Menopause.

For a woman, the reproductive period is demarcated by two main events: the menarche
and the menopause. Traditionally, menopause has been defined as the point in time of the
last menstrual bleeding in a woman's life. In most industrialized countries, natural
menopause occurs on average around the age of 51, but there is a large variation in age at
natural menopause (mean age: 51 yrs; range: 39 - 59 yrs).
Menopause and last ovulatory bleeding are not identical in many cases. Although a
menopause age of 57 and over is regularly reported, the age of the oldest woman
becoming pregnant in a natural way ever reported was 56 years (Guiness Book of
Records).
By definition, menopause occurring before the age of 40 is called precocious or
premature menopause. Today, the term premature ovarian failure (POF) is also used. The
incidence of premature menopause is approximately 1%.
Typically, the date of menopause is established in retrospect, following a full year of
amenorrhea. In a woman around 50 years of age, periods of secondary amenorrhea
shorter than 12 months do not guarantee that menopause has been passed.
Although the "one year amenorrhea"-criterium seems primitive, all other methods of
diagnosing menopause earlier are less accurate. It should be remembered that elevated
FSH and LH levels and severe vasomotor symptoms can be present long before
menopause is reached, while even ovarian biopsies without follicles can be falsenegative.
In some instances it can be difficult to establish the moment of menopause accurately, for
instance after hysterectomy or in case of OC use.
Postmenopause.
The postmenopause is the period of life after the menopause. Increasingly, the term
menopause is used in a different sense to its original meaning. The term menopause then
refers to the total postmenopausal period and thus is synonymous to the term
postmenopause. The World Health Organization defines menopause as the permanent
cessation of menstruation resulting from the loss of ovarian follicular activity.
Early menopause is a term sometimes used to denote the first few years directly after
menopause, in which still considerable, endogenous oestradiol activity can be present.
Late menopause is the period thereafter.
The perimenopause.
The perimenopause can be defined as the period of time around the menopause in which
marked menstrual cycle changes occur, often in conjunction with vasomotor symptoms
and in which no period of 12 consecutive months of amenorrhea has yet occurred. The
median length of the perimenopause is 4 to 5 years (range: 1 - 9 yrs).

The climacteric.
The term climacteric refers to the period of menopausal transition. During this period,
many profound changes take place in a woman's life (Table 1). Many, but not all, are
directly related to the aging process of the ovaries. Body changes and mood swings are
intermingled with changes in family and social environment. All these factors together
can have a profound influence on the psycho-social functioning and general well-being of
the climacteric woman.
There is great variability in climacteric complaints and symptoms, both between cultures
as well as between individuals within a culture. In our Western society, for many women
the menopausal experience with transient climacteric effects is minimal, for others the
impact is severe. Climacteric and perimenopausal women should not be regarded as a
homogeneous group.
Table I: The climacteric: the period of transition from fertility to sterility
transition from via

to

reproductive
capacity

fertility

subfertility

sterility

ovarian
folliculogenesis

regular
recruitment and
maturation

accelerated loss of follicles after total depletion of

38 yrs of age
follicles

ovarian cycles

ovulatory

increasingly anovulatory with

luteal phase defects

anovulatory

regular periods

initial shortening of the cycle,

thereafter longer irregulary
cycles

amenorrhea

hormonal profile

ovulatory cycle
profile

increase in early follicular FSH;

often low progesterone levels in
second half; decreasing inhibin;
LH, E2 and androgen levels stay
long stable

hypogonadotropic, hypooestrogenic status

with low androgen
levels and
undetectable
inhibin

needs,
complaints and
risks

contraception
needs

contraception needs and

climacteric complaints

increased risk of
osteoporosis and
cardiovascular
disease

family life

active family life;

