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

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

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 42-58 years with 90% by age 55.

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.

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

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.

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.

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

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.

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.

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.

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.

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

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;288:321-33. 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 50-79 total of 27347.

WOMEN’S HEALTH INITIATIVE CLINICAL TRIAL ( WHI – US ) OBSERVATIONAL, CLINICAL CORHORT 150,00 POSTMENOPAUSAL WOMEN GRP 1 - 48,000 WOMEN Objective : To evaluate the efficiency of Low Fat diet in the prevention of breast , colorectal cancer and coronary heart disease. GRP 2 - 45,000 WOMEN Objective : To evaluate the effect of Calcium &Vitamin D in fractures and colorectal cancer. GRP 3 - 27,500 WOMEN Objective : To assess HRT’s efficacy in the prevention of cardiovascular diseases and fractures .

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

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

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.

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.

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

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 10-19 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

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

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;289:2663-72. 4532 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;289:2651-62.

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

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

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%

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.

"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.  

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

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.

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

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.

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

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

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

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

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

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

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

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): 503-510 (2004)

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.

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): 1502-1510 (2005)

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; 13:93-101. 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; 13:93-101.

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

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.

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

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

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.

Can Growth Hormone Prevent Aging? NEJM Volume 348:779-780 February 27, 2003 Number 9Next Mary Lee Vance, M.D.

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.

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.

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