Menstrual cycle

Wilfried KarmausReproductive Epidemiology

EPI 824

Overview• 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 agesNumber 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

• 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.

• 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.

Menopause

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

• 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.

Menopause

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%.

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.

Menopause

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 uterus.

Figure taken from

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 growthStages of follicle growth

Initiation

Growth

335 days

Selection: 10 days

Maturation: 10 days

Atresia

20-30%

80%

Endrocrine control of the menstrual cycle

Early to mid-follicular phase Hypothalamu

s

Pituitary gland

FollicleGranulos

a cellsTheca cells

GnRH

FSH LH

Androgens

Estrogens

Feedback: negative

positive

Hypothalamus

Pituitary gland

FollicleGranulos

a cellsTheca cells

GnRH

FSH LH

Androgens

High estrogens

Late follicular phase & ovulation

low progesterone

Inhibin

Progesterone

Pregnenolone

Cholesterol (mitochondria)

Dehydro-epiandrosteron

eAndrostenediol

Androstenedione

Cortisol

Estrone Estradiol

Testosterone

AromatasAromatasee

AromatasAromatasee

Pathway of steroid hormones

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 Menstrual cycle irregularities:irregularities:

1. abnormal frequency1. abnormal frequency

Normal cycle

Duration: 28 d 5

Amount: 3-5 pads or tampons (35 mL)Abnormal

frequency:oligomenorrhea

Duration > 35 days

Duration < 22 daysAbnormal frequency:polymenorrhea

Kaltenbach chart:

Menstrual cycle Menstrual cycle irregularities:irregularities:

2. abnormal amount of 2. abnormal amount of durationduration

Normal cycle

Duration: 28 d 5

Amount: 3-5 pads or tampons

Hypomenorrhea

Amount < 2 per day

Amount > 5 per day

Hypermenorrhea

Duration 7-14 daysMenorhagia

Menstrual cycle Menstrual cycle irregularities:irregularities:

3. others3. 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 Menstrual cycle irregularities:irregularities:

prevalence and risksprevalence 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 Menstrual cycle irregularities:irregularities:

‘causes’‘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 disordersMenstrual 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)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).

EndometriosisEndometriosis• 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.

EndometriosisEndometriosisThe 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 - CausesEndometriosis - Causes• Retrograde menstruation: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:Embryonic tissue:Endometrial tissue was present abnormally when the woman was an embryo. The tissue becomes active in reproductive life.  

• Genetic explanation:Genetic explanation: Women with endometriosis frequently come from families with a high incidence of the disease.

Endometriosis - CausesEndometriosis - Causes

• Lymphatic distribution:Lymphatic distribution:Endometrial material gets distributed throughout the body via the lymphatic system.

• Immune system dysfunctionImmune 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 influencesEnvironmental 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.