Pain 132 (2007) S60–S67
www.elsevier.com/locate/pain

Cross-sex hormone administration changes pain
in transsexual women and men
Anna Maria Aloisi a,*, Valeria Bachiocco a,b, Antonietta Costantino c, Rita Stefani d,
Ilaria Ceccarelli a, Alessandro Bertaccini c, Maria Cristina Meriggiola c
a

c

Department of Physiology, Neuroscience and Applied Physiology Section, University of Siena, Via A. Moro, 2, 53100 Siena, Italy
b
Anaesthesia and Intensive Care Unit, S. Orsola Hospital, Bologna, Italy
Obstetrics and Gynaecology Unit, S. Orsola Hospital, Interdepartmental Centre for Sexual Health, University of Bologna, and M.I.T., Bologna, Italy
d
Anaesthesia and Intensive Care Unit, S. Agostino-Estense New Hospital, Modena, Italy
Received 20 June 2006; received in revised form 26 January 2007; accepted 13 February 2007

Abstract
Chronic pain is gender-related, since there is a clear predominance of one sex with respect to the other in most pain syndromes.
Gonadal hormones are known to aﬀect the occurrence and incidence of pain. Transsexuals receive cross-sex hormones to develop
and maintain somatic characteristics of the opposite sex: male to female transsexuals (MtF) are administered estrogens and antiandrogens, while female to male transsexuals (FtM) are administered androgens. Hence, these subjects represent a model to study
the relationship between sex hormones and pain. Questionnaires dealing with sociodemographic data and pain (occurrence,
frequency, duration, intensity, location and associated symptoms) were administered to both MtF and FtM transsexuals under
hormone treatment for sex reassignment for at least 1 year. Forty-seven MtF and 26 FtM completed the questionnaires. Fourteen
of the 47 MtF (29.8%) reported painful conditions, which in 11 subjects were not present before the beginning of hormone
treatment. Pain consisted mainly of headaches and breast and musculoskeletal pain. Five subjects suﬀered from more than one pain
condition. Sixteen of the 26 FtM (61.5%) reported pain. In 11 subjects, the pain was present before the beginning of hormone intake,
and in 6 of them it improved after testosterone administration. These data suggest that marked changes in sex hormones aﬀect the
occurrence of pain in a high percentage of humans but not in all of them. Whether these eﬀects are due to peripheral or central
actions of sex steroids is unknown.
Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keywords: Sex hormones; Pain; Pain questionnaires; Transsexual; Sex diﬀerences

1. Introduction
In most pain syndromes studied, women have a different risk of developing chronic pain than men of the
same age (LeResche et al., 2005; Wiesenfeld-Hallin,
2005). Diﬀerences in sex steroid levels, receptors and/
or sites of action may play a role in these sex diﬀerences
(Aloisi, 2003; Craft et al., 2004). Androgens, higher in

*

Corresponding author. Tel.: +39 0577234103; fax: +39 0577234037.
E-mail address: aloisi@unisi.it (A.M. Aloisi).

males, appear to protect against the development of
chronic pain in humans, and testosterone was found to
have analgesic eﬀects on experimental pain (Ceccarelli
et al., 2003; Aloisi et al., 2004; Hau et al., 2004). Contradictory results have been reported for estrogens. In both
humans and experimental animals, estrogens have been
found to have both analgesic and hyperalgesic eﬀects
depending on the experimental conditions (Aloisi and
Bonifazi, 2006; Smith et al., 2006).
Transsexualism or gender identity disorder is a nosologic condition in which an otherwise normal person
feels that she/he belongs to the opposite sex to which

0304-3959/$32.00 Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2007.02.006

