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REVIEW ARTICLE Open Access
Induction and Maintenance of Amenorrhea
in Transmasculine and Nonbinary Adolescents
Jeremi M. Carswell*and Stephanie A. Roberts
Abstract
The treatment of persistent uterine bleeding in those patients who identify as transmasculine or nonbinary is
often straightforward, but can be difficult in a subset of patients. This article reviews the physiology of the normal
menstrual cycle and the hormonal influences on the endometrium, and then explores options for the treatment
of persistent bleeding for people both already on testosterone and for those who are either not ready for or who
do not desire testosterone.
Keywords: secondary amenorrhea; progestins; endometrium; uterine bleeding; gonadotropin releasing hormone
analogs; testosterone
Introduction
Uterine bleeding can be a source of distress in those
for whom their gender identity is incongruent. Clinical
experience shows that depressive symptoms and self-
harming behaviors may peak during menstrual bleed-
ing. Menstrual cycling is typically suppressible with
hormonal therapy, although in a significant proportion
of individuals it may persist. This review article ad-
dresses the most common treatment options for persis-
tent uterine bleeding.
A normal menstrual cycle requires an intact hypo-
thalamic–pituitary–gonadal axis and adequate estrogen
and progesterone at the level of the endometrium. The
hypothalamus secretes gonadotropin-releasing hormone
(GnRH) in a pulsatile fashion; this causes release of lutei-
nizing hormone (LH) and follicle-stimulating hormone
(FSH) from the pituitary gland, which promote ovarian
follicle development and estradiol secretion. At the level
of the endometrium, estrogen’s primary action is to pro-
mote growth while progesterone limits proliferation by
stabilizing the glands and halting mitotic division.
1
Local
uterine factors whose contributions are less clearly de-
fined, including prostaglandins, nitric oxide, and others,
are likely responsible for the variability in flow, volume,
and duration of bleeding.
2–4
The rapid decline in both
progesterone and estrogen in the absence of a fertilized
egg is the trigger for shedding of the lining of the uterus,
but only if estrogen has been present.
1
The anovulatory
uterus may be susceptible to erratic bleeding, which is
thought to be due to insufficient levels of progesterone.
When considering hormonal manipulation to halt
menstrual cycling it is important to obtain a menstrual
history. A typical menstrual cycle is between 25 and
35 days, although just after menarche the range may be
from 21 to 45 days.
4
Endometria of patients with menor-
rhagia may require a high dose, local form of progesto-
gen (e.g., intrauterine device), whereas normally cycling
patients may respond to a continuous low-dose oral pro-
gestin.
2
Additionally, when counseling patients it is crit-
ical to remember that there will be individual differences,
even between people with regular menstrual cycles. Per-
sistent bleeding despite adequate therapy should prompt
consideration of alternate etiologies, including coagula-
tion defects, thyroid disease, structural abnormalities
(e.g., endometrial polyps), infection, trauma, and/or
pregnancy.
5
Department of Medicine, Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts.
*Address correspondence to: Jeremi M. Carswell, MD, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, E-mail:
jeremi.carswell@childrens.harvard.edu
ªJeremi M. Carswell and Stephanie A. Roberts 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Transgender Health
Volume 2.1, 2017
DOI: 10.1089/trgh.2017.0021
Transgender
Health
195
We typically avoid giving any form of estrogen, as most
often this is the hormone that most patients would like
to avoid, however, the use of estrogen combined with pro-
gesterone is a highly effective way to stabilize the endome-
trium and avoid breakthrough bleeding; it remains a
viable option for those who are not averse to taking it.
Testosterone
For those adolescents who have met criteria for gender-
affirming hormone use, testosterone (T) is typically highly
effective for induction and maintenance of amenorrhea
within 6 months of its initiation, although may be effec-
tive as early as 1 month.
6
Greater than 90% of transmen
using either biweekly intramuscular or weekly subcuta-
neous forms of testosterone achieve amenorrhea within
6 months (Table 1).
