Menopause:Menopause:a natural eventa natural event

Henry Burger

Definitions (1)Definitions (1)

• Menopause: The permanent cessation of menstruation resulting from loss of ovarian follicular activity. Recognized to have occurred after 12 consecutive months of amenorrhea. Often termed final menstrual period (FMP). There is no independent biological marker

• Perimenopause: The time immediately prior to the menopause (when the endocrinological, biological and clinical features of approaching menopause commence) and the first year after menopause

Definitions (2)Definitions (2)

• Menopausal transition: The time before FMP when variability in the menstrual cycle is usually increased. It may be subdivided into:

– early transition: ≥ 7 days persistent difference in cycle lengths from previous normal range

– late transition: ≥ 60 days amenorrhea observed on at least one occasion

• Climacteric: The period marking the transition from the reproductive to the non-reproductive phase

Definitions (3)Definitions (3)

• Premenopause: The entire reproductive period up to FMP

• Postmenopause: The phase dating from FMP, whether spontaneous or induced. May be subdivided into:– early postmenopause, first 5 years after FMP

and– late postmenopause, more than 5 years after

FMP

Relationships between different time Relationships between different time periods surrounding the menopauseperiods surrounding the menopause

International Position Paper: Women’s Health and Menopause, NIH (2002)

Final menstrual period (FMP)Menopause

Postmenopause

Perimenopause

Menopausal transition

Climacteric

Mean age51 years

1 yearlater

Determinants of age of Determinants of age of menopausemenopause

• Median age 45–55 years world-wide, 50–52 years in white women from industrialized countries

• Premature menopause conventionally defined as FMP occurring < 40 years, may have several causes

• Factors involved in earlier age of menopause:– oophorectomy, e.g. for endometriosis, cancer– chemotherapy, e.g. cyclophosphamide– ovarian irradiation– hysterectomy (up to 4 years advancement)– familial and genetic factors (e.g. ER-α polymorphism,

twinning)– cigarette smoking – by about 2 years

• Factors involved in later age of menopause:– possibly later age at menarche, oral contraceptive use,

longer menstrual cycle length, and parity

The menopausal transitionThe menopausal transition

• A process which takes about a decade

• Earliest signs include– shortening of the menstrual cycle by 2–3 days,

detectable at about age 38–401,2

– infertility – with associated oocyte aging, increased incidence of luteal insufficiency and anovulation3

abnormal basal temperature in 30–50% of cycles after age 404,5

• Menopause is marked by exhaustion of the ovarian supply of oocytes6,7, numbers declining steeply from age 37–38

1Lenton 1984; 2Klein 1996; 3Treloar 1970; 4Dòring 1963; 5Vollmann 1977; 6Baker 1963; 7Richardson 1987

Women in Block's study

Women from the present study with regular menses

Postmenopausal women

Perimenopausal women

Richardson et al. JCEM 1987

Ovarian follicle numbers with ageOvarian follicle numbers with age

BB

BB

B

J

F

FF

F

F

F

F

Age (years)

1

10

100

1000

10000

100000

0

0 10 20 30 40 50 60

Pri

mo

rdia

l fo

llic

les/

ova

ry

GnRH

Inhibin

Pituitary

Gonadotropins: - LH, FSH

Steroids

HypothalamusFeedbackhormones

Hypothalamo-pituitary ovarian Hypothalamo-pituitary ovarian axisaxis

Ovary

Groome et al. JCEM 1996

Hormone levels:Hormone levels:normal menstrual cyclenormal menstrual cycle

80

60

40

20

0

5040302010

0

40

30

20

10

0

15

10

5

0

1500

1000

500

0

200

150

100

50

0-14 -7 0 7 14

-14 -7 0 7 14

-14 -7 0 7 14

Days relative to midcycle LH peak

Inh

ibin

A(p

g/m

l)P

rog

este

ron

e(n

mo

l/l)

LH

(IU

)

Inh

ibin

B(p

g/m

l)E

stra

dio

l(p

mo

l/l)

FS

H(I

U)

Endocrine overviewEndocrine overviewof the transitionof the transition

• Represents the period of change from regular menstrual cyclicity to the postmenopausal state of amenorrhea with elevated gonadotropins, low inhibins A and B, low estradiol and estrone and low anti-Müllerian hormone

• Earliest hormonal change is increase in FSH, most easily detected on cycle days 2–5, occurring in some women, mainly over age 40 (Sherman and Korenman 1976, followed by many others)

Increase in FSHIncrease in FSH

• Results from decreased inhibin feedback (first proposed by Sherman and Korenman 1976), specifically inhibin B secreted by the small antral follicles (Klein 1996, Burger 1999, many others)

• Occurs at a time when estradiol levels are maintained or increased – hence not a resultof decreased estrogen feedback. Theelevated FSH may lead to production of supra-physiological amounts of estradiol (Santoro 1996, Shideler 1989)

