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Original Studies |
Research Institute for Endocrinology, Reproduction and Metabolism, University Hospital Vrije Universiteit, 1007 MB, Amsterdam, The Netherlands
Address correspondence and requests for reprints to: Erik J. Giltay, M.D., Department of Endocrinology, Division of Andrology, University Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. E-mail: giltay{at}dds.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-Androstane-3,17ß-diol glucuronide levels were
only weakly associated with hair growth and sebum production. In
conclusion, administration of estrogens and antiandrogens affects
length and diameter of hairs at different rates. In the virtual absence
of androgens, hair growth continues but at a slower rate. In women,
after 12 months of androgen administration, hair diameters have not
reached values of adult men. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-dihydrotestosterone by 5-reductase. Only a small fraction
of 5-dihydrotestosterone reenters the plasma, whereas a larger
portion is converted to 5-androstane-3,17ß-diol glucuronide
(Adiol G) (2), which is considered an indicator of peripheral tissue
androgen action and metabolism.
Two major clinical conditions of the skin (hirsutism and acne) may
result from an excess peripheral androgenic activity and can be treated
with antiandrogenic medication (3, 4, 5, 6, 7). Hirsutism, an excessive body
hair growth with an adult male pattern affecting approximately 5% of
women, can be idiopathic (without elevated peripheral androgen levels),
drug-induced, or associated with excessive ovarian and/or adrenal
androgen production (8). Acne vulgaris, a skin disease affecting nearly
80 percent of persons at some time between the ages of 11 and 30 yr
(6), is characterized by increased sebum production, cornification
(obstructing the pilosebaceous follicle by desquamated epithelial
cells), microbes (e.g. Propionibacterium acnes),
and inflammation (6, 9). It may occur predominantly on the face (99%)
and, to a lesser extent, on the back (60%) and chest (15%) (9). Sebum
production by the sebaceous glands is under androgen regulation,
clearly demonstrated by the lack of sebum production in
androgen-insensitive subjects (10) but does not completely depend on
the conversion of testosterone into 5-dihydrotestosterone, evidenced
by the lack of suppression in subjects with 5-reductase deficiency
(10). Many studies, but not all (11), have found associations between
elevated levels of Adiol G and hirsutism and acne scores in women
(12, 13, 14, 15), and chest hairiness and acne scores in men (16). Possible
explanations for the correlation found between these disorders and this
raised androgen conjugate are increased levels of 5-reductase (17, 18) and (adrenal) androgen precursors (11), or lower levels of
cytochrome P-450 aromatase (18), which converts testosterone into
17ß-estradiol in the skin pilosebaceous unit. Additional variability
in clinical expression may relate to differences in the number and
properties of androgen receptors, which may increase skin sensitivity
to androgens (19, 20).
We were able to monitor, in detail, the effects of androgen deprivation
in male-to-female (M
F) and androgen administration in female-to-male
(FM) transsexuals (21), who requested hormonal induction of
secondary sex characteristics of the opposite sex. We sought to
clarify: 1) the effects of sex steroids on objective parameters of hair
growth and sebum production; 2) their relationship in time after
androgen deprivation/administration; and 3) the relationship between
these parameters and Adiol G levels.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We included 21 MF (all white; median age, 30 yr; range, 20 to
44 yr) and 17 FM transsexuals (14 white; median age, 25 yr; range,
18 to 37 yr). At baseline, the body mass index (BMI) was 22.0 ±
3.1 kg/m2 (mean ± SD) in MF
and 23.9 ± 4.3 kg/m2 in FM transsexuals;
1 MF and 2 FM transsexuals were overweight (BMI > 28.0
kg/m2). A complete medical history and physical
examination revealed no endocrine diseases, except for one MF
transsexual, who was treated with insulin injections because of
insulin-dependent diabetes mellitus. Hair growth and sebum production
measurements were performed before and again after 4, 8, and 12 months
of cross-sex hormone administration, all by a single observer (E.
J. Giltay). MF transsexuals were treated with oral ethinyl
estradiol, 100 µg/day (Lynoral, Organon, Oss, The
Netherlands; n = 10) or transdermal 17ß-estradiol (Estraderm
TTS 100, Ciba-Geigy, Basel, Switzerland; n = 11),
both in combination with cyproterone acetate (CA), 100 mg/day
(Androcur, Schering AG, Berlin, Germany), which is
a progestational compound with androgen receptor-blocking capacities.
