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Symptothermal and hormonal markers of potential fertility in climacteric women
Symptothermal and hormonal markers of potential fertility in climacteric women Anna M. Flynn, MD, Patricia James, PhD, William P. Collins, DSc, and Patrick Royston, MSc Birmingham, England One hundred seventy-seven menstrual cycles in 36 women between 45 and 53 years of age were studied prospectively. All the women were experienced in the symptothermal method of natural family planning. The objective was to determine the symptothermal and hormonal indices of potential fertility by measuring urinary estrone glucuronide and pregnanediol glucuronide. glucuronide. Thirty-three percent had regular cycles consistent with potential fertility. fertility, 19% had cycles consistent with infertility. infertility, and 47% had a mixture of both types of cycle. (AM J OBSTET GVNECOL 1991 ;165:1987-9.)
Key words: Natural family planning, climacteric, menopause, fertility The climacteric has been defined as a gradual transitory phase in the human female between the ages of reproductive and nonreproductive ability.] ability. I The time when fertility starts to decline is difficult to determine for an individual. The mean marital fertility rate. rate, however, is markedly reduced in women who are over 45 years old! 01d. 2 The menopause (i.e., (i.e .• the last menstrual period) occurs most frequently during the fiftieth year of life. 2 This event is a sign that potential fertility has been lost. but the time can only be determined retrospeclost, tively (usually after 1 year has elapsed). Accordingly, there is a need for reliable methods to to determine the times of potential fertility in women who are over 47 years old and premenopausal.
Use of natural family planning Natural methods of family planning depend on the detection and interpretation of clinical signs of potential fertility. The results from studies of preclimacteric women (aged 25 to 35 years) have shown that symptothermal changes (e.g., in basal body temperature and the characteristics of cervicovaginal mucus) correlate well with indices of ovarian function and the probable fertility.3.4 In addition, the results of times of potential fertility.,·4 prospective clinical trials have shown that methods of contraception based on periodic abstinence can be as From the Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, the Diagnostics Research Unit. Unit, King's College School of Medicine and Dentistry, and The Department of Medical M edical Physics, Physics. Royal Postgraduate Medical School. This investigation received financial support from the Special Programme of Research, Research. Development and Research Training in Human Reproduction, Reproduction. the World Health Organization, Geneva, Switzerland. Switzerland. Reprint requests: Anna M. Flynn, Flynn , MD, Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, Queen Elizabeth M edical Centre, Edgbaston, Edgbaston , Birmingham, B15 2TG, England. England. 610134938
effective as most alternative procedures. procedures."5 • 6 During the climacteric, climacteric. however, the traditional signs of potential fertility are frequently erratic and difficult to interpret. 7.]' - 13 Furthermore, new signs of diminished fertility (e.g., hot flushes, flushes. night sweats, and mastalgia) start to appear, but their significance in natural family planning has not been evaluated. Consequently, Consequently. we have undertaken a prospective, comprehensive study of symptothermal and hormonal indices of potential fertility during the climacteric.
Aims There were five principal aims: (1) to determine the within- and between-women variation in menstrual cycle length during the climacteric; (2) to determine daily changes in the urinary excretion of hormone metabolites; (3) to define criteria for potential fertility; (4) to examine temporal relationships between the times of defined changes in clinical and hormonal indices of ovarian function; and (5) to ascertain the most reliable indicators of potential fertility during the climacteric.
Plan of investigation to study 40 women (aged 45 to 54 years), We planned to who were experienced users of the symptothermal method of natural family planning, for 6 calendar months. All volunteers were asked to to complete a daily record of vaginal bleeding, basal body temperature, the characteristics of the cervix and cervicovaginal mucus. mucus, and climacteric symptoms (hot flushes, night sweats, breast tenderness, and dyspareunia) that occurred during the previous 24 hours. In addition, each woman collected a daily sample of early morning urine for retrospective analysis of estrone glucuronide (EG) and pregnanediol glucuronide (PG) by time-resolved theorescence immunoassay.
1987
1988 Flynn et al.
December 1991 Am J Obstet Gynecol
Table I. Parameters for determining the rise (by CUSUM analysis) and peak days of urinary EC and PC Analyte
I
Baseline
I
h
(Loge)
(Days) 1I to 6 4 to 9
EG EC PG PC
I
k
(Loge)
0.15 0.20
0.40 1.80
NCV
I
Peak
I
Confirm.
