|Embryology - 30 Aug 2016 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Menstrual Parameters
- 4 Environmental Effects
- 5 Last Menstrual Period
- 6 Menstrual Cycle Histology
- 7 Human Oocyte Numbers
- 8 Follicle Development
- 9 Oocyte Development
- 10 Ovulation
- 11 Follicular Waves
- 12 Ovarian Stimulation
- 13 Fertility Window
- 14 Menopause
- 15 Oral Contraceptives
- 16 Abnormalities
- 17 References
- 18 Additional Images
- 19 Terms
- 20 External Links
- 21 Glossary Links
The human reproductive cycle, an cyclic endocrine regulated change in female anatomy and physiology that occur over 28 days (4 weeks, a lunar month) during reproductive life (between puberty and menopause). Endocrine changes during pregnancy block the menstrual cycle, which normally would shed the functional layer of the uterine lining each cycle. A common misunderstanding is that development of the follicles occurs within a single cycle, in fact humans require at least 3 menstrual cycles to occur in the development of an ovulating follicle.
- The average menstrual cycle is 28 days with ovulation (egg release) occuring approximately the middle of the cycle.
- The last menstrual period (LMP) is used clinically in determining developmental ages. (More Birth Date)
- Menstruation phase (menses, period) is the loss of the uterus epithelial functional layer and occurs if fertilization and implantation have not occurred before the end of the current cycle.
This cycle differs from other non-primate female vertebrates (eg rats, mice, horses, pig) that have a reproductive cycle called the estrous cycle (oestrous, British spelling).
- Menstrual Cycle Links: Introduction | Menstrual Cycle - Histology | Ovary | Oocyte | Uterus | Uterine Gland | Estrous Cycle | Pregnancy Test
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
M Almada, C Amaral, M Diniz-da-Costa, G Correia-da-Silva, N A Teixeira, B M Fonseca The endocannabinoid anandamide impairs in vitro decidualization of human cells. Reproduction: 2016, 152(4);351-361 PubMed 27568210
Olga Bikou, Alexander Delides, Aggeliki Drougou, Afroditi Nonni, Efstratios Patsouris, Kitty Pavlakis Fractal Dimension as a Diagnostic Tool of Complex Endometrial Hyperplasia and Well-differentiated Endometrioid Carcinoma. In Vivo: 2016, 30(5);681-690 PubMed 27566091
Cynthia L Harden, Page B Pennell, Jacqueline A French, Anne Davis, Connie Lau, Nichelle Llewellyn, Benjamin Kaufman, Emilia Bagiella, Ariel Kirshenbaum Anti-mullerian hormone is higher in seizure-free women with epilepsy compared to those with ongoing seizures. Epilepsy Res.: 2016, 127;66-71 PubMed 27565413
There is a broad variability in the parameters of the adult human menstrual cycle. The data below is based upon normal mid-reproductive years and using simplified terminology, Table IV from 2007 international agreement discussion. The same group also recommended replacing confusing clinical terms such as amenorrhea, menorrhagia, metrorrhagia, hypermenorrhea and dysfunctional uterine bleeding.
|Clinical dimensions of menstruation and menstrual cycle||Descriptive terms||Normal limits (5th - 95th percentiles)|
|Frequency of menses (days)||Frequent||< 24|
|Normal||24 - 38|
| Regularity of menses (days)
(cycle to cycle variation over 12 months)
|Regular||Variation ± 2 to 20 days|
|Irregular||Variation greater than 20 days|
|Duration of flow (days)||Prolonged||> 8.0|
|Normal||4.5 - 8.0|
|Volume of monthly blood loss (ml)||Heavy||> 80|
|Normal||5 - 80|
See also the article on iron depletion by whole-blood donation harms menstruating females. "The collection of 450 or 500 mL of whole blood, plus an additional 30 to 50 mL for blood tests, results in 480 to 550 mL of blood loss per whole-blood donation. These losses leads to a 60- to 88-g loss of hemoglobin (Hb) per whole-blood donation in women, based on a Hb range of 12.5 to 16.0 g per dL, and 204 to 299 mg of iron loss, based on 3.4 mg of iron per gram of Hb. This iron loss is 9 to 13 percent of the total body iron in an average woman (2300 mg), and it is 66 to 97 percent of the total stored iron in an average menstruating woman (309 mg). Therefore, whole-blood donation is an iron depletion event that causes significant iron loss in women."
