Advanced maternal age

Last updated

Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction. [1] The variability in definitions is in part explained by the effects of increasing age occurring as a continuum rather than as a threshold effect. [1]

Contents

Average age at first childbirth has been increasing, especially in OECD countries, among which the highest average age is 32.6 years (South Korea) followed by 32.1 years (Ireland and Spain). [2] In a number of European countries (Spain), the mean age of women at first childbirth has crossed the 30 year threshold. [3] This process is not restricted to Europe. Asia, Japan and the United States are all seeing average age at first birth on the rise, and increasingly the process is spreading to countries in the developing world such as China, Turkey and Iran. In the U.S., the average age of first childbirth was 26.9 in 2018. [4]

Advanced maternal age is associated with adverse reproductive effects including increased risk of infertility, [5] and chromosomal abnormalities in children. [6] The corresponding paternal age effect is less pronounced. [7] [8]

History

Having children later was not exceptional in the past, when families were larger and women often continued bearing children until the end of their reproductive age. What is so radical about this recent transformation is that it is the age at which women give birth to their first child, which is becoming comparatively high, leaving an ever more constricted window of biological opportunity for second and subsequent children, should they be desired. Unsurprisingly, high first-birth ages and high rates of birth postponement are associated with the arrival of low, and lowest-low fertility. [9]

This association has now become especially clear, since the postponement of first births in a number of countries has now continued unabated for more than three decades and has become one of the most prominent characteristics of fertility patterns in developed societies. A variety of authors (in particular, Lesthaeghe) have argued that fertility postponement constitutes the "hallmark" of what has become known as the “second demographic transition”. [ citation needed ]

Others have proposed that the postponement process itself constitutes a separate "third transition". [10] On this latter view, modern developed societies exhibit a kind of dual fertility pattern, with the majority of births being concentrated either among very young or increasingly older mothers. This is sometimes known as the “rectangularisation” of fertility patterns.

Examples

In the USA, the average age at which women bore their first child advanced from 21.4 years old in 1970 [11] to 26.9 in 2018. [4]

The German Federal Institute for Population Research claimed in 2015 the percentage for women with an age of at least 35 giving birth to a child was 25.9%. This figure rose from 7.6% in 1981. [12]

Possible factors that influence childbearing age

There are many factors that may influence childbearing age in women, although they are mostly correlations without certain causations. For instance, older maternal age at first childbirth is associated with higher educational attainment and income. [13]

Two studies show that generous parental leave allowances in Britain encourage young motherhood and that parental-leave allowance reduces postponement in Sweden. [14]

Effects

Decreased fertility

Cumulative percentage and average age for women reaching subfertility, sterility, irregular menstruation and menopause. Age and female fertility.png
Cumulative percentage and average age for women reaching subfertility, sterility, irregular menstruation and menopause.

A woman's fertility peaks lasts during the twenties and first half of thirties, after which it starts to decline, with advanced maternal age causing an increased risk of female infertility.

According to Henri Leridon, PhD, an epidemiologist with the French Institute of Health and Medical Research, of women trying to get pregnant, without using fertility drugs or in vitro fertilization: [5]

At age 30  75% will have a conception ending  
in a live birth within one year 		91% will have a conception ending  
in a live birth within four years.
At age 35 66% will have a conception ending  
in a live birth within one year 		84% will have a conception ending  
in a live birth within four years.
At age 40 44% will have a conception ending  
in a live birth within one year 		64% will have a conception ending  
in a live birth within four years. [5]

Risk of birth defects

A woman's risk of having a baby with chromosomal abnormalities increases with her age. Down syndrome is the most common chromosomal birth defect, and a woman's risk of having a baby with Down syndrome is: [16] [6]

