Ovarian, breast, and metabolic

changes induced by androgen

treatment in transgender men
Paul Pirtea, M.D.,a Jean Marc Ayoubi, M.D., Ph.D.,a Stephanie Desmedt, M.D., Ph.D.,b
and Guy T’Sjoen, M.D., Ph.D.c
a

de Medicine Paris Ouest
Department of Obstetrics and Gynecology and Reproductive Medicine, Hospital Foch – Faculte
(UVSQ), Suresnes, France; b Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; and
c
Department of Endocrinology and Center for Sexology and Gender, Ghent University Hospital, Ghent, Belgium

Gender-affirming hormone therapy (GAHT) is often provided to transgender people. In this review of the literature, the current knowl-
edge of ovarian, breast, and metabolic changes (body composition, insulin resistance, bone density, cardiovascular risk factors such as
lipids, blood pressure, and hematocrit) observed following GAHT in adult transgender men is discussed.
A body of literature concurs to describe that long-term androgen therapy in transgender men exerts atrophic effects on the breast.
There is currently no evidence of an increased risk of breast cancer. Long-term testosterone treatment induces ovarian effects that
become visible after 6 months of therapy. These changes consist of both macroscopic and microscopic alterations of ovarian
morphology that mimic the typical ovarian aspect encountered in women with polycystic ovary syndrome but without an effect on
antral follicle count. Metabolic effects of long-term androgen treatment in transgender men put them at par with cisgender men in terms
of lipid profile, insulin resistance, and overall mortality. Body composition changes as desired after testosterone administration in most
transgender men, and insulin resistance decreases with virilization. There are no detrimental effects on bone mineral density. Cardio-
metabolic risk and morbidity data are currently reassuring, even if certain studies show conflicting results. An increase in blood pressure
and a decrease in high-density lipoprotein cholesterol have been reported as risk factors, whereas polycythemia is rare and treatable.
Most available data are observational and based on biochemical markers instead of the more direct measures of cardiovascular damage.
An explanation for these observed changes is mostly lacking. Psychological stress and lifestyle factors are often forgotten in a much
needed integrated approach. (Fertil SterilÒ 2021;116:936–42. Ó2021 by American Society for Reproductive Medicine.)
Key Words: Androgen treatment, gender-affirming hormone therapy (GAHT), gender-affirming surgery (GAS), metabolic changes

DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33424

G
ender dysphoria, a dissociation apy as a part of GAHT on ovaries, breast include all research articles addressing
between the sex assigned at tissue, and metabolism. the possible differences in results. The
birth and an inner conviction research database scanned the headers,
of belonging to another particular METHODS abstracts, and main texts for the key
gender, is encountered in approxi- This was a narrative review of published words. Moreover, a manual investiga-
mately 0.6% of individuals worldwide data on the ovarian, breast, and meta- tion of the references cited in the selected
(1). Gender-affirming measures, such bolic changes induced by androgen articles was thoroughly conducted.
as gender-affirming hormone therapy treatment in transgender men. The liter- The literature search was per-
(GAHT) and gender-affirming surgery ature search was conducted on May 21, formed independently by all four au-
(GAS), are available for those undergo- 2021, via PubMed, covering all publica- thors (P.P., J.M.A., S.D., and G.T.) and
ing a transition process. In the present tions in the English language. We used then cross-checked. All authors read
article on transgender men, we have ‘‘transgender men’’ and ‘‘gender affirm- the full text of all relevant articles and
discussed the effects of androgen ther- ing hormone therapy’’ as key words to produced a list of eligible articles that
was further reduced to those included
in the present review.
Received July 5, 2021; revised July 27, 2021; accepted July 28, 2021; published online September 2, Specific exclusion criteria were
2021.
P.P. has nothing to disclose. J.M.A. has nothing to disclose. S.D. has nothing to disclose. G.T. has studies not written in English. Book
nothing to disclose. chapters, case series, review articles,
Correspondence: Paul Pirtea, M.D., Department of Obstetrics and Gynecology and Reproductive Med-

de Medicine Paris Ouest (UVSQ), 82 rue de grenelle, Suresnes 92150,
icine, Hospital Foch – Faculte and abstracts were excluded. Refer-
Paris, France (E-mail: paulpirtea@gmail.com). ences were handled using the Endnote
program (version X9 for MacOS, New
Fertility and Sterility® Vol. 116, No. 4, October 2021 0015-0282/$36.00
Copyright ©2021 American Society for Reproductive Medicine, Published by Elsevier Inc. York, NY).
https://doi.org/10.1016/j.fertnstert.2021.07.1206

