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Gynaecology
' ' ' ' ' '
GYNAECOLOGY
' ' ' ' ' '
DIAGNOSIS OF MENOPAUSE IN PERIMENOPAUSAL WOMEN TAKING ORAL CONTRACEPTIVES Allison M. Case, MD, Robert L. Reid, MD, FRCSC, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Queen's University ABSTRACT
The low-dose aral contraceptive (OC) is frequendy being used by low-risk, non-smoking, perimenopausal women far a variety of indications, including cycle control, management of irregular bleeding and contraception. As the OC masks the signs and symptoms of menopause, the question of when to discontinue the OC, ar switch from OCs to hormone replacement therapy inevitably arises. The "traditional" but insensitive method of diagnosing menopause in warnen taking the OC has been measurement of a serum FSH value of> 30 IU/L on day seven of the piU-free interval. Two recent studies suggest that measurement of serum estradiol and FSH:LH ratio on day seven of the pillfree interval wiU improve diagnostic sensitivity. RESUME
On emploie souvent le contraceptif aral (CO) afaible dose pour uncertain nombre de situations teUes que le controle du cycle menstruel, des saignements im!guliers et de Ia contraception, affectant les femmes perimenopausiques a risque faible et non-fumeuses. Comme le CO cache les signes et les sympt6mes de Ia menopause, Ia question de savoir quand il faut cesser le CO ou passer des CO a Ia therapie de remplacement harmonal se pose invariablement. La methode « traditionneUe » mais insensible pour diagnostiquer Ia menopause chez Ia femme qui prend un CO a ere Ia mesure d' une valeur du serum HFS de >30 UI!lle septieme jour de l'intervalle sans pilule. Deux etudes recentes suggerent que Ia mesure du serum estradiol et du rappart HFS : HL au septieme jour de l'intervalle sans pilule ameliore Ia sensibilite du diagnostique.
J SOC OBSTET GYNAECOL CAN 1998;20(12):1159-62
KEY WORDS
Perimenopause, menopause, aral contraceptives, hormone replacement. Received on January 30th, 1998. Revised and accepted on May 5th, 1998.
JOURNAL SOGC
115 9
OCTOBER 1998
' ' ' In 1994, the Canadian Health Protection Branch Guidelines for the Use of Oral Contraceptives1asserted that the benefits of low-dose (30-35 meg ethinyl estradiol) oral contraceptive (OC) use outweigh the possible risks in low-risk, non-smoking women of any age. This group includes perimenopausal women (age 35 to menopause), a group in whom OC use had previously been deemed a contra-indication.Z As a result, the lowdose OC is being increasingly prescribed for these women in a variety of different clinical circumstances. The perimenopause is characterized by unpredictable and less frequent ovulation. Follicle stimulating hormone (FSH) levels increase as a result of declining follicular inhibin production. Erratic ovulatory function accounts for the unpredictable bleeding that is characteristic of this period. Up to 90 percent of women will experience a change in menstrual cycles at some point in the perimenopause.3 Fifty percent of women will seek medical attention for dysfunctional uterine bleeding. 4 These women benefit from cycle control and subsequent prevention of irregular uterine bleeding afforded by the use of low-dose OCs. 5·7 The provision of effective contraception is another important use for low-dose OCs in these women. 8 While fertility is unquestionably decreased, pregnancy can, and does, occur unexpectedly, particularly considering that contraceptive use among perimenopausal women is even lower than among teenagers. 5·9The increased obstetrical and genetic risks, and consequently greater maternal and fetal morbidity and mortality, make the need for effective contraception vital. Additional non-contraceptive benefits, in particular the decrease in endometrial cancer (50%), ovarian cancer (40 to 50%) and functional ovarian cysts, make the oral contraceptive an attractive option in the perimenopause.5 There is also suggestive evidence that OC use may increase bone mass and optimize bone density as a woman enters the menopause. 10•11 As more women approach menopause, increasing numbers will be using low-dose OCs. As the OC "masks" the signs and symptoms of menopause (i.e. amenorrhoea, hot flashes, vaginal dryness), the question of when to discontinue the OC, or switch from OCs to hormone replacement therapy (HRT) inevitably arises. This is an important question as discontinuation of the OC too soon may result in the return of unpredictable bleeding, or once again may
