What Are Endocrine Disrupters and Where Are They Found?

Philippa D. Darbre, in Endocrine Disruption and Human Health, 2015

1.6.12 Synthetic Hormones

Synthetic hormones have become widely distributed in the environment from their use as pharmaceuticals. Synthetic estrogens [most notably ethinylestradiol (Figure 1.9)], in combination with synthetic progestins, are used in contraceptive [66] and hormone replacement therapy [67] formulations. Synthetic glucocorticoids are prescribed widely as antiinflammatory agents [68]. Antiestrogens, aromatase inhibitors [69], and antiandrogens are prescribed for cancer therapy. Diethylstilbestrol (Figure 1.9) is a synthetic nonsteroidal estrogen that was first synthesized in 1938 [4] and then prescribed to several million women between 1940 and 1971 to prevent threatened miscarriage in the first trimester [5] before untoward side effects stopped this practice [70] (see Chapters 8 and 9Chapter 8Chapter 9). All these compounds may be released into the environment not only as the parent compound, but also as the metabolites in the urine and feces of people who use them as medications.

Figure 1.9. Chemical structures of pharmaceutical products.

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Assuring Purity of Drinking Water

D.A. Birkholz, ... H.S. Elliott, in Comprehensive Water Quality and Purification, 2014

2.11.3.1.9 Hormones

Natural and synthetic hormones are excreted by humans every day and ultimately find their way to STPs where they may not be completely removed. Furthermore, livestock operations may release hormones to the receiving environment without treatment. Natural hormones include 17α-estradiol, 17β-estradiol, estrone, estriol, 17α-dihydroequilin, testosterone, and progesterone. Synthetic hormones are also used in medicine and include gestodene, norgestrel, levonorgestrel, medrogestone, 17α-ethynylestradiol, and trimegestone. Several hormones have been detected in surface water samples and drinking water. See Table 8 for more details on hormones found in the environment. The presence of hormones in the environment causes concern because it has been suggested that estrogens may be linked to certain adverse health effects such as lower sperm counts in adult males and an increase in cancers that are hormone dependent (Velicu and Suri, 2009). Steroid hormones most often detected in surface waters include 17α-estradiol, 17β-estradiol, 17α-dihydroquilin, estriol, estrone, progesterone, 17α-ethynylestradiol, and testosterone (Velicu and Suri, 2009; Arikan et al., 2008). Levels detected are in the range of 0.6–19 ng l−1 (Velicu and Suri, 2009).

Table 8. Levels of hormones found in the environment

Compound/CAS number Matrices Concentration range (ng l−1) Author
Norethindrone (norethisterone) 68-22-4 Waste water effluent 188 Al-Odaini et al. (2010)
Levonorgestrel 797-63-7 Surface water 38 Al-Odaini et al. (2010)
17β-Estradiol (E2) 50-28-2 Surface water and urban waste water ND–3000 Verlicchi et al. (2010)
Sodré et al. (2010a)
Estriol (E3) 50-27-1 Surface water and urban waste water ND–400 Verlicchi et al. (2010)
Sodré et al. (2010a)
Arikan et al. (2008)
Estrone (E1) 53-16-7 Surface water, urban waste water ND–100 Verlicchi et al. (2010)
Sodré et al. (2010a)
Loos et al. (2010)
Ethinylestradiol (EE2) 57-63-6 Surface water and urban waste water ND–8000 Verlicchi et al. (2010)
Sodré et al. (2010a)
Arikan et al. (2008)
Testosterone 58-22-0 Surface Water ND–16 Arikan et al. (2008)
Progesterone 57-83-0 Surface water ND–14 Arikan et al. (2008)
Cholesterol 57-88-5 Tap water 270 Sodré et al. (2010b)
Stigmasterol 83-48-7 Tap water 340 Sodré et al. (2010b)

Abbreviations: CAS, chemical abstracts service; ND, not detected.

Source: Reproduced from Richardson, 2009 and Perez and Barcelo, 2008.

Solid-phase extraction employing RP-C18, LiChrolute EN, and Oasis HLB, followed by LC-tandem-MS is the method of choice. Both ESI and APCI ionization modes are applied, followed by monitoring for both positive and negative ions (Richardson, 2009; Perez and Barcelo, 2008).

