Frequent Menstrual Disturbance Post-COVID-19 Vaccination in Saudi Arabia

Abstract

The increased menstrual disturbances post-vaccination remain unclear. We examined factors, types, frequencies, and emotional challenges. We used a self-administered online questionnaire with the IBM-based SPSSv-24-Windows software for analysis. Of 1372 females, 61.1% (n = 838) were aged 19–29 years, 94.2% (n = 1292) were Saudis, 66.4% (n = 911) were graduates, 70% (n = 965) were single, and 15% (n = 205) had chronic diseases. Moreover, 96.5% (n = 1285/1332) had two vaccine doses, mostly Pfizer’s first- and second doses (82% and 78, respectively), while 3.5% (n = 47) only had one. Vaccine groups significantly differed (Pfizer, Moderna, Oxford, and do not know) after the first (0.047) and second (0.049) doses, while Pfizer vaccines were predictive [OR = 2.09 (0.96–4.10), p = 0.029] at two-doses [OR = 3.21 (1.23–5.21), p = 0.030]. No acute COVID appeared. The majority (77%; n = 1057) had no issues, except, in a subgroup of 23% (n = 315) of participants, 43% (n = 135) experienced worsening issues. However, 47.2% (n = 629) complained only post vaccination. Most issues were (75%; n = 471) cycle-timing disruptions; the rest were minor (decreased blood or bleeding, missed-periods, or pain). Other potential reasons were fear, stress, and mental health problems, which occurred in 51% (n = 674) of the group, while 53% (n = 701) were worried. Intriguingly, the menstrual issues in the remaining 47% (n=631) who were not worried could be due to a direct molecular vaccine interaction, irrespective of any mental issue ([OR = 1.78 (0.76–3.21), p = 0.033]. Age proportionalities were significant (p = 0.05) in the 30–39 year-old group (51%). Postgraduate education [OR = 2.11 (0.98–4.72), p = 0.015) and employment [OR = 2.18 (0.95–4.86), p = 0.049] were also predictors. These findings have significant implications in women’s health and vaccine improvement. Future studies on diverse factors are warranted.

1. Introduction

The aftermath of the most devastating COVID-19 pandemic has brought about several gaps in our understanding of viral–host pathogen interactions. In a short time, the virus spread worldwide, dramatically disrupting what is known about viral transmission dynamics. However, the massive vaccination campaign efforts involving a total of 13.6 billion vaccine doses administered globally brought down the pandemic (WHO coronavirus COVID-19 vaccination data, available online at https://covid19.who.int/ accessed 27 February 2024) [1]. This was the most rapid and extensive concerted campaign by companies with state-of-the-art mRNA and DNA products, including Pfizer Biontech, Moderna, and AstraZeneca. Nevertheless, as with all vaccines, increased cases of immune reactions such as mucocutaneous or major bleeding have been reported. Prothrombotic syndrome (PS) is one of the most prominent adverse effects. This has been explained by different names such as vaccine-induced immune thrombotic thrombocytopenia (VITT), thrombosis with thrombocytopenia syndrome (TTS), and vaccine-induced prothrombotic immune thrombocytopenia [2]. Although a risk of these reactions has been observed, complaints of menstrual disturbances have been reported, particularly in this region.