Log (inhibin B)

5.04.54.03.53.02.52.01.5

Lo

g (

FS

H)

4.5

4.0

3.5

3.0

2.5

2.0

1.5

Burger HG et al. Climacteric 2000

Relationships betweenRelationships betweenFSH and inhibin BFSH and inhibin B

< 40 years of age

> 40 years of age

Significance of FSH increase (1)Significance of FSH increase (1)

• A harbinger of menopause, although the increase may occur in some women many years before and without any change in menstrual cyclicity

• Augurs poorly for future fertility1

• Is a poor predictor of the age at menopause. The clinician cannot make any conclusions on the timing of an individual woman’s menopause based upon the presence or degree of FSH elevation2

1Pearlstone 1992; 2Burger 1995

Significance of FSH increase (2)Significance of FSH increase (2)

• As long as the active follicular phase permitting the maturation of healthy follicles remains stable and the luteal phase normal, fertility is maintained

• Therefore contraception is still needed during the transition despite moderately elevated FSH levels

• An isolated elevation of FSH is not proof of the occurrence of menopause

Menstrual cyclicityMenstrual cyclicity

• Currently the best indicator of menopausal status

• Degree of irregularity highly variable between women, and regular cycles may recur after a period of irregularity, with temporary resolution of menopausal symptoms which may be associated with irregularity

• Variability includes short cycles, prolonged cycles with temporary ovarian inactivity, and skipped cycles with absence of ovulation

• Cycle length shortening is probably due to elevated FSH levels in the early follicular phase/late luteal phase

• Occurs when follicle numbers have fallen to around 100 per ovary1

1Richardson 1987

Regular Perimenopausal Postmenopausal0.1

1

10

100

1000

10000

Pri

mo

rdia

l fo

llic

les/

ova

ry

Richardson et al. JCEM 1987

Ovarian follicle numbersOvarian follicle numbersin regularly cycling womenin regularly cycling women

and peri- and postmenopausal womenand peri- and postmenopausal women (all > 45 years)

CharacterizationCharacterizationof the menopausal transition (1)of the menopausal transition (1)

• Classic description was by Sherman and Korenman (1975) involving six women followed in detail up to and including final menstrual period

• Features include

– monotropic rise in FSH secretion

– continued folliculogenesis and evidence of ovulation up to the final menstrual period

– periods of hypoestrogenemia concomitant with large FSH increases

• The loss of inhibin restraint was first hypothesized by these investigators

CharacterizationCharacterizationof the menopausal transition (2) of the menopausal transition (2)

• Extensive and comprehensive longitudinal study of weekly urinary hormone excretion in 308 women aged over 40 years was reported by Metcalf and colleagues (summarized 1988)

• In 178 premenopausal women with regular cycles, cycle length was 26 days (95% CI 21–34) and 98% met criteria for ovulatory cycle

• FSH, LH compared in matching groups of 52 older women, median age 42, and 48 younger women, median age 33. FSH excretion was > 5 IU/24 h in 31.5% of the older group, 19.5% of the younger group

• A lesser, but significant rise in LH was also identified

CharacterizationCharacterizationof the menopausal transition (3)of the menopausal transition (3)

• In 31 women, all of whom had experienced a sudden break in a previously regular succession of menstrual cycles, median cycle length was 29 days with range 18–260 days. Only 52% met the criteria used to identify an ovulatory cycle

• Ovulatory failure occurred in 80% of the 48 cycles > 40 days compared with 20% of shorter cycles

• Ovulatory cycles were seen at all stages during the menopausal transition; in four women, the last cycle before menopause was ovulatory

• There were marked variations in estrogen excretion with both persistently low and persistently raised levels

• The most characteristic feature was the sporadic appearance of persistently high levels of FSH and LH

• High gonadotropin levels were sometimes associated with high estrogen levels

• There was no evidence for a gradual decline in ovarian function during the transition

Metcalf, NZ Med J 1988

Phases associated with the end of Phases associated with the end of reproductive life in normal womenreproductive life in normal women

PremenopauseMenopausal transition

Perimenopause

Postmenopause

Ovariansenescence

Men

op

ause

En

d o

f re

gu

lar

cycl

es

Start of menstrual bleeding

CharacterizationCharacterizationof the early postmenopauseof the early postmenopause

• Eight women were observed before and in the6 months following last menstruation. The postmenopausal period could not be distinguished from the long anovulatory cycles of the menopausal transition1

• Elevated levels of estrogen excretion were observed after the menopause in five of the women

• The authors concluded that an endometrial rather than a hormonal event might determine the time at which menstruation stops during the menopausal transition

1Metcalf, NZ Med J 1988

CharacterizationCharacterizationof the menopausal transition (4)of the menopausal transition (4)

• Metcalf et al. (1981) classified cycles in perimenopausal women by changes in pregnanediol excretion (Classes I–IV) and in gonadotropin excretion (A–E and L)

