Ovarian reserve

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Model of ovarian reserve from conception to the menopause WallaceKelseyModel.jpg
Model of ovarian reserve from conception to the menopause

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.

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While there is no known method for assessing the ovarian reserve of individual women, [1] indirect determination of ovarian reserve is important in the treatment of infertility. [2]

Establishment

The ovary is generally thought of as an egg bank from which the woman draws during her reproductive life. The human ovary contains a population of primordial follicles. At 18–22 weeks post-conception, the female ovary contains its peak number of follicles (about 300,000 in the average case, but individual peak populations range from 35,000 to 2.5 million [3] ). p The size of the initial ovarian reserve is strongly influenced by genetics. [4] Also, elevated androgen levels during prenatal development have an adverse effect on the early establishment of the ovarian reserve. [4]

The mitosis starts the 3rd week of embryo intrauterine life and between the 5th and 7th week, there are already about 10.000 oogonias. However, the ovarian reserve is at maximum value in sixth month old embryos. Then this amount is only decreasing, as there is no new synthesis and differentiation. There is a huge decrease before the child is born, being this pool reduced from over 8 million potential oocytes to 2 million. The amount continues decreasing progressively until reaching the age of 30 years old, in which there is a dramatic decrease.

There are about 1 to 2 million oocytes when a woman is born. From them, 400000 oocytes will reach the stage of puberty and only 400 will rise maturation and ovulation. The rest of them reach atresia, a natural apoptotic process leading to the breakdown of the follicle.

Decline

Each menstrual cycle one egg cell is released by ovulation. In addition, the remaining follicles that were recruited towards maturation are lost by atresia. Few if any egg cells are replenished during the reproductive years. However, this loss by the menstrual cycle only accounts for approximately up to 10 egg cells per month, thus accounting for only a small fraction of the actual loss of egg cells throughout the lifetime.

One additional contributory mechanism for the decline in the ovarian reserve with age appears to be a decreased gene expression of proteins involved in DNA repair by homologous recombination such as BRCA1, MRE11, Rad51 and ATM. [5] Homologous recombinational repair of DNA double-strand breaks mediated by BRCA1 and ATM weakens with age in oocytes of humans and other species. [6] Women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause than women without these mutations. [6]

Assessment

Women who are 35 years or older who have attempted to get pregnant unsuccessfully for 6 months should undergo testing for ovarian reserve. The most commonly used test to assess this ovarian reserve is the day 3 FSH test. [7] This blood test determines the level of FSH on cycle day 3. Cycle day 3 is chosen because at this time the estrogen level is expected to be low, a critical feature, as FSH levels are subject to a negative feedback. Thus any determination of FSH needs to include the corresponding estradiol level to indicate that the FSH level was drawn when the estrogen level was low. In a patient with infrequent menstruation, an FSH level and estrogen level could be measured at random and is valid if the estrogen level is low. Generally FSH levels are expected to be below 10 miu/ml in women with reproductive potential (levels of 10-15 miu/ml are considered borderline), however the exact numbers returned will depend on the type of assay used in a particular laboratory.

Although FSH and more recently Inhibin B have been shown to have some correlation with ovarian reserve, it is now well established that anti-Müllerian Hormone or AMH is more useful biochemical test.[ citation needed ] AMH appears to play a role not only in the selection of the primary follicle but also in the overall process of recruiting preantral follicles. Around fifteen years before menopause, a gradual decrease in AMH levels follows a logarithmic pattern. This decline continues until about five years before menopause, at which point AMH levels reach a notably low point. However, for people with increased AMH due to PCOS that has been adequately managed with diet, exercise, and/or bariatric surgery, fertility improves even when AMH returns to normal levels. [8] In particular, an AMH level between 7.14-25 pmol/L indicates a normal ovarian response. In contrast, an AMH level of less than 7.14 pmol/L and an AMH level greater than 25 pmol/L indicate a low ovarian response and a high ovarian response, respectively. High levels however can be present in women with Polycystic Ovarian Syndrome which compromises female fertility and therefore a combination of AMH and a transvaginal ultrasound to count the number of antral follicles is probably the best way to assess ovarian reserve and future fertility. This combination is sometimes referred to as the Biological Body Clock Test.[ citation needed ]

A clomiphene challenge test is a variation on this approach. [9]

Another approach is to examine the ovaries by gynecologic ultrasonography and to determine their size as ovaries depleted of egg cells tend to be smaller [10] and to examine the number of antral follicles visible by sonography. [11]

Implications

Women with poor ovarian reserve are unlikely to conceive with infertility therapy. Also see poor ovarian reserve and Follicle-stimulating hormone for treatment options.

