MENOPAUSE AND HRT

Physiology and Morphological changes in the ovary with ageing

endocrinology The major functional unit of the ovary is the ovarian follicle, the
most mature form of which is the Graffian follicle with its oocyte,

of the menopause antrum, lining granulosa cells and surrounding theca (Figure 1).
In each menstrual cycle, about 30 follicles are recruited, of which
normally only one becomes the dominant follicle from which ovu-
Henry G Burger lation occurs. All follicles ultimately develop from the population
of primordial follicles. Granulosa cells are the primary secretory
unit for the steroid and peptide hormones of the ovary, though the
theca is the important source of ovarian androgens.
Numbers of primordial follicles are maximal during fetal life
The menopause is defined as the permanent cessation of menstrua- and decline steadily with increasing age (Figure 2).3 There is an
tion that results from loss of ovarian follicular activity. Clinically, in apparent acceleration in the rate of decline at about age 38 years,
women in their 40s or 50s, it is recognized to have occurred after and by the time of the menopause few if any primordial follicles
twelve consecutive months of amenorrhoea for which no other remain. With the disappearance of follicles, the source of ovarian
obvious pathological or physiological cause can be found. In most estrogens and inhibins is lost. However, secretion of androgens
women, the menopause is preceded by a period of an average dura- (particularly testosterone) continues and is not significantly altered
tion of about 4 years during which the endocrine, biological and by the occurrence of the menopause.
clinical features of changing ovarian function begin. A common
feature is the development of cycle irregularity in women with a
The normal pituitary–ovarian axis
previous history of regular menses. This marks the onset of the
menopausal transition (perimenopause). Under the control of hypothalamic gonadotrophin-releasing
The Stages of Reproductive Aging Workshop (STRAW) proposed hormone, the normal pituitary secretes FSH and luteinizing
a system that divides female reproductive ageing into five stages hormone (LH) in a cyclical pattern, characterized particularly by
before the final menstrual period, and two afterwards.1 an early follicular phase rise in FSH, a mid-cycle peak of both
• Three stages (early (–5), peak (–4) and late (–3) reproductive) gonadotrophins, and relatively low levels of both during the luteal
describe the years before the perimenopause. Stage –3 is charac- phase. Follicular-phase FSH drives ovarian production of estradiol,
terized by regular cycles but elevated levels of follicle-stimulating increasing levels of which in the late follicular phase trigger the
hormone (FSH) in the follicular phase. mid-cycle LH surge. After ovulation, the granulosa cells of the
• Stage –2 (the early menopause transition) is characterized by dominant follicle are luteinized to form the corpus luteum, which
variable cycle length. is the source of progesterone. Granulosa cells are also the source
• Stage –1 (late transition) is characterized by two or more of the ovarian inhibins A and B.
stopped cycles and 60 or more days of amenorrhoea. • In the follicular phase of the cycle, inhibin A is a product of the
• Stage +1 is the first 5 years after the final menstrual period. dominant follicle. Its levels are highest mid-cycle, and concentra-
• Stage +2 is the late postmenopause. tions are also high during the luteal phase, when it is produced
The menopause is a universal phenomenon in women who by the corpus luteum.
live beyond the age of 50–55 years. With current life expectan-
cies, women in most societies can expect to live one-third of their
lives after the event. In 1990, it was estimated that there were
almost 500 million women aged 50 years or over worldwide, and
this number is expected to increase to 1.2 billion by 2030. By that
ThC
time, 76% will be living in developing countries. About 50 million
women worldwide reach the menopause each year.2
A major consequence of the menopause is loss of bone and
potential development of osteoporosis with fracture. Whether GC
atherosclerotic cardiovascular disease and Alzheimer’s demen-
tia are other consequences of the endocrine changes remains
controversial.
O

1 Structure of a small
antral follicle. The oocyte
(O) is surrounded by
Henry G Burger is Emeritus Director of Prince Henry’s Institute of Medical granulosa cells (GC).
Research at Monash Medical Centre, Clayton, Australia. His research Theca cells (ThC) lie
interests include the physiology and pathophysiology of the inhibins. outside the follicular
Conflicts of interest: none declared. basement membrane.