Risk of having a baby with Down syndrome
 Age Risk
201/ 2 000 

24
1/ 1 300 

25
1/ 1 200 

29
1/ 950 

30
1/ 900 
 Age Risk
341/ 450 

35
1/ 350 

39
1/150

40
1/ 100 
 Age Risk
441/ 40 

45
1/ 30 

49
1/ 10 

Other effects

Advanced maternal age is associated with adverse outcomes in the perinatal period, which may be caused by detrimental effects on decidual and placental development. [17]

The risk of the mother dying before the child becomes an adult increases by more advanced maternal age, such as can be demonstrated by the following data from France in 2007: [18]

Maternal age at childbirth (years)    202530354045
Risk of mother not surviving to   
the child's 18th birthday (in %) [18] 		  0.6 %1.0 %1.6 %2.6 %3.8 %5.5 %

The above table is not to be confused with maternal mortality.

Advanced maternal age continues to be associated with a range of adverse pregnancy outcomes including low birth weight, pre-term birth, stillbirth, unexplained fetal death, and increased rates of Caesarean section. However, over time, improvements in (and improvements in access to) medical services and social resources have decreased the negative association between older maternal age and low birth weight. [19]

On the other hand, advanced maternal age is associated with a more stable family environment, higher socio-economic position, higher income and better living conditions, as well as better parenting practices [18] (including better disciplinary methods [20] ). A qualitative study on couples in the United States who used in-vitro fertilization to conceive their first child when the woman was aged 40 or older at the time of delivery found that 72% of the women and 57% of the men believed that they had enhanced emotional preparedness for parenting which benefitted both their children and themselves. [21] In quantitative studies, mother’s older age at first birth has been associated with increases in children’s psychiatric health, [22] language skills, [22] cognitive ability, [23] and fewer social and emotional difficulties. [20] Further, a study in the United Kingdom showed that older maternal age at first birth was associated with fewer hospital admissions and fewer unintentional injuries for children up to age 5 and a greater likelihood of having had all of their immunizations by 9 months of age – all outcomes used as indicators of child wellbeing in reports from the World Health Organisation. [24]

Changes in interpregnancy interval

Kalberer et al. [25] have shown that despite the older maternal age at birth of the first child, the time span between the birth of the first and the second child (the interpregnancy interval) decreased over the last decades. If purely biological factors were at work, it could be argued that interpregnancy interval should have increased, as fertility declines with age, which would make it harder for the woman to get a second child after postponed birth of the first one. This not being the case shows that sociologic factors (see above) prime over biological factors in determining interpregnancy interval.

With technology developments cases of post-menopausal pregnancies have occurred, and there are several known cases of older women carrying a pregnancy to term, usually with in vitro fertilization of a donor egg. A 61 year-old Brazilian woman, aided by the implantation of a donor egg, gave birth to twins in October 2012. [26] [27]

Ovarian aging

As women age, they experience a decline in reproductive performance leading to menopause. [28] This decline is tied to a decline in the number of ovarian follicles. Although about 1 million oocytes are present at birth in the human ovary, only about 500 of them (about 0.05%) ovulate, and the rest do not (ovarian follicle atresia). The decline in ovarian reserve appears to occur at a constantly increasing rate with age, [29] and leads to nearly complete exhaustion of the reserve by about age 51. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors resulting in chromosomally abnormal conceptions.

Titus et al. [30] have proposed an explanation for the decline in ovarian reserve with age. They showed that as women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that normally accurately repairs DNA double-strand breaks. This repair system is referred to as homologous recombinational repair, and it is especially active during meiosis. Meiosis is the general process by which germ cells are formed in eukaryotes, and it appears to be an adaptation for efficiently removing damages in germ line DNA by homologous recombinational repair (see Origin and function of meiosis). Human primary oocytes are present at an intermediate stage of meiosis, that is prophase I (see Oogenesis). Titus et al. [30] also showed that expression of four key DNA repair genes that are necessary for homologous recombinational repair ( BRCA1 , MRE11 , Rad51 and ATM ) decline in oocytes with age. This age-related decline in ability to repair double-strand damages can account for the accumulation of these damages, which then likely contributes to the decline in ovarian reserve.

Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely, [31] suggesting that naturally occurring DNA damages in oocytes are repaired less efficiently in these women, and this inefficiency leads to early reproductive failure. Genomic data from about 70,000 women were analyzed to identify protein-coding variation associated with age at natural menopause. [32] Pathway analyses identified a major association with DNA damage response genes, particularly those expressed during meiosis and including a common coding variant in the BRCA1 gene.

See also

Related Research Articles

<span class="mw-page-title-main">Ovary</span> Female reproductive organ that produces egg cells

The ovary is a gonad in the female reproductive system that produces ova. When an ovum is released, this travels through the fallopian tube into the uterus. There is an ovary found on the left and the right side of the body. The ovaries also secrete hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause. It is also an endocrine gland because of the various hormones that it secretes.

<span class="mw-page-title-main">Menopause</span> Time when menstrual periods stop permanently

Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of reproduction. It typically occurs between the ages of 45 and 55, although the exact timing can vary. Menopause is usually a natural change. It can occur earlier in those who smoke tobacco. Other causes include surgery that removes both ovaries or some types of chemotherapy. At the physiological level, menopause happens because of a decrease in the ovaries' production of the hormones estrogen and progesterone. While typically not needed, a diagnosis of menopause can be confirmed by measuring hormone levels in the blood or urine. Menopause is the opposite of menarche, the time when a girl's periods start.

<span class="mw-page-title-main">In vitro fertilisation</span> Assisted reproductive technology procedure

In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro. The process involves monitoring and stimulating a woman's ovulatory process, removing an ovum or ova from their ovaries and letting a man's sperm fertilise them in a culture medium in a laboratory. After the fertilised egg (zygote) undergoes embryo culture for 2–6 days, it is transferred by catheter into the uterus, with the intention of establishing a successful pregnancy.

Infertility is the inability of an animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species. It is the normal state of a human child or other young offspring, because they have not undergone puberty, which is the body's start of reproductive capacity.

<span class="mw-page-title-main">Oogenesis</span> Egg cell production process

Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage.

<span class="mw-page-title-main">Ovarian follicle</span> Structure containing a single egg cell

An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with the potential to release an egg cell (ovum) at ovulation for fertilization. These eggs are developed once every menstrual cycle with around 450–500 being ovulated during a woman's reproductive lifetime.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<span class="mw-page-title-main">Ovarian reserve</span>

Ovarian reserve is a term that is used to determine the capacity of the ovary to provide egg cells that are capable of fertilization resulting in a healthy and successful pregnancy. With advanced maternal age the number of egg cell that can be successfully recruited for a possible pregnancy declines, constituting a major factor in the inverse correlation between age and female fertility.

<span class="mw-page-title-main">Female infertility</span> Diminished or absent ability of a female to achieve conception

Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Infertility is caused by many sources, including nutrition, diseases, and other malformations of the uterus. Infertility affects women from around the world, and the cultural and social stigma surrounding it varies.

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency, premature menopause, and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.

<span class="mw-page-title-main">Oocyte cryopreservation</span> Procedure to preserve a womans eggs (oocytes)

Oocyte cryopreservation is a procedure to preserve a woman's eggs (oocytes). This technique has been used to postpone pregnancy. When pregnancy is desired, the eggs can be thawed, fertilized, and transferred to the uterus as embryos. Several studies have shown that most infertility problems are due to germ cell deterioration related to aging. The procedure's success rate varies depending on the age of the woman, with the odds being higher in younger, adult women.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

<span class="mw-page-title-main">In vitro maturation</span> Artificial maturation of harvested immature egg cells

In vitro maturation (IVM) is the technique of letting the contents of ovarian follicles and the oocytes inside mature in vitro. It can be offered to women with infertility problems, combined with In Vitro Fertilization (IVF), offering women pregnancy without ovarian stimulation.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

Fertility preservation is the effort to help cancer patients retain their fertility, or ability to procreate. Research into how cancer, ageing and other health conditions effect reproductive health and preservation options are growing. Specifically sparked in part by the increase in the survival rate of cancer patients.