FM transsexuals were all treated with im testosterone esters
(Sustanon, Organon), 250 mg/2 weeks. One MF transsexual
reported intake of several tablets of ethinyl estradiol
before baseline. To suppress their menstruation, 1 FM transsexual
had used oral contraception pills continuously until baseline, and 1
FM transsexual had used oral contraception pills continuously until
1/2 yr before baseline; in all other subjects, there was no
clinical or laboratory evidence of use of sex hormones for 3 yr or more
before baseline. All but one of the FM transsexuals had had regular
menstrual cycles (26–35 days) before cross-sex hormone administration;
endocrine measurements were performed in the follicular phase of the
menstrual cycle (4–13 days after the onset of the preceding menstrual
period) at baseline. Eight- and 12-month measurements were not obtained
in 1 MF and 1 FM transsexual, and some other measurements could
not be obtained successfully for failed compliance with the shaving
protocol or absence of terminal hairs on prefixed skin areas. The lean
body mass and the total body fat were estimated using bioelectrical
impedance analysis (BIA 101/S, RJL Systems, Clinton Twp, Detroit, MI),
using the manufacturer’s sex-specific equations. The investigation
conformed with the principles outlined in the Declaration of Helsinki.
Informed consent was obtained from all subjects, and the study was
approved by the Ethical Review Committee of the University Hospital
Vrije Universiteit.
Endocrine measurements
In all subjects, fasting venous blood samples were taken in the morning, between 0900 h and 1200 h, at baseline and after 4 and 12 months of cross-sex hormone administration. Standardized RIAs were used to determine serum levels of testosterone (Coat-A-Count, Diagnostic Products Corporation, Los Angeles, CA) and 17ß-estradiol (Sorin Biomedica, Saluggia, Italy). To assess peripheral androgen activity, we measured the serum level of Adiol G (2) by an RIA (DSL, Webster, TX). Immunometric luminescence assays were used to determine levels of FSH (Amerlite, Amersham Pharmacia Biotech, UK) and LH (Amerlite, Little Chalfont, UK).
Hirsutism and hair growth evaluation
Degree of hair growth and distribution were subjectively assessed according to the Ferriman and Gallwey method (22) with which 11 sites (lip, chin, chest, upper back, sacroiliac region, upper and lower abdomen, arm and back of forearm, thigh, and leg) were graded (0 = none, 1 = slight, 2 = moderate, 3 = dense, and 4 = very dense). These were performed in conjunction with the endocrine measurements at baseline and after 4, 8, and 12 months of cross-sex hormone administrations. Forearm and leg skin scores are presented separately as the so-called nonhormonal areas, whereas the Ferriman and Gallwey score results from the summation of the other 9 scores, indicating the androgen-dependent area (22). A score for the androgen-dependent area of more than 7 was considered indicative for hirsutism.
In addition, 5 days before each assessment, the patient was asked to
shave, in the morning, prefixed skin areas in front of the left ear and
above the umbilicus, at home, using a safety-razor. During the
evaluation, photographs were taken of those two skin areas with a
camera (Chinon, CM-5, Suwa City, Japan) fitted with a macro lens
(SMC Pentax-A, Macro, 1:2.8, 50 mm) (Fig. 1
). The area, the date, and the patient
reference code were printed at the bottom of each picture (by Chinon,
Info back-2, DP-520). The magnified photographs were scanned by
Viewstation AS6E (v1.3.2., Ultima International, Artec Electronics
GmbH, Berlin, Germany) into a personal computer (AuthenticAMD,
AMD-K6 3D processor). The averaged length of 10 flattened hairs
was divided by the shaving interval (normally 5 days) to calculate the
hair growth rate per day. We measured the number of terminal hair
follicles (using the marquee option) and the length of hairs (using the
measure tool in Photoshop, v5.0; Adobe Systems Incorporated, San Jose,
CA) and, subsequently, converted the area size into actual square
centimeters and the hair length into actual millimeters. The number of
terminal hair follicles was divided by the surface of the area (of
approximately 2 cm2) to yield the hair density
per square centimeter.
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Acne and sebum production evaluation
Clinical assessment of acne was performed on the subjects’ face
and back (posterior part of the neck down to the waist) according to
the Leeds’ classification (23) (0–10); grades 0.25–0.75 represent
physiological acne, and grades 1.0 and above represent clinical acne.