Despite the success of COVID-19 vaccines, some studies have been undertaken to gauge public opinion on the COVID-19 vaccine-induced menstrual disturbances in different geographies. In Columbia, in a total of 950 women aged 18–41 years with normal cycles, nearly 50% of those met the criteria, and a significant number reported an influence on and/or alterations in their menstrual cycle [3]. Similarly, in a total of 14,153 vaccinated Spanish women (mean age 31.5 ± 9.3 years old), 11,017 (78%) reported menstrual changes, mostly in older ages [4]. A more profound change was reported among 3972 young Norwegian women aged 18–30, with 36.7% reporting a cycle disturbance; however, heavier bleeding than usual was reported in 95% after both the first and second vaccine doses, which did not differ based on the vaccine brand [5]. In the USA, among 545 premenopausal non-pregnant women who received a COVID-19 vaccine, 25% reported predominantly temporary changes in the menstrual cycle [6]. Furthermore, among 455 Iranian women aged 15–55 years, the prevalence of menstrual disturbances was higher in those with latency and heavy bleeding than in those with other disorders after vaccination. However, while 50% had no complaints, there was increased risk after vaccination, even in menopausal women (>10%) [7]. In Pakistan, among a total of the 953 students, with a mean age of 20.67 ± 1.56 years, over half (n = 512, 53.7%) experienced menstrual cycle abnormalities post-vaccination who also developed anxiety significantly (p = 0.000) [8]. Among 4170 individuals administered a vaccine, side effects were reported in 85.6% of BNT162b2 and 96.05% of ChAdOx1 vaccines, which were more severe in the former vaccine. However, ChAdOx1 vaccines reported mild, moderate, severe, and critical side effects in 30.13, 28.62, 29.73, and 1.53% of cases, respectively. In contrast, among the majority of BNT162b2 vaccinees (63.92%) the side effects were mild [9].

Although global human genetic population structure is diverse, the universality of the reactions against common vaccine component(s) implies the need for further post-vaccine studies on components. A recent review of key safety outcomes with the Moderna vaccine included the common effects, an association with the menstrual cycle, a 10-fold higher risk of myocarditis and pericarditis in recipients aged 18–29, and increased titers of anti-plyethylene glycol antibodies. While these were temporary but serious, the Moderna expert opinion suggested that large-scale epidemiological studies with longer follow-up periods are required for the surveillance of rare safety outcomes [10]. While both vaccines are efficient and safe, reactions were reported to be less frequent with the Pfizer/BioNTech vaccine than with the Moderna COVID-19 vaccine. However, the latter vaccine is easier to transport and store because it is less temperature sensitive [11]. The universality of vaccine reactions is evident in the vaccine comparisons. Comparisons of T cell, B cell memory, and antibody responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S, and Novavax NVX-CoV2373 were performed for six months. One-hundred percent of individuals produced memory CD4⁺ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8⁺ T cell frequencies, which were only detectable in 60–67% of subjects at six months. While substantial antibody decline was observed in mRNA vaccines, memory T and B cells were comparatively stable. A unique feature of Ad26.COV2.S (JJ) immunization is the high frequency of the CXCR3⁺ memory B cells. These findings imply relevant molecular mimicry in other microbial–pathogen interactions, which is an important confounding factor [12]. In this regard, the mRNA vaccine performed well and implied minimal reactions over whole-virus vaccines across vaccination phases [13].

There is ample evidence regarding the relationship between microbial endocrinology–dysbiosis and menstrual cycle disturbance. Similar to the lower female reproductive tract (FRT), signatures of biomass microbiota exist in the upper FRT [14,15,16,17,18] that influence signal transductions through mental health stimulations. In this context, the association between psychological stress and the menstrual cycle has been well established. Specifically, lifestyle changes during the COVID-19 pandemic affected the patterns and symptoms of the menstrual cycle in women [17,18,19,20,21,22,23]. Similarly, there are several reports on the link between mental health stressors and neurogastrointestinal issues such as irritable bowl diseases and irritable bowl syndromes, where the exact neurochemicals are involved in eliciting gut–brain axis mis-signaling [24,25,26]. Thus, it is plausible that, similar to the gut and other body microbiome compositions, concerted signaling in the upper FRT could result in an inflammatory cascade that manipulates cycle signaling. It is increasingly becoming evident that the array of signals during menstruation is subject to much more complex internal and external senses that regulate the timed patterns of the menstrual cycle. However, there is a paucity of high-quality data regarding the nature of host–viral (or viral components) interactions on the reproductive system in women from different geographies owing to the normal local genetic variations in the structure and balance of microbial signatures and the nature of stressors.

