgen supplementation in women with low functional ovarian reserve. Others relate to diagnostic and potential therapeutic benefits of AMH. N.G. is a shareholder in Fertility Nutraceuticals, and is owner of The CHR., where much of the research reported in this manuscript was performed. N.G. and D.H.B. also receive patent royalties from Fertility Nutraceuticals, LLC. N.G. and P.P. also received research support, travel funding and lecture fees from various Pharma and medical device companies, none, however, over the last 3 years and none in any way related to this manuscript. Other authors have no conflicts to report. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4796372","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":333031782,"identity":"a8eed9ec-41d1-4cef-9627-67dbd38fcbea","order_by":0,"name":"Ariel Benor","email":"","orcid":"","institution":"Center for Human Reproduction","correspondingAuthor":false,"prefix":"","firstName":"Ariel","middleName":"","lastName":"Benor","suffix":""},{"id":333031786,"identity":"c4fd879b-e5cf-44c8-a3be-cbf6d2bfefbe","order_by":1,"name":"Lyka Mochizuki","email":"","orcid":"","institution":"Center for Human Reproduction","correspondingAuthor":false,"prefix":"","firstName":"Lyka","middleName":"","lastName":"Mochizuki","suffix":""},{"id":333031788,"identity":"a76e2f42-295a-4cad-8381-e49ac95cf935","order_by":2,"name":"David H . Barad","email":"","orcid":"","institution":"Center for Human Reproduction","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"H .","lastName":"Barad","suffix":""},{"id":333031790,"identity":"216d50b3-5898-49a8-9e11-94871918315a","order_by":3,"name":"Pasquale Patrizio","email":"","orcid":"","institution":"Yale University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Pasquale","middleName":"","lastName":"Patrizio","suffix":""},{"id":333031791,"identity":"2e681bf0-8b8e-47f8-9a43-f3e037a1cb51","order_by":4,"name":"Norbert Gleicher","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYHACxgMMBgwJDAzMB5iBvASi9EC1sCU2k6AFrJLHkDgt5gzsFw58KLDL45c+8/1xQYVdnnkD88NHN/BosWzgKTg4wyC5WLIvd2PzjDPJxTIH2IyNc/BoMTjAk3CYx+BA4oYzvBubedsOJM5g4GGTJqjlD1DL/jM8D5t5/xGlhf3AYQaQLTw8jM28DcRoOczDcLDHIDlxxhk2w9k8x4AMZkJ+Od7+8MGPP3aJ/T3MDz7z1NglzmBvfvgYnxYGZh4DdBF8ysGA/QFBJaNgFIyCUTDCAQCgpE9rnFHsgAAAAABJRU5ErkJggg==","orcid":"","institution":"Center for Human Reproduction","correspondingAuthor":true,"prefix":"","firstName":"Norbert","middleName":"","lastName":"Gleicher","suffix":""}],"badges":[],"createdAt":"2024-07-24 15:02:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4796372/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4796372/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74799547,"identity":"50f5be2a-00cb-4f8b-8ded-20a24f09297f","added_by":"auto","created_at":"2025-01-27 03:16:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":784389,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4796372/v1/5a6eea44-dee0-4988-9a5d-7867748e4bbc.pdf"}],"financialInterests":"Competing interest reported. N.G. and D.H.B. are listed as co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgen supplementation in women with low functional ovarian reserve. Others relate to diagnostic and potential therapeutic benefits of AMH. N.G. is a shareholder in Fertility Nutraceuticals, and is owner of The CHR., where much of the research reported in this manuscript was performed. N.G. and D.H.B. also receive patent royalties from Fertility Nutraceuticals, LLC. N.G. and P.P. also received research support, travel funding and lecture fees from various Pharma and medical device companies, none, however, over the last 3 years and none in any way related to this manuscript. Other authors have no conflicts to report.","formattedTitle":"Secondary ovarian insufficiency (SOI) and infertility due to glucocorticosteroid-induced adrenal hypoandrogenism","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe hypothalamic \u0026ndash; pituitary - adrenal axis (HPAA) is for several reasons essential for successful reproduction. The definition of under- or over-active adrenal function currently, however, only refers to the two outer layers of the adrenal cortex, the mineralocorticoid-producing zona glomerulosa (zG), and the glucocorticoid-producing zona fasciculata (zF). Paradoxically, Insufficiency or hyperactivity in the androgen-producing zona reticularis (zR) is \u003cem\u003enot\u003c/em\u003e considered part of the diagnosis, an omission we have previously pointed out (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHypoandrogenism in association with low functional ovarian reserve (LFOR) in infertile women is very common and usually the consequence of insufficiency of the zR. The condition has been reported in a range of infertility etiologies, from younger women with premature ovarian aging (POA), also called occult primary ovarian insufficiency (oPOI (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), to older women with physiological ovarian aging causing low functional ovarian reserve (LFOR) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), in the hyper/hypo-androgenic polycystic ovary syndrome (HH-PCOS), which at younger ages is the hyper-androgenic, lean PCOS phenotype-D (by Rotterdam criteria)(\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and in secondary ovarian insufficiency (SOI), a rare condition that is commonly mistaken for primary ovarian insufficiency (POI) and is caused by adrenal androgen insufficiency adversely affecting ovarian folliculogenesis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is this last group of infertile women we are addressing in this communication by describing for the first time the diagnosis of SOI in two women who presented with a longstanding incorrect diagnosis of \u0026ldquo;unexplained\u0026rdquo; infertility, - a diagnosis in textbooks still alleged to represent up to 15\u0026ndash;25% of all female infertility diagnoses. Both of these patients, moreover, were found to experience adrenal androgen insufficiency as a consequence of long-term \u0026ndash; adrenal suppression with glucocorticoid therapy.