Today: 4/24/06

Female Reproductive System Aging

Male Reproductive System Aging

Hormone Replacement Therapy

Terminology• Menopause

– Permanent Cessation of Menstruation

– Permanent Loss of Ovarian Function

– No reproduction

– Functional consequences of low estrogens/progesterone

• Perimenopause

– 1 year before until 1 year after menopause

• Postmenopause

– From menopuase until death

• Premenopause

– Before menopause

Anatomy: Female Reproductive Tract

Ovary Characteristics

• Ovaries– Contain germinal cells

– Contain endocrine producing cells

• Thecal

• Granulosa

– Determine secondary structures and sexual characteristics

•Cells in hypothalamus secrete GnRH (gonadotropin

releasing hormone) •which reaches through the portal blood system the anterior pituitary where it stimulates the secretion of gonadotropins FSH & LH•FSH stimulates ovary to produce estrogens•LH stimulates release of the ovum in oviduct and production of estrogen and progesterone

Endocrinology• GnRH: Gonadotropin Releasing Hormone

– Peptide– Hypothalamus

• FSH, LH: Follicle Stimulating Hormone and Luteinizing Hormone– Peptides– Anterior pituitary gonadotrope cells

• E, P: Estrogens and Progesterone – Steroids– E from follicle cells and corpus luteum– P from corpus luteum

Normal Female Hormone Patterns

Hormonal Changes From Aging

• Gonadotropins:– LH

• Change to pulsatile pattern:

Duration, Frequency

– FSH• “Monotropic FSH ”

• 1st Noticed prior to any change in cycle length

• Ovarian Steroidal Hormones– Estrone levels early in

the cycle in older ovulatory women

• Possible due to LH/FSH alterations

– Eventually, H-P-G axis is unable to generate LH surge needed for ovulation

Fertility Changes and Perimenopause

• Fertility and Fecundity Decrease– Ovulatory cycle continues after onset of

perimenopause– Cycle length becomes more variable

• Shortening of follicular phase

• No change in luteal phase

– Peak fecundity occurs at 24, with a gradual decrease to 35, and a rapid decrease after 35

Ovarian Structural Changes

• Abnormalities in Older Oocyte– Change in microtubule and

chromosome placement at the second metaphase of meiosis

– May be linked to increased aneuploidy (unbalanced chromosomes) seen in offspring of older women

• Declining Follicular Reserve– 2 Million Primordial Follicles

during fetal development– Declines to 1 million at birth

and 250,000 by puberty– Primordial Follicles develop to

primary and secondary follicles independent of hormone status

– In the absence of LH/FSH, follicles undergo atresia

– Once follicles are depleted, ovarian hormone production declines

Menopause Symptoms

• Hot Flashes – Most common reported symptom: 70-80 % of women report signs of hot flashes– Asian women have much lower rate

• 10-25 % Reported• Possibly due to genetics, diet, lack of reporting

• Symptoms– Sweating– Increased Skin Conductance– Increased Core Body Temperature– Increased Metabolic Rate– Increased Skin Temperature– Hot flashes appear to be the result of noradrenergic control independent of estrogen

regulation• ERT alleviates the symptoms of hot flashes• Adrenergic receptor agonists also show promise for treatment

Menopause Effects on the Reproductive Tract

• Reproductive targets for steroidal hormones experience atrophy following menopause

• In addition, these more specific changes are seen:– Vagina

• Dryness• Decreased Vascularity• Decreased Secretions• Increased Risk of Infections

– Ovaries• Become more fibrotic as follicles diminish

– Uterus• Loses Weight and Volume

Effects on Non-Reproductive Steroidal Targets

• Skin– Thinning of epidermis– Atrophy of sebaceous glands– Increased sensitivity to temperature, humidity, and

trauma

• Bladder– General Atrophy

• Results in urinary incontinence

• Hair– Body hair undergoes redistribution

Menopause and Non-reproductive Targets

• Skeletal System– Osteoporosis

• Decreased bone mass following menopause that appears to be the result of declining estrogen level

• Central Nervous System– Psychological

• Anxiety/Depression

– Cognition/Memory

• Cardiovascular System– Possibly due to role of estrogen in lipid metabolism

Osteoporosis

• Cell Types:– Osteoblasts: form new bone (build)– Osteoclasts: resorption of old bone

(chew)– Osteocytes: mature bone cells that

maintain the bone matrix– Osteogensis is the formation of new bone

Why Menopause?

