1. Hormonal Changes at 50 Josephine Carlos-Raboca, MD, FPCP,FPSEM
Section of Endocrinology, Diabetes & Metabolism
Makati Medical Center

2. Outline Menopause: Physiology Treatment: nonhormonal hormonal
Andropause:Physiology
Testosterone
Growth Hormone
Summary

3. Menopause Overview
Menopause is a natural part of a woman's life cycle.
monthly periods end.
freedom from pregnancy and additional child-raising responsibilities.
As you approach mid-life, estrogen begins to drop to low levels. The reproductive organs gradually shut down, just as they gradually became active during puberty. Most women notice that their periods become lighter, farther apart and then eventually, they endf Menopause is defined after 12 months of amenorrehea without pathologic or physiologic cause. Rangeas years with 90% by age 55.

5. Perimenopause covers the period immediately before final menstrual period when clinical biologic and endocrinologic features of approaching menopause begin. It is characterized by waxing and waning of ovarian function. Androgens from both adrenal and ovary decrease.

6. Effects of Menopause
Vasomotor instability- hot flashes, and waking during the night
Mood changes -Mood swings; depression or anxiety
Cognitive function- decreased verbal memory
Sexual function - libido
Urogenital - dryness, itching, pain during sexual intercourse sudden or frequent urinating
Estsrogen has mulitple effects on brain funciotn thru effects on neurotransmittes, brain gulcose metabolism and synaptogenesis.Most affected is verbal memory

7. Menopause Increases Women's Risk for Osteoporosis
women can lose up to 5 percent of their bone mass per year in the first 5 years following menopause.

8. Risk of Cardiovascular Disease Also Increases after Menopause
The risk of CVD increases in women after menopause
By age 60 heart disease becomes as common in women as in men.

9. Managing Menopause
Healthy lifestyle to protect against osteoporosis and cardiovascular disease
Maximize medications for these conditions
A balanced diet, calcium and vitamin D;
Weight reduction if overweight;
Stop smoking;
Weight-bearing exercise
Yearly mammogram and breast examination

10. Treating the Symptoms of Early Menopause:
Individual counseling or support groups
Vaginal moisturizers such as Vagisil or Replens. Lubricants, such as K-Y Jelly or Astroglide
Low-dose vaginal estrogen
Lack of desire may be helped with more open communication with your partner.
Creating a pleasurable atmosphere at home and making a point to enjoy other activities with your partner .
Vaginal extradiol tablet comes in 25ug/week.

11. Treating the Symptoms of Early Menopause with Non-Hormones:
Selective-Serotonin Reuptake Inhibitor (SSRI) drugs and Serotonin Norephinephrine Reuptake Inhibitor (SNRI) drugs.
Gabapentin
Medroxyprogesterone acetate and megestrol acetate, progesterone-type drugs.
Clonidine
Venlaxifine 75 mg od has been the most studied. Fluoxetine, paroxitene and sertralines are also useufl. Veralipide in Europe.

12. Unlike in the past when hormone replacement therapy is almost routinely advised for all postmenopausal women because of its supposedly multiple benefits, currently, one of the most difficult clinical decisions a postmenopausal woman and her physician has to make is whether to take or not to take HRT.
This is because data generated by recent randomized clinical trials tend to show that HRT may increase the risk, not only of breast cancer which is a very serious concern for most women, but also of cardiovascular disease which is the most common cause of mortality among postmenopausal women, and that HRT, based on the so-called global index, appears to be more harmful than good.
So that the current recommendation is to take HRT, if a woman has the indication to take it and if the risk-benefit ratio is favorable, for the shortest duration of time and using the lowest effective dose.

13. Changing Aspects of Hormone Replacement Therapy
Conventional rationale for HRT derived from favorable outcomes of observational studies in perimenopausal women
Recent randomized clinical trials showed potentially adverse effects of HRT in late postmenopausal women
RCTs results have discouraged HRT use in perimenopausal women
In reality, what happened to hormone replacement therapy and to the women taking it and deciding to take it, was unfair.
The conventional rationale for hormone therapy for menopause-related clinical problems was derived from a large body of observational studies in perimenopausal women. Recent randomized clinical trials showed potentially adverse effects of HRT in late postmenopausal women. Ordinarily the results of the randomized clinical trials should be considered as irrelevant to women taking HRT in the perimenopausal period. Inspite of this blatant disregard of logic, however, the RCTs results have severely discouraged HRT use in perimenopausal women worldwide.