- prevalence of iron deficiency in 20- to 49-year-old women before blood donation is 12 percent
- prevalence of iron deficiency in 16- to 69-year-old men is 2 percent
(based on data from the National Health and Nutrition Examination Survey (NHANES 1999-2000)
Changes in Brain Size
A recent MRI studyof women during the normal menstrual cycle correlated with hormone and ultrasound determination of ovulation has shown "that brain morphology varies during the menstrual cycle, with a (grey matter) volume peak at time of ovulation which can be estimated to be ~13,5 ml for a “standard” brain." They also identified "significant grey matter volume peak and CSF loss at the time of ovulation in females. This volume peak did not correlate with estradiol or progesterone hormone levels."
A recent paper has also demonstrated that the human menstral cycle can be modulated postnatally by environmental conditions as measured by changes in progesterone based upon the age of migration from a relatively poor environment (Bangladesh) to a relatively better environment (UnitedKingdom).
Luteal Progesterone Profiles by Age at UK Migration. Women who migrated during infancy and early childhood (ages 0 to 8 years) 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.
Last Menstrual Period
The Last Menstrual Period (LMP), the menstrual period (menses) that occurs before a pregnancy, has been widely used clinically as a date to calculate clinical pregnancy development (GA, gestational age). Note that in humans this is approximately two weeks different from embryonic development, which begins at fertilisation around the mid-point of the menstrual cycle.
The interval between the beginning of the LMP and fertilisation can have a wide range (7 to 25 days). This variation can be due to both maternal (menstrual cycle timing and ovulation) and fetal (blastocyst implantation) effects. The calculation also requires an accurate maternal recall of LMP and can be affected by irregular menses, first-trimester vaginal bleeding, unrecognized spontaneous abortions, oral contraceptive use.
Measurement of fetal size by ultrasound has been used more recently to accurately calculate pregnancy development. The ultrasound measurement tends to be more accurate in early development staging, by the third trimester there can be some individual variations in fetal growth and the effects of abnormalities or fetal growth restriction. Serial ultrasound measurements may identify these abnormal growth effects.
Gestational age GA is the clinical term given in week to describe human development timed from the first day of the last menstrual period (LMP). For gestational age in assisted reproductive technology pregnancy 2 weeks are added to the fertilisation date. Age therefore differs by approximately two weeks from research materials timed from fertilisation (conceptional age), this term is generally not used clinically.
Menstruation is also called menstrual bleeding, menses, catamenia or a period.
Menstrual Cycle Histology
The different stages of the menstrual cycle can be monitored by the cellular appearance of vaginal smears Menstrual Cycle - Histology.
A more invasive technique is dilate and curettage (DnC), which allows sampling of the functional layer of the uterine endometrium Menstrual Cycle - Histology.
Decidualization is the process of converting endometrial stromal cells into decimal cells and requires at least 8–10 days of hormone stimulation.
- initiated during the mid-secretory phase of the menstrual cycle
- in response to elevated progesterone levels
- acts mainly through progesterone receptor (PR) PR-A (other isoform is PR-B)
PMID: 21546446 Prokineticin 1 (PROK1) signalling via prokineticin receptor 1 (PROKR1) regulates Dickkopf 1 (DKK1) expression, a negative regulator of canonical Wnt signaling.
- Links: Placenta - Maternal Decidua
Human Oocyte Numbers
- The graph shows a model of non-growing follicle numbers based upon several histological studies of the human ovary.
- The maximum follicle number occurring around birth.
- These numbers decrease through childhood by apopotic cell death.
- At puberty there remain only about 180,000 remain.
- Only a small percentage will be released through reproductive life.
- At menopause only about 1,000 remain.
A common misunderstanding is that development of the follicle containing the oocyte occurs within a single cycle. In fact humans require at least 3 menstrual cycles to occur in the development of a single ovulating follicle. Most of the other follicles will degenerate in a process described as atresia.
- arrested at early Meiosis 1
- diploid: 22 chromosome pairs + 1 pair X chromosomes (46, XX) autosomes and sex chromosome
- Oogenesis- pre-antral then antral follicle (Graafian follicle is mature antral follicle released)
- 1 Day before ovulation completes (stim by LH) Meiosis 1
- haploid: 22 chromosomes + 1 X chromosome (23, X)
- nondisjunction- abnormal chromosome segregation
- begins Meiosis 2 and arrests at metaphase
- note no interphase replication of DNA, only fertilization will complete Meiosis 2
Laparoscopic observation of human ovulation.
