Ovarian tissue cryopreservation in female-to-male transgender people: insights into ovarian histology and physiology after prolonged androgen treatment

Roo, Chloë De; Lierman, Sylvie; Tilleman, Kelly; Peynshaert, Karen; Braeckmans, Kevin; Caanen, Mirte R.; Lambalk, Cornelis B.; Weyers, Steven; T’Sjoen, Guy; Cornelissen, Ria; Sutter, Petra De

doi:10.1016/j.rbmo.2017.03.008

Cited by 156 publications

(107 citation statements)

References 27 publications

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“…Typically, GRPs are young and have a high follicle density. Although all GRPs undergo androgen-therapy prior to oophorectomy, their follicles do not differ in distribution, number and quality from untreated women [23], and they can achieve pregnancy after discontinued hormone treatment [24]. In support of this, our data show that ovaries from GRPs have the same cell composition as tissue from C-sec patients.…”

Section: Discussionsupporting

confidence: 67%

Single cell map of the human ovarian cortex

Wagner

Yoshihara

Douagi

et al. 2019

Preprint

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22 23 KEY WORDS 24 Adult human ovary, Oogonial stem cells, DDX4 antibody, Germline stem cells, Single cell RNA 25 sequencing, Cell surface marker. 26 27 2 ABSTRACT 28 The human ovary orchestrates sex hormone production and undergoes monthly 29 structural changes to release mature oocytes. The outer lining of the ovary (cortex) has 30 a key role in defining fertility in women as it harbors the ovarian reserve. It has been 31 postulated that putative oogonial stem cells exist in the ovarian cortex and that these 32 can be captured by DDX4 antibody isolation. We analysed on a single cell level the 33 transcriptome and cell surface antigen profiles of over 24,000 cells from high quality 34 ovarian cortex samples from 21 patients. Our single cell mapping reveals transcriptional 35 profiles of six main cell types; oocytes, granulosa cells, immune cells, endothelial cells, 36 perivascular cells, and stromal cells. Cells captured by DDX4 antibody are perivascular 37 cells, not oogonial stem cells. Our data does not support the existence of germline stem 38 cells in adult human ovaries thereby reinforcing the dogma of a limited ovarian reserve. 39 40 65 in a xeno-transplantation model [9]. The biological significance of these cells is poorly 66 understood. In addition, many laboratories have not been able to repeat these findings and 67 confirm the existence of OSCs [14-16].68 4 Recently, somatic cells from the inner part of human ovaries have been characterized 69 by single cell sequencing [17]. Here, we complete the map of cell types in human ovaries by 70 providing the first extensive characterization of germ cells and somatic cells in the outer layer 71 of human ovaries, i.e. in the cortex. We used tissue samples provided by 21 patients with 72 proven healthy follicles. Our results demonstrate six main cell types, but cannot provide 73 support to the existence of OSCs. This dataset will be a valuable tool for studying the role of 74 specific cell populations in ovarian biology, dissecting causes of infertility, and developing 75 novel assisted reproductive technologies or even contraceptives. 76 77 78 79 5 RESULTS 80 Study setup 81 We used single cell RNA-sequencing (scRNA-seq) and surface marker screening to determine 82 transcriptomes and cell surface proteomes of cells present in ovarian cortex (Fig. 1). We used 83 tissue from altogether 21 Caesarean section (C-sec, N=5) and gender reassignment surgery 84 patients (GRPs, N=16) to have a comprehensive coverage of individuals and commonly used 85 donor types. All tissue samples were validated to contain healthy follicles (Fig. 1). In order to 86 relate the findings to OSCs, we marked the cells with DDX4 antibodies (Ab) in all experiments; 87 the scRNA-seq experiments were done on uncultured, unsorted cells and sorted DDX4 Ab+ 88 and Ab-cell fractions as well as on cultured, sorted DDX4 Ab+ and Ab-cells. The surface 89 marker screen included DDX4 Ab as an additional marker. Data analysis included validation 90 of markers by immunostaining of ovarian samples, and mergi...

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Section: Discussionsupporting

confidence: 67%

Single cell map of the human ovarian cortex

Wagner

Yoshihara

Douagi

et al. 2019

Preprint

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“…Androgen excess is a key trait in the majority (~60%) of women with PCOS, and the most frequent common feature, as hyperandrogenism is a diagnostic criteria in three out of the four PCOS phenotypes (A-D) endorsed by the 2018 international evidence-based guidelines (Livadas et al 2014, Teede et al 2018. Interestingly, the presence of elevated androgen levels observed in congenital adrenal hyperplasia patients (Lucis et al 1966, Hague et al 1990 and female-to-male transsexuals treated with testosterone (Futterweit & Deligdisch 1986, Spinder et al 1989, De Roo et al 2017 are reported to cause the appearance of polycystic ovarian morphology (PCOM), similar to that observed in women with PCOS, with enlarged ovaries that exhibit multiple cysts and theca interstitial hyperplasia. Serum levels of testosterone, A4 and DHEAS, and the enzyme required to transform pro-androgens to bioactive androgens -3β-hydroxysteroid dehydrogenase (3β-HSD)have all been reported to be elevated in hyperandrogenic PCOS women (Keefe et al 2014, Palomba et al 2014, O'Reilly et al 2017.…”

Section: Clinical Evidence Supporting a Role For Androgens In Drivingmentioning

confidence: 99%

Androgens and ovarian function: translation from basic discovery research to clinical impact

Walters

Paris

Aflatounian

et al. 2019

Journal of Endocrinology

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In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.

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“…In transsexual patients, the ovaries show similar numbers of primordial and primary follicles in the ovarian cortex as compared with healthy females of the same age (De Roo et al, ). Thus, primordial follicles are not depleted from the ovarian cortex of transsexual females after treatment with testosterone (Van den Broekcke et al, ).…”

Section: Introductionmentioning

confidence: 99%

How do elevated levels of testosterone affect the function of the human fallopian tube and fertility?—New insights

Dulohery

Trottmann

Bour

et al. 2019

Molecular Reproduction Devel

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Excess testosterone levels affect up to 20% of the female population worldwide and are a key component in the pathogenesis of polycystic ovary syndrome. However, little is known about how excess testosterone affects the function of the human fallopian tube-the site of gamete transport, fertilization, and early embryogenesis. Therefore, this study aimed to characterize alterations caused by long-term exposure to male testosterone levels. For this purpose, the Fallopian tubes of nine female-to-male transsexuals, who had been undergoing testosterone treatment for 1-3 years, were compared with the tubes of 19 cycling patients. In the ampulla, testosterone treatment resulted in extensive luminal accumulations of secretions and cell debris which caused ciliary clumping and luminal blockage. Additionally, the percentage of ciliated cells in the ampulla was significantly increased. Transsexual patients, who had had sexual intercourse before surgery, showed spermatozoa trapped in mucus. Finally, in the isthmus complete luminal collapse occurred. Our results imply that fertility in women with elevated levels of testosterone is altered by tubal luminal obstruction resulting in impaired gamete transport and survival.

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Ovarian tissue cryopreservation in female-to-male transgender people: insights into ovarian histology and physiology after prolonged androgen treatment

Cited by 156 publications

References 27 publications

Single cell map of the human ovarian cortex

Single cell map of the human ovarian cortex

Androgens and ovarian function: translation from basic discovery research to clinical impact

How do elevated levels of testosterone affect the function of the human fallopian tube and fertility?—New insights

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