6,7
Testosterone acts directly on the endometrium, caus-
ing both endometrial and vaginal atrophy as shown by
examination of the endometria of transmen who had
been on androgen therapy for at least 6 months.
8
Histo-
logical analysis of endometrial samples of transmen on
testosterone for at least 1 year is similar to that of post-
menopausal women. Both groups expressed similar lev-
els of Ki-67, a marker of endometrial proliferation.
9
There is, however, controversy as some studies have
shown an active endometrium and hypertrophic myo-
metrium in some individuals.
10
While the effects of testosterone on the uterus itself
are fairly clear, less is understood about its effects on
the hypothalamus and pituitary. Reports of unplanned
pregnancies while on testosterone support a lack of in-
hibition of ovulation in at least some individuals.
11
There does appear to be a dose-dependent amenor-
rheic response to T, which supports a trial of increased
dose or frequency in cases of persistent bleeding. An
increase of dose or dose frequency was shown by
Nakamura et al. to be effective in inducing secondary
amenorrhea.
6
The recommended therapeutic range
for testosterone levels is 350–700 ng/dL.
12
However in
conditions in which the sex hormone binding globulin
levels may be low (e.g., obesity and polycystic ovarian
syndrome) total testosterone levels may appear subther-
apeutic while free testosterone levels are in the normal
range for adult males. Current guidelines recommend
monitoring total testosterone levels only.
12
Progestogens
Progestogens, comprised of natural, micronized proges-
terone and synthetic progestins, are an important class
of medications for induction of amenorrhea in the trans-
masculine and nonbinary adolescent. They may be con-
sidered in the postmenarchal adolescent not yet ready
for or desiring of masculinizing hormones, but may be
less effective in inducting amenorrhea than combined
oral contraceptive pills that contain estrogen. Progester-
one and progestins are available in different formulations,
including oral, injectable, implantable, and intrauterine
(Table 2). In our practice we typically start with norethin-
drone or norethindrone acetate.
Progestogens exert most of their effects peripherally at
the level of the endometrium primarily through changes
in angiogenesis. Systemic forms at higher doses may also
suppress the hypothalamic–pituitary–gonadal axis by
inhibiting GnRH activity
13
and therefore induce hypo-
thalamic amenorrhea. Both forms counteract the effects
of estrogen by inhibiting the proliferation of the endo-
metrium and reducing the mitotic rate of the glands
and stromal tissue,
14–16
through reduction of the estro-
gen receptors on the glands.
17
In normally menstruating
women, exposure to a low-dose progestogen may cause
Table 1. Select Testosterone Formulations Available in the United States
Testosterone
formulation How supplied Typical adult dose Typical max dose Comments
Testosterone
cypionate
100 mg/mL (10 mL vial)
200 mg/mL (1 mL or 10mL vial)
100 mg q 2 weeks IM
50–80 mg weekly SQ
200 mg q 2 week (IM)
100 mg weekly (SQ)
Excipient is cottonseed oil, allergic
reaction possible
Testosterone
enanthate
200 mg/mL
5 mL vial (5 mL)
Same as above Same as above Excipient is sesame seed oil, allergic
reaction possible
Gel 1.62% (20.2 mg/pump press)
or 20.25 or 40.5 mg/packet
1% (25 or 50 mg/packet)
20.25–81 mg daily
25–100 mg daily
103.25 mg Q AM
100 mg Q AM
Must be applied to upper
shoulders/back. Beware of
contact transfer
Pellets Each pellet contains 75 mg
testosterone
4–6 pellets every
3–6 months
6 pellets Each pellet releases about 25 mg T;
may last from 3 to 6 months
Axillary gel Axillary gel
30 mg per pump
60 mg (2 pumps) q AM 90–120 mg
(3–4 pumps) q AM
Applied like deodorant
Patch 2 mg/24 h
4 mg/24 h
4 mg/24 h q PM 8 mg/24 h q PM May cut patches in half, 10% risk of
skin irritation
T, testosterone.