14. Benefits of HRT Relief of menopausal symptoms Increase bone density
CVD benefit ?
Improve memory?
Improve sexual function?
Youthful look?
Decrease colon cancer
Decrease macular degeneration

15. Women's Health Initiative 2002
The largest randomized prospective trial evaluating the effects of estrogen plus progestin and estrogen alone versus placebo (no hormone).
53.Roussow JE, Anderson GL, Prentice RL, et al, and the Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288: Originally the study was to continue to 2005 but was brought to an early end because the risks of this treatment were found to outweigh the benefits. At the start of the study, a method to weigh all benefits and risk of therapy under a global score index, or a composite score, was designed. It was decided in the beginning that the study would be stopped if the risks exceeded the benefits based on this composite (global) score. The composite score involved comparison of placebo with estrogen plus progestin on the risks of invasive breast cancer, coronary heart disease, stroke, and blood clots and benefits on the prevention of hip fractures in the women taking estrogen plus progestin. Womwn total of

16. WOMEN’S HEALTH INITIATIVE CLINICAL TRIAL
( WHI – US )
OBSERVATIONAL, CLINICAL CORHORT
150,00 POSTMENOPAUSAL WOMEN
GRP ,000 WOMEN
Objective : To evaluate the efficiency of Low Fat diet in the prevention of breast , colorectal cancer and coronary heart disease.
GRP ,000 WOMEN
Objective : To evaluate the effect of Calcium &Vitamin D in fractures and colorectal cancer.
GRP ,500 WOMEN
Objective : To assess HRT’s efficacy in the prevention of cardiovascular diseases and fractures .

17. Estrogen in Osteoporosis
Prevention of bone loss and fragility fracture
WHI – 33% reduction in fracture ratethe only therapy with efficacy data on prevention of fracture in women with osteopenia

18. Alternate Treatments Are Available
Non-hormonal treatments to prevent and treat osteoporosis bisphosphonates, elective estrogen receptor modulators (SERMs), parathyroid hormone (PTH) calcitonin.

19. HRT and Risk of Cardiovascular Disease
The increase in risk following menopause suggests that estrogen made by the ovary prior to menopause may protect against heart disease.
However, recent studies have shown no benefit to the use of postmenopausal hormone therapy in heart disease prevention and indicate the need to use other modalities to help women fight heart disease.

22. HERS II
Results from extended, open-label evaluation of the HERS (Heart Estrogen/progestin Replacement Study) indicate no cardiovascular benefit of HT in postmenopausal women with previous history of cardiovascular disease
JAMA 2002
51.Grady D, Herrington D, Bittner V, et al. Cardiovascular outcomes during 6.8 years of hormone therapy. Heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 2002; 288:49-57.
52.Hulley S, Furberg C, Barrett-Connor E, Cauley J, et al. Non-cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:58-66.

23. WHI and CVD risk Estrogen + Progestin increased CVD by 29%
Estrogen only in hysterectomized
no increase in CVD risk
HRT increased CVD after 1 year of use

24. Estrogen+Progestin Therapy and Risk of CHD: Results According to Time Since Menopause Women’s Health Initiative – E+P trial
Women <10 years since menopause: RR=0.89
Women yrs since menopause: RR=1.22
Women 20+ years since menopause: RR=1.71 (But no modifying effect of age)
Manson JR et al NEJM 2003

25. Reducing Risk of CVD
Statins have been shown to lower the risk of CVD in individuals with abnormal circulating lipids and those who have a family history of heart disease.
Small doses of aspirin daily

26. HRT and cognitive function WHI Memory Study (WHIMS)
Women aged 65 or older who took estrogen plus progestin had twice the rate of dementia, including Alzheimer’s disease, as those taking placebo. Estrogen plus progestin did not protect against mild cognitive impairment (e.g., trouble paying attention and remembering).
JAMA 2003
54.Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289: women 65 to 79 years old participated. Risk of dementia was 1.76 times higher in hormone vs placebo. Both CEE and CEE+MPA were associated with dementia but was significant only in E+P group.
55.Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study, a randomized controlled trial. JAMA 2003;289:

