American J Hum Biol - 2001 - O Connor - Menstrual Cycle Variability and The Perimenopause

AMERICAN JOURNAL OF HUMAN BIOLOGY 13:465–478 (2001)
Menstrual Cycle Variability and the Perimenopause

KATHLEEN A. O’CONNOR,1,3* DARRYL J. HOLMAN,1,3 AND JAMES W. WOOD2,3
1
Department of Anthropology, Center for Studies of Demography and Ecology, University of
Washington, Seattle, Washington
2
Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania
3
Population Research Institute, Pennsylvania State University, University Park, Pennsylvania
ABSTRACT Menopause, the final cessation of menstrual cycling, occurs when the pool of ovarian
follicles is depleted. The one to five years just prior to the menopause are usually marked by increas-
ing variability in menstrual cycle length, frequency of ovulation, and levels of reproductive hormones.
Little is known about the mechanisms that account for these characteristics of ovarian cycles as the
menopause approaches. Some evidence suggests that the dwindling pool of follicles itself is respon-
sible for cycle characteristics during the perimenopausal transition. Another hypothesis is that the
increased variability reflects “slippage” of the hypothalamus, which loses the ability to regulate
menstrual cycles at older reproductive ages. This paper examines the underlying cause of the increas-
ing variability in menstrual cycle length prior to the menopause. A model of ovarian cycles is devel-
oped, based on the process of follicular growth and depletion. Under this model, the follicular phase
of each menstrual cycle is preceded by an inactive phase, a period of time when no ovarian follicles
have left the resting state and begun secreting steroids in response to gonadotropin stimulation. The
model makes predictions about the variability in menstrual cycles across the reproductive life span
based on the size of the surviving pool of ovarian follicles. We show that the model can explain several
characteristics of the perimenopause in humans and macaques and illustrate how the model can be
applied to research on the biological and cultural correlates of the timing of menopause. J. Hum. Biol.
13:465–478, 2001. © 2001 Wiley-Liss, Inc.
Across most of a woman’s reproductive al., 1996; Wise 1999). The pervasive obser-
life span, menstrual cycles exhibit relatively vation of elevated levels of FSH in women at
little variability in length around a median older reproductive ages is cited as support
of 28 days (Treloar et al., 1967). Beginning for this hypothesis, although the mecha-
from one to five years before menopause nism(s) contributing to elevated FSH or hy-
(the perimenopause), menstrual cycle pothalamic faltering are unspecified (Met-
length becomes increasingly variable. In calf et al., 1982; MacNaughton et al., 1992;
particular, this time period is characterized Klein et al., 1996; Santoro et al., 1996).
by a higher frequency of long cycles (Fig. 1). An alternative hypothesis suggests that
Additionally, a higher proportion of men- the increasing variability in menstrual cycle
strual cycles are anovulatory (Metcalf, length is almost entirely a result of the di-
1983), and hormone levels become increas- minished number of ovarian follicles re-
ingly variable (Burger, 1996). Menopause it- maining in the ovary in the years preceding
self is the complete and irreversible cessa- the menopause (Richardson et al., 1987).
tion of ovarian cycling. We have proposed a mechanism and model
The mechanism responsible for meno- for this hypothesis (O’Connor et al., 1998).
pause has long been recognized to be ex- The current paper presents the theoretical
haustion or near exhaustion of the pool of details and implications of the model, with a
ovarian follicles (Richardson et al., 1987; focus on how it can account for many of the
Gougeon et al., 1994; vom Saal et al., 1994). observed changes in menstrual cycle char-
Less is known about the mechanisms re- acteristics across the perimenopause and
sponsible for the increasingly variable na-
ture of menstrual cycles across the peri-
menopausal transition. At least two major Contract grant sponsor: NIA; Contract grant numbers: 1 RO1
AG15141, 5 T32 AG00208; Contract grant sponsor: NICHD;
ideas have been proposed. One hypothesis is Contract grant numbers: F32 HD 07994, 2 P30 HD28263.
that increasingly variable cycles across the *Correspondence to: Kathleen A. O’Connor, Department of
perimenopausal transition result from a Anthropology, University of Washington, Box 353100, Seattle,
WA 98195. E-mail: [email protected]
breakdown in the signaling between the Received 12 May 2000; Revision received 8 September 2000;
ovary and the hypothalamus (e.g., Wise et Accepted 2 February 2001
© 2001 Wiley-Liss, Inc.