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196
disturbances in endometrial angiogenesis and cause low-
volume irregular bleeding.
2
Prolonged use typically leads
to endometrial atrophy.
18
Oral medroxyprogesterone
has been used historically to suppress the hypothalamic–
pituitary–gonadal axis and may be a more cost-effective
option in some areas compared with GnRH agonist
(GnRHa).
19
The progestin-only contraceptive pill nor-
ethindrone may inhibit ovulation in some women; al-
though up to 40% of cis-females have been reported to
continue ovulating.
20
Intrauterine levonorgestrel may
lead to partial suppression of ovulation, but thought to
act more locally at the endometrium.
21
Although ovula-
tion may be disturbed to some extent, estradiol levels are
normal limiting the concern for impact on bone health
compared with injectable medroxyprogesterone.
22
With any of the progestogens, irregular and unpre-
dictable bleeding is relatively common and may lead
to discontinuation of the agent, particularly in the
first few months of treatment. This is due to vascular
changes in the endometrium rather than hormonal
fluctuation.
23
Frequent and prolonged but light bleed-
ing occurs in a large percentage of patients.
1
When clas-
sified by histological samples (pseudodecidualization
and reduction of mitotic index), the most potent pro-
gesterone is medroxyprogesterone acetate.
24
There has,
however, been concern about the long-term use of
medroxyprogesterone acetate and bone health, first raised
by Cundy et al. who reported a significant decrease in
bone mineral density (6.6% at the femoral neck and
7.5% at the spine) compared with menopausal controls.
25
Other studies have supported this finding. In a large
population-based study in Washington, Scholes et al.
reported a 2.2% difference at the spine and 2.5% difference
at the femoral neck compared with premenopausal con-
trols. Eighteen to twenty-one year olds, however, had
the most impact to their bone mineral density, on average
10.5% lower compared with controls.
26
This was a cross-
sectional study and length of use ranged from 1 to 33
months. Consensus statements issued from the World
Health Organization, the American Society for Adolescent
Medicine, and others do not recommend avoidance of this
agent. They do recommend counseling on advantages and
disadvantages.
27–29
Adverse effects of progestins include bone health
concerns and androgenic effects of lower high-density
lipoprotein cholesterol, fluid retention, headaches,
and mood disturbance. Natural progesterones’ side ef-
fects are limited to fatigue and sedation
30–32
and should
be taken at bedtime. A major benefit to this class of
hormone is that there is no increased risk for thrombo-
embolic events; it is recommended for contraception by
the WHO even in individuals with a history of throm-
bosis and vascular disease.
33
For those minority of patients who are having con-
tinuous bleeding and are not averse to taking estro-
gen, a combination of micronized estrogen (Estrace
1.5 mg daily) for 25 days combined with continuous
low-dose micronized progesterone (100 mg daily)
Table 2. Select Progestogens Available in the United States
Active ingredient Trade names How supplied Dosing patterns Comment
Oral
Norethindrone Micronor
Camila
Deblitane
Heather
Jencycla
Jolivette
Sharobel
0.35 mg tabs Once daily ‘‘Mini-pill’’ for oral contraception.
Must be taken at same time of day
Norethindrone acetate Aygestin 5 mg tabs Once daily (2.5–15 mg daily) May titrate up to effect
Medroxyprogesterone
acetate
Provera 2.5, 5, 10 mg
tabs
Once or twice daily Dosing has ranged from 20 to
80 mg day
19
Micronized progesterone Prometrium 100, 200 mg 100–200 mg nightly Incipient contains peanut oil
Injectable
Medroxyprogesterone
acetate
Depo-Provera 150 mg/1 mL Deep IM injection into gluteal or
deltoid muscle q 12–14 weeks
Depo-SubQ
Provera 104
104 mg/0.65 mL Anterior thigh or abdomen q 12–14
weeks
Intradermal
Etonogestrel Implanon 68 mg single
capsule
Active for 3 years Breakthrough bleeding common
initially
Intrauterine
Levonorgestrel Mirena
Liletta
52 mg May be left in for 5 years Insert within 7 days of onset of
menstruation
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has been shown to control endometrial proliferation,
although this does not fully suppress mitotic activity.
