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Menstrual cycle
Wilfried Karmaus
Reproductive Epidemiology
EPI 824
Overview
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Number of germ cells (oocytes)
Menarche
Menopause
Menstrual cycle
Endocrine regulation
Menstrual cycle disorders:
– Cycle irregularities
– Polycystic ovary syndrome
• Endometriosis
Number of oocytes at different ages
Age
3-6 weeks of
gestation
8 weeks
8-20
20-40 weeks
Birth to puberty
Reproductive
years
# of cells
Endoderm of the
yolk sac
Proliferation by
mitosis
Mitosis, meiosis,
atresia
80% loss
10,000
600,000
6-7,000,000
1-2,000,000
Loss to atresia
300,000
Ovulation
400-500
• Mitosis is the process that facilitates
the equal partitioning of replicated
chromosomes into two identical
groups (Each daugther cell will have a
complete set of chromosomes).
• Meiosis: Process by which a single
parent diploid cell divides to produce
four daughter haploids cells (One
homologous chromosome of the pair).
Menarche
• Puberty: gradual transition form
immaturity to functional capability of
reproduction
• Menarche is the first ovarian controlled
uterine bleed in a women’s lifetime
• Average age at menarche: 13 years
• Normal range in girls:
– Onset: 9-13
– Completion: 12-17
Menarche
• The average age of menarche in
industrialized countries declined by 3
years from 1860 to 1965 (secular trend).
• Age at menarche appear earlier in
countries with the longest life
expectency (poor nutrition delays age at
menarche).
Menarche
• Peak growth precedes the first
menstruation
• 5 stages: Marshall and Tanner
• Thelarche: breast building (5 stages)
• Pubarche: appearance of pubic hear (5
stages)
• Gonadarche: gonadal maturation
• Adrenarche: adrenal androgen secretion
Menopause
• The menopause is the time of a woman's life
when her reproductive capacity stops:
– No period for 12 months
• The ovaries cease functioning and they produce
fewer hormones.
• The body undergoes a variety of changes both
because the ovaries stop functioning and
because of aging.
• The menopause is sometimes marked by
unpleasant symptoms but, even though some
may be disabling, none is life-threatening.
Menopause
• The number of follicles in the ovary determines
the age at which the menopause takes place.
• The number declines steadily until around age
40 and then becomes more rapid until after the
menopause when essentially there are no
follicles left.
After menopause, the typical pattern of the
hormones is:
– Continually high levels of FSH and
– Continually low levels of estrogen and progesterone.
Stages of the climacteric
Climacteric: 47-55 years
Premenopause: 5 years
before
Postmenopause starts
1 year after menopause
Perimenopause: transitional phase between pre- and
postmenopause: 2 years before and 1 year after
Menopause
• The changes in hormone production affect
various parts of the body, for instance the
bones and the cardiovascular system.
• Various hormonal therapies (hormone
replacement therapy=HRT) have been tried to
lessen the consequences of the menopause.
• HRT has in turn raised concerns with regard
to increased risk of diseases such as cancer.
Menopause
• Hot flushes and night sweats are
characteristic of the menopause. Hot
flushes arise as a sudden feeling of heat
in the face, neck and chest. Night sweats
are the night-time manifestation of hot
flushes.
• Insomnia is often cited as a menopausal
complaint, but it usually occurs as a
secondary effect of sleep disruption
caused by the night sweats.
• Flushes may be induced by tension or
nervousness and their frequency.
Prevalence of hot flushes
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Mayan women:
0%
Hong Kong women: 10-22%
Japanese women:
17%
Thai women:
23%
North American:
45%
Dutch women: up to 80%.
Menopause
In general flushes and sweats are more
common in European and North American
women than in other populations.
A high intake of dietary phytoestrogens
(estrogen-like compounds found in plants)
has been suggested as a possible
explanation of the lower frequency of
menopausal symptoms in Japanese as
compared with Caucasian women.
Menopause
• The average age at menopause is about 51 years
in industrialized countries.
The age tends to be lower in women who smoke
and in those who have had no children.
• Lower age at menopause may also be related to
poor socioeconomic status.
• Women with menstrual cycles averaging less
than 26 days seem to reach the menopause 1.4
years earlier than those with longer cycles.
• It is also believed that a woman's age at
menopause may be a biological marker of aging,
and that a later menopause may be associated
with greater longevity.
Menstrual cycle
Timing
• Follicular phase: day 1-14, menses:
day 1-5
• Ovulatory phase: day 14-16
• Luteal phase: day 16-28
Menstrual cycle:
Days 1-5: Estrogen Falls,
FSH Rises.
Menstrual bleeding begins
on Day 1 of the cycle and
lasts approximately 5 days.