Female fertility is affected by age and is a major fertility factor for women. A woman's fertility is in generally good quality from the late teens to early thirties, although it declines gradually over time. Around 35, fertility is noted to decline at a more rapid rate. At age 45, a woman starting to try to conceive will have no live birth in 50–80 percent of cases. Menopause, or the cessation of menstrual periods, generally occurs in the 40s and 50s and marks the cessation of fertility, although age-related infertility can occur before then. The relationship between age and female fertility is sometimes referred to as a woman's "biological clock."

Human reproductive ecology is a subfield in evolutionary biology that is concerned with human reproductive processes and responses to ecological variables. It is based in the natural and social sciences, and is based on theory and models deriving from human and animal biology, evolutionary theory, and ecology. It is associated with fields such as evolutionary anthropology and seeks to explain human reproductive variation and adaptations. The theoretical orientation of reproductive ecology applies the theory of natural selection to reproductive behaviors, and has also been referred to as the evolutionary ecology of human reproduction.

Ovum quality is the measure of the ability of an oocyte to achieve successful fertilisation. The quality is determined by the maturity of the oocyte and the cells that it comprises, which are susceptible to various factors which impact quality and thus reproductive success. This is of significance as an embryo's development is more heavily reliant on the oocyte in comparison to the sperm.

<span class="mw-page-title-main">Ovarian stem cell</span>

Ovarian stem cells are oocytes formed in ovarian follicle before birth in female mammals. They do not form post-natally, and are depleted throughout reproductive life. In humans it is estimated that 500,000–1,000,000 primordial follicles are present at birth, decreasing rapidly with age until roughly age 51 when ovulation stops, resulting in menopause. The origin of these oocytes remains under discussion. The publication of a study in 2004 proposing germ cell renewal in adult mice sparked a debate on the possibility of stem cells in the postnatal ovary. An increasing number of studies suggest that stem cells exist within the mammalian ovary and can be manipulated in vitro to produce oocytes, but whether such ovarian stem cells have the potential to differentiate into oocytes remains uncertain.

Oocytes are immature egg cells that develop to maturity within a follicle in the ovary. Oocyte abnormalities can occur due to several factors, including premature ovarian insufficiency (POI), other maturation abnormalities, maternal ageing, and mitochondrial abnormalities.