“The only generalization which can safely be made about menstrual cycles in perimenopausal women is that they are

richly varied. There are long cycles and short cycles which are anovulatory and cycles resembling those in which ovulation is

known to have occurred. Unpredictability is the norm, in marked contrast to the regular succession of ovulatory cycles

observed in premenopausal women”

proportion resembling normal premenopausal cycles

*

Metcalf et al. J Endocrinol 1981

Classification of menstrual cycles on Classification of menstrual cycles on the basis of the premenstrual rise in the basis of the premenstrual rise in

pregnanediol excretionpregnanediol excretionM

ens

tru

al c

ycle

s (%

)

Number of women having cycles of the stated class

23 12 6 18

100

80

60

40

20

0

10

5

0

Pregnanediol (µmol/24 h)

I II III IV

*

Class

FSHLH

Classification of menstrual cycles into Classification of menstrual cycles into categories on the basis of categories on the basis of

gonadotropin excretiongonadotropin excretion

Metcalf et al. J Endocrinol 1981

10

5

0

10

5

0

Go

na

do

tro

pin

exc

reti

on

(IU

/24

h)

A B C

D E L

Other studiesOther studiesof the menopausal transitionof the menopausal transition

• Longitudinal studies of transition have elucidated the underlying endocrinology (e.g. Burger 1995, 1998, 1999, 2000, 2005; Miro 2004, 2005; Landgren 2004; Gracia 2005)

• Mean FSH levels (based on annual single early cycle sampling) begin to rise ca. 2 years before FMP, increase most rapidly 10 months before, plateau 2 years after – values at FMP are 50% of this plateau (Burger 1999)

• Mean estradiol levels start to decrease 2 years before FMP, fall most rapidly around FMP, plateau 2 years after – values at FMP 50% of those before onset of decline (Burger 1999)

• The first endocrine marker seen at the onset of cycle irregularity is a fall in inhibin B (Burger 1998, Gracia 2005)

• Ovulatory cycles can be observed after the onset of the early and the late menopausal transition (Burger 2005)

Geometric mean annual hormone Geometric mean annual hormone levels relative to date of final menseslevels relative to date of final menses

*

Burger HG et al. JCEM 1999

0

10

20

30

40

50

60

-4 -3 -2 -1 0 1 2 3 4 5

Years around menopause

Inh

ibin

A (

ng

/l)

0

10

20

30

40

50

60

Inh

ibin

B (

ng

/l)

0

50

100

150

200

250

300

-4 -3 -2 -1 0 1 2 3 4 5

Est

rad

iol

(pm

ol/

l)

0

20

40

60

80

100

120

FS

H (

IU/l

)

(InhB)(InhA)

41%36%

71%43%

62%57%

80%65%

80%80%

78%78%

94%94%

* Percent of samples with undetectable inhibin

0

30

60

90

0

80

160

240

0

5

10

a a

bb

a

a

b b

a a

b b

0

20

40

60

1 2 3 40

120

240

360

Category

a

b b b

a a

bb

1 2 3 4Category

FS

H (

IU/l

)R

IA (

IU/l

)In

hib

in A

(n

g/l

)

Est

rad

iol

(pm

ol/

l)In

hib

in B

(n

g/l

)

Burger et al. 1998

1 = Pre meno = STRAW -32 = Early peri = STRAW -23 = Late peri = STRAW -14 = Early post = STRAW +1

Reproductive hormone levels and Reproductive hormone levels and menstrual cycle categoriesmenstrual cycle categories

AndrogensAndrogensin the menopausal transitionin the menopausal transition

• In normal women, there is a 50% decrease in circulating concentrations of testosterone and dehydroepiandrosterone sulfate (DHEAS) from age 20 to age 451,2

• There is little if any decline in testosterone during the transition2,3

• DHEAS levels continue to fall with age, with no specific association with the transition

• The medical ‘myth’ that menopause is associated with an acute drop in androgens does not appear to be tenable any longer

1Zumoff 1995, 2Davison 2005; 3Burger 2000

Burger HG et al. JCEM 2000

Serum testosteroneSerum testosteroneand menopausal transitionand menopausal transition

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Time relative to FMP (years)

Tes

tost

ero

ne

(nm

ol/

l)

-6 -4 -2 0 2 4 6 8

Other endocrine featuresOther endocrine features

• Loss of LH response to an estradiol challenge in the perimenopause1,2

• Predominant circulating estrogen in reproductive life is estradiol, secreted by the ovary; postmenopausally it is estrone, produced by peripheral androgen aromatization3

• Anti-Müllerian hormone (also called Müllerian inhibiting substance), a member of the TGF super family and a product of preantral and small antral follicles, is under investigation as a marker for the size of the ovarian follicle pool4 and a promising predictor for the occurrence of the transition5

1Van Look 1977; 2Weiss 2004; 3Maroulis 1976; 4Visser 2006; 5van Rooij 2004