Associated with follicle rupture is movement of the the ampulla region of the uterine horn.
- Hypothalmus releases gonadotropin releasing hormone (GRH, luteinizing hormone–releasing hormone, LHRH) -> Pituitary releases follicle stimulating hormone (FSH) and lutenizing hormone (LH) -> ovary follicle development and ovulation.
- release of the secondary oocyte and formation of corpus luteum
- secondary oocyte encased in zona pellucida and corona radiata
Rabbit ovulation also available as a movie.
Left or Right Ovulation
In humans, it is assumed that about equal numbers of ovulations occur from each of the ovaries. Whether ovulation in a succeeding cycle occurs ipsilaterally (same ovary; right/right or left/left) and contralaterally (opposite ovary; left/right or right/left) has also been studied. A shorter follicular phase length (less than 13 days) has been identified to correlate with a greater number of contralateral ovulations, while a follicular length greater than 14 days has a random ovulation.
Following ovulation, the ovulating follicle forms a unique endocrine structure, the corpus luteum. The corpus luteum functions to produce both progesterone and estradiol, with maximum function about 6 days following ovulation.
A study of blood flow during corpus luteal development identified:
- active angiogenesis occurs after the ovulatory LH surge
- becomes one of the most highly vascularized organs in the body
- provides luteal cells with large amounts of cholesterol (for progesterone synthesis)
- delivers this progesterone to the circulation
Follicular waves is a term referring to the growth of follicles in coordinated groups or waves, in humans this occurs either 2 to 3 times between ovulations. These waves have previously been described in several other mono-ovulatory species, such as the horse (equine) and cow (bovine).
A variety of drug based techniques are used to stimulate maternal oocyte development, called ovarian stimulation, for many assisted reproductive technology (in vitro fertilization) procedures. The recommended for technique will vary for some procedures and also from clinic to clinic and between countries.
An example of ovarian stimulation (based on PMID20953827)
- Gonadotrophin releasing hormone agonist (GnRHa) triptorelin acetate (Decapeptyl (0.1 mg/day) treatment started on the 22nd day of the preceding menstrual cycle.
- Human menopausal gonadotrophin (HMG) and/or follicular stimulating hormone (FSH) was carried out daily 12 to 15 days later.
- Dosage may vary dependent upon patient response and can be monitored by hourmone levels (oestradiol) and transvaginal ultrasound (follicular size).
- The resulting ovulatory wave generates large follicles (greater than 18 mm in diameter).
- Human chorionic gonadotrophin (HCG) is then administered (36 to 38 h later)
- Clinical transvaginal puncture is used to collect from these follicles cumulus-oocyte complexes.
- Cumulus-oocyte complexes can be processed to isolate oocytes.
- Links: Fertilization
Menopause, the "last period", a term describing the physiological changes that accompany the age related loss of fertility.
There is a decrease in ovarian follicle numbers, gradually elevated FSH levels, onset of cycle irregularity leading to the final cessation of menses. A recent review has looked at genetic factors that could affect the age at natural menopause and identified from linkage analyses (9q21.3 and chromosome 8 at 26 cM) and association studies genomic regions (19q13.42 and 20p12.3), containing two promising candidate genes (Bruck syndrome 1, BRKS1) and Menopause quantitative trait locus 3 (MENOQ3)..
Premature Ovarian Failure
Premature Ovarian Failure (POF) a clinical term describes the absence of normal ovarian function due to the depletion of the primordial follicle pool before 40 years of age a range of factors (autoimmune, iatrogenic, infections, genetic defects). This occurs in approximately 1% of women below 40 years of age.
Premature Ovarian Failure (POF) can be primary or secondary based on puberty.
- primary - absence of puberty, development and primary amenorrhea, generally caused by ovarian dysgenesis (45XO, Turner syndrome).
- secondary - normal puberty, usually present with the later disappearance of menstrual cycles.
A recent 2016 Danish study births from Danish registries between 1997 and 2011 identified that "Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects."
- Links: Abnormal Development
Infrequent Menstrual Cycle
An infrequent menstrual cycle (oligomenorrhea) can be due to a wide range of endocrine and other causes. Abnormal adrenal development, congenital adrenal hyperplasia, can be associated with both menstrual and genital changes.
