Fertility medication

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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. [1] There are very few fertility medication options available for men. [2]

Contents

Agents that enhance ovarian activity can be classified as either gonadotropin releasing hormone, estrogen antagonists or gonadotropins.[ medical citation needed ]

Treatment decision-making involves four major factors: efficacy, burden of treatment (such as frequency of injections and office visits), safety, and financial costs. [3]

Female

Main techniques

The main techniques involving fertility medication in females are:

Gonadotropin-releasing hormone

Either gonadotropin-releasing hormone (GnRH) or any gonadotropin-releasing hormone agonist (such as Lupron) may be used in combination with luteinizing hormone (LH) using an infusion pump to simulate endogenous hormone production. GnRH stimulates the release of gonadotropins (LH and FSH) from the anterior pituitary in the body. This set of therapy is reserved for a subset of women with infertility and have produced ovulation rates of 90% and pregnancy rates of 80% or higher.[ medical citation needed ]

Antiestrogens

Antiestrogens inhibit the effects of estrogen, which include selective estrogen receptor modulators (SERM) and aromatase inhibitors.

Hypothalamic-pituitary-gonadal axis in females, with estrogen exerting mainly negative feedback on FSH secretion from the pituitary gland. Hypothalamic-pituitary-gonadal axis in females.png
Hypothalamic–pituitary–gonadal axis in females, with estrogen exerting mainly negative feedback on FSH secretion from the pituitary gland.

Selective estrogen receptor modulators

Clomiphene is a selective estrogen receptor modulator (SERM). [5] It is the most widely used fertility drug. [6] Other medications in this class include tamoxifen and raloxifene, although both are not as effective as clomiphene and are thus less widely used for fertility purposes. [7] They are used in ovulation induction by inhibiting the negative feedback of estrogen at the hypothalamus. As the negative feedback of estrogen is inhibited, the hypothalamus secretes GnRh which in turn stimulates the anterior pituitary to secrete LH and FSH which help in ovulation. Between 60 and 85% of women, mostly with polycystic ovary syndrome (PCOS), ovulate successfully in response to clomiphene with a cumulative pregnancy rate of 30 to 40%. [8] [9] [10]

Aromatase inhibitors

Although primarily used in breast cancer treatment, aromatase inhibitors (particularly generic letrozole) are also used in ovulation induction. Aromatase inhibitors are a common fertility treatment to treat women with PCOS. A meta-analysis analyzing live birth rates for women with PCOS treated with clomiphene compared to letrozole found that letrozole resulted in higher live birth rates. [11] However, ovulation induction remains an off-label indication, which affects use.

Gonadotropins

Gonadotropins are protein hormones that stimulate the gonads (testes and ovaries). For medication, they can be extracted from urine in postmenopausal women or through genetic modification and bacterial recombination. Examples of recombinant FSH are Follistim and Gonal F, while Luveris is a recombinant LH. FSH and recombinant FSH analogues are mainly used for controlled ovarian hyperstimulation as well as ovulation induction. [12] There has been some controversy over the efficacy between extracted and recombinant FSH for ovulation induction; however, a meta-analysis of 14 trials among 1726 women found that there were no differences in clinical pregnancy or live birth outcomes. [13]

Chemotherapy treatment in premenopausal women can compromise ovarian reserve and function, with gonadotoxic effects ranging from temporary to permanent infertility and premature ovarian failure (POF). Proposed mechanisms for chemotherapy-induced ovarian damage include apoptosis of growing follicles, fibrosis of stromal cells, and injury to blood vessels resulting in ischemia. First-line options for fertility preservation include embryo and oocyte preservation before starting chemotherapy, though these methods do not contribute to the preservation of gonadal function. GnRH agonist therapies have been associated with relatively low risk, time, and cost. [14] There is evidence that chemotherapy cotreatment with gonadotropin-releasing hormone (GnRH) can increase the probability of spontaneous menses and ovulation resumption. However, this cotreatment has not shown an improvement in pregnancy rates. [15]

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG), also known as the “hormone of pregnancy” is a hormone that is normally produced during pregnancy and plays an integral role throughout reproduction. [16] It is crucial in maintaining pregnancy, from the stages of placentation to early embryo development. [16] It is also used in assisted reproductive techniques as it can be used to replace LH in final maturation induction. [16]

