Lecture 28: Menopause

Question 1

What is menopause?

Answer 1

• The menopause is the c_onsequence of the ovaries running out of follicles,_ and occurs between 50 and 52 years of age (45-55).
  
  • Ovaries
  • Atresia and ovulation result in exhaustion of the follicular reserve
• The _last episode of natural menstrual bleedin_g signifies the end of her reproductive life and is referred to as the menopause
  
  • _​_Uterus

Question 2

Why is there a biological mechanism to stop reproduction early?

Answer 2

Human species is unique in that female experiences a relatively early onset of failure of the reproductive system (menopause) compared to other major organ systems.

1. 1) Blessings of modern life

• Most animals reproduce as long as they live, we live longer than expected (mismatched evolution)
• Fixed number of follicles

1. 2) Senescence

• Deterioration of reproductive processes with age
• To protect the aging women from the hazards of childbirth (evolution advantage)

1. 3) Group selection
   * Menopause protects human gene pool against birth defects due to age-related increase in chromosomal abnormalities
2. 4) Good mother/grandmother theory
   * A pause from reproduction to provide extended maternal care of offspring

Question 3

Describe the follicle loss during reproductive life

Answer 3

Follicles have a fixed number at the start, then gradual decline over life, there is no ‘oocyte germ cell’.

• During fetal development, ~7 million follicles develop.
• By birth, the number of follicles has declined to ~1-2 million.
• There is a steady decline of follicles, with puberty (~400,000), through to menopause (>1000 follicles).

While the quantity of follicles declines, the quality of the follicles also decreases (popcorn hypothesis).

Question 4

What is Premature Ovarian Failure?

Answer 4

Premature Ovarian Failure (POF), Primary Ovarian Insufficiency (POI) or Premature Menopause

• Go through menopause very early
  
  • Ovarian failure under the age of 40 years.
  • Affects 1% of all women and 0.1% before the age of 30.
  • Becoming an increasing problem as women delay childbearing.

Question 5

While the quantity of follicles declines, the _____ of the follicles also decreases

Answer 5

Quality

Popcorn hypothesis

Question 6

Describe the popcorn hypothesis

Answer 6

While the quantity of follicles declines, the quality of the follicles also decreases

(the worst follicles ‘pop’ last, and the best ones pop first).

Question 7

Describe the main outcomes of the study by Nate on NZ university students’ knowledge of fertility decline in women

Answer 7

Students correctly identified a fertility decline with age

students overestimated the rates of preg for both sponataneous pregnancy and IVF pregnancies

Students are mainly aware of assistive repro technologies being avaialble but overestimate their effextiveness

Fe students mentioned non-ART or healthy lifestyle as measures to prolong parenthood

Question 8

What greatly decreases the number of follicles?

Answer 8

Smoking!- ~2 years earlier menopause

Question 9

Describe Andropause

Answer 9

• Thought to affect men between 40 and 55.
• T_hought to be a decline in the level of testosterone._
• The bodily changes occur very gradually in men and may be accompanied by changes in attitudes and moods, fatigue, loss of energy, sex drive and physical agility.

Question 10

Describe Phases Associated With The End Of Reproductive Life In Normal Women (Stages of Normal Reproductive Aging in Women STRAW)

Answer 10

The last menstruation is the sign of the uterus. Ovarian senescence is the sign of the ovary.

Regular menstrual cycles occur for ~20-40yrs (fixed luteal phase, slight declining follicular phase due to slight increase FSH).

Older women are more likely to have more anovulatory cycle with longer cycles.

Premanopause (regular cycles)

Menopausal transition

Post-menopause (~52)

Peri-menopause (irregular cycles ~46)

Ovarian senescence

Question 11

Peri-menopause goes from ______ to _______

Answer 11

Pre-menopause

OVARIAN SENESCENCE

Question 12

The length of menstural cycle _______ as the woman reaches menopause

Answer 12

Increases

Regular menstrual cycles occur for ~20-40yrs (fixed luteal phase, slight declining follicular phase due to slight increase FSH).

Older women are more likely to have more a_novulatory cycle_ with longer cycles.

Question 13

What is perimenopause?

Answer 13

Perimenopause is the time of e_rratic hormone fluctuations_ which starts at beginning of menopausal transition and continues through to ovarian senescence.

The term climacteric relates to physical and emotional symptoms associated with perimenopause.

~5 and 10% of women do not experience a transition phase of any significance and abruptly cease menstrual activity.

Question 14

Longer the menstural cycle length _________ likely it is to be ovulatory

Answer 14

LESS

Older women are more likely to have more anovulatory cycle with longer cycles. (no good follicles left, so they aren’t responding to FSH)

Question 15

Describe the events during perimenopause

Answer 15

Follicle levels reduce below a critical threshold (~25,000 follicles)

• Inhibin B levels begin to decline (inhibin B is produced by granulosa cells of primary follicles)
• Inhibin has negative feedback on FSH, so FSH levels rise, results in:
  
  • Shortened follicular phase
  • Increased early follicular oestrogen
    
    • _​_Therefore having twins is more likely in older women

A_cceleration of follicle loss (_women at ~40)

Question 16

Describe the Hormone Changes During the perimenopause

What is the clinical consequence of this?