 A.M. Aloisi et al. / Pain 132 (2007) S60–S67

she/he was born (see Michel et al., 2001 for a review).
For this reason, the masculine transsexual (male to
female, hereafter referred to as MtF) demands feminization of his body, while the feminine transsexual (female
to male, FtM) aspires to masculinization of her body.
Transsexuals undergo a standard cross-sex hormone
treatment, which in most cases is continued for life.
Despite the diﬀerences in dosages, routes of administration, basal conditions of each subject and the responses
to endocrinological treatment, the changes occurring in
the male or female body are constant and due to the
agonistic or antagonistic actions of the sex hormones
used. Estrogens are the cornerstone of the feminization
treatment of MtF transsexuals. To potentiate the eﬀects
of estrogens, subjects often take anti-androgens (i.e.
cyproterone acetate) which lower the endogenous testosterone level and block its binding to the androgen receptors. Testosterone is the key hormone in the treatment
of FtM transsexuals, and a progestin is sometimes
added to stop menstrual bleeding.
The eﬀects induced by sex steroids in transsexuals are
reported in recent articles (Levy et al., 2003; Moore
et al., 2003; De Cuypere et al., 2005; Gooren, 2005). Some
of these eﬀects are considered positive depending on the
target sex (i.e. gynecomastia and decreased hair growth
in MtF and hirsutism and breast atrophy in FtM), while
others are negative (venous thrombosis and depression
in MtF and increased hematocrit in FtM).
The changes in pain have never been described in
detail. Thus, the aim of the present study was to evaluate
pain changes after long-term estrogen/androgen treatment in transsexuals. To collect background information on the current sensitivity to sensory stimuli
(nociceptive and thermal) and the pain history (personal
and familial), we conducted a two-part semi-structured
interview to MtF and FtM transsexuals under hormone
treatment for sex reassignment. If chronic pain was
reported, a standardized questionnaire was given to
deﬁne some features of the pain (occurrence, frequency,
duration, intensity, location and associated symptoms).
Since our hypothesis was that estrogens are pro-nociceptive and androgens are analgesic, we expected diﬀerent
modulation of the painful conditions in males exposed
to prolonged estrogen supplementation (MtF) with
respect to those present in females exposed to prolonged
androgen supplementation (FtM).
2. Methods
2.1. Subjects and procedures
To study the eﬀects of hormone treatments on pain, we contacted transsexuals attending the MIT (Movimento Identità
Transessuale) Centre in Bologna between December 2003
and December 2005. Sex reassignment involves various legal
and medical steps that have to follow a determined course.

S61

In the MIT Centre, the HBIGDA guidelines are followed for
diagnosis and treatment (HBIGDA, 2001). The MIT Centre
has specialists who initiate the hormone treatments and carry
out the periodic controls. These periodic visits are obligatory
but their scheduling usually complies with personal and/or
logistic reasons, so that it is not easily standardized. Thus,
we asked all transsexuals (MtF and FtM) in treatment for at
least one year to be included in the study without any selective
criteria. Seventy-three Caucasian subjects, 47 male to female
(MtF) and 26 female to male (FtM) transsexuals, entered the
study. All subjects fulﬁlled the DSM-IV diagnostic criteria
for gender identity disorder (American Psychiatric Association, 1994). In all the MtF transsexuals, hormone treatment
consisted of cyproterone acetate, an oral progestagen with
strong anti-androgenic activity, combined with oral, injectable
or transdermal estradiol. In the FtM subjects, testosterone
treatment consisted of a mixture of testosterone esters (testosterone enanthate + testosterone propionate) injected intramuscularly, testosterone enanthate or transdermal testosterone.
All participants were informed about the nature of the
study (i.e. to compare the incidence of chronic pain in transsexuals during hormone treatments with the period before hormone treatment) and gave written informed consent. The
study protocol was approved by the Ethics Committee of the
Faculty of Medicine, University of Siena, and was conducted
in accordance with the guidelines proposed in the Helsinki
Declaration. The instruments to collect relevant information
(the same semi-structured interview and questionnaires for
all subjects) were administered at the end of the clinical
assessment and always in the same setting (a visiting room
for out-patients) by the same physician (MCM), an expert in
the management of transsexuals and speciﬁcally trained. Questionnaires were administered as self-report measures.
2.2. Questionnaires
A two-part semi-structured interview was carried out with
ad hoc and standardized questionnaires. The ﬁrst part of the
interview dealt with the socio-demographic data, the duration
of hormone treatment, the kind of hormones taken, the kind of
surgery (if done), and the physical changes occurring after the
hormone administration. Other questions addressed possible
hormone-related changes in the subjects’ sensitivity to painful
and thermal stimuli (warm and cold) and their ability to tolerate them. The subjects were then asked to report if they were
suﬀering any kind of pain in the last few days, weeks, months
or years. If pain was described as persistent or occurring recurrently for a period longer than 4 months (chronic pain), subjects were asked to participate in the second part of the
interview, which concerned the clinical history, past and present pain history, and pain history of the family. A domainlinked questionnaire explored the temporal relationship
between the pain and the hormone intake (if pain was present
before or arose after hormone assumption), its severity with
respect to the hormone therapy (if the pain was getting better
or worse after the start of therapy) and its temporal proﬁle
(how many times it occurred in a day, a week, a month, a year;
how long the pain lasted when it appeared). Other questions
concerned what made the pain worse and how much the pain
inﬂuenced daily activities.