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466 K.A. O’CONNOR ET AL.
Fig. 1. Variation (by percentiles) in menstrual cycle length by age and perimenopausal status. Data are from a
long-term prospective study of American women. Redrawn from Treloar et al. (1967:90).
into the menopause. Under this model the rounded by a layer of granulosa cells, called
increased proportion of long menstrual a follicle, as the ovaries form (Gougeon,
cycles during the perimenopause are a di- 1996). The follicle is the structure that
rect result of periods of ovarian inactivity houses and nourishes the oocyte, and it is
that increase in length as the pool of ovarian the follicle that receives and sends hor-
follicles diminishes. These so-called “inac- monal signals to the other parts of the re-
tive” phases of the menstrual cycle have a productive axis to maintain regular ovarian
distinct endocrine signature, and we pro- cycles.
vide evidence of inactive phases from endo- Since this pool of ovarian follicles and oo-
crine studies in humans and macaques. cytes is non-replenishable, the maximum
number of ovarian follicles peaks in utero at
FOLLICULAR DEVELOPMENT about 7 million (Austin and Short, 1982).
AND DEPLETION From this point on, the pool of follicles is
The story of menopause begins with depleted through a process called follicular
events occurring in utero. Early during em- atresia (Fig. 2). By the time of birth, the pool
bryonic development of the female, a life- of follicles has depleted to roughly one half
time stock of primary oocytes is formed at million per ovary (Block, 1953). By menar-
the gonadal ridge by rounds of mitosis from che, the pool has been reduced to about
a pool of oogonia. Each oocyte then under- 100,000 follicles per ovary. The perimeno-
goes meiosis I through prophase. The final pausal transition, which may last up to five
pool of oocytes is formed by the second tri- or six years, begins when approximately 100
mester of pregnancy, and each oocyte is sur- to 1,000 follicles are left in each ovary (Ri-
CYCLE VARIABILITY AND THE PERIMENOPAUSE 467
(Hsueh et al., 1994; Kaipia and Hsueh,

1997). The few exceptions are those follicles
that continue to grow and become the dom-
inant follicle during a menstrual cycle.
These follicles are the ones that secrete ste-
roid hormones and participate in ovulation
and in luteinization after ovulation.
HYPOTHALAMIC–PITUITARY–
OVARIAN AXIS
The ovarian follicles communicate and
work in conjunction with the hypothalamus
and pituitary to maintain regular ovarian
cycles. The GnRH pulse generator, a neural
complex located in the hypothalamus, con-
trols pulsatile secretion of gonadotropin-
Fig. 2. Surviving numbers of follicles in women by releasing hormone (GnRH) by hypothalamic
age, based on counts of follicles in ovaries removed in neurons. GnRH, in turn, is carried to the
autopsies and oophorectomies. Data are from Block anterior lobe of the pituitary gland by the
(1952, 1953) and Gougeon et al. (1994).
portal capillary system, where it stimulates
secretion of luteinizing hormone (LH) and
chardson et al., 1987; Gougeon, 1996). follicle stimulating hormone (FSH). These
Menopause itself is the ultimate exhaustion hormones stimulate follicular growth and
of the follicle stock. development and are necessary for initiat-
Mathematically, this can be expressed as ing and maintaining follicular production of
an exponential (or log–linear) decline in the the ovarian steroids estradiol and proges-
numbers of surviving follicles with age (Fig. terone. Feedback relationships between the
2). This same pattern of exponential deple- ovarian steroids, on the one hand, and the
tion of follicles throughout life is found in hypothalamic and pituitary gonadotropins,
other primates and mammals (Austin and on the other, maintain the highly regular
Short, 1982; Miller et al., 1999). Data from pattern of ovarian cycles in the adult fe-
autopsy and oophorectomy sources are sug- male.
