口服避孕药的新进展 国家人口计生委科研所 吴尚纯 研究员 The history of contraception is quite bizarre. Certain methods practiced in the old days involved the women performing a jerking motion with the intent to dislodging or rerouting the sperm., Soranus*, a Greek physician in the second century before Christ, suggested that Greek women jump backwards seven times after intercourse. Fortunately women in Europe used “more reliable methods”: they were encouraged to turn the wheel of a grain mill backwards four times at midnight! * = Soranus of Ephesus (2nd century A.D.) Greek physician, whose works were a major influence on gynecology and obstetrics until the 17th century. He described contraception, abortion, and procedures during childbirth and also wrote about fractures and diseases. 国家人口计生委科研所 吴尚纯 研究员

口服避孕药50年 基于对甾体激素80年的研究 第一个临床试验于上世纪50年代进行 1961年1月1日 第一个避孕药—Anovlar在澳大利亚上市 到目前为止全球共有535个产品 2009年 口服避孕药被评为150年来最重大的药物发明

50年代末口服避孕药的问世被誉为节育技术的一次革命，它打破了以往只能靠手术节育或放置宫内节育器，或性生活时采取避孕工具、杀精药，或是更原始的节育方法如禁欲，体外排精、安全期避孕等。口服避孕药这一新的突破，改变了整个节育技术、计划生育的形势。 肖碧莲 院士 （中华妇产科学 第2423页）

短效复方口服避孕药 免 费 提 供 市 场 销 售 复方左炔诺孕酮（21+7） 妈富隆 复方左炔诺孕酮三相片 敏定偶 复方炔诺酮（1号） 美欣乐（低雌素） 复方甲地孕酮（2号） 达英-35 0号片 特居乐（三相片） 按优选顺序排列 优思明/YAZ

短效口服避孕药的进展 降低雌激素剂量 提高安全性 减少副反应 2. 新型孕激素的应用 改进性能 健康益处 3. 多相型产品 提高安全性 减少副反应 2. 新型孕激素的应用 改进性能 健康益处 3. 多相型产品 模仿正常周期 提高安全性 良好周期控制 4. 改进服用方法和包装 提高服用方法的依从性 使用简便

使用低剂量雌激素的COC （炔雌醇≤50μg） 1. 降低雌激素的剂量 使用低剂量雌激素的COC （炔雌醇≤50μg） 我国现行使用的均为低剂量雌激素的COC

Mercilon（先灵葆雅） Meliane（拜耳先灵） Minesse（惠氏—白宫） 炔雌醇 20ug 地索高诺酮 150ug

2. 新型孕激素的使用 口服避孕药中的孕激素种类及特点 孕激素种类 孕激素 产品 药理作用 临床作用 睾酮类 （雄激素家族） 炔诺酮 （一代） 1号片 弱雄作用 可能发生 痤疮 左炔诺孕酮（二代） 21+7 地索 高诺酮 （三代） 妈富隆 无雄作用 保持皮肤 光洁 孕二烯酮 敏定偶 孕酮类 （孕激素家族） 甲地孕酮 2号片 抗雄作用 醋酸环丙孕酮 达英-35 治疗痤疮 螺内酯类 屈螺酮 优思明 抗盐皮质 激素作用 保持体重缓解经前症状

优思明：炔雌醇 30 µg 屈螺酮 3 mg 屈螺酮的药理学特性最接近天然孕酮 + – – (+) + 孕酮 + – 屈螺酮 左炔诺孕酮 + 孕激素 活性 糖皮质激素活性 雄激素 活性 抗雄激素 活性 抗盐皮质激素活性 孕酮 + – – (+) + + – 屈螺酮 左炔诺孕酮 + – (+) – – 孕二烯酮 + – (+) – (+) 去氧孕烯 + – (+) – – 醋酸环丙孕酮 + (+) – + – +:治疗效应 (+):治疗剂量下无显著活性 –:无效应

