June 22, 2005
Contraception During Perimenopause
Perimenopause marks the transition from normal ovulation to anovulation and ultimately to permanent loss of ovarian function. Fecundity, the average monthly probability of conception, declines by half as early as the mid-forties, however women during the perimenopause still need effective contraception. Issues arising at this period such as menstrual cycle abnormalities, vasomotor instability, the need for osteoporosis and cardiovascular disease prevention, as well as the increased risk of gynecological cancer, should be taken into consideration before the initiation of a specific method of contraception. Various contraceptive options may be offered to perimenopausal women, including oral contraceptives, tubal ligation, intrauterine devices, barrier methods, hormonal injectables and implants. Recently, new methods of contraception have been introduced presenting high efficacy rates and minor side- effects, such as the monthly injectable system, the contraceptive vaginal ring and the transdermal contraceptive system. However, these new methods have to be further tested in perimenopausal women, and more definite data are required to confirm their advantages as effective contraceptive alternatives in this specific age group. The use of the various contraceptive methods during perimenopause holds special benefits and risks that should be carefully balanced, after a thorough consultation and according to each woman's contraceptive needs.KEY WORDS Perimenopause, Contraception, Oral contraceptives, IUDs, Tubal ligation, Barrier contraceptive methods, Hormonal injectables and implants
Perimenopause is defined as the period before, during and after the menopause. The length of this period varies, but it is usually considered to last approximately 7 years, beginning with the decline in ovarian function in a woman's forties and continuing until she has not had a menstrual period for 1 year. The average duration of the perimenopause is 5 years, with an average age of onset around the 46th year1. The most important hormonal change during the so- called menopausal transition is anovulation. Although fecundity, i.e. the average monthly probability of conception, declines by 50% at age 43, up to 80% of women between 40 and 43 are still able to conceive2,3. Thus, women in perimenopause need adequate counseling regarding their current contraceptive options.
HORMONAL CHANGES IN PERIMENOPAUSE
Data suggest that during perimenopause ovarian follicles undergo an accelerated rate of loss until they are finally depleted4. It seems that aging follicles lose their productive quality. As a sequence, secretion of inhibin is reduced and the negative feedback influence over follicle-stimulating hormone (FSH) secretion by the pituitary gland is lost. As inhibin A and inhibin B levels decrease with aging, FSH levels rise5,6. In contrast, levels of estradiol and luteinizing hormone remain in the normal range, and start to decline almost 1 year before menopause7,8. All the above lead to chronic anovulation, which explains the low fecundity rates in this age group. Occasionally, ovulation takes place and the risk of an unplanned and unwanted pregnancy is always present. Even with high levels of FSH ( > 20 IU/l), occasional resumption of ovarian function has been demonstrated8,9. Therefore, the need for contraception until the postmenopausal state has been established is recommended, especially in sexually active women.
PERIMENOPAUSE: THE SYMPTOMS
The majority of women during their mid-forties experience unique changes. The most common complaint is abnormal uterine bleeding, which occurs in more than half of all women during the menopausal transition10. The perimenopausal bleeding patterns encountered are sudden amenorrhea (12%), oligomenorrhea or hypomenorrhea (70%) and menorrhagia, metrorrhagia and hypermenorrhea (18%)11. Vasomotor disturbances (hot flushes and cold sweats) are common perimenopausal symptoms. It has been estimated that almost 50% of those women complain of hot flushes12. Finally, atrophic genital changes, including vaginal dryness, itching and dyspareunia, may contribute to sexual dysfunction13.
RISKS OF PREGNANCY DURING PERIMENOPAUSE
It has been estimated that the induced abortion rate of unintended pregnancies among women above 40 is nearly 60%14. These figures clearly demonstrate that a pregnancy in this age group is usually considered an unwanted pregnancy. On the other hand, pregnancy in women over 35 years of age carries increased risks for both the mother and the fetus. In particular, there is an increased frequency of gestational diabetes, placenta previa, breech presentation, postpartum hemorrhage, operative vaginal delivery, emergency or elective Caesarean section, premature delivery, low birthweight and stillbirth15. Women aged > 40 years had even higher risk for the same complications. Also, increased maternal age has been directly related to fetal aneuploidy16, and to increased spontaneous abortion rates17.
