Link between early menstruation and early menopause

Starting periods at a young age is linked to early menopause

Women are more likely to go through menopause early if they started menstruating before their 12th birthday.

This is the conclusion of the largest study of its kind, involving 50,000 postmenopausal women in the UK, Australia, Japan and Scandinavia.

2017 Study Abstract

STUDY QUESTION
Are parity and the timing of menarche associated with premature and early natural menopause?

SUMMARY ANSWER
Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP

WHAT IS KNOWN ALREADY
Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power.

Early menarche, nulliparity and the risk for premature and early natural menopause, Oxford University Press, doi.org/10.1093/humrep/dew350, 25 January 2017.

Image credit Texas.713.

STUDY DESIGN, SIZE, DURATION
This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE).

PARTICIPANTS/MATERIALS, SETTING, METHODS
Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation.

MAIN RESULTS AND THE ROLE OF CHANCE
The median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children.

LIMITATIONS, REASONS FOR CAUTION
Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias.

WIDER IMPLICATIONS OF THE FINDINGS
Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause.

STUDY FUNDING/COMPETING INTEREST(S)
InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

Management of females exposed to DES-type drugs ; 1977 recommendations

Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones

woman-at-hospital
1977 study and recommendations about vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones. all you’ve been through.

1977 Study Abstract

All asymptomatic girls who wore exposed to diethylstilbestrol in utero should receive a thorough pelvic examination at menarche or if they have reached 14 years of age. Younger girls should be examined if they develop abnormal bleeding or discharge. Whenever prenatal exposure is probable and theme are symptoms of discharge, further investigation is imperative, regardless of the patient’s age. This investigation should not be concluded until it is certain that no lesion is present.

Before the examination is undertaken, the entire procedure should be thoroughly discussed with the patient (and her mother on father if she is a minor).

The examination should include inspection and palpation, Papanicolaou smear (cervix and vagina), and an iodine staining test of the entire cervix and vagina. Abnormal areas, including those that do not stain with iodine, should be biopsied.  This procedure can be performed in the physician’s office with small biopsy instruments and without significant discomfort.

For the very young patient who has symptoms that require investigation, anesthesia may occasionally be required be fore an examination. A small speculum permits adequate visualization of the vagina without undue discomfort in younger patients.

With asymptomatic females, if adequate examination is not possible at the initial visit, vaginal tampons should be used for a few months to allow an adequate examination later without discomfort. Colposcopy is a useful adjunct to this examination, but it is not essential. Utilizing its low power magnification to examine the vagina and cervix, the physician can identify areas of glandular tissue (adenosis) in the vagina on on the cervix. This identification permits directed rather than “blind” biopsies. When used in con junction with the iodine staining test and selected biopsy, colposcopy permits precise recording of observed abnormalities and their appraisal at fixed intervals.

The patient exposed to DES-type drugs should be followed on a regular basis. After a normal initial examination, annual pelvic examinations with cervical and vaginal cytology and iodine staining are probably adequate. If any abnormalities are noted during the initial evaluation, more frequent follow-up examinations are suggested (every 3 to 6 months, depending on the severity of the findings).

Locally destructive measures such as cauterization, cryosurgery, or excision can be utilized if atypical changes such as marked squamous dysplasia on carcinoma in situ of the vagina or cervix are found on biopsy.

Sources and more information
  • Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones, Cancer Research, 1977 Apr.
More DES DiEthylStilbestrol Resources

Age at menarche among diethylstilbestrol granddaughters

Age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal DES exposure

girl-ocean-sskennel-text
In this 1995 study, age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal diethylstilbestrol exposure. However the 2011 study showed DES-exposed girls were somewhat more likely to have begun menstruating at age 10 or younger.

1995 Study Abstract

American journal of obstetrics and gynecology, NCBI PMID: 7573253, 1995 Sep.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women’s daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother’s prenatal diethylstilbestrol exposure.

Sources and more information
More DES DiEthylStilbestrol Resources

The Influence of Prenatal DES Exposure on the Associations of Reproductive Factors and Osteoporosis

Prenatal DES exposure may reduce osteoporosis protection

DES Follow-up Study Summary

National Cancer Inst logo image
Lifetime cumulative exposure to estrogens is protective against osteoporosis ; prenatal exposure to estrogen appears to modify these associations.

