Apropos of menstrual changes and abnormal uterine bleeding after COVID-19 vaccination

Abstract

It is news of 28 October 2022 that the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency has recommended to add heavy menstrual bleeding among the side effects of unknown frequency inside the package insert of nucleoside-modified messenger ribonucleic acid vaccines to prevent coronavirus disease 2019 (COVID-19). The decision has been made in the light of the numerous reports of unexpected menstrual changes or abnormal uterine bleeding following COVID-19 vaccination. Here we advance a possible involvement of the particular adenohypophyseal microcirculation in these strange and still unexplained events.

It is news of 28 October 2022 that the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has recommended to add heavy menstrual bleeding among the side effects of unknown frequency inside the package insert of nucleoside-modified messenger ribonucleic acid (modRNA) vaccines to prevent coronavirus disease 2019 (COVID-19), the ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1, 2 Previously, we have pointed out the numerous reports of unexpected menstrual changes or abnormal uterine bleeding following COVID-19 vaccination recorded on the United Kingdom “Yellow Card” surveillance system.³ In this regard, we have described a similar case of amenorrhea due to hyperprolactinemia in a 28-year-old Caucasian female with pituitary apoplexy (PA) accompanied by de novo headache, temporally after adenoviral vector-based COVID-19 vaccination.³ To complete this clinical case, we here specify the full absence of SARS-CoV-2 infection by molecular swab, of visual disturbance by ophthalmologic investigation, of micro-/macroadenoma by cerebral imaging (performed only after the second dose when the patient came to our attention), and of cardiovascular risk factors, such as diabetes, arterial hypertension, hyperlipidemia, atrial fibrillation, smoking and anti-contraceptive pill. All these additional data allow us to advance a possible alternative explanation for PA and transient menstrual changes concerning with an acute microvascular damage. In fact, the particular microcirculatory apparatus of the adenohypophysis consists of a rich network of fenestrated capillaries which account for the high metabolic exchanges of the gland, strictly dependent on the hypothalamus by feedback mechanism [Fig. 1 ]. It is known that the main arterial supply for the adenohypophysis is represented by the two superior hypophyseal arteries; the branches of each artery terminate in a primary capillary plexus, which allows for the rapid passage of hypothalamic-releasing hormones and inhibitory factors into the hypophyseal portal system.4, 5 Once the blood reaches the adenohypophysis, it spreads within a secondary capillary plexus precisely consisting of fenestrated capillaries, in direct contact with the secretory cells [Fig. 1]. The main venous return is towards the cavernous sinus, but supplementary collaterals are connected with the hypothalamus’ basis, allowing a direct arrival of blood enriched with pituitary hormones to the hypothalamus.⁴ Given that COVID-19 can rarely complicate with pituitary apoplexy and that any vaccination represents an attenuated form of the disease by definition,³ a resulting hypercoagulative state may rarely occur and involve fenestrated capillaries, where the blood flow is significantly decelerated.6, 7, 8 The pre-existing interconnected small branches and the trans-sellar arterial blood supply usually are sufficient collaterals,⁹ but sometimes they could be inadequate to the high blood demand from the pituitary gland, thus promoting the onset of microischemic events and subsequent menstrual abnormalities.¹⁰

Fig. 1.

Histology and immunohistochemistry of the adenohypophysis from an adult woman in course of autopsy: a rich network of capillaries in direct contact with the secretory cells is well noticeable (A, haematoxylin & eosin, 200X) and highlighted by the immunoreaction for the cluster of differentiation 31 (CD31), which specifically stains in brown the blood endothelia (B, JC70 clone, 200X).

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Statement of ethics

This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki of 1975, as revised in 2008.

Data availability statement

All relevant data generated or analyzed during this research were included in the article; further enquiries can be directed to the corresponding author upon reasonable request.

Author contributions

LR: study concept and design, image acquisition, drafting of the manuscript and caption, study supervision. AM: drafting of the manuscript, critical revision. All authors approved the final version of the manuscript.

Declaration of Competing Interest

The authors declare no competing interest.