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Induction and Maintenance of Amenorrhea in Transmasculine and Nonbinary Adolescents



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.
Induction and Maintenance of Amenorrhea
in Transmasculine and Nonbinary Adolescents
Jeremi M. Carswell*and Stephanie A. Roberts
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
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.
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.
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.
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.
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-
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
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:
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
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.
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.
Greater than 90% of transmen
using either biweekly intramuscular or weekly subcuta-
neous forms of testosterone achieve amenorrhea within
6 months (Table 1).
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.
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.
There is, however, controversy as some studies have
shown an active endometrium and hypertrophic myo-
metrium in some individuals.
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.
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
The recommended therapeutic range
for testosterone levels is 350–700 ng/dL.
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.
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
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,
through reduction of the estro-
gen receptors on the glands.
In normally menstruating
women, exposure to a low-dose progestogen may cause
Table 1. Select Testosterone Formulations Available in the United States
formulation How supplied Typical adult dose Typical max dose Comments
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
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
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.
Carswell and Roberts; Transgender Health 2017, 2.1
disturbances in endometrial angiogenesis and cause low-
volume irregular bleeding.
Prolonged use typically leads
to endometrial atrophy.
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
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.
Intrauterine levonorgestrel may
lead to partial suppression of ovulation, but thought to
act more locally at the endometrium.
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.
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
Frequent and prolonged but light bleed-
ing occurs in a large percentage of patients.
When clas-
sified by histological samples (pseudodecidualization
and reduction of mitotic index), the most potent pro-
gesterone is medroxyprogesterone acetate.
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.
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.
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
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
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.
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
Norethindrone Micronor
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
Provera 2.5, 5, 10 mg
Once or twice daily Dosing has ranged from 20 to
80 mg day
Micronized progesterone Prometrium 100, 200 mg 100–200 mg nightly Incipient contains peanut oil
Depo-Provera 150 mg/1 mL Deep IM injection into gluteal or
deltoid muscle q 12–14 weeks
Provera 104
104 mg/0.65 mL Anterior thigh or abdomen q 12–14
Etonogestrel Implanon 68 mg single
Active for 3 years Breakthrough bleeding common
Levonorgestrel Mirena
52 mg May be left in for 5 years Insert within 7 days of onset of
Carswell and Roberts; Transgender Health 2017, 2.1
has been shown to control endometrial proliferation,
although this does not fully suppress mitotic activity.
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-
tissues throughout the body, including skin, bone, brain,
and adipose tissue.
Aromatase inhibitors (AIs) are used
most often in hormone receptor–positive breast cancer
in postmenopausal women.
They are also effective at
increasing testosterone levels in cis-men.
In the pediat-
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.
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.
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.
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.
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.
Other side effects may
include menopausal-like symptoms and increased risk
of thrombosis.
For these reasons, these are not com-
monly used in the treatment of uterine bleeding in
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.
In the pediatric population SERMs have been used suc-
cessfully for gynecomastia in adolescent cis-males.
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.
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
; 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.
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.
When used in
a precocious puberty population, there seem to be no
long-term consequences on fertility or bone health.
In an individual who has already experienced puberty,
and sex steroids (gender affirming or endogenous) are
Carswell and Roberts; Transgender Health 2017, 2.1
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.
Performed with or without salpingectomy/oophorec-
of uterine bleeding. Hysterectomy may be performed
abdominally, laparoscopically, robotically, or transva-
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.
Additionally it is
recommended that the patient be the age of majority
and have two letters of referral from mental health
The Endocrine Society Practice Guide-
lines recommend the risks and benefits be evaluated by
the individual.
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
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.
MD, for his expert guidance, patience, and wisdom
in treating adolescent patients and imparting his
FIG. 1. A simplified flowchart for inducing and maintaining amenorrhea. SERM, selective estrogen receptor
Carswell and Roberts; Transgender Health 2017, 2.1
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/
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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Carswell and Roberts; Transgender Health 2017, 2.1
... Although there are minimal published reports about menstrual-management and contraceptive methods in transgender adolescents or adults, this information is very limited and purely descriptive. [4][5][6][7][8][9][10] There are no known data on outcomes of different menstrualmanagement methods in gender-diverse patients, including continuation rates, bleeding patterns, and side effects (Ovid, PubMed, CINAHL, and SCOPUS database searches for articles published 2000-2022 using keywords including menses, menstruation, and contraception; full search available on request). This information is crucial for counseling patients and helping them choose appropriate options. ...