屈螺酮 抗盐皮质激素活性 抗雄激素活性 对抗水钠潴留 肿胀 /乳房触痛  体重  经前期症状  阻断雄激素受体 皮脂溢 痤疮  多毛 

ñ ñ ð ò ñ ò ð ñ 抗雄激素作用的原理 = = 第三代的COC不具 有雄激素活性，降 低游离睾酮水平 雌激素 SHBG 游离 CBG 睾酮 ñ CP 雄激素样作用 ò Anderson DC. Sex Hormone Binding Globulin. Clin Endocrinol 1974; 3: 69-96 复合口服避孕药 (COC)包括雌、孕激素，雌、孕激素相互拮抗。 例如，雌激素增加SHBG，雄激素（或孕激素的雄激素特性）降低SHBG，在体内，SHBG与睾酮结合，减少游离睾酮的水平，游离睾酮在皮肤与雄激素受体结合，诱使皮脂分泌，导致油性皮肤，在细菌影响下导致痤疮。 与其他孕激素不同，去氧孕烯具有极低的雄激素特性，不会对抗雌激素使SHBG的增加。此结果使游离睾酮下降。 . Estrogens and progestogens counteract one another. For instance, estrogens increase the Sex Hormone-Binding Globulin (SHBG) levels and androgens (or progestogens with androgenic properties) decrease SHBG. In the body, SHBG binds to testosterone, which reduces the level of free testosterone. Free testosterone is capable of binding to the androgen receptors in the skin, which can induce increased sebum output. Increased sebum output leads to a fatty and oily skin which can turn into acne under the influence of the bacteria Propionibacterium acnes. Unlike some other progestogens, desogestrel has low androgenic properties and so does not counteract the estrogen-induced increase in SHBG. This results is a decrease of free testosterone concentrations. SHBG 第三代的COC不具 有雄激素活性，降 低游离睾酮水平 ð 游离 ñ = CBG 睾酮 = CP SHBG=性激素结合球蛋白; CBG=皮质类固醇结合蛋白; CP=铜蓝蛋白 Anderson DC. Clin Endocrinol 1974; 3: 69-96

妈富隆与LNG对SHBG水平的影响 因此妈富隆可改善痤疮 妈富隆 150 LNG / 30 EE SHBG nmol/l 200 妈富隆 150 LNG / 30 EE * 150 SHBG nmol/l 1 00 Hammond GL, Langley MS, Robinson PA, Nummi S, Lund L. Serum steroid-binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertility and Sterility 1984; 42: 44-51 Twenty healthy women (20-36 years of age) with regular menstrual cycle and normal liver function were included in this study. Ten women received Marvelon and ten women received and oral contraceptive containing levonorgestrel. The amount of free testosterone was determined in order to examine the influence of the use of the oral contraceptive on the bioavailability of endogenous androgen. Marvelon increased SHBG and CBG levels, whereas the levonorgestrel containing oral contraceptive only increased CBG levels.(no changes in serum albumin levels occurred). Increases in SHBG and CBG returned to pretreatment levels 1 month after treatment ceased. 50 * p<0.001 (N=10) 治疗前 3个周期 因此妈富隆可改善痤疮 Hammond et al. Fertility and Sterility 1984; 42: 44-51

优思明对体重的影响 20个周期的欧洲试验：体重改变 (N = 884) 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 预计18-35岁女性在此期间的正常体重增加* 去氧孕烯150 µg/ EE 30 µg 体重变化 (kg) P<0.0001 屈螺酮 3mg/EE 30 µg 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 周期 *NHANES III.Foidart et al. Eur J Contracept Reprod Health Care. 2000:5:124-134.

