Hormonal Changes at

50

Josephine Carlos-Raboca, MD, FPCP,FPSEMJosephine Carlos-Raboca, MD, FPCP,FPSEM

Section of Endocrinology, Diabetes & Section of Endocrinology, Diabetes & MetabolismMetabolism

Makati Medical CenterMakati Medical Center

Outline

Menopause: PhysiologyMenopause: Physiology

Treatment: Treatment:

nonhormonalnonhormonal

hormonalhormonal

Andropause:PhysiologyAndropause:Physiology

Treatment: Treatment:

TestosteroneTestosterone

Growth HormoneGrowth Hormone

SummarySummary

Menopause Overview

Menopause is a natural part of a woman's Menopause is a natural part of a woman's life cycle.life cycle.

monthly periods end.monthly periods end.

freedom from pregnancy and additional freedom from pregnancy and additional child-raising responsibilities. child-raising responsibilities.

Effects of Menopause

Vasomotor instability-Vasomotor instability- hot flashes, and hot flashes, and waking during the nightwaking during the night

Mood changesMood changes -Mood swings; depression -Mood swings; depression or anxietyor anxiety

Cognitive function-Cognitive function- decreased verbal decreased verbal memorymemory

Sexual function - libidoSexual function - libido

UrogenitalUrogenital - dryness, itching, pain during - dryness, itching, pain during sexual intercourse sudden or frequent sexual intercourse sudden or frequent urinatingurinating

Menopause Increases Women's Risk for Osteoporosis

women can lose up to 5 percent of their women can lose up to 5 percent of their bone mass per year in the first 5 years bone mass per year in the first 5 years following menopause. following menopause.

Risk of Cardiovascular Disease Also Increases after Menopause

The risk of CVD increases in women after The risk of CVD increases in women after menopausemenopause

By age 60 heart disease becomes as By age 60 heart disease becomes as common in women as in men.common in women as in men.

Managing Menopause

Healthy lifestyle to protect against Healthy lifestyle to protect against osteoporosis and cardiovascular diseaseosteoporosis and cardiovascular disease

Maximize medications for these conditionsMaximize medications for these conditions

A balanced diet, calcium and vitamin D; A balanced diet, calcium and vitamin D;

Weight reduction if overweight;Weight reduction if overweight;

Stop smoking; Stop smoking;

Weight-bearing exerciseWeight-bearing exercise

Yearly mammogram and breast Yearly mammogram and breast examination examination

Treating the Symptoms of Early Menopause:

Individual counseling or support groups Individual counseling or support groups

Vaginal moisturizers such as Vagisil or Vaginal moisturizers such as Vagisil or Replens. Lubricants, such as K-Y Jelly or Replens. Lubricants, such as K-Y Jelly or AstroglideAstroglide

Low-dose vaginal estrogen Low-dose vaginal estrogen

Lack of desire may be helped with more Lack of desire may be helped with more open communication with your partner.open communication with your partner.

Creating a pleasurable atmosphere at Creating a pleasurable atmosphere at home and making a point to enjoy other home and making a point to enjoy other activities with your partner .activities with your partner .

Treating the Symptoms of Early Menopause with Non-Hormones:

Selective-Serotonin Reuptake Inhibitor (SSRI) Selective-Serotonin Reuptake Inhibitor (SSRI) drugs and Serotonin Norephinephrine Reuptake drugs and Serotonin Norephinephrine Reuptake Inhibitor (SNRI) drugs. Inhibitor (SNRI) drugs.

Gabapentin Gabapentin

Medroxyprogesterone acetate and megestrol Medroxyprogesterone acetate and megestrol acetate, progesterone-type drugs. acetate, progesterone-type drugs.

Clonidine Clonidine

Changing Aspects of Hormone Replacement Therapy

Conventional rationale for HRT Conventional rationale for HRT derived from favorable derived from favorable outcomes of observational outcomes of observational studies in studies in perimenopausalperimenopausal womenwomen

Recent randomized clinical Recent randomized clinical trials showed potentially trials showed potentially adverse effects of HRT in adverse effects of HRT in late late postmenopausalpostmenopausal women women

RCTs results have discouraged RCTs results have discouraged HRT use in HRT use in perimenopausalperimenopausal women women

Benefits of HRT

Relief of menopausal symptomsRelief of menopausal symptoms

Increase bone densityIncrease bone density

CVD benefit ?CVD benefit ?