Other medications

Although metformin has been used off-label to treat oligomenorrhea and ovarian hyperstimulation syndrome (OHSS) in women with PCOS, metformin is no longer recommended as infertility treatment per the American Society for Reproductive Medicine (ASRM) in 2017. Its use to treat anovulatory infertility was based on an association of insulin resistance in non-obese women with PCOS. While metformin may increase ovulation in women with PCOS, there is no evidence of increased pregnancy rates or live-birth rates, and the combination therapy of metformin and clomiphene citrate did not provide a significant benefit compared to clomiphene citrate alone. First-line therapy for ovulation induction in women with PCOS remains the anti-estrogen clomiphene citrate or the aromatase inhibitor letrozole. [17]

Male

Treatment for oligospermia is centered around underlying causes, such as endocrine and systematic disorders that can cause hypogonadism. [18]

Typically, other assisted reproductive technologies are used. Although there is no FDA indication for use of aromatase inhibitors improving spermatogenesis, testolactone has been shown to be effective when compared to placebo. [19]

Though there is no FDA indication for the use of clomiphene in male infertility, it has been prescribed since the 1960s. [20] As of 2013, there is not substantial evidence to suggest that clomiphene can treat male infertility. [20]

Combinations of vitamins and minerals, including selenium, co-enzyme Q10, L-carnitine, folic acid, zinc, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have been shown to improve male infertility, but due to the low amounts of studies and participants, more clinical studies are needed. [21] Folate in combination with zinc supplementation was shown to have a statistically significant effect on sperm concentration and morphology when compared to placebo. [22] There is evidence suggesting a significant association between vitamin D serum concentrations and the quality of sperm in men, characterized by the sperm's motility and progress motility. [23] Because the quality of men's sperm is influenced by genetics, results should be interpreted cautiously. There is little evidence that supplementation with antioxidants, such as pentoxifylline will increase male fertility. [24] [25]

As of September 2017, mesenchymal stem cell therapy for infertility has been studied in animals, but has not entered clinical trials. [26] Stem cells collected from bone marrow and umbilical cord have shown the most ability to rehabilitate fertility in animals, but more studies are needed to determine efficacy. [26]

Adverse effects

Cancer

Since infertility increases the risk of ovarian cancer, fertility drugs have been used to combat this but the cancer risks are still not completely known. [27] As of 2019, there have been studies that have shown the risk of developing ovarian cancer is higher when taking fertility medications. However, due to the low number of studies, lack of follow-up time and other contribution factors, the risk is unclear. [27] Most studies conducted have shown that fertility drugs do not increase the risk of other gynecologic cancers (cervical and endometrial) or other malignant cancers (thyroid, colon, melanoma, breast). [28] The validity of these data may be affected by patient-reported biases, small subject numbers, and other confounding variables. [28]

Children born to mothers who use fertility medication to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children. [29]

Ovarian hyperstimulation syndrome

Estrogen antagonists and gonadotropins may stimulate multiple follicles and other ovarian hormones leading to multiple birth and possible ovarian hyperstimulation syndrome (OHSS). [30] Development of OHSS is dependent on the administration of hCG and is mediated through vascular endothelial growth factor (VEGF). OHSS is characterized as cystic enlargement of the ovaries. Multiple birth is especially deleterious due to compounding risks including premature delivery and low birthweight, pre-eclampisa, and increased risk of neonatal mortality. While triplet births have been declining in ART, multiple births remain over 50% of births from IVF. However, there are limitations to measure, as 4% to 8% IVF clinics to do not report their data to the CDC.

Discontinuation

Main reasons for discontinuation across all types of fertility treatment and treatment stage, are "postponement of treatment, physical and psychological burden and relational and personal problems". [31]

See also

Related Research Articles

<span class="mw-page-title-main">Polycystic ovary syndrome</span> Set of symptoms caused by abnormal hormones in females

Polycystic ovary syndrome, or polycystic ovarian syndrome (PCOS), is the most common endocrine disorder in women of reproductive age. The syndrome is named after cysts which form on the ovaries of some people with this condition, though this is not a universal symptom, and not the underlying cause of the disorder.

<span class="mw-page-title-main">Ovulation</span> Release of egg cells from the ovaries

Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized by sperm. In addition, the uterine lining (endometrium) is thickened to be able to receive a fertilized egg. If no conception occurs, the uterine lining as well as the egg will be shed during menstruation.

Amenorrhea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

<span class="mw-page-title-main">Clomifene</span> Infertility treatment for women

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for five days.

Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in very rare cases. Most cases are mild, but rarely the condition is severe and can lead to serious illness or death.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<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">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">Letrozole</span> Breast cancer drug

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

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.

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.