27. Cognitive function
The Women's Health Initiative data suggest that women who initiate hormone therapy at age 65 or older have worsening dementia than women who take no hormones.
Until more is known, hormone therapy cannot be recommended for prevention of Alzheimer's disease.
Estrogen loss may be linked with Alzheimer's disease, a fact that led to the notion that taking estrogen after menopause might help to prevent this disease. However, the Women's Health Initiative data suggest that women who initiate hormone therapy at age 65 or older have worsening dementia than women who take no hormones. Whether there is an optimal age to initiate estrogen treatment, or whether the results would have been different if estrogen had been started at the time of the menopause is unclear. Until more is known, hormone therapy cannot be recommended for prevention of Alzheimer's disease. A small recent study in Harvard however showed that HRT use in early perimenopause 45 to 50 may improve verbal memory in women

28. Other Benefits
Taking estrogen plus progestin lowers the risk of developing colon cancer by 37%
Taking estrogen lowers the risk of developing age-related macular degeneration, a degeneration of the retina of the eye.
Estrogen loss may be linked with Alzheimer's disease, a fact that led to the notion that taking estrogen after menopause might help to prevent this disease. However, the Women's Health Initiative data suggest that women who initiate hormone therapy at age 65 or older have worsening dementia than women who take no hormones. Whether there is an optimal age to initiate estrogen treatment, or whether the results would have been different if estrogen had been started at the time of the menopause is unclear. Until more is known, hormone therapy cannot be recommended for prevention of Alzheimer's disease

29. Risks of HRT Stroke WHI 39% increased in E 41% increased in E+P
Breast cancer
WHI no significant increase in E
26% increased in E+P
Venous thromboembolism 47%

30. Discordance between observational and randomized studies: different populations
Characteristics
Healthier, less comorbidities, leaner, less smokers
Less healthier, more comorbidities, fatter, more smokers
Age at start of HRT
Typically 35 to 55 years
Typically >60 years
HERS: 66.7 years
ERA: 65.8 years
WHI: 63.2 years
Time since menopause
Peri- or early postmenopausal
Late menopause
HERS: 17.7 years
ERA: 15.8 years
WHI: 18.0 years
It seems that the best place to start in an effort to understand why the observational studies and randomized trials gave different results is to focus on differences in the patient populations studied, rather than on inherent methodological differences between these 2 study designs.
When one looks at the patient populations, one finds that the women in the observational studies tended to be healthier and have less comorbidities, in addition to being leaner and less likely to smoke. The most striking difference between these patient populations, however, relates to their age and the duration of time they were postmenopausal. The majority of women studied in the observational studies were in the perimenopausal or early postmenopausal period when they initiated HRT because they sought HRT for relief of menopausal symptoms. As a result, they were typically between the ages of 35 and 55 at the time of initiation of HRT. In stark contrast, the women in HERS were on average 67 years old and 18 years postmenopause and the women in ERA were on average 66 years old and 16 years postmenopause. Similarly, in the combined HRT arm of the WHI, these women were 63 years old, on average and 184 years postmenopause.1
Karas RH, 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.
Adapted from Karas RH. Clin Obstet Gynecol 2005;47:489.

31. "Designer Estrogens"
Selective Estrogen Receptor Modulators (SERMs). Act as beneficially as estrogen on some tissues and as estrogen-blockers on other tissues
Tamoxifen-used to prevent breast cancer
Raloxifene - used to prevent osteoporosis,
Selective estrogen tissue
Tibolone
Tamoxifen, however, acts like an estrogen on the uterus, increasing the risk of uterine cancer.
Raloxifene blocks harmful effects of estrogen on the breast and does not stimulate the lining of the uterus, so women who still have a uterus may want to try this drug. Unfortunately, some women experience hot flashes with raloxifene or tamoxifen.

32. Commonly Used Alternatives to Hormone Replacement Therapy
Black Cohash-
Camomile-
Chasteberry-
Dong Quai-
Ginseng-
Licorice Root-
St. John's Wort-
Valerian-
Soy Products

33. Testosterone/DHEA Supplement in Women
Not approved
Variable to no benefit
Data shows benefit in hypopituirarism, premature ovarian failure, bilateral oophorectomy and primary adrenal insufficiency
Heightens sexuality in older women not men. Unrelaibale preparations variable to no benefit. Improves well being and QOL and libido DHEA 50 kg OD.

