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UNSW Embryology

Human Menstrual Cycle

© Dr Mark Hill (2011)

Acknowledgements

Introduction

The human menstrual cycle involves a complex and regular change in female anatomy and physiology over an approximate monthly time period. This cycle commences at puberty and ceases at menopause.

The program includes images of both routine vaginal smears (identifying cell populations) and dilatation and curettage sampling of endometrium (identifying the epithelial changes).

In other species of non-primate vertebrates (eg rats, mice) a similar occurs in females called an estrous cycle

Page Links: Introduction | Some Recent Findings | Menstrual Cycle-Graph | Oogenesis | Human Vaginal Smears | Human Uterus Endometrium | Ovulation | Postnatal Cycle Flexibility | History of the Pap Smear | Dilate and Curettage | Circulating Blood Cells | Uterine Tube | Abnormalities | Endometriosis | The Pill | Menopause | Histology | WWW Links | Menstrual Terms | Glossary

Other Pages: Genital System - Female Uterus | Genital System - Female | Week 1 - Oogenesis

Some Recent Findings

Bryant GA, Haselton MG. Vocal cues of ovulation in human females. Biol Lett. 2008 Oct 8.

"Recent research has documented a variety of ovulatory cues in humans, and in many nonhuman species, the vocal channel provides cues of reproductive state. ...When speaking a simple introductory sentence, women's pitch increased during high- (the 2 days just before ovulation) as compared with low-fertility"

Nunez-de la Mora A, Chatterton RT, Choudhury OA, Napolitano DA, Bentley GR. Childhood Conditions Influence Adult Progesterone Levels. PLoS Med. 2007 May 15;4(5):e167 (More? Postnatal Cycle Flexibility | PLoS Medicine - Article)

"This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults."

Masuda H, Maruyama T, Hiratsu E, Yamane J, Iwanami A, Nagashima T, Ono M, Miyoshi H, Okano HJ, Ito M, Tamaoki N, Nomura T, Okano H, Matsuzaki Y, Yoshimura Y. Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/{gamma}cnull immunodeficient mice. Proc Natl Acad Sci U S A. 2007 Jan 29

"singly dispersed endometrial cells have potential applications for tissue reconstitution, angiogenesis, and human-mouse chimeric vessel formation, providing implications for mechanisms underlying the physiological endometrial regeneration during the menstrual cycle and the establishment of endometriotic lesions."

Brandes JL. The influence of estrogen on migraine: a systematic review. JAMA. 2006 Apr 19;295(15):1824-30.

"The influence of estrogen on migraine is evident by a 3-fold greater prevalence among women compared with men, and by significant changes in migraine incidence with changes in female reproductive status. ...Epidemiological, pathophysiological, and clinical evidence link estrogen to migraine headaches."

Smellie WS. Cases in primary care laboratory medicine: testing pitfalls and summary of guidance on sex hormone testing. BMJ. 2007 Jan 13;334(7584):91-4.

"Hormone testing has very limited use in diagnosing the menopause
Monitoring patients on hormone replacement therapy relies on clinical response in most situations
Early investigation of subfertility is recommended only in specific groups of patients
A detailed menstrual history is essential to interpret gonadotrophin results
A luteal progesterone concentration above 20-30 nmol/l seven days before onset of menses effectively excludes endocrine related subfertility; intermediate concentrations may necessitate a repeat test"

Wintermantel TM, Campbell RE, Porteous R, Bock D, Grone HJ, Todman MG, Korach KS, Greiner E, Perez CA, Schutz G, Herbison AE. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron. 2006 Oct 19;52(2):271-80. Using a mouse knock out model they have shown "...ovulation is driven by estrogen actions upon estrogen receptor alpha-expressing neuronal afferents to gonadotropin-releasing hormone (GnRH) neurons"

Menstrual Cycle- hormones, temperature, ovulation

Oogenesis

The graph below shows the changes in human germ cell numbers in the ovary with age, peaking at about 7 million (occuring in early fetal development) and then decreasing by apopotic cell death. At puberty there remain only about 400,000 and only about 10% of these will be released through reproductive life. (More? Genital Notes)

Oocyte number

(Based on data from: Hassold, etal., Environ Mol Mutagen 1996. 28: 167-175)

Human Vaginal Smears

Clicking on the small images on this page links to the full size images of Vaginal Pap smears (More? Pap Smear) and Uterine D&C endometrium (More? DnC). Compare the appearance of the uterine endometrium with that seen during pregnancy.