\u003c/p\u003e \u003cp\u003eSince adrenals by weight produce approximately half of women\u0026rsquo;s androgens and since normal androgen levels are especially at small growing follicle stages essential for normal ovarian follicle maturation (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), insufficiency of the zR can affect ovarian function, in extreme cases even leading to follicle maturation arrest and, therefore, SOI (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This was first demonstrated in a knock-out mouse model (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), with further evidence developed in several animal models and clinical studies since (\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). As insufficiencies of zG and zF uniformly have been considered autoimmune, and since other hypo-androgenic infertility diagnoses have been associated with autoimmunity (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), adrenal hypoandrogenism likely is also the consequence of an autoimmune process, but this fact remains to be confirmed.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eWe here for the first time report two patients in the literature in whom we, with great certainty, established insufficiency in androgen production in their adrenal zR, leading to peripheral hypoandrogenism and, consequentially, SOI. We, moreover, also were able to establish that the underlying cause of their adrenal androgen insufficiency was long-term corticosteroid treatments. Both women presented from other fertility centers with a diagnosis \u0026ldquo;unexplained\u0026rdquo; infertility, a widely accepted diagnosis in the fertility literature, though in our opinion an oxymoron, considering the fact that what remains \u0026ldquo;unexplained,\u0026rdquo; always depends on the depth of a patient\u0026rsquo;s diagnostic work-up. Patients with this diagnosis at our center, therefore, always undergo a more thorough diagnostic evaluation than they had been exposed to before, which in almost all cases leads to previously overlooked diagnoses (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics Approval\u003c/h2\u003e \u003cp\u003eBoth patients consented in writing to use of their medical record for research and publication purposes, as long as their anonymity was maintained. As case reports extracted from the center\u0026rsquo;s anonymized medical record bank this condition was met and their publication was approved by our Institutional Review Board {IRB) based on expedited review.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCase reports\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003eAfter elsewhere diagnosed with secondary \u0026ldquo;unexplained\u0026rdquo; infertility, a 34-year-old gravida 1 para 1 presented for second opinion. Her BMI was 26 kg/m\u003csup\u003e2\u003c/sup\u003e and she reported regular menses. Her medical history was significant for irritable bowel syndrome, lumbar spinal discomfort, and eczema, treated with 0.05% clobetasol propionate ointment, a super-potent (Class I) topical steroid. Her sister had psoriatic arthritis.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eBefore presentation to our center, she had failed two fresh in-vitro fertilization (IVF) cycles and one frozen-thawed embryo transfer (FET). Both fresh cycles produced normal oocyte yields, - but few embryos, a typical presentation of HH-PCOS (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Hormonal testing revealed secondary adrenal androgen insufficiency and undetectable estradiol, suggestive of SOI (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): Her free testosterone (FT) was 0.4 pg/mL, total testosterone (TT) 5.0 ng/dL, DHEA 103.0 ng/dL and DHEA-S only 92.0 ug/dL. Her SHBG was 64.0 nmol/L, FSH was 6.2 mIU/mL, her estradiol was undetectable at \u0026lt;\u0026thinsp;25.0 pg/mL, and her AMH was at 1.8 ng/mL. Her cortisol was abnormally high at 17.7 ug/dL and her ACTH was undetectable at \u0026lt;\u0026thinsp;5.0 pg/mL (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A repeat hormone panel two months after tapering her corticosteroids revealed resumption of normal ovarian and adrenal activity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). She since conceived at her initial fertility center and delivered a healthy child.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003eA second female presented to our center as a 40-year-old gravida 1 para 0 with three years of primary \u0026ldquo;unexplained\u0026rdquo; infertility followed by a spontaneous pregnancy loss after fetal heart at 10 weeks. Her BMI was 29.3 kg/m\u003csup\u003e2\u003c/sup\u003e and she reported a history of allergic asthma, treated with inhaled fluticasone/salmetero. Fittingly, her CRP of 8.0 mg/L was elevated, as was her IgE at 530.4 IU/mL, and she also demonstrated eosinophilia of 6.9%.