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A.M. Aloisi et al. / Pain 132 (2007) S60–S67

For each type of pain, the validated Italian version (Maiani
and Sanavio, 1985, 1989) of the full-scale McGill Pain Questionnaire (MPQ) (i.e. 78 descriptors) was administered. The
MPQ measures the components of pain (Melzack and Casey,
1968; Melzack, 1975). The interviews and questionnaires were
evaluated by two researchers, diﬀerent from the examiner, and
were quantiﬁed according to the answer format (category or
number). These researchers were blind to the transsexuals’
gender.
The subjects were also asked to mark their pain sites on a
body map. Lastly, a battery of Visual Analogue Scales (0–
10) was used to rate the intensity of pain at various times
according to the anchor words: no pain/the highest pain during: (a) the last 24 h (VAS1), (b) the last week (VAS2), (c)
the pain attacks (VAS3), (d) the night in general (VAS4).
2.3. Hormone plasma levels
Serum levels of the hormones (testosterone, estradiol, FSH
and LH) were measured only in subjects that carried out all
phases of the sex reassignment in the MIT Centre in Bologna.
It was possible to obtain hormonal data for only some of the
other subjects who started the hormone treatments in other
places. Hormone levels were determined by the immunoradiometric method using commercial kits (Adaltis Italia, Bologna,
Italy) in the centralized service of the Sant’Orsola Hospital
(Bologna).
2.4. Analysis
In subjects for whom hormone values were available, Student’s t-test was used to identify signiﬁcant diﬀerences between
the hormone levels determined before the start of hormonal
treatment and during stable treatment. Signiﬁcance was
accepted with p < 0.05. The questionnaire data were analyzed
by grouping the subjects (MtF and FtM separately) into those
suﬀering chronic pain (persistent or recurrent pain lasting
longer than 4–6 months) and those without chronic pain (suffering only sporadic/physiological pain episodes). Basic statistics (mean, SEM, percentages) were computed when required.
The McGill Pain Questionnaire ratings were calculated using
the Pain Rating Index rank method (PRI; Melzack, 1975)
for each component (sensory, aﬀective, evaluative, miscellaneous). Data are reported as the sum of rank values of the
descriptors (Pain Rating Index rank Total, PRIrT) and as percentage for each component.

3.2. Hormones
Table 1 includes data on the serum hormone levels
determined in 25 of the 47 MtF and in 19 of the 26
FtM before the start of treatment and during the clinical
assessment, when the interview was carried out.
Although it was not possible to obtain data at the same
time after the start of treatment in all subjects, the second value refers to steady-state conditions in the period
of hormone peaks.
In the MtF subjects, serum estradiol levels were signiﬁcantly increased with respect to baseline levels
(p = 0.048) after estrogen and anti-androgen intake; in
contrast, testosterone, LH and FSH were signiﬁcantly
lowered (p < 0.01 for all). In FtM subjects, serum testosterone levels were signiﬁcantly raised with respect to
baseline levels (p < 0.01), while estradiol and LH levels
were signiﬁcantly decreased (p < 0.03 and p < 0.02,
respectively) and there were no signiﬁcant changes in
serum FSH levels.
3.3. Results of questionnaires
The main results of the questionnaires are described
in the following sections. Subjects were divided into
those with pain and those without pain. The number
of subjects who underwent surgery and the average
duration of hormone treatment (in months) are also
speciﬁed. All data concerning the qualitative characteristics of the sensations elicited by acute pain episodes
and thermal stimuli refer to subjective evaluations.
3.4. Male to female subjects (MtF)
All contacted subjects entered the study. As reported
in detail in Tables 2 and 3, 14 of the 47 MtF transsexuals
reported ongoing pain (Pain group, 29.8%), while 33
declared that they were not experiencing any kind of
chronic pain (Pain-free group, 70.2%). The duration of
hormone administration in these two groups was: Pain
group 55.7 ± 25.5 months; Pain-free group 37.7 ± 5.8
months. Only 12 of the 47 subjects underwent breast
surgery and/or vaginoplasty, and only one of these subjects was in pain.