JOURNALSOGC
place the woman at risk for an unwanted pregnancy. A post-menopausal woman, however, no longer requires the relatively higher estrogen doses present in the OC, necessary to block ovulation through suppression of gonadotrophins. Many women who experience premenstrual syndrome (PMS)-type side effects on the OC secondary to the progestin component prefer HRT, as the incidence of such symptoms appears, in part, to be dose-related. It has also been increasingly recognized that the risks of both acute myocardial infarction (AMI) and venous thromboembolism (VTE) are elevated with OC use among women of any ageY These risks multiply with increasing age, and are amplified by the presence of other risk factors, in particular smoking, a positive family history of premature atherosclerotic heart disease or VTE and, in the case of AMI, other recognized cardiac risk factorsY Even in non-smokers, the risk of AMI in women over 35 taking OCs is ten times higher than in women less than 35 (31 versus 2.75 per 100,000 woman-years). 14 Assuming a baseline risk of one per 10,000, the risk of VTE is three times higher with HRT, and up to seven times higher with the OC. 13•15-19 While these risks represent a small increase over an already low baseline risk, and need to be weighed against the many potential benefits of the OC, it nevertheless makes sense that, once a woman reaches menopause, the minimum estrogen dose that provides effective relief of menopausal symptoms and protection from cardiovascular disease and osteoporosis should be used. Switching from oral contraception to HRT at an arbitrary age (e.g. 50 or 51), or discontinuing the OCto see if regular menses resume or menopausal symptoms develop, are insensitive and time-consuming methods for diagnosing menopause, 20 and potentially put the woman at risk of unintended pregnancy or abnormal bleeding. Biochemical methods of diagnosing menopause have, therefore, been recommended. An arbitrary method of diagnosing menopause in women on OCs has been to measure serum FSH on the seventh day of the pill-free interval. An FSH value greater than 30 IU/L has been considered highly suggestive of menopause. 21 Until recently, however, this method was largely untested. Two recent studies suggest that FSH measurement on day seven of the pill-free interval is not a sensitive test for menopause. In a prospective study of 28 postmenopausal women taking either a monophasic or
1160
OCTOBER 1998
' ' ' FIGURE 1 ALGORITHM FOR DISCONTINUING ORAL CONTRACEPTIVES IN PERIMENOPAUSAUMENOPAUSAL WOMEN Age 51 - 52
Serum FSH on day 7 of pill-free week
--------,
---------------
FSH < 30 lUll
FSH > 30 IU/ L
Discontinue OC
+/- switcn to HRT
OR
Serum E2, FSH :LH ratio on day 7 of pill-free week
ContinueOC X 12 montn
l.______ E2 < 20 pg/ml (73 pmoVI) FSH :LH ratio > 1
has elapsed to allow FSH to rise into the menopausal range. Two options exist for such women. The first option is to continue the OC and have a repeat serum FSH measured in twelve months. The second option is to measure a serum Ez and FSH:LH ratio the following month on day seven of the pill-free week, to increase the accuracy of the diagnosis of menopause. Values of each in the menopausal range (i.e. E 2 < 20 pg/ml or< 73 pmol/1; FSH:LH ratio > 1) will be at least 95 percent sensitive in diagnosing menopause, 25 and indicate that the timing is appropriate for discontinuation of the oral contraceptive, and initiation of hormone replacement therapy (Figure 1). REFERENCES 1.
