Menstrual abnormalities post-COVID vaccination: a cross-sectional study on adult Lebanese women.

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This study of 505 Lebanese women found that COVID-19 vaccination increased heavy or light bleeding, decreased regular cycles, and correlated irregularity with worse PMS and certain pre-existing conditions.

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Abstract

BackgroundIn the year 2020, the coronavirus pandemic invaded the world. Since then, specialized companies began to compete, producing many vaccines. Coronavirus vaccines have different adverse events. Menstrual disorders have been noticed as a common complaint post-vaccination.AimOur study fills an important gap by evaluating the relationship between coronavirus vaccines and menstrual disorders.MethodsThis is a cross-sectional study between 20 September 2021, and 1 October 2021, using an online survey. The questionnaire consisted of 36 questions divided into 4 sections: demographics, COVID-19 exposure and vaccination, hormonal background, and details about the menstrual cycle. Sample t-test, ANOVA test, chi-square, and McNemar test were used in bivariate analysis.ResultsThis study includes 505 Lebanese adult women vaccinated against COVID-19. After vaccination, the number of women having heavy bleeding or light bleeding increased (p = 0.02 and p < 0.001, respectively). The number of women having regular cycles decreased after taking the vaccine (p < 0.001). Irregularity in the cycle post-vaccination was associated with worse PMS symptoms (p = 0.036). Women using hormonal contraception method or using any hormonal therapy had higher menstrual irregularity rates (p = 0.002 and p = 0.043, respectively). Concerning vaccine adverse events, those who had headaches had a higher rate of irregularity (p = 0.041). Those having PCOS, osteoporosis, or blood coagulation disorders had higher irregularity rate (p < 0.001 and p = 0.005, respectively).ConclusionVaccine adverse events may include specific menstrual irregularities. Moreover, some hormonal medications and diseases are associated with the alteration of the menstrual cycle. This study helps in predicting vaccines' menstrual adverse events, especially in a specific population prone to menstrual disorders.
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Results