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Hormones

Abdulmumeen A. Hamid, ... Nina Naquiah Ahmad Nizar, in Preparation and Processing of Religious and Cultural Foods, 2018

13.6.1 Synthetic/artificial hormone exploitation in human

Currently, synthetic hormone treatment for several diseases in human is not uncommon. The number of approved and proposed uses of synthetic hormone has grown and the number of patients being treated with them has increased worldwide. Controlled use of synthetic hormones, with appropriate advice from medical experts would help in curing diseases such as Diabetes or Turner's syndrome, however, if misused; a lot of bad effects could take place. Here, we would discuss on the usage of common synthetic/artificial hormones namely human growth hormone, sex hormones and insulin.

Synthetic Human Growth Hormone (HGH) was developed over 30 years ago and approved by the FDA for specific uses in children and adults. HGH is used in children as treatment for short physique of unidentified reason, or poor growth due to a number of medical causes, including Turner's syndrome and Prader-Willi syndrome. On the other hand, HGH is used to overcome short bowel syndrome, HGH deficiency caused by rare pituitary tumors and muscle-wasting disease linked with HIV/AIDS in adults (Human Growth Hormone (HGH), 2018). Too much or too little GH in adults and children may cause health problems that could be treated with synthetic (manufactured) HGH.

Sometimes HGH is used illegally for nonmedical purposes (Goldberg et al., 2009). However, these uncontrolled uses for HGH are not FDA-approved. In some cases, this hormone is used with other performance-enhancing drugs such as anabolic steroids for muscle building and improvement of athletic performance. Nonetheless HGH's effect on athletic performance is unknown. The misuse of HGH in sport has steadily increased as HGH has been considered as an ergogenic drug. It is believed to be efficient, almost undetectable and harmless if well dosed (Saugy et al., 2006). Likewise, the use of HGH for antiaging is not FDA-approved (Human Growth Hormone (HGH), 2018).

As explained in earlier sections, estrogen and progesterone are two common female sex hormones important in menstrual cycle, ovulation and pregnancy. It is well known that the contraceptive quality of progesterone led to the development of structurally modified progestins and estrogens—the oral contraceptives known as birth-control pills, used by women to prevent unwanted pregnancy. On the other hand, sole intake of estrogen could cause breast soreness and increase of appetite. In long term, uncontrolled use of this hormone could cause cervical, ovarian or breast cancer. Usually, misuse of sex hormones such as estrogen and testosterone are due to the belief that these hormones could enhance womanly and manly characteristics respectively and inappropriate practice could lead to negative consequences (Myhealth, 2018).

Diabetes mellitus results from the damage in pancreas that affects production of insulin (Sonksen and Sonksen, 2000; Banks et al., 2010; Bilous and Donnelly, 2010). Over the years, extraction and purification of insulin was from either porcine or bovine pancreases; however there were several differences with human insulin even though the animal insulin was chemically similar to human insulin. Many patients suffered inflammation and antibody attack and inactivation. Besides, only minimal amount of insulin could be extracted at one time and this is not enough to cater worldwide demand. Later, the advancement of recombinant DNA technology has allowed syntheses of human insulin in laboratories (Anon, 2018). This lab-synthesized insulin is well accepted by human systems and could be synthesized in a large amount. Though permitted as medication, the dosage of insulin taken must be monitored at all times by health experts.

Consequently, the usage of common synthetic/artificial hormones as mentioned above could affect people either positive or negatively according to the objectives of treatments. Medically and FDA approved hormones could give better effects on patients or users, however, mistreatment could cause long term damage, or death. Hence, synthetic/artificial hormones need to be used wisely with guidance and advice from medical professionals.

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Management of Safety in the Feed Chain

Arnaud Bouxin, in Food Safety Management (Second Edition), 2023

Background

Medroxyprogesterone acetate (MPA) is a synthetic hormone having progestogen activity used in human and veterinary medicine. It is no longer permitted for use as growth promoters in the EU.

Fertility problems occurred in three pig farms in The Netherlands on 20 May 2002. Animals were fed with wet feed containing a high concentration of contaminated glucose syrup sourced directly by farmers from a Belgian company, which happened to be also a waster processor. The first step of investigations carried out by the Dutch authorities as regards the origin of the contamination was completed on 20 June 2002 and notified to the EU Commission and other member States through the Rapid Alert System Food and Feed. Further investigations enabled to identify two other contamination tracks. The whole tracking and tracing operation was completed on 24 July 2002.

The MPA-contamination found its origin in Ireland in the illegal mixture of pharmaceutical non-hazardous waste with hazardous waste containing MPA at some point in the waste disposal chain. From September 2000 to June 2002, 1,850 kg of MPA was illegally classified as non-hazardous waste and shipped without notification to the Belgian waste processor. This company then mixed up the waste with glucose syrup.