gestive of an increase in the rate of follicular The four main hormones involved in these
depletion in the years prior to menopause in feedback relationships, and how they
women (Faddy and Gosden, 1995), although change across the menstrual cycle are
the mechanism responsible for this accel- shown in the upper two panels of Figure 3.
eration is unclear. These data are from collection and analysis
The process by which follicular depletion of daily urine samples across three men-
occurs is not well understood. A resting fol- strual cycles from a normally cycling
licle (one that has not begun to grow) ini- woman. The first day of menses is labeled as
tiates growth by a process that is poorly un- cycle day one on the x axis. The top graph
derstood. Definitive endocrine, autocrine, or shows the main urinary metabolites, es-
paracrine factors have not been identified, trone-3-glucuronide (E3G) and pregnane-
but gonadotropin hormones are not believed diol-3␣-glucuronide (PDG), of the ovarian
to be necessary to trigger the initial growth steroids estradiol and progesterone. These
of the follicle (Gougeon, 1996; McGee and metabolites parallel serum levels of estra-
Hsueh, 2000). Each and every follicle ap- diol and progesterone (Munro et al., 1991).
pears to have a small and nearly constant The pituitary hormones LH and FSH are
probability of entering into this initial grow- shown in the lower graph of the top panel of
ing state at any point in time across the life Figure 3.
span. In a typical menstrual cycle, steroid hor-
Growing follicles usually survive for only mones are low at the start of each men-
a short time before undergoing atresia. The strual cycle (day 1 of menses), reflecting the
mechanisms that determine when and why absence of any follicles large enough to pro-
atresia occurs to particular follicles are still duce measurable levels of estradiol. In the
unknown. The vast majority of follicles un- absence of ovarian steroids, the gonadotro-
dergo atresia, which is a form of apoptosis pin hormones LH and especially FSH be-
Fig. 3. Urinary steroid and gonadotropin profiles for a regularly cycling woman (top panels) and a menopausal
woman (bottom panels). Each cycle day 1 is the first day of menses. Hormone values are corrected by specific
gravity. Source: Pennsylvania State University Reproductive Endocrinology Laboratory.
K.A. O’CONNOR ET AL.
468
come elevated. The elevated gonadotropins ENDOCRINE PATTERNS OF THE

stimulate follicular growth and steroid pro- MENOPAUSE AND PERIMENOPAUSE
duction in any follicles that have matured to
the point of developing receptors for FSH. In menopause, one part of the HPO sys-
Follicles responding to FSH will continue to tem breaks down as the ovaries become de-
the next stage of growth and begin to se- pleted of follicles. When there are no ovari-
crete estradiol. This estradiol then acts in a an follicles, there is no ovarian production of
negative feedback loop with the hypothala- estrogen or progesterone. There is, there-
mus to down-regulate gonadotropin secre- fore, a loss of negative feedback at the hy-
tion. Hence, as estradiol secretion begins, pothalamus so that pituitary secretion of
LH and FSH increases to high levels. In
LH and FSH secretion declines. Because
post-menopausal women, LH and FSH lev-
growing follicles secrete estradiol in propor- els are consistently high, reflecting this lack
tion to their size, estrogen rises slowly at of feedback from ovarian steroids.
first and then more rapidly as one or more This can be clearly seen in the lower two
follicles grow to larger sizes. One follicle will graphs of Figure 3, which show daily con-
eventually become the dominant follicle centrations of urinary steroids and gonado-
through a poorly understood process called tropins across 3 months in a postmeno-
follicular selection. pausal woman. There are negligible levels of
Once the estrogen reaches very high lev- ovarian steroids, and in the absence of ovar-
els (around day 14 or mid-cycle), a surge of ian steroid feedback, gonadotropin concen-
LH (and to a lesser extent, FSH) is trig- trations are about 4-fold higher than those
gered. This surge causes the dominant fol- found in a cycling woman.