(Days) -18to-9 -18 to-9 > -20
4
1I 3
Limits
Where: baseline is the set of days over which the mean of ofloge loge analyte values was calculated to give a base level for the CUSUM; k is the value added to the base level, and h is the CUSUM decision level; NCV is the number of consecutive values required to be above the reference value (base level + h); peak continuation is the number of subsequent lower values that must occur after the highest arithmetic value; limits refer to to an acceptable interval between the peak EG EC or rise in CL GL and the end of the cycle (day 0).
Table II. Classification of menstrual cycles according to defined changes in the concentration of urinary EC and PC Presence of Analyte
Rise
EC EG
Absent Absent Present Present Absent Present Present
PG PC
I
1
Peak
Absent Present Present Present
In limits*
No Yes No Yes
Class
0 1I 2 3 0 1I 2
No.
%
22
12 6 10 72 23 8 69
II 11
17 127 40 14 123
EC or rise of PG PC to day of next menses. *Interval from peak EG
Table III. Cross tabulation of menstrual cycles by class according to changes in urinary EC and PC PC class EC class
0a
1
2
Total
0 1I 2 3 Total
12 7 6 15 40
2 0 8 4 14
8 4 3 108 123
22 II 11
17 127 177
Preliminary results
Thirty-six women (aged 45 to 53 years; median, 45Y2 45\!2 years) were recruited, and 177 menstrual cycles were identified retrospectively (length, 16 to lO3 103 days; me1/2 days). The number of cycles per woman dian, 27 27Y2 ranged from two to seven. Potential fertility
Defined changes in the daily concentrations of EC and PC were used to classify each menstrual cycle retrospectively as potentially fertile or not potentially fertile (i.e. infertile). The parameters for the algorithms" used to identify a rise and peak in the urinary excretion of EC and a rise in PC were derived from a second analysis of the data obtained from a similar study of 73 women (aged 21 to 35 years) over 118 menstrual or conception cycles. 15 The values and additional criteria
to determine potential fertility for this study are shown in Table I. The menstrual cycles during the oelimacteric were classified according to the changes in EC and PC as shown in Table II. A cross tabulation of the classification is shown in Table III. Sixty-one percent (lO8/177) (108/177) of the menstrual cycles were defined as potentially fertile on the basis of criteria for EC and PC appearing normal. The numbers of all women (and menstrual cycles) showing the characteristics consistent with potential fertility, infertility, and a mixture of cycles that produced periods of potential fertility are shown in Table IV. Of the 88 cycles from women in group 3, 45 were potentially fertile and 43 were infertile. Comment
The results from this preliminary analysis of the data suggest that about 33% of women between the ages of 45 and 54 years experienced regular menstrual cycles that were consistent with periods of potential fertility. About 19% had menstrual cycles without signs of potential fertility, and the remainder (47%) had a mixture of both types of cycle. This method of classification is likely to overestimate the number of potentially fertile cycles (because ovulation need not necessarily occur even in the presence of normal hormonal changes). This probability means that we will error on the side of caution when the results are used to develop a strategy for contraceptive practice. The data are also consistent with epidemiologic ev-
Symptothermal and hormonal markers of potential fertility
Volume 165 Number 6, Part 2
1989
Table IV. Number of all women (and menstrual cycles) classified according to potential fertility
Potentially fertile No . No.
Women Cycles
12 63
I
Mixture potentially fertile and infertile
Infertile
%
No.
33 36
7 26
I
idence of a gradual transition over time from regular cycles of potential fertility to total infertility. An analysis of the data from women with potentially fertile cycles has shown that the cycle length and clinical indicators have similar usefulness for predicting the start and finish of a defined fertile period to those observed in younger women." women. 14 Conversely, a first analysis of our data has shown that the same clinical indicators may not always reflect the underlying physiology in women with infertile cycles (data not shown). These aspects will be a smaller proportion of the subjects of a subsequent publication. Consequently, it is apparent that new markers are required to predict those cycles in which a period of potential fertility will occur from those in which it will not. A simple dipstick for a urinary metabolite that provided this information would greatly reduce the false-positive rate of subsequent tests to define precisely the time of potential fertility. fertility. REFERENCES 1. Utian WHo The true clinical features of the postmenopause and oophorectomy, and their response to estrogen therapy. SS Afr MedJ Med J 1972;46:732-7. therapy. 2. Gray RH, Doyle PE. The epidemiology of conception and fertility. In: Barron SL, Thomson AM, fertility. AM , eds. Obstetrical epidemiology. London: Academic Press, 1983:25-60. 3. Flynn AM, Docker M, Morris R, Lynch S, RoystonJP. The reliability of women's subjective assessment of the fertile period relative to urinary gonadotrophins and follicular ultrasonic measurements during the menstrual cycle. In: Bonnar J, J , Thompson W, Harrison RF, eds. Research in family planning. Lancaster, England: MTP Press, 1983:311.