triphasic OC, Creinin measured serum FSH, luteinizing hormone (LH) and estradiol (Ez) levels on days 14 and 28 (i.e. day seven of the pill-free interval) of the third cycle of pills. Sixty-two percent of menopausal women still had a serum FSH < 30 IU/L on day seven of the pill-free interval. In distinction, all subjects had a serum FSH:LH ratio > one, and 95 percent had E2 values that were< 20 pg/ml ( < 73 pmol/1). A similar study by Castracane et al., 23 comparing postmenopausal, perimenopausal and premenopausal women taking OCs, also demonstrated that postmenopausal women fail to show a universal rise in FSH values into the menopausal range by the end of the pillfree week. These women all had serum E2 values that were < 20 pg/ml (< 73 pmol/1) at one and two weeks off OCs. Both these studies demonstrate that the anticipated return of gonadotrophin values to baseline levels by the seventh oral contraceptive-free day is by no means a certainty-casting into doubt the value of a single FSH determination for diagnosis of menopause. Recognizing that these are both preliminary studies with small numbers, their findings are nevertheless important. In a woman who is happy with the OC, there is no urgency to make the diagnosis of menopause. It is reasonable to continue the OC until age 51 or 52. At age 51, 50 percent of women will be menopausal (range 48 to 55). 24 A serum FSH can then be measured on day seven of the pill-free week. If the value is > 30 IU/L, the OC can be discontinued, and the woman switched to HRT if that is her choice. A serum FSH value< 30 IU/L suggests that the woman is either not yet menopausal, or insufficient time 22
JOURNAL SOGC
1994 HPB Oral Contraceptive: Guidelines for the Directions for Use of Estrogen-Progestin Combination Oral Contraceptives. Special Advisory Committee on Reproductive Physiology to the Health Protection Branch, Health and Welfare Canada-Health Protection Branch, Ottawa, 1994.
2.
3.
4. 5. 6.
Casper R, Senoz S, Ben-Chetrit A. Impact of the New Health Protection Branch (HPB) Guidelines for the Use of Oral Contraceptives in the Perimenopausal Patient. J Soc Obstet Gynaecol Can 1994;16(7) suppl:1-6. Bachmann GA. The changes before "the change." Strategies for the transition to the menopause. Postgrad Med 1994;94(4): 113-24. Metcalf MG. The approach of menopause: a New Zealand study. N Z Med J 1988;101(841):103-6. Haney AF. Hormonal needs of the perimenopausal woman. J Soc Obstet Gynaecol Can 1993;15(10):1129-38. Derzko CM. Perimenopausal dysfunctional uterine bleed-
ing: physiology and management. J Soc Obstet Gynaecol Can 1997;19(6):589-600. 7. Casper RF, Dodin S, Reid RL, and Study Investigators. The effect of 20flg ethinyl estradiol/1 mg norethindrone acetate (Minestrin™), a low dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic peri menopausal women. Menopause 1997;4(3):139-47 8. Farrell SA. Contraception in the perimenopause. J Soc Obstet Gynaecol Can 1994;16(4)suppl:1-7. 9. Bachrach CA. Contraceptive practice among American women, 1973-1982. Fam Plann Perspect 1984;16:253-9. 10. Lindsay R, Tohme J, Kanders B. The effect of oral contra0
ceptives on vertebral bone mass in pre- and postmenopausal women. Contraception 1986;34:333-40. 11. Enzelsberger H, Metka M, Heytmanek G, Schurz B, Kurz CH, Kusztrich M. Influence of oral contraceptive use on bone density in climacteric women. Maturitas 1988;9:375-8. 12. Carr BR, Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception 1997;55:267-72.
1161
OCTOBER 1998
' ' ' 13. Collins JA. Gunby J. Oral contraceptive use and the cardiovascular health of Canadian women. J Soc Obstet Gynaecol Can 1997;19:125-37. 14. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1997;349:1202-9. 15. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80. 16. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-2. 17. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multi centre casecontrol study. Lancet 1995;346:1575-82. 18. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-8. 19. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low estrogen oral contraceptives. J Obstet Gynecol1995;15:195-200. 20. Gebbie AE, Glasier A, Sweeting V. Incidence of ovulation in perimenopausal women before and during hormone replacement therapy. Contraception 1995;52:221-2. 21. Oral Contraception. In: Speroff L, Glass RH, Kase NG (Eds). Clinical Gynecologic Endocrinology and Infertility, 5th edition. Williams and Wilkins Company, Baltimore, 1994:715-63. 22. Creinin MD. Laboratory criteria for menopause in women using oral contraceptives. Fertil Steril 1996;66: 101-4. 23. Castracane VD, Gimpel T, Goldzieher JW. When is it safe to switch from oral contraceptives to hormone replacement therapy? Contraception 1995;52:371-6. 24. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14: 103-15. 25. Creinin MD. Diagnosis of menopause: ratios of FSH/LH? Fertil Steril 1996:866.
