Prepubertal Gynecomastia Linked to Lavender and Tea Tree - 芳療

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不過過年當然是要當個otaku狂看卡通才是。
有版友說要看期刊全文，但是全文很難貼，因為還有實驗圖表不能貼
除非你真的很有興趣再私下跟我要PDF檔
我能貼多少就貼多少囉，大家就加減看。
如果有版友願意出來接手翻譯也是大感激啦～喔～啾咪
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Prepubertal Gynecomastia Linked to Lavender and Tea Tree Oils

Derek V. Henley, Ph.D., Natasha Lipson, M.D., Kenneth S. Korach, Ph.D.,
and Clifford A. Bloch, M.D.


Summary

Most cases of male prepubertal gynecomastia are classified as idiopathic. We
investigatedpossible causes of gynecomastia in three prepubertal boys who
were otherwisehealthy and had normal serum concentrations of endogenous
steroids. In all three boys, gynecomastia coincided with the topical
application of products that contained lavender and tea tree oils. Gynecomastia resolved in each patient
shortly after the use of products containing these oils was discontinued.
Furthermore, studies in human cell lines indicated that the two oils had
estrogenic and antiandrogenic activities. We conclude that repeated topical
exposure to lavender and tea tree oils probably caused prepubertal
gynecomastia in these boys.

大多數的男性女乳症案例是自發性的，但是我們研究三個前青春期的小男孩，以及

Gynecomastia is generally attributed to conditions that disrupt sex-steroid
signaling pathways, resulting in increased or unopposed estrogen action on
breast tissue.1 In contrast to gynecomastia in adolescent boys and men,
prepubertal gynecomastia is rare and should always be considered
pathological, prompting a search for a source of estrogen. Although
hyperestrogenemia may be endogenous or exogenous in origin, most persons with
prepubertal gynecomastia have normal serum concentrations of sex steroids,
and an underlying cause is not identified.2,3 In such cases, possible
exposure to exogenous sources of estrogen should be considered. We
investigated the cause of prepubertal gynecomastia in three otherwise healthy
boys with normal serum concentrations of endogenous steroids.

Case Reports

Patient 1

A boy who was 4 years 5 months old presented with gynecomastia of apparently
2 to 3 weeks' duration. He had no exposure to any known exogenous form of
estrogens (ingestants, salves, or ointments). His height and weight were at
the 97th percentile and between the 75th and 90th percentiles, respectively.
He had bilateral gynecomastia with firm, nontender breast tissue measuring 2
cm by 2 cm in diameter.His testes were 3 ml in volume and of normal
consistency. His genitalia were prepubertal (Tanner stage 1). Laboratory
investigation showed normal thyroid function; the follicle-stimulating
hormone (FSH) concentration was 1.04 IU per liter (reference range, 0.25 to
1.92), luteinizing hormone 0.47 IU per liter (referencerange, 0.02 to 1.03),
testosterone 0.08 ng per milliliter (0.27 nmol per liter) (reference range,
0.02 to 0.25 ng per milliliter), estradiol less than 20 pg per milliliter (73
pmolper liter) (normal value, <20), dehydroepiandrosterone (DHEA) sulfate
less than 5.0 μg per deciliter (0.14 μmol per liter) (reference range, 1 to
40), 17-alpha-hydroxyprogesterone 0.32 μg per liter (0.97 nmol per liter)
(reference range, 0.2 to 0.8), and prolactin 8.0 μg per liter per liter
(reference range, 2 to 29); the serum biochemistry values, including
liver-function tests, were normal. On evaluation 3 months later, the
breast budswere tender to palpation and had increased to 2.5 cm by 2.5 cm in
diameter with an increased breast mound. The patient's mother reported
applying a compounded "healing balm" containing lavender oil to his skin
starting shortly before the initial presentation. The gynecomastia partially
resolved within 4 months after application of the healing balm was discontinued
, at which time the breast buds measured 1.5 cm by 1.5 cm in diameter and
were soft in consistency. Several months later, his pediatrician stated that
the gynecomastia had resolved completely.