licle to rupture and release the oocyte The transition to menopause thus in-
within it, i.e., ovulation. The part of the volves a switch from a well-orchestrated
cycle from cycle day 1 until ovulation is system of feedback and control to one of un-
called the follicular phase, because the main regulated gonadotropin release in the ab-
activity in this part of the cycle is follicular sence of ovarian production of steroids. The
growth. final transition can be seen in Figure 4,
After ovulation, the follicle from which which tracks a 48-year-old woman across
the egg erupted differentiates into the cor- approximately 2 months as she experiences
pus luteum, an endocrine gland that se- her last-ever menstrual bleed. It is clear
cretes mostly progesterone but also some es- from plasma progesterone levels that the
cycle preceding her final menses was anovu-
trogen. The second half of the ovarian cycle
latory. Following the last menses is an in-
is called the luteal phase, after the corpus
terval of about 2 weeks during which some
luteum. The function of progesterone and estradiol is present, presumably reflecting
estrogen in this phase is to finish preparing some degree of partial follicular activity. Af-
the uterus for pregnancy. The elevated lev- ter this interval, the levels of both estradiol
els of progesterone and estrogen prevent and progesterone are very low and unchang-
significant secretion of LH or FSH. In the ing, and will remain so for the rest of the
absence of pregnancy, the corpus luteum re- woman’s life. Coinciding with the decline in
gresses until levels of progesterone are too ovarian steroids is a marked elevation in
low to maintain the uterine lining. The uter- LH and FSH, indicating that the hypotha-
ine lining is then shed, resulting in menses lamic–pituitary axis has been freed from
and the start of the next menstrual cycle. As negative feedback by ovarian steroids. Her
the steroid levels decline at the end of an gonadotropins are likely to be high and vari-
ovarian cycle, LH and FSH slowly elevate as able throughout the rest of her life (Hee et
they are released from negative feedback al., 1993).
control. The elevated level of FSH then The period of transition from regular
stimulates the next cohort of follicles to de- ovarian cycles to a complete absence of ovar-
velop. This set of feedback relationships of ian cycles is characterized by increasingly
the hypothalamic–pituitary–ovarian (HPO) irregular cycle length, and a rapidly dwin-
axis thus serves to maintain regular ovari- dling pool of follicles. Increasingly variable
an cycles throughout the reproductive life hormone profiles also occur during this
span. transitional period. In fact, hormone pro-
Fig. 4. Plasma concentrations of ovarian steroids (top panel) and gonadotropins (bottom panel) during the
menopausal transition in a 48-year-old woman. Redrawn from van Look et al. (1977).
files in the perimenopause often contain el- like menopause. If we had analyzed a single
ements of both menopausal and cycling hor- urine or blood specimen during this 10-day
mone profiles. period, we might have concluded that this
Figure 5 shows three menstrual cycles for woman was menopausal. But clearly she is
a perimenopausal 45-year-old woman. not; this brief period of “false menopause” is
Throughout most of the period of observa- followed by ovulation. One effect of the
tion, she experiences normal, ovulatory 2-week period of ovarian quiescence is that
cycles. Beginning, however, at about cycle this particular cycle is inordinately long, as
day 3 of the third cycle (boxed-in area), she is often the case during the perimenopause.
goes through about a 10-day period with no
sign of ovarian steroidogenesis. At the same THREE-PHASE MODEL OF THE
time, her LH and FSH rise rapidly, presum- MENSTRUAL CYCLE
ably because of an absence of negative feed- These transient episodes of ovarian qui-
back from steroids. We believe that this is escence are called “inactive phases” of the
evidence that there are no follicles at the menstrual cycle. Our hypothesis is that in-
appropriate developmental state to begin active phases are direct reflections of the
further growth under the influence of FSH. very small pool of remaining follicles. Inac-
Eventually, however, one or more follicles tive phases are characterized by the absence
begins growing, as evidenced by the rising of steroid production and correspond to
estrogen; LH and FSH levels decline as the those periods of time when no follicles have
steroids down-regulate the hypothalamus, begun growing. When the stock of follicles is
and the cycle continues normally through large, as at young reproductive ages, inac-
ovulation and the luteal phase. tive phases will be rare as there will nearly
This period of time when no follicles are always be a cohort of follicles at the right
developing looks, hormonally, very much stage of development (the antral stage,
Fig. 5. Urinary steroid and gonadotropin excretion in a 45-year-old perimenopausal woman (as assessed by
self-reports of irregular cycle lengths), showing an inactive phase (boxed-in area) at the beginning of the third
menstrual cycle. Each cycle day 1 is the first day of menses. Hormone values are corrected by specific gravity.