... Limited prior data on hormonal medication use in this population do not focus specifically on menstrual suppression, and there are no previous reports on outcomes of menstrual management. [4][5][6]10 This study provides the first known data on outcomes of menstrual management use in transgender and gender-diverse adolescents. ...
Objective: To describe and compare the outcomes of various menstrual-management methods, including method choice, continuation, bleeding patterns, amenorrhea rates, effect on moods and dysphoria, and side effects, in transgender and gender-diverse adolescents. Methods: This was a retrospective chart review of all patients seen in a multidisciplinary pediatric gender program from March 2015 to December 2020 who were assigned female at birth, had achieved menarche, and used a menstrual-management method during the study period. Data were abstracted on patient demographics and menstrual-management method continuation, bleeding patterns, side effects, and satisfaction at 3 months (T1) and 1 year (T2). Outcomes were compared between method subgroups. Results: Among the 101 included patients, 90% chose either oral norethindrone acetate or a 52-mg levonorgestrel (LNG) intrauterine device (IUD). There were no differences in continuation rates for these methods at either follow-up time. Almost all patients had improved bleeding at T2 (96% for norethindrone acetate and 100% for IUD users), with no difference between subgroups. Amenorrhea rates were 84% for norethindrone acetate and 67% for IUD at T1 and 97% and 89%, respectively, at T2, with no differences at either point. The majority of patients had improved pain, menstrually related moods, and menstrually related dysphoria at both follow-up points. There were no differences in side effects between subgroups. There were no differences in method satisfaction between the groups at T2. Conclusion: Most patients chose norethindrone acetate or an LNG IUD for menstrual management. Continuation, amenorrhea, and improved bleeding, pain, and menstrually related moods and dysphoria were high for all patients, indicating that menstrual management is a viable intervention for gender-diverse patients who experience increased dysphoria related to menses.
... While small, there is a growing body of literature about trans and nonbinary menstruation that addresses gender dysphoria and menstruation (e.g., Chrisler et al., 2016;Schwartz et al., 2022;Weiselberg); menstrual suppression as a response (e.g., Carswell and Roberts, 2017;Pradhan and Gomez-Lobo, 2019); and physiological effects of hormone therapy (e.g., White HughtoJaclyn and Reisner, 2016). Validating the emerging research, the Standards of Care for the Health of Transgender and Gender Diverse People Version 8 acknowledge that menstruation can contribute to worsening dysphoria in adolescents and gives guidance on menstrual suppression alongside recommendations to use patient-directed gender-inclusive language (Coleman et al., 2022: S54-S55, 5116). ...
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Trans and nonbinary experiences of menstruation are subject to menstrual discourse that is deeply gendered. Terms such as "feminine hygiene" and "women's health" make trans and nonbinary people acutely aware that they fall outside of the ideal of the default menstruator. To better understand how such language affects menstruators who are not cis women and what alternative linguistic strategies they adopt, we conducted a cyberethnography of 24 YouTube videos created by trans and nonbinary menstruators, along with their 12,000-plus comments. We observed a range of menstrual experiences-dysphoria, tensions between femininity and masculinity, and transnormative pressures. Using grounded theory, we identified three distinct linguistic strategies vloggers adopted to navigate these experiences: (1) avoiding standard and feminizing language; (2) reframing language through masculinization; and (3) challenging transnormativity. The avoidance of standard and feminizing language, coupled with a reliance on vague and negative euphemisms, revealed feelings of dysphoria. Masculinizing strategies, on the other hand, navigated dysphoria through euphemisms-or even hyper-euphemisms-that showed an effort to reclaim menstruation to fit within the trans and nonbinary experience. Vloggers responded through tropes of hegemonic masculinity, using puns and wordplay, and sometimes relying on hypermasculinity and transnormativity. Transnormativity, however, can be polarizing, and vloggers and commenters who rejected stratification of trans and nonbinary menstruation challenged it. Taken together, these videos not only uncover an overlooked community of menstruators who demonstrate unique linguistic engagement with menstruation, but they also reveal destigmatization and inclusion strategies that can inform critical menstruation activism and research as a whole.