 

Phase

Days

Smear

Description

Uterine (D&C)

Menstrual

1 - 4

Click on image to see full size.

Both stratum corneum (red) and stratum spinosum (blue) epithelial cells will mostly blood. Leukocytes and bacteria may also be present.

Early Proliferative

5 - 9

mainly large and small basophilic (blue) stratum spinosum cells.

 

Mid Proliferative

9 - 13

Stratum spinosum (blue) increase in size. Dark precipate outside cells are bacteria.

Late Proliferative, Ovulatory

13-14

mainly stratum corneum (red) which are large and flat, appear due to high estrogen levels.

Secretory

15 - 22

stratum spinosum cells (blue) which are folded or with curled edges, appear immediately after ovulation due to increase in progesterone. Leukocytes (small black cells) becoming more numerous.

Late Secretory, (Ischemic) Premenstrual

23 - 28

stratum spinosum cells (blue) mainly with a few stratum corneum cells (red). Clustering of cells occurs at this stage and both leukocytes and bacteria are prevelant.

Ovulation

Ovulation can be determined by a number of different luteinizing hormone (LH) urinary tests.

Commercial tests: OvuQuick, Clearplan, OvuKit, Sure Step, Q Test Ovulation Predictor, and EZ LH (Note: commercial information is listed only for educational information purposes and is not an endorsement)

Reference:

Nielsen MS, Barton SD, Hatasaka HH, Stanford JB. Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick. Fertil Steril. 2001 Aug;76(2):384-7.

Miller PB, Soules MR. The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal women. Obstet Gynecol. 1996 Jan;87(1):13-7.

Matijevic R, Grgic O. Predictive values of ultrasound monitoring of the menstrual cycle. Curr Opin Obstet Gynecol. 2005 Aug;17(4):405-10.

Postnatal Cycle Flexibility

A recent paper has demonstrated that the human menstral cycle can be modulated postnatally by environmental conditions as measured by changes in progesterone based upon age of migration from a relatively poor environment (Bangladesh) to a relatively better environment (UK). Nunez-de la Mora A, Chatterton RT, Choudhury OA, Napolitano DA, Bentley GR. Childhood Conditions Influence Adult Progesterone Levels. PLoS Med. 2007 May 15;4(5):e167 (More? PLoS Medicine - Article)

Average Luteal Progesterone Profiles by Group

SYL - resident Bangladeshi sedentees from Sylhet

ADU - adult migrants

CHI - child migrants

2ndGEN - second-generation British-Bangladeshis

WHI - British women of European descent

Unadjusted mean luteal progesterone index values. Ovulation dates were estimated from oestradiol data available for the same individual menstrual cycles.

(More? PLoS Medicine - Article)

Average Luteal Progesterone Profiles by Categories of Age at Migration to the UK

Women who migrated during infancy and early childhood (ages 0–8 y) had a significantly earlier age at menarche.

Women who migrated after menarche, length of time spent in the UK had no significant impact on luteal progesterone levels.

(More? PLoS Medicine - Article)

Data: Nunez-de la Mora A, Chatterton RT, Choudhury OA, Napolitano DA, Bentley GR. Childhood Conditions Influence Adult Progesterone Levels. PLoS Med. 2007 May 15;4(5):e167 (More? PLoS Medicine - Article)

Circulating Blood Cells

Blood Cells

Historic analysis of circulating blood cell counts (not smear analysis) over the course of the normal menstrual cycle showed:

(Bain BJ, England JM., 1975)

Neutrophil

Changes in neutrophil count seem to follow changes in oestrogen level with a delay of one to two days.

Normally in other tissues neutrophils (neutrophil granulocytes) are granulocytes that have a central role in the inflammatory process, containing enzymes with strong bactericidal actions. Cell nucleus has a characteristic lobed appearance (3-5 lobes), the number of lobes increases with cell age.

During menstruation increased neutrophils presence aids anti-bacterial protection when the epithelial barrier is disrupted.

Neutrophils are a source of several anti-microbials including: alpha-defensins, lactoferrin, lysozyme and WAP motif protein, elafin.

Neutrophil Numbers during Menstrual cycle
 

Changes in circulating Neutrophil Number and other parameters during menstrual normal cycle

(Image: Bain BJ, England JM., 1975)

Reference:

Bain BJ, England JM. Variations in leucocyte count during menstrual cycle. Br Med J. 1975 May 31;2(5969):473-5.