34. Conclusion 1
Short-term hormone therapy is approved by the U.S. Food and Drug Administration in younger women for some symptoms of menopause, including hot flashes, vaginal dryness and painful intercourse
the lowest effective dose possible.
Individualized and time dependent

35. WHAT IS ANDROPAUSE? (Late Onset Hypogonadism) [PADAM / ADAM]
A clinical condition characterized by a partial deficiency of androgens in blood and/or decreased testosterone availability to various systems or organ functions.

36. Clinical Symptomatology
Usual appearance of young men
Typical appearance of
testosterone deficiency

37. Recent Insights into the Andropause
Low testosterone levels affect mood, vitality, sexuality
brain: decreased libido
depressed mood
heart: increase in cardiovascular risk
muscle: decrease in strength & mass
kidney: anemia due to < erythropietin
production
bone: decreased bone mineral density
sexual organs: erectile dysfunction

38. Endogenous Androgen Production
Testes: >95%
 testosterone
Adrenals: <4%
 dehydroepiandrosterone

39. Pathophysiology Testosterone decreases with aging
SHBG increases with aging with a decrease in bioavailable testosterone
Decline in testicular Leydig cells
Due to abnormal hypothalamic –pituitary- testicular axis

40. Testosterone Replacement: Is it necessary?
BPH AND PROSTATE CANCER RISK
CV EVENTS, ETC
IMPROVEMENT OF SXS OF ANDROPAUSE

41. Expectations from testosterone treatment
Bone density 
Lean body mass / muscles 
Erythropoesis 
Physical activity 
Mental activity 
Mood 
Cognitive abilities 
Libido 
Quality of life 

42. Gooren L Lecture Int. Symposium of Andropause Society, London, 2003
Osteoporosis
Not just a female disease!
25–30% of hip fractures occur in men!
Serious ! 25% die of it in the short term
25% die of it in the longer term
Only 20% return to their former quality of life; many more need assistance 51 % suffer from depression (Cowith activities of daily living
olsaet, Aging Male congress 2002)
Gooren L Lecture Int. Symposium of Andropause Society, London, 2003

43. Amory JK et al. J Clin Endocrinol Metab 89(2): 503-510 (2004)
Bone Mineral Density (Lumbar Spine) after 36 Months of Testosterone Treatment in 70 Elderly Men (mean age 71, T<350 ng/dL)
* p<0.05 * * * * *
No trial reporting on bone fracture outcome. RCTs gave inconsistent and imprecise results. Long trials 2% increase in lumbar density.
Amory JK et al. J Clin Endocrinol Metab 89(2): (2004)

44. Body Composition, Strength and Function
Role of testosterone
Increases nitrogen retention
Increases protein synthesis
Bhasin (NEJM, 1996)
TRT dose related increase in skeletal muscle mass and strength
In a systematic review of 6 trials T reduced fat mass and increased lean body mass
The most consistent efct of T is reduced fat mass by 1.5 tp 2.5 kg increawse muscle mass by 2 kg. platues after 3 months. This is not necessary accompanied by improvement in strength although grip strenght was improved after 12 months in a a 36 month study on
T 200mg fortnightly. Low T have been suugested to predispose to visceral obesioty and DM2. T has been shown to decrease visceral fat, BP and increase insulin sensitivity in abdominally obese men. Causal and effect rel of
T and Dm 2 is not clear.

45. Page ST et al. J Clin Endocrinol Metab 90(3): 1502-1510 (2005)
Testosterone Improves Physical Performance in 70 Elderly Men (mean age 71, T<350 ng/dL) * * * * * * *
Muscle strength gains are proprotional ti increase in muscle mass.In rcts testosteron increased muscle grip strength over placebo in iddle aged and older men.
left
right
*p<0.05
Page ST et al. J Clin Endocrinol Metab 90(3): (2005)