This study includes 505 premenopausal women vaccinated against COVID-19. We received complete responses for each section, as participants were not able to submit the survey without completing all of the parts. Participants were distributed to all governments. The majority were not married (68.7%), and the average age of participants was 26.9 years (ranging from 18 to 55 years). Most of the participants received the Pfizer vaccine (81.2%), followed by AstraZeneca (11.9%). A total of 84.4% of our sample had a second dose of the vaccine, 79.6% were not previously pregnant, and 99% were not breastfeeding (Table 1 ). Table 1 Description of the survey respondents for the whole sample Factor Category N % Residency Bekka 25 5 Nord 202 40 Jabal Lebnen 128 25.3 Beirut 49 9.7 Baalbak-Hermel 12 2.4 Nabatiye 27 5.3 South 35 6.9 Akkar 23 4.6 Jbeil 4 0.8 Marital status Married 117 23.2 Not married 347 68.7 Engaged 31 6.1 Divorced 8 1.6 Widowed 2 0.4 Vaccine name AstraZeneca 60 11.9 Pfizer 410 81.2 Sputnik 20 4 Sinopharm 10 2 Moderna 1 0.2 Do not know 4 0.8 Second dose Yes 426 84.4 No 79 15.6 Previously pregnant Yes 103 20.4 No 402 79.6 Breastfeeding Yes 5 1 No 500 99 Description of the survey respondents for the whole sample The majority of respondents did not use anti-pregnancy hormone therapy (89.1%) nor any hormonal therapy (93.7%). Around two-thirds had no change in menstruation after taking the vaccine. Regarding vaccine adverse events, 77.6% experienced pain near the vaccine injection location, 65.7% had fatigue, 42.6% had a headache, 7.7% had vomiting or diarrhea, and 6.1% had easy brushing. Overall, 90.5% experienced at least one adverse event of vaccination. A total of 5.5% of the participants have previously been diagnosed with heavy menstrual bleeding, 12.9% have previously been diagnosed with PCOS, 0.4% had osteoporosis, 0.4% had coagulation disorders, and 1% was previously diagnosed with endometriosis (Table 2 ). Table 2 Description of the general health of survey respondents for the whole sample Factor Category N % Used hormonal anti-pregnancy Yes 55 10.9 No 450 89.1 Use of any hormonal treatment Yes 32 6.3 No 473 93.7 Change in menstrual cycle after vaccination Yes 138 27.3 No 367 72.7 Pain near injection location after vaccine Yes 392 77.6 No 113 22.4 Fatigue after vaccine Yes 332 65.7 No 173 34.3 Headache after vaccine Yes 215 42.6 No 290 57.4 Vomiting and diarrhea after vaccine Yes 39 7.7 No 466 92.3 Easy bruising after vaccine Yes 31 6.1 No 474 93.9 Did not face any vaccine adverse events Yes 48 9.5 No 457 90.5 Previously diagnosed with heavy bleeding in menstruation Yes 28 5.5 No 477 94.5 Previously diagnosed with PCOS Yes 65 12.9 No 440 87.1 Previously diagnosed with osteoporosis Yes 2 0.4 No 503 99.6 Previously diagnosed with blood coagulation disorders Yes 2 0.4 No 503 99.6 Previously diagnosed with endometriosis Yes 5 1 No 500 99 Description of the general health of survey respondents for the whole sample Heavy menstrual bleeding was decreased after vaccination, where the number of women having heavy bleeding decreased by 6% after vaccine ( p  = 0.003). Light menstrual bleeding was increased by 7% after vaccination ( p  < 0.001). In addition, regularity was affected by vaccination, where the number of women having regular cycles decreased after taking the vaccine by 8% ( p  < 0.001). Concerning the duration, it shifted to less than 5 days or more than 7 days after vaccination ( p  = 0.001) (Table 3 ). Table 3 Comparison of participant’s menstrual disorders before and after taking the COVID-19 vaccine Factors Category Before N  = 505 After N  = 505 p -value Heavy bleeding Yes 199 (39.4) 168 (33.3) 0.003 No 306 (60.6) 377 (66.6) Light bleeding Yes 135 (26.7) 169 (33.5)  < 0.001 No 370 (73.3) 336 (66.5) Pain Yes 381 (75.4) 380 (75.2) 1 No 124 (24.6) 125 (24.8) Irregularity in cycle duration No 317 (62.8) 345 (68.3)   4 months 58 (11.5) 77 (15.2) Duration 1–3 days 40 (7.9) 50 (9.9) 0.001 3–5 days 148 (29.3) 163 (32.3) 5–7 days 288 (57) 248 (49.1)  > 7 days 29 (5.7) 44 (8.7) Regularity of cycle Regular 442 (87.5) 402 (79.6)  < 0.001 Irregular 63 (12.5) 103 (20.4) Comparison of participant’s menstrual disorders before and after taking the COVID-19 vaccine Among women having regular cycles after vaccination, the majority had similar PMS symptoms as those before vaccination, and only 12.43% of them had worse PMS symptoms. However, having irregular cycles post-vaccination was associated with a higher rate of worse PMS symptoms (21.35%). This shows that the irregularity in the cycle post-vaccination is significantly associated with worse PMS symptoms ( p  = 0.036) (Table 4 ). Table 4 Effect of cycle regularity post-vaccination on PMS symptoms Cycle after vaccine p -value Regular Irregular PMS symptoms Same 337 75 0.036 Worse 50 22 Better 15 6 p -value 0.036 Effect of cycle regularity post-vaccination on PMS symptoms Table 5 shows the association between sociodemographics, general gynecological health, vaccination, and post-vaccine adverse events with the menstrual cycle’s regularity and PMS. Table 5 Association between cycle regularity and PMS symptoms with sociodemographics, general gynecological health, vaccination details, and post-vaccine adverse events Factor Regularity PMS N (%) p -value N (%) p -value Category Regular Irregular Same