Focus test. Yuuiehh bgdhyyte nvdebdndnd jjehdhje jjje53647n dhjhhhhdh STOP HERE PARE AQUI

Transcription

1 Focus test Yuuiehh bgdhyyte nvdebdndnd jjehdhje jjje53647n dhjhhhhdh STOP HERE PARE AQUI

2

3

4

5 The Transition from Reproductive to non-reproductive years by Manuel Neves-e-Castro Lisboa-Portugal 12 th International Congress of Endocrinology Aug / Sept. 2004

6 I shall review for you The Perimenopause Symptoms Estrogen levels From Ovulation to Anovulation Inhibin The Metabolic Syndrome Cardiovascular Risks Osteoporosis Breast Cancer Preventive and Treatment Strategies Conclusions

7 The transition from reproductive to non reproductive years What is it? When does it occur? How is it manifested? Why does it happen? What must be done to help those women? MNC/04

8 What is it?

9 The transition is a crisis a) Psychosocial - Loss of capacity to reproduce - Loss of femininity? - Loss of libido? - Loss of stability b) Biological - Fluctuating levels of estrogens - Hypoestrogenism - Lack of progesterone MNC/04

10 CLIMACTERIC is the period of time when a woman passes from the reproductive stage of life through the perimenopausal transition and from the menopause to the postmenopausal years. MNC/04

11 MENOPAUSAL TRANSITION includes only the portion of the perimenopause before the final menstrual period. The WHO also urges that the term climacteric be abandoned to avoid confusion. WHO Scientific Group Research on the menopause in the 1990 s. A report of the WHO Scientific Group. World Health Organization, Geneva, Switzerland, 1996; 866:1 79

12 M.Soules et al. Executive summary:straw. Menopause 2001;8:

13 The climacteric is similar to a mirror image of puberty

14 The Perimenopausal Transition Average age of onset 46 years Age of onset for 95% of women 39 to 51 years Average duration 5 years Duration for 95% of women 2 to 8 years Speroff L -Menopause and the Premenopausal Transition.In Speroff L,Glass RH and Kase NG,eds.Clinical Endocrinology and Infertility (6th edition).lippincott Williams & Wilkins,Philadelphia Pa (Chapter 17)

15 Symptoms and Complaints result from: Decreased ovarian activity with subsequent hormonal deficiency causing early symptoms (hot flushes, perspiration, and atrophic vaginitis) and late symptoms related to changes in various end organs. Sociocultural factors determined by the woman's environment. Psychological factors, resulting from the individual woman's character. The variety of symptomatology results from interaction between these three components. Utian WH. Semantics, menopause-related terminology, and the STRAW reproductive aging stating system. Menopause 2001; 8:

16

17 Neves-e-Castro M. The last pre-menopausal years. Pharmatherapeutica 1980:2;132-49

18 Perimenopausal Transition There is only one marker : menstrual irregularity, that defines and establishes what is called the perimenopausal transition. Speroff L -Menopause and the Premenopausal Transition.In Speroff L,Glass RH and Kase NG,eds.Clinical Endocrinology and Infertility (6th edition).lippincott Williams & Wilkins,Philadelphia Pa (Chapter 17)

19 PERIMENOPAUSE It is demonstrably more complex than it was previously understood to be; it is clearly not a time of declining ovarian function. Nelson LM et al - Premature ovarian failure.in: Adashi EY, Rock JA, Rosenwacks Z (eds) Reproductive Endocrinology Surgery and Technology. Lippincott-Raven Publishers, Philadelphia, 1996 pp

20 The duration of the folicular phase is the major determinant of cycle lenght. This menstrual cycle change prior to menopause is marked by elevated follicle-stimulating hormone (FSH) levels and decreased levels of inhibin, but normal levels of luteinizing hormone (LH) and slightly elevated levels of estradiol. Evans RM. The steroid and thyroid hormone receptor family. Science 1988;240:889