Despite the magnitude of the daily menstrual problems, occurring in more than 300 million globally, studies on the intricacies of these changes remain scarce. There has been a rapid growth in evidence about an emerging subtle biologically plausible connection between vaccines and menstrual periods such as the hypothalamic–pituitary–ovarian (HPO) axis [27]. An informatics flow analysis of gene expression in response to BNT162b2 on menstrual irregularity, followed by network biology, identified five transcription factors involved in menstrual disruptions similar to prolactin signaling [28]. Direct vaccine effects on human granulosa cells exposed to the Pfizer COVID-19 vaccine BNT162b2 in vitro revealed no change in their viability but altered mRNA transcripts of the key regulatory factors by upregulating InhibinB and downregulating anti-Müllerian hormone. These findings were further confirmed by pre- and post-vaccination blood with a 2–3-fold change in the post-vaccination FSH/InhibinB protein level ratio compared to their pre-vaccination values. These differential expressions impacted the HPO axis in vaccinated individuals and eventually affect the endometrium causing changes in menstrual bleeding patterns [29]. Menorrhea consists of arrays of signaling routes, and cycle disruptions can be impacted by a myriad of internal as well as external stimuli. It was recently discovered that the presence of low-biomass microbiota in the upper FRT functions as an alert like an immune signaling pattern similar to the gut–brain axis in the endocervix and endometrium. While distinct microbiome structures that are in balance exist in the vagina, cervical canal, uterus, and fallopian tubes, the upper FRT is not yet fully explored. Uterine tissues and immune cells are distinct and transform cyclically during the menstrual cycle as well as during pregnancy and are influenced by microbiota [30]. It is increasingly evident that menstrual health is influenced by complex internal and external factors regulating the timing and patterns of the menstrual cycle. However, there is a lack of high-quality data on how host–viral interactions or viral components, such as COVID-19 vaccination, affect reproductive systems across different geographies. This gap is particularly significant given regional variations in genetic and microbial compositions, as well as the potential role of chronic diseases and emotional stressors. Since the region in this study is characterized by a stable population structure and microbiome composition, we aimed to investigate changes in menstrual health during the COVID-19 era, focusing on potential risk factors for menstrual disturbances, including vaccination, demographic characteristics, chronic diseases, and medications. Additionally, we sought to explore participants’ perceptions of whether menstrual changes were linked to pandemic-related emotional challenges.

2. Materials and Methods

2.1. Study Design

This study was a cross-sectional design and used a web-based online public questionnaire sent to different regions of Saudi Arabia. A gap was considered from the time of vaccine administration (17 December 2020) until the expected significant antibody titer was obtained (April to December 2021). All responses were recorded after this period including a second dose from July 2021.

2.2. Sample Size and Sampling Procedure

The sample was a self-administered, non-probability sample of Saudi Arabian social media users. The web-based data collection tool was designed using Google Forms and distributed via social media applications, mainly WhatsApp and Twitter. The invitation letters were sent via WhatsApp groups and posted on Twitter community groups. The invitation letter explained the aim of this study and the approximate time required to complete the questionnaire. Participants were asked to distribute the survey on their social networks. Inclusion criteria: females aged 12–50 years, vaccinated during the study period, and able to provide informed consent. Exclusion criteria: pregnant participants, those with severe pre-existing menstrual disorders, those diagnosed with psychiatric disorders, and responses recorded before the critical antibody titer gap period. After applying these criteria, the final sample was reduced from 1467 to 1372 participants.

2.3. Data Collection Tool and Interpretations of Patients’ Responses

The questionnaire comprised four domains: consent forms, demographic information, health status, and COVID-19 vaccine related questions. The questionnaire was prepared in English and was translated into Arabic. Language validity was undertaken by retranslating the Arabic version of the questionnaire into English to ensure that the original meaning of the questions was preserved (back translation). This was conducted by the authors, who are bilingual speakers of both English and Arabic. Data included self-reported menstrual changes and perceived associations with stressors such as fear, anxiety, emotional problems, and worries related to the pandemic.

2.4. Ethics Approval

Ethics approval was provided by the Research Ethics Standing Committee of the University of Hail #UOH 2021-631. All participants were asked to provide consent before participating in this study.