936 VOL. 116 NO. 4 / OCTOBER 2021

 Fertility and Sterility®

RESULTS PCOS-like ovaries (13). Studying the texture profile of ovaries

Ovarian Effects of GAHT of transgender men, De Roo et al. (14) documented a stiffer
ovarian cortex in ovaries exposed to GAHT. Several reports
On average, the ovaries produce 0.7 mg of testosterone per 24
support the concept that long-term exposure to high doses
hours in women during the reproductive years. This is more
of exogenous testosterone induces morphologic features of
than the production of estradiol—0.05–0.5 mg/24 h, depend-
PCOS (15). These findings generated the concept that andro-
ing on the phases of the menstrual cycle—but 10 times less
gens may constitute the primary cause of ovarian alteration
than the production of testosterone observed in adult cisgen-
encountered in PCOS (15, 16).
der men. Ovarian androgens stimulate the growth and devel-
More recently, however, Ikeda et al. (17) challenged this
opment of follicles (2, 3). Several animal studies have
view on the effect of GAHT and its role in inducing PCOS-
suggested that androgens influence folliculogenesis by hav-
like effects on the ovaries. These authors indicated that
ing proatretic effects on growing follicles and antiapoptotic
high-dose androgen therapy causes pathognomonic changes
action on granulosa cells (4–6).
to the ovarian cortex and stroma that resemble Stein-
The relationship between polycystic ovary syndrome
Leventhal syndrome but does not induce full polycystic ovary
(PCOS)—a common functional ovarian disorder—and andro-
morphology (17). Compared with controls, cycling women
gens is complex. First, androgen excess has long been recog-
receiving no hormone therapy, the ovaries of treated trans-
nized as an emblematic feature of PCOS and the associated
gender men had a thicker ovarian cortex, more hyperplastic
disorder of polycystic ovary morphology (7, 8). Second,
collagen, ovarian stromal hyperplasia, and stromal luteiniza-
ovarian wedge resection, a procedure known to restore men-
tion. Yet, the number of primordial, early follicles—primary,
strual cyclicity by removing a fragment of ovarian tissue in
preantral, and early antral—was similar in the two groups,
women with PCOS, is associated with a sharp decline in circu-
contrary to the emblematic findings made in polycystic
lating testosterone levels (9). Conversely, 3-month treatment
ovaries (17).
with a long-acting gonadotropin-releasing hormone agonist,
According to a recent report, 50% of transgender men
which completely blocks the ovarian production of testos-
who were questioned before GAHT expressed the desire to
terone, does not restore ovarian cyclicity (10). Hence, ovarian
have children (18) and, according to another study, 76%
factors other than testosterone are involved in the pathophys-
had thought about preserving their fertility before undergoing
iology of PCOS.
the transition process (19). These considerations led to
The impact of high doses of testosterone treatment
questions regarding whether oocyte quality is affected by
administered as a part of GAHT in transgender men has
prolonged testosterone treatment. A recent retrospective
been studied by different investigators. In a seminal study
case-control study reported unaltered assisted reproductive
in 1991, Pache et al. (11) reported an extensive analysis of
technology outcomes in transgender men who had received
ovarian morphology observed in 17 transgender men taking
(and stopped) testosterone therapy, despite the fact that
GAHT for 21 months on average before undergoing GAS.
higher total doses of gonadotropins were needed during the
All but 4 transgender men—13 in total—had regular cycles
ovarian stimulation process (20). In line with these findings,
prior to taking hormone therapy. Thirteen cisgender women
a recent study on ovarian histology and morphology of
undergoing surgery for nonendocrine reasons served as con-
cumulus-oocyte complexes in transgender men revealed
trols. In both groups, ovaries were measured and bisected and
normal morphology of follicular complexes (21), which
their appearance was analyzed. Microscopically, ovaries were
were similar to that previously reported in fertile, cisgender
assessed for collagenization and thickness of the cortex, the
women (22). Moreover, these authors also reported a good
presence of primordial follicles, the number and size of antral
in vitro maturation rate of approximately 34% in cumulus-
follicles, and stromal morphology—hyperplasia and luteiniza-
oocyte complexes retrieved from transgender men, a finding
tion (11). Macroscopically, one thirds of the ovaries of trans-
similar to that reported by De Roo et al. (23) in cisgender
gender men appeared grossly enlarged. The mean ovarian
women.
volume was 7.6
3.6 mL, which was significantly larger
than that of controls (2.7
1.4 mL; P< .0001) (11). Micro-
scopically, all but one ovary in transgender men exhibited a
thickened, collagenized cortex. The mean thickness was 817 Breast Effects of GAHT