Improve memory?Improve memory?

Improve sexual function?Improve sexual function?

Youthful look?Youthful look?

Decrease colon cancerDecrease colon cancer

Decrease macular degenerationDecrease macular degeneration

Women's Health Initiative 2002

The largest randomized prospective trial The largest randomized prospective trial evaluating the effects of estrogen plus evaluating the effects of estrogen plus progestin and estrogen alone versus progestin and estrogen alone versus placebo (no hormone). placebo (no hormone).

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 Prevention of bone loss and fragility fracturefracture

WHI – 33% reduction in fracture ratethe WHI – 33% reduction in fracture ratethe only therapy with efficacy data on only therapy with efficacy data on prevention of fracture in women with prevention of fracture in women with osteopenia osteopenia

Alternate Treatments Are Available

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

HRT and Risk of Cardiovascular Disease

The increase in risk following menopause The increase in risk following menopause suggests that estrogen made by the ovary suggests that estrogen made by the ovary prior to menopause may protect against prior to menopause may protect against heart disease. heart disease.

However, recent studies have shown no However, recent studies have shown no benefit to the use of postmenopausal benefit to the use of postmenopausal hormone therapy in heart disease hormone therapy in heart disease prevention and indicate the need to use prevention and indicate the need to use other modalities to help women fight other modalities to help women fight heart disease. heart disease.

HERS II

Results from extended, open-label Results from extended, open-label evaluation of the HERS (Heart evaluation of the HERS (Heart Estrogen/progestin Replacement Study) Estrogen/progestin Replacement Study) indicate no cardiovascular benefit of HT in indicate no cardiovascular benefit of HT in postmenopausal women with previous postmenopausal women with previous history of cardiovascular disease history of cardiovascular disease

JAMA 2002JAMA 2002

WHI and CVD risk

Estrogen + Progestin Estrogen + Progestin

increased CVD by 29%increased CVD by 29%

Estrogen only in hysterectomized Estrogen only in hysterectomized

no increase in CVD riskno increase in CVD risk

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: Women <10 years since menopause: RR=0.89RR=0.89

Women 10-19 yrs since menopause: Women 10-19 yrs since menopause: RR=1.22RR=1.22Women 20+ years since menopause: Women 20+ years since menopause: RR=1.71RR=1.71(But no modifying effect of age)(But no modifying effect of age)

Manson JR et al NEJM 2003 Manson JR et al NEJM 2003

Reducing Risk of CVD

Statins have been shown to lower the risk Statins have been shown to lower the risk of CVD in individuals with abnormal of CVD in individuals with abnormal circulating lipids and those who have a circulating lipids and those who have a family history of heart disease.family history of heart disease.

Small doses of aspirin dailySmall doses of aspirin daily

HRT and cognitive functionWHI Memory Study (WHIMS)

Women aged 65 or older who took Women aged 65 or older who took estrogen plus progestin had twice the rate estrogen plus progestin had twice the rate of dementia, including Alzheimer’s of dementia, including Alzheimer’s disease, as those taking placebo. Estrogen disease, as those taking placebo. Estrogen plus progestin did not protect against mild plus progestin did not protect against mild cognitive impairment (e.g., trouble paying cognitive impairment (e.g., trouble paying attention and remembering).attention and remembering).

JAMA 2003 JAMA 2003

Cognitive function

The Women's Health Initiative data The Women's Health Initiative data suggest that women who initiate hormone suggest that women who initiate hormone therapy at age 65 or older have worsening therapy at age 65 or older have worsening dementia than women who take no dementia than women who take no hormones.hormones.

Until more is known, hormone therapy Until more is known, hormone therapy cannot be recommended for prevention of cannot be recommended for prevention of Alzheimer's disease. Alzheimer's disease.