The Sebutape technique (CuDerm Corp., Dallas, TX) (24, 25) provides
information about sebaceous gland function. It consists of a
hydrophobic, polymeric film that measures sebum production through the
use of air-filled microspores. When each active sebaceous gland pours
out a certain amount of sebum, the film becomes transparent because the
numerous tiny air-filled microspores in the film become filled with
sebum. After thorough cleaning with alcohol swabs, areas in the midline
of the forehead, nose, chin, and back were tested because, at these
sites, sebaceous glands are largest and most numerous (9). A sebutape
patch was affixed for exactly 1 h. Afterwards, sebutape patches
were photographed, with black background, by the camera described above
(Fig. 1
), and the pattern of sebum droplet depositions was scored
according to the reference card (grades 0–5 with increasing sebum
levels). Because skin temperature may influence sebum excretion rate
(25), an electronic thermometer (MD3040, Beckmann + Egle, Kernen,
Germany) was used to assess skin temperature on the forehead, and sebum
production was measured in a temperature-controlled room.
Statistical analysis
Data are mean ± SD or median (interquartile
range), based on available cases. All other analyses are based on
complete cases. In the MF and the FM groups separately, the ANOVA
test for repeated measurements or Friedman’s two-way ANOVA was used to
explore the effects of cross-sex hormones on variables of interest. To
compare 12-month values in FM transsexuals with baseline values in
MF transsexuals, Student’s t tests for independent
samples were used. Absolute changes, between base-line and 12 months,
were correlated using partial correlation coefficients, adjusted for
the biological sex (and testosterone levels).
To explore changes over time in relation to Adiol G levels, we created mean standard deviation scores for hair growth and for sebum production for each subject. This approach was used to reduce the influences of biological variability of each measure and to reduce the number of associations explored (26). For each subject, each absolute change (baseline vs. 12 months) was expressed as standard deviations of difference from the mean. If values were missing, the mean was substituted. The scores were calculated as the mean of these standard deviation scores as follows: hair growth score = (Ferriman & Gallwey score +cheek hair growth rate + upper abdomen hair growth rate + cheek hair density + upper abdomen hair density + cheek hair diameter + upper abdomen hair diameter)/7; and sebum production score = (Leeds acné-score of face + Leeds acné-score of back + forehead sebutape score + nose sebutape score + chin sebutape score + back sebutape score)/6.
If terminal hairs were absent on prefixed skin areas, hair growth rate and hair density were considered zero. If hormonal values were below the lower limit of detection, the value of that lower limit was used for statistical calculations (for testosterone, 1.0 nmol/L; for LH, 0.3 IU/L; for FSH, 0.5 IU/L). A two-tailed P-value of less than 0.05 was considered statistically significant. The software used was SPSS, Inc. for Windows 8.0 (Chicago, IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After estrogen plus antiandrogen administration to MF
transsexuals, serum levels of total testosterone, Adiol G, LH, and FSH
were significantly suppressed, mostly to undetectable levels for
testosterone, LH, and FSH (Table 1). The
ethinyl estradiol that had been administered could not be
detected by the assay used, but there were clear physical signs of
estrogenic effects (as gynecomastia) and strong changes in body
composition, as evidenced by an increased BMI and total body fat (Table 1) in these subjects. After parenteral testosterone administration to
FM transsexuals, the serum levels of total testosterone and Adiol G
significantly increased, which was paralleled by an increased BMI and
lean body mass (Table 2). Serum levels of
17ß-estradiol, LH, and FSH were significantly suppressed (Table 2).
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After estrogen plus antiandrogen administration to male subjects,
male hair growth subsided in all subjects. The Ferriman and Gallwey
score decrease progressively from median 21 (at baseline) to 10 (after
12 months) (Table 1), yet only three subjects (15%) had scores of 7 or
less. The hair diameter fell sharply within 4 months and remained
rather constant thereafter, whereas the median growth rate and density
on the cheek and upper abdomen dropped only slowly but
progressively(Fig. 2 and Table 1). There
was no statistically significant difference in any of the endocrine or
hair measurements between the groups of MF transsexuals treated with
either oral ethinyl estradiol or transdermal
17ß-estradiol, who both received treatment with the antiandrogen
CA.
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). After 4 months of testosterone
treatment, already 14 of 17 FM transsexuals (82%) had scores above
7, which indicates hirsutism in biological women. After 12 months, 15
FM transsexuals (94%) had scores above 7. Especially the skin areas
that already exhibited terminal hairs at baseline showed a marked and
fast (within 4 months) increase in hairiness scores: leg, from median 1
to 3; and forearm, from median 1 to 2. The median hair growth rate,
density, and diameter increased progressively over the 12 months (Fig. 3 and Table 2).