Included in this study were 5,573 women who participated in the NCI DES Follow-up Study between 1994 and 2006. Data on reproductive history and medical conditions were collected on the first follow-up questionnaire in 1994 and subsequently on the 1997, 2001, and 2006 questionnaires.

The results of the study showed that women who had fewer than 25 years of menstruation (between the start of menstrual cycles and menopause) had a higher incidence of osteoporosis when compared with women who menstruated for 35 years or more. The association of years of menstruation with osteoporosis was shown observed in both DES-exposed and unexposed women, but was stronger among women who had not been prenatally exposed to DES.

The study’s results support the hypothesis that total lifetime exposure to estrogens that occur naturally through a woman’s reproductive years protects against the development of osteoporosis. Furthermore, prenatal exposure to estrogen, in the form of DES, may reduce this protection, although we do not yet know how.

2014 Study Abstract:

CONTEXT:
Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause.

OBJECTIVE:
The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations.

DESIGN, SETTING, AND PARTICIPANTS:
Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994-2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models.

MAIN OUTCOME MEASURE:
Osteoporosis was the main outcome measure.

RESULTS:
The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES.

CONCLUSIONS:
Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown.

Sources:

  • Menarche, menopause, years of menstruation, and the incidence of osteoporosis: the influence of prenatal exposure to diethylstilbestrolNCBI, PMID: 24248183, 2014 Feb;99(2):594-601. doi: 10.1210/jc.2013-2954. Epub 2013 Nov 18. Full text link.
  • NCI, DES Follow-up Study Published Papers.
More DES DiEthylStilbestrol Resources

Preterm Birth, Fetal Growth, Age at Menarche among Women exposed prenatally to DiEthylStilbestrol

DES exposed daughters more likely to have begun menstruating at younger age

DES Follow-up Study Summary

National Cancer Inst logo image
DES exposed daughters appeared to weigh slightly less and have a higher risk of being born prematurely than unexposed daughters. They also were somewhat more likely to have begun menstruating at age 10 or younger.

Research has suggested that early life characteristics, such as size at birth and age at menarche, may be associated with health conditions later in life. For example, some studies have suggested that low birth weight babies tend to have a higher risk of cardiovascular disease later in life. Other studies have shown that women who begin having periods at a young age have a slightly higher risk of breast cancer than those who begin menstruation later.

Although there has been a great deal of research on health of the 2nd generation (DES daughters) later in life, little attention has been paid to whether they were similar in terms of birth weight and other early life factors. Results from one of the early clinical trials of DES suggested that it might be related to lower birth weight and a higher risk of preterm birth. We conducted a systematic evaluation of DES daughters participating in the NCI DES Follow-up Study to determine whether there were any differences in birth weight, length of gestation, and the average age of first menstruation in the DES-exposed compared to unexposed daughters.

We found that there was a 2 to 3 fold increase in risk of having been born prematurely (before 37 weeks gestational age) among the DES-exposed compared to unexposed daughters. On average, DES daughters tended to weigh slightly less at birth, and there was also a 60% higher risk of being born too small, or small for gestational age (SGA), defined as less than the 10th percentile of birth weight at each gestational age. We found stronger effects for birth weight, SGA, and preterm birth among women who were participants in the original DESAD study, as compared to those who were in the Dieckmann clinical trial, suggesting that part of the effect may have been due to the higher risk pregnancies among the exposed women and not solely to DES exposure.

When we evaluated the risk of having started menstruation before age 11, we found no difference between the DES exposed and unexposed daughters. However, DES daughters did have a small increased risk (40%) of starting menarche very young-at age 10 or less-but this was based on very small numbers of participants who had very early menstruation.

In summary, DES exposed daughters appeared to weigh slightly less and have a higher risk of being born prematurely than unexposed daughters. They also were somewhat more likely to have begun menstruating at age 10 or younger. These effects may have a small impact on the risk of some diseases occurring later in life.

2011 Study Abstract:

Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.

Sources:

  • Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES),NCBI, PMID: 21130156, 2011 Feb;31(2):151-7. doi: 10.1016/j.reprotox.2010.11.006. Epub 2010 Dec 2. Full text link.
  • NCI, DES Follow-up Study Published Papers.
More DES DiEthylStilbestrol Resources