CONTRACEPTION OPTIONS FOR THE PERIMENOPAUSAL WOMAN
The above information leads to the certain conclusion that contraception during perimenopause is of paramount importance. An unplanned pregnancy during the perimenopausal years leads to high induced or spontaneous abortion rates. In addition, the age-related increased maternal morbidity and mortality have to be taken into consideration, as well as the perinatal mortality under those circumstances. Also, contraception may offer improved sexual relationships and therefore, a higher quality of living. Therefore, health-care providers have to be familiar with today's contraceptive methods and capable of proper counseling, regarding the benefits and risks of each one.
As mentioned above, the menstrual cycles of perimenopausal women are grossly irregular, shorter or longer than normal. The menstrual period is also abnormal, either heavier or lighter. Intermenstrual bleeding is common as well. Therefore, ovulation prediction may be difficult, and probably unreliable.
Female sterilization is currently the most common method of contraception used by perimenopausal women in the United States , and probably in many other developed countries. Contrary to general belief, it is not more effective than other methods. However, female sterilization remains a very effective contraceptive method for the perimenopausal woman, with a reported failure rate from 0.75 to 3.65%, according to the method used19. Currently, modern laparoscopic sterilization takes place as a 1-day surgical procedure, with operative risks directly related to laparoscopy and anesthesia. Female sterilization seems to protect from ovarian cancer probably because of reduced 'carcinogen transmission' through the closed tubes20. Tubal ligation afforded a risk reduction even 20 or more years after the surgery21. On the other hand, it does not seem to affect the menstrual cycle22. A major disadvantage of the method is the lack of protection against sexually transmitted diseases. Sterilization regret and reversal request, although common in younger women, are not of major concern in older women23.
Perimenopausal women, especially those with infrequent sexual intercourse, may find barrier methods extremely suitable. Female condoms, cervical caps and vaginal diaphragms have not gained wide acceptance, whereas male condoms are much easier to use, and therefore remain widely accepted both in developing and developed countries. Efficacy rates are estimated to be around 86-88%24. Barrier methods, especially condoms and diaphragms, present the advantage of decreasing sexually transmitted diseases25, cervical intraepithelial neoplasia and invasive cervical cancer26, without major side-effects. On the other hand, they must be used during each sexual intercourse and more important, they do not reduce menstrual irregularities and perimenopausal symptoms, such as hot flushes and cold sweats.
Injectable hormonal contraceptives
Depomedroxyprogesterone acetate (DMPA), in the form of an intramuscular injection every 3 months, is a highly efficient contraceptive method27. On the other hand, its use is associated with common side-effects, such as depression, headache and weight gain. Furthermore, DMPA causes abnormal spotting and irregular bleeding, which are unacceptable for the perimenopausal woman. In addition, there is evidence that medroxyprogesterone increases bone lose and osteoporosis, both of which are also unacceptable28. Another available injectable combination, recently approved in the United States, called Lunelle, consists of 25 mg DMPA plus 5 mg estradiol cyprionate. Given once a month, this combination produces excellent contraceptive effects29. It does not cause abnormal bleeding, and because of the estrogen it contains it may relieve climacteric symptoms and prevent osteoporosis. Up to now, it has not been adequately studied in perimenopausal women.
Currently, contraceptive implant technology has been used by millions of women throughout the world, however there are not sufficient data regarding its use by women in perimenopause. The three marketed implant systems today are levonorgestrel-releasing implants (Norplant and Jadelle), and a single etonogestrel- releasing implant \(Implanon)30. The subcutaneous hormonal contraceptive systems present high efficacy rates as well as safety, long duration of action (3-5 years) and reversibility30-32. Unfortunately, they cause common side-effects such as abnormal bleeding, headache and depression. Additionally, a health-care provider is needed to insert and remove them. For these reasons, they have not gained wide acceptance among perimenopausal women.