MEDICINE 34:1 27 © 2006 Elsevier Ltd

 MENOPAUSE AND HRT

The pituitary–ovarian axis is an example of a classical closed-

Number of ovarian follicles decreases with age
loop endocrine feedback system in which pituitary gonadotrophin
secretion is under negative feedback control by ovarian steroids
and inhibins. The steroids exert negative feedback effects on
both FSH and LH (except mid-cycle), whereas the inhibins
100,000
(particularly inhibin B) specifically inhibit FSH production. The
endocrinology of the menopause can be summarized as a series
10,000
of phenomena that results in replacement of the cyclical secretory
Primordial follicles/ovary

pattern of gonadotrophins and gonadal steroids and peptides by

a monophasic pattern of elevated gonadotrophins and low levels
1000 of estrogens, progesterone and inhibins (Figure 3).
The most important hormone in menopausal endocrinology
is estradiol, which has multiple target tissues including the
100
brain, breasts, bone, cardiovascular system, liver, uterus and
vagina.
10

Changes in reproductive endocrinology with ageing

1
Levels of serum FSH during the follicular phase increase
progressively with age in women who continue to have regular
0
cycles, particularly in those over the age of 40–45 years (STRAW
0 10 20 30 40 50 60 stage –3). 5 During that time, levels of circulating estradiol
Age (years) increase slightly, if anything, as do levels of inhibin A. The con-
centration of inhibin B changes little until the age of 40 years,
Perimenopausal women Postmenopausal women when there is a decline that is inversely correlated with the
increasing FSH.
2 Recent research indicates that inhibin B, particularly, is
the major regulator of follicular-phase FSH levels in normally
cycling women.6 Thus, reproductive ageing after 40 years is
• Inhibin B is a product of the granulosa cells of the cohort of marked by a relatively rapid reduction in the number of primordial
antral follicles from which the dominant follicle is derived. Its follicles and a consequent decrease in inhibin B secretion, with an
levels are highest in the early follicular phase; after a mid-cycle increase in FSH that can maintain or increase estradiol and inhibin
peak, it decreases throughout the luteal phase.4 A secretion until follicular exhaustion occurs.

Endocrine features of the menstrual cycle and postmenopause

Premenopause Postmenopause

Follicle-stimulating hormone
Luteinizing hormone

7 14 21 7 14 21
Day Day

Estradiol
Estrone
Progesterone

7 14 21 7 14 21
Day Day
3

MEDICINE 34:1 28 © 2006 Elsevier Ltd

 MENOPAUSE AND HRT

Follicle-stimulating hormone, luteinizing hormone, estradiol and total inhibin levels in the first long cycle of the
menopausal transition
Note the fluctuating hormonal levels
40 1600
Follicle-stimulating hormone

Follicle-stimulating hormone Estradiol

Estradiol (pmol/litre)
Luteinizing hormone

30 1200
Luteinizing hormone Inhibin
(IU/litre)

20 800 400

Inhibin (U/litre)
300

10 400 200

100

0 0 0
10 20 30 40 50 60 70 80 90 10 20 30 10 20 10 20 10 20 30 40 50 60 70 80 90 10 20 30 10 20 10 20
Day Day
99 days 31 days 27 days 27 days 99 days 31 days 27 days 27 days

