ArticlePDF Available

Neither lavender oil nor tea tree oil can be linked to breast growth in young boys

Authors:
  • Robert Tisserand Essential Training
Neither lavender oil nor tea tree oil can be linked to breast growth in young boys
Robert Tisserand
Introduction
In 2007, a correlation was alleged between commercial products containing lavender and
tea tree oils and breast growth in young boys. Three cases were seen in boys aged 4-7,
who had all been using such products. In each case, the breast growth reduced to normal
parameters within several months of ceasing to use the products. Subsequent laboratory
testing showed that both essential oils had estrogen-like properties (Henley et al 2007).
In the report, no information was given about any of the product ingredients, and there is
scant information on product use. No analysis was carried out to confirm or rule out the
presence of essential oil constituents.
Case one
In the first case, “The patient’s mother reported applying a “healing balm” containing
lavender oil to his skin starting shortly before the initial presentation.” No further details
of the product or its use are given, but a healing balm sounds like something that might
only be applied to a small area of skin. If so, then it is unlikely that any ingredient could
have entered the boy’s blood in sufficient concentration to cause gynecomastia within a
short time period.
Case two
In the second case, a styling hair gel was applied to the hair and scalp every morning,
along with regular use of a shampoo. Both tea tree oil and lavender oil are cited on the
ingredient list of both products.
In a subsequent website report, it is claimed that the two hair products used in this case
were manufactured by Paul Mitchell®, and that these were analyzed by a competitor.
The shampoo was said to contain “very low concentrations” of tea tree oil, and the
content in the hair gel was “virtually undetectable”. Lavender oil concentration was not
checked (Neustaedter 2007).
Dermal absorption of fragrance from shampoo ap p lication has been estimated to be 80
times less than that from body lotion (Cadby et al 2002) and tea tree oil constituents are
poorly absorbed by human skin. In one study, only 3% of the essential oil volume,
applied as a 20% concentration in ethanol, was absorbed in a 24 hour period (Cross and
Roberts 2006). If the website report is reliable, considering that shampoo is a wash-off
product, and that there was only a negligible amount of tea tree oil in the hair gel, tea tree
oil can be ruled out as a possible cause of this boy’s gynecomastia. However, liberal use
of a hair gel rich in lavender oil could result in moderate dermal absorption of lavender oil
constituents (Cal 2006).
Case three
The third case involved “lavender-scented soap, and intermittent use of lavender-scented
commercial skin lotions”. This sounds as if there may not be very much natural lavender
oil present. Since soap is a wash-off product, and use of the skin lotions is described as
“intermittent”, whether any meaningful absorption of lavender oil constituents took place
at all seems doubtful.
As dermal absorption of soap fragrance is some 266 times less than that from body
lotion, it is virtually impossible that the fragrance in a soap could be absorbed in sufficient
quantity to cause any physiological effect (Cadby et al 2002).
Of great interest is the statement that, in this third case, a fraternal twin used the same
skin lotions, but not the soap, and did not develop gynecomastia. It would be reasonable
to assume that, since the soap could not be responsible for the effect, and since the twin
used the lotions without any problem, the gynecomastia in this third case must have been
due to some cause other than essential oils.
The in vitro testing
The in vitro evidence shows weak but definite endocrine disrupting effects for both
lavender and tea tree oils.
The second case was the only one in which tea tree oil was involved. Tea tree oil was
tested because it was deemed to be “chemically similar” to lavender oil. However, apart
from the fact that both are essential oils, they have very little in common chemically.
The composition of the essential oils tested is not given, nor is any other information
about them, apart from the supplier. Since they do not appear to be organically grown,
biocide content is a possibility.
Discussion
It is unusual in such reports not to name the products suspected as being responsible for
the effects in question. In the circumstances, it is also curious that the labeled ingredients
were not cited. It is even more surprising that no attempt was made to ascertain,
retrospectively, whether any constituents of lavender or tea tree oil were detectable, and
if so at what concentrations. If the products are not named, no one else can test them
either.
Subsequent research has confirmed that tea tree oil does show weak in vitro estrogenic
action in MCF-7 cells (Nielsen 2008). However, none of the tea tree oil constituents that
penetrate human skin (terpinen-4-ol, α-terpineol, 1,8-cineole) act as estrogens, either
singly or in combination, in fact α-terpineol is anti-estrogenic (Cross et al 2008, Nielsen
2008, Reichling et al 2006). Tea tree oil is not a skin penetration enhancer, and in one
study reduced the quantity of other substances (benzoic acid and methiocarb) crossing the
dermal barrier (Nielsen and Nielsen 2006).