2.5. Statistical Analysis

The updated Statistical Package for Social Sciences software (IBM SPSS; Version 24 SPSS version 23.0, for Windows (SPSS, Inc., Chicago, IL, USA)) was used for data analysis. Descriptive and stratified analyses were conducted, and absolute numbers, proportions, and graphical distributions are presented. We conducted Chi square statistical tests and showed p-values, where appropriate (p-value < 0.05, considered statistically significant). In addition, we have carried out a multivariate logistic regression analysis to identify the risk factors associated with menorrhea disturbances in females.

3. Results

We examined responses of 1372 females who mostly comprised the following groups: 61% (n = 838) were aged 19–29 years, 94% (n = 1292) were Saudi citizens, 66.4% (n = 911) were graduates, 70% (n = 965) were single, and only 15% (205) had chronic diseases, mostly in the respiratory system (n = 33/205;16%). Most of the respondents (30%) were from the eastern region of KSA, while similar frequencies, i.e., 22.8% (n = 305), 22.7% (n = 303), and 21.6% (n = 289), were from Northern, Central, and Western regions of KSA, respectively, and only 5.4% (n = 73) were from a southern region. Of the respondents, 15% had chronic diseases, and 14% had taken some form of medication. The detailed characteristics are shown in

Table 1. Baseline characteristics of patients.

Characteristics (n = 1372)		Frequency	Percent
Age (years)	<18	216	15.7
	19–29	838	61.1
	30–39	175	12.8
	40–50	143	10.4
Nationality	Non-Saudi	80	5.8
	Saudi	1292	94.2
Region	Central Region	303	22.1
	Eastern Region	402	29.3
	Southern area	73	5.3
	Northern area	305	22.2
	Western Region	289	21.1
Educational	No primary education	7	0.5
	Elementary or Intermediate	70	5.1
	Secondary	331	24.1
	Graduate	911	66.4
	Postgraduate	53	3.9
Employment status	Employed	182	13.3
	Housewife	306	22.3
	Retired	25	1.8
Social status	Married	407	29.7
	Single	965	70.3
Chronic diseases	No	1167	85.1
	Yes	205	14.9
Type of Chronic diseases (n = 205)	Cardiovascular disease	3	1.5
	Blood diseases	28	13.7
	Diabetes	15	7.3
	Hypertension	20	9.8
	Kidney disease	2	1.0
	Respiratory system diseases	33	16.1
	Rheumatic diseases	10	4.9
	Liver diseases	1	0.5
	Other diseases	60	29.3
	Multiple diseases	33	16.1
Medications	No	1177	85.8
	Yes	195	14.2
Type of medications used (n = 195)	Anti-hypertensive medications	24	12.3
	Insulin	22	11.3
	Cardiovascular medications	4	2.1
	Salbutamol	11	5.6
	Other medications	107	54.9
	Multiple medications	27	13.8

.

Table 2. Participant responses to COVID-19 and vaccine-related questions.

Questions	Responses	Number	Percent
Infected with SARS-CoV-2, prior vaccination	No	1058	77.1
	Yes	314	22.9
Received COVID-19 vaccine	No	40	2.9
	Yes	1332	97.1
Doses taken (n = 1332)	One dose	47	3.5
	Two doses	1285	96.5
First dose taken (n = 1332)	Pfizer	1091	81.9
	Oxford	209	15.7
	Moderna	12	0.9
	Don’t know	20	1.5
Second dose taken (n = 1285)	Pfizer	1006	78.3
	Oxford	187	14.6
	Moderna	61	4.7
	Don’t know	31	2.4

and Figure 1 (and Figure S1 in Suppl) show whether the respondents had a SARS-CoV-2 viral infection, the vaccination details and types of vaccines taken, or if they were infected with the virus despite vaccination. Most of the respondents were not infected with acute COVID-19 syndromes (77%) with SARS-CoV-2 before vaccination except 314 (22.9%) who had been infected but symptoms were similar to common vaccinated signs. About 96.5% (n = 1285) of the 97% (n = 1332) of participants that were vaccinated reported taking two doses of the COVID-19 vaccine while only approximately 3.5% (n = 47) took only one dose. No acute COVID syndromes were reported except for the reactions and side effects. The overwhelming majority had taken Pfizer’s first and second doses of the COVID-19 vaccine (82% and 78, respectively), and the other two vaccines were taken by low percentages of respondents. Table 2 illustrates this information. Subgroups of responses to infection and vaccination are illustrated in Figure 1.