References

  1. 1 2 Fretts, Ruth C. (3 December 2012). "Effect of advanced age on fertility and pregnancy in women". UpToDate . Wilkins-Haug, Louise (Section Editor); Barss, Vanessa A. (Deputy Editor). Archived from the original on 19 June 2016.
  2. ↑ "¿A qué edad tienen las madres su primer hijo?" [At what age do mothers have their first child?]. El Orden Mundial (elordenmundial.com) (in Spanish). 12 August 2020.
  3. ↑ Mean age of mothers at first childbirth (PDF). oecd.org (Report). Paris, FR: Organisation for Economic Co-operation and Development. SF2.3. Archived from the original (PDF) on 22 December 2014. Retrieved 27 May 2014.
  4. 1 2 Births and natality. cdc.org (Report). U.S. Centers for Disease Control. Archived from the original on 12 November 2019. Retrieved 8 September 2017.
  5. 1 2 3 Leridon, H. (1 July 2004). "Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment". Human Reproduction. 19 (7): 1548–1553. doi: 10.1093/humrep/deh304 . PMID   15205397.
  6. 1 2 Morris, J.K.; Mutton, D.E.; Alberman, E. (March 2002). "Revised estimates of the maternal age specific live birth prevalence of Down's syndrome". Journal of Medical Screening. 9 (1): 2–6. doi:10.1136/jms.9.1.2. PMID   11943789.
  7. ↑ Tournaye, Herman (June 2009). "Male reproductive ageing". In Bewley, Susan; Ledger, William; Nikolaou, Dimitrios (eds.). Reproductive Ageing. Cambridge University Press. pp. 95–104. ISBN   978-1-906985-13-4. Archived from the original on 4 November 2020. Retrieved 24 October 2020.
  8. ↑ Kidd, Sharon A.; Eskenazi, Brenda; Wyrobek, Andrew J. (February 2001). "Effects of male age on semen quality and fertility: A review of the literature". Fertility and Sterility. 75 (2): 237–248. doi: 10.1016/s0015-0282(00)01679-4 . PMID   11172821.
  9. ↑ "U.S. women more likely to have children than a decade ago". Pew Research Center’s Social & Demographic Trends Project. 18 January 2018. Retrieved 29 October 2020.
  10. ↑ Kohler, Hans-Peter; Billari, Francesco C.; Ortega, Jose Antonio (December 2002). "The emergence of lowest-low fertility in Europe during the 1990s". Population and Development Review. 28 (4): 641–680. doi:10.1111/j.1728-4457.2002.00641.x.
  11. ↑ Mathews, T.J. (2009). Delayed childbearing: More women are having their first child later in life (PDF) (databrief). U.S. Centers for Disease Control. Archived (PDF) from the original on 25 November 2017. Retrieved 26 August 2013.
  12. ↑ "Jedes vierte Neugeborene hat eine Mutter über 34 Jahre" [Every fourth newborn has a mother aged over 34 years](PDF). bib-demografie.de (Press release) (in German). Wiesbaden, DE: Bundesinstitut für Bevölkerungsforschung [Federal Institute for Population Research]. Archived from the original (PDF) on 22 December 2017. Retrieved 20 December 2017.
  13. ↑ Shadyab, Aladdin H.; Gass, Margery L.S.; Stefanick, Marcia L.; Waring, Molly E.; Macera, Caroline A.; Gallo, Linda C.; et al. (January 2017). "Maternal age at childbirth and parity as predictors of longevity among women in the United States: The Women's Health Initiative". American Journal of Public Health. 107 (1): 113–119. doi:10.2105/AJPH.2016.303503. PMC   5308150 . PMID   27854529.
  14. ↑ Balbo, Nicoletta; Billari, Francesco C.; Mills, Melinda (February 2013). "Fertility in Advanced Societies: A Review of Research". European Journal of Population. 29 (1): 1–38. doi:10.1007/s10680-012-9277-y. PMC   3576563 . PMID   23440941.
  15. ↑ te Velde, E. R.; Pearson, PL (1 March 2002). "The variability of female reproductive ageing". Human Reproduction Update. 8 (2): 141–154. doi: 10.1093/humupd/8.2.141 . PMID   12099629.
  16. ↑ "About Down syndrome". ndss.org. National Syndrome Down Society.
  17. ↑ Nelson, S.M.; Telfer, E.E.; Anderson, R.A. (1 January 2013). "The ageing ovary and uterus: New biological insights". Human Reproduction Update . 19 (1): 67–83. doi:10.1093/humupd/dms043. PMC   3508627 . PMID   23103636.