The two main lavender oil constituents, linalool and linalyl acetate, are absorbed by
human skin (Jäger et al 1992). However, transcutaneous absorption from fragrances takes
some time. The amount that could find its way into the blood from a wash-off product
such as a shampoo or soap is negligible, because the time of skin contact is so short. Skin
absorption from tea tree oil and lavender oil constituents is measured in hours rather than
minutes, and in some instances even leave-on products result in minimal dermal
penetration (Cal 2006, Reichling 2006).
No attempt was made to identify the constituent(s) responsible for the in vitro effect, but
it is reasonable to expect that any hormonal action in an essential oil would be due to one
or two constituents, or even contaminants. It is noteworthy that, while in vitro hormonal
effects from essential oil constituents have been previously reported, these are generally
very weak, and have been estimated as being at least 10,000 times less potent than 17
β
-
estradiol (Howes et al 2002). Very weak activity is typical of estrogens from plant
sources (Chadwick et al 2006).
There is no evidence that the effect seen in vitro would take place in vivo, and much more
research would be needed before any such conclusion could be drawn. The report
mentions that none of the boys had been exposed to any known endocrine disruptor, such
as medications, oral contraceptives(!), marijuana or soy products. However, no mention is
made of other known endocrine disruptors, including organochlorine pesticides, PCBs,
polychlorinated dioxins, alkyl phenols, pthalates and parabens (Darbre 2006). Both
pesticides and phthalates have been found in essential oils, and both phthalates and
parabens are commonly found in cosmetic products.
Personal care products have been identified as contributing to phthalate body burden in
adult men (Duty et al 2005); phthalates are commonly found in cosmetic products, and
are potential hormone disruptors (Darbre 2006). DEHP, for example, has hormone
disrupting effects in both male and female rats (Lovekamp-Swan and Davis 2003, Parks
et al 2000), and high levels of several phthalates were found in the blood of 28 of 41 pre-
pubertal girls (68%) with premature breast development compared to only 1 of 35
controls (3%) (Colón et al 2000).
It is, therefore, entirely possible that other ingredients or contaminants in the products
caused the gynecomastia. Pesticides, PCBs and dioxins are found in the environment,
often in food, and it is also possible that a local surge of environmental hormone
disruptors caused these cases in Colorado.
Conclusions
As the report states, breast growth in pre-pubertal boys is extremely uncommon, yet
three cases were reported within a short period of time, and all in the same clinic.
Considering that some 200 tonnes per annum are produced of both lavender oil and tea
tree oil, that most of this goes into personal care products, and that very little of the
evidence presented for these three cases is convincing, the initial press reports of caution
were premature, as are the cautions now found on many websites.
Even if one or more of these cases was linked to product use, any connection with either
lavender or tea tree oil is unproven. Other endocrine disrupting ingredients in the products
could have played a role. Furthermore, we do not know what other factors, such as
dietary or environmental, may have played a part.
The in vitro work reported by Henley et al (2007) does indicate a hormonal effect.
However, this cannot be extrapolated to estimate actual human risk, especially without
knowing more about the essential oil constituents causing the in vitro effects seen, the
amounts being applied to the body, and their bioavailability.
No connection was established between the in vitro work and the three cases, and the
evidence for tea tree oil having an effect on prepubertal gynecomastia is non-existent.
Phytoestrogens generally have a very weak hormonal activity, and it is implausible that
the amounts of essential oil that enter the body from product use would have a significant
effect.