The details of the major issues related to the COVID-19 vaccine administration are shown in

Table 3. Predominant menstrual problems related to the COVID-19 vaccinations.

Questions.	Responses	Number	Percent
1.Have you suffered from any menstrual problems before taking the vaccine (n = 1332)	No	1057	77.0
	Yes	315	23.0
1.1 If yes, got worsened after taking the vaccine	No	180	57.1
	Yes	135	42.9
1.2 If not, did you have any menstrual problems after taking the vaccine (n = 1332)	No	703	52.8
	Yes	629	47.2
2. Time of menstrual problems (of n = 629 who responded Yes to issues after vaccination)	After the first dose	259	41.2
	After the second dose	370	58.8
2.1. Types of menstrual problems reported by participants (n = 629)	Decrease the time between the two menstrual cycles	12	1.9
	2.1.1 Decrease amount of blood	18	2.9
	2.1.2 Increase amount of blood	23	3.7
	2.1.3 Decreased number of days of bleeding	7	1.1
	2.1.4 Increase in numbers of days of bleeding	12	1.9
	2.1.5 Irregular menstruation	53	8.4
	2.1.6 Missed periods after taking vaccine	26	4.1
	2.1.7 Severe pain than usual	7	1.1
	2.1.8 Simultaneous multiple menstrual problems	471	74.9
3. Perception that menstrual problems were linked to pandemic vaccine-related emotional challenges (n = 1332)	Yes	674	50.6
	No	658	49.4
4. Worried about pandemic/vaccine (n = 1332)	Yes	701	52.6
	No	631	47.4

. The overwhelming majority (77%; n = 1057) reported that they experienced no menstrual problems before vaccination except 23% (n = 315) who had issues. Of the latter group, 43% (n = 135/315) reported that their menstrual problems worsened after vaccination. However, 47.2% (n = 629) of all respondents experienced specific menstrual problems only after taking the vaccine. Of these, 59% (n = 370) reported that the issues increased after the second dose, and 41% (n = 259) had them after the first dose. The majority (75%; n = 471) reported the occurrence of multiple issues together in their cycles. The dndependent occurrence of each issue was also surveyed; these were mostly irregularities in cycle times (8.4%; n = 53), followed by approximately 2 to 4% experiencing either decreased days or amount of blood, missed periods, increased blood volume, or increased bleeding days. More importantly, 51% (n = 674) of the participants thought that the menstrual problems were due to pandemic-related emotional challenges while 47.4% (n = 631) were not worried. A similar percentage of respondents (53%; n = 701) indicated their worries about the pandemic as their reason for menstrual problems.

Analysis of the relationship between menstrual problems and age indicated that the difference in proportions between age groups was significant regarding outcomes (menstrual problems) (p = 0.05). Although age groups had similar relative frequencies, they were higher in the 30–39 (51%) age group. No statistically significant differences were observed in menstrual problems between nationalities (p = 0.833) or social status (p value = 0.592). This study also found that menstrual problems after vaccination did not show any statistically significant association with the presence of chronic diseases (p = 0.592) or those who took medications (p = 0.913). Participants who received Moderna and Pfizer as the first doses reported more menstrual problems. However, the statistical analysis indicated that there were significant differences in proportions between the study groups (Pfizer, Moderna, Oxford, and do not know) regarding outcomes (menstrual problems) in the first (0.047) as well as in the second dose (0.049). Nevertheless, frequences of mild menstrual problems were higher among females who received both doses of Pfizer and Moderna, as seen in

Table 4. Relationship between menstrual problems after taking the vaccine with baseline characteristics.