3. Results
3.1. Clinical
Forty-seven MtF and 26 FtM completed the questionnaires (age range 25–40 years); all subjects reported
that the body changes occurred as expected after the
start of hormone treatment. Indeed, male to female
(MtF) subjects reported an increase in breast size and
hip circumference, while female to male (FtM) subjects
reported a deepening of the voice, body hair and beard
growth, and an increase in waist circumference.

3.4.1. MtF Pain group
Eleven of the 14 subjects belonging to the Pain group
speciﬁed that the pain started after the beginning of hormone intake (headache appeared in 3 subjects, breast
pain in 11, musculoskeletal pain in 2 and an unusual
post-surgical pain in one); the other 3 subjects were
already experiencing pain before the start of treatment
(2 headache, 1 musculoskeletal pain). As reported in
Table 3, 9/14 of these subjects described a single type
or single location of pain, while the others (5/14)
reported more than one type of pain.

 A.M. Aloisi et al. / Pain 132 (2007) S60–S67

S63

Table 1
Hormone serum levels determined in transsexual male to female (MtF)
and female to male (FtM) subjects

Table 3
Males to females: number of subjects suﬀering chronic pain and kind
of pain

Mean ± SE

Pain

Subjects n = 14

Single pain or site
Headache
Breast
Musculoskeletal

N=
1
7
1

Multiple pains or site
Headache + breast
Headache + musculoskeletal
Breast + musculoskeletal
Headache + breast + visceral

2
1
1
1

Baseline
MtF

E (pg/mL)
T (ng/mL)
LH (IU/mL)
FSH (IU/mL)

Post Txt
No. 25
145 ± 43*
0.8 ± 0.3*
0.4 ± 0.2*
0.5 ± 0.1*

32 ± 2
5.7 ± 0.5
4.8 ± 0.5
3.6 ± 0.2
FtM

T (ng/mL)
E (pg/mL)
LH (IU/mL)
FSH (IU/mL)

p = 0.048
p < 0.01
p < 0.01
p < 0.01

No. 19
*

0.67 ± 0.1
113 ± 17
12.1 ± 2.6
6.2 ± 0.9

7.54 ± 0.9
67 ± 8*
6.7 ± 1.5*
4.6 ± 0.6

p < 0.01
p = 0.037
p = 0.022

Subjects are divided depending on the kind and number of pains.

Estradiol (E), testosterone (T), LH and FSH were determined before
the start of the hormonal treatment (baseline) and during stable
treatment (Txt).
*
Student’s t-test p < 0.05.

In general, all subjects reported that acute pain episodes were getting more frequent and their duration
was progressively increasing after the start of treatment.
They also reported that they perceive pain earlier and
more easily and their tolerance of painful experiences
was decreased by hormone treatment. Moreover, subjects reported being more sensitive to and less tolerant
of high or low temperatures.
3.4.1.1. Headache. Five MtF suﬀered from headaches.
Headaches appeared several times during the week,
sometimes lasting all day. Each subject marked more
than one pain location on the head map. Environmental
stimuli, especially light and sounds, exacerbated pain
severity, and subjects reported that sometimes pain
was so great they could no longer carry out daily activities. Pain greatly increased after hormone intake in the
two subjects in which it was already present before treatment. The McGill Pain Rating Index rank Total (PRIrTot) was 53.4 ± 6.7 (Table 4); in particular, the sensory
(% 74.2 ± 7.7) and evaluative components (% 76 ± 16.0)
had higher values than the others (aﬀective 54.2 ± 15.7;
miscellaneous 63.4 ± 13.3). The highest score in the
VASs was during the crisis (VAS3: 6.5 ± 1.5).
3.4.1.2. Breast pain. This kind of pain was present in 11
of the 14 MtF who reported chronic pain. They all stated that it arose after the start of hormone treatment. It