... Menses can be a source of distress for genderdiverse youth, and several hormonal medications are frequently used for menstrual suppression. 46 These medications include progesterone-only oral pills (norethindrone, norethindrone acetate), injections (depot medroxyprogesterone acetate), or implants such as intrauterine devices. Intrauterine devices can be placed at any age after menarche occurs and have been studied in adolescents as young as 13 years. ...
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Nonbinary individuals, or those who identify outside of the traditional gender binary, are currently present in up to 9% of the general population of youth or up to 55% of gender-diverse youth. Despite the high numbers of nonbinary individuals, this population continues to experience barriers to healthcare due to providers’ inability to see beyond the transgender binary and lack of competence in providing nonbinary care. In this narrative review, we discuss using embodiment goals to individualize care of nonbinary individuals, and review hormonal and nonhormonal treatment options for gender affirmation. Hormonal treatments include those often used in binary transgender individuals, such as testosterone, estradiol, and anti-androgens, but with adjustments to dosing or timeline to best meet a nonbinary individual’s embodiment goals. Less commonly used medications such as selective estrogen receptor antagonists are also discussed. For nonhormonal options, alterations in gender expression such as chest binding, tucking and packing genitalia, and voice training may be beneficial, as well as gender-affirming surgeries. Many of these treatments lack research specific to nonbinary individuals and especially nonbinary youth, and future research is needed to ensure safety and efficacy of gender-affirming care in this population.
Transgender and gender-diverse (TGD) youth may pursue gender-affirming medical therapy in the form of gonadotropin-releasing hormone analogues (GnRHa), or “puberty blockers,” if pubertal changes result in the development or worsening of gender dysphoria. GnRHa monotherapy can allow TGD youth to explore gender without the distress of unwanted secondary sexual characteristics. However, given the potential effects of GnRHa on growth, skeletal development, neurodevelopment, fertility, and future surgical outcomes, it is critical to accurately assess pubertal status to facilitate fully informed conversations with TGD youth and families about risks, benefits, and unknown consequences of GnRHa monotherapy. The focus of this discussion will be on the approach to puberty assessment in TGD youth as well as the different effects of GnRHa monotherapy that may be important to TGD youth and their families. [ Pediatr Ann . 2023;52(12):e462–e466.]
The field of transgender health has grown exponentially since the early 2010s. While this increased visibility has not been without controversy, there is growing acknowledgement of the needs of transgender, nonbinary, and gender expansive (TNG) patients and the health disparities they experience compared to the cisgender population. There is also increased interest among clinicians and trainees in providing gender-affirming care in all medical specialties. This is particularly relevant in psychiatry as mental health disparities in TNG patients have been well-documented. TNG patients experience significant minority stress and higher rates of psychiatric illness, self-harm, suicidality, and psychiatric hospitalization compared to their cisgender peers. In this review, we will cover potential interactions and side effects relevant to psychiatric medication management for the three most common medication classes prescribed as part of gender-affirming hormone therapy (GAHT): gonadotropin-releasing hormone receptor agonists, estradiol, and testosterone. Although no studies directly examining the efficacy of psychiatric medications or their interactions with GAHT for TNG patients have been published yet, we have synthesized the existing literature from both cisgender and TNG patients to shed light on health care disparities seen in TNG patients. Since clinicians' lack of comfort and familiarity with gender-affirming care contributes significantly to these disparities, we hope this narrative review will help psychiatric prescribers provide TNG patients with the same quality of care that cisgender patients receive.