		Menstrual Problems After Taking the Vaccine for Each Character = (Yes + No)		p Value
		No	Yes
Age	12–18	109	95	0.05
		53.4%	46.6%
	19–29	439	380
		53.6%	46.4%
	30–39	85	88
		49.1%	50.9%
	40–50	70	66
		51.5%	48.5%
Nationality	Non-Saudi	41	35	0.833
		53.9%	46.1%
	Saudi	662	594
		52.7%	47.3%
Social status	Married	214	183	0.592
		53.9%	46.1%
	Single	489	446
		52.3%	47.7%
Chronic disease	No	593	542	0.351
		52.2%	47.8%
	Yes	110	87
		55.8%	44.2%
Taking medication	No	605	540	0.913
		52.8%	47.2%
	Yes	98	89
		52.4%	47.6%
First dose	Pfizer (n = 1091)	561	530	0.047
		51.4%	48.6%
	Oxford (n = 209)	121	88
		57.9%	42.1%
	Moderna (n = 12)	6	6
		50.0%	50.0%
	I do not know (n = 20)	15	5
		75.0%	25.0%
Second dose	Pfizer	515	491	0.049
		51.2%	48.8%
	Oxford	106	81
		56.7%	43.3%
	Moderna	32	29
		52.5%	47.5%
	I do not know	23	8
		74.2%	25.8%

.

A multivariate logistic regression analysis was carried out to identify the risk factors associated with menorrhea disturbances in females (

Table 5. Logistic regression to predict the risk factors of menorrhea disturbances in females.

Dependent Variable = Menorrhea Disturbances	Odd’s Ratio	95% Confidence Interval		p Value
Age (=19–29 years)	2.07	0.66	6.50	0.209
Nationality	0.57	0.25	1.29	0.181
Region	1.17	0.62	2.19	0.624
Education = Postgraduate	2.11	0.98	4.72	0.015
Employment	2.18	0.95	4.86	0.049
Social status	1.76	0.94	3.31	0.076
Chronic diseases	0.91	0.47	1.74	0.781
Medications	0.95	0.65	1.39	0.775
Type of vaccine taken = Pfizer	2.09	0.96	4.10	0.029
Doses taken = 2 doses	1.59	0.74	3.29	0.014
Suffered from any menstrual problems before taking vaccine	0.91	0.45	2.21	0.412
Menstrual problems occurred after the second dose	3.21	1.23	5.21	0.030
Perception that menstrual problems changes were linked to pandemic-related emotional challenges	1.78	0.76	3.21	0.033

). This study included various independent variables such as age, nationality, region, education level, employment status, social status, presence of chronic diseases, medication history, vaccination status (type and doses), pre-existing menstrual problems, and emotional factors related to the COVID-19 pandemic. Among these variables, education level and employment status emerged as statistically significant predictors, with postgraduate education [OR = 2.11 (0.98–4.72), p = 0.015) and employment [OR = 2.18 (0.95–4.86), p = 0.049] being associated with increased odds of menorrhea disturbances. Additionally, the Pfizer vaccine [OR = 2.09 (0.96–4.10), p = 0.029] and experiencing menstrual problems after the second vaccine dose [OR = 3.21 (1.23–5.21), p = 0.030] were also significant predictors. Mental health and emotional factors such as periods affected by fear, worries, and emotional problems or other similar issues that triggered stress were also associated with increased odds of menorrhea disturbances [OR = 1.78 (0.76–3.21), p = 0.033]. However, variables such as nationality, region, chronic diseases, medication history, vaccine status, and pre-existing menstrual problems did not show significant associations with menorrhea disturbances.

4. Discussion

The findings of this study provided valuable insights into the impact of vaccination on menstrual health and highlighted the need for further research. This study investigated changes in menstrual health during the COVID-19 era, with a particular focus on identifying factors that may contribute to menstrual disturbances, such as vaccination, demographic characteristics, chronic conditions, and medication use. An additional aim was to explore participants’ perspectives on whether these changes could be linked to emotional challenges related to the pandemic, such as fear, anxiety, and stress. Given the nature of this study as a public health surveillance using an anonymous questionnaire, it was not feasible to include clinical or biomarker assessments of stress. Instead, participants’ perceptions were collected through self-reports, which are valuable for understanding subjective experiences and beliefs.

