The Toxicity Of Contraceptives

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  • The Toxicity Of Contraceptives

toxicity [tok-sis´ĭ-te]
The degree to which a substance can cause harm or damage.[1,2]

Research increasingly implicates a link between the significant array of exogenous chemicals humans are continually exposed to, and many suboptimal health and chronic disease states experienced by the population.[3] One such source of chemical exposure are pharmaceutical contraceptives, which have provided birth control benefits to millions of women.[4] However, they have also been associated with various toxic effects on both the body and the environment.  

Pharmaceutical contraceptives: types and pharmacokinetics

The most commonly used pharmaceutical contraceptives are combined oral contraceptive pills (COCs), progestin-only contraceptive pills (POPs) and intrauterine devices (IUDs).

COCs contain various combinations and doses of synthetic oestrogen and progesterone, while POPs are synthetic progesterone only medications. Each are available in pill, patch or vaginal ring dosage forms.

Ethinyl estradiol (EE) is the most common type of synthetic oestrogen used, with others including chlorotrianisene, dienestrol, diethylstilbestrol, fosfestrol, mestranol and quinestro. Progestins (synthetic progesterone) can be old (norethisterone, levonorgestrel, gestodene) or new forms (drospirenone, dienogest, trimegestone). The two types of IUDs available are the copper-bearing (Cu-IUD) and hormonal-releasing (levonorgestrel-releasing LNG-IUD) forms.[1,5-7] There are variations in the pharmacokinetics of the different types and dosage forms of these synthetic hormones, with oral medications having more significant biological effects compared with topical, vaginal or intrauterine forms.[4]

Following ingestion, EE is absorbed quickly, though the rate of absorption can range from 20-65% between individuals and can vary day-to-day and with long-term use. Once it is absorbed, it undergoes hepatic metabolism via the glucuronidation and sulfation pathways, and is excreted or reabsorbed via enterohepatic recirculation following bacterial hydrolysis in the colon.[4,8] Conversely, progestins only undergo hepatic metabolism and are not reabsorbed via enterohepatic recirculation, though the rate of hepatic metabolism varies according to progestin type.[8]

The pharmacokinetics of these pharmaceutical contraceptives can vary between individuals due to the type, concentration, duration and timing of medication used.[4] The specific physiological response of an individual to these substances, and consequently the potential toxic impact, will also vary due to epigenetic, structural and functional differences.

Endogenous toxic effects

Pharmaceutical contraceptives can contribute to endogenous toxicity through their impact on gut and vaginal microbiomes, hepatic function, nutrient status, copper toxicity, oxidative stress and chemical accumulation.[9-16]

Gut and vaginal microbiome

The link between contraceptive medications and the gut microbiome is multifaceted. Certain intestinal bacterial species, with beta-glucuronidase and beta-glucosidase enzyme activity in the colon (known as the estrobolome), deconjugate oestrogen in bile, therefore influencing the amount of exogenous oestrogen that is reabsorbed.[17,18] Oestrogen can also influence gut microbiome diversity and composition.[9-16]

Both oral COC and IUDs can alter gut microbiota and vaginal microbiome composition.[9-16] Oral oestrogens have been associated with dysregulation of intestinal microbiota,[9,10,14] and both COCs and LNG-IUDs resulted in an increased comparable risk of bacterial vaginosis, Trichomonas vaginalis and Candida albicans infection in sexually active women.[11,19]

Oestrogen levels can also be correlated with microbiome alpha diversity.[15] Gut microbiome variations can occur following increased intestinal permeability, and OCPs were observed to modify tight junction expression and permeability by influencing zonulin mRNA protein expression and promoter activity.[13] Significant modifications in vaginal microbiota was seen with use of the COC after 6 months, with increased inflammatory and yeast colonisation markers observed.[16]

By contributing to large bowel dysbiosis and increasing intestinal permeability, contraceptives may indirectly contribute to body toxicity by adversely affecting the capacity of the gut to metabolise and excrete other xenobiotics (e.g. polycyclic aromatic hydrocarbons, nitrotoluenes, pesticides, polychlorobiphenyls, heavy metals, benzene derivatives, azo dyes, artificial sweeteners) and endogenous metabolic by-products.[20]

Liver function

Both the GIT microbiome and contraceptives can influence hepatic metabolism, thereby influencing endogenous detoxification processes. The GIT microbiome can affect the expression of phase 2 hepatic enzymes[21] and both oral and vaginal contraceptives influence hepatic metabolism.