Source: Pennsylvania State University Reproductive Endocrinology Laboratory.
when follicles are able to respond to FSH from our laboratory and in Figure 6 from
and begin production of estradiol; see Mc- two published studies of the perimenopause
Gee and Hsueh, 2000, for a review of follic- (Fig. 6 bottom panel from Santoro et al.,
ular development) at the start of any given 1996; top panel from Shideler et al., 1989).
menstrual cycle. At older ages, however, Note that in each example the length of the
when the follicle reserve is low, there will, cycle containing the inactive phase is con-
by chance, be periods of time when no fol- siderably longer than the cycles preceding
licles are at the antral stage of development or following it.
at the start of a menstrual cycle. The ovary If our hypothesis that inactive phases are
is, in essence, “sputtering” when the follicle direct reflections of the very small pool of
reserve is very low. Inactive phases are a remaining follicles is correct, then the dis-
natural statistical outcome of repeated sam- tribution of inactive phases by age should be
pling from a stock containing small absolute predictable, given an underlying rate at
numbers of items. Menopause is effectively which follicles initiate growth. The fre-
a permanent inactive phase. quency and mean length of inactive phases
We have observed several examples of in- should increase with age, as the follicular
active phases in our laboratory and the pub- reserve approaches exhaustion.
lished literature (Sherman et al., 1976; We model the distribution of inactive
Shideler et al., 1989; Hee et al., 1993; San- phase lengths by decomposing the ovarian
toro et al., 1996). The characteristic endo- cycle into three distinct phases (Fig. 7): the
crine pattern is one of low and unchanging inactive phase, the follicular phase, and the
levels of reproductive steroids, coupled with luteal phase (O’Connor et al., 1998). The
elevated concentrations of FSH and to some first phase is the inactive phase—the period
extent LH. This pattern is seen in Figure 5 of time in which no antral follicles have ini-
Fig. 6. Urinary endocrine profiles showing inactive phases (boxed-in areas). The top panel shows two menstrual
cycles in a 45-year-old woman (redrawn from Shideler et al., 1989), and the bottom panel shows an inactive phase
in a perimenopausal woman (redrawn from Santoro et al., 1996). Shaded bars are days of menses; E1 is estrone-
3-glucuronide and other urinary metabolites.
tiated growth or matured to the point of pro- The inactive phase is followed by the follic-
ducing estradiol. This phase should usually ular phase, which encompasses the period
be vanishingly small in younger women but from the first follicular secretion of estradiol
may be longer in perimenopausal women. to the time of ovulation. The luteal phase
Fig. 7. The three-phase model of the ovarian cycle.

The inactive phase corresponds to periods of no detect-
able ovarian steroidogenesis. The shaded box denotes
menses. See text for discussion of each phase.
remains as traditionally defined, the time

from ovulation to menses. The entire inter-
menstrual interval is the sum of these three
phases (Fig. 7).
In this model, the rate at which follicles
initiate growth is assumed to be propor-
tional to the rate of follicular depletion. All
follicles are assumed to have the same haz-
ard of initiating growth, and this hazard
does not change across the life span. We also Fig. 8. Hypothetical example of times spent in inac-
assume homogeneity across women in the tive phase, under a simple model that assumes an ini-
size of the initial follicle pool and in the rate tial follicle pool (at birth) of 1,000,000 follicles and a
daily hazard of a follicle entering the growing state of ␭
of atresia. Other versions of the model in- ⳱ 0.00065 (based on data from Block, 1952, 1953, and
corporate unmeasured heterogeneity in the Gougeon et al., 1994). The top panel shows the probabil-
rate of atresia or follicle pool size or explic- ity of no follicles initiating growth, at five different ages.
itly incorporate covariates (such as cigarette The bottom panel shows the mean and variance in in-
active phase length by age of a woman.
