Environmental exogenous estrogens, otherwise referred to as xenoestrogens, are endocrine disruptors, structurally similar to estrogens. Xenoestrogens are clinically significant because they can mimic the effects of endogenous estrogen and thus have been implicated in precocious puberty and other disorders of the reproductive system. Exogenous estrogens can be found in pesticides, flexible plastics, flame retardants, interior lining of canned foods, various cosmetics and numerous other products. Exogenous estrogens are thought to cause many detrimental health effects such as precocious puberty in girls.

Trends in pubertal timing

Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function. The first sign of puberty is an acceleration of growth followed by the development of a palpable breast bud (thelarche). The median age of thelarche is 9.8 years. Although the sequence may be reversed, androgen dependent changes such as growth of axillary and pubic hair, body odor and acne (adrenarche) usually appears 2 years later. Onset of menstruation (menarche) is a late event (median 12.8 years), occurring after the peak of growth has passed.

Puberty is considered precocious if secondary sex characteristics occur before the age of 8 in girls and 9 years in boys. Increased growth is often the first change in precocious puberty, followed by breast development and growth of pubic hair. However, thelarche

Thelarche

Thelarche is the onset of secondary breast development, usually occurring at the beginning of puberty in girls. Its etymology is from Greek θηλή [tʰelḗ], “nipple” and ἀρχή [arkʰḗ], “beginning, onset”. Thelarche is usually noticed as a firm, tender lump directly under the centre of the nipple...

, adrenarche

Adrenarche

Adrenarche is an early sexual maturation stage in some higher primates that in humans typically occurs at around 6 to 8 years of age. During adrenarche the adrenal cortex secretes increased levels of androgens such as DHEA and DHEAS, but without increased cortisol levels. Adrenarche is the result...

, and linear growth can occur simultaneously and although uncommon, menarche

Menarche

Menarche is the first menstrual cycle, or first menstrual bleeding, in female human beings. From both social and medical perspectives it is often considered the central event of female puberty, as it signals the possibility of fertility....

 can be the first sign. Precocious puberty can be classified into central (gonadotropin-dependent) precocious puberty or peripheral (gonadotropin-independent) puberty. Peripheral precocious puberty has been linked to exposure to exogenous estrogenic compounds.

Age of onset of puberty is influenced by many factors such as genetics, nutritional status, ethnicity and environmental factors including socio-economic conditions and geographical location. A decline of age at onset of puberty from 17 years of age to 13 years of age has occurred over a period of 200 years until the middle of the 20th century. Trends toward earlier puberty have been attributed to improved public health and living conditions. A leading hypothesis for this change toward early puberty is improved nutrition resulting in rapid body growth, increased weight and fat deposition.

Two recent epidemiologic studies in the United States (PROS and NMANES III) highlighted a recent unexpected advance in sexual maturation in girls. American, European and Asian studies suggest breast development in girls occurs at a much younger age than a few decades ago, irrespective of race and socioeconomic conditions. Environmental chemical exposure is one of the factors implicated in the recent downward trend of earlier sexual maturation.

Atrazine

Atrazine

Atrazine

Atrazine, 2-chloro-4--6--s-triazine, an organic compound consisting of an s-triazine-ring is a widely used herbicide. Its use is controversial due to widespread contamination in drinking water and its associations with birth defects and menstrual problems when consumed by humans at concentrations...

 is widely used as an herbicide to control broad-leaf weed species that grow in crops such as corn, sugarcane, hay and winter wheat. Atrazine is also applied to Christmas trees, residential lawns, golf courses, and other recreational areas. Atrazine is the second largest selling pesticide in the world and estimated to be the most heavily used herbicide in the United States.

BPA

BPA (Bisphenol A

Bisphenol A

Bisphenol A is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications....

) is the monomer used to manufacture polycarbonate

Polycarbonate

PolycarbonatePhysical PropertiesDensity 1.20–1.22 g/cm3Abbe number 34.0Refractive index 1.584–1.586FlammabilityV0-V2Limiting oxygen index25–27%Water absorption – Equilibrium0.16–0.35%Water absorption – over 24 hours0.1%...

 plastic and epoxy resins used as a lining in most food and beverage cans. BPA global capacity is in excess of 6.4 billion lbs per year and thus is one of the highest-volume chemicals produced worldwide. The ester bonds in these BPA-based polymers are subject to hydrolysis and leaching of BPA has led to widespread human exposure.

DDT

DDT (Dichlorodiphenyltrichloroethane) was widely used in pesticides for agriculture until it was banned in 1972 in the United States due to its hazardous effects on the environment. DDT continues to be used in many parts of the world for agricultural use, insect control and to fight the spread of malaria. DDT and its metabolites DDE and DDD are persistent in the environment and accumulate in fatty tissues.

Dioxin

Dioxin

Dioxin

Polychlorinated dibenzodioxins , or simply dioxins, are a group of organic polyhalogenated compounds that are significant environmental pollutants. They are commonly but inaccurately referred to as dioxins for simplicity, because every PCDD molecule contains a dioxin skeletal structure as the...