was mainly unilateral (6 subjects) and continuous, and
was exacerbated by rubbing and touching.
The Pain Rating Index rank Total (PRIrTot, Table 4)
was 14.7 ± 2.8, with the evaluative component (%
27.3 ± 8.2) having higher scores than the others (sensory
% 14.9 ± 4.6; aﬀective % 5.8 ± 3.8; miscellaneous %
16.7 ± 5.6). Four subjects did not select any adjective
in the aﬀective class.
3.4.1.3. Other kinds of pain. Three of the 14 MtF with
chronic pain reported severe and diﬀuse musculoskeletal
pain. This type of pain was present before the start of
hormone therapy in one subject but greatly increased
afterwards. Movements and posture shifts greatly worsened pain. The Pain Rating Index rank Total (PRIrTot,
Table 4) was 29.0 ± 22.7, with the sensory component
(% 61.0 ± 16.4) having higher values than the others
(evaluative % 46.7 ± 17.6, aﬀective % 36.0 ± 32.0, miscellaneous % 47.3 ± 28.8). In addition to headache and
breast pain, an extremely severe and unusual post-surgical pain (orchiectomy for cancer, a rare kind of pain)
was reported by another MtF subject.
3.4.2. MtF Pain-free group
This group includes all MtF subjects (33/47, 70.2%)
who did not report chronic pain. Nevertheless, some
of them (6/33) reported that they perceive pain earlier
and more easily with respect to the period before hormone treatment; in fact, acute pain episodes recurred
more frequently than in the past, with the painful sensation lasting longer than usual. Independently of changes
in pain, the sensitivity to thermal stimuli (both warm

Table 2
Number of subjects belonging to the diﬀerent groups divided for the presence or absence of pain both before and after the beginning of hormonal
treatment
Subjects

Total
number N=

Pain before
treatment N=

Pain after
treatment N=

Pain group
N=

% subjects
in pain

Pain free
group N=

% subjects
without pain

MtF
FtM

47
26

3
14

11
2

14
16

29.8
61.5

33
10

70.2
38.5

 S64

A.M. Aloisi et al. / Pain 132 (2007) S60–S67

Table 4
Males to females: results of the MPQ and VAS
Pain

Subjects McGill Pain Questionnaire (MPQ)

Headache
Breast
Musculoskeletal
Visceral referred

5
11
3
1

Visual Analogue Scale (VAS 0–10)

Total PRIrTot Sensory %

Aﬀective % Evaluative % Miscellaneous % VAS1

53.4 ± 6.7
14.7 ± 2.8
29.3 ± 22.7
42

54.2 ± 15.7
76 ± 16.0
5.8 ± 3.8
27.3 ± 8.2
36.0 ± 32.0 46.7 ± 17.6
7.1
100

74.2 ± 7.7
14.9 ± 4.6
61.0 ± 16.4
78.5

63.4 ± 13.3
16.7 ± 5.6
47.3 ± 28.8
17.6

VAS2

VAS3

VAS4

2.6 ± 0.9 5.2 ± 1.4 6.5 ± 1.5 2.5 ± 1.04
4.1 ± 0.8 4.2 ± 0.8 3.5 ± 1.2 4.4 ± 0.6
4.7 ± 2.4 5.3 ± 2.7 4.3 ± 2.6 3.7 ± 1.4
0
10
10
0

Data refer to each kind of pain. MPQ. PRIrTot = Pain Rating Index rank Total. The total score is obtained summing the rank values of the
adjectives chosen. Separate score for the sensory, aﬀective, evaluative and miscellaneous classes is also computed. For each class, the percentage with
respect to maximum values has been calculated. VAS1 = during the last 24 h VAS2 = during the last week VAS3 = during attacks VAS4 = during the
night.

and cold temperatures) was reported to be enhanced in
all MtF belonging to this group, while their ability to
tolerate the stimuli was reported to be decreased.
3.5. Female to male subjects (FtM)
All contacted subjects entered the study. Sixteen of the
26 FtM subjects reported being in pain (Pain group,
61.5%, Table 2), whereas 10 reported being pain-free
(Pain-free group, 38.5%). The average duration of hormone treatment was: Pain group 33.5 ± 7.2 months;
Pain-free group 43.3 ± 10.1 months. All but six of the 26
FtM subjects had undergone surgery of the uterus and
ovaries (hystero-annexiectomy) with mastectomy; of
these 20 subjects, 11 belonged to the chronic pain group.
3.5.1. FtM Pain group
Sixteen of the 26 FtM were suﬀering chronic pain. As
reported in detail in Table 5, the most common painful
conditions were headache (present in 13 subjects), musculoskeletal pain (present in 7 subjects) and visceral
referred pain (present in 2 subjects); 10/16 FtM reported
only one kind of pain, while the others (6/16) reported
more than one kind of pain. Most of the subjects
belonging to the Pain group (14/16) stated that pain
was already present before the beginning of the hormone treatment.
3.5.1.1. Headache. Headache was present in 13 of the 16
FtM subjects in pain; the majority of them (10/13)
reported that the pain was already present before horTable 5
Females to males: number of subjects suﬀering chronic pain and kind
of pain
Pain