Patient 2

A boy who was 10 years 1 month old presented with a 5-month history of
gynecomastia. He and his mother reported that the condition seemed more
prominent in the evening and a little less so in the morning. His medical
history and family history were unremarkable. His height and weight were
above the 97th percentile, and his body-mass index (the weight in kilograms
divided by the squareof the height in meters) was 21.1. He had firm,
tender breast buds, measuring 3.5 cm by 4.0 cm in length and width and
approximately 3.5 cm in depth, with stretching of the areolae. His testes
were 3 ml in volume and of normal consistency. His pubic hair was Tanner
stage 2 (a small amount of long hair at the base of the scrotum), and his
genitalia were Tanner stage 1. Laboratory testing showed a testosterone
concentration of 0.36 ngper milliliter (1.25 nmol per liter) (normal value,
<0.25), free testosterone 0.0066 ng per milliliter(0.0229 nmol per liter)
(reference range, 0.0006 to 0.0057), and DHEA sulfate 278 μg per deciliter
(7.6 μmol per liter) (normal value, <75). On questioning, it was determined
that the patient was not currently using drugs, herbal supplements, or herbal
lotions but was applying a styling gel to his hair and scalp every morning
and regularly using a shampoo. The labels of both the gel and the shampoo
listed Lavandula angustifolia (lavender) oil and Melaleuca alternifolia (tea
tree) oil as ingredients. Reevaluation 9 months after use of these products
was discontinued showed that his areolar mounds had decreased in depth to
approximately 1 cm with almost no palpable glandular tissue.

Patient 3

A boy who was 7 years 10 months old presented with a 1-month history of
gynecomastia that had appeared gradually. His height was between the 75th and
90th percentiles, and his weight was at the 50th percentile. He had bilateral
gynecomastia with firm, nontender breast tissue that corresponded to Tanner
stage 2. His testes were 3 ml in volume and of normal consistency. His
genitalia were Tanner stage 1, and there was no pubic hair present.
Laboratory testing showed normal thyroid function, FSH 0.49 IU per liter
(reference range, 0.25 to 1.92), luteinizing hormone 0.16 IU per liter
(reference range, 0.02 to 1.03), estradiol 5 pg per milliliter (18 pmol per
liter) (normal value, <10), estriol less than 0.1 ng per milliliter (0.3 nmol
per liter) (normal value, <0.1), estrone less than 13 pg per milliliter (48
pmol per liter) (normal value, <13), total estrogens 61 pg per milliliter
(225 pmol per liter) (normal value, <130 in adult men), DHEA sulfate 22 μg
per deciliter (0.6 μmol per liter) (reference range, 2.5 to 145),
17-alpha-hydroxyprogesterone 0.13 μg per liter (0.39 nmol per liter)
(reference range, 15 to 65), and free beta subunit of human chorionic
gonadotropin less than 2 mIU per milliliter (normal value, <5); the serum
biochemistry values, including liverfunction tests, were normal. His history
was positive for the use of lavender-scented soap and intermittent use of
lavender-scented commercial skin lotions. The gynecomastia resolved
completely a few months after use of scented soap and skin lotions was
discontinued (personal communication from the patient's family). His
fraternal twin used the same skin lotions, but not the lavenderscented soap,
and did not have any gynecomastia.

Methods

Mammalian Cell Culture

Human breast-cancer (MCF-7) cells that express estrogen receptors were grown
in phenol red-free Dulbecco's modified Eagle's medium containing 10%
fetal-calf serum (Atlanta Biologicals), penicillin (100 U per milliliter),
and streptomycin (100 μg per milliliter). Human breast-cancer (MDA-kb2)
cells that express the androgen receptor were maintained as previously
described.4 Cell-culture reagents were obtained from Invitrogen Life
Technologies, unless otherwise indicated. For all experiments, the lavender
oil (L. officinalis, which is a synonym for L. angustifolia) and tea tree
oil (M. alternifolia)(both from Sigma Chemical) were diluted in
dimethylsulfoxide before they were added to culture media.