The contaminated syrup was then sold to soft drink producers until December 2001. The Belgian company supplied its glucose syrup to (i) wet feed companies which resold the product directly to home-mixers and to a compound feed manufacturer who mixed up the glucose-syrup with molasses, the mixture being then included in compound feed distributed to farmers and (ii) a molasses trader who mixed up the glucose syrup with molasses, the mixture being sold to feed manufacturers for inclusion in compound feed. As a consequence, the spread of the contamination involved a large number of feed business operators in the Netherlands and Belgium and almost half of the Dutch livestock farms were subject to temporary blockage.

A product recall for contaminated glucose-syrup, molasses and feed was undertaken according to a procedure approved by the EU authorities in Belgium, Germany and The Netherlands, as well as in other Member States concerned to a less extend. The pig market prices fell down in mid-July 2002. The cost of the MPA contamination was estimated between EUR 107 and 132 million.

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Quantitative Neuroendocrinology

Martin Straume, ... Johannes D. Veldhuis, in Methods in Neurosciences, 1995

Introduction

A computational strategy is described for generating synthetic hormone concentration time series that accurately reproduce both (i) the types of temporal patterning observed in empirical studies examining pulsatile hormone release as well as (ii) the distribution and magnitudes of uncertainties encountered in experimental determinations of hormone concentrations in unknown samples. The model is constructed in a manner to facilitate embodying the types of quantitative relationships frequently used to characterize endocrine secretory activity.

Because endocrine systems appear to communicate information by intermittent secretory bursts rather than direct modulation of continuous secretory activity (1–6), analysis and interpretation of experimentally determined hormone concentration time-series profiles often require quantitative consideration of complex temporal patterns. The inherent uncertainty encountered when experimentally estimating unknown hormone concentrations further confounds profiles of concentration time series, requiring accommodation during analysis of considerable contributions from noise. A variety of computational algorithms have been developed to identify peaks in hormone concentration time-series profiles (7–12), as well as to quantitatively characterize in greater detail particular properties of underlying secretory events and associated elimination kinetics (13–22). However, application of even very sophisticated, theoretically sound interpretive algorithms to real data sets requires some effort at validation of the analytical protocol before resulting conclusions can be accepted with confidence. Extensive testing, by comparative analyses, modeling efforts, and the analysis of simulations, has become an important ingredient in efforts to validate procedures and to determine expected false-positive and false-negative rates at peak detection (23–30).

The motivation for constructing a pulse simulator in the particular manner described here was to provide a mechanism for recreating as realistically as possible the temporal patterning of peak locations and amplitudes of hormone concentration time series observed in actual empirical studies. The model is thus defined within the context of the same quantifiable properties commonly elucidated from analysis of real data that are used to interpret time-dependent behavior of hormone secretory activity (1, 2, 13, 15, 17, 21, 22). The pulse simulator described here additionally has incorporated within it a specific mechanism for superimposing variability on and providing uncertainty estimates for individual concentration time points that realistically reflect the actual distribution and magnitude of uncertainty expected from hormone concentration determinations carried out in the experimental setting (31). The structure of the model is described in detail and its performance is demonstrated with reference to experimentally determined growth hormone secretory activity in the normal human male model.

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Female Reproduction

Lucia Speroni, ... Ana M. Soto, in Encyclopedia of Reproduction (Second Edition), 2018

Humans

Fetal breast is particularly vulnerable to carcinogenic insults such as synthetic hormones and endocrine disruptors that cause organizational defects that permanently alter the anatomy and function of the gland (Soto and Sonnenschein, 2010). Most of what is currently known about fetal mammogenesis in humans resulted from observations of postmortem, difficult-to-obtain specimens. Processes involved in morphogenesis have been mostly inferred from animal studies, mostly carried out in mice. Like in rodents, there is individual variability regarding the timing of developmental events. Breast development is visible by 4 weeks of gestation as paired areas of proliferating epithelial cells in the epidermis of the thoracic region. These areas extend in a line from the axilla to the inguinal region and form two mammary ridges or milk lines. By week 6 of gestation, the mammary ridges have regressed back and only two epithelial masses, the mammary buds, are visible and begin to penetrate into the underlying mesenchyme. The epithelium then becomes surrounded by fibroblast-like cells and collagenous stroma. Until week 9 the placode grows further inward (cone stage) and between weeks 10 and 12, the mammary buds sprout from the placode (budding stage) and become lobular in shape creating an indentation along the epithelial–stromal border. Meanwhile the nipple begins to form in the overlying epidermis and the mesenchyme differentiates into fibroblasts, smooth muscle cells, endothelial cells, and adipocytes. At week 15, the epithelium branches into solid epithelial cords (branching stage) which develop lumen at around week 20. The mammary pit is formed as a depression of the epidermis in the region of the nipple. The ductal epithelium first appears as a bilayer of cuboidal cells. The luminal layer rapidly differentiates into secretory cells and the basal layer into myoepithelial cells. By 6 months of gestation, a rudimentary ductal system has formed and the ducts are separated by fat islands within a fibrous connective tissue. The secretory epithelium becomes functional near the end of gestation in response to lactogenic hormones (Parmar and Cunha, 2004). The human mammary gland develops similarly in female and male fetuses (Howard and Gusterson, 2000).