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M transsexuals,
the mean hair-shaft diameter on the cheek and abdomen had not reached
those values of MF transsexuals at baseline (for both,
P < 0.001 by t-tests). Compared with
baseline values in MF transsexuals, the hair growth rate and hair
density were slightly lower on the cheek (P = 0.01 and
P = 0.04) but did not significantly differ
(P = 0.16 and P = 0.51) on the abdomen
in FM transsexuals after 12 months of treatment. Acne and sebum production
After 4 months of estrogen plus antiandrogen administration
to male subjects, acne subsided in all six subjects with physiological
acne at baseline. The sebutape scores decreased sharply in all four
skin areas in all subjects already within 4 months (Fig. 2 and Table 1). None of the acne or sebum production scores showed statistically
significant differences between the groups of MF transsexuals
treated with either oral ethinyl estradiol or transdermal
17ß-estradiol.
At baseline, 5 FM transsexuals had facial physiological acne and 3
FM transsexuals had physiological acne on the back, according to the
Leeds classification. After 4 months of androgen administration to
female subjects, facial physiological acne was present in 15 (94%).
Most remarkable was the acne development on the back at 4 months, which
was in the physiological range in 14 (88%) and clinical in 1 subject.
Sebutape scores slowly and progressively increased in all subjects
(Fig. 3 and Table 2). Skin temperature increased moderately over time
(Table 2), but absolute changes in skin temperature did not correlate
significantly with any change in sebutape scores.
Intercorrelations and correlations with serum Adiol G levels
Intercorrelation data of absolute changes in hair parameter in
both MF and FM transsexuals are shown in Table 3. In both groups, changes in hair growth
rate and hair density correlated positively. After antiandrogen plus
estrogen administration in MF transsexuals, hair growth declined;
but correlations between (on the one hand) hair growth rate and hair
density and (on the other) hair-shaft diameter were less strong or even
inverse (Table 3). Changes in the subjective Ferriman and Gallwey score
were only weakly and, in MF transsexuals, inconsistently associated
with changes in objective parameters of hair growth.
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and 5 show the partial correlation
coefficients between absolute changes of 12-month vs.
baseline values in serum Adiol G levels and in parameters of hair
growth and sebum production. The partial correlation coefficients,
adjusting for the biological sex, of the absolute change in Adiol G
levels showed weak associations, with the absolute changes in the hair
growth score (partial r = 0.29;
r2 = 8,3%; P = 0.097)
and the sebum production score (partial r = 0.30;
r2 = 9.0%; P =
0.086). The changes in the hair growth and sebum production scores were
not significantly associated (partial r = 0.12;
P = 0.49).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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F transsexuals, the pilosebaceous unit was inhibited
in its function on estrogen plus antiandrogen administration, as has
been shown in hirsute women (7, 27). Estrogen plus antiandrogen
administration decreases hirsutism scores, hair growth rate, and hair
density. Interestingly, the decrease in hair-shaft diameter had already
reached its maximum after 4 months and did not progress any further.
Similar changes, over time, were found in hair growth measurements on
the abdomen (as a measure of the truncal hair growth) and on the cheek
(as a measure of facial hair growth), as evidenced by strong
intercorrelations (Table 3). The clinical observation that beard
growth, as compared with the hair growth on the abdomen, is relatively
resistant to androgen suppression may be explained by the larger facial
hair density and hair-shaft diameter, and, therefore, most patients
find facial hair reduction upon androgen deprivation rather slow.
Remarkably enough, whereas androgen deprivation led to a decrease of
hair diameter, growth of hair length was relatively preserved, pointing
to a differential regulation of growth of hair length and hair width.
Although skin sebum production dropped quickly to almost undetectable
levels, male hair growth nevertheless remained substantial (even after
12 months), in spite of the rapid and considerable suppression of
androgenicity in MF transsexuals. Thus, circulating androgens do not
seem necessary to sustain some degree of male hair growth once it has
been established. This is consistent with our clinical observation in
MF transsexuals, who (years after orchiectomy) continue to have
beard growth, with thinner hairs though.
In FM transsexuals, testosterone administration induced hirsutism in
most subjects already within 4 months, though with a wide range of
variation. Our findings indicate that virilization probably occurs
rather rapidly in women with an androgen-secreting adrenal or ovarian
tumor. The relatively slow increase in hair diameter in FM
transsexuals, on testosterone administration, is reminiscent of the
developing beard growth in male puberty. Beard hairs are initially
rather thin as well (so-called baby fuzz). Physiological acne developed
in most FM transsexuals, remarkably enough to a similar extent in
the face and on the back, which may be ascribed to androgenic
stimulation of sebocyte differentiation, proliferation, turn-over, and
lipogenesis (9, 28). However, sebum production scores were much lower
on the back, as compared with the face, which may point to the
importance of the other factors [cornification, microbes, and
inflammation (9)] in the etiology of acne and may relate to putative
immunomodulatory effects of androgens (29).