References
Cadby PA, Troy WR, Vey MG 2002 Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology & Pharmacology 36:
246-252
Cal K 2006 How does the ty pe of vehicle influence the in vitro skin absorption and
elimination kinetics of terpenes? Archives of Dermatological Research 297: 311-315
Chadwick LR, Pauli GF, Farnsworth NR 2006 The pharmacognosy of Humulus lupulus
L. (hops) with an emphasis on estrogenic properties. Phytomedicine 13: 119-131
Colón I, Caro D, Bourdony CJ et al 2000 Identification of phthalate esters in the serum
of young Puerto Rican girls with premature breast development. Environmental Health
Perspectives 108:895-900
Cross S, Roberts M 2006 In-vitro human epidermal membrane penetration of tea tree oil
components from pure oil and a 20% formulation. A report to RIRDC (Australian Rural
Industry Research and Development Corporation)
Cross SE, Russell M, Southwell I et al 2008 Human skin penetration of the major
components of Australian tea tree oil applied in its pure form and as a 20% solution in
vitro. European Journal of Pharmaceutics & Biopharmaceutics 69:214-222
Darbre PD 2006 Environmental oestrogens, cosmetics and breast cancer. Best Practice &
Research Clinical Endocrinology & Metabolism 20: 121-143
Duty SM, Ackerman RM, Calafat AM et al 2005 Personal care product use predicts
urinary concentrations of some phthalate monoesters. Environmental Health Perspectives
113:1530-1535
FMA 2007 http://www.fmafragrance.org/sub_pages/020107henleyresponse.pdf
Henley DV, Lipson N, Korach KS, Bloch CA 2007 Prebubertal gynecomastia linked to
lavender and tea tree oils. New England Journal of Medicine 365(5): 479-485
Howes M-JR, Houghton PJ, Barlow DJ et al 2002 Assessment of estrogenic activity in
some common essential oil constituents. Journal of Pharmacy & Pharmacology 54:1521–
1528
Jäger W, Buchbauer G, Jirovetz L et al 1992 Percutaneous absorption of lavender oil from
a massage oil. Journal of the Society of Cosmetic Chemists 43:49-54
Lovekamp-Swan T, Davis BJ 2003 Mechanisms of phthalate ester toxicity in the female
reproductive system. Environmental Health Perspectives 111:139-145
Neustaedter R 2007 htt p://www.cure-
guide.com/Natural_Health_Newsletter/Lavender_Dangers/lavender_dangers.html
Nielsen JB 2008 What you see may not always be what you get - bioavailability and
extrapolation from in vitro tests. Toxicology in Vitro 22:1038-1042
Nielsen JB, Nielsen F 2006 Topical use of tea tree oil reduces the dermal absorption of
benzoic acid and methiocarb. Archives of Dermatological Research 297:395-402
Parks LG, Ostby JS, Lambright CR et al 2000 The plasticizer diethylhexyl phthalate
induces malformations by decreasing fetal testosterone synthesis during sexual
differentiation in the male rat. Toxicological Sciences 58:339-349
Reichling J, Landvatter U, Wagner H et al 2006 In vitro studies on release and human skin
permeation of Australian tea tree oil (TTO) from topical formulations. European Journal
of Pharmaceutics & Biopharmaceutics 64: 222-228
Robert Tisserand
... Tisserand has previously postulated [15] that phthalates may have contributed to the endocrine effect noted by Henley et al. [2]. Tisserand [15] also noted: ...
... Tisserand has previously postulated [15] that phthalates may have contributed to the endocrine effect noted by Henley et al. [2]. Tisserand [15] also noted: ...
Full-text available
Article
Lavender (Lavandula angustifolia) and tea tree (Melaleuca alternifolia) essential oils have been linked to endocrine disruption manifested as pre-pubertal breast development in children. The link is casual and based on weak in vitro data suggesting the oils have estrogenic activity. More work is required to explain the in vitro results. Any link, casual or causal, between lavender or tea tree oil product use and the pre-pubertal breast development has public health, regulatory, ecotoxicological and/or commercial consequences. It is worth considering that the chemical constituents of lavender and tea tree essential oils are not unique to those oils. They are found in hundreds of other essential oils. If these two oils did possess estrogenic activity, then it is likely that other essential oils would also have estrogenic activity by virtue of the constituents they share with lavender and tea tree oil. Each year thousands of tonnes of essential oils are ubiquitously ingested by and applied to humans and other animals in products such as foods, beverages, personal care products and pharmaceutical agents. Consequently, it is important that the nature of any link between essential oils and endocrine disruption be clarified.
Full-text available
Article
Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequately tested for transgenerational reproductive toxicity. This is cause for concern, because several recent investigations have shown that DEHP, BBP, DBP, and DINP disrupt reproductive tract development of the male rat in an antiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by (1) inhibiting testosterone (T) production, or by (2) inhibiting androgen action by binding to the androgen receptor (AR). Maternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to postnatal day (PND) 3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also reduced testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3ss-HSD staining and increased numbers of multifocal areas of Leydig cell hyperplasia as well as multinucleated gonocytes as compared to controls at GD 20 and PND 3. In contrast to the effects of DEHP on T levels in vivo, neither DEHP nor its metabolite MEHP displayed affinity for the human androgen receptor at concentrations up to 10 microM in vitro. These data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
Full-text available
Article
Estrogenic responses have not only been associated with endocrine function, but also with cognitive function. Several studies have indicated that estrogen replacement therapy has favourable effects on cognition, and may have potential in the prevention and treatment of Alzheimer's disease. Thus, ligands for the estrogen receptor, that have a better efficacy and adverse-effect profile than drugs currently available, require investigation. This study was undertaken to investigate the potential estrogenic activity of a number of essential oil constituents. Initially, estrogenic activity was determined by a sensitive and specific bioassay using recombinant yeast cells expressing the human estrogen receptor. At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed anti-estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol with the ligand-binding domain of the estrogen alpha-receptor, using the computer program HyperChem. Citral, geraniol, nerol and eugenol were also able to displace [(3)H]17beta-estradiol from isolated alpha- and beta-human estrogen receptors, but none of these compounds showed estrogenic or anti-estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti-androgenic activity. The potential in-vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.