14
This regimen may be more acceptable than a tradi-
tional combined oral contraceptive pill given continu-
ously, which will achieve the same result. In practice,
given its increased effectiveness over progestins in lead-
ing to menstrual suppression, a combined oral contra-
ceptive pill may be amenable to some patients and is
commonly used by some practitioners over progestins.
Oral contraceptive pills containing first- and second-
generation progestins have a higher androgenic profile
and lower risk of venous thromboembolism and may
be preferable preparations for this population com-
pared with oral contraceptive pills containing later gen-
eration of progestins.
Aromatase Inhibitors
These agents inhibit Cytochrome P450 aromatase en-
zyme that converts testosterone to estradiol and andros-
tenedionetoestrone.Thisenzymeisactiveinperipheral
tissues throughout the body, including skin, bone, brain,
and adipose tissue.
34
Aromatase inhibitors (AIs) are used
most often in hormone receptor–positive breast cancer
in postmenopausal women.
35
They are also effective at
increasing testosterone levels in cis-men.
36
In the pediat-
ricpopulationtheyhavebeenusedinhyperestrogenic
states such as McCune–Albright syndrome, hyperan-
drogenic states such as familial male-limited peripheral
puberty, pubertal gynecomastia, short stature, and/or
pubertal delay in cis-gender males.
37
Third-generation AIs, including anastrozole and
letrozole are the most potent, selective, and least toxic
AIs available. These agents may be of particular benefit
in the obese patient, as aromatase is highly expressed in
adipocytes. In many obese trans-patients with low T, in-
creasing the T levels may only serve to be converted to
estradiol in adipocytes.
38
Although generally well toler-
ated, menopausal-like side effects may occur, including
fatigue, headache, hot flashes, and vaginal dryness. The
serum testosterone level is expected to increase and
therefore there may be an increase in hematocrit, and
decrease in high-density lipoprotein. In a growing ado-
lescent there is a concern for adverse impact on bone
health, decrease in height velocity, and delayed epiphy-
seal maturation.
36
Selective Estrogen Receptor Modulators
These agents interact with intracellular estrogen recep-
tors in target organs as estrogen receptor agonists or an-
tagonists in a tissue-specific manner.
39
Tamoxifen, the
oldest member of this class, is a competitive inhibitor
of estrogen at the breast, but an agonist in the endome-
trium. For this reason, there is a risk of endometrial
hyperplasia, polyps, carcinoma, and uterine sarcoma
as well as ovarian cysts, which is thought to be highest
in postmenopausal cis-women.
40
Other side effects may
include menopausal-like symptoms and increased risk
of thrombosis.
39
For these reasons, these are not com-
monly used in the treatment of uterine bleeding in
transmen.
Selective estrogen receptor modulators (SERMs) are
typically used in infertility treatment, estrogen receptor–
positive breast cancer, and in the prevention and treat-
ment of osteoporosis in postmenopausal cis-women.
41
In the pediatric population SERMs have been used suc-
cessfully for gynecomastia in adolescent cis-males.
42,43
It has been used with limited clinical experience to help
induce amenorrhea (personal correspondence, Norman
Spack), which was inspired by a small cohort of McCune–
Albright patients who demonstrated a reduction in vagi-
nal bleeding.