Answer 16

When women reach around 40, inhibin levels go down. This results in higher level of FSH.

The higher plasma levels of FSH during perimenopause stimulate a greater proportion of primordial follicles to enter the growing pool, which accelerates the depletion of the primordial reserve (instead of ~20-40/day, get ~80/day follicles recruited instead).

• Higher chance of more than one dominant follicle
• So higher chance of twining.

Loss of inhibin affects FSH more than LH

Mean serum levels of FSH and LH and oestrodiol and osterone during the perimenopause

Question 17

What are the features of the perimenopause?

Answer 17

• Accelerated depletion of follicular reserve
• Menstural Changes
  
  • Irregular longer cycles
  • Annovulatory cycles are common
• Hormone Changes
  
  • _Gonadotrophins often elevated (_especially FSH)
  • Oestrogen levels are often high (early perimenopause), but are sometimes low (late perimenopause)
  • Unpredictable hormone patterns
• Ovulation is always possible
• Contraception is difficult

Question 19

Define Menopause

Answer 19

It can be stated that a woman over _45 year_s of age who has had amenorrhoea for at least 12 months is highly unlikely to ovulate again and is very probably (98%) postmenopausal.

Marked fluctuations in hormone levels, including oestrogen, can continue more than six months.

Some follicles may be left, however, they may be nonresponsive (popcorn hypothesis).

Question 20

Describe the postmenopausal Oestrogen Production

Answer 20

REDUCTION and LESS VARIATION in both oestradiol and estrogen.

By ~one year after the menopause, _ovary has essentially ceased producing hormones (_ovarian senescence).

Amount of oestrogen produced daily is <1/10 of what she produced in earlier years in late preovulatory phase of menstrual cycle.

• Circulating oestradiol levels are accordingly very low and show little variation from day to day.

Oestrogen now occurs from extraglandular production, mainly from aromatisation in s_tromal cells of adipose tissue_ of androstenedione secreted by adrenal cortex.

• Oestrone is product of aromatisation and while some of it is converted to oestradiol, it is predominant oestrogen of the postmenopausal years.
• Oestrone is only weakly oestrogenic having approximately 1/10 the biological activity of oestradiol.

Question 21

After post-menopause, where are the oestrogen being produced from?

Answer 21

Oestrogen now occurs from extraglandular production, mainly from aromatisation in s_tromal cells of adipose tissue_ of androstenedione secreted by adrenal cortex.

• Oestrone is product of aromatisation and while some of it is converted to oestradiol, it is predominant oestrogen of the postmenopausal years.
• Oestrone is only weakly oestrogenic having approximately 1/10 the biological activity of oestradiol.

Question 22

Describe the perimenopausal symptoms.

Answer 22

Most women experience variety of clinical symptoms of oestrogen (and perhaps progesterone) deprivation during perimenopause.

These symptoms usually follow onset of menopausal transition but they may precede it and they sometimes continue for a time after menopause.

Most women manage menopause by themselves, but ~10% seek medical help to deal with the symptoms.

Vasomotor (vascular instability causes by fluctuating estrogen)

• Hot flushes
• Night sweats
• Often associated with palpitations, weakness, faintness

Genitourinary symptoms (vaginal dryness due to reduced estrogen)

• Atrophic changes
• Decline in epithelial growth and vaginal lining elasticity
• Reduction in vaginal lubrication
• Rise in pH of vaginal fluids
• Dyspareunia, incontinence, urethritis, recurrent urinary infections

Reduction in size of uterus and breasts (due to reduced estrogen)

Bone metabolism

• Increased catabolism
• Osteoporosis

Blood lipid changes

Behavioural/psychological changes

• Depression, tension, anxiety, mental confusion
• Loss of libido

Question 23

Describe the Hormone Replacement Therapy

Answer 23

Most of these symptoms of the menopause may be prevented or arrested by oestrogen treatment.

There is no uniform agreement about safety and advisability of using oestrogen therapy in postmenopausal women, the adverse risks of osteoporosis need to be balanced with the risk of breast or uterine cancer, heart disease, stroke and Alzheimers disease.

HRT remains an appropriate treatment for women with moderate to severe menopausal symptoms

HRT should be at the l_owest dose_ for the shortest time necessary to control symptoms

Question 24

After menopause, Oestrogen now occurs from extraglandular production, mainly from aromatisation in stromal cells of adipose tissue of ________ secreted by _________cortex.

Answer 24

Oestrogen now occurs from extraglandular production, mainly from aromatisation in stromal cells of adipose tissue of androstenedione secreted by adrenal cortex.

Question 25

_______ is product of aromatisation and while some of it is converted to oestradiol, it is predominant oestrogen of the postmenopausal years.

Answer 25

Oestrone is product of aromatisation and while some of it is converted to oestradiol, it is predominant oestrogen of the postmenopausal years.

Oestrone is only weakly oestrogenic having approximately 1/10 the biological activity of oestradiol.