PREMATURE AND EARLY MENOPAUSE: RISK FACTORS IN JORDANIAN WOMEN

Methods

This study was started in August 2007 at Princess Aisha Medical Complex, Amman. The aim was to collect information about the time of menopause from 1,000 women, to identify the fraction who had had premature or early menopause, and to detect any responsible factors.

Many women were excluded; exclusion criteria included hysterectomy and/or bilateral oophorectomy before the onset of natural menopause, history of radio- and/or chemotherapy, and history of primary amenorrhoea.

All the clinics of the medical centre helped in gathering the data. The ladies were questioned regarding age at menarche, menopause, first delivery, and parity, number of miscarriages, ovarian, tubal and/or uterine surgeries, history of smoking and family history of premature menopause in first-degree relatives (parents, offspring and siblings). Since most of the answers given were from memory, recall bias proved to be the most significant limitation.

The women were divided into three groups: Group-P (premature), Group-E (early), and Group-N (normal).

Statistical analysis was done using GraphPad® Instat software. The data was analysed using a contingency table which determined the chi-square and   the   p-value,   where  p<0.05  was   considered statistically significant.

Results

Table I compares the premature and normal groups. No statistically significant differences were noted with regard to age at menarche, age at first pregnancy, parity and miscarriages. Nevertheless, a positive family history of premature menopause in first-degree relatives proved to be statistically significant.

Table II, compares the early and normal groups. This proved to be similar to the premature group where a positive family history of premature menopause in first-degree relatives was statistically significant. An interesting finding was that women with normal-onset menopause (≥ 46 years) had a statistically significant increase in the rate of hysterectomies that were performed. The percentage of women who smoked was higher in the early group when compared to the rest (23.5% versus 16.6%), but this did not prove to be statistically significant (p=0.0965).

Table III compares the premature and the early groups. Here, we also note that there were no statistically significant differences with regard to age at menarche, age at first pregnancy, parity and miscarriages, however, a positive family history of premature menopause in first-degree relatives also proved to be statistically significant.

Discussion

Normal menopause generally occurs after the age of ≥ 46 years with an average age of 51.3 years.⁽¹⁾ In contrast, menopause is regarded as premature when it begins before the age of 40 years.⁽⁶⁾  

Early menopause describes women who develop menopause between 40-45 years of age. This happens in approximately 10% of women.^(1,7)

Premature menopause generally describes a syndrome consisting of amenorrhea (three or more months’ duration), elevated gonadotrophin levels and decreased oestrogen levels typical of those found in postmenopausal women.⁽⁶⁾  It affects 1% of women by the age of 40 years and 0.1% by the age of 30 years.⁽⁸⁾  Previously, follicle-stimulating hormone levels in the menopausal range were regarded as evidence of depletion of ovarian follicles, resulting in irreversible and permanent cessation of ovarian function. It is now clear, however, that approximately 50% of women with apparent premature menopause may have intermittent and unpredictable ovarian function; 25% may ovulate, and 6% to 10% may conceive after the diagnosis is made.^(6,9)

In women who present with 46 XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis.⁽¹⁰⁾

Fragile X mental retardation 1 (FMR1) gene is the gene responsible for fragile X syndrome, the most common hereditary cause of mental impairment and developmental delay. Practice guidelines from the American College of Obstetricians and Gynecologists Committee on Genetics recommend FMR1 carrier testing for women with premature ovarian insufficiency, particularly if they have a family history of fragile X, or family members with premature ovarian insufficiency, unexplained mental impairment, developmental delay, dementia, or a tremor/ataxia syndrome.⁽¹¹⁾

In our study, a total of 1,000 women were questioned regarding the time of their menopause and 129 women had had menopause before the age of 46 years. Out of this group, 27 (2.7%) had had premature menopause, leaving 102 women (10.2%) with early-onset menopause. This agrees with Margaret-Mary Wilson as the accepted percentage of women with early menopause.⁽¹⁾ In these ladies, there was a positive family history of premature menopause in first-degree relatives.

Premature menopause, however, is a different story. Our results are much higher than figures mentioned by Kalantaridou et al.⁽⁸⁾  which states that approximately 1% of women will experience premature menopause. This may be secondary to social aspects in our community where inter-familial marriages are common. Needless to say, there was a statistically significant association of a positive family history of premature menopause in first-degree relatives in women who had had premature menopause themselves when compared to the rest. 

Although cigarette smoking is often mentioned as a risk factor to premature and early menopause, it was not so in our study. The percentage of women who had had premature and early menopause, and who were current smokers was high but this did not reach statistical significance. This is in contrast to the findings of Mikkelsen et al.⁽¹²⁾ and Parazzini et al.⁽¹³⁾ who concluded that current cigarette smoking is associated with lower age menopause.

Although we excluded women who had had premenopausal hysterectomy from our study, we asked all women whether they underwent this operation after having the menopause. An interesting finding that we had was that the number of women who underwent hysterectomy was significantly higher in women who had normal-onset menopause when compared to the women with early and premature menopause. This was just a finding with no reasonable explanation. Perhaps if the number of women was higher, we would not have had this result.

Conclusion

Early and premature menopause was strongly associated with history of premature menopause in first-degree relatives. No other factors studied proved to have any statistical significance.

More studies with larger numbers of women need to be undertaken in order to determine factors responsible for early and premature menopause.

References

1. Wilson MG. Menopause. Clin Geriatr Med 2003;19(3):483– 506

2. Nelson HD. Menopause. The Lancet 2008; 371(9614):760-70

3. Weismiller DG. The perimenopause and menopause experience. Clin Fam Prac 2002;4(1):1-12

4. Sherma S. Defining the menopausal transition. Am J Med 2005;118(12B):3S-7S

5. Johnson BD, Merz NB, Braunstein GD, et al. Determination of menopausal status in women: The NHLBI-sponsored women’s ischemia syndrome evaluation (WISE) study. J Wom Hlth 2004;13(8):872-87

6. Rebar RW. Mechanisms of premature menopause. Endocrinol  Metab  Clin  N  Am  2005;34(4):923-33.

7. van Kasteren YM, Hundscheid RDL, Smits APT, et al. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Rep 1999;14(10):2455-9

8. Kalantaridou SN, Nelson LM. Premature ovarian failure is not premature menopause. Ann NY Acad Sci 2000; 900(1):393-402

9. Nelson LM, Covington SN, Rebar RW.  An update:  Spontaneous premature ovarian failure is not an early menopause. Fertil Steril 2005; 83(5): 1327-32.