%
No . No.
19 15
17 88
I
Total
%
No.
47 50
36 177
I
% 100 100
4. World Health Organization. Temporal relationships between indices of the fertile period. Fertil Steril 1983;39:647-55. 5. Barbato M, Bertolotti G. Natural methods for fertility In : Proceedings of the IVth control. A prospective study. In: European Congress of IFFLP, Instute fiir fur Ehe und Familie, Vienna, 1988 1988:: 14-6. 6. Frank-Herrmann P, Bremme M, Rosmus T, Kunkel W. The use-effectiveness of a symptothermal method in Germany. In: Proceedings of the IVth European Congress of IFFLP, Instute fUr fur Ehe und Familie, Vienna, 1988:27-45 1988:27-45.. 7. Treloar AE, Boynton RE, Benn BC, Brown BW. Variation of the human menstrual cycle through life. life. Int J Fertil 1967; 12:77-126. West JH, Korenman SG. The menopausal 8. Sherman BM, WestJH, transition: analysis of LH, FSH, estradiol and progesterone concentrations during the menstrual cycles in older 1976;42 :629-34. women. J Clin Endocrinol Metab 1976;42:629-34. 9. Van Look PFA, Lothian H, WM , Mitchie EA, H , Hunter WM, Baird DT. Hypothalamic-pituitary-ovarian function in perimenopausal women. J Clin Endocrinol Metab 1977;10:13-31. 1977; 10: 13-31. 10. Metcalf MG. Incidence of ovulatory cycles in women apmenopause. JJ Biosoc Sci 1979; 11 :39-48. proaching the menopause. II. Metcalf MG, Donald RA, Livesey JH. Classification of 11. menstrual cycles in pre- and perimenopausal women. J Endocrinol Metab 1981;91:1-10. RA , Livesey JH. JH . Pituitary-ovarian 12. Metcalf MC, Donald RA, function in normal women during the menopausal transition. J Clin Endocrinol Metab 1981; 14:245-55. 13. Metcalf MG, Livesey JH. Gonadotrophin excretion in fertile women: effect of age and the onset of the menopausal transition.J Endocrinol Metab 1985;105:357-62. 14. Royston JP. Identifying the fertile phase of the human menstrual cycle. Stat Med 1991; 1991;10:221-40. 10:221-40. 15. Schiphorst LEM, Collins WP, RoystonJP. An estrogen test to determine the times of potential fertility in women. 1985 ;44:328-34. Fertil Steril 1985;44:328-34.
Key words: Natural family planning, climacteric, menopause, fertility The climacteric has been defined as a gradual transitory phase in the human female between the ages of reproductive and nonreproductive ability.] ability. I The time when fertility starts to decline is difficult to determine for an individual. The mean marital fertility rate. rate, however, is markedly reduced in women who are over 45 years old! 01d. 2 The menopause (i.e., (i.e .• the last menstrual period) occurs most frequently during the fiftieth year of life. 2 This event is a sign that potential fertility has been lost. but the time can only be determined retrospeclost, tively (usually after 1 year has elapsed). Accordingly, there is a need for reliable methods to to determine the times of potential fertility in women who are over 47 years old and premenopausal.
Use of natural family planning Natural methods of family planning depend on the detection and interpretation of clinical signs of potential fertility. The results from studies of preclimacteric women (aged 25 to 35 years) have shown that symptothermal changes (e.g., in basal body temperature and the characteristics of cervicovaginal mucus) correlate well with indices of ovarian function and the probable fertility.3.4 In addition, the results of times of potential fertility.,·4 prospective clinical trials have shown that methods of contraception based on periodic abstinence can be as From the Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, the Diagnostics Research Unit. Unit, King's College School of Medicine and Dentistry, and The Department of Medical M edical Physics, Physics. Royal Postgraduate Medical School. This investigation received financial support from the Special Programme of Research, Research. Development and Research Training in Human Reproduction, Reproduction. the World Health Organization, Geneva, Switzerland. Switzerland. Reprint requests: Anna M. Flynn, Flynn , MD, Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, Queen Elizabeth M edical Centre, Edgbaston, Edgbaston , Birmingham, B15 2TG, England. England. 610134938
effective as most alternative procedures. procedures."5 • 6 During the climacteric, climacteric. however, the traditional signs of potential fertility are frequently erratic and difficult to interpret. 7.]' - 13 Furthermore, new signs of diminished fertility (e.g., hot flushes, flushes. night sweats, and mastalgia) start to appear, but their significance in natural family planning has not been evaluated. Consequently, Consequently. we have undertaken a prospective, comprehensive study of symptothermal and hormonal indices of potential fertility during the climacteric.