"empty nest" situation; midlife
professional
crisis
career

menstrual
periods

re-orientation; reintegration

PHYSIOLOGY OF CLIMACTERIC AND POSTMENOPAUSE

Ovarian physiology.
The onset of menopause is determined by the ovary. All other functional body changes
are secondary to this change in ovarian function. This includes also changes in
hypothalamic and uterine functioning.
The primary event is the loss of the capacity of the ovary to sustain the process of
ovulation as a direct consequence of the (nearly complete) loss of ovarian follicles. It has
been estimated that in the ovaries a minimum of around 1000 follicles has to be present,
for ovulation still to occur. Natural menopause occurs when this stage of near depletion
of oocytes and follicles is reached.
Normally, at birth, a few million primordial follicles are present, each containing an
oocyte. After the time of menarche, around 250,000 follicles are still present in the
ovaries. During the fertile period, there is continuing loss of follicles, of which only a
maximum of about 500 will reach the stage of a Graafian follicle and then disappear by
ovulation. All other follicles, including the non-growing primordial follicles as well as
those in which growth has been initiated, disappear spontaneously, probably via a process
of apoptosis and atresia, which is only partly understood.
After the age of approximately 38 years, the disappearance of follicles becomes even
more accelerated. Additionally, further increased loss of follicles can also be the result of
damage to the ovary through surgery, radiation, chemotherapy, a virus or other factors
such as smoking (Table II).
Table II: Factors associated with early onset of menopause
Genetic factors

- e.g. micro deletions X-chromosome, mosaic 45X0/46XX

- e.g. mutation in FSH receptor gene

Viral factors

- e.g. mumps

- surgery (e.g. oophorectomy, hysterectomy)

Iatrogenic factors - chemotherapy (e.g. for breast cancer , lymphoma)
- radiotherapy (e.g. for cervix cancer, morbus Hodgkin)
Life style factors

- e.g. cigarette smoking, vegetarian diet

Other factors

- e.g. autoimmune diseases (myastenia gravis)

- e.g. low body weight

Idiopathic premature menopause will be increasingly shown to be, at least in part,

genetic in origin. Both X chromosome micro-deletions as well as auto-chromosomal
abnormalities can be a cause.
Surgery, not only surgical castration per s, can bring down the age of menopause
substantially. Early removal of one ovary or a substantial part of a functional ovary (e.g.

by a large wedge resection) can provoke menopause by reducing the actual amount of
follicles still present.
Hysterectomy with uni- or bilateral conservation of the ovary can also advance
menopause, possibly through disturbance of the ovarian circulation.
Radiation therapy in the pelvic area (in particular in women with cervical cancer or
Hodgkin's disease) can lead to irreversible damage to the ovary resulting in permanent
amenorrhea, especially in older premenopausal women who have a limited follicular
reserve.
Chemotherapy may do the same, however the possibility of a temporary hypergonadotrophic amenorrhea (during treatment and months or years thereafter, but with a
full recovery of the ovulatory cycle) is also frequently seen, especially where cytotoxic
drugs damage the theca and granulosa cells, and not primarily the oocytes.
Viral infections (e.g. mumps) and other exotoxins might impair follicular function.
Cigarette smoking can accelerate follicular loss. Heavy smokers reach menopause
significantly earlier than non-smokers, on average 1 to 2 years earlier.
Premature menopause, on the basis of premature permanent ovarian failure, with a fair
amount of follicles still present has also been described. These irresponsive follicles (the
'resistant ovary syndrome') can be found in various conditions such as auto-immune
diseases (e.g. Myastenia gravis) and genetic mutations affecting the FSH receptor and its
function.
Ovarian failure, secondary to conditions such as diabetes mellitus, thyroid disease and
anorexia nervosa is, in principle, transient and ovarian function will be restored by
treatment directed to the underlying disease. Therefore, these conditions do not belong to
the POF syndrome. Race, socioeconomic status, age of menarche and prior use of oral
contraceptives are all factors not affecting age of menopause. Increased parity may be
associated with a later onset of the menopause.
Ovarian function and perimenopausal cycle changes.
The last ovulation is a milestone event, heralding a new phase in a woman's life.
Generally, this final ovulation is the end result of a long process over many years of
gradual changes in reproductive and endocrine functions of the ovaries, resulting long
before menopause in anovulatory cycles, menstrual disorders and subfertility. From the
mid-thirties, the duration of the menstrual cycle gradually and continuously declines up
to approximately 4 to 6 years before menopause. Then many women start to notice
changes in their menstrual cycle, sometimes accompanied by night sweats, hot flushes
and vaginal dryness, all long before the actual moment of menopause.
Generally, the ovulatory cycle remains intact until the mid-forties, with 17b-oestradiol
and progesterone secretion unchanged, however, with a gradual increase of FSH levels.
Thereafter, cycles may get longer due to disturbed folliculogenesis and impaired corpus