300 mm, which was significantly larger (P< .001) than Studies on breast tissue exposed to long-term androgen ther-
that of controls (241
85 mm) (11). The number of antral fol- apy have reported generally fibrous transformation. These al-
licles found in transgender men (27
13) was larger than that terations range from intralobular fibrous transformation of
found in controls (11
5). Moreover, multiple cystic atretic the stroma to extralobular fibrous alteration of the stroma
follicles were seen in the ovaries of transgender men. and lobular atrophy (24–26). Burgess and Shousha (24)
Other investigators looking at ovarian histology in trans- reported no specific effect of long-term androgen administra-
gender men receiving GAHT confirmed the findings reported tion on breast tissue but rather a marked reduction of glan-
by Pache et al. (11) by describing ovarian architecture as hav- dular tissue and an extension of fibrous connective tissue in
ing macroscopic and microscopic characteristics of polycystic 93% of the studied cases. Other modifications reported in
ovaries (12). Moreover, androgenized in vivo models, such as the breast tissue of transgender men included involuted lobu-
those encountered in patients with congenital adrenal hyper- loalveolar structures embedded in dense, hyalinized fibrous
plasia or virilizing tumors, have also been reported to exhibit tissue. In addition, severe lobular atrophy was observed in

VOL. 116 NO. 4 / OCTOBER 2021 937

VIEWS AND REVIEWS
7% of the cases, with mildly atrophic or stromal changes
noted in 86% and 7% of cases, respectively (12). Fibrocystic
lesions were reported in 34 participants, and 2 adenofibromas
were observed. None of the cases had atypical hyperplasia, in
situ breast carcinomas, or features of gynecomastia. No intra-
ductal papilloma or papillomatosis was observed.
Some authors reported a link between testosterone levels
and the risk of developing breast cancer in postmenopausal
women (27, 28). Recent findings have shown that epithelial
hyperplasia was associated with increased androgen concen-
trations; however, no significant increase in the incidence of
breast carcinoma was found (29). These findings are consis-
tent with those of reports emanating from women with hyper-
androgenism, as it is notably the case in patients with PCOS or
women affected by virilizing tumors. Thus, androgen therapy
given to transgender men as a part of their GAHT does not
appear to increase the risk of developing malignant lesions
of the breast (30).
Body Composition
Androgen treatment is used to induce virilization in trans-
gender men, including changing their physical contours
with increased muscle mass (31). Gender-affirming hormone
therapy commonly overshoots the effects on muscle mass
commonly seen in cisgender men with a significant increase
in creatinine levels compared with cisgender men. This in-
crease in creatinine levels directly correlates with serum
testosterone levels and reflects the increase in muscle mass
(32, 33). A significant increase in muscle mass observed in
transgender men receiving GAHT results in a 15% increase
in thigh volume (34).
An Australian cross-sectional study compared trans-
gender men (n ¼ 43) receiving intramuscular testosterone un-
decanoate with age-matched cisgender women (n ¼ 30). In
this study, transgender men had a mean gain in lean mass
of 7.8 kg (P< .001; confidence interval [CI], 4.0–11.5) with a
significantly higher android-to-gynoid fat ratio (35).
Similarly, an increase in waist-to-hip ratio was observed in
the Belgian European Network for the Investigation of Gender
Incongruence (ENIGI) cohort of 53 transgender men who
received testosterone undecanoate every 3 months. Similar
results were observed in another cross-sectional study of 50
transgender men receiving long-term testosterone treatment
after GAS (36, 37).
There was no difference in insulin resistance and over-