21 Fluctuating hormone levels are characteristic of perimenopause and may result in irregular menstrual cycles, hot flashes, sleep disturbances, mood swings, and other symptoms. MNC/04

22 The PERIMENOPAUSE HOW does it happen?

23 The onset of the perimenopause has been identified with decreasing competence of the granulosa cells within the ovary Seiler DB and Naftolin F. Moving toward an earlier and better understanding of perimenopause. Fertil Steril 1998;69:387-8

24

25 The Perimenopause is perceived as a loss of ability for cyclic renewal of ovarian reproductive competence governed normally by several endogenous and exogenous factors affected by climactic conditions. Garai J et al. Short communication: seasonal onset of menopause? Human Reproduction 2004;19:1666-7

26 Garai J et al. Short communication: seasonal onset of menopause? Human Reproduction 2004;19:1666-7

27

28 Melatonin binding is found in the ovaries, and ovarian steroid hormone production is influenced by melatonin Ayre EA and Pang SF. iodomelatonin binding sites in the testis and ovary: putative melatonin receptors in the gonads. Biol Signals 1994;3: Brzezinski A et al. Effects of melatonin on progesterone production by human granulosa lutein cells in culture. Fertil Steril 1992;58,

29 Symptoms of the pre and postmenopause - hormone related - age related

30 Neves-e-Castro M. The last pre-menopausal years. Pharmatherapeutica 1980:2;132-49

31 Significantly more than any other group of women, the perimenopausal women experienced weight gain, cold hands and feet, skin crawls, headaches, feeling blue, cold sweats, tired feelings, excitable, can t concentrate, crying spells.

32 The perimenopausal syndrome may include breast tenderness and enlargement, fluid retention, heavy, prolonged, or unpredictable menstrual bleeding, onset of migraine headaches,and new or unpredictable mood swings.

33 Hot flushes are a phenomenon of women who are in the transition to, or have become menopausal. Most physicians believe VMS imply low estrogen levels and are therefore synonymous with established menopause Kronenberg F. Hot flashes: epidemiology and physiology. Ann NY Acad Sci 1990;592:52 86

34 Neves-e-Castro M. The last pre-menopausal years. Pharmatherapeutica 1980:2;132-49

35 VMS commonly start when estrogen levels are high and erratic in the early perimenopause, (and occur during premenopausal years in women with PMS and frequent high estrogen levels) They are highly associated with a decreased quality of life. Wang M et al Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone,prenenolone sulfate, 5a-Pregnane-3,20-Dione, and 3a- Hydroxy-5a-Pregnan-20-one. JCEM 1996;81:

36 VMS are triggered by estrogen withdrawal rather than simply being caused by low estrogen levels. Estrogen withdrawal, or rapidly decreasing estrogen levels,as a cause for VMS, appears highly plausible and likely explains some or all of perimenopausal women s experiences Ginsburg J, Hardiman P Oestrogen deficiency and oestradiol implants (letter). Br Med J 1989;229:

37 There is no correlation between the severity of vasomotor symptoms and the levels of E2. Rannevik G et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995; 21:

38 Can hot flushes occur when estrogen levels are high? The answer is YES based on the data in two very different physiological studies Gangar KF et al. Symptoms of oestrogen deficiency associated with supraphysiological plasma estradiol concentrations in women with oestradiol implants. Br Med J 1993;99: Bider D et al.hot flushes during GnRH analogue administration despite normal serum oestradiol levels. Maturitas 1989;11:

39 Why? The mechanism responsible for the appearance of the menopausal syndrome is not known, but it is likely due to neuroendocrinologic factors related to changes in catechol-amines, perhaps resulting from decreased estrogen levels. Jaffe RB. Menopause and Aging.In Yen SCC,Jaffe RB, Barbieri RL eds. Reproductive Endocrinology, 4th edition.,w.b.saunders Co. Philadelphia,1999 (Chaper 11).

