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Induction and Maintenance of Amenorrhea in Transmasculine and Nonbinary Adolescents

Authors:

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.
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.
Carswell and Roberts; Transgender Health 2017, 2.1
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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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197
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,thisisadenitiveoptionfortheelimination
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.
References
1. Illingworth P. Amenorrhea, anovulation, and dysfunctional uterine
bleeding. In: Endocrinol ogy: Adult and Pediatric, 6th ed. ( Jame son IL, De
Groot LJ; eds). Philadelphia: Saunders Elsevier, 2010, pp. 2341–2355.
2. Fraser I. Regulating menstrual bleeding. J Reprod Med. 1999;44:158–164.
3. Campbell S, Cameron IT. The origins and physiology of menstruation. In:
Clinical Disorders of the Endometrium and Menstrual Cycle. (Cameron IT,
Fraser IS, Smith SK; eds). Oxford: Oxford University Press, 1998, pp. 13–30.
4. Marshall JC, Rame NK. Hormonal regulation of the menstrual cycle,
mechanisms of ovulation, premenstrual syndromes. In: Endocrinology:
Adult and Pediatric, 6th ed. ( Jameson IL, De Groot LJ; eds). Philadelphia:
Saunders Elsevier, 2010, pp. 2327–2340.
5. The American College of Obstetricians and Gynecologists: diagnosis of
abnormal uterine bleeding in reproductive aged women. Practice Bulletin
No. 128. American College of Obstetricians and Gynecologists. Obstet
Gynecol. 2012;120:197–206.
6. Nakamura A, Watanabe M, Sugimoto M, et al. Dose-response analysis of
testosterone replacement therapy in patients with female to male gender
identity disorder. Endocr J. 2013;60:275–281.
7. Spratt DI, Stewart I, Savage C, et al. Subcutaneous injection of testoster-
one is an effective and preferred alternative to intramuscular injection:
demonstration in female-to-male transgender patients. J Clin Endocrinol
Metab. 2017;102:2349–2355.
8. Grynberg M, Fanchin R, Dubost G, et al. Histology of genital tract and
breast tissue after long-term use testosterone administration in a female-
to-male transsexual population. Reprod Biomed Online. 2010;20:553–558.
9. Perrone AM, Cerpolini S, Maria Salfi NC, et al. Effect of long-term testos-
terone administration on the endometrium of female-to-male (FtM)
transsexuals. J Sex Med. 2009;6:3193–3200.
10. Loverro G, Resta L, Dellino M, et al. Uterine and ovarian changes during
testosterone administration in young female-to-male transsexuals.
Taiwan J Obstet Gynecol. 2016;55:686–691.
11. Light AD, Obedin-Maliver J, Sevellius JM, Kerns JL. Transgender men who
experienced pregnancy after female-to-male gender transitioning.
Obstet Gynecol. 2014;124:1120–1127.
12. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al.
Endocrine treatment of transsexual persons: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab. 2009;94:3132–3154.
13. Pfizer. Product Information: PROVERA(R) oral tablets, medroxyprogester-
one acetate oral tablets. New York, NY: Pharmacia and Upjohn Company
(Per Daily Med), 2009.
14. Moyer DL, de Lignieres D, Driguez P, Pez JP. Prevention of endometrial
hyperplasia by progesterone during long-term estradiol replacement:
influence of bleeding pattern and secretory changes. Fertile Steril.
1993;59:992–997.
15. Moyer DL, Felix JC. The effects of progesterone and progestins on en-
dometrial proliferation. Contraception. 1998;57:399–403.
16. Gillet JY, Andre G, Vaguer B, et al. Induction of amenorrhea during hor-
mone replacement therapy; optimal micronized progesterone dose. A
multicenter study. Maturitas. 1994;19:103–115.
17. Giudice LC. Genes associated with embryonic attachment and implanta-
tion and the role of progesterone. J Reprod Med. 1999;44(2 suppl):165–171.
18. Deligdisch L. Hormonal pathology of the endometrium. Mod Pathol.
2000;13:285–294.
19. Lynch MM, Khandheria MM, Meyer WJ. A retrospective study of the
management of childhood and adolescent gender identity disorder
using medroxyprogesterone acetate. Intl J Transgenderism. 2015;16:
201–208.
20. McCann MF, Potter LS. Progestin-only oral contraception: a comprehen-
sive review. Contraception. 1994;50:S1–S195.
21. Barbosa I, Bakos O, Olsson SE, et al. Ovarian function during use of a
levonorgestrel-releasing IUD. Contraception. 1990;42:51–66.
22. La
¨hteenma
¨ki P, Jukarainen H. Novel delivery systems in contraception. Br
Med Bull. 2000;56:739–748.
