31.1 Embryologic Origin

The uterus is an organ which derives embryologically from the Mullerian ducts which merge medially and caudally to form the uterus, cervix, Fallopian tubes, and upper one-third of the vagina. The uterus is composed of the endometrium, myometrium, and serosa. Irrespective of possible Mullerian variations which may result in changes in the shape of the uterus, the number of Mullerian structures present, incomplete Mullerian development, or discontinuity with the vagina, the response to hormonal exposure of myometrium and, if present, endometrium remains similar. This chapter will address the changes noted in these tissues following supraphysiologial androgen exposure. Existing literature presents a diverse view of the effects of exogenous androgens on the uterus.

31.2 The Uterus and Endogenous Androgen Production

All uteri are exposed to androgens as all persons have some degree of androgen production [Reference Fritz and Speroff1]. Fifty percent of a typical cisgender female’s circulating androgens arise from peripheral conversion with androstenedione, the main precursor, followed by 25% from the ovary and 25% from the adrenal cortex. A typical total testosterone level of a cisgender female with ovaries at reproductive age is 20–80 ng/dl (0.5–2.5 nmol/l). Under these levels ovaries have uninhibited function and can ovulate, subsequently inducing the characteristic endometrial growth and shedding cycle of menstruation.

Additionally, certain conditions (e.g. polycystic ovary syndrome (PCOS), hyperthecosis ovarii, or congenital adrenal hyperplasia) can contribute to elevated levels of endogenous androgens which then expose the uterus to these elevated levels. PCOS is associated with free androgen levels of twice the normal level, generally through depression of sex hormone binding globulin (SHBG) [2]. While elevated, testosterone levels caused by PCOS are generally less than 150 ng/dl (5 nmol/l) [Reference Fritz and Speroff1]. Below these levels, ovulation impairment can be seen as well as abnormal uterine bleeding, in part due to dysregulation of endometrial growth [2].

When transmasculine people utilize testosterone gender-affirming hormone therapy, the goal, according to various guidelines, is to create physiological range levels of testosterone for cisgender men, and suppress endogenous estrogen, which leads to a different hormonal milieu than most of these aforementioned endogenous conditions [Reference Hembree, Cohen-Kettenis and Gooren3]. While estrogen levels on supraphysiological testosterone are often lower than that of cisgender females, they are still present and may be in the range of cisgender male levels. Thus it is important to understand how these supraphysiological ranges of testosterone can influence the corpus uteri. This can help clinicians provide better counseling on expected histopathologic and clinical changes as well as inform workups for pelvic concerns (e.g. pain, bleeding) which patients may present with while on testosterone.

31.3 Androgen Receptor Activity

Androgen receptors (ARs) are demonstrable in all phases of the menstrual cycle in the endometrium and myometrium [Reference Simitsidellis, Saunders and Gibson4]. Under average endogenous cisgender female androgen exposure, AR-activity appears to be highest in the endometrium, especially in the proliferative phase glandular cells, with subsequently lower expression in the endometrial stroma and least expressive in the myometrium. AR-expression in the endometrium declines in the early secretory phase but is upregulated once again (particularly in the luminal and glandular epithelial cells) in the late secretory phase. Due to the cyclic expression, some of this regulation is theorized to be due to estrogen and progestins [Reference Gibson, Simitsidellis, Collins and Saunders5]. However, the further upregulation of ARs in the myometrium and stroma when exposed to supraphysiological androgen doses also suggests a possible feed forward mechanism [Reference Loverro, Resta and Dellino6]. Given the changes during the secretory phases, progestins are thought to decrease AR-expression in the endometrium [Reference Simitsidellis, Saunders and Gibson4].

In a small study of uteri from hysterectomies in transmasculine persons on testosterone, androgen expression patterns appeared inverted [Reference Loverro, Resta and Dellino6]. Highest expression of AR-activity was seen in the myometrium, with second highest concentration in the endometrial stroma followed by lowest expression in the endometrial epithelium. It is unclear how this upregulation of AR expressivity under supraphysiological testosterone translates into direct physiologic changes in the uterus compared to indirect changes from the ovaries.

31.4 Endometrial Changes

As stated above, physiologic androgens appear to have the most influence on the endometrium during the proliferative phase, when there is the highest AR activity. Studies show supraphysiological doses of androgens have significant depression effects [Reference Grimstad, Fowler and New7]. In vitro studies find androgens (and synthetic androgen-like medications such as danazol) suppress endometrial activity and cause cellular atrophy [Reference Simitsidellis, Saunders and Gibson4,Reference Rose, Dowsett, Mudge, White and Jeffcoate8]. In vivo studies of short course oral testosterone undecanoate (with only modestly elevated mean serum total testosterone levels of 46 ng/dl) have also shown to inhibit endometrial cell growth and produce thin endometrial linings on ultrasound [Reference Zang, Sahlin, Masironi, Eriksson and Lindén Hirschberg9].

Five cohort studies have been performed following hysterectomy in transmasculine persons on supraphysiological doses of androgens evaluating uterine pathology [Reference Grimstad, Fowler and New7,Reference Khalifa, Toyama, Klein and Santiago10]. The three smaller cohort studies (12–27 uteri) within this group noted higher rates (59–100%) of inactive endometrium (tubular glands with cuboidal epithelium with low nucleo-cytoplasmic ratio and compact stroma) compared to the two larger studies (94 and 112 uteri) in which up to 49–65% of specimens had proliferative endometrium (glandular proliferation lined with stratified columnar epithelium and high nucleo-cytoplasmic ratio with a large number of mitotic figures and cystically dilated glands), with inactive endometrium being the second most common. The lack of secretory endometrium is in line with early data showing high rates of ovulatory suppression and thus lacking progestins [Reference Taub, Ellis and Neal-Perry11].

Only one study has evaluated estrogen and progesterone receptor expressivity in the uteri on testosterone [Reference Loverro, Resta and Dellino6]. It found a mean glandular expression of 54% estrogen receptors (ERs) and 59% progesterone receptors (PgRs) and 24% AR expressivity with low cellular activity. In the same small study, receptor expressivity in the stroma of estrogen and progesterone was 40% while AR expression was higher at 39%.

Endometria across all studies were generally found to be thin (<4 mm) [Reference Grimstad, Fowler and New7,Reference Khalifa, Toyama, Klein and Santiago10]. This is in line with rapid onset of amenorrhea in the majority (85%) of patients [Reference Deutsch, Bhakri and Kubicek12]. Proliferative endometrium prevalence does not change with longer testosterone usage, higher BMI, or older age [Reference Grimstad, Fowler and New7]. Abnormal uterine bleeding on supraphysiological testosterone was not found to be associated with thicker endometrial linings or a greater likelihood of proliferative activity (as compared to inactive endometria) [Reference Grimstad, Fowler and New7].

Rarer cases of endometrial hyperplasia without atypia have been seen in the large cohort studies, with only one cohort having a single case of focal adenocarcinoma, suggesting that while the incidence does not appear to be increased, it is still present in persons on testosterone [Reference Grimstad, Fowler and New7]. This data, however, has limitations, as some patients may undergo hysterectomy before hyperplasia or malignancy occur. As increasing numbers of patients remain on supraphysiological androgens for their lifetime and do not undergo hysterectomy, longitudinal studies will be beneficial to understanding risk. Until then, continuing routine age-appropriate gynecological care is recommended.

Common endometrial pathology continues to be found on exogenous testosterone including polyps and adenomyosis [Reference Shim, Laufer and Grimstad13].