Transmasculine patients may present to gynecologists for non-procreative concerns and care. These patients may be on gender-affirming testosterone or have undergone (or desire to undergo) gender-affirming surgeries, including masculinizing chest reconstruction, gender-affirming hysterectomy, metoidioplasty, or phalloplasty. Non-procreative aspects of transmasculine gynecology involve the spectrum of gynecologic care and may include pelvic pain, contraception, gender-affirming hysterectomies, or uterine bleeding. Under testosterone exposure, the reproductive organs are relatively hypoestrogenic due to ovarian suppression and do not appear to be at increased risk for malignant pathology. The uterine lining is thin but may still be active in some persons. Amenorrhea occurs in many patients on testosterone. Vulvovaginal atrophy is also seen in some patients due to a lack of estrogen. Despite the general dormant state of reproductive organs, typical pathology such as ovarian cysts, leiomyomata, and endometriosis can still occur in transmasculine persons on testosterone. At present, guidelines for routine gynecologic care and cancer screening are no different in persons on testosterone. Masculinizing chest surgery does not remove all glandular tissue, and as such, patients may still be at risk for breast cancer, although that risk appears to be similar to that of cisgender men. Cervical cancer screening in transmasculine patients on testosterone should be based on ASCCP guidelines just as with cisgender women. This chapter will review the history and physical considerations of a transmasculine patient presenting for gynecologic care, the gynecologic changes seen following the use of gender-affirming testosterone or genital affirmation surgeries, the guidelines for screening of cervical and breast cancer, and approaches to care for common concerns of transmasculine patients including contraception, vulvovaginal atrophy, genital bleeding on testosterone and pelvic pain on testosterone.
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Context: Testosterone is commonly administered intramuscularly (IM) to treat hypogonadal males and female-to-male transgender (FTM) patients. However, these injections can involve significant discomfort and may require arrangements for administration by others. Objective: We assessed whether T could be administered effectively and safely by the subcutaneously (SC) as an alternative to IM injections. Design: Retrospective cohort study. Setting: Outpatient Reproductive Endocrinology Clinic at an academic medical center. Patients: Sixty-three FTM transgender patients aged >18 years electing to receive SC T therapy for gender transition were included. Fifty-three patients were premenopausal. Intervention: Patients were administered T cypionate or enanthate weekly at an initial dose of 50mg. Dose was adjusted if needed to achieve serum total T levels within the normal male range. Main outcome measurements: Serum concentrations of free and total T and total estradiol (E2), masculinization and surveillance for reactions at injection sites. Results: Serum T levels within the normal male range were achieved in all 63 patients with doses of 50-150mg (median 75/80 mg). Therapy was effective across a wide range of body mass index (BMI) (19.0-49.9 kg/m2). Minor and transient local reactions were reported in 9/63 patients. Among 53 premenopausal patients, 51 achieved amenorrhea and 35 achieved serum E2 concentrations <50 pg/mL. Twenty-two patients were originally receiving IM and switched to SC therapy. All 22 had a mild (n=2) or marked (n=20) preference for SC injections; none preferred IM injections. Conclusions: Our observations indicate that SC T injections are an effective, safe and well-accepted alternative to IM T injections.
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Objective: Female-to-male transition remains a specific clinical indication for long-term testosterone administration. There is a limited number of studies dealing with the effect of androgen treatment on their female receptive targets (mainly breast and uterus) and the knowledge in this field is scarce and, sometimes, contradictory. Materials and Methods: We performed a prospective study including 12 patients aged between 20 years and 32 years, with a diagnosis of gender dysphoria, treated with parenteral testosterone administration before sexual reassignment surgery. Results: Endometrial histology revealed the presence of active endometrium in 10 cases and secretive endometrium in two cases. Multifollicular ovaries were observed in all cases of active endometrium, while corpus luteum was present in the two cases of secretory endometrium. Fibroids or hypertrophic myometrium were observed in 58% of the patients. Estrogen receptor was very high (59%) in the endometrial epithelial cells and low (17%) in the myometrium. Androgen receptor expression was modest in endometrial epithelial cells (24%) and sustained in myometrium (69%). Ki67 expression is steadily present in all uterine compartments, varying from 8% in epithelial endometrium to 2% in the myometrium. Conclusion: Our data suggest that long-term testosterone administration to female-to-male patients during reproductive age induces a low proliferative active endometrium, associated with some hypertrophic myometrial changes.