, a group of highly toxic chemicals are released during combustion processes, pesticide manufacturing and chlorine bleaching of wood pulp. Dioxin is discharged into waterways from pulp and paper mills. Consumption of animals fats is thought to be the primary pathway for human exposure.

Endosulfan

Endosulfan

Endosulfan

Endosulfan is an off-patent organochlorine insecticide and acaricide that is being phased out globally. Endosulfan became a highly controversial agrichemical due to its acute toxicity, potential for bioaccumulation, and role as an endocrine disruptor...

 is an insecticide used on numerous vegetables, fruits, cereal grains and trees. Endosulfan can be produced as a liquid concentrate, wettable powder or smoke tablet. Human exposure occurs through food consumption or ground and surface water contamination.

PBB

PBB (Polybrominated biphenyls) are chemicals added to plastics used in computer monitors, televisions, textiles and plastics foams to make them more difficult to burn. Manufacturing of PBBs in the United States stopped in 1976, however because they do not degrade easily PBBs continue to be found in soil, water and air.

PCBs

PCBs (Polychlorinated biphenyls) are man made organic chemicals known as chlorinated hydrocarbons. PCBs were manufactured primarily for use as insulating fluids and coolants given their chemical stability, low flammability and electrical insulating properties. PCBs were banned in 1979 but like DDT continue to persist in the environment.

Phthalates

Phthalates

Phthalates

Phthalates , or phthalate esters, are esters of phthalic acid and are mainly used as plasticizers . They are used primarily to soften polyvinyl chloride...

 are plasticizers providing durability and flexibility to plastics such as polyvinyl chloride. High molecular weight phthalates are used in flooring, wall coverings and medical device such as intravenous bags and tubing. Low molecular weight phthalates are found in perfumes, lotions, cosmetics, varnishes, lacquers and coatings including timed releases in pharmaceuticals.

Zeronal

Zeronal has been used as an anabolic growth promoter for livestock in the US. Zeranol has been banned but is still present as a contaminant in our food through meat products that were exposed to zeronal.

Mechanism of action (biological plausibility)

The onset of puberty is characterized by increased levels of hypothalamic gonadotropin releasing hormone (GnRH). GnRH triggers the secretion of luteinizing hormone

Luteinizing hormone

Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...

 (LH) and follicle-stimulating hormone

Follicle-stimulating hormone

Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...

 (FSH) from the anterior pituitary gland, which in turn causes the ovaries to respond and secrete estradiol

Estradiol

Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...

. Increases in gonadal estrogen promote breast development, female fat distribution and skeletal growth. Adrenal androgen and gonadal androgen result in pubic and axillary hair. Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.

Hormones or substances with hormone disrupting capability may interfere with pubertal development by actions at different levels – hypothalamic-pituitary axis, gonads, peripheral target organs such as the breast, hair follicles and genitals. Exogenous man made chemicals that mimic estrogen can alter the functions of the endocrine system and cause various health defects by interfering with synthesis, metabolism, binding or cellular responses of natural estrogens.

Although the physiology of the reproductive system is complex, the action of environmental exogenous estrogens is hypothesized to occur by two possible mechanisms. Xenoestrogens may temporarily or permanently alter the feedback loops in the brain, pituitary, gonads, and thyroid by mimicking the effects of estrogen and triggering their specific receptors or they may bind to hormone receptors and block the action of natural hormones. Thus it is plausible that environmental estrogens can accelerate sexual development if present in a sufficient concentration or with chronic exposure. The similarity in the structure of exogenous estrogens and the estrogens has changed the hormone balance within the body and resulted in various reproductive problems in females. The overall mechanism of action is binding of the exogenous compounds that mimic estrogen to the estrogen binding receptors and cause the determined action in the target organs.

Animal studies

Animal studies have shown that exposure to environmental contaminants with estrogenic activity can accelerate the onset of puberty. A potential mechanism has been described in rats exposed to DDT or beta-estradiol in which GnRH pulsatile secretion was found to be increased. Oral exposure of female rats to xenoestrogens has been shown to cause pseudo precocious puberty (early vaginal opening and early first estrus). A study of dioxin in immature female rats induced early follicular development and phthalates are known to decrease the anogenital distance

Anogenital distance

Anogenital distance is the distance from the anus to the genitalia, the base of the penis or vagina. It is considered medically significant for a number of reasons, in both humans and animals. It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics...

 in newborn rats. Although this article focuses on the effects of xenoestrogens and reproductive function in females, numerous animal studies also implicate environmental estrogens' and androgens' adverse effects on the male reproduction system. Administration of estrogens to developing male animals reduces testicular weight and decreases sperm production. The small phallus size of male alligators has been linked to contamination of their natural Florida habitat with DDT. Data from animal research is abundant demonstrating the adverse effects on reproduction of hormonally active compounds found in the environment.

Case control study of thelarche in Puerto Rico

Since 1979 pediatric endocrinologists in Puerto Rico recognized an increase in number of patients with premature thelarche. The presence of phthalates were measured in the blood of 41 girls experiencing early onset breast development and matched set of controls. The average age of girls with premature thelarche was 31 months. They found high phthalate levels in the girls suffering from premature thelarche compared to the controls. Not all cases of premature thelarche in the study sample contained elevated levels of phthalate esters and there was concern whether artificial contamination from vinyl lab equipment and tubing invalidated the results, hence weakening the link between exposure and causation.

