Menarche:Too soon or too late

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1 女性生殖內分泌學 : 從青春期到更年期奇美醫院蔡永杰

2 下視丘 - 腦下垂體 - 性腺 2

3 Childhood 3

4 青春期的生理變化 Period of Infancy and Childhood: the hypothalamic-pituitary system (the gonadostat ) is highly sensitive to negative feedback of estrogen(estrodiol concentrations are as low as 10 pg/ml) gonadotropins and gonadal steroids remain at very low levels until age 6-8 FSH and LH remain low but are still secreted in pulsatility 4

5 青春期生理 Prepubertal Period( 前青春期 ): 3 critical changes in the low endocrine state of childhood emerge: 1. Adrenarche: maturation of the adrenal cortex associated with increased secretion of adrenal androgens namely, DHEA, DHEAS 2. Decreasing repression of the gonadostat 3. Gradual amplification of the GnRH-gonadotropin interaction 5

6 青春期生理 Adrenarche ( 腎上腺 [ 皮質 ] 機能初現 ) Increase in production of adrenal androgens resulting in growth of pubic and axillary hair. Precedes menarche by 2 years Mechanisms initiating adrenarche are NOT associated with the mechanisms initiating gonadarche Evidence *Kallman s syndrome: adrenarche occurs despite absence of gonadarche *Addison s Dz: gonadarche occurs despite absence of adrenarche *Precocious Puberty: gonadarche precedes adrenarche Initiating Mechanisms: Suggested factors: 1. Pituitary adrenal androgen stimulating factor 2. Local steroid inhibition of key enzymes within the adrenals **Mechanisms still remain unclear **Adrenarche may be simply the attainment of a level of maturation that requires a particular amount of time. 6

7 青春期生理 Decreasing Repression of the Gonadostat ( 下視丘 - 腦下垂體 - 性腺的抑制降低 ) Mechanisms: 1. Decreasing the negative feedback of low levels of gonadal estrogen on hypothalamus and pituitary sites 2. Decreasing the intrinsic central inhibitory influence on GnRH Neuropeptides involved in inhibition: GABA and neuropeptide Y 7

8 青春期生理 Alteration of GnRH-Gonadotropin Interactions: increased amplitude and frequency of pulsatile GnRH provoke progressively enhanced responses of FSH and LH. FSH levels rise, then plateau in mid-puberty and LH levels rise slowly, then peak in late-puberty Increases in gonadotropin secretion stimulates increased secretion of estrogen. Dichotomous Effects of Estrogen Feedback Positive Feedback: increases LH secretory response to GnRH Negative Feedback: combines with inhibin to inhibit FSH response 8

9 A model of the effect of the neurobiologic brake on pulsatile gonadotropin-releasing hormone (GnRH) release during juvenile development (childhood) in boys (top) and girls (bottom) 9 Topic Endocrinol 20:1, 2002.

10 決定青春期早晚的因子 Major Determinant: Genetics good correlation of times of menarche of mothers and daughters and between sisters Minor Determinant: nutritional status general health geographic location Children in urban areas, closer to the equator, at lower altitudes, mildly obese start puberty earlier Role of Total Body Fat in Timing of Puberty Lipostat Hypothesis critical body weight must be reached to achieve menarche. Supportive Evidence: moderately obese girls have earlier menarche Opposing Evidence: morbidly obese girls and intense exercisers with normal weight have delayed menarche --- controversial 10

11 瘦素在決定青春期早晚扮演重要的角色 Leptin( 瘦素 ) proposed hormone responsible for initiation and progression of puberty produced by adipocytes serum leptin concentration correlated to body fat content Observations 1. Mice deficient in leptin fail to undergo puberty 2. Fertility is restored if leptin-deficient mice are administered the hormone 3. Leptin inhibits neuropeptide Y gene expression Leptin levels increase in puberty, suggesting a threshold level of leptin (and therefore a critical amount of adipose tissue, the source of leptin) *the higher levels of leptin, the earlier the age of menarche *girls with idiopathic precocious puberty have higher levels of leptin 11

12 青春期發育的階段 Pubertal Sequence Accelerated growth thelarche adrenarche pubarche growth spur menarche requires 4.5 years (range 1.5 to 6 years) 12

13 青春期的分期 : Tanner Staging Stage 1 Elevation of papilla only. No pubic hair. Stage 2 Elevation of breast and papilla as small mound, areola diameter enlarged. Median age: 9.8 Sparse, long, pigmented hair, along labia majora. Median age: 10.5 Stage 3 Further enlargement without separation of breast and areola. Median age: 11.2 Dark, course, curled hair sparsely spread over mons. Median age: 11.4 Stage 4 Secondary mound of areola and papilla above the breast. Median age: 12.1 Adult type hair, abundant but limited to mons. Median age: 12 Stage 5 Recession of areola to contour of breast. Median age: 14.6 Adult type spread in quantity and distribution. 13 Median age: 13.7