During the last few days
prior to Day 1, a sharp fall
in the levels of estrogen
and progesterone signals
the uterus that pregnancy
has not occurred during
this cycle. This signal
results in a shedding of the
endometrial lining of the
Figure taken from
uterus.
Robert J. Huskey
Since high levels of estrogen suppress the
secretion of FSH, the drop in estrogen now
permits the level of follicle stimulating
hormone (FSH) to rise.
FSH stimulates follicle development.
By Day 5 to 7 of the cycle, one of these
follicles responds to FSH stimulation more
than the others and becomes dominant. As it
does so, it begins secreting large amounts of
estrogen.
Days 6-14: Estrogen Is
Secreted, FSH Falls.
Estrogen is secreted by
the follicle during this
phase of the menstrual
cycle. It
 stimulates the
endometrial lining of
the uterus
 suppresses the further
secretion of FSH.
Figure taken from
Robert J. Huskey
At about mid-cycle (Day 14), the estrogen
helps stimulate a large and sudden release of
luteinizing hormone (LH).
This LH surge, which is accompanied by a
transient rise in body temperature, is a sign
that ovulation is about to happen.
The LH surge causes the follicle to rupture
and expel the egg into the Fallopian tube.
Days 14-28: Estrogen And
Progesterone Secretion
First Rise, then Fall.
After rupture of the
follicle, it is transformed
into the corpus luteum and
produces progesterone.
P supports to prepare the
endometrial lining for
implantation of the
fertilized egg.
(If the egg is fertilized, a
small amount of human chorionic
gonadotrophin (hCG) is released
that stimulates further
progesterone production.)
Figure taken from Robert J. Huskey
After implantation, the trophoblast will secrete human
Chorionic Gonadotropin (hCG) into the maternal
circulation.
HCG keeps the corpus luteum viable.
The corpus luteum continues to produce estrogen and
progesterone, which keep the endometrial lining intact.
By about week 6 to 8 of gestation, the newly formed
placenta takes over the secretion of progesterone.
If the egg is not fertilized, the corpus luteum shrinks,
and the levels of estrogen and progesterone drop, the
uterus sheds its lining, and menstruation begins.
In addition, with no estrogen to suppress it, FSH
levels again start to rise. Thus, one cycle ends and
another begins.
Stages of follicle growth
Growth
335 days
20-30%
Atresia
80% Selection: 10 days
Initiation
Maturation: 10 days
Endrocrine control of the menstrual cycle
Early to mid-follicular phase
Hypothalamus
Late follicular phase & ovulation
Hypothalamus
GnRH
GnRH
Pituitary gland
FSH
Pituitary gland
LH
FSH
Follicle
Granulosa
cells
LH
Follicle
Theca
cells
Granulosa
cells
Theca
cells
Inhibin
Estrogens
Androgens
High estrogens
Androgens
low progesterone
Feedback: negative
positive
Cholesterol
(mitochondria)
Pathway of steroid hormones
Pregnenolone
Dehydroepiandrosterone
Androstenediol
Progesterone
Androstenedione
Testosterone
Cortisol
Aromatase
Aromatase
Estrone
Estradiol
Estrogens stand for a group of hormones:
 Estradiol (approximately 10-20% of circulating estrogens)
 Estrone (approximately 10-20% of circulating estrogens)
 Estriol (approximately 60-80% of circulating estrogens)
Estradiol is produced by the ovaries. It is the primary
circulating estrogen before menopause. It is also the
strongest estrogen and is responsible to the monthly
ovulation and normal menstrual cycles.
Estrone is produced by the fatty tissues. It is less
potent than estradiol, but more important after the
menopause
Estriol is an estrogen that is prominent mostly during
pregnancy.
Progesterone is made by the adrenal glands in both sexes
and by the testes in males. It is a precursor of
testosterone and of all the important adrenal cortical
hormones.
Progesterone is made from the sterol pregnenolone that
derives from cholesterol,
Progesterone stimulates the growth of a endometrial lining,
prepares breast tissue for the secretion of breast milk, and
generally maintains the advancement of pregnancy.
Androgens stands for a group of primarily
male hormones:
- testosterone
- androstenedione
- dehydroepiandrosterone).
Androgens are also produced in the ovaries.