Worse Better Residency Bekka 21 (84) 4 (16) 0.866 22 (88) 2 (8) 1 (4) 0.014 Nord 160 (79.2) 42 (20.79) 168 (83.16) 27 (13.36) 7 (3.46) Jabal Lebnen 102 (79.68) 26 (20.31) 104 (81.25) 18 (14.06) 6 (4.68) Beirut 37 (75.51) 12 (24.48) 36 (73.46) 13 (26.53) 0 (0) Baalbak-Hermel 9 (75) 3 (25) 10 (83.33) 0 (0) 2 (16.66) Nabatiye 23 (85.18) 4 (14.81) 23 (85.18) 3 (11.11) 1 (3.7) South 26 (74.28) 9 (25.71) 27 (77.14) 8 (22.85) 0 (0) Akkar 20 (86.95) 3 (13.04) 18 (78.26) 1 (4.34) 4 (17.39) Jbeil 4 (100) 0 (0) 4 (100) 0 (0) 0 (0) Vaccine name Astrazeneca 49 (81.66) 11 (18.33) 0.174 48 (80) 10 (16.66) 2 (3.33) 0.963 Pfizer 324 (79.02) 86 (20.97) 337 (82.19) 56 (13.65) 17 (4.14) Sputnik 19 (95) 1 (5) 15 (75) 3 (15) 2 (10) Sinopharm 7 (70) 3 (30) 8 (80) 2 (20) 0 (0) Moderna 0 (0) 1 (100) 1 (100) 0 (0) 0 (0) Do not know 3 (75) 1 (25) 3 (75) 1 (25) 0 (0) Second dose Yes 336 (78.87) 90 (21.12) 0.344 341 (80.04) 66 (15.49) 19 (4.46) 0.116 No 66 (83.54) 13 (16.45) 71 (89.87) 6 (7.59) 2 (2.53) Previously pregnant Yes 83 (80.58) 20 (19.41) 0.782 90 (87.37) 10 (9.7) 3 (2.91) 0.235 No 319 (79.35) 83 (20.64) 322 (80.09) 62 (15.42) 18 (4.47) Used hormonal contraception Yes 35 (63.63) 20 (36.36) 0.002 40 (72.72) 11 (20) 4 (7.27) 0.177 No 367 (81.55) 83 (18.44) 372 (82.66) 61 (13.55) 17 (3.77) Use of any hormonal treatment Yes 21 (65.62) 11 (34.37) 0.043 24 (75) 7 (21.87) 1 (3.12) 0.436 No 381 (80.54) 92 (19.45) 388 (82.02) 65 (13.74) 20 (4.22) Change in menstrual cycle after vaccination Yes 85 (61.59) 53 (38.4)  < 0.001 76 (55.07) 56 (40.57) 6 (4.34)  < 0.001 No 317 (86.37) 50 (13.62) 336 (91.55) 16 (4.35) 15 (4.08) Pain near injection location Yes 310 (79.08) 82 (20.91) 0.587 318 (81.12) 58 (14.79) 16 (4.08) 0.808 No 92 (81.41) 21 (18.58) 94 (83.18) 14 (12.38) 5 (4.42) Fatigue Yes 259 (78.01) 73 (21.98) 0.219 259 (78.01) 61 (18.37) 12 (3.61) 0.001 No 143 (82.65) 30 (17.34) 153 (88.43) 11 (6.35) 9 (5.2) Headache Yes 162 (75.34) 53 (24.65) 0.041 170 (79.06) 38 (17.67) 7 (3.25) 0.129 No 240 (82.75) 50 (17.24) 242 (83.44) 34 (11.72) 14 (4.82) Vomiting and diarrhea Yes 27 (69.23) 12 (30.76) 0.094 24 (61.53) 11 (28.2) 4 (10.25) 0.003 No 375 (80.47) 91 (19.52) 388 (83.26) 61 (13.09) 17 (3.64) Easy bruising Yes 21 (67.74) 10 (32.25) 0.091 19 (61.29) 9 (29.03) 3 (9.67) 0.01 No 381 (80.37) 93 (19.62) 393 (82.91) 63 (13.29) 18 (3.79) Not experienced any adverse event after the vaccine Yes 39 (81.25) 9 (18.75) 0.079 40 (83.33) 5 (10.41) 3 (6.25) 0.016 No 363 (79.43) 94 (20.56) 372 (81.4) 67 (14.66) 18 (3.93) Previously diagnosed with heavy menstrual bleeding Yes 2 (50) 2 (50) 0.269 17 (60.71) 6 (21.42) 5 (17.85)  < 0.001 No 400 (79.84) 101 (20.15) 395 (82.8) 66 (13.83) 16 (3.35) Previously diagnosed with PCOS Yes 41 (63.07) 24 (36.92)  < 0.001 52 (80) 11 (16.92) 2 (3.07) 0.739 No 361 (82.04) 79 (17.95) 360 (81.81) 61 (13.86) 19 (4.31) Previously diagnosed with osteoporosis Yes 0 (0) 2 (100) 0.005 0 (0) 2 (100) 0 (0) 0.002 No 402 (79.92) 101 (20.07) 412 (81.9) 70 (13.91) 21 (4.17) Previously diagnosed with blood coagulation disorders Yes 0 (0) 2 (100) 0.005 1 (50) 1 (50) 0 (0) 0.345 No 402 (79.92) 101 (20.07) 411 (81.7) 71 (14.11) 21 (4.17) Previously diagnosed with endometriosis Yes 3 (60) 2 (40) 0.274 3 (60) 0 (0) 2 (40)  < 0.001 No 399 (79.8) 101 (20.2) 409 (81.8) 72 (14.4) 19 (3.8) Association between cycle regularity and PMS symptoms with sociodemographics, general gynecological health, vaccination details, and post-vaccine adverse events Regarding cycle’s regularity, women using the hormonal contraception method or using any hormonal therapy had higher menstrual irregularity rates (around 35% in users vs 20% in nonusers; p  = 0.002 and p  = 0.043, respectively). Moreover, those who stated having changes in menstrual cycle after vaccination had a higher irregularity than those who did not (38.4% vs 13.62%; p  = 0.000). Concerning vaccine adverse events, those who had headache had a higher rate of irregularity (24.65% vs 17.24%; p  = 0.041). Regarding previous health issues, those having PCOS, osteoporosis, or blood coagulation disorders had a higher irregularity rate (36.92% vs 17.95%; p  = 0.000, 100% vs 20.07%; p  = 0.005, 100% vs 20.07%; p  = 0.005, respectively). Regarding PMS, having changes in menstrual cycle after vaccination is associated with worse PMS (40.57% vs 4.35%; p  < 0.001). Moreover, those who experienced fatigue, vomiting with diarrhea, or easy bruising after vaccination had worse PMS (18.37% vs 6.35%; p  = 0.01, 28.2% vs 13.09%; p  = 0.003, and 29.03% vs 13.29%; p  = 0.01, respectively). Furthermore, those who did not experience any adverse event after the vaccine had better PMS (6.25% vs 3.93; p  = 0.016). Concerning women that were previously diagnosed with heavy menstrual bleeding, they significantly had worse or better PMS (21.42% vs 13.83% and 17.85% vs 3.35%, respectively; p  = 0.000). Women previously diagnosed with osteoporosis had worse PMS (100% vs 13.91%; p  = 0.002), while those previously diagnosed with endometriosis had better PMS (40% vs 3.8%; p  < 0.001). None of the sociodemographic characteristics or other independent variables were significantly associated with menstrual irregularities variables, except for the use of hormonal therapy ( p  = 0.002). None of the vaccines was significantly associated with menstrual irregularities.

