The Journal of Clinical Endocrinology & Metabolism, 2023, 108, e191–e192

https://doi.org/10.1210/clinem/dgac757
Advance access publication 30 December 2022
Commentary

Are Adrenal Androgens Altered by Gender-Affirming

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Hormone Therapy?
Tamar Reisman1,2 and Joshua D. Safer1,2
1
Mount Sinai Center for Transgender Medicine and Surgery, New York, NY 10001, USA
2
Division of Endocrinology, Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Correspondence: Joshua D. Safer, MD, FACP, FACE, Mount Sinai Center for Transgender Medicine and Surgery, Icahn School of Medicine at Mount Sinai, 275
7th Avenue - 15th Floor, New York, NY 10001, USA. Email: jsafer0115@gmail.com.
Key Words: transgender, androgens, adrenal androgens, transgender women, estrogens, gender affirming hormone therapy
Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; GAHT, gender-affirming hormone therapy; LH, Luteinizing hormone;
hCG, human chorionic gonadotropin.

Testosterone suppression is a central tenet of gender-affirming
hormone therapy (GAHT) in transgender women. Feminizing
hormone regimens typically combine a testosterone-suppressing
agent with estradiol to induce breast development, fat redistri­
bution, and decreased terminal hair growth. Typical approaches
to feminizing therapy attempt to shift testosterone levels from
the typical physiologic male range (300-100 ng/dL) to the
typical physiologic female range (<50 ng/dL) (1, 2). However,
at present, the implications of adrenal androgen levels on
gender-affirming feminization are murky at best.
Adrenal androgens contribute significantly to the hormonal
milieu of cisgender women. Excessive adrenal androgen con­
centrations are associated with cystic acne, hirsutism, andro­
genic alopecia, irregular menstrual periods, and even
clitoromegaly. What happens to adrenal androgens during
feminizing GAHT?
Collet et al’s (1) data suggest feminizing GAHT suppresses
both testosterone and adrenal androgens, with both levels sta­
bilizing at 3 months and 1 year respectively after treatment
was initiated. This stability in their analysis was maintained
following gonadectomy, even after the cessation of the ad­
junct antiandrogen, cyproterone acetate.
These data confirm what other studies to date have found,
namely that testosterone levels plateau and remain stable fol­
lowing initiation of feminizing hormone therapy (3). The con­
comitant decline in adrenal androgens is fascinating, and
highlights the notion that the control of adrenal androgens
is not well established.
Adrenal androgens include dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate (DHEAS), Δ5-androstene-
3β,17β-diol (androstenediol), 11β-hydroxyandrostenedione, and
androstenedione. DHEA and DHEAS have cortisol axis control
and are adrenocorticotropic hormone dependent (4). Why should
adrenal androgens be affected by feminizing hormone therapy
at all?
It may be pertinent that Collet et al’s study participants were
treated with GAHT regimens containing cyproterone acetate
for their adjunct antiandrogen component. Cyproterone acet­
ate is a progestin that acts as an androgen receptor antagonist
peripherally (5). Moreover, its feedback on the hypothalamus
and pituitary acts to suppress testosterone production. Would
Collet et al’s findings differ had any other adjunct antiandro­
gen, for instance, spironolactone, been used? While cyproter­
one acetate is commonly used in GAHT regimens in Europe,
it is worth noting that it is not available in the United States
due to concerns about hepatotoxicity. Instead, spironolactone
is the most frequently used antiandrogen (2, 5). Cyproterone
acetate notably is associated with an increase in prolactin,
which is not the case for spironolactone (6). The observation
that adrenal androgen levels remained stable after cyproterone
acetate was discontinued suggests that the cyproterone acetate
was not solely responsible for stabilizing the adrenal androgens.
Nevertheless, it would be interesting to test for adrenal andro­
gens in cohorts where an antiandrogen other than cyproterone
acetate is used.
One distinct possibility is that the participants’ adrenal an­
drogen levels would have trended down over time regardless
of GAHT regimen, as adrenal androgens have been observed
to decline with age (7). However, if age alone explained the de­
cline in adrenal androgens, they would not be expected to
plateau at 1 year.
For many laboratories, the standard reference ranges for
DHEA and DHEAS are lower for women than they are for
men (8). Could exogenous estrogen use, and subsequent go­
nadotropin suppression explain the ongoing suppression of
adrenal androgens both before and after gonadectomy?
Luteinizing hormone (LH)/human chorionic gonadotropin
(hCG) receptors are present in the zona reticularis and zona
fasciculata. The LH/hCG receptors are upregulated in gona­
dectomized mice (9, 10). Moreover, transgenic mice express­
ing bLHβ-CTP (a chimeric protein derived from the
beta-subunit of bovine luteinizing hormone) have observably
enlarged adrenal glands with increased adrenal steroid hor­
mone production (11). These findings, together with the

Received: 7 November 2022. Editorial Decision: 27 December 2022. Corrected and Typeset: 17 January 2023
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:
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e192
observation that adrenal steroid levels are elevated in women
with polycystic ovarian syndrome, all point to a role for LH in
adrenal androgen production. Unfortunately, Collet et al did
not report gonadotropin measurements, which may have pro­
vided some insight into the mechanism of action.
Because elevated adrenal androgen levels can result in viril­
ization, it follows that adrenal androgen suppression may be a
goal of care in transfeminine patients. Indeed attempts have
been made to measure relative androgenic potency for some
adrenal androgens (12). At this time, there are no recom­
mended target values for adrenal androgen levels in trans­
gender women, although it may be clinically relevant
information.
Disclosures
The authors have no disclosures.
Data availability
Any data in the authors’ possession is available upon request.
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