46. TRT and Depression Testosterone decreases with advancing age in males
Lower bio-T in depressed aging males
Testosterone deficiency and depression symptoms overlap, current treatments are often insufficient for depression
The use of testosterone for depressed hypogonadal males (with documented low Bio-T) holds promise
T decreases with advancing age in human males. Depression is a common late-life condition for which current available treatments are often insufficient. The use of T as an antidepressant or adjuvant to currently available antidepressants holds promise for depressed elderly males. At present this therapy can only be considered in hypogonadal males who have documented low bioavailable T. Furthermore, the treatment is not benign, and those considering the use of T should do so in a multidisciplinary setting in which urologists and/or endocrinologists are part of a comprehensive team.
When patients fail to respond to several adequate trials of conventional antidepressants, and meet the criteria for andropause (low T syndrome), laboratory confirmation of this clinical impression is warranted. If hypogonadism is confirmed by a low bioavailable T level, and a rare pituitary source is ruled out, T administration as an adjuvant antidepressant should be considered after performing a risk-benefit analysis for each patient.
___________________________________________________
Margolese, HC, J Geriatr Psychiatry Neurol 2000; 13:
In a most recent study by Shores 2004:
278 men >45 yrs
TT,200 ng/dL, FT,0.9 ng/dL
2 year follow up
Incidence of diagnostic depression illness was 21.7% in hypogonadal men vs 7.1% in others
Hypogonadal men showed an increased incidence of depressive illness and shorter time to diagnosis of depression.
Margolese, HC, J Geriatr Psychiatry Neurol 2000; 13:

47. Sexual Function Jain Meta-analysis (J Urol, 2000)
TRT 57% overall improvement rate for ED
TRT improved nocturnal erection and penile rigidity in hypogonadal males (Cunningham 1990, J Clin Endoc Metab; Arver, 1996 J Urol)
TRT –direct vascular effect on the corpora cavernosa mediating nitric oxide effects (Aversa 2003, Clin Endocrin)
TRT potentiates libido by a central effect and erection by central and peripheral effects

48. TRT and CV Old dogma: T is a risk factor for cardiac disease
Men have both high incidence of CV and higher T levels than women
But:
Little data support a causal relationship between higher T levels and heart disease. (Rhoden & Morgentaler 2004)
Indirect data suggesting T reduce CVD risk as shown by reductionin ST T depression and improved angina threshold in
T treatment vs placebo. Not mediated by lipid changes supraphysiologic dose of
T decreased HDL no change in trigly and LDL.

49. Hematopoietic Effects of TRT
Red Blood Cells
T stimulates erythropoietin secretion by the kidneys and bone marrow RBC precursors

50. Indications for testosterone substitution
Symptoms of hypogonadism and
morning testosterone levels below 12 nmol / l
Absolute contraindications for
testosterone substitution
Prostate carcinoma
Desired paternity (for secondary hypogonadism,
gonadotropin administration is required)
Relative contraindications for
Benign prostate hyperplasia, sleep apnea, polycythemia,
criminal sexual behavior
Effect of
T on prostate is dose dependent. No conclusive evidence that physiologic doses of
T causes high PSA levels or increases prostate cancer.
Nieschlag and Behre, Andrology, 2000, Springer

51. Conclusion 2
Late Onset Hypogonadism can lead to dysfunction of multiple organ systems and detriment of the quality of life of the aging male
Diagnosis can be made by clinical and biochemical parameters
Testosterone replacement is indicated in carefully selected patients and leads to improvement of symptoms
Testosterone treatment be justified on individual basis. Relatively low T does not necessaryily mean hypogonadism. Some men are aymptomatic and feel well.
T levels hould be used in conjunction with symptoms.

52. Can Growth Hormone Prevent Aging?
NEJM Volume 348: February 27, 2003 Number 9Next
Mary Lee Vance, M.D.

53. The Bottom Line on growth hormone
Although growth hormone levels decline with age, it has not been proven that trying to maintain the levels that exist in young persons is beneficial. Considering the high cost, significant side effects, and lack of proven effectiveness, HGH shots appear to be a very poor investment. So called "growth-hormone releasers," oral "growth hormone," and "homeopathic HGH" products are fakes.

54. Summary
Menopause and Andropause are characterized by decreasing sex hormones and clinical features that go with it.
Hormone replacement in men and women has benefits and risks.
Hormone replacement should be used in the perspective of current available data.

55. “ In the autumn years of life , a woman or a man deserves an Indian summer rather than a winter of discontent .“
by : Robert Greenblatt