all fat mass observed in transgender men (n ¼ 43) receiving
GAHT and age-matched cisgender women (35). An increase
in lean mass without an increase in body mass index
(BMI) was also observed in the Belgian cohort described
by Auer et al. (38). Suppakitjanusant et al. (39) confirmed
that the BMI remained stable during androgen therapy
but did not describe lean body mass. Other studies found
an increase in BMI, attributed to an increase in muscle
mass (33, 40–43). Overall, an increase in lean mass is
observed with testosterone therapy with a reduction in
body fat (31, 36, 40, 43–46).
Long-term changes in body composition seem to persist.
A cohort of 50 transgender men who had undergone GAS
938
showed a reduction of approximately 30% in body fat with
GAHT and an approximately 10% increase in lean body
mass compared with cisgender female controls after a mean
follow-up of 9.9 years (37). A randomized trial by Pelusi
et al. (43) showed a significant increase in lean body mass
measured by dual energy x-ray absorptiometry, with a signif-
icant increase in body weight and BMI after 54 weeks of treat-
ment. There was no difference among the various testosterone
preparations used.
However, in an observational cohort subanalysis within
the ENIGI study, 19 (20.2%) of the 94 transgender men
showed no change in lean body mass at 24 months of
follow-up. The lack of change in lean body mass was associ-
ated with an increase in mean luteinizing hormone levels and
lower serum testosterone levels. This finding suggested a
dose-response effect, with the failure of clinical change in
body composition likely being the reflection of insufficient
hormone therapy dosages. Hence, GAHT should be individu-
alized on the basis of its effects rather than by simply applying
standardized dosing of testosterone therapy (47).
Insulin Resistance
The effect of sex hormones on insulin sensitivity in cisgender
people is not yet fully understood. Increased levels of testos-
terone in cisgender women, such as in cases of PCOS, are
associated with increased insulin resistance. However,
increased insulin resistance is also observed in men with hy-
pogonadism. In these men, testosterone substitution is associ-
ated with a slight improvement in the degree of insulin
sensitivity (48, 49). Polderman et al. (50) investigated the
effect of testosterone treatment in transgender men in the
early 1990s. Glucose utilization decreased with physiologic
levels of insulin during a three-step hyper insulinemic-
euglycemic clamp with stable endogenous glucose
production. The authors concluded that insulin resistance
increases with testosterone therapy (50).
Insulin sensitivity is addressed by the homeostatic model
assessment of insulin resistance formula using the product of
fasting glucose and insulin levels. Auer et al. (45) found a
reduction in fasting insulin levels in transgender men with
a decrease in homeostatic model assessment of insulin resis-
tance. These findings were confirmed in an observational
cohort study of 35 transgender men within the ENIGI trial
(45, 46). A trend toward decreasing fasting glucose levels
was observed in 11 transgender men treated in Italy with
testosterone esters every 2–4 weeks (P ¼ .06; n ¼ 11) (32).
This was also confirmed in a Dutch cohort of 17 transgender
men treated with intramuscular testosterone esters (250 mg)
every 2 weeks. After 12 months of treatment, fasting glucose
levels decreased compared with baseline levels (5.0
0.5
mmol/L vs. 4.6
0.3 mmol/L) (51).
Compared with cisgender women, there was no differ-
ence in insulin resistance in transgender men with GAHT
(35, 52, 53). These findings are consistent with those of the
study by Shadid et al. (46), in which no difference in incretin
response was observed in transgender men after 12 months
of GAHT. In a Belgian cohort of 20 transgender men, fasting
glucose and insulin levels remained stable with GAHT (38).
VOL. 116 NO. 4 / OCTOBER 2021