Immune Factors

In addition to the nutritional role of endometrium a number of factors released have a role in innate immune defence.

Secretory leukocyte protease inhibitor - expressed during the secretory phase of the cycle and possible roles include anti-protease and anti-microbial activity.

Beta-Defensin - anti-microbials

Whey acidic protein (WAP) motif proteins - anti-microbials

Reference:

King AE, Critchley HO, Kelly RW. Innate immune defences in the human endometrium. Reprod Biol Endocrinol. 2003 Nov 28;1:116.

Uterine Tube

Right Ovary and Uterine Tube

The uterine tube (Fallopian tube, oviduct) is paired (left and right tubes) and the typical site of fertilization and the first week of human development. The most common form of ectopic pregnancy, tubal pregnancy, also occurs here.

At ovulation the egg is released into the peritoneal cavity and enters at the uterine ostium (opening). The egg and its surrounding cells is then moved along the lining of the tube by ciliated columnar epithelium and uterine contractions.

The uterine tube has been described in 4 anatomical regions.

  1. Infundibulum - funnel-shaped open end of the uterine tube with fimbriae (finger-like extensions), which are closely associated with the ovary. Opens into the peritoneal cavity (abdominal ostium, ostium abdominale)
  2. Ampulla - uterine tube with highly folded structure with plicae (mucosal folds) and secondary folds dividing the lumen, usual site for fertilization.
  3. Isthmus - narrow portion of the uterine tube with fewer mucosal folds and a thick muscularis layer.
  4. Intramural - uterine tube which passes through the muscular wall of the uterus. (an alternative interpretation is that it is an extension of the body of the uterus)

Histologically the uterine tube has four layers (tunicas) beginning at the lumen they are:

  1. tunica mucosa
  2. tunica submucosa
  3. tunica muscularis
  4. tunica serosa

Tubal abnormalities include: scarring, ciliated cysts, adenoma, salpingitis isthmica nodosa

(More? Genital System - Female Uterus)

History of the Pap Smear

"Luckily, we have the famous Pap Smear - an excellent way to find cancer of the cervix before it digs in locally and/or spreads throughout the body. The Pap Smear is named after a certain Dr. Papanicolaou - who did a Pap Smear on his wife virtually every day for 20 years.

George Nikolas Papanicolaou was born in 1883 in Kymi, a small town overlooking the Aegean Sea on the Island of Euboea in Greece. His father, Nikolas Papanicolaou was both the Major of Kymi and a medical doctor. His older brother, Naso, had studied law, so his father convinced George to continue in the family medical tradition. So George studied medicine, and did well, graduating with a degree in honours in 1904............" (text excerpt from WWW Link below)

source: ABC-Great Moments in Science "The Pap Smear" (AUS)

Dilate and Curettage

Uterine endometrium collected by Dilate and Curettage (D&C). This medical procedure is used to diagnose or treat uterine abnormalities or in association with a miscarriage.

Reference: Bidus MA, Elkas JC, Rodriguez M, Maxwell GL, Rose GS.   [See Related Articles] The clinical utility of the diagnostic endocervical curettage. Clin Obstet Gynecol. 2005 Mar;48(1):202-8.

Links: MedlinePlus- D and C - series: Procedure | MedlinePlus- Tutorial |

Abnormalities

Amenorrhea is the absence of a menstrual period, it can be either primary (before menarche, not yet had a period by age 16) or secondary (after menarche, regular period that has now stopped for 3 months). There are many different causes of this condition.

Reference: American Academy of Family Physicians Information from your family doctor. Amenorrhea: what you should know. Am Fam Physician. 2006 Apr 15;73(8):1387.

Menorrhagia or heavy menstrual bleeding, is common in women of reproductive age (WHO data, affected 1011 out of 5322 women).

Dysmenorrhea or painful menstrual period, can be common with no associated abnormality (primary) or in association with ovarian cysts or endometriosis (secondary). Primary period pain is generally due to an increased sensitivity to the prostaglandins.

Search PubMed: term = Amenorrhea | Menorrhagia | Dysmenorrhea

Endometriosis

Left Ovary Endometreosis

This condition is a painful, chronic disease that affects 5.5 million women and girls in the USA and Canada, and millions more worldwide. It occurs when tissue that lines the uterus (called the endometrium) is found outside the uterus. This can occur in the abdomen on the ovaries, fallopian tubes, and ligaments that support the uterus; the area between the vagina and rectum; the outer surface of the uterus; and the lining of the pelvic cavity. Left Uterosacral Ligament Endometreosis

Other sites for these endometrial growths may include the bladder, bowel, vagina, cervix, vulva, and in abdominal surgical scars. Less commonly they are found in the lung, arm, thigh, and other locations.

