1. Today: 4/24/06 Female Reproductive System Aging
Hormone Replacement Therapy

2. 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

3. Anatomy: Female Reproductive Tract

4. Ovary Characteristics
Ovaries
Contain germinal cells
Contain endocrine producing cells
Thecal
Granulosa
Determine secondary structures and sexual characteristics

5. 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

6. 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

7. Normal Female Hormone Patterns

8. Hormonal Changes From Aging
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
Gonadotropins: LH
Change to pulsatile pattern:
Duration, Frequency
FSH
“Monotropic FSH ”
1st Noticed prior to any change in cycle length

9. 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

10. 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

11. Menopause Symptoms Hot Flashes Symptoms
Most common reported symptom: % 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

12. 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

13. 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

14. 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

15. 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

16. 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”

17. 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?

18. Aging of the Male Reproductive System

19. 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 in
the scrotum
Secondary male sex organs include:
EPIDIDYMIS,
VAS DEFERENS,
EJACULATORY DUCTS
which carry sperm to the urethra
SEMINAL VESISCLES, PROSTATE, & BULBOURETHRAL GLANDS
which secrete seminal fluid
PENIS with URETHRA
through which flow both urine and semen

20. 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.

21. The testis, the male primary reproductive
organ, contains three types of cells, all
necessary for reproduction:
the GERM CELLS or GAMETES,
involved in fertilization.
the INTERSTITIAL CELLS of LEYDIG
that secrete testosterone, the major androgen
the SERTOLI CELLS with secretory and reproductive functions

23. 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

24. Serum LH concentration
Young Older
Young Older
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

25. Aging of the Prostate

26. The Prostate and Testosterone
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

27. Normal Aging of the Prostate
Table 19-13
Normal Aging of the Prostate
After age 40:
Outer regions:
Atrophy of smooth muscle and proliferation of connective tissue
Flattening of secretory epithelium
Inner region:
Increase in the number of cells present (hyperplasia)
After age 60:
Slower, but more uniform atrophy of the prostate
Accumulation of prostate concretions

30. Treatment of Prostate Cancer
Depends on
Life expectancy
Overall health status
Personal preferences
Size of the prostate
State of disease
Treatments include:
Watchful waiting
Surgery
Radiation Therapy
Hormonal Therapy
Cryotherapy
**PSA controversy pp. 353, 354**

31. 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?

32. Hormone Replacement Therapy

33. 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

34. 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

35. Hormone Replacement Strategies
Adrenal Sex Steroids and DHEA
Growth Hormone
Insulin (as in Laura Epstein’s lecture 4/14)
Reproductive Hormones

36. Dihydroepiandrosterone (DHEA)
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

37. DHEA and Aging DHEA Replacement beneficial in:
Epidemiological 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?

38. 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

39. 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

40. 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

41. 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

42. Risks of HT Estrogen + Progestin Increases Risk of: Decreased Risk of:
Breast Cancer
Heart Disease
Stroke
Blood Clots
Dementia
Decreased Risk of:
Hip Fractures (Osteoporosis)
Colon Cancer

43. 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

44. 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.

45. Questions
What are the risks and benefits of post-menopausal hormone replacement therapy?
What are some of the challenges of hormone replacement therapy?