Ovarian drilling, also known as multiperforation or laparoscopic ovarian diathermy, is a surgical technique of puncturing the membranes surrounding the ovary with a laser beam or a surgical needle using minimally invasive laparoscopic procedures. It differs from ovarian wedge resection, which involves the cutting of tissue. Minimally invasive ovarian drilling procedures have replaced wedge resections. Ovarian drilling is preferred to wedge resection because cutting into the ovary can cause adhesions which may complicate postoperative outcomes. Ovarian drilling and ovarian wedge resection are treatment options to reduce the amount of androgen producing tissue in women with polycystic ovarian syndrome (PCOS). PCOS is the primary cause of anovulation, which results in female infertility. The induction of mono-ovulatory cycles can restore fertility.

<span class="mw-page-title-main">Fertility testing</span>

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.

Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility. Polycystic ovary syndrome causes more than 75% of cases of anovulatory infertility.

Induction of final maturation of oocytes is a procedure that is usually performed as part of controlled ovarian hyperstimulation to render the oocytes fully developed and thereby resulting in optimal pregnancy chances. It is basically a replacement for the luteinizing hormone (LH) surge whose effects include final maturation in natural menstrual cycles.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

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

<span class="mw-page-title-main">Non steroidal aromatase inhibitors</span>

Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.