• Life span of a species and survivability of offspring– Women have survived to an age where natural selection

is no longer favored as the maintenance of the reproductive system

– Menopause may be a pleiotropic effect of genes that had value earlier in life

• Menopause may carry advantage for survival of species– Non-reproducing species members to care for young

• “Surrogate Mothers”

Questions

• What are the major female reproductive changes with aging?

• What is menopause?• What are some of the non-reproductive

effects of menopause?• What are the reproductive hormones in the

female reproductive tract and how are they controlled?

Aging of theMale Reproductive System

Anatomy of the Male Reproductive Tract• In humans the principal reproductive organ is the brain• In addition to the brain, the male reproductive system

consists of the:TESTIS

Primary sex organ suspended outside of the body inthe scrotum

Secondary male sex organs include:EPIDIDYMIS,

VAS DEFERENS,EJACULATORY DUCTS

which carry sperm to the urethra

SEMINAL VESISCLES, PROSTATE, & BULBOURETHRAL GLANDSwhich secrete seminal fluid

PENIS with URETHRAthrough which flow both urine and semen

A simplified version of the male reproductive

endocrinology:

The hypothalamus releases GnRH into the circulatory system and, through blood, directly into the pituitary.

GnRH triggers the release of the pituitary LH and FSH that stimulate the testes to testosterone secretion and sperm production.

the GERM CELLS or GAMETES,involved in fertilization.

the INTERSTITIAL CELLS of LEYDIGthat secrete testosterone, the major androgen

the SERTOLI CELLSwith secretory and reproductive functions

The testis, the male primary reproductiveorgan, contains three types of cells, all

necessary for reproduction:

With Age:

• On the average, the male reproductive function remains normal (or only slightly diminished in some individuals) until advanced old age (80+ years) when it decreases

• Subtle changes include:

GnRH

Sensitivity of androgen secretion to LH

Sensitivity of negative feedback between GnRH and LH

Serum LH concentration

With aging, loss of high-amplitude LH pulses despite normal or increased pituitary LH stores

Serum testosterone concentration

With aging, decreased responsiveness of testis androgen secretion to LH

Young OlderYoung Older

Aging of the Prostate

Table 19-12 The Prostate and Testosterone

The healthy prostate is dependent on androgens for growth

In the prostate: testosterone dihydrotestosterone (DHT)

The enzyme catalyzing this reaction is 5--reductase

DHT stimulates growth of the prostate

Table 19-13 Normal Aging of the Prostate

After age 40:Outer regions:Atrophy of smooth muscle and proliferation of connective tissueFlattening of secretory epitheliumInner region:Increase in the number of cells present (hyperplasia)

After age 60:Slower, but more uniform atrophy of the prostateAccumulation of prostate concretions

Table 19-14 Synopsis of Benign Prostatic Hyperplasia (BPH)Characteristics

Caused by growth of the prostate from about age 40 until death Affects 50% of men > 50 years old Affects 95% of men > 70 years old Clinical symptoms due to obstruction of the urethra are present up to

25% of men with histologic evidence of BPH BPH tissue resembles normal prostate tissue with increased amounts

of smooth muscle, glandular, and/ or stromal components An enlarged prostate can strangle the urethra

BPH is not found in men who have been castrated or men who lack 5--reductase

Table 19-15 Possible Risk Factors for Benign ProstaticHyperplasia (BPH) and Prostate Cancer

Possible Risk Factors for BPH Possible Risk Factors for Prostate Cancer Aging Genetic predisposition Use of anabolic steroids To bacco exposure Dietary factors Cadmium exposure Genetic predisposition Vitamin A deficiency Environmental toxins Vasectomy No other major risk factors Sexually transmitted diseases

Mutagenic hormonal factors Dietary factors (particularly high level of

animal fat)

Treatment of Prostate CancerDepends on

Life expectancyOverall health statusPersonal preferencesSize of the prostate

State of disease

Treatments include:Watchful waiting

SurgeryRadiation TherapyHormonal Therapy

Cryotherapy

**PSA controversy pp. 353, 354**

Questions

• What are the male reproductive changes with aging?