优思明可改善经前期症状 * * * * p < 0.001 基线期 周期 6 平均评分 8 MDQ (经期不适问卷) 6 4 2 MDQ (经期不适问卷) * p < 0.001 * 基线期 周期 6 * 平均评分 * 注意力 消极 水 食欲 身心 不集中 情绪 潴留 增加 健康 Boschitsch E., et al. The acceptability of a novel oral contraceptive containing drospirenone and its effect on well-being. Eur J Contracept Reprod Health Care. 2000 12;5 Suppl 3:34-40.

3. 多相型COC 单相：雌孕激素的含量固定 多相：雌孕激素的含量随“月经周期”而变化 复方左炔诺孕酮三相片 炔雌醇 左炔诺孕酮 第 1-6片 0.03 mg 0.05 mg 第 7-11片 0.04 mg 0.075 mg 第12-21片 0.125 mg

多相型口服避孕药 三相片

4.改进服药方法和包装 提高依从性 服药方法 月经第5天开始服用，连服22天，停药后3~5天来月经，月经第5天再开始服药

21片包装 28片包装 （21+7） （24+4）（YAZ，超低剂量复方屈螺酮） 延长服法 3包装连服 4包装连服（季经）

复方左炔诺孕酮 改变服用方法—第1天开始服药 加空白片—连续服药 无停药间隔 改进包装—日期提示

服药方法 月经第1天开始服用，连服21天黄片，然后继续服7天粉片。之后，即开始一个新的包装

COC对健康的益处 对子宫和卵巢恶性肿瘤的发生有保护作用 月经周期规律，经期缩短，经量减少 减轻痛经

保护妇女的生育能力 —使用方法正确，避孕效果极高 避免非意愿妊娠减少人工流产 —防止宫外孕的发生 —防止盆腔感染

激素避孕方法与卵巢癌 卵巢癌流行病学研究协作组 汇总了 45 项观察性研究的23,257 例 (31%) 观察对象 汇总了 45 项观察性研究的23,257 例 (31%) 观察对象 和 87,303 例对照对象(37% ) 停药后 30 年以上的 RR 0.73, 长期使用者的RR为 0.5 使用 10 年，每1000妇女中发病的例数，从 12 降至 8 死亡例数从 7 降至 5 绝对数值，对于每年预期发生的30000例卵巢癌 防止了20000例的发生和10000例的死亡 Source: Beral et al. Lancet 2008; 371:303- 14

随服药时间的延长，卵巢癌风险降低 10.0 (对数模式) 相对风险 1.0 0.1 1 2 3 4 5 6 7 8 9 10 11 12 CASH, 1987 La Vecchia et al, 1986 Wu et al, 1988 Beral et al, 1988 (对数模式) 相对风险 1.0 Ovarian Cancer and OCs: Risk Reduction by Years of Use The longer OCs are used, the more they appear to protect against ovarian cancer. Several major studies, including the largest one to date (Cancer and Steroid Hormone [CASH] Study of the Centers for Disease Control/National Institute of Health), report that the relative risk (RR) of ovarian cancer declines the longer women take the pill, and that protection is evident even with 3 to 6 months of OC use. The reduction in RR occurs with most commonly used OCs, regardless of the formulation’s ethinyl estradiol, progestin, or dose. Reduction in risk has translated into decreased mortality. In England and Wales, ovarian cancer mortality has declined steadily in women under 55 years of age. The decline in mortality was compatible in timing and magnitude to exposure to OCs and not due to treatment effect or attributable to a changed rate of oophorectomy.   References: Grimes DA, Wallach M, eds. Oral contraceptives. In: Modern Contraception: Updates from The Contraception Report. Totowa, NJ: Emron; 1997:1-100. Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Results of the Royal College of General Practitioners’ oral contraception study. Lancet. 1988;2:1331-1335. The 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;316:650-655. La Vecchia C, Decarli A, Fasoli M, et al. Oral contraceptives and cancers of the breast and of the female genital tract: interim results from a case-control study. Br J Cancer. 1986;54:311-317. Wu ML, Whittemore AS, Paffenbarger RS, et al. Personal and environmental characteristics related to epithelial ovarian cancer. I. Reproductive and menstrual events and oral contraceptive use. Am J Epidemiol. 1988;128:1216-1227. Villard-Mackintosh L, Vessey MP, Jones L. The effects of oral contraceptives and parity on ovarian cancer trends in women under 55 years of age. Br J Epidemiol. 1989;96:783-788. POSTED: August 29, 2001 REVIEWED: August 29, 2001 0.1 1 2 3 4 5 6 7 8 9 10 11 12 使用口服避孕药的年数 Grimes DA et al, eds. Modern Contraception: Updates from The Contraception Report. Emron, 1997. www.contraceptiononline.org