We have shown that the major menstrual cycle problems were significantly associated with COVID-19 vaccination (p = 0.049) either in those who did or did not have issues prior to vaccination. The evidence became stronger with increasing complaints after the second dose, consistent with other studies [3]. Examination of menstrual disruptions in the context of diverse factors, including patients’ demographic characteristics, revealed significant findings. For instance, the increase in menstrual issues after the second dose mostly affecting cycle-time disruptions was associated with young women of reproductive age (p = 0.0575). This observation is in contrast to the fact that the post-COVID problems disproportionately affect premenopausal women [31]. This finding indicates a pattern in the region where most affected women were relatively young, healthy, educated, and of childbearing age [32,33]. Prevalence rates of post-COVID cycle irregularities were higher in Saudi vaccinated women of childbearing age implying certain selections [34]. Although SARS-CoV-2 does not adversely affect issues such as ovarian reserve directly [35] vigilance has become imperative regarding how the virus disrupts menstrual cycles in young healthy women, in contrast to reported issues in older ages [36]. This supports the notion that indirect stressors such as fear, stress, and emotional problems are plausible factors that disrupt periods, particularly cycle timings [20]. Even though it is widely reported and observed that indirect stressors such as work environments and healthcare settings play significant roles in irregularities in menorrhea, there is a limitation in the reported data on the mechanisms of indirect stimulations. For instance, there is a significant association between the COVID-19 pandemic-induced perceived stress and depressive symptoms and increased menstrual cycle irregularity among healthcare providers [37]. These findings are also interesting in the context of the previously reported youth and female resistance to SARS-CoV-2 infections [38]. However, the reported findings on women’s resistance to infections is partly due to estrogen, which curtails pro-inflammatory cytokines [39]; albeit, distinct evidence exists on immune modulation by the uterine microbiome [40], with further proof of the concept from those undergoing hysterectomy [15]. Thus, it is not clear how indirect mechanisms, primarily stress and other mental health issues, affect irregularities in the normal period.

In the current study, stress was also a major factor implying potential concerted actions through dysbiosis. A majority of patients reported fear, stress, mental health, worries about the pandemic, and/or emotional problems. However, a little less than half reported issues but were not worried. Intriguingly, the appearance of menstrual issues in the remaining 47% (n = 631) who were not worried could be due to direct molecular vaccine interactions, irrespective of any mental issue. This is in agreement with the growing evidence on direct microbiome-induced immune modulations of vaccine molecules. The types, structure, numbers, and genetic structures of the human microbiome signatures involved are not distinctly clarified in the region. However, the region has been well known for its population genetic stability since ancient times implying a relatively stable microbiome component. We and others have previously reported on stress, mental health, and/or anxiety as leading factors in the cycle and immune reaction issues in this and different regions [41,42]. Thus, while the immune response to infections is often envisioned as similar in both sexes, the FRT imparts sex bias differences with increased autoimmune reactions in women [39]. Thus, there is an association between increased menstrual disturbances, vaccines, and mental health issues. However, the exact mechanism(s) on a potential concerted action is not yet clear.