40 Kirschbaum C et al. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. JCEM 1998;81:

41 Estrogen withdrawal may cause an increase in the ratio of norepinephrine to dopamine levels that is independent of the aging processs Jaffe RB. Menopause and Aging.In Yen SCC,Jaffe RB, Barbieri RL eds. Reproductive Endocrinology, 4th edition.,w.b.saunders Co. Philadelphia,1999 (Chaper 11).

42 Kirschbaum C et al. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. JCEM 1996;81:

43 Kirschbaum C et al. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. JCEM 1996;81:

44 Kirschbaum C et al. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. JCEM 1996;81:

45 ESTROGEN LEVELS

46

47

48

49

50 Neves-e-Castro M. The last pre-menopausal years. Pharmatherapeutica 1980:2;132-49

51 Burger HG, et al.the Endocrinology of the Menopausal Transition: A Cross-Sectional Study of a Population-Based Sample*. JCEM 1995;80:

52

53 Mean estradiol levels are normal or high in perimenopausal women, and FSH levels are often not suppressed despite these high estradiol levels. Klein NA 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. JCEM 1996;81:

54 Santoro N et al. Characterization of Reproductive Hormonal Dynamics in the perimenopause. JCEM 1996;81:

55 PERIMENOPAUSE Increases in estrogen levels are produced from an increase in the number of follicles in a stimulated cohort responding to rising FSH levels. Prior JC. Perimenopause:The complex endocrinology of the Menopausal transition. End Rev 1998;19:

56 Factors responsible for the increase in FSH levels before the menopause without a concomitant increase in LH remain to be completely elucidated. MNC/04

57 The construct that menopause is a time of low estrogen production likely led to an inability of scientists and clinicians to see that (intermitently) high estrogen levels were present Prior JC et al.the controversial endocrinology of the menopausal transition (letter). JCEM 1996;81:

58 from OVULATION to ANOVULATION

59 The Ovary Is an exocrine gland oocytes Is an endocrine gland estrogens progesterone androgens

60 The ovary in perimenopausal and menopausal women is an active endocrine organ!

61 Pattern of ovulation and cycle lenght in the peri-menopause O O O O M O O A O A A A O O O A A O M O O O A M A O O O A M Note: O=ovulatory cycle, A=anovulatory cycle, M=menopause Neves-e-Castro M. The last pre-menopausal years. Pharmatherapeutica 1980;2:

62 Cessation of Ovarian Function is a process from regular toward irregular control and IS NOT merely due to the exhaustion of the gonadal tissue in its capacity to produce developing follicles Garai J et al.- Short communication: seasonal onset of menopause? Human Reproduction 2004;19:1666-7

63 INHIBIN

64 Inhibin is produced by the granulosa cells of the corpus luteum and, in a lesser amount, by granulosa cells of the growing follicle during the FP. FSH stimulates inhibin, which in turn suppresses FSH. Hee JP et al Follicle-stimulating hormone induces dose-dependent stimulation of immunoreactive inhibin secretion during the follicular phase of the human menstrual cycle. JCEM 1993;76:

65

66 It is proposed that decreasing ovarian production of inhibin plays a role in the high average estrogen levels documented during the perimenopause. More specifically, the B subtype of inhibin. Burger HG Editorial: Clinical utility of inhibin measurements. JCEM 1993;76:

67 It is clear that perimenopausal inhibin levels are lower than premenopausal levels. Why do inhibin levels appear to decrease in the perimenopause? Burger HG Editorial: Clinical utility of inhibin measurements. JCEM 1993;76:

68 Inhibin A (ng/l) RIA (IU/L) FSH (IU/L) Estradiol (pmol/l) Inhibin B (ng/l) Reproductive hormone levels and menstrual cycle categories b b a 30 a a 20 b b b a a a a b b a a b b Category Category b b 1 = pre meno = STRAW -3 2 = early peri = STRAW -2 3 = late peri = STRAW -1 4 = early post = STRAW +1 Burger H. 6th International Symposium on Women s Health and Menopause.Lorenzini