Oophorectomy results in a decrease of about 50% in circulating

Hormonal changes in the menopausal transition
testosterone concentrations, indicating that the ovary contributes
FSH, estradiol and the inhibins about 50% of circulating testosterone.
Because menstrual irregularity begins before the cessation of The other major androgen is dehydroepiandrosterone sulphate
menses, an early change is a profound decrease in the levels of (DHEAS), which is primarily a product of the adrenal cortex. Serum
early follicular-phase inhibin B (STRAW stage –2).7 FSH levels DHEAS levels decrease progressively and slowly with age and are
begin to increase further, and women whose menses occur at not related specifically to the menopausal transition.
intervals of more than 3 months (late perimenopause, approxi-
mately equivalent to STRAW stage –1) exhibit increased FSH, with
The postmenopausal phase
a substantial decrease in circulating estradiol and the inhibins.
It is estimated that, at the time of the final menses, FSH levels The postmenopausal state (STRAW stages +1 and +2) is charac-
have reached about 50% of their final postmenopausal concentra- terized by elevated FSH and LH, low estradiol and progesterone,
tions, which are 10–15-fold higher than those found in the follicular and well-preserved levels of testosterone. DHEAS decreases
phase of reproductive-age women.8 Estradiol levels are about 50% progressively.
of those seen in the follicular phase during reproductive life, and The major circulating estrogen at this time is estrone, which
continue to decline after the final menses to reach their nadir is derived principally from the conversion of adrenally secreted
2–3 years later. By this time, estradiol levels have decreased by androstenedione, via aromatase situated predominantly in adipose
90% or more.
The menopausal transition is a time of marked hormonal
instability. Repetitive sampling in an individual woman may show
various patterns, with high or low FSH, estradiol and inhibin Geometric mean levels of follicle-stimulating
(Figure 4).5 In a population of women, the major changes around hormone and estradiol around the time of the final
the final menses are a progressive increase in FSH and a progres-
menses
sive decrease in estradiol (Figure 5).
300 120
Follicle-stimulating hormone (IU/litre)

Changes in progesterone and androgens 250 100

The frequency of anovulatory cycles is increased throughout the Follicle-stimulating
Estradiol (pmol/litre)

menopausal transition, though there is wide variation between 200 hormone 80

women. Repetitive measurements of progesterone show progres-
sively fewer concentrations indicative of normal ovulation. 150 60
Changes in circulating androgens are controversial. Recent
data indicate that serum testosterone concentrations decrease 100 40
by about 50% between the ages of 20 years and 40 years.9 When
studied longitudinally throughout the menopausal transition and 50 Estradiol 20
early postmenopausal period, total serum testosterone concentra-
tions show no change and serum sex hormone-binding globulin 0 0

(SHBG) levels decrease. As a result, free androgen levels increase –4 –3 –2 –1 0 1 2 3 4 5

during the menopausal transition.10 It can therefore be said that the Years around menopause
postmenopausal ovary is primarily an androgen-secreting organ,
the testosterone being derived from the ovarian interstitial cells. 5