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OBJECTIVE: To conduct a cross-sectional study of transgender men who had been pregnant and delivered after transitioning from female-to-male gender to help guide practice and further investigation. MATERIALS AND METHODS: We administered a web-based survey from March to December 2013 to inquire about demographics, hormone use, fertility, pregnancy experience, and birth outcomes. Participants were not required to have been on hormone therapy to be eligible. We used a mixed-methods approach to evaluate the quantitative and qualitative data. RESULTS: Forty-one self-described transgender men completed the survey. Before pregnancy, 61% (n=25) had used testosterone. Mean age at conception was 28 years with a standard deviation of 6.8 years. Eighty-eight percent of oocytes (n=36) came from participants' own ovaries. Half of the participants received prenatal care from a physician and 78% delivered in a hospital. Qualitative themes included low levels of health care provider awareness and knowledge about the unique needs of pregnant transgender men as well as a desire for resources to support transgender men through their pregnancy. CONCLUSION: Transgender men are achieving pregnancy after having socially, medically, or both transitioned. Themes from this study can be used to develop transgender-appropriate services and interventions that may improve the health and health care experiences of transgender men.
In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer. (C) 2016 by American Society of Clinical Oncology
Puberty is highly important for the accumulation of bone mass. Bone turnover and bone mineral density (BMD) can be affected in transgender adolescents when puberty is suppressed by gonadotropin-releasing hormone analogues (GnRHa), followed by treatment with cross-sex hormone therapy (CSHT). We aimed to investigate the effect of GnRHa and CSHT on bone turnover markers (BTMs) and bone mineral apparent density (BMAD) in transgender adolescents. Gender dysphoria was diagnosed based on diagnostic criteria according to the DSM-IV (TR). Thirty four female-to-male persons (transmen) and 22 male-to-female persons (transwomen)were included. Patients were allocated to a young (bone age of < 15 years in transwomen or < 14 in transmen) or old group (bone age of ≥ 15 years in transwomen or ≥ 14 years in transmen). All were treated with GnRHa triptorelin and CSHT was added in incremental doses from the age of 16 years. Transmen received testosterone esters (Sustanon, MSD) and transwomen received 17-β estradiol. P1NP, osteocalcin, ICTP and BMD of lumbar spine (LS) and femoral neck (FN) were measured at three time points. In addition, BMAD and Z-scores were calculated. We found a decrease of P1NP and 1CTP during GnRHa treatment, indicating decreased bone turnover (young transmen 95% CI − 74 to − 50%, p = 0.02, young transwomen 95% CI − 73 to − 43, p = 0.008). The decrease in bone turnover upon GnRHa treatment was accompanied by an unchanged BMAD of FN and LS, whereas BMAD Z-scores of predominantly the LS decreased especially in the young transwomen. Twenty-four months after CSHT the BTMs P1NP and ICTP were even more decreased in all groups except for the old transmen. During CSHT BMAD increased and Z-scores returned towards normal, especially of the LS (young transwomen CI 95% 0.1 to 0.6, p = 0.01, old transwomen 95% CI 0.3 to 0.8, p = 0.04). To conclude, suppressing puberty by GnRHa leads to a decrease of BTMs in both transwomen and transmen transgender adolescents. The increase of BMAD and BMAD Z-scores predominantly in the LS as a result of treatment with CSHT is accompanied by decreasing BTM concentrations after 24 months of CSHT. Therefore, the added value of evaluating BTMs seems to be limited and DXA-scans remain important in follow-up of bone health of transgender adolescents.