Full-text available
Article
Phthalates are multifunctional chemicals used in a variety of applications, including personal care products. The present study explored the relationship between patterns of personal care product use and urinary levels of several phthalate metabolites. Subjects include 406 men who participated in an ongoing semen quality study at the Massachusetts General Hospital Andrology Laboratory between January 2000 and February 2003. A nurse-administered questionnaire was used to determine use of personal care products, including cologne, aftershave, lotions, hair products, and deodorants. Phthalate monoester concentrations were measured in a single spot urine sample by isotope dilution-high-performance liquid chromatography coupled to tandem mass spectrometry. Men who used cologne or aftershave within 48 hr before urine collection had higher median levels of monoethyl phthalate (MEP) (265 and 266 ng/mL, respectively) than those who did not use cologne or aftershave (108 and 133 ng/mL, respectively). For each additional type of product used, MEP increased 33% (95% confidence interval, 14-53%). The use of lotion was associated with lower urinary levels of monobutyl phthalate (MBP) (14.9 ng/mL), monobenzyl phthalate (MBzP) (6.1 ng/mL), and mono(2-ethylhexyl) phthalate (MEHP) (4.4 ng/mL) compared with men who did not use lotion (MBP, 16.8 ng/mL; MBzP, 8.6 ng/mL; MEHP, 7.2 ng/mL). The identification of personal care products as contributors to phthalate body burden is an important step in exposure characterization. Further work in this area is needed to identify other predictors of phthalate exposure.
Article
Synopsis In the present study, the percutaneous absorption of the essential oil of lavender from a massage oil was investigated. It was shown that lavender oil penetrates the skin of a male subject. Within five minutes of finishing, the massage traces of linalool (1) and linalyl acetate (2) as the main constituents of lavender oil could be detected in the blood. After 20 minutes, 100 ng/ml for 2 and 121 ng/ml for 1 showed up as the maximum concentration. Within 90 minutes, most of the lavender oil was eliminated. The sedative and relaxing effect of lavender oil after a massage may be based on two different ways of incorporation: the inhalation of fragrant molecules and the penetration through the skin.
Article
Premature breast development (thelarche) is the growth of mammary tissue in girls younger than 8 years of age without other manifestations of puberty. Puerto Rico has the highest known incidence of premature thelarche ever reported. In the last two decades since this serious public health anomaly has been observed, no explanation for this phenomenon has been found. Some organic pollutants, including pesticides and some plasticizers, can disrupt normal sexual development in wildlife, and many of these have been widely used in Puerto Rico. This investigation was designed to identify pollutants in the serum of Puerto Rican girls with premature thelarche. A method for blood serum analysis was optimized and validated using pesticides and phthalate esters as model compounds of endocrine-disrupting chemicals. Recovery was > 80% for all compounds. We performed final detection by gas chromatography/mass spectrometry. We analyzed 41 serum samples from thelarche patients and 35 control samples. No pesticides or their metabolite residues were detected in the serum of the study or control subjects. Significantly high levels of phthalates [dimethyl, diethyl, dibutyl, and di-(2-ethylhexyl)] and its major metabolite mono-(2-ethylhexyl) phthalate were identified in 28 (68%) samples from thelarche patients. Of the control samples analyzed, only one showed significant levels of di-isooctyl phthalate. The phthalates that we identified have been classified as endocrine disruptors. This study suggests a possible association between plasticizers with known estrogenic and antiandrogenic activity and the cause of premature breast development in a human female population.