This misplaced tissue develops into growths or lesions which respond to the menstrual cycle in the same way that the tissue of the uterine lining does: each month the tissue builds up, breaks down, and sheds. Menstrual blood flows from the uterus and out of the body through the vagina, but the blood and tissue shed from endometrial growths has no way of leaving the body. This results in internal bleeding, breakdown of the blood and tissue from the lesions, and inflammation -- and can cause pain, infertility, scar tissue formation, adhesions, and bowel problems.

Diagnosis is considered uncertain until proven by laparoscopy, a minor surgical procedure done under anesthesia. A laparoscopy usually shows the location, size, and extent of the growths.

Ectopic endometrial implants respond to natural or induced decreases in estrogen levels (the disorder is "estrogen dependent"), with the most common pharmacological treatment being a class of drugs called gonadotropin-releasing hormone (GnRH) agonists.

(Text modified from: Endometriosis Association USA and other sources)

Recent studies suggest that mechanisms underlying endometriosis pains and sensitivity to estrogen, involve growth into ectopic endometrial tissue of a nerve supply. This may have a varied and widespread influence on the activity of neurons throughout the central nervous system. (More? The Pains of Endometriosis Science 308:1587-1589, 10 June 2005)

Links: Endometriosis Association USA | Endometriosis Information Brochures | Merck- Womens Health | Science 2005- The Pains of Endometriosis

Search PubMed: term = Endometriosis

The Pill

The birth control pill is made up of two hormones, oestrogen and progestogen and these stop a woman's ovaries from releasing an egg each month (ovulation), which means that a pregnancy cannot begin.

"Offering a method of birth control of unprecedented reliability, the Pill's introduction in (Australia)1961 gave birth to a worldwide anti-spawning revolution. The new contraceptive offered women greater control over their fertility and in several countries, was timed with a societal shift that saw greater sexual freedom for women. In the wider picture, the world suddenly had a potential tool for tackling the problem of unrestrained population growth. Since 1961 over 200 million women throughout the world have used the Pill......." (text excerpt from: ABC (AUS) - A Pill a Day)

Additional Links: ABC (AUS)- TimeFrame | Family Planning Association | The Pill Factsheet

Menopause

A complex physiological change that occurs generally as women age and falling hormone levels lead eventually to fertility loss. Also begun in the 1930's controversial hormone replacement therapy (HRT) has been used to treat some of the physiological changes that occur with menopause. The ABC website below gives an excellent review of Meopause, its history and physiological changes.

"During the 1800s , the term 'menopause' (first used by the French physician, de Gardanne in 1812) became more widely known; and throughout the 1800s, growing interest in anatomy led to a search for the causes of disease not in bodily fluids, but in particular organs. For women, whose most important social role was to have children, the reproductive organs were central. From them, "women's nature, their essence, their total wellbeing" was thought to originate.........." (text excerpt from: ABC (AUS) Menopause Myths and Medicine )

Search PubMed: term = Menopause

Histology

Histology images of the ovary during the menstrual cycle can be seen on the page Week 1 - Oogenesis and images of the uterus on the page Genital System - Female Uterus.

Links: (require internet connection) Blue Histology - Female Reproductive System | Virtual Slidebox of Histology - Female Reproductive System

WWW Links

Menstrual Terms

endometriosis-
dilatation and curettage-
(dnc) a clinical method for sampling the endometrium (identifying the epithelial changes)
endometrium-
hormone replacement therapy (HRT)- The artificial treatment of women with Oestrogen and Progesterone to treat some physiological changes that occur with Menopause. There is evidence that treatment with Oestrogen alone can lead to an increase risk of endometrial cancer. (see ABC- Menopause HRT)
menopause- A complex physiological change that occurs generally as women age and falling hormone levels lead eventually to fertility loss.
menstrual cycle-
myometrium-
oestrous cycle-
Pap Smear- Named after George Nikolas Papanicolaou who developed a vaginal smear technique now used in the early detection of cancer.
pubery-
smears- a simple technique for collecting surface cells and identifying cell populations.

Glossary of Terms

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