23. Fraser IS, Hickey M, Song JY. A comparison of mechanisms underlying
disturbances of bleeding caused by spontaneous dysfunctional uterine
bleeding or hormonal contraception. Hum Reprod. 1996;11(suppl 2):
165–178.
24. Stanczyk FZ. Structure-function relationships, potency and pharmacoki-
netics of progestogens. In: Treatment of the Postmenopausal Woman,
Basic and Clinical Aspects. (Lobo RA, ed.) New York: Raven Press, 1994.
25. Cundy T, Evans M, Roberts H, et al. Bone density in women receiving
depot-medroxyprogesterone acetate for contraception. BMJ. 1991;
303:13–16.
26. Scholes D, LaCroix AZ, Ott SM, et al. Bone mineral density in women using
depot medroxyprogesterone acetate for contraception. Obstet Gynecol.
1999;93:233–238.
27. Guilbert ER, Brown JP, Kaunitz AM, et al. The Use of depot-
medroxyprogesterone acetate in contraception and its potential impact
on skeletal health. Contraception. 2009;79:167–177.
28. World Health Organization. Department of Reproductive Health and
Research. WHO statement on hormonal contraception and bone health.
Wkly Epidemiol Rec. 2005;35:302–304.
29. Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone
acetate and bone mineral density in adolescents—the black box warning:
a position paper of the Society for Adolescent Medicine. J Adolesc Health.
2006;28:305–315.
30. Apgar BS, Greenberg G. Using progestins in clinical practice. Am Fam
Physician. 2000;62:1839–1846.
31. Ottosson UB, Johansson BG, von Schoultz B. Subfractions of high-density
lipoprotein cholesterol during estrogen replacement therapy: a com-
parison between progestogens and natural progesterone. Am J Obstet
Gynecol. 1985;151:746–750.
32. Sherwin BB. The impact of different doses of estrogen and progestin on
mood and sexual behavior in postmenopausal women. J Clin Endocrinol
Metab. 1991;72:336–343.
33. Speroff L, Glass RH, Kase NG. Oral contraception. In: Clinical Gynecologic
Endocrinology and Infertility, 7th ed. (Speroff L, Fritz M, eds). Philadelphia:
Lippincott Williams & Wilkins, 2005:Chapter 22 (accessed online).
34. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Der-
matol. 2001;45:S116–S124.
35. Chumsri S, Howes T, Bao T, et al. Aromatase, aromatase inhibitors, and
breast cancer. J Steroid Biochem Mol Biol. 2011;125:13–22.
36. de Ronde W, de Jong FH. Aromatase inhibitors in men: effects and
therapeutic options. Reprod Biol Endocrinol. 2011;9:93–99.
37. Shulman DI, Francis GL, Palmert MR, Eugster EA. Use of aromatase in-
hibitors in children and adolescents with disorders of growth and ado-
lescent development. Pediatrics. 2008;121:e975–e983.
38. Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in en-
dometrial cancer risk, prevention, and treatment. J Clin Oncol.
2016;34:4225–4230.
39. Maximov PY, Lee TM, Jordan VC. The discovery and development of se-
lective estrogen receptor modulators (SERMS) for clinical practice. Curr
Clin Pharmacol. 2013;8:135–155.
40. Polin SA, Ascher SM. The effect of tamoxifen on the genital tract. Cancer
Imaging. 2008;8:135–145.
41. Martinkovich S, Shah D, Planey SL, Arnott JA. Selective estrogen receptor
modulators: tissue specificity and clinical utility. Clin Interv Aging.
2014;9:1437–1452.
42. Lapid O, van Wingerden JJ, Perleuter L. Tamoxifen therapy for the man-
agement of pubertal gynecomastia: a systematic review. J Pediatr
Endocrinol Metab. 2013;26:803–807.
43. Kreher NC, Eugster EA, Shankar RR. The use of tamoxifen to improve
height potential in short pubertal boys. Pediatrics. 2005;116:1513–1515.
44. Eugster EA, Shankar R, Feezle LK, Pescovitz OH. Tamoxifen treatment of
progressive precocious puberty in a patient with McCune-Albright syn-
drome. J Pediatr Endocrinol Metab. 1999;12:681–686.
45. Eugster EA, Rubin SD, Reiter EO, et al.; McCune-Albright Study
Group. Tamoxifen treatment for precocious puberty in McCune-Albright
syndrome: a multicenter trial. J Pediatr. 2003;143:60–66.
46. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of
gonadotropin-releasing hormone analogs in children. Pediatrics. 2008;
123:e752–e762.