14 子宮的發育 The pre pubertal uterus is tear-drop shaped, with the neck and isthmus accounting for up to two-thirds of the uterine volume; then, with the production of estrogens, it becomes pear shaped, with the uterine body increasing in length and thickness proportionately more than the cervix. 14

15 不同年紀的子宮大小 Childhood puberty adult menopause 15

16 子宮的發育 PREPUBERTAL Ratio of Corpus : Cx 1:2 Tubular shape Length cm Volume Endometrium single layer of cuboidal cells PUBERTAL ---ADULT Ratio of Corpus : Cx 2:1 Pear shape Length cm Volume Endometrium thickness 16

17 子宮和卵巢重量的改變 17 Human Reprod.Bio.2006

18 卵巢的發育 Prepubertal Volume ml Non functional Pubertal- adult Volume ml Multicystic In prepuberty, the ovarian size volume extends from 0.3 to 0.9cm3. More than 1.0 cm3 indicates that puberty has begun. During puberty, the ovarian size increases rapidly to a mean postpubertal volume of 4.0 cm3 (1.8 to 5.3 cm3). 18

19 不同年紀的卵巢大小 Childhood puberty adult 19 menopause

20 陰道的發育 Prepubertal Reddish in color Thin atrophic columnar epithelium PH ---neutral Length Pubertal - Adult Thickening of the epithelium Cornification of the superficial layer stratified squamous epithelium Dulling of the reddish color PH ----acidic Secretion of clear whitish discharge in the months before menarche Length cm 20

21 外陰的發育 External Genitalia Under the effect of estrogens 1-Labia majora & minora in size & thickness Rugation & change in color of the labia majora 2-The hymen thickens 3-Clitoris enlarge 4-Vestibular glands begin secretion Under the effect of adrenal androgens & ovarian androgens growth of pubic & axillary hair 21

22 身高 average girl reached growth peak 2 years after breast budding and one year prior to menarche *limited growth potential after menarche due to estrogen and concomitant increase in growth hormone peak bone mineralization occurs as well. *half total body calcium laid down during puberty. Calcium supplementation during adolescence results in increase bone density (GIVES PROTECTION AGAINT FUTURE OSTEOPOROSIS!!) 22

23 青春期的發育 23

24 Teenager 24

25 Adolescence( 青少年 ) Puberty( 青春期 ) Adolescence Refers to the stage of human development encompassing the transition from childhood to adulthood Early Adolescence Middle Adolescence Late Adolescence Puberty Refers to biological changes and sexual maturation that occur during the transition from childhood to adulthood 25

26 Menarche 初經 Menarche: the beginning of menstrual cycles Menarche occurs, on average, between 12½ and 13½ years of age 95% of all girls experience menarche between the ages of 11 and 15 Men= Menses arche =beginning First Period 26

27 Menarche 初經 Menarche follows an anovulatory cycle and generally occurs 2 to 3 years after the onset of breast development. Menstrual cycles during the first year after menarche are typically irregular and anovulatory, with most ranging in duration from 21 to 45 days. Within 5 years of menarche, most cycles are regular and range from 21 to 35 days. Although primordial and preantral follicles predominate during the prepubertal years, small antral follicles develop during this phase of maturation. 27

28 Menarche 初經 Requires: GnRH from the hypothalamus FSH and LH from the pituitary Estrogen and progesterone from the ovaries Normal outflow tract Control of the onset of menarche By increasing the sensitivity of the gonads to pulsatile secretion of GnRH from hypothalamic-pituitary axis, Menarche occurs. 28

29 初經的年齡 29

30 臺北學齡女童初經年齡與身高體重及身體質量指數之關連 30

31 臺北學齡女童初經年齡與身高體重及身體質量指數之關連 31

32 臺北學齡女童初經年齡與身高體重及身體質量指數之關連女學童初經年齡為 12.1±1.04 歲與十五年前相仿研究相比初經年齡提早 0.37 歲於國小五六年級及國中一年級有月經之女童生長指標皆高於未有月經者且呈現統計學上有意義差異 32

33 初經早晚的城鄉差距 33

34 飲食營養和初經早晚的關係 Menarche is delayed in malnourished girls, obesity is associated with early breast development and menarche. Diets high in animal protein -- early menarche Diets high in vegetable grains -- delayed onset or tempo of gonadarche. The delay in gonadarche in malnourished girls is probably mediated at the hypothalamic level by reduced availability of metabolic fuels or altered hormonal signals that interrupt or attenuate the pubertal resurgence of GnRH pulse generator 34

