Information for Women: MENOPAUSE, PERIMENOPAUSE AND POSTMENOPAUSE


Information for Women



MENOPAUSE, PERIMENOPAUSE AND POSTMENOPAUSE


DEFINITIONS, TERMS AND CONCEPTS.


Prof. Peter Kenemans


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 false-negative.


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 ageing 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 transcient climacteric effects is minimal, for others the impact is severe. Climacteric and perimenopausal
women should not be regarded as a homogeneous group.


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 countinuing 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).


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 sé, 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 hyper- gonadotrophic
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, transcient 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 progesteron 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 androgen-associated 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



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 38 yrs of age total depletion of follicles
ovarian cycles ovulatory increasingly anovulatory with luteal phase defects anovulatory
menstrual periods 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
hypogonado-tropic, hypo-oestrogenic 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; professional career "empty nest" situation; midlife crisis re-orientation; re-integration



Table II – Factors associated with early onset of menopause



    1. Genetic factors – e.g. micro deletions X-chromosome, mosaic 45X0/46XX

    – e.g. mutation in FSH receptor gene


    2. Viral factors – e.g. mumps


    3. Iatrogenic factors- surgery (e.g. oophorectomy, hysterectomy)

    – chemotherapy (e.g. for breast cancer, lymphoma)

    – radiotherapy (e.g. for cervix cancer, morbus Hodgkin)


    4. Life style factors – e.g. cigarette smoking, vegetarian diet

    5. Other factors – e.g. autoimmune diseases (myastenia gravis)

    – e.g. low body weight