MEDICINE 34:1 29 © 2006 Elsevier Ltd

 MENOPAUSE AND HRT

tissue. Estrone levels are higher in obese women, who have more 3 Richardson S J, Senikas V, Nelson J F. Follicular depletion during the
adipose tissue than lean women; this may explain why obese menopausal transition: evidence for accelerated loss and ultimate
women are at greater risk of estrogen-related malignancies such exhaustion. J Clin Endocrinol Metab 1987; 65: 1231–7.
as breast and endometrial cancer. 4 Groome N P, Illingworth P J, O’Brien M et al. Measurement of dimeric
There is evidence that testosterone may increase further with INH-B throughout the human menstrual cycle. J Clin Endocrinol Metab
advancing age. The elevated gonadotrophins may provide an 1996; 81: 1401–5.
important drive to continued androgen secretion by the ovary, and 5 Lee S J, Lenton E A, Sexton L et al. The effect of age on the cyclical
administration of exogenous estrogen results in gonadotrophin patterns of plasma LH, FSH and estradiol and progesterone in women
suppression and consequent suppression of testosterone secretion. with regular menstrual cycles. Hum Reprod 1988; 3: 851–5.
Because oral exogenous estrogens also raise SHBG concentrations, 6 Burger H G, Dudley E, Mamers P et al. Early follicular phase serum
circulating concentrations of free testosterone may decrease pro- FSH as a function of age: the roles of inhibin B, inhibin A and
foundly in women treated with oral hormone therapy. estradiol. Climacteric 2000; 3: 17–24.
7 Burger H G, Cahir N, Robertson D M et al. Serum inhibins A and B fall
differentially as FSH rises in perimenopausal women. Clin Endocrinol
Clinical consequences of changes in hormones at and around
(Oxf) 1998; 48: 809–13.
the menopause
8 Burger H G, Dudley E C, Hopper J L et al. Prospectively measured
Menopausal symptoms – the most common symptoms of the levels of serum FSH, estradiol and the dimeric inhibins during the
menopause include hot flushes, night sweats, vaginal dryness and menopausal transition in a population-based cohort of women. J Clin
dyspareunia. These symptoms result from withdrawal of circulating Endocrinol Metab 1999; 84: 4025–30.
estradiol from target tissues in the brain and the vagina, and can 9 Zumoff B, Strain G W, Miller L K et al. Twenty-four hour mean
be reversed by administration of estrogen. plasma testosterone concentration declines with age in normal
The hot flush is particularly characteristic of the late peri- premenopausal women. J Clin Endocrinol Metab 1995; 80: 1429–30.
menopause and early postmenopause. It comprises a short-lived 10 Burger H G, Dudley E C, Cui J et al. A prospective longitudinal study
(3–5 minutes) sensation of heat in the upper body, face and neck, of serum testosterone dehydroepiandrosterone sulphate and sex
often with sweating, and is accompanied by increases in heart rate, hormone binding globulin levels through the menopause transition.
peripheral blood flow and skin temperature. The precise cause is J Clin Endocrinol Metab 2000; 85: 2832–938.
unclear. 11 Dennerstein L, Dudley E C, Hopper J L et al. A prospective
Loss of mastalgia, which is a common symptom, is also charac- population-based study of menopausal symptoms. Obstet Gynaecol
teristic of achievement of the menopause, and this, and the pres- 2000; 96: 351–8.
ence of hot flushes and vaginal dryness, are the only symptoms 12 Do K A, Green A, Guthrie J R et al. Longitudinal study of risk factors
that could be statistically specifically related to the occurrence of for coronary heart disease across the menopausal transition. Am J
the menopause in a recently published longitudinal study.11 Epidemiol 2000; 51: 584–93.
Bone loss – an important consequence of the decline in estradiol
is an increase in the rate of bone loss, which occurs particularly
during the late perimenopause and the first months after the
menopause.
Cardiovascular risk – on the basis of cross-sectional studies of
menopausal women, it has been classically taught that the meno-
pause is associated with adverse changes in cardiovascular risk
factors. Recent longitudinal studies have cast doubt on the validity
of this observation, however, suggesting that the only risk factor
that changes (to a very small degree) around the menopause is the
circulating concentration of high-density lipoprotein cholesterol.12
Previously reported changes in total cholesterol and low-density
lipoprotein cholesterol may be the result of ageing rather than a
specific effect of the menopause.
Epidemiological studies do not show any clear-cut relationship Practice points
between the occurrence of the menopause and an increased inci-
dence of cardiovascular events (e.g. myocardial infarction), which • The menopausal transition is a time of marked hormone
might be expected if the menopause is a specific factor contributing instability; thus, hormonal measurements at a single point in
to cardiovascular risk. However, it must be emphasized that this time are of little diagnostic value
is a highly controversial area.  • Recent studies have indicated a central role for ovarian
inhibin B in the endocrine changes of the menopause
• At the time of the final menses, FSH and estradiol have
REFERENCES reached about 50% of their final levels postmenopausally
1 Soules M R, Sherman S, Parrott E et al. Executive summary: Stages of • Free androgen levels increase during the menopausal
Reproductive Aging Workshop (STRAW). Fertil Steril 2001; 76: 874–8. transition
2 WHO. Report of a WHO scientific group. Research on the menopause
in the 1990s. WHO Tech Rep Ser 1996; 866.

MEDICINE 34:1 30 © 2006 Elsevier Ltd