1. Wilfried Karmaus Reproductive Epidemiology EPI 824
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

3. Number of oocytes at different ages
# 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

4. 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).

5. 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

6. 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).

7. 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

8. 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.

9. 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.

10. Stages of the climacteric
Climacteric: 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

11. 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.

12. 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.

13. Prevalence of hot flushes
Mayan women: %
Hong Kong women: %
Japanese women: 17%
Thai women: %
North American: %
Dutch women: up to 80%.

14. 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.

15. 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.

16. Menstrual cycle Timing
Follicular phase: day 1-14, menses: day 1-5
Ovulatory phase: day 14-16
Luteal phase: day 16-28

17. Days 1-5: Estrogen Falls, FSH Rises.
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

18. 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.

19. 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.

21. 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.

23. Stages of follicle growth
335 days
20-30%
Atresia
Selection: 10 days
80%
Maturation: 10 days
Initiation

24. 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
Estrogens
Androgens
Androgens
High estrogens
low progesterone
Feedback: negative
positive

25. Pathway of steroid hormones
Cholesterol (mitochondria)
Dehydro-epiandrosterone
Pregnenolone
Androstenediol
Androstenedione
Testosterone
Progesterone
Aromatase
Aromatase
Estrone
Estradiol
Cortisol

26. 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.

28. 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.

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

30. Menstrual cycle irregularities: 1. abnormal frequency
Kaltenbach chart:
Duration: 28 d 5
Amount: 3-5 pads or tampons (35 mL)
Normal cycle
Abnormal frequency: oligomenorrhea
Duration > 35 days
Abnormal frequency: polymenorrhea
Duration < 22 days

31. Menstrual cycle irregularities: 2. abnormal amount of duration
Duration: 28 d 5
Amount: 3-5 pads or tampons
Normal cycle
Hypomenorrhea
Amount < 2 per day
Hypermenorrhea
Amount > 5 per day
Menorhagia
Duration 7-14 days

32. 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

33. 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.

34. 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.

35. 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

36. 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.

37. 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).

38. 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.

39. 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
% of women undergoing diagnostic laparoscopy,
30 -40% of infertile women having laparoscopy,
% of women with pelvic pain.

40. 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.

41. 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.

42. 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.