Materials

This is a cross-sectional study conducted on Lebanese adult women vaccinated against COVID-19 between 20 September 2021, and 1 October 2021. An online questionnaire was generated using Google Forms and spread via social media platforms, applying the snowball method, in order to obtain a larger sample. A pilot study was inducted on 30 women before distributing the questionnaire. All participants assured that everything was clear. Out of the 537 participants that filled the self-administered Arabic survey, 32 were excluded due to one of the following reasons: not residing in Lebanon, being postmenopausal, age less than 18 years old, or have not taken the COVID vaccine. The total response rate was 991.15%. Afterward, 505 participants that met the following inclusion criteria were eligible for the study: menstruating women, residing in Lebanon and having taken any of the COVID-19 vaccines. All participants were informed that their anonymity is preserved. Since we addressed a large population from different sociodemographic backgrounds, we made sure that all questions were clear by providing an explanation for the following terms: menstrual cycle, period, and irregular menstrual cycle. The questionnaire consisted of 36 questions divided into 4 sections, taking an average of 15 min to fill. The survey sections were as follows: demographics (age, weight, height, place of residency, and marital status), COVID-19 exposure and vaccination (previous infection with COVID-19, vaccine name, and adverse events experienced after the vaccine), hormonal background, and details about the menstrual cycle. The last two sections investigated thoroughly the participants’ reproductive health and menstrual patterns and thus included questions about: contraceptive use, hormone replacement therapy, menstruation habits, PMS patterns, previous pregnancies, history of hysterectomy, and related medical conditions. The survey contained 6 sets of comparative binary questions (before vaccine/after vaccine). These questions are intended to check for specific changes in participants’ menstrual cycle after the vaccine, such as menstrual cycle duration, heavy bleeding, light bleeding, and menorrhagia. Sahel General Hospital Ethical Committee waived the need for approval because this was an observational study. The study respected participants’ anonymity and confidentiality and was conducted according to the research ethics guidelines in the Declaration of Helsinki [ 17 ]. Participants’ consent was obtained from the first question of the questionnaire. The collected data was entered in Microsoft Excel and was analyzed using the Statistical Package of the Social Sciences (SPSS) v.25. A p -value < 0.05 was considered statistically significant. Descriptive statistics were conducted where continuous variables were expressed as mean ± standard deviation (SD), while categorical variables were presented as numbers and percentages. Concerning the bivariate analysis, the independent was used to compare percentages before and after vaccination, and a multivariable logistic regression was conducted taking into account sociodemographic variables and vaccination as a major independent variable to assess the odds of menstrual irregularities variables as major dependent variables.