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eShe had failed 5 IVF cycles elsewhere, one of which resulted in above noted spontaneous miscarriage. Her AMH was 1.9 ng/mL and her baseline FSH was 6.6 mIU/mL. Her estradiol of \u0026lt;\u0026thinsp;25 pg/mL was at undetectable level and her androgens were extremely low (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Because of low DHEA-S, her hypoandrogenism apparently was of adrenal origin, likely caused by long-term chronic inhalation of corticosteroids. Her SOI was likely caused by her adrenal hypoandrogenism.\u003c/p\u003e \u003cp\u003eFollowing cessation of her steroid therapy and initiation of DHEA supplementation (25mg TID), adrenal and ovarian hormones returned to normal: DHEA rose from 39.0 to 188.0 ng/dL, DHEA-S rose from 28.8 to 365.0 \u0026micro;g/dL, TT rose from 9.0 to 22 ng/dL and FT rose from 1.7 to 3.7 pg/mL, with SHBG rising from 17.8 to 21.4 nmol/L. At the time of this report, this patient is still in IVF treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs noted earlier, hypoandrogenism is a characteristic feature of several female infertility diagnoses (\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). This includes the 2017 discovery that phenotype-D under Rotterdam PCOS criteria with advancing age significantly differs in ontogeny from all other PCOS phenotypes, with changing androgen levels being one of the typical characteristics. Like the other 3 PCOS phenotypes after menarche hyperandrogenic, between ages 25\u0026ndash;35 years only the D phenotype transitions from hyper- to hypo-androgenism, thereby becoming treatment-resistant, - unless low androgen levels are corrected (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), therefore, recently given the acronym hyper/hypo- androgenic PCOS (HH-PCOS) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A ten-year transition period between ages 25\u0026ndash;35 through normo-androgenic range, likely explains why phenotype D in the literature is generally described as normo-androgenic.\u003c/p\u003e \u003cp\u003eThough we remain impressed by how frequently we diagnose this PCOS phenotype in our patient population, the adrenal hypoandrogenism caused by insufficiency of the zR in most HH-PCOS and other hypo-androgenic infertile women is usually not severe enough to cause complete arrest of follicle maturation. Complete cessation of estradiol production by granulosa cells, as seen in here reported two cases, therefore, is rare. Most women with hypoandrogenism, indeed, do not present with a picture of complete SOI, though they may be already relatively treatment-resistant to standard infertility treatments because of their low androgen levels. And, like here reported two patients, they, therefore, may often have a diagnosis of \u0026ldquo;unexplained\u0026rdquo; infertility because most fertility centers do not routinely assess androgen levels in their female patients.\u003c/p\u003e \u003cp\u003eHypo-androgenism, however, significantly affects oocyte yields as well as oocyte quality (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and, as recently reported, will make patients treatment resistant to IVF (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Though still a somewhat controversial subject, androgen supplementation appears to reverse in such patients this treatment resistance (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBy first, shutting down adrenal androgen production through suppression of ACTH, in here presented cases, exogenous steroids, rather than autoimmunity, appear to have been the primary culprits in shutting down adrenal androgen production and, secondarily, ovarian folliculogenesis. Under the believe that systemic side-effects are rare, steroids are commonly prescribed for a large variety of clinical conditions. Here presented two cases, to the best of our knowledge, are the first ever reported suggesting that steroid medications are able induced female infertility as a consequence of insufficient adrenal androgen production.\u003c/p\u003e \u003cp\u003eAs previously noted, hypo-androgenism adversely affects follicular growth at small growing follicle stages, thereby reducing estradiol production by follicles (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Here reported two cases demonstrate that long-term maternal steroid use may impair adrenal androgen production through interruption of the HPAA by suppressing ACTH secretion from the pituitary. ACTH regulates all three zonas of the adrenal corte. Through adrenal androgen production, ACTH, thus, also -secondarily - exerts influence over ovarian function.\u003c/p\u003e \u003cp\u003eAndrogen-driven interplay between adrenals and ovaries should not surprise, considering both stem from a common embryonic primordium (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Moreover, after ovaries, adrenal glands contain the highest density of anti-M\u0026uuml;llerian hormone (AMH) receptors of any other organ in the female human body (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), an observation that strongly suggests that AMH may play an important, still undiscovered, role in adrenal-ovarian hormone homeostasis. It may also lead to an answer why in both here presented cases AMH levels were surprisingly normal, yet estradiol production by follicles was completely absent.