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C

In Drugs for the Geriatric Patient, 2007

calcitonin

(kal-si-toe'-nin)

Brand Name(s): Calcimar, Cibacalcin, Fortical, Miacalcin, Miacalcin Nasal

Chemical Class: Polypeptide hormone

Clinical Pharmacology:

Mechanism of Action: A synthetic hormone that decreases osteoclast activity in bones, decreases tubular reabsorption of sodium and calcium in the kidneys, and increases absorption of calcium in the GI tract. Therapeutic Effect: Regulates serum calcium concentrations.

Pharmacokinetics: Injection form rapidly metabolized (primarily in kidneys); primarily excreted in urine. Nasal form rapidly absorbed. Half-life: 70-90 min (injection); 43 min (nasal).

Available Forms:

Injection (Miacalcin): 200 international units/ml (calcitonin-salmon), 500 mg (calcitonin-human).

Nasal Spray (Fortical, Miacalcin Nasal): 200 international units/activation (calcitonin-salmon).

Indications and Dosages:

Skin testing before treatment in patients with suspected sensitivity to calcitonin-salmon: Intracutaneous Prepare a 10-international units/ml dilution; withdraw 0.05 ml from a 200-international units/ml vial in a tuberculin syringe; fill up to 1 ml with 0.9% NaCl. Take 0.1 ml and inject intracutaneously on inner aspect of forearm. Observe after 15 min; a positive response is the appearance of more than mild erythema or wheal.

Paget's disease: IM, Subcutaneous Initially, 100 international units/day. Maintenance: 50 international units/day or 50-100 international units every 1-3 days. Intranasal 200-400 international units/day.

Osteoporosis imperfecta: IM, Subcutaneous 2 international units/kg 3 times a week.

Postmenopausal osteoporosis: IM, Subcutaneous 100 international units/day with adequate calcium and vitamin D intake. Intranasal 200 international units/day as a single spray, alternating nostrils daily.

Hypercalcemia: IM, Subcutaneous Initially, 4 international units/kg q12h; may increase to 8 international units/kg q12h if no response in 2 days; may further increase to 8 international units/kg q6h if no response in another 2 days.

Unlabeled Uses: Treatment of secondary osteoporosis due to drug therapy or hormone disturbance

Contraindications: Hypersensitivity to gelatin desserts or salmon protein

▪ Side Effects

Frequent

IM, Subcutaneous (10%): Nausea (may occur 30 min after injection, usually diminishes with continued therapy), inflammation at injection site

Nasal (12%-10%): Rhinitis, nasal irritation, redness, sores

Occasional

IM, Subcutaneous (5%-2%): Flushing of face or hands

Nasal (5%-3%): Back pain, arthralgia, epistaxis, headache

Rare

IM, Subcutaneous: Epigastric discomfort, dry mouth, diarrhea, flatulence

Nasal: Itching of earlobes, pedal edema, rash, diaphoresis

▪ Serious Reactions

Patients with a protein allergy may develop a hypersensitivity reaction.

▪ Patient/Family Education

Before 1st dose of new bottle of nasal spray, pump must be activated by holding upright and pumping nozzle 6 times until a faint spray is emitted.

Nausea usually decreases with continued therapy.

Notify the physician immediately of itching, rash, shortness of breath, or significant nasal irritation.

