{"paper_id":"a490b444-9f8f-47da-8593-a156711d4dc6","body_text":"David Barker first associated low birth weight with subsequent cardiovascular\ndisease over 30 years ago, framing mechanistic understanding of sub-optimal\ngestational environments as major contributors to developmental origins of adult\ndisease. Rapid onset, maternal immunological tolerance of the semi-allogeneic fetus\nis essential for optimal endothelial cell reprogramming within uterine spiral\narteries, enabling optimal placental function. Not surprisingly, therefore,\nsub-optimal gestational environments arise when pre-existing maternal immunological\n(inflammatory), metabolic and endocrine disorders impair placental development and\nfunction. Increasing mechanistic insights into sub-optimal gestation are now\ninspiring technological innovations targeting the placenta, so as to engender a\nparadigm shift in clinical management towards early preventive intervention.\nThe steroid hormones testosterone and estradiol play vital roles in\ndifferentiating sex-specific fetal characteristics. Sufficient placental\naromatization of maternal and fetal androgens is crucial, not only for placental\nvascular health and function, but also for protection of female fetuses against\nmaternal androgen-mediated virilization. In excess, testosterone can oppose\nestradiol action in females, diminishing estrogen receptor alpha (ESR1)-mediated\nprogesterone receptor expression, thus diminishing progesterone action and\ncompromising gestational environments. In addition, excess testosterone in female\nfetuses, from mice to nonhuman primates and humans, increases the likelihood of\npolycystic ovary syndrome (PCOS) at adolescence and throughout adult life,\nfaithfully reconfirming developmental origins of adult disease, with altered\nanogenital and finger length ratio parameters providing quantifiable infant and\nadult biomarkers of fetal androgen and estrogen exposure. Human and nonhuman primate\nmid-gestational fetal ovaries express the full complement of steroidogenic enzymes\nand androgen receptors necessary to generate fetal female hyperandrogenism ( 1 ).\nIn this issue, Peters and Lambalk describe a case-control study in which they\ndemonstrate several associations between adult female anogenital parameters in 172\nnormal-to-overweight Dutch women in a control group (n=43), and those diagnosed with\none of three female reproductive disorders with complex genetic-endocrine\ninteractions: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome (n=43), PCOS (n=43) and\nsevere endometriosis (n=43) ( 2 ). The authors\npropose gestational steroid-mediated contributions to the developmental origins of\neach of these disorders. Their study examined women with MRKH, characterized by\nincomplete mullerian duct development with (type 1, 74% of MRKH subjects) or without\n(type 2, 26%) concomitant renal, skeletal or other anomalies; PCOS defined by\nRotterdam criteria; and severe endometriosis of whom ~58% had undergone\nsurgery ( 2 ). The control group comprised women\nundergoing IVF/ICSI due to male infertility. The authors measured anogenital lengths\nand finger length ratios as two accepted biomarkers of fetal androgen ( 1 ) and estrogen ( 3 ) exposure, demonstrating a high (>90%) degree of intra- and\ninter-observer reliability. Anogenital measurements were from the center of the anus\nto either the anterior labial commissure (AGDac), or the posterior fourchette\n(AGDaf). Caliper-assisted or digitally-imaged measurements of the 2 nd  and\n4 th  digit length ratios (2D:4D) were taken from the ventral hand\nbetween the basal crease and fingertip, along the finger midline ( 2 ).\nAGDaf was longer in women with MKRH compared to the other three groups, while\nAGDac was longer in women with PCOS versus those with endometriosis. The longer\nAGDaf measure in MRKH subjects, however, was significantly associated with natural\nvaginal dilation due to sexual intercourse ( 2 ), therefore limiting applicability of these findings to MRKH in general,\nsince vaginal construction, sexual activity and Frank’s method of vaginal\ndilation can affect the AGDaf. In this regard, it would be interesting to know the\nAGDaf of the 20.9% of women with MKRH who did not use any therapy for the creation\nof a vagina.\nDespite non-significant differences in AGDac lengths between women with these\nfemale disorders and controls, those with endometriosis tended to have shorter AGDac\nlengths, while hyperandrogenic women with PCOS tended to have longer AGDac lengths,\nwith the women with MRKH in between compared to controls. AGDaf positively\ncorrelated with hirsutism score in women with MRKH, as did AGDac with hirsutism\nscore across the entire study population, and also with biochemical hyperandrogenism\nin women with PCOS. 2D:4D finger length ratios were not associated with female group\ndifferences or reproductive measures.\nThe significant female-type differences in anogenital measures, but not 2D:4D\nfinger length ratios, suggest a transient midgestational exposure to androgen or\nestrogen excess. This is because anogenital distance and 2D:4D finger length ratios\nare unaffected by later gestation androgen excess, while earlier gestation onset of\nandrogen excess virilizes external female genitalia and increases the 2D:4D finger\nlength ratio ( 1 ). Such findings agree with\nprevious reports implicating mid-gestational androgen excess exposure as a\ncontributing factor in the pathogenesis PCOS, and is reinforced by multiple animal\nmodels ( 1 ).\nThe inclusion of women with MRKH within the concept of prenatal androgen\norigins of disease, however, is unexpected. The authors speculate that\nhyperandrogenic women with MRKH, possibly from WNT4 gene variants ( 4 ), represent a discrete MRKH phenotype, possibly through\nprenatal androgen excess and overexpression of AMH. In support of this idea,\ndiminished functional WNT4 gene variants among women with MRKH might prevent\nMullerian duct development and impair inhibition of prenatal androgen production in\na manner analogous to findings in female 46XX individuals with WNT4 deficiencies\n( 5 ). It is unlikely, however, that\nexaggerated fetal ovarian AMH production can inhibit Mullerian duct development by\nnine weeks of gestation, since ovarian AMH is produced in late fetal life. More\nprobable, any prenatal androgen excess in women with MRKH due to diminished\nfunctional WNT4 gene variants ( 4 ,  5 ) may represent an epiphenomon rather than an\nunderlying causal mechanism.\nThe findings of a relatively diminutive anogenital length in women with\nendometriosis agrees with previous reports and the possibility of a mid-gestational\nestrogenic environment from androgen deficiency ( 3 ), as exemplified by both an increased risk of endometriosis in women\nprenatally exposed to diethylstilbestrol, and the postmortem findings of\nendometriosis in midgestational human female fetuses ( 3 ). Taken together, these findings raise environmental concerns about\nfetal female exposure not only to common estrogenic chemical disruptors in packaging\nand consumables as developmental programmers of endometriosis, but also to\nandrogenic chemical disruptors such as the organometallic xenobiotic tributyltin in\nwood preservatives, fungicides, molluscicides, rodent repellants and antifouling\npaints as analogous programmers of PCOS and MRKH-associated hyperandogenemia.\nIn closing, Peters and Lambalk’s paper ( 2 ) provides additional insight into the potential importance of\ngestational hormonal environments in contributing pathogenic origins to major\nreproductive disorders in women. Although the technological abilities to safely\nquantify circulating hormone concentrations in, or to obtain tissue from, human\nfetuses do not yet exist, improvements in measuring postnatal biomarkers of prenatal\nhormone exposure may provide clinically relevant indicators to target preventative\ninterventions during maternal-placental-fetal development, infancy and/or\nchildhood.","source_license":"public-domain-us","license_restricted":false}