停药后对卵巢的保护作用持续存在 10.0 相对风险 1.0 0.1 .5 1 1–4 5 5 5–9 10 停用口服避孕药的年数 CASH, 1987 La Vecchia et al, 1986 Rosenberg et al, 1982 WHO, 1989 相对风险 1.0 OCs Protect Against Ovarian Cancer After Discontinuation The longer OCs are used, the more they appear to protect against ovarian cancer. Several major studies, including the largest one to date (Cancer and Steroid Hormone [CASH] Study of the Centers for Disease Control/National Institute of Health), report that the relative risk (RR) of ovarian cancer declines the longer women take the pill, and that protection is evident even with 3 to 6 months of OC use. The reduction in RR occurs with most commonly used OCs, regardless of the formulation’s ethinyl estradiol, progestin, or dose. Reduction in risk has translated into decreased mortality. In England and Wales, ovarian cancer mortality has declined steadily in women under 55 years of age. The decline in mortality was compatible in timing and magnitude to exposure to OCs and not due to treatment effect or attributable to a changed rate of oophorectomy. References: Grimes DA, Wallach M, eds. Oral contraceptives. In: Modern Contraception: Updates from The Contraception Report. Totowa, NJ: Emron; 1997:1-100. Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Results of the Royal College of General Practitioners’ oral contraception study. Lancet. 1988;2:1331-1335. The 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;316:650-655. La Vecchia C, Decarli A, Fasoli M, et al. Oral contraceptives and cancers of the breast and of the female genital tract: interim results from a case-control study. Br J Cancer. 1986;54:311-317. Wu ML, Whittemore AS, Paffenbarger RS, et al. Personal and environmental characteristics related to epithelial ovarian cancer. I. Reproductive and menstrual events and oral contraceptive use. Am J Epidemiol. 1988;128:1216-1227. Villard-Mackintosh L, Vessey MP, Jones L. The effects of oral contraceptives and parity on ovarian cancer trends in women under 55 years of age. Br J Epidemiol. 1989;96:783-788. POSTED: August 29, 2001 REVIEWED: August 29, 2001 0.1 .5 1 1–4 5 5 5–9 10 停用口服避孕药的年数 Stanford JL. Contraception. 1991;43:543-556.

随服药时间的延长子宫内膜癌发生的风险降低 服用口服避孕药的总时间（年） 相对危险度 0.01 10 2 4 6 8 12 0.1 1 年 RR 4 0.44 8 0.33 12 0.28 CASH, 1987 Levi et al, 1991 Stanford et al, 1993 Hulka et al, 1982 Kaufman et al, 1980 Weiss et al, 1980 OCs Reduce Risk of Endometrial Cancer: By Years of Use Further, the risk of endometrial cancer is significantly decreased with increasing duration of OC use. A meta-analysis of relative risk (RR) of endometrial cancer showed a 60% decrease of RR with 4 years of OC use and a 70% or more decrease with 12 years of use. Reference: Schlesselman JJ. Risk of endometrial cancer in relation to use of combined oral contraceptives: a practitioner’s guide to meta-analysis. Hum Reprod. 1997;12:1851-1863. POSTED: August 29, 2001 REVIEWED: August 29, 2001 Schlesselman JJ. Hum Reprod. 1997;12:1851-1863.