In this study, the majority (77%, n = 1057) of participants had no menstrual problems before vaccination, and in those who had issues pre-vaccination (23% n = 315), their menstrual problems worsened after vaccination. Interestingly, there was not much difference in the signs and types of irregularities neither before nor after vaccination as well as in the few who had infection before vaccination. This similar response to stressors implies a common mechanism(s) of stimulation owing to genome stability and human microbiome homogeneity in the region. The issues were predominantly minor multiple transient nonspecific problems that simultaneously occurred, except for the irregularity in the timing of the cycle, which was the most common issue. The minor issues ranged from 2 to 4%, comprising decreased days or amount of blood, missed periods, increased blood volume, or increased bleeding days. A systematic review represented the most contemporary and largest evidence on the predictors and rates of menstrual problems after COVID-19 vaccination in 78,138 patients. In the aforementioned study, although 52.05% revealed menstrual problems post-COVID-19 vaccination, there were significant heterogeneities, and most studies were unable to report on distinct profiles of menorrhagia (heavy bleeding), oligomenorrhea (irregularities), and dysmenorrhea (pain during period). One known factor in heterogeneity is the genetic diversity in different geographics compared to that in the region. Furthermore, in three studies, advanced age predicted menstrual problems after the COVID-19 vaccination. Other predictors included smoking, drinking, addiction, history of an unstable family, and pregnancy [43]. Given that women in this study were younger and that these latter issues are largely irrelevant in them, it is plausible that stress and dysbiosis in the female reproductive tract were inducers in our study. Dysbiosis has been widely reported in a sequalae of gastrointestinal tract functional disorders. However, despite the similar complexity and structure of neurophysiology and neurochemicals in the reproductive tract and gut–brain axis dysbiosis, the involvement in the former has been overlooked. More importantly, recent studies employing pyrosequencing concluded that the upper FRT is not sterile. Significant differences were found in microbial communities in the endocervix and endometrium; these signatures’ compositions were out of balance in women with menorrhagia versus dysmenorrhea (p = 0.024) [16]. Thus, “post-acute COVID-19 syndrome”, as dubbed by Meringer and Mehandru (2022) [44] as well as the post-COVID-19 vaccination syndrome have created significant gaps in women’s response indicating important areas for research in the aftermath of SARS-CoV-2 pandemic. The post-vaccination menorrhea syndrome in this study is associated with vaccination and stress in young women. These findings warrant further future studies for the similar mechanisms of stress-induced gut microbiome dysbiosis and the consequences of gastroesophageal and inflammatory bowel syndromes post COVID-19 (IBS) [24,25,26,45,46,47,48,49].

Genome stability and the absence of major predictors such as smoking, drinking, addiction, history of unstable family, and pregnancy issues in this region were observed. This study has several limitations that should be considered:

• Self-Reported Data: Although it gives a good presumptive assessment, the reliance on anonymous self-reports introduces potential recall bias and limits the ability to build further interpretations.
• Due to the nature of the study, there was an absence of clinical and biomarker assessments: Stress, emotional challenges, and their perceived link to menstrual disturbances were based on participants’ perceptions rather than validated psychometric tools or biological measures. future studies should incorporate clinical and psychometric tools to objectively validate these findings, further understand the interplay between stress and menstrual health, and explore the role of other stressors beyond pandemic-related fears.
• Differentiation Between Infection and Vaccination Effects: This study could not distinguish whether menstrual disturbances were influenced by prior COVID-19 infection or vaccination due to the expected overlap between natural infection and vaccine titers. This can be delt with through further investigation.
• Sample Size: Larger sample sizes would enable more insights.

5. Conclusions

The devastating COVID-19 pandemic has created several gaps in our understanding of host–viral interactions during acute as well as long-COVID phases including post-vaccination syndromes. While many syndromes were directly associated with host–SARS-CoV2 molecular interaction, the gender-specific mechanism(s) such as that of menstrual disturbance post COVID-19 vaccination has been quite subtle. In this study, we have surveyed and identified major factors and patterns of disruptive menorrhea post COVID-19. We present statistically significant evidence that menstrual disturbances were associated with COVID-19 vaccinations in healthy, mostly young women of reproductive age. In addition, participants perceived that pandemic-related emotional challenges were potential factors contributing to menstrual disturbances. While the majority thought worries were the reason for their menstrual issues, the appearance in a similar percentage of those who were not worried (47%; n = 631) makes direct molecular vaccine interaction, irrespective of any mental issue, plausible. The findings have significant clinical implications for women’s health awareness, public recommendations for gender-based interpretations, and vaccine improvement strategies. Future vertical studies on vaccines, cortisol response age, and uterine dysbiosis in mis-signaling are warranted.