Article
To fully apply already published procedures for the safety evaluation of fragrance ingredients, it is necessary to estimate exposure through different routes and leading to different potential endpoints. Worst-case scenario calculations indicate that deposition on the surface of the skin following use of cosmetics represents the major route of exposure to fragrance ingredients when conservative estimates for evaporation, rinsing, and other forms of product removal are employed. Hydroalcoholic perfumes and colognes deliver the highest dose after single product use. Surveys of formulas used in this type of product allow the calculation of average maximum or upper 97.5th percentile concentration of the ingredient in formulas. With this type of exaggeration, the use of estimates of "typical" cosmetic use can be maximized to take account of excessive consumption patterns for both short-term and long-term exposure estimates. In the latter case, multiple product use must be considered. Short-term exposure (single product doses) of an ingredient found at an average maximum use level of P% in fragrances is taken to be 0.2 x P% or 3P microg/cm(2). Using upper 97.5th percentile concentrations (P(97.5)) of individual ingredients in fragrances, the long-term exposure is taken to be P(97.5) x 2,547 microg/kg body wt/day. The estimates of long-term exposure incorporate a number of highly conservative assumptions (e.g., over a long period, every product used will contain a fragrance with this ingredient at this high (P(97.5)) level).
Article
Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
Article
Tea tree oil (TTO) is a complex mixture of terpene hydrocarbons. Intensive topical use of TTO in different cosmetics and investigations into its potential as an antimicrobial or anti-inflammatory agent has accentuated the need for studies on the toxicity of TTO. We have applied an experimental in vitro model using static diffusion cells with human skin to study penetration characteristics of terpinen-4-ol and the way TTO affects the barrier integrity of the skin and the percutaneous penetration of two chemicals covering a range of solubilities from 0.03 g/l (methiocarb) to 3.0 g/l (benzoic acid). Through GC–MS analysis we identified the major constituents of TTO. In our experimental set-up with full-thickness skin, only the least lipophilic ingredients of TTO penetrated the skin. Barrier integrity was evaluated through measurement of percutaneous penetration of tritiated water. Data indicate that 1% TTO does not affect barrier conditions. The K p value for tritiated water was increased significantly at 5% TTO, which demonstrate that the barrier integrity is affected at this relatively low concentration of TTO. The barrier integrity is, however, not seriously damaged, but our data indicate an initiated and concentration-dependent effect on the barrier integrity. TTO changed the penetration characteristics for benzoic acid as well as for methiocarb. The general effect was that TTO reduced the maximal flux. For methiocarb, the lag-time was also prolonged by increasing the TTO concentration in the donor phase to 5%. Thus, TTO reduced the overall amount of benzoic acid as well as methiocarb entering the receptor chamber.
Article
Terpenes are widely used in the topical dermal preparations, cosmetics and toiletries and also in the experimental dermopharmacy, as penetration enhancers. Terpenes do not need to penetrate into viable skin tissue and this event is not even desired. The aim of this study was to investigate skin absorption and elimination kinetics of two terpenes, namely linalool and terpinen-4-ol, incorporated in three different dermatological vehicles: oily solution, hydrogel and o/w emulsion. The preparations were applied onto the human skin in vitro, and after 1-4 h the content of terpenes in the stratum corneum layers and in the epidermis/dermis was determined using GC. Similarly, the amounts of terpenes in the skin were analysed during 4 h elimination process following 1 h absorption. The highest skin absorption was observed when terpenes were applied in hydrogel--their total content in the skin after 4 h was 385 and 705 microg/cm2 for linalool and terpinen-4-ol, respectively. After 1 h of the elimination process about 10-20% drop of the total content of both terpenes in the skin was noted for all formulations. The skin penetration of both terpenes from the vehicles is increasing in the following order: emulsion < oily solution < hydrogel, while the elimination phase is relatively slower for terpenes applied in hydrogel.
Article
As the population ages, there is an ever-increasing need for therapeutic agents that can be used safely and efficaciously to manage symptoms related to postmenopausal estrogen deficiency. Endogenous estrogens, e.g., 17beta-estradiol, of exogenous mammalian origin, e.g., horses, have long been used to manage such symptoms. There are more than 20 different classes of phytochemicals that have demonstrated affinity for human estrogen receptors in vitro. Some studies on exogenous estrogenic substances of botanical origin (phytoestrogens), such as standardized formulations of plant extracts with in vitro and in vivo estrogenic activity from soy (Glycine max Merill.) and red clover (Trifolium pratense L.), suggest clinical efficacy. Few clinical data for phytoestrogens other than isoflavonoids are available. In an exhaustive review of the literature through 2003, only two clinical trials were identified that were designed to evaluate the effect of hops (Humulus lupulus L.) on symptoms related to menopause. Folkloric, chemical, and biological literature relating primarily to the use of hops for their estrogenic activity, and two human clinical trials, are reviewed.