停用COC后对子宫内膜的保护作用持续存 10 1 相对危险度 0.1 0.01 2 4 6 8 10 12 14 16 18 24 20 年 RR 5 0.33 10 0.41 20 0.51 10 1 相对危险度 La Vecchia, 1986 CASH, 1987 Levi et al, 1991 Stanford et al, 1993 Hulka et al, 1982 Kaufman et al, 1980 Weiss et al, 1980 0.1 OCs Protect Against Endometrial Cancer After Discontinuation The risk of endometrial cancer after women stop taking OCs gradually returns toward the levels observed in non-OC users. However, even 20 years after pill discontinuation, risk is still reduced by almost 50%. Reference: Schlesselman JJ. Risk of endometrial cancer in relation to use of combined oral contraceptives: a practitioner’s guide to meta-analysis. Hum Reprod. 1997;12:1851-1863. POSTED: August 29, 2001 REVIEWED: August 29, 2001 0.01 2 4 6 8 10 12 14 16 18 24 20 22 停止服用复合口服避孕药的年数 Schlesselman JJ. Hum Reprod. 1997;12:1851-1863.

美欣乐能明显改善痤疮和脂溢性皮炎 N = 3,242 15 基线 3个周期 6个周期 10 妇女百分比（%) 5 痤疮 脂溢性皮炎 NB: Please note that this slide should only be used as a defense to show the benefits of a 3rd generation product. Mercilon should not be promoted on skin; Laurina should be promoted on seborrhea and Gracial on mild to moderate acne Kahn-Nathan et al found a clear reduction in both acne as seborrhea during 6 cycles of Mercilon use. 5 痤疮 脂溢性皮炎 Kahn-Nathan, Lapousterle. Reprod Hum Horm 1991;4, Suppl.1:15-20

激素避孕方法与静脉栓塞 育龄妇女不常见 (5 ～ 21/100,000 w y ) 基因与获得性危险因素的之间的协同作用 复方制剂的危险性与总剂量和孕激素的类型相关 在使用的头4个月危险性最高，其后降低， 停药后3个月恢复到停药前水平 健康妇女的总危险性很低

COC使用者和未使用者及妊娠妇女发生VTE的危险 Dinger Contraception 2007

COC对体重的影响 使用低剂量的口服避孕药时，只有很少部分使用者会遇到这种情况，80%以上体重无改变或减轻 服用COC对体重的影响可能: 原因： 1.食欲增加导致脂肪增加 2.水钠潴留造成暂时的体重增加 处理： 控制饮食，养成健康的生活方式 Rekers H. Multicenter trial of a monophasic oral contraceptive containing ethinylestradiol and desogestrel. Acta Obstet Gynecol Scand 1988; 67: 171-4 The effect of Marvelon on body weight has been studied in a large multicenter study involving 1,613 women. The study did revealed an increase of 0.2 kilograms after 12 cycles of use. However, when the results were analysed by age groups, it became clear that the weight increase had occurred in the group of women below 20 years of age, an age group that experiences natural weight gain. The negligible effect of Marvelon on weight was further endorsed by the fact that only 12 (0.7%) women dropped out because of weight gain. Reckers et al. Acta Obstet Gynecol Scan，1988，67，171

妈富隆对体重的影响 周期 < 20岁 20-29岁 1 0.3 3 0.5 6 0.7 12 1.2 N=330 N=1,613 上表显示：体重增加只出现在年龄小于20岁的妇女, 反映了那个年龄组妇女体重的自然增加。 服用妈富隆24个周期，80％以上的妇女体重不受影响或减轻 [1] Reckers et al. Acta Obstet Gynecol Scan，1988，67，171 　　　[2] Bilotta P, et al. Arzneimittelforsch / Drug Res 1988; 38: 932-4.