Subjects n = 16

Single pain or site
Headache
Musculoskeletal
Visceral

N=
8
1
1

Multiple pains or site
Headache + musculoskeletal
Musculoskeletal + visceral

5
1

Subjects are divided depending on the kind and number of pains.

mone treatment and they all stated that their relatives
also suﬀered from this pathology. Most of them (7/13
subjects) marked a single pain location on the head map.
In the 10 subjects with headache before the hormone
therapy, testosterone intake improved pain in six, did
not change it in three and increased its severity in one.
Subjects who said that pain was getting better reported
a decrease in the number of pain attacks (from several
times per week to once a month or less); furthermore,
they stated that the headache duration was usually
shorter than before (no more than 1–2 h).
In the three subjects in whom headache was not present before the start of treatment, this pathology was
absent in the clinical history of the family and the pain
features worsened progressively. These subjects indicated more than one site of pain on the head map and
stated that pain sometimes impeded usual activities.
The Pain Rating Index rank Total (PRIrTot, Table 6)
was 20.1 ± 4.3, with the sensory (% 30.5 ± 6.1) and evaluative components (% 31.0 ± 5.6) exceeding the others
(aﬀective 14.2 ± 5.2; miscellaneous 21.3 ± 5.4). The
highest score in the VASs was during the attacks
(4.9 ± 1.01).
3.5.1.2. Musculoskeletal pain. Musculoskeletal pain was
present in 7 of the 16 subjects. In 2 of them, it appeared
after the hormone treatment. Pain severity was high,
with very frequent pain attacks or continuous pain.
Indeed, in most subjects, pain usually occurred several
times per day (5 subjects), while in a few cases (2 subjects) it occurred only several times per week. Movements, posture changes and anxiety enhanced pain.
The Pain Rating Index rank Total (PRIrTot, Table 6)
was 29.5 ± 5.4, with the evaluative (% 51.4 ± 13.0) and
sensory components (% 43.5 ± 7.5) having higher values
than the others (aﬀective 29.5 ± 9.1; miscellaneous
26.8 ± 8.8). The VAS scores were high in the ratings
referring to the attack (7.2 ± 1.7) and during the last
week (6.8 ± 1.5).
3.5.2. FtM Pain-free group
The 10 FtM subjects not suﬀering chronic pain
reported no change in the occurrence or perception of

 A.M. Aloisi et al. / Pain 132 (2007) S60–S67

S65

Table 6
Females to males: results of the MPQ and VAS
Pain

Subjects McGill Pain Questionnaire (MPQ)

Visual Analogue Scale (VAS 0–10)

Total PRIrTot Sensory % Aﬀective % Evaluative % Miscellaneous % VAS1
Headache
13
Musculoskeletal 7
Visceral referred 2

20.1 ± 4.3
29.5 ± 5.4
36 ± 5.0

30.5 ± 6.1 14.2 ± 5.2 31.0 ± 5.6
43.5 ± 7.5 29.5 ± 9.1 51.4 ± 13.0
53.5 ± 3.5 28.5 ± 14.3
30 ± 10.0

21.3 ±5.4
26.8 ± 8.8
47 ± 11.8

VAS2

VAS3

VAS4

1.0 ± 0.6 2.8 ± 0.7 4.9 ± 1.01 1.2 ± 0.66
4.6 ± 1.5 6.8 ± 1.5 7.2 ± 1.7 5.3 ± 0.9
1.5 ± 0.5
2±0
6
6

Data refer to each kind of pain. MPQ. PRIrTo = Pain Rating Index rank Total. The total score is obtained summing the rank values of the adjectives
chosen. Separate score for the sensory, aﬀective, evaluative and miscellaneous classes is also computed for each class. The percentage with respect to
maximum values has been calculated. VAS1 = during the last 24 h VAS2 = during the last week VAS3 = during attacks VAS4 = during the night.