smoking) that might influence the rate of
atresia and thus the timing of menopause
(discussed below). ber of surviving follicles in her ovaries and
A probability model of inactive phase the probability that no follicles initiate
lengths is given to illustrate the implica- growth. An inactive phase occurs when all
tions of the model for menstrual cycle length na surviving follicles have not begun grow-
variability. Assume that women begin with ing at the beginning of a menstrual cycle.
an initial pool of n0 follicles, that follicles From this it follows that the probability of
initiate growth with a constant hazard ␭ per an inactive phase exceeding length t at age
follicle (roughly corresponding to the con- a is Pr(T > t|␭, n0, a) ⳱ exp(−t␭n0e−␭a). The
stant rate of follicular atresia seen in Fig. mean time in the inactive phase at age a is
2), all follicles eventually initiate growth, E(T|a) ⳱ (␭n0e−␭a)−1 and the variance is
and all but a small fraction of follicles un- V(T|a) ⳱ (␭n0e−␭a)−2.
dergo atresia. For this version of the model Figure 8 shows the distribution of inac-
we assume that ␭ does not vary across fol- tive phases by age, predicted by this simple
licles and that there is no variation in n0 model. The top panel illustrates the prob-
among women (most of these assumptions ability of remaining in an inactive phase for
are relaxed in more complicated versions). a given number of days, at five different
From these assumptions, the number of fol- ages. Clearly, a 30-year-old woman will al-
licles remaining in the ovaries at age a is na most always have extremely short, and
⳱ n0exp(−␭a). This gives rise to the distri- largely undetectable, inactive phases. By
bution of times for a woman age a to be in age 40, the median length is still quite short
the inactive phase as a function of the num- but there is now some non-negligible prob-
Fig. 9. Urinary steroid and gonadotropin excretion in a 25-year-old cycling woman showing a short inactive
phase at the beginning of the second menstrual cycle (boxed-in area). Each cycle day 1 is the first day of menses.
Hormone values are corrected by specific gravity. Source: Pennsylvania State University Reproductive Endocri-
nology Laboratory.
ability of an inactive phase being up to 12 25-year-old woman. The boxed-in area high-
days long. By 50 years of age, many cycles lights a brief period where the steroid hor-
are expected to have long inactive phases. mones are quite low and constant and LH
The age-specific mean lengths for inactive and FSH are elevated due to the absence of
phases are shown in the bottom panel of negative feedback from reproductive ste-
Figure 8. At younger ages, the length of the roids. There are several missed days of col-
inactive phase is short enough so that the lection following the inactive phase in this
inactive phase almost always adds no mea- study participant, but the rising estrogen
surable time to the overall length of the and LH peak after the inactive phase indi-
menstrual cycle, and the variability is low cate that follicular development and ovula-
enough that we would rarely expect an in- tion ultimately did occur.
active phase of any discernible length. As Another prediction following from our
menopause approaches, both the mean and model is that we should expect to see inac-
variability in the length of the inactive tive phases in other animals with similar
phase increases greatly, showing a pattern reproductive biology and life history traits.
that is strikingly similar to the increased If the follicular depletion system is the ulti-
variability in menstrual cycle length during mate cause of the hormonal and ovarian
the perimenopause (compare Fig. 1 with cycle features characteristic of the peri-
Fig. 8 lower panel). menopause and menopause, then inactive
One prediction that follows from the phases should be present in those species
model and Figure 8 is that we should very possessing follicular depletion. The follicu-
occasionally see inactive phases in young lar depletion system is in fact a primitive
women. Figure 9 shows an example from trait that is highly conserved across most
our laboratory that we believe is a short in- mammals (Austad, 1997) and many verte-
active phase in a healthy, normally cycling brates (Norris, 1997). In most mammalian
Fig. 10. Urinary estrone conjugates (E1C) and progesterone excretion for three rhesus macaques. The top panel
is from a normally cycling macaque. The stippled bars show days of menses. The middle panel is from a menopausal
macaque. The bottom panel is from a perimenopausal macaque and shows a long inactive phase followed by
follicular development, ovulation and menses. Redrawn from Gilardi et al. (1997).
