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      A mouse model mimicking gender-affirming treatment with pubertal suppression followed by testosterone in transmasculine youth

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          Abstract

          STUDY QUESTION

          Can mice serve as a translational model to examine the reproductive consequences of pubertal suppression with GnRH agonist (GnRHa) followed by testosterone (T) administration, a typical therapy in peripubertal transmasculine youth?

          SUMMARY ANSWER

          An implanted depot with 3.6 mg of GnRHa followed by T enanthate at 0.45 mg weekly can be used in peripubertal female mice for investigating the impact of gender-affirming hormone therapy in transmasculine youth.

          WHAT IS KNOWN ALREADY

          There is limited knowledge available in transgender medicine to provide evidence-based fertility care, with the current guidelines being based on the assumption of fertility loss. We recently successfully developed a mouse model to investigate the reproductive consequences of T therapy given to transgender men. On the other hand, to our knowledge, there is no mouse model to assess the reproductive outcomes in peripubertal transmasculine youth.

          STUDY DESIGN, SIZE, DURATION

          A total of 80 C57BL/6N female mice were used in this study, with n = 7 mice in each experimental group.

          PARTICIPANTS/MATERIALS, SETTING, METHODS

          We first assessed the effectiveness of GnRHa in arresting pubertal development in the female mice. In this experiment, 26-day-old female mice were subcutaneously implanted with a GnRHa (3.6 mg) depot. Controls underwent a sham surgery. Animals were euthanized at 3, 9, 21 and 28 days after the day of surgery. In the second experiment, we induced a transmasculine youth mouse model. C57BL/6N female mice were subcutaneously implanted with a 3.6 mg GnRHa depot on postnatal day 26 for 21 days and this was followed by weekly injections of 0.45 mg T enanthate for 6 weeks. The control for the GnRH treatment was sham surgery and the control for T treatment was sesame oil vehicle injections. Animals were sacrificed 0.5 weeks after the last injection. The data collected included the day of the vaginal opening and first estrus, daily vaginal cytology, weekly and terminal reproductive hormones levels, body/organ weights, ovarian follicular distribution and corpora lutea (CL) counts.

          MAIN RESULTS AND THE ROLE OF CHANCE

          GnRHa implanted animals remained in persistent diestrus and had reduced levels of FSH (P = 0.0013), LH (P = 0.0082) and estradiol (P = 0.0155), decreased uterine (P < 0.0001) and ovarian weights (P = 0.0002), and a lack of CL at 21 days after GnRHa implantation. T-only and GnRHa+T-treated animals were acyclic throughout the treatment period, had sustained elevated levels of T, suppressed LH levels (P < 0.0001), and an absence of CL compared to controls (P < 0.0001). Paired ovarian weights were reduced in the T-only and GnRHa+T groups compared with the control and GnRHa-only groups.

          LARGE SCALE DATA

          N/A.

          LIMITATIONS, REASONS FOR CAUTION

          Although it is an appropriate tool to provide relevant findings, precaution is needed to extrapolate mouse model results to mirror human reproductive physiology.

          WIDER IMPLICATIONS OF THE FINDINGS

          To our knowledge, this study describes the first mouse model mimicking gender-affirming hormone therapy in peripubertal transmasculine youth. This model provides a tool for researchers studying the effects of GnRHa-T therapy on other aspects of reproduction, other organ systems and transgenerational effects. The model is supported by GnRHa suppressing puberty and maintaining acyclicity during T treatment, lower LH levels and absence of CL. The results also suggest GnRHa+T therapy in peripubertal female mice does not affect ovarian reserve, since the number of primordial follicles was not affected by treatment.

          STUDY FUNDING/COMPETING INTEREST(S)

          This work was supported by the Michigan Institute for Clinical and Health Research grants KL2 TR 002241 and UL1 TR 002240 (C.D.C.); National Institutes of Health grants F30-HD100163 and T32-HD079342 (H.M.K.); University of Michigan Office of Research funding U058227 (A.S.); American Society for Reproductive Medicine/Society for Reproductive Endocrinology and Infertility grant (M.B.M.); and National Institutes of Health R01-HD098233 (M.B.M.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core Facility was supported by the Eunice Kennedy Shriver NICHD/NIH grants P50-HD028934 and R24-HD102061. The authors declare that they have no competing interests.

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          Most cited references45

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          Diagnostic and Statistical Manual of Mental Disorders

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            Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7

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              Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears.

              Microscopic evaluation of the types of cells present in vaginal smears has long been used to document the stages of the estrous cycle in laboratory rats and mice and as an index of the functional status of the hypothalamic-pituitary-ovarian axis. The estrous cycle is generally divided into the four stages of proestrus, estrus, metestrus, and diestrus. On cytological evaluation, these stages are defined by the absence, presence, or proportion of 4 basic cell types as well as by the cell density and arrangement of the cells on the slide. Multiple references regarding the cytology of the rat and mouse estrous cycle are available. Many contemporary references and studies, however, have relatively abbreviated definitions of the stages, are in reference to direct wet mount preparations, or lack comprehensive illustrations. This has led to ambiguity and, in some cases, a loss of appreciation for the encountered nuances of dividing a steadily moving cycle into 4 stages. The aim of this review is to provide a detailed description, discussion, and illustration of vaginal cytology of the rat and mouse estrous cycle as it appears on smears stained with metachromatic stains.
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                Author and article information

                Contributors
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                Journal
                Human Reproduction
                Oxford University Press (OUP)
                0268-1161
                1460-2350
                February 01 2023
                February 01 2023
                December 09 2022
                February 01 2023
                February 01 2023
                December 09 2022
                : 38
                : 2
                : 256-265
                Article
                10.1093/humrep/deac257
                36484619
                529160bc-3c28-448e-b591-9deb19a7c0ae
                © 2022

                https://academic.oup.com/pages/standard-publication-reuse-rights

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