Menstrual cycle

1
Menstrual cycle

• Wilfried Karmaus
• Reproductive Epidemiology
• EPI 824

2
Overview

• Number of germ cells (oocytes)
• Menarche
• Menopause
• Menstrual cycle
• Endocrine regulation
• Menstrual cycle disorders
• Cycle irregularities
• Polycystic ovary syndrome
• Endometriosis

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Number of oocytes at different ages
Age of cells
3-6 weeks of gestation Endoderm of the yolk sac 10,000
8 weeks Proliferation by mitosis 600,000
8-20 Mitosis, meiosis, atresia 6-7,000,000
20-40 weeks 80 loss 1-2,000,000
Birth to puberty Loss to atresia 300,000
Reproductive years Ovulation 400-500
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• 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).

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Menarche

• Puberty gradual transition form immaturity to
  functional capability of reproduction
• Menarche is the first ovarian controlled uterine
  bleed in a womens lifetime
• Average age at menarche 13 years
• Normal range in girls
• Onset 9-13
• Completion 12-17

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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).

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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

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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.

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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.

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Stages of the climacteric

• Climacteric 47-55 years

Premenopause 5 years before
Menopause
Postmenopause starts 1 year after menopause
Perimenopause transitional phase between pre-
and postmenopause 2 years before and 1 year after
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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
  therapyHRT) 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.

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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.

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Prevalence of hot flushes

• Mayan women 0
• Hong Kong women 10-22
• Japanese women 17
• Thai women 23
• North American 45
• Dutch women up to 80.

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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.

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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.

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Menstrual cycle Timing

• Follicular phase day 1-14, menses day 1-5
• Ovulatory phase day 14-16
• Luteal phase day 16-28

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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 uterus.
Figure taken from Robert J. Huskey
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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.
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• 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
20
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.
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• 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
22
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.
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Stages of follicle growth
Growth 335 days
20-30
Atresia
Selection 10 days
?80
Maturation 10 days
Initiation
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Endrocrine control of the menstrual cycle
Early to mid-follicular phase
Late follicular phase ovulation
Hypothalamus
Hypothalamus
GnRH
GnRH
Pituitary gland
Pituitary gland
FSH
LH
FSH
LH
Follicle
Follicle
Granulosa cells
Theca cells
Granulosa cells
Theca cells
Inhibin
Androgens
Estrogens
Androgens
High estrogens
low progesterone
Feedback negative
positive
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Pathway of steroid hormones
Cholesterol (mitochondria)
Dehydro-epiandrosterone
Pregnenolone
Androstenediol
Androstenedione
Testosterone
Progesterone
Aromatase
Aromatase
Estrone
Estradiol
Cortisol
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• 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.

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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.
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• Androgens stands for a group of primarily male
  hormones
• testosterone
• androstenedione
• dehydroepiandrosterone).
• Androgens are also produced in the ovaries.

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Menstrual cycle irregularities1. abnormal
frequency
Kaltenbach chart
Duration 28 d ?5 Amount 3-5 pads
or tampons (?35 mL)



Normal cycle
Abnormal frequencyoligomenorrhea



Duration gt 35 days
Abnormal frequencypolymenorrhea



Duration lt 22 days
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Menstrual cycle irregularities2. abnormal
amount of duration



Duration 28 d ?5 Amount 3-5 pads
or tampons
Normal cycle



Hypomenorrhea
Amount lt 2 per day



Hypermenorrhea
Amount gt 5 per day



Menorhagia
Duration 7-14 days
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Menstrual cycle irregularities3. others

• Spotting bleeding unrelated to menses
• Ovulatory bleeding
• Metorrhagia gt 14 days, no clear cycle
• Amenorrhea absence of bleeding for more
  than 3 months

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Menstrual cycle irregularitiesprevalence 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.

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Menstrual cycle irregularitiescauses

• 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.

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Menstrual disorders

• Irregular patterns of bleeding
• Hypothalamic ovarian insufficiencyPsychogenic
  stress, anorexia nervosa
• Pituitary causesfor 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

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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.

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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).

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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.

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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.

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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 tissueEndometrial 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.

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Endometriosis - Causes

• Lymphatic distributionEndometrial material gets
  distributed throughout the body via the lymphatic
  system.
• Immune system dysfunctionWomen 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.

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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.