  18. 1 2 3 Schmidt, L.; Sobotka, T.; Bentzen, J.G.; Nyboe Andersen, A.; et al. (ESHRE Reproduction and Society Task Force) (1 January 2012). "Demographic and medical consequences of the postponement of parenthood". Human Reproduction Update . 18 (1): 29–43. doi: 10.1093/humupd/dmr040 . PMID   21989171.
  19. ↑ Goisis, Alice; Schneider, Daniel C.; Myrskylä, Mikko (2 September 2018). "Secular changes in the association between advanced maternal age and the risk of low birth weight: A cross-cohort comparison in the UK". Population Studies . 72 (3): 381–397. doi: 10.1080/00324728.2018.1442584 . PMID   29582702. S2CID   2977607.
  20. 1 2 Trillingsgaard, Tea; Sommer, Dion (4 March 2018). "Associations between older maternal age, use of sanctions, and children's socio-emotional development through 7, 11, and 15 years" (PDF). European Journal of Developmental Psychology . 15 (2): 141–155. doi:10.1080/17405629.2016.1266248. S2CID   53061283. Archived (PDF) from the original on 19 July 2018. Retrieved 19 July 2019.
  21. ↑ Mac Dougall, K.; Beyene, Y.; Nachtigall, R.D. (1 April 2012). "'Inconvenient biology': Advantages and disadvantages of first-time parenting after age 40 using in vitro fertilization". Human Reproduction . 27 (4): 1058–1065. doi:10.1093/humrep/des007. PMC   3303492 . PMID   22333985.
  22. 1 2 Goisis, A. (2 September 2015). "How are children of older mothers doing? Evidence from the United Kingdom" (PDF). Biodemography and Social Biology. 61 (3): 231–251. doi:10.1080/19485565.2014.1001887. PMID   26652679. S2CID   10071445. Archived (PDF) from the original on 20 July 2018. Retrieved 19 July 2019.
  23. ↑ Goisis, Alice; Schneider, Daniel C.; Myrskylä, Mikko (1 June 2017). "The reversing association between advanced maternal age and child cognitive ability: Evidence from three U.K. birth cohorts". International Journal of Epidemiology . 46 (3): 850–859. doi:10.1093/ije/dyw354. PMC   5837600 . PMID   28177512.
  24. ↑ Sutcliffe, A.G.; Barnes, J.; Belsky, J.; Gardiner, J.; Melhuish, E. (21 August 2012). "The health and development of children born to older mothers in the United Kingdom: Observational study using longitudinal cohort data". BMJ: British Medical Journal. 345 (7876): e5116. doi:10.1136/bmj.e5116. PMC   3424227 . PMID   22915663.
  25. ↑ Kalberer, Urs; Baud, David; Fontanet, Arnaud; Hohlfeld, Patrick; de Ziegler, Dominique (December 2009). "Birth records from Swiss married couples analyzed over the past 35 years reveal an aging of first-time mothers by 5.1 years while the interpregnancy interval has shortened" (PDF). Fertility and Sterility. 92 (6): 2072–2073. doi:10.1016/j.fertnstert.2009.05.078. PMID   19608170. Archived (PDF) from the original on 19 July 2018. Retrieved 19 July 2019.
  26. ↑ "Woman, 61, pregnant". The Sydney Morning Herald . 27 September 2011. Archived from the original on 27 April 2016. Retrieved 8 February 2013.
  27. ↑ Moreno, Carolina (26 October 2012). "Look: 61 year-old woman gives birth to twins". HuffPost (huffingtonpost.com). Archived from the original on 3 August 2016. Retrieved 13 October 2017.
  28. ↑ "Menopause". medlineplus.gov. Archived from the original on 16 October 2020. Retrieved 29 October 2020.
  29. ↑ Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA (2008). "A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause". Human Reproduction . 23 (3): 699–708. doi: 10.1093/humrep/dem408 . PMID   18192670.
  30. 1 2 Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K (2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Sci Transl Med. 5 (172): 172ra21. doi:10.1126/scitranslmed.3004925. PMC   5130338 . PMID   23408054.
  31. ↑ Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A (2006). "Premature menopause in patients with BRCA1 gene mutation". Breast Cancer Res. Treat. 100 (1): 59–63. doi:10.1007/s10549-006-9220-1. PMID   16773440. S2CID   19572648.
  32. ↑ Day FR, Ruth KS, Thompson DJ, et al. (2015). "Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair". Nat. Genet. 47 (11): 1294–303. doi:10.1038/ng.3412. PMC   4661791 . PMID   26414677.

Sources

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.