\u003c/p\u003e \u003cp\u003eIn summary, we here presented for the first time a new cause for SOI, likely often going undiagnosed and miscategorized as \u0026ldquo;unexplained\u0026rdquo; infertility (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003csup\u003e15\u003c/sup\u003e By publishing these two cases, we hope to provide an impetus for further studies. Our observation also coincides with the relatively recent publication in \u003cem\u003eNature Medicine\u003c/em\u003e which demonstrated that adrenal suppression as a consequence of inhaled steroids is much more common than has been so-far appreciated (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), making it only that more likely that SOI as consequence of long-term steroid treatments is currently an underappreciated diagnosis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHormone levels of both patients before and after steroid withdrawal.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHormone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNormal range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWithdrawal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWithdrawal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFSH (mIU/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAge-dependent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEstradiol (pg/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;26.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAMH (ng/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAge-dependent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSHBG (nmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17.0\u0026ndash;124.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFree testosterone (pg/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u0026ndash;6.4\u003c/p\u003e \u003cp\u003e(Age-dependent)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal testosterone (ng/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.0\u0026ndash;45.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDHEA (ng/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e103.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e188.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e385.0\u0026ndash;2030.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDHEAS (\u0026micro;g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e365.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23.0\u0026ndash;266.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eACTH (pg/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.0\u0026ndash;50.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCortisol (\u0026micro;g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 (AM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.5 (AM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.0\u0026ndash;18.4 (AM)\u003c/p\u003e \u003cp\u003e2.7\u0026ndash;10.5 (PM)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTH, adrenocortical hormone; AMH, anti-M\u0026uuml;llerian hormone; BMI, bod mass index;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eCRP, C-reactive protein; \u0026nbsp;DHEA, dehydroepiandrosterone;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eFSH, follicle stimulating hormone; \u0026nbsp;FT, free testosterone;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eHH-PCOS, hyper/hypo-androgenic polycystic ovary syndrome;\u0026nbsp;HPAA, hypothalamic- pituitary-adrenal axis;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eIVF, in vitro fertilization, LFOR, low functional ovarian reserve; oPOI, occult primary insufficiency; PCOS, polycystic ovarian syndrome; POI, primary ovarian insufficiency; SHBG, sex hormone binding globulin; SOI, secondary ovarian insufficiency; TT, total testosterone; zF, zona fasciculata; zG, zona glomerulosa; zR, zona reticularis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests\u003c/strong\u003e\u003cp\u003eN.G. and D.H.B. are listed as co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgen supplementation in women with low functional ovarian reserve. Others relate to diagnostic and potential therapeutic benefits of AMH. N.G. is a shareholder in Fertility Nutraceuticals, and is owner of The CHR., where much of the research reported in this manuscript was performed. N.G. and D.H.B. also receive patent royalties from Fertility Nutraceuticals, LLC. N.G. and P.P. also received research support, travel funding and lecture fees from various Pharma and medical device companies, none, however, over the last 3 years and none in any way related to this manuscript. Other authors have no conflicts to report.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eStudy concept A.B. and N.G.; data collection and literature search, A.B. and L.M.; First manuscript draft, N.G.; Multiple subsequent revisions, L.M., D.H.B., P.P., N.G. All authors agreed on the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSTUDY FUNDING\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eIntramural funds from the Center for Human Reproduction (CHR), where the study was conducted and unrestricted funds form the Foundation for Reproductive Medicine, a not-for-profit foundation.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGleicher N, Kushnir VA, Albertini DF, Barad DH. Including the zona reticularis in the definition of hypoadrenalism and hyperadrenalism. J Clin Endocrinol Metab 2017a;102(9):3569\u0026ndash;3570\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Kim A, Weghofer A, Kush. J Endocrinol 2014;222(3)nir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH. Hypoandrogenism in association with diminished functional ovarian reserve. Hum Reprod 2013;28(4):1084\u0026ndash;1091.