lntrauterine devices (IUDs) seem to be very appealing for contraception during the perimenopause. Both the copper-containing IUD and the 20 g/day levonorgestrel intrauterine system (Mirena), especially the latter, show remarkably low pregnancy rates33,34. The method requires insertion by a health-care provider, but no other effort thereafter. Standard risks include pelvic inflammatory disease (PID), usually within 20 days after insertion, and uterine perforation during the procedure. As far as ectopic pregnancy is concerned, intrauterine devices reduce the risk by 80-90%35. The copper IUD may increase menstrual bleeding and dysmenorrhea, an unwanted side-effect during perimenopause. The levonorgestrel IUD produces atrophic endometrium, and reduces menstrual flow and dysmenorrhea. It also increases the risk of amenorrhea, which actually could be a benefit instead of a risk for many women36. Recently, a new 14-g/day levonorgestrel-releasing IUD has been tested in peri- and postmenopausal women. It has shown excellent compliance along with contraceptive efficacy37. Since the effectiveness of all the above systems lasts for 5-10 years, both can offer adequate contraception during the perimenopause.
Without doubt, the oral contraceptive pill (OC) is one of the most effective contraceptive methods available. The reported efficacy rates are about 99% with perfect use38. Unfortunately, only a minority of women during perimenopause uses the OCs, mainly because of major fears regarding the relationship between the OCs and breast cancer, or cardiovascular events in this age group. Only 11% of women aged 40-44 years and 4% of women aged 45-50 are using oral contraceptives39. The reduction of the estrogen and progestogen concentrations in modem OCs during the last decades, especially the reduction of estrogen to less than 50 g, has led to a corresponding reduction in the incidence of the above health risks. As far as breast cancer is concerned, data show a small increase during OC use, which begins to decline shortly after stopping and which disappears 10 years after discontinuation40. In addition, many studies suggest that long-term use of OCs possibly increases the risk of cervical cancer, and the relative risk increases with increasing duration of use41-43. In normotensive and nonsmoking perimenopausal women, without other risk factors, there is no additional risk for myocardial infarction or stroke44-48. Finally, there is only a small risk associated with venous thromboembolism in OC users, actually half the risk observed during pregnancy48,49. The highest risk of venous thromboembolism is observed with preparations containing third-generation progestogens (desogestrel or gestodene)48.
On the other hand, OCs demonstrate major health benefits beyond the female reproductive system. The best-established health benefit is the reduction of ovarian cancer risk, with suppression of ovulation being the mechanism responsible50. A series of reports and meta-analyses in the last 15 years, clearly support a risk reduction for ovarian cancer with OC use. Women taking OCs for 10 or more years, showed the greatest risk reduction, around 80%51. The protection against ovarian cancer seems to last up to 15 years after discontinuation and is independent of the contraceptive formulation taken52. There is no definite information regarding the new OCs containing 20 g of ethinylestradiol, and there is no definite answer whether carriers of the BRCA1 and BRCA42 mutations are protected as well53,54. The incidence of endometrial cancer and colorectal cancer increases particularly during the perimenopausal years. The risk for a woman who has ever used an OC, of endometrial cancer is reduced by 50-80% in comparison to that for a nonuser, depending on duration of use55,56. The protective effect is independent of the formulation or dose and lasts for at least 15-20 years after discontinuation56,57. The protective mechanism seems to be the antimitotic effect of the OC progestogen on the proliferative endometrium and the reduction of estrogen-associated endometrial hyperplasia. Information regarding the relation between OCs and colorectal cancer is less clear. Recent data however, suggest a significant reduction in the incidence of colorectal cancer among OC users58.
PID is one of the commonest benign disorders of the female reproductive tract, responsible for serious complications such as infertility and pelvic pain. The risk of PID is reduced by 50% among OC users in comparison to nonusers59,60. It is believed that the OCs act by thickening the cervical mucus, decreasing retrograde menstruation and reducing menstrual now. Both high-dose and low- dose OCs cause a marked reduction in both functional cysts and corpus luteum cysts61,62. Studies have also demonstrated a reduction in breast fibroadenomas and chronic breast cysts63. Recent data suggest that OCs may decrease the risk of osteoporosis and postmenopausal hip fracture by 30% in perimenopausal women64. OC use has been proved to decrease both the incidence and progression of rheumatoid arthritis65. Finally, OCs relieve dysmenorrhea, reduce the amount and duration of the menstrual period and thus deal with perimenopausal dysfunctional bleeding66,67.