JOURNAL SOGC
1162
OCTOBER 1998
GYNAECOLOGY
' ' ' ' ' '
DIAGNOSIS OF MENOPAUSE IN PERIMENOPAUSAL WOMEN TAKING ORAL CONTRACEPTIVES Allison M. Case, MD, Robert L. Reid, MD, FRCSC, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Queen's University ABSTRACT
The low-dose aral contraceptive (OC) is frequendy being used by low-risk, non-smoking, perimenopausal women far a variety of indications, including cycle control, management of irregular bleeding and contraception. As the OC masks the signs and symptoms of menopause, the question of when to discontinue the OC, ar switch from OCs to hormone replacement therapy inevitably arises. The "traditional" but insensitive method of diagnosing menopause in warnen taking the OC has been measurement of a serum FSH value of> 30 IU/L on day seven of the piU-free interval. Two recent studies suggest that measurement of serum estradiol and FSH:LH ratio on day seven of the pillfree interval wiU improve diagnostic sensitivity. RESUME
On emploie souvent le contraceptif aral (CO) afaible dose pour uncertain nombre de situations teUes que le controle du cycle menstruel, des saignements im!guliers et de Ia contraception, affectant les femmes perimenopausiques a risque faible et non-fumeuses. Comme le CO cache les signes et les sympt6mes de Ia menopause, Ia question de savoir quand il faut cesser le CO ou passer des CO a Ia therapie de remplacement harmonal se pose invariablement. La methode « traditionneUe » mais insensible pour diagnostiquer Ia menopause chez Ia femme qui prend un CO a ere Ia mesure d' une valeur du serum HFS de >30 UI!lle septieme jour de l'intervalle sans pilule. Deux etudes recentes suggerent que Ia mesure du serum estradiol et du rappart HFS : HL au septieme jour de l'intervalle sans pilule ameliore Ia sensibilite du diagnostique.
J SOC OBSTET GYNAECOL CAN 1998;20(12):1159-62
KEY WORDS
Perimenopause, menopause, aral contraceptives, hormone replacement. Received on January 30th, 1998. Revised and accepted on May 5th, 1998.
JOURNAL SOGC
115 9
OCTOBER 1998
' ' ' In 1994, the Canadian Health Protection Branch Guidelines for the Use of Oral Contraceptives1asserted that the benefits of low-dose (30-35 meg ethinyl estradiol) oral contraceptive (OC) use outweigh the possible risks in low-risk, non-smoking women of any age. This group includes perimenopausal women (age 35 to menopause), a group in whom OC use had previously been deemed a contra-indication.Z As a result, the lowdose OC is being increasingly prescribed for these women in a variety of different clinical circumstances. The perimenopause is characterized by unpredictable and less frequent ovulation. Follicle stimulating hormone (FSH) levels increase as a result of declining follicular inhibin production. Erratic ovulatory function accounts for the unpredictable bleeding that is characteristic of this period. Up to 90 percent of women will experience a change in menstrual cycles at some point in the perimenopause.3 Fifty percent of women will seek medical attention for dysfunctional uterine bleeding. 4 These women benefit from cycle control and subsequent prevention of irregular uterine bleeding afforded by the use of low-dose OCs. 5·7 The provision of effective contraception is another important use for low-dose OCs in these women. 8 While fertility is unquestionably decreased, pregnancy can, and does, occur unexpectedly, particularly considering that contraceptive use among perimenopausal women is even lower than among teenagers. 5·9The increased obstetrical and genetic risks, and consequently greater maternal and fetal morbidity and mortality, make the need for effective contraception vital. Additional non-contraceptive benefits, in particular the decrease in endometrial cancer (50%), ovarian cancer (40 to 50%) and functional ovarian cysts, make the oral contraceptive an attractive option in the perimenopause.5 There is also suggestive evidence that OC use may increase bone mass and optimize bone density as a woman enters the menopause. 10•11 As more women approach menopause, increasing numbers will be using low-dose OCs. As the OC "masks" the signs and symptoms of menopause (i.e. amenorrhoea, hot flashes, vaginal dryness), the question of when to discontinue the OC, or switch from OCs to hormone replacement therapy (HRT) inevitably arises. This is an important question as discontinuation of the OC too soon may result in the return of unpredictable bleeding, or once again may