47. Vlot MC, Klink DT, den Heijer M, et al. Effect of pubertal suppression and
cross-sex hormone therapy on bone turnover markers and bone min-
eral apparent density (BMAD) in transgender adolescents. Bone.
2017;95:11–19.
Carswell and Roberts; Transgender Health 2017, 2.1
http://online.liebertpub.com/doi/10.1089/trgh.2017.0021
200
48. Carel JC, Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot
gonadotropin-releasing hormone agonist treatment of central preco-
cious puberty: final height, body proportions, body composition, bone
mineral density, and reproductive function. J Clin Endocrinol Metab.
1999;84:4583–4590.
49. Finkelstein JS, Klibanski A, Neer RM. A longitudinal evaluation of bone
mineral density in adult men with histories of delayed puberty. J Clin
Endocrinol Metab. 1996;81:1152–1155.
50. Finkelstein JS, Neer RM, Biller BM, et al. Osteopenia in men with a history
of delayed puberty. N Engl J Med. 1992;326:600–604.
51. American College of Obstetricians and Gynecologists (ACOG) Committee on
Gynecologic Practice. ACOG Committee Opinion No. 444: choosing the route
of hysterectomy for benign disease. Obstet Gynecol. 2009;114:1156–1158.
52. World Professional Association for Transgender Health (WPATH). Stand-
ards of Care for the Health of Transsexual, Transgender, and Gender
Nonconforming People, 7th Version. WPATH, 2012.
53. National Center for Transgender Equality and the National Gay and Les-
bian Task Force: National Transgender Discrimination Survey Report on
health and health care Findings of a Study. 2010. www.thetaskforce.org/
static_html/downloads/resources_and_tools/ntds_report_on_health.pdf
Accessed July 15, 2017.
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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... Medroxyprogesterone is a more potent progestogen compared to others, but it has more adverse effects. 22 • Finasteride (2.5-5 mg/d orally). 20 It is a 5-alpha reductase inhibitor and does not reduce testosterone levels. ...
... Clinical experience shows that depressive symptoms and self-harm behaviours can peak with menstrual bleeding. 22 When it comes to the induction of amenorrhoea: ...
... The interval between doses can be shortened if needed. • If the patient refuses GnRH analogues and menstruation persists after 3-6 months of androgen therapy at adequate doses, a progestogen can be added in patients without underlying gynaecological abnormalities 15,22 : norethisterone acetate, 5-15 mg/d orally, among other options. • Combine with oral contraceptives if the patient does not refuse administration of oestrogens. ...
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Some people, including minors, have a gender identity that does not correspond to the sex assigned at birth. They are known as trans* people, which is an umbrella term that encompasses transgender, transsexual, and other identities not conforming to the assigned gender. Healthcare units for trans* minors require multidisciplinary working, undertaken by personnel expert in gender identity, enabling, when requested, interventions for the minor and their social–familial environment, in an individualized and flexible way during the gender affirmation path. This service model also includes hormonal treatments tailored as much as possible to the individual's needs, beyond the dichotomic goals of a traditional binary model. This guide addresses the general aspects of professional care of trans* minors and presents the current evidence-based protocol of hormonal treatments for trans* and non-binary adolescents. In addition, it details key aspects related to expected body changes and their possible side effects, as well as prior counselling about fertility preservation.
... • Progestágenos (acetato de noretisterona 5-15 mg/d vía oral, dienogest 2 mg/d vía oral, progesterona micronizada 100-300 mg/d vía oral, entre otros) para inducir amenorrea de forma más rápida durante la inducción puberal con testosterona si fobia a las agujas. La medroxiprogesterona es un progestágeno más potente respecto a otros, pero con más efectos secundarios 22 . ...
... El sangrado uterino puede ser una fuente de angustia para los adolescentes trans. La experiencia clínica muestra que los síntomas depresivos y las conductas autolesivas pueden alcanzar su punto máximo durante el sangrado menstrual 22 ...
... Si es preciso, acortar el intervalo de administración. • Si se rechaza los análogos de GnRH y tras tres a seis meses de tratamiento androgénico, a dosis que se consideran adecuadas, persiste la menstruación, en usuarios sin una anomalía ginecológica subyacente, añadir un gestágeno 15,22 : acetato de noretisterona 5-15 mg/d vía oral, entre otros. • Anticonceptivos orales combinados si no hay rechazo a utilizar estrógenos. ...