• What are the changes in the prostate with aging?

• What are the hormones involved in the male reproductive tract and how is their release controlled?

Hormone Replacement Therapy

Hormone Replacement Therapy

Involves the attempt to replace, or substitute, the lost constituent with a similar exogenous substance with comparable properties and actions

• Dose, duration, metabolism, target cells, and side effects

Replacement Therapy Problems in Aging

• Complexity of endocrine system• Loss or insufficiency of endogenous

hormones• Target cells for hormones are themselves

aging and this may effect their responsiveness

• Changes in hormones and their targets due to disease and degenerative processes

Hormone Replacement Strategies

• Adrenal Sex Steroids and DHEA

• Growth Hormone

• Insulin (as in Laura Epstein’s lecture 4/14)

• Reproductive Hormones

• DHEA is the principal adrenal androgen

*Note-Does not bind androgen receptor

• DHEA(S) concentrations change throughout the human life

• DHEA(S) levels are lower in women than men

• Increased mortality is associated in men with a lower DHEA(S) baseline, but not in women

Dihydroepiandrosterone (DHEA)

DHEA and AgingEpidemiological

Evidence (DHEA low levels)

• cardiovascular mortality

• Found in:– Autoimmune diseases– Dementia– Breast cancer

• DHEA(S) levels may be indicative of a severe disease or predictive of a future disease

DHEA Replacement beneficial in:

• Adrenal Insufficiency• Healthy Elderly?

– No increase in well being, cognition, nor sexuality

• Elderly with impaired mood, cognition and sexual function?

Growth Hormone and Aging

• Study in 1990 demonstrated in small group of elderly men that GH and IGF I levels were reduced:– 12 out of 21 men injected with hGH over a 6

month period showed small increases in muscle mass and bone density (10-14%)

– Suggests that GH might be responsible in part for decreased muscle and bone in elderly

Role of GH in Aging

• GH and IGF-I serum levels decrease in some elderly and nocturnal peak is lower or absent– Possibly due to:

• Decreased GHRH

• Increased GHIH (somatostatin)

• Stress

Effects of GH Treatment

• 1998 study of ICU patients found:– Mortality increased from 19% to 44% in patients

having GH therapy for 7-14 days

– Length of hospital stay was prolonged by GH therapy

• Attributed to:– Decreased immune function

– Increased insulin resistance

– Multi-Organ Failure

Types of Hormones Used in Post-Menopause

• Estrogens– Alone or with progestin

– Types and route of administration

– Optimal dose is the lowest dose to treat symptoms over the shortest duration

• Progestins– With Estrogen to reduce

risk of endometrial cancer

– Cardiovascular risks outweigh benefits

– Other products for osteoporosis treatment

Risks of HT

• Estrogen + Progestin– Increases Risk of:

• Breast Cancer

• Heart Disease

• Stroke

• Blood Clots

• Dementia

• Decreased Risk of:• Hip Fractures (Osteoporosis)• Colon Cancer

Benefits of HRT

• Relieves Short-Term Symptoms of Menopause:– Hot Flashes

– Sweats

– Disturbed Sleep

• May also help prevent colon cancer and age-related vision loss

Alternatives to Hormone Therapy?

(Recommendations from the Mayo Clinic)

• Maintain a Healthy Heart:– Don't smoke. – Be physically active. – Eat a low-fat, high-fiber diet, plentiful in fresh fruits and vegetables. – Maintain a healthy weight. – Manage high blood pressure. – Keep cholesterol and triglyceride levels in check. – Control diabetes. – Avoid excess alcohol.

• Healthy Bones– Calcium and vitamin D. Make sure you're getting enough of these

nutrients in your diet to keep your bones strong. – Exercise. Regular physical activity — especially weight-bearing

exercises such as walking or dancing — can help keep your bones strong and healthy.

Questions

• What are the risks and benefits of post-menopausal hormone replacement therapy?

• What are some of the challenges of hormone replacement therapy?