Menstrual cycle irregularities:
1. abnormal frequency
Kaltenbach chart:
Normal cycle
Abnormal
frequency:
oligomenorrhea
Abnormal
frequency:
polymenorrhea
Duration: 28 d 5
Amount: 3-5 pads
or tampons
(35 mL)
Duration > 35 days
Duration < 22 days
Menstrual cycle irregularities:
2. abnormal amount of duration
Normal cycle
Duration: 28 d 5
Amount: 3-5 pads
or tampons
Hypomenorrhea
Amount < 2 per day
Hypermenorrhea
Amount > 5 per day
Menorhagia
Duration 7-14 days
Menstrual cycle irregularities:
3. others
• Spotting: bleeding unrelated to menses
• Ovulatory bleeding
• Metorrhagia: > 14 days, no clear cycle
• Amenorrhea: absence of bleeding for
more than 3 months
Menstrual cycle irregularities:
prevalence and risks
• 9-30% of reproductive-aged women have
menstrual irregularities requiring medical
evaluation.
• Regular vigorous exercise is associated with
decreased estrogen levels in the blood.
– Healthy women who began training for a marathon
developed new menstrual cycle irregularity.
• Any risk factor that may alter endocrine control
(e.g. stress, endocrine disruptor) can result in
cycle irregularities.
Menstrual cycle irregularities:
‘causes’
• Menstrual period changes are usually a
symptom of endocrine imbalance.
• Changes in the amount or timing of
hormones released by the thyroid,
adrenal and pituitary glands, or
hypothalmus may cause the ovary to
delay or skip ovulation.
Menstrual disorders
• Irregular patterns of bleeding
• Hypothalamic ovarian insufficiency:
Psychogenic stress, anorexia nervosa
• Pituitary causes:
for instance: acromegaly – increased somatotropic
hormones (STH)
Cushings diseas: impaired cortisol rhythm
• Ovary: polycystic ovary
• Thyroid:  hypothyroidism: anovulatory
cylces and dysfunctional bleeding
 hyperthyroidism: hypomenorrhea/
oligomenorrhea
• Adrenal: Cushings syndrome: impaired cortisol rhythm
Polycystic Ovary Syndrome (PCOS)
• PCOS is a common cause of menstrual
irregularity in premenopausal women.
• According to the initial description by Stein
and Leventhal in 1935, the diagnosis of PCOS
was based on the clinical symptoms
(oligo/amneorrhea, infertility, hirsutism, and
obesity) in the presence of histologically
verified polycystic ovaries.
• PCOS affects between 3-10% of women of
reproductive age.
Polycystic Ovary Syndrome (PCOS)
The ovaries contain many small follicles or cysts. Each has an
egg, but they do not grow normally and shrink before
ovulation. Each month, new follicles develop and shrink into
cysts.
The fertility is reduced.
Most PCOS cases are unexplained.
• The disorder may be inherited.
• Deficiency in luteinizing hormone (LH)
• Resistance to insulin. A similar effect on the ovaries
can occur in women with eating disorders (anorexia or
bulimia), or women whose bodies do not properly make
estrogen and other steroids (for example, women with
congenital adrenal hyperplasia).
Endometriosis
• Endometriosis is a condition where
endometrium (the lining of the uterus) is
found in locations outside the uterus:
–
–
–
–
–
Ovaries
Uterus
Bowel
Bladder
Utero-sacral ligaments (ligaments that hold the
uterus in place)
– Peritoneum (covering lining of the pelvis and
abdominal cavity)
– On rare occasions: other distant sites.
Endometriosis
 The tissue reacts to estrogen and progesterone:
- same cyclic responses as the endometrium
 Some therapies for endometriosis attempt to
reduce estrogen production.
 Endometriosis causes pelvic pain.
 Endometriosis is affecting approximately
• 7% of reproductive-aged women
• 10 - 15% of women undergoing diagnostic
laparoscopy,
• 30 -40% of infertile women having laparoscopy,
• 14 - 53% of women with pelvic pain.
Endometriosis - Causes
• Retrograde menstruation:
Endometrial cells from the uterus are pushed
backward through the fallopian tubes and exit
into the abdomen where they implant and grow.
• Embryonic tissue:
Endometrial tissue was present abnormally when
the woman was an embryo. The tissue becomes
active in reproductive life.
• Genetic explanation:
Women with endometriosis frequently come
from families with a high incidence of the
disease.
Endometriosis - Causes
• Lymphatic distribution:
Endometrial material gets distributed throughout
the body via the lymphatic system.
• Immune system dysfunction
Women with endometriosis have been found to
carry cells with reduced ability to attack
‘abnormal’ cells and high levels of autoantibodies
that attack their own cells.
• Environmental influences
A study, designed to examine the affects of
dioxins on reproduction in rhesus monkeys, found
that 79% of the monkeys exposed to dioxins
developed endometriosis.
Summary
• Begin and end of reproductive period
varies between different societies.
• Menstrual cycle irregularities and
disorders are frequent (3-30%) and can
be determined with standardized
charts.
• Events of/in the reproductive period,
such as age at menarche, irregularities,
age at menopause, etc. are markers for
increased risk for health outcomes in
later life.