Congenital Adrenal Hyperplasia
|Congenital Adrenal Hyperplasia|
|classic virilizing adrenal hyperplasia|| 21-hydroxylase, 11-beta-hydroxylase,
or 3-beta-hydroxysteroid dehydrogenase
|ambiguous genitalia at birth - complete or partial fusion of the labioscrotal folds and a phallic urethra to clitoral enlargement (clitoromegaly), partial fusion of the labioscrotal folds, or both||normal genitalia, present at age 1-4 weeks with salt wasting (salt-wasting adrenal hyperplasia)|
|simple virilizing adrenal hyperplasia||mild 21-hydroxylase||identified later in childhood because of precocious pubic hair, clitoral enlargement (clitoromegaly), or both, often accompanied by accelerated growth and skeletal maturation||early genital development (pubic hair and/or phallic enlargement) accelerated growth and skeletal maturation|
|nonclassic adrenal hyperplasia|| milder deficiencies of 21-hydroxylase
or 3-beta-hydroxysteroid dehydrogenase
|present at puberty or adult with infrequent menstruation (oligomenorrhea), abnormal hair growth (hirsutism), and/or infertility|
|17-hydroxylase deficiency syndrome|| 17-hydroxylase deficiency or
|rare, phenotypically female at birth do not develop breasts or menstruate in adolescence and may have hypertension||steroidogenic acute regulatory (StAR) deficiency have ambiguous genitalia or female genitalia, at puberty may lack breast development and may have hypertension|
- Jean-Christophe Lousse, Jacques Donnez Laparoscopic observation of spontaneous human ovulation. Fertil. Steril.: 2008, 90(3);833-4 PubMed 18440526
- Marcelo H Ratto, Yvonne A Leduc, Ximena P Valderrama, Karin E van Straaten, Louis T J Delbaere, Roger A Pierson, Gregg P Adams The nerve of ovulation-inducing factor in semen. Proc. Natl. Acad. Sci. U.S.A.: 2012, 109(37);15042-7 PubMed 22908303
- Donna D Baird, Anne Z Steiner Anti-Müllerian hormone: a potential new tool in epidemiologic studies of female fecundability. Am. J. Epidemiol.: 2012, 175(4);245-9 PubMed 22247047
- Ian S Fraser, H O D Critchley, M G Munro, M Broder Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum. Reprod.: 2007, 22(3);635-43 PubMed 17204526 | Hum Reprod.
- L Hallberg, A M Högdahl, L Nilsson, G Rybo Menstrual blood loss--a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand: 1966, 45(3);320-51 PubMed 5922481
- S D Harlow, S A Ephross Epidemiology of menstruation and its relevance to women's health. Epidemiol Rev: 1995, 17(2);265-86 PubMed 8654511
- Hagemann, G., etal., Changes in Brain Size during the Menstrual Cycle PLoS One. 2011; 6(2): e14655 PMC3033889
- Alejandra Núñez-de la Mora, Robert T Chatterton, Osul A Choudhury, Dora A Napolitano, Gillian R Bentley Childhood conditions influence adult progesterone levels. PLoS Med.: 2007, 4(5);e167 PubMed 17503960 | PLoS Medicine
- William A Engle, American Academy of Pediatrics Committee on Fetus and Newborn Age terminology during the perinatal period. Pediatrics: 2004, 114(5);1362-4 PubMed 15520122 | Pediatrics
- Antonin Bukovsky, Michael R Caudle, Marta Svetlikova, Nirmala B Upadhyaya Origin of germ cells and formation of new primary follicles in adult human ovaries. Reprod. Biol. Endocrinol.: 2004, 2;20 PubMed 15115550
- S Begum, V E Papaioannou, R G Gosden The oocyte population is not renewed in transplanted or irradiated adult ovaries. Hum. Reprod.: 2008, 23(10);2326-30 PubMed 18596027
- W Hamish B Wallace, Thomas W Kelsey Human ovarian reserve from conception to the menopause. PLoS ONE: 2010, 5(1);e8772 PubMed 20111701 | PLoS One.
