Anogenital distance (AGD) is the distance from the midpoint of the anus to the genitalia, the underside of the vagina, the clitoris or the scrotum. It is considered medically significant for a number of reasons, in both humans and other animals, including sex determination and as a marker of endocrine disruptor exposure. [1] It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics.
The anogenital index (AGI) is an index used to compare the AGD relative to a model based on body weight. [2] It is computed as the AGD divided by weight [AGI = AGD/weight (mm/kg)]. [3]
The AGD is usually measured as follows: from the center of the anus to the posterior convergence of the fourchette (where the vestibule begins) in females (AGD-AF); and from the center of the anus to the junction of the smooth perineal skin with the rugate skin of the scrotum in males (AGD-AS). [4] An alternative measurement, AGD-AC, defined only in females, is measured from the anus to the clitoris. [5]
Early studies showed that the human perineum was half as long in females as in males, but it has since been found to be three quarters the male distance in females, [6] although males have more variance. Measuring the anogenital distance in neonatal humans has been suggested as a noninvasive method to determine male feminisation and female virilization and thereby predict neonatal and adult reproductive disorders. [7]
A study by Swan et al. determined that the AGD is linked to fertility in males, and penis size. [3] Males with a short AGD (lower than the median around 52 mm (2 in)) have seven times the chance of being sub-fertile as those with a longer AGD. It is linked to both semen volume and sperm count. [8] A lower than median AGD also increases the likelihood of undescended testes, and lowered sperm counts and testicular tumors in adulthood. Babies with high total exposure to phthalates were ninety times more likely to have a short AGD, despite not every type of the nine phthalates tested being correlated with shorter AGD. [3]
Swan et al. report that the levels of phthalates associated with significant AGD reductions are found in approximately one-quarter of Americans tested by the Centers for Disease Control and Prevention (CDC) for phthalate body burdens. [3]
Women who had high levels of phthalates in their urine during pregnancy gave birth to sons who were ten times more likely to have shorter than expected AGDs. [9]
A 2018 study by Barrett et al. found that infant girls born to women with polycystic ovary syndrome (PCOS) had longer AGD, suggesting higher fetal testosterone exposure, than girls born to women without PCOS. [10]
Hypospadias and cryptorchidism are conditions which may be induced in males with short AGD. [11] [12] Other problems in males include risk of testicular dysgenesis syndrome. [2]
There have been extensive studies of AGD effects on animals. In some animals, it is routinely measured to determine health.
Experiments have demonstrated that in rodent studies this distance is shortened when the mother is exposed to chemicals that are anti-androgenic, such as dibutyl phthalate (DBP) or benzyl butyl phthalate (BBzP).
Bisphenol A in certain doses increases the AGD of both genders of a study on mice. [13]
In 2017, Gobikrushanth et al. studied the relationship between AGD (the distance from the center of the anus to the base of the vagina and the clitoris) and fertility in Canadian Holstein cows. They found that in first and second parity cows an increase in AGD has an inverse correlation with pregnancy success after first artificial insemination. This correlation was not found in third+ parity cows. [14]
The perineum in mammals is the space between the anus and the genitals. The human perineum is between the anus and scrotum in the male or between the anus and vulva in the female. The perineum is the region of the body between the pubic symphysis and the coccyx, including the perineal body and surrounding structures. The perineal raphe is visible and pronounced to varying degrees. The perineum is an erogenous zone. This area is also known as the taint or gooch in American slang.
The digit ratio is the ratio taken of the lengths of different digits or fingers on a hand. In modern sciences, the 2D:4D ratio has become the most commonly studied digit ratio and is calculated by dividing the length of the index finger of a given hand by the length of the ring finger of the same hand. On average, males have a lower 2D:4D ratio than females.
Phthalates, or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften polyvinyl chloride (PVC). Note that while phthalates are usually plasticizers, not all plasticizers are phthalates. The two terms are specific and unique and cannot be used interchangeably.
Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek κρυπτός 'hidden' and ὄρχις 'testicle'. It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis. However, about 80% of cryptorchid testes descend by the first year of life, making the true incidence of cryptorchidism around 1% overall. Cryptorchidism may develop after infancy, sometimes as late as young adulthood, but that is exceptional.
Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine systems. These disruptions can cause numerous adverse human health outcomes including, alterations in sperm quality and fertility, abnormalities in sex organs, endometriosis, early puberty, altered nervous system function, immune function, certain cancers, respiratory problems, metabolic issues, diabetes, obesity, cardiovascular problems, growth, neurological and learning disabilities, and more. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis ."
Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives in what would be considered a genetically and otherwise physically normal male animal by typical human based standards. In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives. PMDS can also present in non-human animals.
Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.
Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) is an organic compound with the formula C6H4(CO2C8H17)2. DEHP is the most common member of the class of phthalates, which are used as plasticizers. It is the diester of phthalic acid and the branched-chain 2-ethylhexanol. This colorless viscous liquid is soluble in oil, but not in water.
Diisobutyl phthalate (DIBP) is a phthalate ester having the structural formula C6H4(COOCH2CH 2)2. It is formed by the esterification of isobutanol and phthalic anhydride. This and other phthalates are used as plasticizers due to their flexibility and durability. They are found in many industrial and personal products, such as lacquers, nail polish and cosmetics. DIBP can be absorbed via oral ingestion and dermal exposure. When it comes to excretion, DIBP is first converted into the hydrolytic monoester monoisobutyl phthalate (MIBP). The primary excretory route is urine, with biliary excretion being noted in minor amounts. DIBP has lower density and freezing point than the related compound dibutyl phthalate (DBP).
Semen quality is a measure of male fertility, a measure of the ability of sperm in semen to accomplish fertilization. Semen quality involves both sperm quantity and quality. Semen quality is a major factor for fertility.
Bisphenol S (BPS) is an organic compound with the formula (HOC6H4)2SO2. It has two phenol functional groups on either side of a sulfonyl group. It is commonly used in curing fast-drying epoxy resin adhesives. It is classified as a bisphenol, and a close molecular analog of bisphenol A (BPA). BPS differentiates from BPA by possessing a sulfone group (SO2) as the central linker of the molecule instead of a dimethylmethylene group (C 2), which is the case of bisphenol A.
Diethyl phthalate (DEP) is a phthalate ester. It occurs as a colourless liquid without significant odour but has a bitter, disagreeable taste. It is more dense than water and insoluble in water; hence, it sinks in water.
Reproductive toxicity refers to the potential risk from a given chemical, physical or biologic agent to adversely affect both male and female fertility as well as offspring development. Reproductive toxicants may adversely affect sexual function, ovarian failure, fertility as well as causing developmental toxicity in the offspring. Lowered effective fertility related to reproductive toxicity relates to both male and female effects alike and is reflected in decreased sperm counts, semen quality and ovarian failure.
Xenohormones or environmental hormones are compounds produced outside of the human body which exhibit endocrine hormone-like properties. They may be either of natural origin, such as phytoestrogens, which are derived from plants, or of synthetic origin. These compounds can cause endocrine disruption by multiple mechanisms including acting directly on hormone receptors, affecting the levels of natural hormones in the body, and by altering the expression of hormone receptors. The most commonly occurring xenohormones are xenoestrogens, which mimic the effects of estrogen. Other xenohormones include xenoandrogens and xenoprogesterones. Xenohormones are used for a variety of purposes including contraceptive & hormonal therapies, and agriculture. However, exposure to certain xenohormones early in childhood development can lead to a host of developmental issues including infertility, thyroid complications, and early onset of puberty. Exposure to others later in life has been linked to increased risks of testicular, prostate, ovarian, and uterine cancers.
Bisphenol F is an organic compound with the chemical formula (HOC
6H
4)
2CH
2. It is structurally related to bisphenol A (BPA), a popular precursor for forming plastics, as both belong to the category of molecules known as bisphenols, which feature two phenol groups connected via a linking group. In BPF, the two aromatic rings are linked by a methylene connecting group. In response to concern about the health effects of BPA, BPF is increasingly used as a substitute for BPA.
Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.
Antiandrogens in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides, exhibit antiandrogen activity in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.
Bisphenol A controversy centers on concerns and debates about the biomedical significance of bisphenol A (BPA), which is a precursor to polymers that are used in some consumer products, including some food containers. The concerns began with the hypothesis that BPA is an endocrine disruptor, i.e. it mimics endocrine hormones and thus has the unintended and possibly far-reaching effects on people in physical contact with the chemical.
Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen which was previously used clinically to support pregnancy, has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy and in their offspring.
Kelly K. Ferguson is an American public health researcher who is a Senior Investigator in the National Institute of Environmental Health Sciences. She leads the Perinatal and Early Life Epidemiology Group, which studies how maternal exposure to chemicals impacts pregnancy and development. In 2021, she was awarded the inaugural Lou Guillette Jr. Outstanding Young Investigator Award.