Personalized Reproductive Hormone Monitoring in Sweat

Estradiol is the primary female sex hormone produced by the ovaries and is of paramount importance to assessing ovarian function. Measuring female hormones on an individualized basis is particularly significant for fertility monitoring where repeat blood draws are traditionally required (1). Quantitative measurement of serum estradiol is commonly performed by immunoassays and LC-MS/MS methods for most clinical applications (2). The use of sweat as a diagnostic body fluid presents an exciting opportunity to explore real-time, noninvasive measurement of a variety of analytes without the need for external specimen collection (3). Despite significant progress in this field, sweat analysis also presents numerous challenges including variable sweat rate, composition and sample matrix, pH, and temperature within and among individuals, in addition to relatively low analyte concentrations in the picomolar (pM) range (4). A recent article published by Ye et al. details the design, characterization, and on-body clinical trial of a novel wireless wearable nanobiosensor capable of real-time detection and quantification of sub-pM concentrations of estradiol in sweat (5). Inside the sensor, a microfluidic reservoir is formed by 2 opposing surfaces: an aptamer-based biorecognition surface and a detection working electrode that are bridged upon filling of the reservoir with sweat. Estradiol present in the sweat selectively binds to a single-stranded DNA aptamer specific for the hormone’s secondary structure. This binding causes the release of a redox probe that is captured on the opposing working electrode surface, leading to a change in current proportional to estradiol concentration. The design of this particular nanobiosensor overcomes some of the challenges posed by intra- and interindividual sweat variability by integrating simultaneous measurements of skin temperature and pH with real-time sensor calibration. Electronic circuitry contained within the device allows for signal processing and wireless communication to an external source for remote data analysis, including real-time monitoring using a smartphone app. During validation of the sensor, a linear correlation (r = 0.921) was observed between sensor- and ELISA-based quantitation at very low (0–50 pM) sweat estradiol concentrations. Additional testing in a small patient cohort (n = 6) of premenopausal females and adult males showed that sweat estradiol concentrations strongly correlated with serum estradiol (r = 0.837). Notably, there was poor intermethod agreement between sensor- and serum-based quantitation, with estradiol concentrations orders of magnitude lower in sweat vs serum. However, there was a striking similarity in the cyclical pattern of serum and sweat estradiol as both peaked at day 13 during the follicular phase prior to ovulation with a secondary peak on day 20 during the luteal phase in all 3 female study participants during on-body trials. Though not yet FDA approved, this study offers a promising look into a future of wearable devices that utilize aptamer-based detection of biomolecules in sweat. Monitoring the rise and fall of reproductive hormones, like sweat estradiol, could provide immediate clinical utility in fertility management where timing of ovulation is critical (e.g., in women undergoing induction of ovulation with gonadotropins) (1). In conclusion, this study showcases a budding field with promise for individualized reproductive health monitoring. The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Robert Maynard (Writing—original draft-Lead, Writing—review & editing-Lead) Upon manuscript submission, all authors completed the author disclosure form. None declared. R.D. Maynard was the recipient of the 2022 American Association for Clinical Chemistry Society for Young Clinical Laboratorians Travel Grant to attend the 2022 AACC Annual Scientific Meeting.