Luciferase Assays and Reverse-Transcriptase and
Real-Time Polymerase-Chain-Reaction（RT-PCR） Analysis

MCF-7 and MDA-kb2 cells were assayed for luciferase activity with the use of
the Dual-Luciferase reporter assay system (Promega) and an LMAX II384
luminometer (Molecular Devices). Total RNA was isolated from MCF-7 cells and
MDA-kb2 cells with the use of the RNeasy Mini Kit (Qiagen), according to the
manufacturer's protocol. Synthesis of complementary DNA (cDNA) and analyses
of gene-specific cDNA concentrations were performed by real-time polymerase
chain reaction (PCR), as previously described.5 The PCR primers were designed
with the use of Primer Express software, version 2.0 (Applied Biosystems)
(see the Supplementary Appendix, available with the full text of this article
at www.nejm.org).

Statistical Analysis

The data were analyzed for statistical significance by the Mann-Whitney
nonparametric test.

Result

Estrogen-receptor-dependent Estrogenic Activity in Vitro

To determine whether lavender oil and tea tree oil are estrogenic, we
performed dose-response experiments in MCF-7 cells that were positive for
estrogen receptors and were transiently transfected with an estrogen-inducible
luciferase reporter plasmid containing three copies of an estrogenresponse
element (3X-ERE-TATA-luciferase). Both oils stimulate ERE-dependent luciferase
activity in a dose-dependent manner, with the maximum activity observed at
0.025% volume per volume (vol/vol) for each oil, corresponding to approximately
50% of the activity elicited by 1 nM 17β-estradiol (Fig. 1A and 1B).
Treatment with higher doses of the oils was cytotoxic. The pure
estrogen-receptor antagonist fulvestrant inhibited transactivation of the
3X-ERE-TATA-luciferase reporter plasmid by both oils, indicating that their
activity is estrogen-receptor-dependent (Fig. 1A and 1B). Additional experiments
indicated that lavender oil wasable to transactivate the estrogen-inducible
reporter plasmid in estrogen-receptor-negative SK-BR-3 human breast-cancer
cells only after simultaneous transfection with an estrogen-receptor-expression
vector (data not shown).

Further experiments in MCF-7 cells indicated that the two oils modulated the
expression of theestrogen-regulated endogenous genes MYC (also called C-MYC),
6 CTSD,7 and IGFBP3.8 Lavender oil and tea tree oil increased the expression
of messenger RNA (mRNA) for MYC and CTSD and decreased the expression of mRNA
for IGFBP3, as compared with the dimethylsulfoxide controls, ina manner that
was similar to the effect of 1 nM 17β-estradiol on the magnitude and timing
of the responses (Fig. 1C). These responses were attenuatedin the presence of
1 μM fulvestrant (Fig. 1C).

In Vitro Antiandrogenic Activity

To evaluate the potential androgenic propertiesof lavender oil and tea tree
oil, we performed dose-response experiments in MDA-kb2 cells, a line of human
breast-cancer cells that are positive forthe androgen receptor and were
stably transfected with an androgen-inducible and glucocorticoid-inducible
mouse mammary-tumor virus (MMTV)-luciferase reporter plasmid. Treatment of
MDA-kb2 cells with the androgen-receptor agonist dihydrotestosterone
(DHT) at 0.1 nM, the lowest observed effective dose in this cell line,4
resulted in an increase in luciferase activity that was almost four times
higher than that in the dimethylsulfoxide controls (Fig. 2A and 2B). In
contrast, neither lavender oil nor tea tree oil transactivated the
MMTV-luciferase reporter plasmid at any concentration tested (Fig. 2A and 2B).