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Kushnir VA, Darmon SK, Wang Q, Zhang L, Albertini DF, Barad DH. New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens. J Steroid Biochem Mol Biol. 2017; 167:144\u0026ndash;152\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Kushnir VA, Darmon SK, Wang Q, Zhang L, Albertini DF, Barad DH. Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age. Endocrine. 2018;59(3):661\u0026ndash;676.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Darmon S, Patrizio P, Barad DH. Reconsidering the polycystic ovary syndrome. Biomedicines 2022;10:1505\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Darmon S, Molinari E, Zhang L, Hu J, Albertini DF, Barad DH. A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as a new fertility diagnosis. Endocrine 2020; PMID: 3309651\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrizant H, Gleicher N, Sen A. Androgen actions in the ovary: balance is key. J Endocrinol 2014;2014;222(3):R141-151\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen A, Hammes SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Edocrinol 2010;24(7):1393\u0026ndash;1403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen A, Prizant H, Hammes. Understanding extranuclear (nongenomic) androgen signaling what a frog oocyte can tell us about human biology. Steroids 2011;76(9):822\u0026ndash;828\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen A, Prizant H, Light A, Biswas A, Hayes E, Lee HJ, Barad D, Gleicher N, Hammes SR. Androgens regulate ovarian follicle development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci USA 2014;111(8):3008\u0026ndash;3013\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Weghofer A, Oktay K, Barad D. Do etiologies of premature ovarian aging (POA) mimic those of premature ovarian failure (POF). Hum Reprod 2009;24(10:2395\u0026ndash;2400\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Barad D. Unexplained infertility: does it really exist. Hum Reprod 2006;21(8):1951\u0026ndash;1955\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang CC, Yao HH. Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs. Mol Reprod Dev 2010;77(6):489\u0026ndash;496\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNCBI Resources. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/gene/269\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/gene/269\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed March 13, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGelbaya TA, Potdar N, Jeve YB, Nardo LG. Definition and epidemiology of unexplained infertility. Obstet Gynecol Surv 2014;69(2):109\u0026ndash;115\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKachroo P, Stewart ID, Kelly RS, Stav M, Mendez, et al. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat Med 2022;28:814\u0026ndash;822\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"premature ovarian aging (POA), primary ovarian insufficiency (POI), secondary ovarian insufficiency (SOI), hypoandrogenism, iatrogenic ovarian insufficiency, unexplained infertility, female infertility","lastPublishedDoi":"10.21203/rs.3.rs-4796372/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4796372/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThat ovarian insufficiency and resulting infertility can have iatrogenic causes is well known; but that never before included corticosteroid therapy. We now report two longstanding so-called \u0026ldquo;unexplained\u0026rdquo; infertility cases which, upon presentation to our center were diagnosis with secondary ovarian insufficiency (SOI) as a consequence of abnormally low adrenal androgen production following prolonged corticosteroid therapy. Androgens at small growing follicle stages act synergistically to follicle stimulating hormone (FSH) in fostering follicle growth and maturation. Hypoandrogenism, therefore, reduces numbers and quality of follicles and oocytes and, in most severe cases, can lead to complete arrest of folliculogenesis and SOI. Both women demonstrated caseation of pituitary ACTH secretion, leading to very low peripheral androgen levels. Discontinuation of exogenous corticosteroid therapies and exogenous androgen supplementation with dehydroepiandrosterone (DHEA) reversed their abnormal endocrine profiles. One patient since conceived through in vitro fertilization, while the second patient is still in treatment. Here presented observation suggests that iatrogenic-induced ovarian insufficiency - and, in most severe case SOI - may be more common than is currently appreciated and, frequently, may be misdiagnosed as \u0026ldquo;unexplained\u0026rdquo; infertility.\u003c/p\u003e","manuscriptTitle":"Secondary ovarian insufficiency (SOI) and infertility due to glucocorticosteroid-induced adrenal hypoandrogenism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-21 10:51:31","doi":"10.21203/rs.3.rs-4796372/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d5c2acb-7077-4d35-9f34-20f89f786584","owner":[],"postedDate":"August 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T03:08:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-21 10:51:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4796372","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4796372","identity":"rs-4796372","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}