species, the stock of follicles tends to last pause of captive rhesus macaques. The top
longer than the average life span, therefore panel of Figure 10 shows daily urinary es-
evidence of inactive phases should be ex- trogen and progesterone metabolites for a
pected only in long-lived species that sur- 20- to 25-year-old regularly cycling rhesus
vive beyond reproductive ages. macaque from this study. Unfortunately,
Hormonal data for large-bodied or long- there are no LH or FSH data for these ma-
lived mammals are rare. Some excellent caques, but we can see clearly here that this
data are available from a study by Gilardi animal is experiencing regular cycles, and
and colleagues (1997) that examines the en- they are remarkably like those seen in hu-
docrinology, ovarian histology and bleeding man females. The middle panel shows hor-
patterns of the perimenopause and meno- mone data for another macaque from the
same study, but this animal is 29 years old A second useful extension explicitly mod-
and amenorrheic. This is the hormone pro- els the requirement that early growing
file of a menopausal macaque. The bottom follicles must survive until they begin pro-
panel shows a perimenopausal macaque in ducing estradiol in the presence of gonado-
her mid-twenties. The first 40 or so days of tropins (which typically happens at a size of
collection for this animal look menopausal, about 2 mm; Gougeon, 1996) before they can
but then there is a period of sustained es- terminate the inactive phase. One simple
trogen production indicative of follicular de- way to accommodate this extension is to as-
velopment. This is followed by a rise in pro- sume a proportional fraction ␩ of early
gesterone, suggesting ovulation has growing follicles survive to the 2 mm stage.
occurred, and then a menses. Without LH This revision gives Pr(T > t|␭, n0, ␩) ⳱
and FSH it is hard to be absolutely sure that exp(−t␭␩n0e−␭␩a). Essentially, this model is
the prolonged period of steroid inactivity the same as the simplest model, except that
here is an inactive phase, but this profile ␭ has been rescaled by ␩. More complex ver-
looks exactly as we would predict during the sions would treat the survival to the 2 mm
perimenopause. stage as a multistate process.
The simple model presented above can be Some applications of the inactive phase
extended to accommodate more realistic as- model include estimating the rate of follicu-
sumptions. For example, we can explicitly lar atresia, estimating the initial follicle
model the increase in the rate at which fol-
pool size, and examining the independent
licles are depleted at later reproductive ages
effects of covariates on the rate of follicular
(Faddy and Gosden, 1995). One possible
mechanism for the increased rate of deple- atresia. The rate of atresia is typically esti-
tion, which has found experimental support mated by counting follicles in ovaries over
in the work of Flaws et al. (1997), is that the lifespan (Block, 1952, 1953; Gougeon et
exposure to high gonadotropin levels may al., 1994; Richardson et al., 1987). The ova-
directly damage ovarian follicles. If so, then ries for this research are obtained from au-
gonadotropin damage may increase at later topsy and oophorectomy cases. The inactive
reproductive ages when LH and FSH con- phase model provides another way of esti-
centrations periodically increase during in- mating the rate of atresia as well as the size
active phases. Thus, there would be two of the initial follicle pool. The data for this
common routes by which follicles are de- approach consist of observations of inactive
pleted from the ovaries: atresia, which is ex- phases over some period of the lifecourse,
pected to remain a negative exponential derived from daily urine (or blood) samples
process, and gonadotropin damage, which assayed for reproductive steroids and go-
would be some function of inactive phase nadotropins. A hormonal criterion deter-
length at a given age. Together these two mines the start and end of each inactive
causes of depletion describe a multifactorial phase. For each menstrual cycle we observe
process proposed by Leidy et al. (1998). an inactive phase of t days length for a
Under one such multifactorial model, woman of age a. The probability for the ith
some proportion ␾ of surviving follicles such observation is rnexp{−r[a i + t i n
would die in proportion to the expected exp(−rai)]}, where n is the size of the initial
length of the inactive phase at age a. A first pool of follicles and r is the rate of atresia
order approximation of this model (which ig- under the simple model. If r and n are ho-
nores second-order effects when the follicle mogenous among women, then the likeli-
pool is very small) is dna/da ⳱ −[␭na + hood for N such observations of inactive
␾na(␭na)−1], and simplifies to dna/da ⳱ phases is
−[ ␭na + ␾/␭]. The term ␾na(␭na)−1 is the
expectation from the exponential atresia N
process, weighted by the fraction of suscep-
tible follicles (␾na) that might be damaged L= 兿 rn exp关−r共a + t ne
i=1
i i
−rai
兲兴
by a long inactive phase. The surviving
number of follicles at age a is S(a) ⳱
exp(−␭a) + ␾[exp(−␭a) − 1]/(n 0 ␭ 2 ), and and the values of parameters r and n that
shows a nearly log–linear decline in follicle maximize the likelihood are the estimates
numbers with an accelerated depletion at for the rate of atresia and the initial pool of
the oldest ages, similar to Figure 2. follicles, respectively.