Other Benefits

Taking estrogen plus progestin lowers the Taking estrogen plus progestin lowers the risk of developing colon cancer by 37%risk of developing colon cancer by 37%

Taking estrogen lowers the risk of Taking estrogen lowers the risk of developing age-related macular developing age-related macular degeneration, a degeneration of the degeneration, a degeneration of the retina of the eye. retina of the eye.

Risks of HRT

StrokeStroke

WHI 39% increased in EWHI 39% increased in E

41% increased in E+P41% increased in E+P

Breast cancerBreast cancer

WHI no significant increase in EWHI no significant increase in E

26% increased in E+P26% increased in E+P

Venous thromboembolism 47%Venous thromboembolism 47%

"Designer Estrogens"

Selective Estrogen Receptor Modulators Selective Estrogen Receptor Modulators (SERMs). Act as beneficially as estrogen on (SERMs). Act as beneficially as estrogen on some tissues and some tissues and as estrogen-blockers as estrogen-blockers on other tissueson other tissues

Tamoxifen-used to prevent breast cancerTamoxifen-used to prevent breast cancer

Raloxifene - used to prevent osteoporosis, Raloxifene - used to prevent osteoporosis,

Selective estrogen tissueSelective estrogen tissue

Tibolone Tibolone

Commonly Used Alternativesto Hormone Replacement Therapy

Black Cohash- Black Cohash-

Camomile-Camomile-

Chasteberry-Chasteberry-

Dong Quai- Dong Quai-

Ginseng-Ginseng-

Licorice Root- Licorice Root-

St. John's Wort-St. John's Wort-

Valerian- Valerian-

Soy ProductsSoy Products

Testosterone/DHEA Supplement in Women

Not approved Not approved

Variable to no benefitVariable to no benefit

Data shows benefit in hypopituirarism, Data shows benefit in hypopituirarism, premature ovarian failure, bilateral premature ovarian failure, bilateral oophorectomy and primary adrenal oophorectomy and primary adrenal insufficiencyinsufficiency

Conclusion 1

Short-term hormone therapy is approved Short-term hormone therapy is approved by the U.S. Food and Drug Administration by the U.S. Food and Drug Administration in younger women for some symptoms of in younger women for some symptoms of menopause, including hot flashes, vaginal menopause, including hot flashes, vaginal dryness and painful intercoursedryness and painful intercourse

the lowest effective dose possible. the lowest effective dose possible.

Individualized and time dependentIndividualized and time dependent

WHAT IS ANDROPAUSE? (Late Onset Hypogonadism) [PADAM /

ADAM]A clinical condition A clinical condition characterized by a characterized by a partial deficiency of partial deficiency of androgens in blood androgens in blood and/or decreased and/or decreased testosterone availability testosterone availability to various systems or to various systems or organ functions.organ functions.

Typical appearance of testosterone deficiency

Clinical SymptomatologyClinical Symptomatology

Usual appearance of young men

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 Endogenous Androgen ProductionProduction

Testes: >95%Testes: >95% testosteronetestosterone

Adrenals: <4%Adrenals: <4% dehydroepiandrosteronedehydroepiandrosterone

Pathophysiology

Testosterone decreases with agingTestosterone decreases with aging

SHBG increases with aging with a SHBG increases with aging with a decrease in bioavailable testosteronedecrease in bioavailable testosterone

Decline in testicular Leydig cellsDecline in testicular Leydig cells

Due to abnormal hypothalamic –pituitary- Due to abnormal hypothalamic –pituitary- testicular axistesticular axis

Testosterone Replacement: Is it necessary?

IMPROVEMENT OF SXS OF ANDROPAUSE

BPH AND PROSTATE CANCER RISK

CV EVENTS, ETC

OsteoporosisNot just a female disease!Not just a female disease!

25–30% of hip fractures occur25–30% of hip fractures occur in men!in men!