The pilosebaceous unit in the skin is sensitive to androgens and
can convert testosterone into its 5-reductase product
5-dihydrotestosterone and, subsequently, into Adiol G (17, 30).
Serum levels of Adiol G are considered a marker of this peripheral
metabolic pathway (12, 13, 14, 15, 16). However, Adiol G levels were only weakly,
or even inconsistently (11), associated with scores for hirsutism in
most studies. Accordingly, in our study, changes in Adiol G were only
weakly associated with both changes in hair growth and sebum production
parameters, indicating that, besides the above mentioned metabolic
pathway, other (possibly androgen receptor and postreceptor) mechanisms
play a more important role in the sex steroid sensitivity of the
pilosebaceous unit. Our experimental data show that serum levels of
Adiol G may predict only about 8% of the variability in hair growth
and 9% in sebum production. Moreover, the strong association between
serum testosterone and Adiol G levels, in our population of healthy,
relatively young, transsexual men and women, suggests that an increased
or a decreased availability of precursor androgens (i.e.
testosterone) largely determined androgen metabolism in peripheral
tissue. In addition, changes in adrenal androgens (31), not measured in
the present study, may account for the changes found in Adiol G levels
(11).
Some limitations of our study should be noted. We did not include
a control group because of the nature of the treatment indication, and
that clinical evaluation could not be done blinded. Differentiation
between vellus and terminal hairs was difficult to assess, especially
in the FM transsexuals, and the duration of the anagen phase and the
degree of pigmentation and medullation were not measured. Furthermore,
we asked the MF transsexuals to refrain from hair removal (by
shaving, tweezing, waxing, or electrolysis) for 3 days or more before
their visit to the clinic, but their compliance cannot always be
guaranteed. The absence of more strong and statistically significant
correlations between Adiol G and hair and sebum measurements may be
attributable to a type-2 statistical error, in view of the small number
of subjects tested, and to the marked variability of hair and sebum
measurements. Adiol G is also produced by sources other than the
pilosebaceous unit, such as the adrenals and the liver; hepatic
5-reductase is the major determinant of the conversion of precursors
to Adiol G (2). There are differences of opinion about the value of
photography in assessment of hirsutism, but some studies report
satisfactory results (27, 32). However, this is, to the best of our
knowledge, the first experimental study that reports on the effects of
androgen administration, in women, on the pilosebaceous unit in the
skin. Moreover, measurements of hair growth and sebum production were
performed by a single observer.
In conclusion, estrogens plus antiandrogens in biological males block circulating androgens and sebum production almost completely, but inhibit hair growth only slowly. A strong reduction in hair-shaft diameter was the first sign of androgen deprivation, reaching its maximum already after 4 months. Changes in hair-shaft diameter were inversely associated with hair growth rate. Testosterone administration to biological females increases sebum production and induces hirsutism and physiological acne already after 4 months. After 12 months of androgens exposure, the hair diameter had not yet reached the value found in adult eugonadal men. The facial and body hair diameter is particularly sensitive to androgen deprivation, whereas only prolonged androgen administration (>12 months) might produce an adult male hair diameter. We showed experimentally that there is a wide range of sensitivity of the pilosebaceous unit to androgens; changes in serum levels of Adiol G predict only a small fraction of this variability of the sensitivity of the pilosebaceous unit to androgens.
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Acknowledgments |
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Received December 30, 1999.
Revised April 4, 2000.
Accepted April 18, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-androstanediol glucuronide
concentrations in women with various causes of hirsutism and its
correlation with degree of hirsutism and androgen levels. J Clin
Endocrinol Metab. 75:243–248.[Abstract]
,17ß-androstanediol glucuronide in plasma, a marker of androgen
action in idiopathic hirsutism. J Clin Invest. 69:1203–1206.
-reductase
activity in idiopathic hirsutism. Fertil Steril. 43:74–78.[Medline]
-androstanediol glucuronide with acne and
chest hair density in men. J Clin Endocrinol Metab. 67:986–991.[Abstract]
-Reductase
activity in the genital skin of hirsute women. J Clin Endocrinol
Metab. 60:349–355.[Abstract]
,17ß-androstanediol glucuronide in serum and
urine and the correlation with skin 5-reductase activity. Fertil
Steril. 46:222–226.[Medline]
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