JOURNALSOGC
place the woman at risk for an unwanted pregnancy. A post-menopausal woman, however, no longer requires the relatively higher estrogen doses present in the OC, necessary to block ovulation through suppression of gonadotrophins. Many women who experience premenstrual syndrome (PMS)-type side effects on the OC secondary to the progestin component prefer HRT, as the incidence of such symptoms appears, in part, to be dose-related. It has also been increasingly recognized that the risks of both acute myocardial infarction (AMI) and venous thromboembolism (VTE) are elevated with OC use among women of any ageY These risks multiply with increasing age, and are amplified by the presence of other risk factors, in particular smoking, a positive family history of premature atherosclerotic heart disease or VTE and, in the case of AMI, other recognized cardiac risk factorsY Even in non-smokers, the risk of AMI in women over 35 taking OCs is ten times higher than in women less than 35 (31 versus 2.75 per 100,000 woman-years). 14 Assuming a baseline risk of one per 10,000, the risk of VTE is three times higher with HRT, and up to seven times higher with the OC. 13•15-19 While these risks represent a small increase over an already low baseline risk, and need to be weighed against the many potential benefits of the OC, it nevertheless makes sense that, once a woman reaches menopause, the minimum estrogen dose that provides effective relief of menopausal symptoms and protection from cardiovascular disease and osteoporosis should be used. Switching from oral contraception to HRT at an arbitrary age (e.g. 50 or 51), or discontinuing the OCto see if regular menses resume or menopausal symptoms develop, are insensitive and time-consuming methods for diagnosing menopause, 20 and potentially put the woman at risk of unintended pregnancy or abnormal bleeding. Biochemical methods of diagnosing menopause have, therefore, been recommended. An arbitrary method of diagnosing menopause in women on OCs has been to measure serum FSH on the seventh day of the pill-free interval. An FSH value greater than 30 IU/L has been considered highly suggestive of menopause. 21 Until recently, however, this method was largely untested. Two recent studies suggest that FSH measurement on day seven of the pill-free interval is not a sensitive test for menopause. In a prospective study of 28 postmenopausal women taking either a monophasic or
1160
OCTOBER 1998
' ' ' FIGURE 1 ALGORITHM FOR DISCONTINUING ORAL CONTRACEPTIVES IN PERIMENOPAUSAUMENOPAUSAL WOMEN Age 51 - 52
Serum FSH on day 7 of pill-free week
--------,
---------------
FSH < 30 lUll
FSH > 30 IU/ L
Discontinue OC
+/- switcn to HRT
OR
Serum E2, FSH :LH ratio on day 7 of pill-free week
ContinueOC X 12 montn
l.______ E2 < 20 pg/ml (73 pmoVI) FSH :LH ratio > 1
has elapsed to allow FSH to rise into the menopausal range. Two options exist for such women. The first option is to continue the OC and have a repeat serum FSH measured in twelve months. The second option is to measure a serum Ez and FSH:LH ratio the following month on day seven of the pill-free week, to increase the accuracy of the diagnosis of menopause. Values of each in the menopausal range (i.e. E 2 < 20 pg/ml or< 73 pmol/1; FSH:LH ratio > 1) will be at least 95 percent sensitive in diagnosing menopause, 25 and indicate that the timing is appropriate for discontinuation of the oral contraceptive, and initiation of hormone replacement therapy (Figure 1). REFERENCES 1.