Oral OCPs are metabolised via the glucuronidation and sulfation enzyme pathways. When toxin exposure (including from exogenous oestrogens) exceeds liver biotransformation capacities, this can disrupt the balance between liver detoxification phases, resulting in higher levels of circulating (unconverted) toxic metabolites, further contributing to overload of hepatic detoxification pathways.[4,8,22]

Animal and human studies have demonstrated that OCPs, Cu-IUDs and vaginal rings interfere with hepatic metabolism by increasing bilirubin, alanine aspartate (AST), alkaline phosphatase (ALT), sex-hormone binding globulin (SHBG) and oestrogen-sensitive hepatic proteins levels, inhibiting hepatic microsomal function (cytochrome P450 activity) and increasing hepatic lipid concentrations (HDL-C, LDL-C and TG).[23-30]

Consequently, contraceptives can contribute to endogenous toxicity by adversely influencing hepatic metabolism and its capacity to detoxify toxic exogenous and endogenous substances.

Nutrient and trace mineral status

Contraceptive medications may contribute to endogenous toxicity by modifying endogenous nutrient, heavy metal and trace mineral levels, subsequently influencing (nutrient-dependent) hepatic detoxification and cellular antioxidant enzyme activity.

In a study of women using OCPs, IUDs or injectable contraceptives, mean serum zinc, selenium, phosphorus and magnesium levels were significantly lower than non-contraceptive users, with reductions proportionate to the duration of contraceptive use, while copper and cadmium levels were significantly higher. [31] A separate study of OCP users found that serum vitamin B12 levels were significantly lower compared with control subjects.[32]

Elevated copper levels have long been associated with OCPs. This was observed in a meta-analysis of 26 studies that demonstrated that use of the COC increased mean serum/plasma copper levels by between 1.5-2mg/L, noted by the authors to exceed reference values.[33] Similar results were observed in a separate study of Cu-IUD users who were found to have increased amounts of copper released from the IUD.[34]

In a separate study involving PCOS subjects, an association was observed between OCP use and decreased circulating hepcidin and increased ferritin levels, resulting in enhanced iron absorption, potentially contributing to iron overload.[35]

Lower levels of selenium, zinc and magnesium can influence body toxicity as they are required for the synthesis and activity of antioxidant enzymes in the body, including glutathione (magnesium), superoxide dismutase (zinc), glutathione peroxidase and selenoprotein enzymes (selenium).[36]

The toxic effects of cadmium in the body deplete glutathione levels, inhibiting antioxidant enzyme activity and increasing the synthesis of superoxide ion, hydrogen peroxide and hydroxyl radicals.[37] Copper can contribute to pathological oxidative processes in much of the body, including inactivation of glutathione peroxidase and oxidation of hepatic mitochondrial cells. While excess iron results in the formation of superoxide or hydroxyl free radicals.[33,38,39]

Oxidative stress

Alterations in oxidative stress levels as a consequence of contraceptive use has been observed in a number of studies. In two separate clinical trials, OCP use resulted in increased oxidative stress levels, with significant elevations of malondialdehyde and catalase activity, and reduced levels of whole blood reduced and oxidised glutathione and plasma glutathione enzymes (glutathione peroxidase and reductase).[40,41] This was also observed in female athletes using the OCP, with high levels of oxidative stress as measured by blood hydroxyperoxides and free radical levels compared with non-OCP users observed.[42]

Other contraceptive dosage forms have also been implicated in elevated oxidative stress, with significantly lower levels of coenzyme Q10, alpha-tocopherol and total antioxidant capacity values also found in women using the OCP, vaginal ring and transdermal patch contraceptives compared with control subjects not using any contraception.[43]

Overall these studies demonstrate that an endogenous environment of elevated oxidative stress in body cells and tissues can occur with use of contraceptives, which can have a detrimental impact on detoxification processes and overall body toxicity and functional capacities.   