Conclusion

Our findings support the fact that the COVID vaccine has effects on the menstrual cycle, explaining the findings reported by many women post-vaccination. Moreover, it shows that some diseases are associated with the alteration of the menstrual cycle. This helps in predicting vaccines’ menstrual adverse events, especially in a specific population with a higher risk. Our study highlights the need for more studies on the management of menstrual irregularities, leading to clear guidelines for managing the cases.

Discussion

Several studies revealed that COVID-19 vaccines may have several adverse events. Whatever the vaccine type (mRNA, Vector, etc.), a considerable number of recipients affirmed experiencing local and/or systemic adverse events after receiving either dose of the vaccine [ 18 , 19 ]. Some of these adverse effects were related to menstruation. Our study focused on menstrual disturbances post-vaccination, showing that 27% affirmed having changes in the menstrual cycle after vaccination. Similar findings were seen in other countries (i.e., the UK) but were not sufficient to confirm a firm relation between the menstrual changes and vaccination [ 15 ]. Going further into the details, the responders were interrogated about their menstrual disorders before and after taking the COVID-19 vaccine. Around a third of the participants (33%) declared having heavy bleeding after the vaccine, being less than those who had this problem before the vaccine (39%) ( p -value = 0.003). However, heaving heavier periods after vaccination was noticed in other studies [ 20 ]. On the other hand, a smaller number of the participants affirmed having light bleeding (33.5%) post-vaccination, while 26.7% had light bleeding before the vaccine ( p -value < 0.001). This decrease in the number of participants experiencing light bleeding following the vaccine was also reported in a study characterizing post-vaccine menstrual bleeding changes [ 21 ]. These bleeding irregularities may raise concerns for women who are willing to get vaccinated or to get another vaccine dose, especially since there are reports about the induction of thrombotic thrombocytopenia syndrome (TTS) by some vaccines [ 22 ]. Nevertheless, the experts emphasize that the risk of developing COVID-19 disease outweighs the risk of the less likely undesired vaccine effects, including TTS [ 22 ], in a way that even patients with bleeding disorders are advised to get the vaccine [ 23 ]. Moreover, 12.5% of participants experienced irregular cycles before the vaccine; this number increased to 20.4% after the vaccine ( p -value < 0.001), supporting another study regarding this concern [ 24 ]. One possible explanation for this irregularity is the psychological stress perceived by the woman before, during, and/or after receiving the vaccine, as higher stress levels were associated with menstrual irregularity. However, these stress levels were not associated with menstrual bleeding changes [ 25 ], which renders this possibility less likely. Additionally, our study found that irregular cycles were associated with worse PMS symptoms. The physiopathological mechanism of PMS can be explained by the endocrine system alterations [ 26 ], which may be caused by the cycle irregularity. The heavy bleeding experienced by many participants can also be a contributor to a worse PMS [ 27 ]. Concerning cycle regularity, several factors were noticed to influence the menstrual cycle. The use of hormonal contraception in some of the participants was associated with higher rates of menstrual irregularity, which backs up other studies regarding the effects of contraception on the cycle [ 28 ]. Similar effects were also seen with the use of any hormonal treatment, which may be explained by the fact that these treatments interfere with the normal physiological hormonal sequences, especially the hormonal physiology of ovulation [ 29 ]. Additionally, participants who experienced post-vaccine headaches had higher cycle irregularity rates. A more defined relation between this type of headache and menstrual abnormalities should be established, possibly mimicking the association between chronic migraine and menstruation disorders [ 30 ]. Moreover, higher rates of irregular cycles were also seen in patients with PCOS, osteoporosis, and/or blood coagulation disorders, which was previously described in other studies [ 31 – 33 ]. Furthermore, numerous variables were seen to impact the PMS intensity. Participants who experienced fatigue, vomiting, diarrhea, and/or easy bruising post-vaccine were associated with having worse PMS. It is not rare for these signs to be seen before/during menstruation [ 34 ]; however, the fact that they seem to be worse after the vaccination is worth mentioning. Likewise, women who were previously diagnosed with osteoporosis before the vaccine also experienced a worse PMS. The vaccine might have an aggravating effect on the already described severe PMS in osteoporosis patients [ 35 ]. Additionally, participants who were previously diagnosed with endometriosis had better PMS. This might be explained by the retrograde migration of the endometrial tissue towards the ovaries in the case of endometriosis [ 36 ], thus affecting its secretion of progesterone, which, in turn, is responsible for the severity of PMS symptoms [ 37 ].