- M Fukuda, K Fukuda, C Y Andersen, A G Byskov Contralateral selection of dominant follicle favours pre-embryo development. Hum. Reprod.: 1996, 11(9);1958-62 PubMed 8921071
- A R Baerwald, G P Adams, R A Pierson Form and function of the corpus luteum during the human menstrual cycle. Ultrasound Obstet Gynecol: 2005, 25(5);498-507 PubMed 15846762
- N Ferrara, H Chen, T Davis-Smyth, H P Gerber, T N Nguyen, D Peers, V Chisholm, K J Hillan, R H Schwall Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat. Med.: 1998, 4(3);336-40 PubMed 9500609 | PMC2633338
- A J Wilcox, D Dunson, D D Baird The timing of the "fertile window" in the menstrual cycle: day specific estimates from a prospective study. BMJ: 2000, 321(7271);1259-62 PubMed 11082086 | PMC27529 | BMJ
- F J Broekmans, M R Soules, B C Fauser Ovarian aging: mechanisms and clinical consequences. Endocr. Rev.: 2009, 30(5);465-93 PubMed 19589949 | Endocr Rev
- Marlies Voorhuis, N Charlotte Onland-Moret, Yvonne T van der Schouw, Bart C J M Fauser, Frank J Broekmans Human studies on genetics of the age at natural menopause: a systematic review. Hum. Reprod. Update: 2010, 16(4);364-77 PubMed 20071357
- Lisette Stolk, Guangju Zhai, Joyce B J van Meurs, Michael M P J Verbiest, Jenny A Visser, Karol Estrada, Fernando Rivadeneira, Frances M Williams, Lynn Cherkas, Panos Deloukas, Nicole Soranzo, Jules J de Keyzer, Victor J M Pop, Paul Lips, Corinne E I Lebrun, Yvonne T van der Schouw, Diederick E Grobbee, Jacqueline Witteman, Albert Hofman, Huibert A P Pols, Joop S E Laven, Tim D Spector, André G Uitterlinden Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat. Genet.: 2009, 41(6);645-7 PubMed 19448619
- Paolo Beck-Peccoz, Luca Persani Premature ovarian failure. Orphanet J Rare Dis: 2006, 1;9 PubMed 16722528
- Brittany M Charlton, Ditte Mølgaard-Nielsen, Henrik Svanström, Jan Wohlfahrt, Björn Pasternak, Mads Melbye Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. BMJ: 2016, 352;h6712 PubMed 26738512 | BMJ
- Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Walker HK, Hall WD, Hurst JW, editors. Boston: Butterworths; 1990. Birth Control | Figure 174.1 A 28-day menstrual cycle. Not all cycles are 28 days long. It is the phase before ovulation that varies in length.
- Endocrinology: An Integrated Approach. Nussey S, Whitehead S. Oxford: BIOS Scientific Publishers; 2001. Box 6.42 The human menstrual cycle | Box 6.43 Feedback control of the hypothalamo-pituitary-ovarian axis
- The primordial pool of follicles and nest breakdown in mammalian ovaries. Tingen C, Kim A, Woodruff TK. Mol Hum Reprod. 2009 Dec;15(12):795-803. Epub 2009 Aug 26. Review. PMID: 19710243 | Mol Hum Reprod.
Ilkka Y Järvelä, Aimo Ruokonen, Aydin Tekay Effect of rising hCG levels on the human corpus luteum during early pregnancy. Hum. Reprod.: 2008, 23(12);2775-81 PubMed 18694877
A J Wilcox, D Dunson, D D Baird The timing of the "fertile window" in the menstrual cycle: day specific estimates from a prospective study. BMJ: 2000, 321(7271);1259-62 PubMed 11082086
David B Dunson, Bernardo Colombo, Donna D Baird Changes with age in the level and duration of fertility in the menstrual cycle. Hum. Reprod.: 2002, 17(5);1399-403 PubMed 11980771
M Fukuda, K Fukuda, C Y Andersen, A G Byskov Contralateral selection of dominant follicle favours pre-embryo development. Hum. Reprod.: 1996, 11(9);1958-62 PubMed 8921071
- File:Ovary- histology secondary follicle 01.jpg
- arteric corpora lutea -
- corpora - (singular corpus) a number of bodies.
- corpus - (plural corpora) body, aggregate, or mass.
- corpus heamorrhagicum - (corpus hemorrhagicum, bloody body) ovulating (Graffian) follicle immediately following ovulation, also described as an early corpus luteum.
- corpus luteum - (Latin, yellow body)
- metrorrhagia - Clinical term used to describe uterine bleeding at irregular intervals between the normal menstrual cycle periods (menses).
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Cite this page: Hill, M.A. (2016) Embryology Menstrual Cycle. Retrieved August 30, 2016, from https://embryology.med.unsw.edu.au/embryology/index.php/Menstrual_Cycle
- © Dr Mark Hill 2016, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G