35 初經年齡有下降的趨勢 35

36 初經年齡有下降的趨勢 36

37 初經年齡下降的可能因素 37 Human Reprod Update 2001:3:287-91

38 Early Puberty linked to Shampoos Containing Estrogen Some cosmetics contain estrogens, representing a potential source of exogenous estrogen for children. In contrast to pharmaceutical preparations, the Food and Drug Administration (Rockville, Md) does not regulate cosmetics containing less than IU of estrogen per ounce, only stating that the label should direct consumers to limit the amount of product used to less than IU/mo.1, 2 A therapeutic dose of oral ethinyl estradiol for hormonereplacement therapy in adults is 0.02 to 0.05 mg/d ( IU/d). An equivalent therapeutic transdermal estradiol dose for hormone-replacement therapy is 0.05 mg/d. Pediatrics & Adolescent Medicine / volume:156 (page: 85) 38 Use in Prepubertal Children Hormone-Containing Hair Product January 2002

39 Adult heights (cm) in historical series of children with untreated central precocious puberty 39 Human Reprod Update 2004:2:135-47

40 Adult height in girls treated with GnRH agonists for precocious puberty: results of selected studies 40 Human Reprod Update 2004:2:135-47

41 REPRODUCTIVE RISK FACTORS Early age at menarche (before age 12 years) and late age at menopause are associated with an increased risk of breast cancer. For every 2-year delay in menarche, there is a 10% reduction in the risk of breast cancer. For each year that menopause is delayed, there is a 3% increase in the risk of breast cancer. 41

42 Early Age at Menarche Associated with Cardiovascular Disease and Mortality 42 J. Clin. Endocrinol. Metab :

43 初經延遲可能的原因 1 發育遲緩性晚熟類型身高成長緩慢以及第二性徵表現遲緩者初經的年齡也多會延遲 2 遺傳因素母親來得晚女兒初經年齡也多晚出現 3 壓力因素如果身體發育正常身高和體重也符合標準第二性徵也出現了但是月經還沒有來則多與精神壓力因素相關 4 營養不良營養不良女孩子的初經年齡會較晚 43

44 Delayed puberty For girls, the absence of thelarche or menarche by age 13 and 16 years, respectively, is considered delayed puberty. For boys, delayed puberty is defined as absence of testicular enlargement by age 14 years. 44

45 Causes of delayed puberty 45 Human Reprod Update 2003:5:

46 Amenorrhea Primary amenorrhea When menarche has failed to occur for more than 3 years after thelarche, or beyond 16 years of age, the delay is referred to as primary amenorrhea About age 14 in girls who have not gone through puberty (eg, growth spurt, development of secondary sexual characteristics) Usually genetic or anatomic causes 46

47 Causes of primary amenorrhea 47

48 Reproductive Woman 48

49 月經週期天數 49

50 50

51 月經週期的荷爾蒙控制月經週期分為四期 1. 濾泡期 2. 排卵期 3. 黃體期 4. 月經期 51

52 Follicular phase 濾泡期 FSH 分泌在月經來潮前兩天就開始增加使濾泡開始生長 LH 在濾泡後期後穩定增加刺激鞘細胞分泌雄性素進入排卵前期後動情素量持續增加到足以誘導 LH surge 的濃度經由其接受器,LH 使顆粒細胞層黃體化並產生黃體素萎縮的濾泡則分泌雄性素這可能與排卵時性慾的增高有關 52

53 Ovulatory phase 排卵期排卵約出現於 hours after LH peak. LH surge, 大約發生於 follicle rupture 前時 LH surge 可刺激卵子減數分裂的完成顆粒細胞的黃體化及濾泡內黃體素與前列腺素的合成卵子的釋放與前列腺素黃體素與及其他濾泡內的酵素有關使濾泡壁被消化而破裂 53

54 Luteal phase( 黃體期排卵後濾泡會萎縮, 顆粒細胞的大小變大黃體形成黃體除分泌動情素雄性素外最重要的就是黃體素黃體素大約在 LH surge 後八天達到高峰 LH surge 到月經大約是 14 天在此時期黃體的退化是相當快而穩定的除非有懷孕使 hcg 能維持黃體素的作用而供應動情素與黃體素來維持早期妊娠的需要直到胎盤發育完成 54

55 Menstrual phase( 月經期 ) 下一次週期中濾泡的發生取決於前一次黃體的消退 inhibin 降低 FSH 在月經前 2 天開始上升造成濾泡的發育 55

56 內分泌調節系統 56

57 濾泡刺激素 (follicle-stimulating hormone FSH) 和黃體生成素合稱性腺刺激素刺激睪丸製造精子與支持細胞分泌抑制素刺激濾泡的發育與動情素的分泌 57

58 黃體刺激素 (Luteinizing hormone LH) 和濾泡刺激素合稱性腺刺激素刺激卵巢的排卵作用刺激黃體的生成並分泌黃體激素促進纖維溶解蛋白原的分泌增加加速磷化脂肪的轉化促進前列腺素的分泌促成卵子的成熟刺激睪丸的間質細胞生成與分泌睪固酮 58