Likewise, there was no significant change in glycated hemo-
globin levels (54).
Berra et al. (55) and Auer et al. (45) found a significant
decrease in adiponectin levels in transgender men after 6
months of testosterone therapy. An Italian observational
study detected significantly lower adiponectin levels in trans-
gender men than that in transgender women. However, there
was no difference between adiponectin levels in transgender
men and matched cisgender women (53). A decrease in adipo-
nectin level may be associated with increased cardiovascular
risk, as adiponectin is involved in the pathogenesis of athero-
sclerosis. Further studies are needed to investigate the role of
GAHT in adiponectin levels. Ghrelin and leptin levels were not
different in transgender men compared with transgender
women and control groups (cisgender men and women) (53).
Bone Density
Contrary to earlier beliefs, we now know that estrogens pro-
duced by the aromatization of androgens are the primary
regulator of bone homeostasis in adult men. Testosterone
and estradiol levels must decline substantially to impact the
skeleton (56). In transgender men, bone metabolism transito-
rily increases at the initiation of testosterone therapy; howev-
er, no major changes are ultimately found in bone density
(57). Following long-term testosterone therapy, larger cortical
bone size was observed in transgender men compared with
that in age-matched cisgender women (57). Short-term and
long-term studies have shown that hormonal treatment
does not have detrimental effects on bone mineral density
in transgender men (58). As mentioned earlier, bone mineral
density is maintained by the positive effect of estradiol pro-
duced by the aromatization of testosterone, together with
the effects of testosterone on body composition (59). In addi-
tion, a more recent study concluded that bone mineral density
increased in transgender persons after 1 year of hormonal
treatment.
Cardiovascular Risk Factors
Lipid parameters differ between genders. It is well-known that
the male gender is associated with higher levels of total
cholesterol, triglycerides, and low-density lipoprotein (LDL)
cholesterol and lower levels of high-density lipoprotein
(HDL) cholesterol. Testosterone substitution therapy in
testosterone-deficient men tends to decrease blood pressure
and improve the lipid profile (60). However, in transgender
men, supplemental testosterone is given in nonhypogonadal
patients.
The effect of testosterone therapy on lipid profile and
blood pressure in transgender men has been studied in multi-
ple cohorts. Lipid levels were not affected by testosterone
therapy (1000 mg of testosterone undecanoate every 3
months) in a Belgian observational study (38). Similar find-
ings were observed in other observational studies with stable
triglycerides and LDL cholesterol levels with variable doses
and length of testosterone treatment (40, 54).
VOL. 116 NO. 4 / OCTOBER 2021
Fertility and Sterility®
In a prospective, observational study conducted in 53
transgender men (ENIGI), triglycerides (36.9%; 95% CI,
29.8–44.1), total cholesterol (4.1%; 95% CI, 1.5–6.6),
and LDL cholesterol (13.0%; 95% CI, 9.2–16.8) levels
increased after 1 year of intramuscular testosterone therapy.
Likewise, HDL cholesterol levels decreased (10.8%; 95%
CI, 14.0 to 7.6) (36). Similar trends were observed in
retrospective analyses, with a variable impact on triglyceride
levels (33, 36, 41, 45, 61, 62). Overall, a meta-analysis by
Makara et al. that included 20 studies (n ¼ 1500) confirmed
the increase in LDL cholesterol and triglycerides levels and
the decrease in HDL cholesterol level with GAHT compared
with the respective baseline levels (63).
There is firm evidence that increasing levels of LDL
cholesterol are associated with increased cardiovascular
risk. Therefore, if LDL levels increase with GAHT, transgender
men may be at higher risk of cardiovascular disease. A recent,
multicenter, prospective trial comprising 165 transgender
men (ENIGI) investigated the impact of initiating GAHT on
cardiovascular risk using the 30-year Framingham cardiovas-
cular disease (CVD) risk estimate. After the initiation of
testosterone treatment, the risk of hard CVD events based
on the Framingham risk calculation increased (þ0.68%;
95% CI, 0.21–1.16) after 2 years. Notably, transgender men
already had a higher long-term CVD risk at inclusion
compared with the estimated optimal CVD risk in the control
group (cisgender women) (62). Nota et al. (64) found a signif-
icantly higher occurrence of myocardial infarction in trans-
gender men undergoing testosterone treatment than that in
cisgender women (standardized incidence ratio, 3.69; 95%
CI, 1.94–6.42) without a significant increase in venous throm-
boembolism or stroke occurrence. The risk of myocardial