Michigan Anglers Cohort

The Great Lakes have been polluted with industrial wastes (mainly PCBs and DDT) since the beginning of the 20th century. These compounds have accumulated in birds and sports fish. A study was designed to assess the impact of consumption of contaminated fish on pregnant women and their children. Concentrations of maternal serum PCB and DDE and their daughters’ age at menarche were reviewed. In multivariate analysis, DDE but not PCB was linked with a lowered age of menarche. Limitations of the study included indirect measurement of the exposure and self reporting of menarche.

Tuscany precocious puberty cases

Dr. Massart and colleagues from the University of Pisa

University of Pisa

The University of Pisa , located in Pisa, Tuscany, is one of the oldest universities in Italy. It was formally founded on September 3, 1343 by an edict of Pope Clement VI, although there had been lectures on law in Pisa since the 11th century...

studied the increased prevalence of precocious puberty in a region of northwest Tuscany. This region of Italy is represented by a high density of navy yards and greenhouses where exposures to pesticides and mycoestrogens (estrogens produced by fungi) are common. Although unable to identify a definitive cause of the high rates of precocious puberty, the authors concluded environmental pesticides and herbicides may be implicated.

Animal feed and PBB

Animal feed was contaminated with several thousand pounds of polybrominated biphenyl in Michigan in 1973 resulting in high exposures of PBB in the population via milk and other products from contaminated cows. Perinatal exposure of children was estimated by measuring PBB in serum of mothers some years after exposure. Girls that had been exposed to high PBB levels through lactation had an earlier age of menarche and pubic hair development than girls who had less perinatal exposure. The study noted there no differences found in the timing of breast development among the cases and controls.

Implications

Precocious puberty has numerous significant physical, psychological and social implications for a young girl. Unfortunately, premature pubertal growth spurt and accelerated bone maturation will result in premature closure of distal epiphysis which causes reduced adult height and short stature. Precocious puberty has also been implicated in pediatric and adult obesity. Some studies have suggested precocious puberty places girls at a higher risk of breast cancer later in life. Precocious puberty is linked with other gynecologic disorders such endometriosis, adenomyosis, polycystic ovarian syndrome and infertility. Precocious puberty can lead to psychosocial distress, a poor self-image, and poor self-esteem. Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse Studies indicate that girls who become sexually mature at earlier ages are also more likely to engage in risk-taking behaviors such as smoking, alcohol or drug use, and engage in unprotected sex. In 1999, US Food and Drug Administration has recommended to not take estrogen in food of more than 3.24 ng per day for females.

Conclusion

The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty. Gaps in our knowledge are the result of limitations in the designs of studies, small sample sizes, challenges to conducting exposure assessment and the few number of chemicals studied. Unfortunately exposure is inferred and not actually measured in available studies. The ability to detect the possible role of chemicals in altering pubertal development is confounded by many nutritional, genetic and lifestyle factors capable of affecting puberty and the complex nature of the reproductive endocrine system. Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds.
Overall the literature does not with certainty support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. However data does not refute such a hypothesis either. Accelerated sexual development is plausible in individuals exposed to high concentration of estrogenic substances. There is a concerning steady increase in exposure to a wide variety of xenoestrogens in the industrial world. Further research is needed to assess the impact of these compounds on pubertal development.

Recommendations

Recommendations one may consider to limit unnecessary exposure to xenoestrogens might include the following:

• Avoid using pesticides, herbicides or insecticides when young children could become exposed.
• Teach children good hand washing practices to reduce possible exposures.
• Encourage children to get plenty of exercise to promote elimination of contamination through perspiration.
• Pediatricians can teach parents and children the dangers of pesticides and herbicides and the importance of judicial and proper use of insect repellents.
• Prevent children from chewing on plastic toys.
• Avoid consumption of fish more than three times a week and avoid consumption of fatty meat products.
• Avoid canned foods, dental sealants and polycarbonated plastic products that contain BPA.
• Do not cook foods packaged in plastics in the microwave oven; instead consider glass or ceramic products.
• Avoid food storage in plastic containers and plastic wraps. Avoid freezing water in plastic containers.
• Consider filtered water for drinking and cooking.
• Do not forget to thoroughly wash fresh fruit and vegetables. Consider buying hormone free meats when possible.
• Avoid using plastic bottles for drinking water; instead use a stainless steel or glass container.
• Do not leave the plastic containers in the sun and if they are exposed in the sun, do not use the container for drinking or food.
• Read labels for ingredients containing parabens and stearal konium chloride, rapidly absorbed xenoestrogens commonly used in cosmetics.
• Consider natural and organic cosmetic products, soaps and laundry detergents.
• Check web sites for hormone mimicking chemicals to increase one’s awareness of possible sources of contamination. These may include environmental estrogens but also other chemicals that potentially disrupt the endocrine system.