59 卵巢的細胞與所分泌的荷爾蒙顆粒細胞 --- 動情素鞘細胞 --- 雄性素, 黃體素顆粒細胞鞘細胞 59

60 雙細胞理論 60

61 濾泡的分類與成長 Primordial follicle Primary(Preantral) follicle Secondary(Antral) follicle Mature(Preovulatory, Graafian) follicle 61

62 荷爾蒙的合成代謝與分泌 62

63 膽固醇和性荷爾蒙的構造式 63

64 女性一生的卵巢濾泡數 64

65 女性一生的卵巢濾泡數及生育能力 The declining oocyte/follicle pool according to Faddy et al. (1992) and the corresponding reproductive events. 65 Human Reproduction Update 8(2) 2002

66 Menopause Wowan 66

67 停經前後的賀爾蒙變化 67

68 更年期後女性荷爾蒙大量降低 68

69 雌激素的血中濃度 (pg/ml) 69

70 70

71 71

72 72

73 更年期常見的症狀 ( 依頻率 ) 73

74 更年期婦女身體出現的症狀與變化症狀出現的時間與早晚月經異常潮紅睡眠困擾情緒失調陰道壁萎縮尿失禁骨質疏鬆 74 動脈硬化

75 潮紅熱汗約有三分之二的停經後婦女會出現潮紅的現象潮紅到底是一種什麼樣的感覺呢大致說來每次當潮紅即將發生的時候婦女本身會有一種先兆接著大約一分鐘後會有一股突然發生的熱浪襲蓋著臉頸胸部其持續時間約數分鐘並伴隨著皮膚的變紅在此同時某些人會有上半身大量的出汗昏眩頭痛和心跳加速其發作的時間可能在白天也可能在晚上其發作的次數可從每週一或二次到一天數次 75

76 thermoregulatory center 下視丘溫度控制中心 76

77 Sex frequency according to age 77

78 萎縮的陰道上皮細胞 78

79 動情素對陰道上皮的作用 79

80 80

81 女性因心血管疾病死亡比率隨年齡上升而上升 81 National Center for Health Statistic

82 各年齡層婦女停經與否心血管疾病比率停經前停經後 CVD incidence per 1000 women Age (years) 82 DHEW No 74, 1974 Adapted from the Framingham Study,

83 停經後血脂蛋白的變化 Cholesterol Triglycerides LDL Apo B HDL HDL2 HDL3 Apo AI Lipoprotein(a) % Change 83 Stevenson et al. Atherosclerosis 1993;98:83 90

84 糖尿病與更年期的關係 120 Premenopause Postmenopause Number of women newly diagnosed with diabetes Years from menopause Seige K, et al. 6th Symposium of the German Endocrinological Society:84 Modern Developments in Progestagenic Hormones in Veterinary Medicine; 1959, 1960; Kiel: Springer Verlag; p

85 停經與體脂肪分佈 85

86 女性體重與心血管疾病的關係 Relative Risk of CHD Mortality 3 Compared to BMI< BMI 86 Source: Adapted from Manson 1995 P for trend < 0.001

87 Prevalence of High Blood Pressure by Age and Race 87 Source: Data from National Vital Statistics System, Health, United States,

88 台灣地區高血壓高血糖高血脂盛行率調查計畫主持人陳建仁教授協同主持人游山林博士白其卉博士蘇大成醫師曾慶孝醫師簡國龍醫師黃麗卿醫師 88

89 15 歲以上國人收縮壓之年齡趨勢 89 台灣地區高血壓高血糖高血脂盛行率調查

90 15 歲以上國人總膽固醇平均值之年齡趨勢 90 台灣地區高血壓高血糖高血脂盛行率調查

91 15 歲以上國人三酸甘油脂平均值之年齡趨勢 91 台灣地區高血壓高血糖高血脂盛行率調查

92 Menopause Metabolic Syndrome 92

93 骨質疏鬆正常骨質緻密度骨質流失後的骨質疏鬆狀況 93

94 94

95 95

96 造骨細胞 Osteoblast 與嗜骨細胞 Osteoclast 96

97 動情素可抑制嗜骨細胞的功能預防骨質疏鬆 97

98 98

女性生殖器官介紹/月經和排卵的關係 (I) (II) (III)

女性生殖器官介紹/月經和排卵的關係 (I) (II) (III) 女性生殖器官介紹 / 月經和排卵的關係 (I) (II) (III) By: 李碧雪 (October 4, 11, 18 & 25, 2010) 女性生殖器官 : 1. 卵巢 2. 內生殖器官 : 輸卵管, 子宮, 陰道 3. 外生殖器官 : 大陰唇, 小陰唇, 陰蒂 4. 乳腺輸卵管 (uterine tubes)