acute pain episodes after the start of therapy. The same
subjects did not reveal any change in the sensitivity to
hot or cold temperatures.
4. Discussion
In this study, we analyzed the eﬀects on pain of crosssex steroid administration in transsexuals. The main
results indicate that sex steroid hormones not only have
the expected sex-speciﬁc eﬀects on the somatic characteristics of the subjects but also change their pain. About
one-third of the male to female (MtF) subjects developed chronic pain concomitantly with estrogen/antiandrogen treatment, while about half of the female to
male (FtM) subjects treated with testosterone reported
a signiﬁcant improvement of the chronic pain (headache) already present before the start of treatment.
These ﬁndings support experimental data in animals
and clinical data in humans suggesting that sex steroid
hormones play an important role in pain.
The role of male or female steroid hormones in enhancing or reducing the development and maintenance of
chronic pain has been shown in many animal models
(see Craft et al., 2004). However, the extension of such
research to human studies has been hindered by the lack
of ‘‘experimental’’ models. In humans, the hormonal variations induced by common hormone treatments (birth
control pills, HRT) are never very great, and the male
or female gonadal hormones are given to the genetically
appropriate sex, males or females, respectively, i.e. subjects who have experienced high levels of that kind of hormone throughout their life. In patients who have to
drastically change their hormones (i.e. for breast or prostate cancer), it is diﬃcult to study pain.
Therefore, transsexuals provide a unique opportunity
to study human subjects who undergo a drastic change
of their hormonal status as healthy adults (25–40 years);
indeed, sex reassignments cannot be carried out before
the age of majority. It must be stressed that although gender identity disorder is already present in adolescence,
transsexuals are eugonadal before their sex reassignment
(i.e. they have sex steroid concentrations and secondary
sexual characteristics that are appropriate for their
genetic sex). Moreover, the percentage of chronic pain

present before the hormone treatment recorded in this
study (13/73, 17.8%) is similar to the values repeatedly
reported in European countries, including the incidence
of chronic pain in the two sexes (see Wiesenfeld-Hallin,
2005). Hence, it is not surprising that only a few of the
males reported the presence of pain before the start of hormone treatment (MtF 3/47, 6%), while many of the
females were already in pain (FtM 10/26, 38%). Likewise,
it was not unexpected that the estrogen/anti-androgen
treatment induced changes in pain sensitivity in a high
number of MtF subjects, whereas the beginning of androgen treatment corresponded to an improvement of pain in
the FtM subjects who suﬀered headache before the hormone treatment. These results conﬁrm our working
hypothesis, but only partially.
Indeed, although the hormone treatment was largely
equivalent among subjects, there were individuals in
each group who showed a clear change of their pain,
while in other subjects the health condition did not
change in spite of long-lasting hormone intake. The ability of hormone treatment to induce signiﬁcant changes
in these subjects was conﬁrmed by the modiﬁcations
observed in hormone serum levels and by the strong
somatic changes occurring in all transsexuals. For
instance, in the MtF subjects taking estrogens, the testosterone levels decreased to the normal ‘female’ range
and serum estradiol increased to reach the steady-state
level normally present in the pre-ovulatory and midluteal peaks in normal women (Becker et al., 2005).
However, only about 1/3 of the subjects (29.8%)
described here developed chronic pain.
These data suggest that the change from a male hormone environment to a female one exposed a ‘background’ (genetic?) condition able to induce a painful
state. This condition was obviously already present
before the start of treatment, but it became clinically relevant only after the hormonal change. Nevertheless, in
view of the 70.2% of MtF subjects who did not develop
any pain, it is evident that high estrogen levels alone are
not able to induce pain.
To study pain, we used the McGill Pain Questionnaire (MPQ). The MPQ scores in the MtF group were
high (PRIrTot: headache 53.4, musculoskeletal 29.3, visceral 42.0) compared to those reported by Gagliese and

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A.M. Aloisi et al. / Pain 132 (2007) S60–S67