GnRH analogues are the standard therapy but expensive therapy for the suppression of pubertal changes in transsexual individuals. In the 1960s, medroxyprogesterone acetate was found to be efficacious in treating central precocious puberty by inhibiting the secretion of gonadotropins and/or interfering with gonadal steroid synthesis. To avoid the adverse effects and prohibitive cost of gonadotropin releasing hormone analogues, this study utilized medroxyprogesterone as an alternative treatment for puberty sex hormone suppression. The goal of this retrospective chart review is to determine the efficacy and safety of medroxyprogesterone. Sixteen subjects with Gender Identity Disorder less than 19 years were offered medroxyprogesterone to suppress puberty sex steroids. Seven male-to-female individuals were treated with the oral form of medroxyprogesterone. Six female-to-male individuals used depot medroxyprogesterone acetate; one used oral; and two refused. One decided to change back to being female. None of the patients discontinued therapy because of unwanted side-effects. In conclusion, medroxyprogesterone is an effective, safe, and affordable option for the suppression of pubertal hormones in teens desiring gender change. It is also an excellent option for those who have needle phobia. Response to treatment and compliance were favorable.
It is essential to gain a better understanding of the pharmacokinetics and potency of oral progestins so that physicians can treat postmenopausal women more efficiently with these drugs. Progestins can be divided into natural (progesterone) and synthetic types. There are a variety of synthetic progestins which can be subdivided into those structurally related to progesterone (e.g., medroxyprogesterone acetate) and those structurally related to testosterone (norethindrone [norethisterone], levonorgestrel and their derivatives, as well as dienogest). Relatively little is known about the pharmacokinetics of progesterone and progestins structurally related to progesterone compared to that of the testosterone derivatives. Natural progesterone is not efficiently absorbed unless it is micronized. Both progesterone and medroxyprogesterone acetate reach peak circulating levels between 1 and 4 h and then the levels fall precipitously. Progesterone undergoes extensive metabolism. In the circulation, essentially all of the medroxyprogesterone acetate is bound to albumin, whereas approximately 20% of progesterone is bound to corticosteroid-binding globulin and the rest to albumin. Progesterone is metabolized extensively and has a relatively short half-life (< 1 h) in contrast to the half-life of medroxyprogesterone (24 h). Several of the progestins structurally related to testosterone are prodrugs. Lynestrenol, norethindrone acetate, ethynodiol diacetate and possibly norethynodrel, serve as prodrugs of norethindrone. Two levonorgestrel derivatives, namely, desogestrel and norgestimate, also act as prodrugs. Desogestrel acts via 3-ketodesogestrel, whereas norgestimate is, in part, a prodrug of levonorgestrel. Neither gestodene nor dienogest are prodrugs. In the circulation, the progestins structurally related to testosterone are bound in varying proportions to albumin or sex hormone-binding globulin (SHBG), or are unbound (free). All of the progestins are bound mostly to albumin, with the exception of gestodene, which is bound primarily to SHBG. After gestodene, levonorgestrel has the highest binding to SHBG followed by norethindrone and 3-ketodesogestrel. Dienogest does not bind to SHBG. Approximately 90% of dienogest is bound to albumin and about 10% is unbound. Pharmacokinetic studies of commonly used doses of progestins structurally related to testosterone show the following: Dienogest gives the highest maximum concentration, which is 1.5 times higher than that of norethindrone and 6-12 times higher than the maximum values of the other progestins. The time to reach maximum levels is 1-2 h. The absolute bioavailabilities of levonorgestrel, gestodene and dienogest are 89-99%. These values are considerably higher than those of norethindrone and 8-ketodesogestrel. The half-life of elimination is higher for levonorgestrel, 3-ketodesogestrel and gestodene (10-13 h) and lowest for dienogest and norethindrone (6.5 and 8.1 h, respectively). However, the clearance and volume of distribution is highest for norethindrone and lowest for gestodene and dienogest. Although problems in estimating progestin potencies are well recognized, some general conclusions can be drawn about relative potencies of progestins. Binding affinity studies of progestins for the human uterine progesterone receptor show that medroxyprogesterone acetate, levonorgestrel, 3-ketodesogestrel and gestodene bind with high affinity to the progesterone receptor. No measurable binding affinity to the human progesterone receptor has been demonstrated for desogestrel or norgestimate. Dienogest shows only 10% of the binding obtained for progesterone. Norethindrone is about 10-20 times less potent than levonorgestrel.