Aims There were five principal aims: (1) to determine the within- and between-women variation in menstrual cycle length during the climacteric; (2) to determine daily changes in the urinary excretion of hormone metabolites; (3) to define criteria for potential fertility; (4) to examine temporal relationships between the times of defined changes in clinical and hormonal indices of ovarian function; and (5) to ascertain the most reliable indicators of potential fertility during the climacteric.
Plan of investigation to study 40 women (aged 45 to 54 years), We planned to who were experienced users of the symptothermal method of natural family planning, for 6 calendar months. All volunteers were asked to to complete a daily record of vaginal bleeding, basal body temperature, the characteristics of the cervix and cervicovaginal mucus. mucus, and climacteric symptoms (hot flushes, night sweats, breast tenderness, and dyspareunia) that occurred during the previous 24 hours. In addition, each woman collected a daily sample of early morning urine for retrospective analysis of estrone glucuronide (EG) and pregnanediol glucuronide (PG) by time-resolved theorescence immunoassay.
1987
1988 Flynn et al.
December 1991 Am J Obstet Gynecol
Table I. Parameters for determining the rise (by CUSUM analysis) and peak days of urinary EC and PC Analyte
I
Baseline
I
h
(Loge)
(Days) 1I to 6 4 to 9
EG EC PG PC
I
k
(Loge)
0.15 0.20
0.40 1.80
NCV
I
Peak
I
Confirm.
(Days) -18to-9 -18 to-9 > -20
4
1I 3
Limits
Where: baseline is the set of days over which the mean of ofloge loge analyte values was calculated to give a base level for the CUSUM; k is the value added to the base level, and h is the CUSUM decision level; NCV is the number of consecutive values required to be above the reference value (base level + h); peak continuation is the number of subsequent lower values that must occur after the highest arithmetic value; limits refer to to an acceptable interval between the peak EG EC or rise in CL GL and the end of the cycle (day 0).
Table II. Classification of menstrual cycles according to defined changes in the concentration of urinary EC and PC Presence of Analyte
Rise
EC EG
Absent Absent Present Present Absent Present Present
PG PC
I
1
Peak
Absent Present Present Present
In limits*
No Yes No Yes
Class
0 1I 2 3 0 1I 2
No.
%
22
12 6 10 72 23 8 69
II 11
17 127 40 14 123
EC or rise of PG PC to day of next menses. *Interval from peak EG
Table III. Cross tabulation of menstrual cycles by class according to changes in urinary EC and PC PC class EC class
0a
1
2
Total
0 1I 2 3 Total
12 7 6 15 40
2 0 8 4 14
8 4 3 108 123
22 II 11
17 127 177
Preliminary results
Thirty-six women (aged 45 to 53 years; median, 45Y2 45\!2 years) were recruited, and 177 menstrual cycles were identified retrospectively (length, 16 to lO3 103 days; me1/2 days). The number of cycles per woman dian, 27 27Y2 ranged from two to seven. Potential fertility
Defined changes in the daily concentrations of EC and PC were used to classify each menstrual cycle retrospectively as potentially fertile or not potentially fertile (i.e. infertile). The parameters for the algorithms" used to identify a rise and peak in the urinary excretion of EC and a rise in PC were derived from a second analysis of the data obtained from a similar study of 73 women (aged 21 to 35 years) over 118 menstrual or conception cycles. 15 The values and additional criteria
to determine potential fertility for this study are shown in Table I. The menstrual cycles during the oelimacteric were classified according to the changes in EC and PC as shown in Table II. A cross tabulation of the classification is shown in Table III. Sixty-one percent (lO8/177) (108/177) of the menstrual cycles were defined as potentially fertile on the basis of criteria for EC and PC appearing normal. The numbers of all women (and menstrual cycles) showing the characteristics consistent with potential fertility, infertility, and a mixture of cycles that produced periods of potential fertility are shown in Table IV. Of the 88 cycles from women in group 3, 45 were potentially fertile and 43 were infertile. Comment
The results from this preliminary analysis of the data suggest that about 33% of women between the ages of 45 and 54 years experienced regular menstrual cycles that were consistent with periods of potential fertility. About 19% had menstrual cycles without signs of potential fertility, and the remainder (47%) had a mixture of both types of cycle. This method of classification is likely to overestimate the number of potentially fertile cycles (because ovulation need not necessarily occur even in the presence of normal hormonal changes). This probability means that we will error on the side of caution when the results are used to develop a strategy for contraceptive practice. The data are also consistent with epidemiologic ev-
Symptothermal and hormonal markers of potential fertility
Volume 165 Number 6, Part 2
1989
Table IV. Number of all women (and menstrual cycles) classified according to potential fertility
Potentially fertile No . No.