Serious ! 25% die of it in the short termSerious ! 25% die of it in the short term

25% die of it in the longer term25% die of it in the longer term

Only 20% return to their former quality of Only 20% return to their former quality of life; many more need assistance 51 % life; many more need assistance 51 % suffer from depression (Cowith activities of suffer from depression (Cowith activities of daily livingdaily living

olsaet, Aging Male congress 2002)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 MonthsBone Mineral Density (Lumbar Spine) after 36 Monthsof Testosterone Treatment in 70 Elderly Men of Testosterone Treatment in 70 Elderly Men

(mean age 71, T<350 ng/dL) (mean age 71, T<350 ng/dL)

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Body Composition, Strength and Function

Role of testosteroneRole of testosterone

Increases nitrogen retentionIncreases nitrogen retention

Increases protein synthesisIncreases protein synthesisBhasin Bhasin (NEJM, 1996)(NEJM, 1996)

TRT dose related increase in skeletal TRT dose related increase in skeletal muscle mass and strengthmuscle mass and strength

In a systematic review of 6 trials T In a systematic review of 6 trials T reduced fat mass and increased lean reduced fat mass and increased lean body massbody mass

Testosterone Improves Physical Performance Testosterone Improves Physical Performance in 70 Elderly Men (mean age 71, T<350 ng/dL)in 70 Elderly Men (mean age 71, T<350 ng/dL)

Page ST et al. J Clin Endocrinol Metab 90(3): 1502-1510 (2005)

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TRT and DepressionTRT and Depression

Margolese, HC, J Geriatr Psychiatry Neurol 2000; 13:93-101.

• 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

Sexual Function

Jain Meta-analysis Jain Meta-analysis (J Urol, 2000)(J Urol, 2000)

TRT 57% overall improvement rate for EDTRT 57% overall improvement rate for EDTRT improved nocturnal erection and penile TRT improved nocturnal erection and penile rigidity in hypogonadal males rigidity in hypogonadal males (Cunningham 1990, J Clin (Cunningham 1990, J Clin Endoc Metab; Arver, 1996 J Urol)Endoc Metab; Arver, 1996 J Urol)

TRT –direct vascular effect on the corpora TRT –direct vascular effect on the corpora cavernosa mediating nitric oxide effects cavernosa mediating nitric oxide effects (Aversa (Aversa 2003, Clin Endocrin)2003, Clin Endocrin)

TRT potentiates libido by a central effect and TRT potentiates libido by a central effect and erection by central and peripheral effectserection by central and peripheral effects

Hematopoietic Effects of TRT

Red Blood CellsRed Blood Cells

T stimulates erythropoietin secretion by T stimulates erythropoietin secretion by the kidneys and bone marrow RBC the kidneys and bone marrow RBC precursorsprecursors

Indications for testosterone substitutionSymptoms of hypogonadism and morning testosterone levels below 12 nmol / l

Absolute contraindications for testosterone substitutionProstate carcinomaDesired paternity (for secondary hypogonadism,

gonadotropin administration is required)

Relative contraindications for testosterone substitutionBenign prostate hyperplasia, sleep apnea, polycythemia,criminal sexual behavior

Nieschlag and Behre, Andrology, 2000, Springer

Conclusion 2

Late Onset Hypogonadism can lead to Late Onset Hypogonadism can lead to dysfunction of multiple organ systems and dysfunction of multiple organ systems and detriment of the quality of life of the aging detriment of the quality of life of the aging malemale

Diagnosis can be made by clinical and Diagnosis can be made by clinical and biochemical parameters biochemical parameters

Testosterone replacement is indicated in Testosterone replacement is indicated in carefully selected patients and leads to carefully selected patients and leads to improvement of symptoms improvement of symptoms

Can Growth Hormone Prevent Aging?

NEJM Volume 348:779-780NEJM Volume 348:779-780 February 27, 2003 Number 9Next

Mary Lee Vance, M.D.Mary Lee Vance, M.D.

The Bottom Lineon growth hormone

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

SummarySummary

Menopause and Andropause are Menopause and Andropause are characterized by decreasing sex characterized by decreasing sex hormones and clinical features that go hormones and clinical features that go with it.with it.

Hormone replacement in men and women Hormone replacement in men and women has benefits and risks. has benefits and risks.

Hormone replacement should be used in Hormone replacement should be used in the perspective of current available data.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