triphasic OC, Creinin measured serum FSH, luteinizing hormone (LH) and estradiol (Ez) levels on days 14 and 28 (i.e. day seven of the pill-free interval) of the third cycle of pills. Sixty-two percent of menopausal women still had a serum FSH < 30 IU/L on day seven of the pill-free interval. In distinction, all subjects had a serum FSH:LH ratio > one, and 95 percent had E2 values that were< 20 pg/ml ( < 73 pmol/1). A similar study by Castracane et al., 23 comparing postmenopausal, perimenopausal and premenopausal women taking OCs, also demonstrated that postmenopausal women fail to show a universal rise in FSH values into the menopausal range by the end of the pillfree week. These women all had serum E2 values that were < 20 pg/ml (< 73 pmol/1) at one and two weeks off OCs. Both these studies demonstrate that the anticipated return of gonadotrophin values to baseline levels by the seventh oral contraceptive-free day is by no means a certainty-casting into doubt the value of a single FSH determination for diagnosis of menopause. Recognizing that these are both preliminary studies with small numbers, their findings are nevertheless important. In a woman who is happy with the OC, there is no urgency to make the diagnosis of menopause. It is reasonable to continue the OC until age 51 or 52. At age 51, 50 percent of women will be menopausal (range 48 to 55). 24 A serum FSH can then be measured on day seven of the pill-free week. If the value is > 30 IU/L, the OC can be discontinued, and the woman switched to HRT if that is her choice. A serum FSH value< 30 IU/L suggests that the woman is either not yet menopausal, or insufficient time 22
JOURNAL SOGC
1994 HPB Oral Contraceptive: Guidelines for the Directions for Use of Estrogen-Progestin Combination Oral Contraceptives. Special Advisory Committee on Reproductive Physiology to the Health Protection Branch, Health and Welfare Canada-Health Protection Branch, Ottawa, 1994.
2.
3.
4. 5. 6.
Casper R, Senoz S, Ben-Chetrit A. Impact of the New Health Protection Branch (HPB) Guidelines for the Use of Oral Contraceptives in the Perimenopausal Patient. J Soc Obstet Gynaecol Can 1994;16(7) suppl:1-6. Bachmann GA. The changes before "the change." Strategies for the transition to the menopause. Postgrad Med 1994;94(4): 113-24. Metcalf MG. The approach of menopause: a New Zealand study. N Z Med J 1988;101(841):103-6. Haney AF. Hormonal needs of the perimenopausal woman. J Soc Obstet Gynaecol Can 1993;15(10):1129-38. Derzko CM. Perimenopausal dysfunctional uterine bleed-
ing: physiology and management. J Soc Obstet Gynaecol Can 1997;19(6):589-600. 7. Casper RF, Dodin S, Reid RL, and Study Investigators. The effect of 20flg ethinyl estradiol/1 mg norethindrone acetate (Minestrin™), a low dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic peri menopausal women. Menopause 1997;4(3):139-47 8. Farrell SA. Contraception in the perimenopause. J Soc Obstet Gynaecol Can 1994;16(4)suppl:1-7. 9. Bachrach CA. Contraceptive practice among American women, 1973-1982. Fam Plann Perspect 1984;16:253-9. 10. Lindsay R, Tohme J, Kanders B. The effect of oral contra0
ceptives on vertebral bone mass in pre- and postmenopausal women. Contraception 1986;34:333-40. 11. Enzelsberger H, Metka M, Heytmanek G, Schurz B, Kurz CH, Kusztrich M. Influence of oral contraceptive use on bone density in climacteric women. Maturitas 1988;9:375-8. 12. Carr BR, Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception 1997;55:267-72.
1161
OCTOBER 1998
' ' ' 13. Collins JA. Gunby J. Oral contraceptive use and the cardiovascular health of Canadian women. J Soc Obstet Gynaecol Can 1997;19:125-37. 14. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1997;349:1202-9. 15. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80. 16. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-2. 17. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multi centre casecontrol study. Lancet 1995;346:1575-82. 18. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-8. 19. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low estrogen oral contraceptives. J Obstet Gynecol1995;15:195-200. 20. Gebbie AE, Glasier A, Sweeting V. Incidence of ovulation in perimenopausal women before and during hormone replacement therapy. Contraception 1995;52:221-2. 21. Oral Contraception. In: Speroff L, Glass RH, Kase NG (Eds). Clinical Gynecologic Endocrinology and Infertility, 5th edition. Williams and Wilkins Company, Baltimore, 1994:715-63. 22. Creinin MD. Laboratory criteria for menopause in women using oral contraceptives. Fertil Steril 1996;66: 101-4. 23. Castracane VD, Gimpel T, Goldzieher JW. When is it safe to switch from oral contraceptives to hormone replacement therapy? Contraception 1995;52:371-6. 24. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14: 103-15. 25. Creinin MD. Diagnosis of menopause: ratios of FSH/LH? Fertil Steril 1996:866.
JOURNAL SOGC
1162
OCTOBER 1998