44,45
GnRH Agonists
GnRHa mimic the hypothalamic hormone GnRH;
when given continuously they act as an inhibitor of
the pituitary gonadotropins LH and FSH; they also
cause downregulation of the GnRH receptors on the pi-
tuitary gland, thus affecting the downstream products
of LH and FSH, or gonadal steroids (testosterone and
estrogen). In practice, this is a highly effective way to
halt production of estradiol or testosterone. GnRHa
are available in intramuscular 1-, 3-, and 6-month for-
mulations, as well as an intradermal capsule that typi-
cally is effective for greater than 1 year.
GnRHa are typically used in pediatrics for treatment
of central precocious puberty
46
; for adults they are used
for the treatment of metastatic prostate cancer or other
sex steroid-fueled malignancies. In the transgender
population, they are commonly referred to as ‘‘puberty
blockers’’ as they are used to halt and/or prevent devel-
opment of secondary sexual characteristics of the
assigned gender.
12
Side effects are primarily local and related to the type
of insertion used, although there are concerns about
bone health as this has been shown to decline in both
transgirls and transboys on GnRHa.
47
When used in
a precocious puberty population, there seem to be no
long-term consequences on fertility or bone health.
48
In an individual who has already experienced puberty,
and sex steroids (gender affirming or endogenous) are
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198
not present, people may experience symptoms similar
to those seen in menopause such as hot flashes. We
do not recommend routine use in patients who desire
a prolonged agonadal state; the lack of sex steroids in
these individuals is detrimental to bone health, as in-
ferred by the observation that men without estrogen re-
ceptors and those with very delayed puberty have poor
bone health.
49,50
Hysterectomy
Performed with or without salpingectomy/oophorec-
tomy,thisisadefinitiveoptionfortheelimination
of uterine bleeding. Hysterectomy may be performed
abdominally, laparoscopically, robotically, or transva-
ginally.
51
Current guidelines set forth by the World
Professional Association for Transgender Health rec-
ommend persistent, well-documented gender dyspho-
ria, the capacity to make a fully informed decision and
consent to treatment, well-controlled mental health or
medical concerns if significant, and 1 year of gender-
affirming hormones unless not desired or medically
contraindicated for the individual.
51
Additionally it is
recommended that the patient be the age of majority
and have two letters of referral from mental health
professionals.
52
The Endocrine Society Practice Guide-
lines recommend the risks and benefits be evaluated by
the individual.
12
In the National Transgender Dis-
crimination Survey, 21% of transmen surveyed had
undergone hysterectomy, 58% desired a hysterectomy
at some time in the future, and 21% had no desire for a
hysterectomy.
53
Conclusion
Management of uterine bleeding is vital for the mental
health of the transmasculine or nonbinary patient who
desires amenorrhea. Our typical work flow is presented
in Figure 1. Progestogens may be initiated early in
medical transition if they are not ready for or not desir-
ing testosterone. If, while on testosterone amenorrhea
is not achieved, a trial of an increased dose or change
in dose frequency is usually the first step. For persistent
bleeding, particularly in the obese individual, a trial of
an AI may be beneficial. Other options remain viable,
but a decision to utilize them must be the result of an
informed discussion and consent between the treating
physician and patient.
Acknowledgment
TheauthorswouldliketothankNormanSpack,
MD, for his expert guidance, patience, and wisdom
in treating adolescent patients and imparting his
knowledge.
FIG. 1. A simplified flowchart for inducing and maintaining amenorrhea. SERM, selective estrogen receptor
modulators.
Carswell and Roberts; Transgender Health 2017, 2.1
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199
Author Disclosure Statement
No competing financial interests exist.
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Cite this article as: Carswell JM, Roberts SA (2017) Induction and
maintenance of amenorrhea in transmasculine and nonbinary ado-
lescents, Transgender Health 2:1, 195–201, DOI: 10.1089/
trgh.2017.0021.
Abbreviations Used
AI ¼aromatase inhibitors
FSH ¼follicle-stimulating hormone
GnRH ¼gonadotropin-releasing hormone
GnRHa ¼gonadotropin-releasing hormone agonists
LH ¼luteinizing hormone
SERMs ¼selective estrogen receptor modulators
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