Environmental chemicals

Another mechanism whereby contraceptives may contribute to endogenous toxicity is by their association with environmental chemical accumulation in the body.

In an analysis from the Norwegian Mother and Child Cohort study of 1090 women over a 5-year period, characteristics of OCP use (type, duration, timing) and plasma concentrations of seven perfluoroalkyl substances (PFAFs), including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS) and perfluorooctane sulfonate (PFOS), were assessed.[44]

Higher levels of five of the PFAF types (PFOA, PFNA, PFHxS, PFHpS, PFOS) were observed in women who had used OCPs in the previous 12 months (12.9-35.7% higher), in the past (7.2-32.1% higher) and for more than 10 years (18.9-46.2%) compared with never-OCP users. Separate studies have also observed higher PFAF concentrations in women with endometriosis, with 13-16% estimated to be attributed to OCP use.[44] Elevated PFAF levels have been associated with infertility, cancer and adverse effects on the liver and thyroid organs and endocrine activity.[45,46]  

Exogenous/environmental toxic effects

A further aspect of toxicity in relation to pharmaceutical contraceptives is their impact on the environment.

Internationally, approximately 700kg/year of synthetic oestrogens derived from contraceptives (OCPs, patches and vaginal rings) are released in the environment, with EE in particular estimated to be directly responsible for at least 16% of the oestrogenic load present in waterways.[47,48]

Such oestrogenic load has been found in various water bodies, soil water, ground water and soils, with the half-life varying depending on conditions found in the immediate environment that influence degradation – being anywhere from 23 hours to 108 days. In some conditions such oestrogens persist, as they are not degraded at all or are interconverted by some bacteria to other types of oestrogen (e.g. E1).[48]

As well as polluting water-ways, synthetic oestrogens are considered to pose a significant risk to the environment by detrimentally impacting the physiology of fish and other aquatic animals (i.e. feminisation, inhibited reproductive capacity and reduced fish biomass) and plant growth.[47,48]

They are also a concern to human health, with their presence in drinking water potentially contributing to an increased risk of cancer and cardiovascular disease, and reproductive issues including premature female development, menopause and reduced male fertility.[48]

Progestins, particularly levonorgestrel, norethisterone and oestodene in waterways has also been associated with abnormal fish egg production.[49]

The use of pharmaceutical contraceptives have a place in the population for birth control and family planning purposes. However, their potential detrimental impact on the body is an important consideration from a naturopathic and nutritional clinical treatment perspective, as well as in the context of their use for non-contraceptive purposes.

Table 1: Adverse effects associated with contraceptives (OCP, IUD)

Effect

Reference

Irregular menstruation, amenorrhoea

1,50

Infertility

1

Nausea, loss of appetite

1

Weight gain

1,50

Increased cardiovascular disease risk (in heavy smokers or those with family history)

50,51

Increased risk of Crohn’s disease and ulcerative colitis

9,10

Increased risk of cancer (breast, cervical, endometrial, ovarian)

5,51-54

Increased risk of deep vein thrombosis/venous thromboembolism

51,55-57

Depression, mood swings

1,50,51,58-60

Vaginal atrophy and inflammation (IUD)

19,61

Increased risk of HPV infection

62

Perforation, bleeding, infection (IUD)

63,64

Toxic shock syndrome (IUD)

65-67

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georgia.marrion's picture
Georgia Marrion
Georgia is a naturopath and nutritionist of more than 12 years in the complementary medicine industry, with experience in areas including clinical practice, practitioner consultant, writing, lecturing, product development and regulatory affairs. With a Masters in Human Nutrition, her main interest areas are gastrointestinal and women's health, and she is passionate about providing information to people to help them optimise their overall health.