美欣乐对体重几乎没有影响 kg 60 50 40 30 20 10 12 12 周期 年龄 < 20 年龄 20 - 29 55.1 55.5 56.8 56.8 50 40 30 20 Changes in body weight have in the past been reported with the use of older and high dosed oral contraceptives. However, with the new lower dosed version, it has been consistently observed that body weight is no longer affected to a significant extent. A relevant and crucial improvement in view of the importance of a stable body weight in especially younger women. The multicenter study with Mercilon showed that in the group of women under 20 years of age a small increase in mean weight was observed of 380 grams in 1 year time. This increase is, however, comparable with that of women of the same age not using the pill. Therefore this small increase can be attributed to natural growth. This is confirmed by the data in the older age group, in which no effect on mean body weight was observed. 10 12 12 周期 年龄 < 20 年龄 20 - 29 Lammers, Op ten Berg, Acta Obstet Gynecol Scand 1991 25

美欣乐对体重的影响 65％以上妇女，体重没有改变 19％以上妇女，体重减少2公斤或以上 15.6％的妇女，体重增加2公斤或以上 第六周期与基线比较 100 美欣乐 20 EE / 75 GSD 80 60 妇女所占百分比（％） 40 20 In an open, randomized multicenter study, a negligible effect on body weight was observed after 6 cycles of Mercilon use. In more than 65% of the women, the body weight was not changed, in 15.6% the body weight increased by 2 kg or more, in addition the body weight decreased by 2 kg or more in 19% of the women. In conclusion, Mercilon shows a negligible effect on body weight, this effect is slightly favorable compared with that of a 20 EE / 75 GSD pill. 减少2公斤以上 稳定 增加2公斤以上 65％以上妇女，体重没有改变 19％以上妇女，体重减少2公斤或以上 15.6％的妇女，体重增加2公斤或以上 Serfaty et al. Eur J Contracept Reprod Health Care 1998;3:179-189

激素避孕方法与不同癌症的发生率

激素避孕与乳腺癌相关性的证据 英国的队列，100万 妇女年的随访 无论是长期的既往使用还是现用，危险性均不增加 CARE，以人群为基础 的病例对照研究 对浸润/原位癌均无增加， 包括40岁以上的使用者 美国，以人群为基础 不增加死亡的危险性， 包括30岁以上的使用者 有家族史的加拿大人 的前瞻性研究 既往和现用的使用者均无增加

COC 对胎儿无负面影响 Harlap 等对33545个孕妇进行临床观察分析 因此，服用现代COC停药即可怀孕，无需等待3～6个月 其他避孕措施或未避孕 P值 观察妊娠数 8522 25023 畸形发生率(‰) 17.2 15.0-20.1 >0.05 因此，服用现代COC停药即可怀孕，无需等待3～6个月 Int J Fertil. 1985;30(2):39-47.

怀孕时误服COC不会导致新生儿生理性缺陷 Bracken 等采用荟萃分析，评估在孕早期服用口服避孕药后发生先天畸形的风险，分别对先天性的心脏缺陷和肢体短小缺陷进行分析 研究发现：先天性的心脏缺陷的发生风险为1.06，而肢体短小缺陷的发生风险为1.04 ，提示孕早期服用口服避孕药同新生儿生理缺陷之间无相关性 Obstet Gynecol. 1990 Sep;76(3 Pt 2):552-7.

新研发的COC— NOMAC/E2 NOMAC = 醋酸诺美孕酮 2.5mg E2 = 雌二醇 1.5mg 天然刺激素成分 24＋4 方案(24 活性片＋4 空白片) 避孕效果和安全性与其他领先的单相片相似 出血模式与同类产品接近或相同

与21＋7方案相比 可能的优越性 对卵泡发育有更强的抑制作用 减少出血天数 使女性激素的周期性波动趋于平稳 缓解周期性不适和经期紧张症状

谢 谢！