luteum function, causing very low luteal phase progesteron serum levels and periods
characterized by irregular bleeding.
In the last 5 years before menopause, in three-quarters of all women, mean cycle length
gradually increases from 28 days (range 26 - 32 days) to 60 days (range 35 - >100 days).
Individual hormone levels may fluctuate and can be highly variable between cycles in
this climacteric period. Where an increasing frequency of low luteal progesterone levels
can be seen during the climacteric years, oestradiol tends to stay within the normal fertile
range (400 - 600 pmol/L), but may fluctuate considerably over time, decreasing sharply
in the few months directly before and after the moment of menopause, to reach levels
below 200 pmol/L at one year after menopause. Although oestradiol levels will decline
further with increasing menopausal age, detectable levels of circulating oestradiol will be
present long after natural (and also after surgical) menopause.
Postmenopausally, non-ovarian tissues like fat, liver and kidney, produce small amounts
of oestrogens by peripheral conversion of androgens. Obese postmenopausal women
have higher circulating oestradiol levels therefore, with less oestrogen bound to the rather
low SHBG concentrations found in adipose women.
After natural menopause, oestrone may rise. The secretion of androgen by the ovary is
reduced, resulting in a decline of peripheral androgen levels by 20 - 40 percent. After
menopause, an increased androgen to oestrogen ratio can be related to an androgenassociated facial hair pattern and a deepening of the voice that can be seen in some
postmenopausal women.
The hypothalamic-pituitary-ovarian axis.
From the mid-thirties on, for many years, a diminishing ovarian potential for normal
folliculogenesis is counterbalanced by a growing hypothalamic-pituitary stimulation, as is
evident from early follicular phase FSH levels (cycle day 3 FSH), that start to rise
typically 10 years before the menopause. Finally, although FSH (essential for maturation
and survival of the follicle after the pre-antal stage) and LH (important for ovulation,
corpus luteum development and steroidogenesis) reach high serum levels, ovarian follicle
stimulation becomes ineffective.
In the perimenopausal period, the ovaries become also progressively less responsive to
exogenous gonadotrophins. At the time of menopause, the small population of follicles
still present has been shown to be refractory to stimulation with exogenous
gonadotrophins as well.
Partially independent from GnRH control, secretion of FSH is influenced by various
substances of which oestradiol and inhibin are the most important. Both these substances
are products of the ovarian granulosa cells and both suppress the pituitary secretion of
FSH, each in its own way. As LH serum levels remain remarkably unchanged during the
climacteric, it can be hypothesized that increasing serum FSH levels result from
decreasing serum inhibin levels that follow the decline in a number of ovarian follicles.

Concluding remarks
Menopause results from the definite cessation of ovarian function. In the years around
this final ovulation, the climacteric and early postmenopausal years, typical symptoms
can be present, such as flushes and vaginal dryness, that reflect the process of gradual
transition from fertility via subfertility to sterility.
The late menopause is a state of hypergonadotrophic hypo-estrogenism, which is
associated with an increase in osteoporotic fractures and coronary heart disease.
Supplementation of oestrogens will prevent these diseases (and possibly some other
diseases as well, such as Alzheimer's disease), but might induce breast cancer.
References
Burger HG, EC Dudley, JL Hopper et al. The endocrinology of the menopausal transition:
a cross-sectional study of a population-based sample.J Clin Endocrinol Metab
1995;80:3537-3545.
Faddy MJ, RG Gosden. A mathematical model of follicle dynamics in the human ovary.
Human Reprod 1995;10:770-775.
Kenemans P, R Barentsen, PHM van de Weijer.Practical HRT (second edition). Medical
Forum International, Zeist, The Netherlands, ISBN 90-5698-008-4, 1996, 215 pp.
Rannevik G, S Jeppsson, O Johnell et al. A longitudinal study of the perimenopausal
transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral
density. Maturitas 1995;21:103-113.
Treloar AE. Menstrual cyclicity and the premenopause. Maturitas 1981;3:249-264.
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