The antiandrogenic properties of the two oilswere assessed by simultaneously
treating the MDA-kb2 cells with DHT and increasing the concentration of
lavender oil or tea tree oil. The androgen-receptor antagonist flutamide was
also included in these assays, as a positive control for androgen-receptor a
ntagonism. Transactivation of the MMTV-luciferase reporter plasmid by 0.1 nM
DHT was inhibited in a concentration-dependentmanner by both lavender oil and
tea tree oil, as well as by flutamide (Fig. 2A and 2B). Maximuminhibition
occurred at 0.005% vol/vol for both lavenderoil and tea tree oil,
corresponding to a decrease in luciferase activity of 52% and 41%,
respectively, in the presence of 0.1 nM DHT. The observed inhibitory effects
appear to be specific to the androgen receptor, since neither of the two
oils attenuated the glucocorticoid-receptor-mediated transactivation of the
MMTV-luciferase reporter plasmid in the presence of 5 nM dexamethasone, the
lowest observed effective dose in this cell line9 (data not shown). Further
experiments in MDA-kb2 cells indicated that the antiandrogenicproperties of
lavender oil and tea tree oil extended to inhibition of DHT-stimulated
expression of the androgen-inducible endogenous genesCYP4F8, C1orf116,
UGT2B28, and SEC14L210 (Fig. 2C).The antiandrogenic effects of the two oils
are not caused by down-regulation of the expression of the androgen receptor,
since neither of the oils altered the amount of androgen-receptor mRNAor
protein in these experiments (data not shown).


Discussion

In contrast to gynecomastia, which occurs in more than 60% of boys during
puberty, prepubertal gynecomastia is extremely uncommon. Since there is no
known physiologic cause of prepubertal gynecomastia, pathologic causes should
be considered However, a specific cause is rarely identified, and in 90% of
patients, prepubertal gynecomastiais labeled idiopathic.2,3 In such patients,
the condition may be caused by exposure to an environmentalchemical that disrupts
the endocrine system and leads to disproportionate estrogen and androgen
pathway signaling, a finding reported in a limited number of adults with
gynecomastia. 11,12

In this report, we describe three otherwise healthy boys with prepubertal
gynecomastia, all of whom had normal serum concentrations of endogenous
steroids and none of whom had been exposed to any known exogenous endocrine
disruptor such as medications, oral contraceptives,marijuana, or soy
products.1 The repeated topical application of one or more over-the-counter
personal care products that contained lavender oil or lavender oil and tea
tree oil was documented for all three patients. Case 1 provided the clinical
clue
to lavender oil as a potential source, because it was the only topically
applied agent used by that child.Use of lavender oil was considered trivial
by the child's mother, who acknowledged its use only after repeated
questioning. In Case 2, the boy had biochemical evidence of physiologic
adrenarche, but the evidence was unrelated to his gynecomastia, which
resolved after discontinuation of the use of products containing lavender oil
and tea tree oil, despite the persistence of adrenarche. The daily temporal
fluctuation in the severity of the gynecomastia reported by the patient's
mother might have been caused by the transdermal absorption kinetics of the
oils after application each morning. In Case 3, the patient was exposed
intermittently to various over-thecounter personal-care products containing
lavender oil. His twin brother used the same lotions but not the scented
soap, and gynecomastia did not develop in him.

The common use of products containing lavender oil, tea tree oil, or both by
the three boys and the resolution of their gynecomastia within months after
ceasing use of those products suggest that these oils may possess
endocrine-disrupting activity that causes an imbalance in estrogen and
androgen pathway signaling. Other components in these products may also
possessendocrine-disrupting activity that contributed to the gynecomastia,
but those components were not tested because we chose to evaluate only the
component that was found in all the products used by the patients (lavender
oil) and a chemically similar component that was found in some of the
products (tea tree oil).



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白什麼爛兒 白自己的爛 白自己和大家無聊的爛 白體驗和經歷的爛 白凍傷深刻的爛
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冰的精彩冰的出色冰的深情冰的智慧 冰得天真浪慢返樸歸真 冰得屍橫遍野無怨無悔
冰的恍然大誤破鏡一地冰得心靜自然涼冰的日日是寒日年年無好年如處南極企鵝同舞
我的天啊 什麼人這麼強 啪啦 就是荷諾 他凍的了我 一次O.K

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