Contraceptive vaginal ring
A new contraceptive vaginal ring containing ethinylestradiol and etonogestrel, traded as Nuvaring, has become available in the United States and in Europe recently. The ring delivers the hormonal combination for 3 weeks on a monthly basis, like modern OC regimens. Data suggest high efficacy rates, high compliance rates and minor side-effects68. It seems that the contraceptive vaginal ring, having as a major advantage its easy method of use, might represent a promising contraceptive method during perimenopause. It has not been tested in that specific age group, so more definite data are required.
Transdermal contraceptive system
The first transdermal contraceptive patch has been recently approved in the USA and many European countries, called Ortho Evra. It delivers ethinylestradiol and norelgestromin (17- deacetylnorgestimate), over a 3-week period, like the OCs and the contraceptive vaginal ring. The reported failure rate is about 0.70 pregnancies per 100 woman-years for perfect use, except individuals weighing over 90 kg, in whom use is associated with lower efficacy rates69. The above regimen offers cycle control similar to that offered by the OCs, with a similar side-effect profile70. The main advantage of the method, compared to the OC, is the higher compliance rates, making it very attractive both for nonmenopausal and menopausal women. Like the contraceptive vaginal ring, more studies are needed to confirm these preliminary suggestions.
Women during the perimenopausal years, have to be aware of the risks of an unwanted pregnancy and the variety of the contraceptive methods offered. There is no contraceptive method that is contraindicated merely by age, consequently a variety of contraceptive methods are suggested for perimenopausal women, including female sterilization, barrier methods, IUDs, injectables, implants and OCs. Clearly, the ideal contraceptive method has not yet been found, and each one presents certain advantages and disadvantages. Modern OCs, compared to other common methods of contraception such as female sterilization, barrier methods, and the levonorgestrel-releasing IUDs, demonstrate high contraceptive efficacy together with significant noncontraceptive benefits for the perimenopausal woman. Moreover, based on accumulating data over the last few years, there is a clear shift from OC-related risks to health benefits, and for that reason OCs probably represent the first choice during the perimenopause. Nevertheless, new preparations, like the monthly injection, the vaginal contraceptive ring, and the transdermal contraceptive system, seem to be promising as well. That remains however to be proved by further large studies specifically in women in perimenopause.
1. McKinley SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103-15.
2. Toner JP, Flood JT. Fertility after the age of 40. Obstet Gynecol Clin North Am 1993;20:261-72.
3. Schmidt-Sarosi C. Infertility in the older woman. Clin Obstet Gynecol 1998;41:940-50.
4. Richardson SJ, Senicas V, Nelson JF. Follicular depletion during the menopausal transition - evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231-7.
5. Klein NA, Illingworth PJ, Groome NP, et al. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 1996;81:2742-5.
6. Welt CK, McNicholl DJ, Taylor AE, et al. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999;84:105-11.
7. MacNaughton J, Bangah M, McCloud P, et al. Age-related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and imimmoreactive inhibin in women of reproductive age. Clin Endocrinol 1992;36:339.
8. Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Pros Horm Res 2002;57:257-75.
9. Hee J, MacNaughton J, Bangah M, et al. Perimenopausal patterns of gonadotropins, imunoreactive inhibin, oestradiol and progesterone. Maturitas 1993;18:9-20.
10.Treloar AE. Menstrual cyclicity and the premenopause. Maturitas 1981;3:249-64.
11. Seltzer VL, Benjamin F, Deutch S. Perimenopausal bleeding patterns and pathologic findings. J Am Med Womens Assoc 1990;45:132- 4.
12. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86.
13. Bachmann G. Sexual issues at menopause. Ann N Y Acad Sci 1990;592:87-92.
14. Forrest JD. Epidemiology of unintended pregnancy and contraceptive use. Am J Obstet Gynecol 1994;170:1485-9.
15. Jolly M, Sebire N, Haris J, et al. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 2000;15:2433- 7.
16. Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:2034-8.