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 released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocrine glands, secreting various hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause.

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days. Menarche usually occurs around the age of 12 years; menstrual cycles continue for about 30–45 years.

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

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

Oogenesis or ovogenesis 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.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Anti-Müllerian hormone</span> Mammalian protein found in humans

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis. In humans, it is encoded by the AMH gene, on chromosome 19p13.3, while its receptor is encoded by the AMHR2 gene on chromosome 12.

<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">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<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.

<span class="mw-page-title-main">Follicular atresia</span>

Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency 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">Antral follicle</span> Part of an ovary

An antral or secondary follicle, also known as Graafian follicle and tertiary follicle, is an ovarian follicle during a certain latter stage of folliculogenesis.

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.

<span class="mw-page-title-main">Fertility testing</span> Process for assessing human fertility

Fertility testing is the process by which fertility is assessed, both generally and also to find the "fertile window" in the menstrual cycle. General health affects fertility, and STI testing is an important related field.

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."

Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter growth and developmental changes that change them into pre-ovulatory follicles, ready to be released during ovulation. The process of development from a primordial follicle to a pre-ovulatory follicle is called folliculogenesis.

Ovarian follicle dominance is the process where one or more follicles are selected per cycle to ovulate.

References

  1. ↑ Broekemans FJ; et al. (1998). "Ovarian reserve tests in infertility practice and normal fertile women". Maturitas. 30 (2): 205–14. doi:10.1016/S0378-5122(98)00075-9. PMID   9871914.
  2. ↑ Broekemans FJ; et al. (2006). "A systematic review of tests predicting ovarian reserve and IVF outcome". Hum Reprod Update. 12 (6): 685–718. doi: 10.1093/humupd/dml034 . PMID   16891297.
  3. ↑ Wallace WHB, Kelsey TW (2010). "Human Ovarian Reserve from Conception to the Menopause". PLOS ONE. 5 (1): e8772. arXiv: 1106.1382 . Bibcode:2010PLoSO...5.8772W. doi: 10.1371/journal.pone.0008772 . PMC   2811725 . PMID   20111701.
  4. 1 2 Richardson, M. C.; Guo, M.; Fauser, B. C. J. M.; Macklon, N. S. (2013). "Environmental and developmental origins of ovarian reserve". Human Reproduction Update. 20 (3): 353–369. doi: 10.1093/humupd/dmt057 . ISSN   1355-4786. PMID   24287894.
  5. ↑ Titus, Shiny; Li, Fang; Stobezki, Robert; Akula, Komala; Unsal, Evrim; Jeong, Kyungah; Dickler, Maura; Robson, Mark; Moy, Fred; Goswami, Sumanta; Oktay, Kutluk (2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Science Translational Medicine. 5 (172): 172ra21. doi:10.1126/scitranslmed.3004925. PMC   5130338 . PMID   23408054.
  6. 1 2 Turan, Volkan; Oktay, Kutluk (January 2020). "BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging". Human Reproduction Update. 26 (1): 43–57. doi:10.1093/humupd/dmz043. PMC   6935693 . PMID   31822904.
  7. ↑ Scott, Richard T.; Toner, James P.; Muasher, Suheil J.; Oehninger, Sergio.; Robinson, Shirley.; Rosenwaks, Zev. (April 1989). "Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome". Fertility and Sterility. 51 (4): 651–654. doi: 10.1016/s0015-0282(16)60615-5 . PMID   2494082.
  8. ↑ Deadmond, Amanda; Koch, Christian A.; Parry, J. Preston (2000). "Ovarian Reserve Testing". Endotext. MDText.com, Inc.
  9. ↑ Practice Committee of the American Society for Reproductive Medicine (2003). "Use of clomiphene citrate in women". Fertil Steril. 80 (5): 1302–1308. doi: 10.1016/s0015-0282(03)01184-1 . PMID   14607612.
  10. ↑ Wallace, W. Hamish; Kelsey, Thomas W. (July 2004). "Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography". Human Reproduction. 19 (7): 1612–1617. doi: 10.1093/humrep/deh285 . PMID   15205396.
  11. ↑ Kwee; et al. (2007). "Ovarian volume and antral follicle count for the prediction of low and hyper responders with in vitro fertilization". Reprod Biol Endocrinol. 5: 9. doi: 10.1186/1477-7827-5-9 . PMC   1847823 . PMID   17362511.
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