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Resumen Algunas personas, también las menores de edad, tienen una identidad de género que no se corresponde con el sexo asignado al nacer. Se les conoce como personas trans*, que es el término paraguas que engloba transgénero, transexual y otras identidades no conformes con el género asignado. Las unidades de asistencia sanitaria a menores trans* requieren un trabajo multidisciplinario, realizado por personal experto en identidad de género, que permita, cuando así lo soliciten, intervenciones para el menor y su entorno sociofamiliar, de forma individualizada y flexible durante el camino de afirmación de género. Este modelo de servicio también incluye tratamientos hormonales adaptados en la medida de lo posible a las necesidades del individuo, más allá de los objetivos dicotómicos de un modelo binario tradicional. Esta guía aborda los aspectos generales de la atención profesional de menores trans* y presenta el protocolo actual basado en evidencia de tratamientos hormonales para adolescentes trans* y no binarios. Además, detalla aspectos clave relacionados con los cambios corporales esperados y sus posibles efectos secundarios, así como el asesoramiento previo sobre preservación de la fertilidad.
... For transmasculine youth, suppression of menses is often desired, not only to help relieve menstruation-associated GD, but also given prevalent safety concerns in accessing bathrooms (34). Options include a progestogen, such as medroxyprogesterone (orally or injectable depot), oral lynestrenol, or norethisterone, either alone or in a continuous combined oral contraceptive pill (although many transmasculine youth may decline this because of concerns regarding estrogen use) (35,36). Highest rates of amenorrhoea are reported with depot medroxyprogesterone (35), although concerns regarding adverse impacts on bone health limit its use as a first-line choice. ...
... Pelvic ultrasound to confirm sufficient uterine cavity size may be beneficial in such cases, especially in individuals presenting soon after menarche, and some TGD adolescents will require light sedation or a short anesthetic to tolerate insertion. Irregular, unpredictable bleeding may occur with all progestogens, which may lead to discontinuation (36). Ultimately, for those who use testosterone as masculinizing GAH therapy, circulating testosterone levels in the adult male range will induce menstrual suppression in >90% of cases (35). ...
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... First-and second-generation progestins may be preferable due to their increased androgenic effects. The MiniPill, containing first-generation norethindrone, acts at the endometrium and is the only progesterone-only pill approved for contraception by the FDA [52]. Irregular bleeding is common, and it has a relatively high contraceptive failure rate. ...
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... Current guidelines recommend highly effective birth control for transmasculine persons at risk of being pregnant. Nevertheless, some transmasculine patients may avoid COCs due to concerns of potential feminizing effects, risk of spontaneous bleeding if not consistently adherent, and potential adverse effects such as nausea, weight gain, and breast tenderness [58,59]. Progestin-only contraceptives, such as norethindrone, may be used by hormone providers to cease uterine bleeding, but may exacerbate acne due to their androgenic property and, unlike other hormonal contraceptive options, would not be considered as a primary contraceptive method if isotretinoin is ultimately required [60]. ...
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... Medications in the US include pubertal suppression (GnRH agonists), affirming hormones (estrogen, testosterone, progesterone), antiandrogens (spironolactone, bicalutamide, dutasteride, finasteride), selective estrogen receptor modulators, and approaches for menstrual suppression (including levonorgestrel intrauterine device). 31 Although there are limited recommendations on medical care for genderqueer persons, 19 providers modify traditional guidelines 14,18,27 (see Table 2) to support patient goals. Gradual titration or tapering of doses for individual response and effect, using lower doses, intermittent dosing, using both estrogen and testosterone, adding adjunctive medications, and other approaches to "fine tuning" medications are part of the repertoire of individualized gender care. ...
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Menstruation is a female normative process. Physiologically, it indicates that the hypothalamic-pituitary-ovarian axis is functioning appropriately, and all the correct female end-organs are intact. Menarche also heralds a girl's arrival into womanhood, which culturally is often celebrated. It is a sign of the possibility of fertility, pregnancy and motherhood. However, menstruation for transgender males, and other gender diverse individuals assigned female at birth, may be anything but celebratory. For these adolescents, menstruation is an indication that one's body is not functioning appropriately and that one does not have the correct organs congruent to their gender identity. Menstruation or the anticipation of menarche for many transgender males is often met with worsening of dysphoria, anxiety, depression and suicidal ideation. Therefore, to meet the physiologic and psychologic needs of transgender males, one needs to be aware of issues that may be present in relation to menstruation and be knowledgeable on how to medically proceed with sensitivity and respect toward one's gender identity. Research on menstruation, both from a physical and psychologic perspective, has been historically based on women and cannot be simply extrapolated to be the same for transgender males. Although there is a paucity of literature on the subject, over the past decade there has begun to be a great interest in the care of transgender individuals. This article focuses on concerns related to menstruation among transgender adolescent males and gender diverse individuals assigned female at birth, including suppression of menses, fertility, contraception, and pregnancy.
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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.
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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.
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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.