69 Luteal phase inhibin levels (or reserves, perhaps specifically of inhibin B) become low before the absolute number of potentially responsive follicles has decreased. This allows FSH levels to rise and in turn results in what is descriptively termed endogenous perimenopausal ovarian hyperstimulation. Hughes EG et al. Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. JCEM 1990;70:

70 Perimenopausal Endogenous Ovarian Hyperstimulation Syndrome. This name was chosen because, in hormone levels and pathogenesis, the perimenopausal state is similar to exogenous ovarian hyperstimulation therapy used for infertility treatment. Prior JC. Perimenopause:The complex endocrinology of the Menopausal transition. End Rev 1998;19:

71 It is likely that the production of inhibin diminishes with ovarian age pari passu with a decreasing number of folicles. Waning ovarian follicular activity and its eventual cessation, but with atriking episodic increased secretion of estradiol, are key events in the endocrinologic changes occuring in the menopausal transition. Jaffe RB. Menopause and Aging.In Yen SCC,Jaffe RB, Barbieri RL eds. Reproductive Endocrinology, 4th edition.,w.b.saunders Co. Philadelphia,1999 (Chaper 11).

72 METABOLIC SYNDROME

73

74 The insulin resistance-dyslipidemic syndrome of visceral obesity IR may represent the most prevalent cause of atherogenic dyslipidemic satates associated with CHD. Depres JP. Obes Res 1998;6:8S-17S

75 Clinical observations indicate that female sex steroid hormones are involved in the determination of body fat distribution, i.e., greater accumulation of subcutaneous fat in the gluteofemoral region. Kissebah AH et al. Endrocrine characteristics in regional obesities:role of sex steroids. In: Vague J, Bjontorp P, Guy Grand B, Rebuffe -Scrive M, Vague P (eds) Metabolic Complications of Human Obesities. Elsevier Science Publishers, Amsterdam, 1985;

76 Menopause, or the ovarian hormonedeficient state, is associated with a redistribution of fat toward the abdominal compartment Tchernof A et al. Ovarian hormone status and abdominal visceral adipose tissue metabolism. JCEM 2004;89:

77 In women, visceral obesity is associated with elevated levels of total and free testosterone and low SHBG levels as observed in hyperandrogenic women. Wachenberg BL. Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome. End Rev 2000;21:

78 Omental adipocyte size and basal lipolysis as well as the omental/sc LPL activity ratio are significantly higher in ovarian hormonedeficient women Tchernof A et al. Ovarian hormone status and abdominal visceral adipose tissue metabolism. JCEM 2004;89:

79 The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue whereas estrogen treatment downregulates the density of this receptor, which might be a mechanism whereby estrogens protect adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women from visceral fat accumulation. Therefore, when estrogen levels become sufficiently low, visceral fat accumulation may occur. Haarbo J et al Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism 1991;40:

80 The female distribution of body fat tends to disappear, at least partially, with the menopause in as much as women tend to accumulate visceral fat that can be prevented by hormonal replacement therapy. Haarbo J et al. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism 1991;40:

81 Studies have suggested a direct effect of estrogens on lipolysis Paline SL et al Metabolism 2003;52: Jensen MD et al Am J Physiol 1994;266:E914-E920

82 Transdermal estradiol treatment significantly decreased gluteal adipose tissue LPL activity, and this phenomenon was attributable to posttranscriptional modification. Price TM et al. Estrogen regulation of adipose tissue lipoprotein lipasepossible mechanism of body fat distribution. Am J Obstet Gynecol 1998;178:101-7

83 Ageing and lack of estrogens... - insulin resistance - increase in blood pressure - changes in lipid metabolism - decrease in immune function - increase in stored fat M.N.C. 10/99

84

85

86 CARDIOVASCULAR RISK

87

88 Karas R, Clarkson TB. Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI:Timing is everything. Menopausal Medicine 2003;10:8-12