Melzack (2003), who administered the full-scale MPQ to
278 patients suﬀering from diﬀerent pain disorders
(PRIrTot: 30). In particular, the sensory and evaluative
components of headache were very high in our subjects
(PRI: 74.2 and 76, respectively).
Patient self-evaluations of changes in pain are commonly utilised by clinicians and researchers (Marks
et al., 1992) to estimate the eﬃcacy of a treatment. This
implies that patients remember the intensity of pain felt
before and after the treatment, compare it to their current level of pain and operationally deﬁne the diﬀerence.
The accuracy of this process is highly dependent on the
accuracy of recollection. However, the reliability of
memory for pain is still controversial and conﬂicting
results have been reported (Erskine et al., 1990; Beese
and Morley, 1993; Feine et al., 1998). For our subjects,
the time before and after treatment was marked by the
start of hormone intake. The changes involved the
appearance of pain (if absent before), its magnitude (if
already present) and the most common symptoms and
signs associated with pain, including the impact of pain
on the daily activity and of daily activity on the pain
severity. In essence, the patients were required to reconstruct their pain experience and its context. The process
of reconstruction is considered to enhance the accuracy
of memory retrieval and thus its reliability (Rainville
et al., 2004). The ﬁndings that emerged were consistent.
That is, when hormone intake was accompanied by an
improvement of pain, the associated signs and pain
characteristics were weak, whereas when hormone
intake was accompanied by a worsening of pain or its
appearance, the features were sometimes dramatic.
Concerning the development of chronic headache,
Pringsheim and Gooren (2004) suggested a direct eﬀect
of estrogens on peripheral mechanisms able to induce
pain. In addition, several studies on the action of estrogens in central and peripheral sites suggested an overall
involvement of the body (Boulware and Mermelstein,
2005). Estrogen receptors (ER) are present in almost
all peripheral neural and non-neural structures and in
most CNS circuits (Lanlua et al., 2001; Patchev et al.,
2004). In particular, ER are present in the dermal and
epidermal structures, and changes in estrogen plasma
levels are able to modify the sensory characteristics of
peripheral nerves, as shown (in agreement with the present results) by the enlargement of the peripheral receptor
ﬁeld and the decrease of the pain threshold in animals
treated with these hormones (Bereiter et al., 1980; Bradshaw and Berkley, 2003). The higher incidence of pain in
the MtF subjects after hormone treatment could be due
not only to the pro-nociceptive eﬀects of estrogens but
also to the drop in their testosterone levels. In fact, pharmacological treatment of men with estrogens and antiandrogen induces a hypogonadal state (Morelli et al.,
2004). While ER are commonly indicated as a CNS
stimulant, androgen receptor (AR)-mediated actions

are often related to CNS inhibition. This inhibitory
action has been invoked to explain the lower incidence
of many forms of chronic pain in men (see Aloisi,
2003). Interestingly, the hypothesis of testosterone-mediated analgesia is only partially conﬁrmed by the data
from the other group of transsexuals, FtM. Most of
these women were already in pain before the hormone
treatment; however, although most of them beneﬁted
from the hormone intake (the number and length of
pain attacks were signiﬁcantly reduced), for some of
them the pain features did not change and in others they
worsened. These eﬀects can be mediated by the AR
modulation that occurs with hormone changes. For
instance, ongoing testosterone treatment in FtM transsexuals is accompanied by upregulation of AR in
peripheral tissues (van der Kwast et al., 1994).
To explain the breast pain and/or diﬀuse musculoskeletal pain present in almost all MtF subjects with
chronic pain (13/14), we must remember that such pain
is very common in women during the luteal phase of the
menstrual cycle and diﬀerent mechanisms have been
proposed to explain its development (Wallace et al.,
1996; Allen and McCarson, 2005). For example, the
ability of estrogens to induce the production of TRPV1
in the intra-epidermal ﬁbres has been shown in breast
tissue (Gopinath et al., 2005); TRPV1 is the capsaicin
or vanilloid receptor 1 required for thermal hyperalgesia
in rodents. It was suggested that the abnormal intra-epidermal innervation found in women suﬀering breast
pain reﬂects re-innervation of the skin following nerve
stretch damage and/or collateral sprouting.
Finally, we cannot exclude that the pain changes
reported by the transsexual subjects were related not
only to changes in hormone levels but also to psychosociocultural aspects. Studies on the psychological aspects
of these subjects have focused on the conformity to selfperceived gender, the presence of mental disorders and
the motivations underlying the sex reassignment (Michel
et al., 2001; Herman-Jeglinska et al., 2002). In general,
the gender identiﬁcation appears to match their request
of sex reassignment, whereas the ﬁndings on the other
aspects are variable. On the whole, a condition of anxiety and fear emerges from these investigations. Such a
cognitive and emotional state might inﬂuence the severity of pain or its self-report, even though a true biological condition may substantially determine the intensity
and incidence of pain.
5. Conclusion
Cross-sex hormone treatment inﬂuenced the occurrence and characteristics of pain in FtM and MtF transsexuals. These results may help to interpret the sex
diﬀerences in pain and to clarify the potential beneﬁts
and risks of administration of exogenous steroids in
general.

 A.M. Aloisi et al. / Pain 132 (2007) S60–S67

Acknowledgements
The authors thank Mirella Izzo and the ‘Associazione
Culturale Crisalide Azione Trans’.
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