infarction in transgender men was not increased compared
with that in cisgender men. Unfortunately, there was no
adjustment for smoking or psychological stressors (64).
Further research in larger cohorts with a longer follow-up is
needed to establish the cardiovascular risk in transgender
men.
In most cohorts, no difference in blood pressure was
observed, and there was no significant impact of hormone
levels on blood pressure (33, 40, 45). However, diastolic blood
pressure slightly increased with GAHT (2.5%; 95% CI, 0.6–
4.4) in a prospective, observational study within ENIGI.
Observational data in 35 transgender men showed a signifi-
cant increase in diastolic and systolic blood pressure after
the initiation of long-acting testosterone undecanoate every
3 months (41, 65). This was clinically relevant in two patients
in whom testosterone treatment had to be temporarily inter-
rupted (41). The change in systolic and diastolic blood pres-
sure was clinically relevant in two female-to-male
transsexuals, who discontinued testosterone administration
because hypertension developed in them after the first injec-
tion, although they had shown no hypertension at baseline.
Similar results were observed in a Japanese cohort after initi-
ation of biweekly intramuscular injections of testosterone es-
ters with an increase in systolic blood pressure (110.4
9.4
mm Hg vs. 117.4
10.2 mm Hg; P< .01) and diastolic blood
939
VIEWS AND REVIEWS
pressure (64.6
6.9 mm Hg vs. 68.6
8.4 mm Hg; P< .02) in
transgender men undergoing testosterone treatment (n ¼ 48)
compared with those in untreated transgender men (n ¼ 63)
(66). A rise in hematocrit levels was seen in a large cohort
(n ¼ 192) of transgender men within ENIGI after 3 months
of GAHT (þ2.7 Hct%; 95% CI, 1.94–3.29) with a more pro-
nounced increase in patients receiving testosterone esters
compared with those receiving testosterone undecanoate
(67). There is, however, little good literature on this topic.
We have already mentioned the large prospective study by
Defreyne et al. (67). Polycythemia depends on the definition
used; however, in this cohort, there were low rates of erythro-
cytosis, with a maximum measured hematocrit of 54.0%, and
none of the transgender men experienced any thromboem-
bolic events during follow-up. They reported 11.5% hemato-
crit >50% during the investigation period (22 of 192
transgender men). Therefore, regular laboratory follow-up is
recommended after initiation of GAHT, with dose or interval
adjustments when needed or investigation of other causes.
Observational studies showed no increase in mortality
among transgender men undergoing GAHT compared with
that in the general population (68). In a Dutch cohort
comprising 365 transgender men with a mean follow-up
time of 18.8 years, only six transgender men were aged
R65 years; therefore, no firm conclusions can be drawn
about transgender men in older age groups (69).
CONCLUSION
A large body of literature concurs to describe that long-term
androgen therapy in transgender men—GAHT—primarily ex-
erts atrophic effects on the breast during the process, leading
to sex reassignment surgery. There is no evidence of an
increased risk of breast cancer. In parallel, long-term exoge-
nous testosterone exposure induces changes in the ovarian
structure that start becoming visible after 6 months of ther-
apy. These changes consist of macroscopic and microscopic
alterations of ovarian morphology that mimic some but not
all typical ovarian characteristics encountered in women
with PCOS.
General and metabolic effects of long-term androgen
treatment as typically taken by transgender men put
them at par with cisgender men in terms of lipid profile, in-
sulin resistance, and overall mortality. Body composition
changes as desired after testosterone administration in
most transgender men, and insulin resistance decreases
with virilization. There are no detrimental effects on bone
mineral density.
Cardiometabolic risk and morbidity data are currently re-
assuring, even if available studies show conflicting results.
An increase in blood pressure and a decrease in HDL choles-
terol have been reported as risk factors, whereas polycythemia
is rare and treatable. However, available research is weak,
methodologically speaking. Most available data are observa-
tional and based on biochemical markers instead of the more
direct measures of cardiovascular damage. Finally, factors
such as psychological stress and lifestyle characteristics are
940
often forgotten in most available studies, a fact that under-
scores the much needed integrated approach.
DIALOG: You can discuss this article with its authors and
other readers at https://www.fertstertdialog.com/posts/
33424
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