89 In a clinical context, the inhibition of progression from complicated plaques to clinical events is what is often referred to as primary prevention. The timing of HRT initiation influences its cardiovascular effects. Karas R, Clarkson TB. Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI:Timing is everything. Menopausal Medicine 2003;10:8-12

90 The data support that ERT / H RT may be able to maintain vascular health when initiated early in younger women without advanced atherosclerotic plaque, but may be either ineffective or potentially harmful when initiated in older women with more advanced disease, regardless of whether that disease has become clinically evident. Karas R, Clarkson TB. Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI:Timing is everything. Menopausal Medicine 2003;10:8-12

91

92 OSTEOPOROSIS

93 Paradoxically, despite elevated estradiol levels, the perimenopause is associated with a significant rate of spinal BMD loss. Early studies suggest that this loss exceeds that during the early menopausal period. Prior JC. Perimenopause:The complex endocrinology of the Menopausal transition. End Rev 1998;19:

94 almost 2% per year, spinal bone loss occurs in the year before and after the last flow. Pouilles JM et al The effects of menopause on longitudinal bone loss from the spine. Calcif Tissue Int 1993;52:

95 BREAST CANCER

96 Breast cancer may have one of its two peaks in incidence during and perhaps related to the high estrogen levels in the perimenopausal years Metcalf MG, MacKenzie JA Menstrual cycle and exposure to estrogens unopposed by progesterone: relevance to studies on breast cancer incidence. J Endocrinol 1985;104:

97

98 PREVENTIVE AND TREATMENT STRATEGIES

99 1/3 of a woman s life (30 years!) is spent after the menopause

100 What happens in the Perimenopause? Hyperestrogenism dominates the Transition period Vasomotor symptoms develop prior to the menopause The endometrium and the breast are at risk Quality of life deteriorates MNC/04

101 What should be done? Cyclic progesterone: protects the endometrium Sequential HRT improves symptoms and may prevent CVD, osteoporosis, colon cancer and the metabolic syndrome, if not contraindicated and started early Nutrition, moderate alchool ingestion,exercise, smoking abstention,and low dose statins and aspirin, for all, may prevent colon and breast cancer,cvd MNC/04

102

103 CONCLUSIONS

104

105 Health Is a condition of physical, mental and social wellbeing and not only the absence of disease WHO

106 THIS IS ALSO THE TIME WHEN WELL INFORMED DOCTORS AND WOMEN MUST DECIDE WHAT SHOULD/MUST BE DONE

107 If you are a clinician, you must believe that you know what will help your patient; otherwise, you cannot counsel, you cannot prescribe If you are a scientist, however, you must be uncertain a scientist who no longer asks questions is a bad scientist.. Pickering G. Physician and scientist. Br Med J 1964;2:1615 9

108 What do we KNOW today?

109 130 meters???

110 Preventing a woman from the sound benefit of a properly instituted hormonal therapy only for the fear of rare side effects does not seem to be satisfactory Medicine! Neves-e-Castro,M.

111 Women want Longevity but with good quality of life!

112 Like this one?...

113 Secret for longevity

114 Secret for longevity A passerby noticed an old lady sitting on her front step: I couldn t help noticing how happy you look! What is your secret for such a long, happy life?

115 Secret for longevity A passerby noticed an old lady sitting on her front step: I couldn t help noticing how happy you look! What is your secret for such a long, happy life?! I smoke 4 packs of cigarettes a day, she said. Before I go to bed, I smoke a nice big joint. Apart from that, I drink a whole bottle of Jack Daniels every week, and eat only junk food. On weekends I pop a huge number of pills and do no exercise at all.

116 Secret for longevity A passerby noticed an old lady sitting on her front step: I couldn t help noticing how happy you look! What is your secret for such a long, happy life?! This is absolutely amazing at your age!!!!, says the passerby. How old are you?

117 I m 24 years old...

118 or like these?

119 HEALTHY WOMEN (life style, nutrition, exercise, hormonal and/or non hormonal medicines,psychological support,etc)

120 Dear Colleagues: What is your answer? the ANSWER is in your hands! Thank you.