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Menstrual changes after covid-19 vaccination

BMJ 2021; 374 doi: (Published 16 September 2021) Cite this as: BMJ 2021;374:n2211

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Re: Menstrual changes after covid-19 vaccination

Dear Editor,

In response to V. Male 'Menstrual Changes after COVID-19 Vaccination' published 16 September 2021,[1] further information suggests a separate hypothesis to the suggestion that any connection, if present, ‘is likely to be the result of immune response’. While there may be no association between new onset menstrual irregularities, postmenopausal bleeding and COVID-19 vaccines, clarifying research will also need to consider any possible theoretical toxicology in addition to immune responses.

The excipient polyethylene sorbitan monooleate, also known as polysorbate 80 and Tween 80, is present in the ChAdOx1-S COVID-19 Vaccine (AstraZeneca®), and is related to a polyethylene glycol nanoparticle constituent in BNT162b2 COVID-19 Vaccine (Pfizer®). Polyethylene glycol resembles polysorbate 80, minus the oleic acid component. Gajdova et al.[2] explored a possible association between polysorbate 80 and oestrogenic changes in rats. Polysorbate 80 doses of 1mg, 5mg and 10mg were injected into newborn rats on days 4, 5, 6 and 7. At 5 months of age the effects were compared with those in cohorts of untreated, water injected and diethylstilboestrol (50 microgram) injected rats. Authors reported ‘findings in the ovaries similar to those in the positive control [diethyl stilboestrol] group were also observed in all of the groups given Tween 80 [polysorbate 80]’. There was significant prolongation of the oestrous cycle and induction of persistent vaginal oestrous. There was a statistically significant (P <0.001) decrease in the relative weight of the ovaries in all polysorbate 80 treated groups.

While there are no known adverse reproductive effects of oral or topical polysorbate 80, these forms do not enjoy the 100% bioavailability of injected forms. Rats showed no adverse reproductive effects from oral ingestion until the polysorbate 80 dose comprised 20% of the rat diet.[3]

It has to be remembered that the effects of polyethylene sorbitan monooleate on human ovaries are unknown, and may not exist. However, it needs to be ascertained whether the increased concentration of radiolabelled lipid nanoparticles measured in rat ovaries following a 50 microgram dose administered in a Pfizer conducted biodistribution study,[4] could have any potentiating effect. There is no evidence of an infertility association with these vaccines. IVF clinics, as V. Male indicates, have described no such effect. Infertility is described by the World Health Organization as a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse.[5]

Assessment of ongoing ovarian health aided by serial Anti-Mullerian Hormone [6] evaluations post COVID-19 vaccination, compared with those of an unvaccinated cohort, would be reassuring to know and hopefully neutralize infertility concerns. It is to be hoped the multiple centres between which the $1.67m research funding will be divided will be sufficiently financed to consider all plausible aetiological relationships that might exist between 30,000 reported cases of new onset menstrual irregularities and post-menopausal bleeding and the much-needed COVID-19 vaccines in use.

[1] Male V. Menstrual changes after covid-19 vaccination. BMJ 2021; 374. doi:
[2] Gajdova M, Jakubovsky J, Valky J. Delayed effects of neonatal exposure to Tween 80 on female reproductive organs in rats. Food Chem Toxicol 1993;31:183-190. doi:
[3] Oser BL, Oser M. Nutritional studies on rats of diets containing high levels of partial ester emulsifiers. II. Reproduction and lactation. J Nutr 1956;60:489-505.
[4] Australian Government, Department of Health, Therapeutic Goods Administration, ‘Nonclinical Evaluation Report BNT162b2 [mRNA] COVID-19 vaccine (COMIRNATY TM)’. January 2021. Submission No: PM-2020-05461-1-2. p. 45. FOI 2389 Document 6.
[5] Infertility. 2020., citing World Health Organization (WHO). International Classification of Diseases, 11th Revision (ICD-11) Geneva: WHO 2018.
[6] Moolhuijsen LM, Visser JA. Anti-Mullerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function. The Journal of Clinical Endocrinology & Metabolism 2020;105:3361-3373.

Competing interests: No competing interests

21 September 2021
Deirdre Little
Medical Practitioner
Bellingen District Hospital