Women Cycles
12 63
I
Mixture potentially fertile and infertile
Infertile
%
No.
33 36
7 26
I
idence of a gradual transition over time from regular cycles of potential fertility to total infertility. An analysis of the data from women with potentially fertile cycles has shown that the cycle length and clinical indicators have similar usefulness for predicting the start and finish of a defined fertile period to those observed in younger women." women. 14 Conversely, a first analysis of our data has shown that the same clinical indicators may not always reflect the underlying physiology in women with infertile cycles (data not shown). These aspects will be a smaller proportion of the subjects of a subsequent publication. Consequently, it is apparent that new markers are required to predict those cycles in which a period of potential fertility will occur from those in which it will not. A simple dipstick for a urinary metabolite that provided this information would greatly reduce the false-positive rate of subsequent tests to define precisely the time of potential fertility. fertility. REFERENCES 1. Utian WHo The true clinical features of the postmenopause and oophorectomy, and their response to estrogen therapy. SS Afr MedJ Med J 1972;46:732-7. therapy. 2. Gray RH, Doyle PE. The epidemiology of conception and fertility. In: Barron SL, Thomson AM, fertility. AM , eds. Obstetrical epidemiology. London: Academic Press, 1983:25-60. 3. Flynn AM, Docker M, Morris R, Lynch S, RoystonJP. The reliability of women's subjective assessment of the fertile period relative to urinary gonadotrophins and follicular ultrasonic measurements during the menstrual cycle. In: Bonnar J, J , Thompson W, Harrison RF, eds. Research in family planning. Lancaster, England: MTP Press, 1983:311.
%
No . No.
19 15
17 88
I
Total
%
No.
47 50
36 177
I
% 100 100
4. World Health Organization. Temporal relationships between indices of the fertile period. Fertil Steril 1983;39:647-55. 5. Barbato M, Bertolotti G. Natural methods for fertility In : Proceedings of the IVth control. A prospective study. In: European Congress of IFFLP, Instute fiir fur Ehe und Familie, Vienna, 1988 1988:: 14-6. 6. Frank-Herrmann P, Bremme M, Rosmus T, Kunkel W. The use-effectiveness of a symptothermal method in Germany. In: Proceedings of the IVth European Congress of IFFLP, Instute fUr fur Ehe und Familie, Vienna, 1988:27-45 1988:27-45.. 7. Treloar AE, Boynton RE, Benn BC, Brown BW. Variation of the human menstrual cycle through life. life. Int J Fertil 1967; 12:77-126. West JH, Korenman SG. The menopausal 8. Sherman BM, WestJH, transition: analysis of LH, FSH, estradiol and progesterone concentrations during the menstrual cycles in older 1976;42 :629-34. women. J Clin Endocrinol Metab 1976;42:629-34. 9. Van Look PFA, Lothian H, WM , Mitchie EA, H , Hunter WM, Baird DT. Hypothalamic-pituitary-ovarian function in perimenopausal women. J Clin Endocrinol Metab 1977;10:13-31. 1977; 10: 13-31. 10. Metcalf MG. Incidence of ovulatory cycles in women apmenopause. JJ Biosoc Sci 1979; 11 :39-48. proaching the menopause. II. Metcalf MG, Donald RA, Livesey JH. Classification of 11. menstrual cycles in pre- and perimenopausal women. J Endocrinol Metab 1981;91:1-10. RA , Livesey JH. JH . Pituitary-ovarian 12. Metcalf MC, Donald RA, function in normal women during the menopausal transition. J Clin Endocrinol Metab 1981; 14:245-55. 13. Metcalf MG, Livesey JH. Gonadotrophin excretion in fertile women: effect of age and the onset of the menopausal transition.J Endocrinol Metab 1985;105:357-62. 14. Royston JP. Identifying the fertile phase of the human menstrual cycle. Stat Med 1991; 1991;10:221-40. 10:221-40. 15. Schiphorst LEM, Collins WP, RoystonJP. An estrogen test to determine the times of potential fertility in women. 1985 ;44:328-34. Fertil Steril 1985;44:328-34.