17. Nybo Andersen AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320(7251):1708-12.
18. Williams JK. Contraceptive needs of the perimenopausal woman. Obstet Gynecol Clin North Am 2002;29:575-88, ix.
19. Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: findings from the US Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174:1161-70.
20. Hankinson SE, Hunter DJ, Colditz GA, et al. Tubal sterilization, hysterectomy, and the risk of ovarian cancer: a prospective study. JAMA 1993;270:2813-19.
21. Ness RB, Grisso JA, Cottreau C, et al. Factors related to inflammation of the ovarian epithilium and risk of ovarian cancer. Epidemiology 2000;11:111-17.
22. Peterson HB, Jeng G, Folger SG, et al. The risk of menstrual abnormalities after tubal sterilization: findings from the US Collaborative Review of Sterilization. N Engl J Med 2000;343:1681- 7.
23. Hillis SD, Marchbanks PA, Tylor LR, et al. Posterilization regret: findings from the United States Collaborative Review of Sterilization. Obstet Gynecol 1999;93:889-95.
24. Fu H, Darroch JE, Haas T, et al. Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth. Fam Plann Perspect 1999;31:56-6
25. Kelaghan J, Rubin GL, Ory HW, et al. Barrier-method contraceptives and pelvic inflammatory disease. JAMA 1982;248:184- 7.
26. Parazzim F, Negri E, La Vecchia C, et al. Barrier methods of contraception and the risk of cervical neoplasia. Contraception 1989;40:519-30.
27. Kaunitz AM. Current concepts regarding use of DMPA. J Reprod Med 2002;47(Suppl.):785-9.
28. Berenson AB, Radecki CM, Grady JJ, et al. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 2001;98:576-82.
29. Kaunitz AM. Lunelle monthly injectable contraception: an effective, safe, and convenient new birth control option. Arch Gynecol Obstet 2001;265:119-23.
30. Brache V, Faundes A, Alvarez F. Risk-benefit effects of implantable contraceptives in women. Expert Opin Drug Saf 2003;2:321- 32.
31. Darney PD. Hormonal implants: contraception for a new century. Am J Obstet Gynecol 1994;170:1536-43.
32. Davies GC, Li XF, Newton JR, et al. Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3 Keto desogestrel. Contraception 1993;47:251-61.
33. Pakarinen P, Toivonen J, Luukkainen T. Randomized comparison of levonorgestrel- and copper-releasing intrauterine systems immediately after abortion, with 5 years' follow-up. Contraception 2003;68:31-4
34. Sivin I, Stem J, Coutinho E. Prolonged intrauterine contraception: a seven-year Contraception 1991;44:473-80.
35. Sivin I, Stern J. Health during prolonged use of levonogestrel 20 micrograms/d and the copper Tcu 380A intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994;61:70- 7.
36. Onyeka BA. Levonorgestrel-releasing (20mcg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. Br J Obstet Gynecol 2001;108:770-1.
37. Wildemeersch D, Schacht E, Wildemeersch P. Performance and acceptability of intrauterine release of levonorgestrel with a miniature delivery system for hormonal substitution therapy, contraception and treatment in peri and postmenopausal women. Maturitas 2003;44:237-45.
38. Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W Jr, Stewart GK, Guest F, et al., eds. Contraceptive Technology, 17th edition. New York: Ardent Media Inc. 1998:779-844.
39. Ortho-McNeil P. Ortho Annual Birth Control Study 1999. Raritan, NJ: Ortho-McNeil Pharmaceutical, 2000.
40. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives:collaborative reanalysis of individual data on 53,297 with breast cancer and 100,239 women without breast cancer from 54 epidimiological studies. Lancet 1996;347:1713-27.
41. Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives : a systematic review. Lancet 2003;361:1159-67.
42. Beral V, Hermon C, Kay C, et al. Mortality associated with oral contraceptive use: 25 year follow-up of cohort of 46000 women from Royal College of General Practitioners' oral contraceptive study. BMJ 1999;318(7176):96-100.