We can also estimate the independent ef- depletion model is attractive because it is
fects of covariates (e.g., parity, cigarette parsimonious: one biological process can ex-
smoking, age at menarche, breastfeeding, plain many of the salient menstrual cycle
particular hormonal environments, genetic features of the perimenopause and meno-
makeup) on the rate of atresia. Covariates pause. In contrast, hypothalamic aging
that are fixed across the lifespan as well as models cannot account for all of these vari-
those that change over time can be exam- ous characteristics of reproductive aging,
ined, although here we only illustrate how nor do they specify the mechanism(s) pro-
to do this for fixed covariates with the ducing, for example, elevated gonadotropin
simple model. Suppose covariates act by di- levels. Moreover, if an aging hypothalamus
rectly increasing or decreasing the rate of were the primary biological mechanism
atresia. Call xi the value of a measured co- driving the breakdown in communication
variate for the ith individual. The effect of between the ovary and pituitary, we might
the covariate will be modeled by parameter expect a more random pattern of gonadotro-
␤. For the ith individual the rate of atresia pin secretion throughout the ovarian cycle.
is thus ri ⳱ r exp(xi␤), and we replace r with The current formulation of the model does
ri in the likelihood above. In addition to not offer an explanation for one other sa-
finding estimates for r and n, we can also lient feature of the perimenopausal period:
estimate a value for the ␤ parameter, which the slight increase in shorter than average
gives us the magnitude of the covariate ef- menstrual cycles observed in the years be-
fect on the rate of atresia. Additional covari- fore menopause (e.g., Treloar et al., 1967,
ates can be included as an additive array of see Fig. 1). These short cycles may be
covariates and parameters so that ri ⳱ xi1␤1 caused by an altogether different mecha-
+ xi2␤2 + . . . . Other extensions control for nism, related to the higher frequency of an-
the non-independence of repeated observa- ovulation seen during the perimenopausal
tions within women and provide for covari- years (Metcalf, 1983). Further work will be
ates that vary with time. necessary to examine the relationship of
short cycles with anovulation.
CONCLUSIONS
We have proposed that follicular deple- ACKNOWLEDGMENTS
tion and the inactive phase are the mecha- We thank Eleanor Brindle, Susannah
nisms underlying the increasing variability Barsom, Kenneth Campbell, Fortüne Ko-
in menstrual cycle length and hormone pat- hen, Bill Lasley, John O’Connor, Phyllis
terns of the perimenopause. The cases of in- Mansfield, and Cheryl Stroud for their as-
active phases that we have found in our sistance with the laboratory component of
laboratory studies and the literature are this work. Anti-human LH␤1 and FSH␤ an-
broadly consistent with our theoretical tisera (AFP #1) and LH (AFP4261A) and
model. We are currently collecting the data FSH (LER907) standards were provided by
necessary to critically test this model: pro- the National Hormone and Pituitary Pro-
spective daily hormone and bleeding data gram through NIDDK, NICHD, and USDA.
from approximately 120 women aged 30–58
years, followed for 6 months of each year for LITERATURE CITED
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AMERICAN JOURNAL OF HUMAN BIOLOGY 13:465–478 (2001)

Menstrual Cycle Variability and the Perimenopause

© 2001 Wiley-Liss, Inc.

(Hsueh et al., 1994; Kaipia and Hsueh,

come elevated. The elevated gonadotropins ENDOCRINE PATTERNS OF THE

Fig. 7. The three-phase model of the ovarian cycle.

remains as traditionally defined, the time

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