Geriatric side effects at a glance:

CNS

Bowel Dysfunction

Bladder Dysfunction

Falls

▪ U.S. Regulatory Considerations

FDA Black Box

OBRA regulated in U.S. Long Term Care

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Endocrine Disruption and Female Reproductive Health

Philippa D. Darbre, in Endocrine Disruption and Human Health, 2015

8.3 Sources of Endocrine Disruption for Female Reproductive Health

There has been an unprecedented rise over recent decades in the global use of synthetic hormones both as oral contraceptives to enable freedom of sexual activity without consequent pregnancy and as hormone replacement therapy (HRT) to counter menopausal symptoms. Use of these pharmaceuticals has become engrained as an integral part of the social fabric of society and are taken by many women without any regard to the wider implications of the long-term use of such drugs not only for their own long-term endocrine health, but also for the distribution of the drugs into the environment. Ethinyl estradiol (Figure 8.4), the main synthetic estrogen in oral contraceptives, is now detectable in waterways in the United States [2] and Europe [3] and is known to have adverse effects on reproduction in fish [4,5]. Little regard has been paid by the women who consume these pharmaceuticals to the burdens placed on water companies to develop systems capable of adequately removing these drugs for the recycling of drinking water supplies. And furthermore, inadequate attention has been paid to the consequences of the loss of normal estrogen/progesterone homeostasis in the drive for sexual freedom.

Figure 8.4. The chemical structures of diethylstilbestrol and ethinyl estradiol compared with 17β-estradiol.

The effectiveness of plant-based phytoestrogens has also been embraced by the populations of women who consume dietary supplements of plant extracts such as soy, black cohosh, red clover, or aloe vera to counter menopausal symptoms. These phytoestrogens have potent estrogenic activity [6] and can help to relieve the symptoms of menopause, which arise from the drop in endogenous estradiol levels [7]. The publication of a study of a million women that linked HRT to increased risk of breast cancer [8] served to drive many women to seek more “natural” alternatives to the synthetic hormones of HRT [7].

In addition to the pharmaceuticals and plant products, the many environmental contaminants with endocrine-disrupting properties found in diet, the domestic environment, and personal care products have potential to further add to the threat to female reproductive health. A large body of literature testifies to the reproductive effects of environmental EDCs on female reproduction in wildlife [5], but many hundreds of these same chemicals now have been measured in human body tissues. Since the effects of exposure to chemicals cannot be tested directly in humans, it is a sad fact that consequences are often first assessed following accidents or inadvertent exposure. The long-term consequences of exposure of women to high doses of estrogen has become visible following the exposure of many women to the synthetic estrogen DES, which was administered from the 1940s to the 1970s to prevent miscarriage, and the consequences extend from not only the women exposed, but also to their offspring who were exposed in utero (see Section 8.4) [9].

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Interactions in Metal Toxicology

GUNNAR F. NORDBERG, ... BRUCE A. FOWLER, in Handbook on the Toxicology of Metals (Third Edition), 2007

2.1.1 Drugs

Oral contraceptives are among the drugs taken by a large number of healthy women. Intake of such synthetic hormones is known to cause changes in copper metabolism, influencing the synthesis of ceruloplasmin and bringing about higher serum concentrations of copper. Zinc metabolism and iron metabolism are also influenced by oral contraceptives. In studies on women exposed to metals such as cadmium and lead, which might interfere with the metabolism of essential metals, the use of contraceptive pills should be taken into account. Some of the drugs for the treatment of hypertension, which essentially act as chelating agents, also affect metal metabolism. Prolonged treatment with some of these may increase zinc excretion, but not cadmium excretion. Thus, such treatment may, in the long run, cause changes in the cadmium/zinc ratios. The use of chelating agents such as DMSA and penicillamine in the treatment of metal poisoning is a way of using interactions for therapeutic purposes (for details, see Chapter 15). Attempts have also been made to change the kinetics of methylmercury by the use of resins that prevent the reabsorption of methylmercury excreted through the bile (Chapter 15).

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General Considerations

Gunnar F. Nordberg, ... Bruce A. Fowler, in Handbook on the Toxicology of Metals (Fourth Edition), 2015

2.1.1 Drugs

Oral contraceptives are among the drugs taken by a large number of healthy women. The intake of such synthetic hormones is known to cause changes in copper metabolism, thus influencing the synthesis of ceruloplasmin and bringing about higher serum concentrations of copper. Zinc and iron metabolism are also influenced by oral contraceptives. In studies on women exposed to metals such as cadmium and lead, which might interfere with the metabolism of essential metals, the use of contraceptive pills should be taken into account. Some drugs for the treatment of hypertension, which essentially act as chelating agents, also affect metal metabolism. Thus, prolonged treatment with these drugs may cause changes in cadmium:zinc ratios. The use of chelating agents such as dimercaptosuccinic acid (DMSA) and penicillamine in the treatment of metal poisoning is a way of such using interactions for therapeutic purposes (for details, see Chapter 23, “Diagnosis and Treatment”). Attempts have also been made to change the kinetics of methylmercury by the use of resins that prevent the reabsorption of methylmercury excreted through the bile (Chapters 23, 46Chapter 23Chapter 46).

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