43. Moreno V, Bosch FX, Munoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:1085-92.
44. Lewis MA, Heinemann LAJ, Spitzer WO, et al. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: results from the transnational study on oral contraceptives and the health of young women. Contraception 1997;56:129-40.
45. WHO Scientific Group. Cardiovascular disease and steroid contraception: report of a WHO scientific group. Technical Report 877. Geneva: World Health Organisation, 1998.
46. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose contraceptives. N Engl J Med 1996;335:8-15.
47. Sidney S, Petitti DB, Quesenberry CP. Myocardial infarction in user of low-dose oral contraceptives. Obstet Gynecol 1996;88:939- 44.
48. Consensus conference on combination oral contraceptives and cardiovascular disease. Fertil Steril 1999;71(suppl. 3):1S-6S.
49. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynecol 1995;15:195-200.
50. Purdie DM, Bain CJ, Siskind V, et al. Ovulation and risk of epithelial ovarian cancer. Int J Cancer 2003;20:104:228-32.
51. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. N Engl J Med 1987;316:650-5.
52. Siskind V, Green A, Bain C, et al. Beyond ovulation: oral contraceptives and epithelial ovarian cancer. Epidemiology 2000;11:106-10.
53. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424-8.
54. Modan B, Hartge P, Hirsch-Yechezkel G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;26:345:235-40.
55. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Combination. Oral contraceptive use and the risk of endometrial cancer. JAMA 1987;257:796-800.
56. Weiderpass E, Adami HO, Baron JA, et al. Use of oral contraceptives and endometrial cancer risk (Sweden). Cancer Causes Control 1999;10:277-84.
57. Schlesselman JJ. Oral contraceptives and neoplasia of the uterine corpus. Contraception 1991;43:557-79.
58. Fernandez E, LaVecchia C, Balducci A, et al. Oral contraceptives and colorectal cancer risk: a meta-analysis. Br J Cancer 2001;84:72-727.
59. Rubin GL, Ory HW, Layde PM. Oral contraceptives and pelvic inflammatory disease. Am J Obstet Gynecot 1982;144:630-5.
60. Wolner-Hanssen F, Eschenbach DA, Paavonen J, et al. Decreased risk of symptomatic chlamydial pelvic inflammatory disease associated with oral contraceptives. JAMA 1990;263:54-9.
61. Vessey M, Metcalfe A, Wells C, et al. Ovarian neoplasms, functional ovarian cysts, and oral contraceptives. BMJ 1987;294:1518- 20.
62. Lanes SF, Birmann B, Walker AM, et al. Oral contraceptive type and functional ovarian cysts. Am J Obstet Gynecol 1992;166:956- 61.
63. Brinton LA, Vessey MP, Flavel R, et al. Risk factors for benign breast disease. Am J Epidemiol 1981;113:203-14.
64. Michaelsson K, Baron JA, Farahmand BY, et al. Oral contraceptive use and the risk of hip fracture:a case-control study. Lancet 1999;353:1481-4.
65. Jorgensen C, Picot MO, Bologna C, et al. Oral contraception, parity, breastfeeding, and severity of rheumatoid arthritis. Ann Rheum Dis 1996;55:94-8.
66. Apgar BS. Dysmenorrhea and dysfunctional uterine bleeding. Prim Care 1997;24:161-78.
67. Larsson G, Milsoni I, Lindstedt G, et al. The influence of a low-dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992;46:327-34.
68. Mulders TM, Dieben TO. Use of the novel combined cotraceptive vaginal ring (Nuvaring) for ovulation inhibition. Fcrtil Steril 2001;75:865-70.
69. Smallwood GH, Meador ML, Lenihan JP, et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol 2001;98:799-805.
70. Burkman RT. The transdermal contraceptive patch:a new approach to hormonal contraception. Int J Fertil Womens Med 2002;47:69-76.
N. A. Kailas, S. Sifakis and E. Koumantakis
Department of Obstetrics and Gynecology, University of Crete, Heraklion, Greece
Correspondence: Dr E. Koumantakis, Department of Obstetrics and Gynecology, University of Crete, Heraklion, Crete
2005 European Society of Contraception
Copyright CRC Press Mar 2005