Limitations

This study had several limitations, mainly concerning the targeted population. Postmenopausal women were excluded from this study, eliminating the ability to correlate vaccination to post-menopausal gynecological adverse events. Additionally, this study was done soon after the vaccine had reached Lebanon (around 20% got two shots [ 38 ]); the priority of vaccination was for those being at risk of developing COVID-19 complications, thus increasing the proportion of participants with comorbidities, possibly affecting our study’s outcome. This might cause a confounding bias. In addition, this study had a low number of participants diagnosed with certain diseases expected to affect the menstrual cycle, such as osteoporosis, blood coagulation disorders, and endometriosis, lowering the value of results obtained. This may have contributed to the low power of the sample, hampering significant results in the multivariable analysis. Finally, our sample was not homogeneous in terms of residency location and type of vaccine received, disrespecting the exact proportions.

Introduction

Throughout history, epidemics and diseases such as plague, influenza, and smallpox have invaded many civilizations and wiped out millions of people. Edward Jenner presented a scientific invention that contributed to the development of a vaccine achieving the protection against smallpox, which subsequently led to the complete eradication of the smallpox virus in 1979 [ 1 ]. Scientific and medical progress has led to the invention of hundreds of vaccines that reduced the risk of many diseases and lowered their death rates. In the year 2020, the coronavirus pandemic invaded the world from China as the original epicenter, causing horrific damage on various levels [ 2 ], in addition to claiming millions of lives around the world [ 3 ]. Since then, specialized companies began to compete, producing many vaccines with high rates of effectiveness, causing a significant fade of most of the negative consequences resulting from this pandemic. According to the Food and Drug Administration (FDA), Pfizer-BioNTech was the first vaccine introduced into the global market with an effectiveness of up to 95% [ 4 ]. Many vaccines have also been released and became available for use. Among them is AstraZeneca, with an effectiveness of 76% [ 5 ], Sinopharm, with an effectiveness of 79% [ 6 ], and Sputnik V vaccine, with an effectiveness of 80% [ 7 ]. Despite the presence of some negative attitudes toward vaccination, these vaccines were widely spread [ 8 ]. It is worth noting that the coronavirus vaccines, as all other vaccines, have adverse events related to their use [ 9 ]. With the start of the vaccination campaigns globally, many adverse events began to appear, ranging from low burden, such as fever, fatigue, tiredness, chills, nausea [ 10 ], to life threatening, such as stroke [ 11 ]. As coronavirus vaccines are still relatively new to the market, further studies should be conducted focusing primarily on the effects of these vaccines on various disorders and physical problems. Menstrual disorders have been noticed to be a common complaint post-vaccination [ 12 – 15 ]. This fact is unsurprising based on the similar effects of other vaccines [ 16 ]. For these reasons, our study fills an important gap by evaluating the relationship between coronavirus vaccines and menstrual disorders, thus helping and guiding producing companies to reduce the burden accompanied by vaccines as much as possible. The primary objective of this study is to assess the self-declared menstrual irregularities following the use of the COVID-19 vaccines. A secondary objective would be to assess menstrual regularity and premenstrual symptoms associated factors.

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