References

  1. ↑ Crowley F, Martin KA (2020). "Patient Education: Infertility in Women". In Post TW (ed.). UpToDate. Waltham, MA: UpToDate.
  2. ↑ Drobnis EZ, Nangia AK (2017). Impacts of Medications on Male Fertility. Cham, Switzerland: Palgrave Macmillan. ISBN   978-3-319-69535-8 . Retrieved 23 February 2019.
  3. ↑ Dancet EA, Fleur Dancet EA, D'Hooghe TM, d'Hooghe TM, van der Veen F, Bossuyt P, et al. (April 2014). ""Patient-centered fertility treatment": what is required?". Fertility and Sterility. 101 (4): 924–6. doi: 10.1016/j.fertnstert.2013.12.045 . PMID   24502889.
  4. ↑ "Fertility problems: assessment and treatment". NICE clinical guideline CG156. U.K. National Institute for Health and Care Excellence (NICE). February 2013.
  5. ↑ Stute P, Birkhauser M (2015). "Selective estrogen receptor modulators (SERM)/Selektive Ostrogenrezeptormodulatoren (SERM)" (PDF). Gynakologische Endokrinologie. 13 (2): 126. doi:10.1007/s10304-015-0003-9. S2CID   23400904.
  6. ↑ Fauser BC (December 2014). "Reproductive endocrinology: revisiting ovulation induction in PCOS". Nature Reviews. Endocrinology. 10 (12): 704–5. doi:10.1038/nrendo.2014.156. PMID   25178733. S2CID   8380091.
  7. ↑ Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L (2000). "A pharmacological review of selective oestrogen receptor modulators". Human Reproduction Update. 6 (3): 212–24. doi: 10.1093/humupd/6.3.212 . PMID   10874566.
  8. ↑ Dickey RP, Holtkamp DE (1996). "Development, pharmacology and clinical experience with clomiphene citrate". Human Reproduction Update. 2 (6): 483–506. doi: 10.1093/humupd/2.6.483 . PMID   9111183.
  9. ↑ Gorlitsky GA, Kase NG, Speroff L (March 1978). "Ovulation and pregnancy rates with clomiphene citrate". Obstetrics and Gynecology. 51 (3): 265–9. doi:10.1097/00006250-197803000-00002. PMID   628527.
  10. ↑ Gysler M, March CM, Mishell DR, Bailey EJ (February 1982). "A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test". Fertility and Sterility. 37 (2): 161–7. doi: 10.1016/s0015-0282(16)46033-4 . PMID   7060766.
  11. ↑ Franik, Sebastian; Le, Quang-Khoi; Kremer, Jan Am; Kiesel, Ludwig; Farquhar, Cindy (2022-09-27). "Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 2022 (9): CD010287. doi:10.1002/14651858.CD010287.pub4. ISSN   1469-493X. PMC   9514207 . PMID   36165742.
  12. ↑ Conforti A, Esteves SC, Di Rella F, Strina I, De Rosa P, Fiorenza A, et al. (February 2019). "The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis". Reproductive Biology and Endocrinology. 17 (1): 18. doi: 10.1186/s12958-019-0460-4 . PMC   6366097 . PMID   30728019.
  13. ↑ Weiss NS, Kostova E, Nahuis M, Mol BW, van der Veen F, van Wely M (January 2019). "Gonadotrophins for ovulation induction in women with polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 1 (1): CD010290. doi:10.1002/14651858.CD010290.pub3. PMC   6353048 . PMID   30648738.
  14. ↑ Hickman LC, Llarena NC, Valentine LN, Liu X, Falcone T (April 2018). "Preservation of gonadal function in women undergoing chemotherapy: a systematic review and meta-analysis of the potential role for gonadotropin-releasing hormone agonists". Journal of Assisted Reproduction and Genetics. 35 (4): 571–581. doi:10.1007/s10815-018-1128-2. PMC   5949114 . PMID   29470701.
  15. ↑ Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-Nashar SA, et al. (March 2011). "Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis". Fertility and Sterility. 95 (3): 906–14.e1–4. doi: 10.1016/j.fertnstert.2010.11.017 . PMID   21145541.
  16. 1 2 3 Leão R, Esteves SC (2014). "Gonadotropin therapy in assisted reproduction: an evolutionary perspective from biologics to biotech". Clinics (Review). 69 (4): 279–93. doi:10.6061/clinics/2014(04)10. PMC   3971356 . PMID   24714837.
  17. ↑ Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, et al. (September 2017). "Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline". Fertility and Sterility. 108 (3): 426–441. doi: 10.1016/j.fertnstert.2017.06.026 . PMID   28865539.
  18. ↑ de Kretser DM (March 1997). "Male infertility". Lancet (Review). 349 (9054): 787–90. doi:10.1016/s0140-6736(96)08341-9. PMID   9074589. S2CID   12928678.
  19. ↑ Ribeiro MA, Gameiro LF, Scarano WR, Briton-Jones C, Kapoor A, Rosa MB, El Dib R (May 2016). "Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials". JBRA Assisted Reproduction (Review). 20 (2): 82–8. doi: 10.5935/1518-0557.20160019 . PMID   27244767.
  20. 1 2 Willets AE, Corbo JM, Brown JN (July 2013). "Clomiphene for the treatment of male infertility". Reproductive Sciences (Review). 20 (7): 739–44. doi:10.1177/1933719112466304. PMID   23202725. S2CID   206804686.
  21. ↑ Buhling K, Schumacher A, Eulenburg CZ, Laakmann E (August 2019). "Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review". Reproductive Biomedicine Online. 39 (2): 269–279. doi: 10.1016/j.rbmo.2019.03.099 . PMID   31160241.
  22. ↑ Irani M, Amirian M, Sadeghi R, Lez JL, Latifnejad Roudsari R (August 2017). "The Effect of Folate and Folate Plus Zinc Supplementation on Endocrine Parameters and Sperm Characteristics in Sub-Fertile Men: A Systematic Review and Meta-Analysis". Urology Journal. 14 (5): 4069–4078. PMID   28853101.
  23. ↑ Arab A, Hadi A, Moosavian SP, Askari G, Nasirian M (November 2019). "The association between serum vitamin D, fertility and semen quality: A systematic review and meta-analysis". International Journal of Surgery. 71: 101–109. doi: 10.1016/j.ijsu.2019.09.025 . PMID   31561004. S2CID   203580672.
  24. ↑ Smits RM, Mackenzie-Proctor R, Fleischer K, Showell MG (September 2018). "Antioxidants in fertility: impact on male and female reproductive outcomes". Fertility and Sterility. 110 (4): 578–580. doi: 10.1016/j.fertnstert.2018.05.028 . PMID   30196940.
  25. ↑ Chehab M, Madala A, Trussell JC (March 2015). "On-label and off-label drugs used in the treatment of male infertility". Fertility and Sterility (Review). 103 (3): 595–604. doi: 10.1016/j.fertnstert.2014.12.122 . PMID   25660648.
  26. 1 2 Fazeli Z, Abedindo A, Omrani MD, Ghaderian SM (February 2018). "Mesenchymal Stem Cells (MSCs) Therapy for Recovery of Fertility: a Systematic Review". Stem Cell Reviews and Reports. 14 (1): 1–12. doi:10.1007/s12015-017-9765-x. PMID   28884412. S2CID   44236281.
  27. 1 2 Rizzuto I, Behrens RF, Smith LA (June 2019). "Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility". The Cochrane Database of Systematic Reviews. 2019 (6): CD008215. doi:10.1002/14651858.cd008215.pub3. PMC   6579663 . PMID   31207666.
  28. 1 2 Kroener L, Dumesic D, Al-Safi Z (August 2017). "Use of fertility medications and cancer risk: a review and update". Current Opinion in Obstetrics & Gynecology. 29 (4): 195–201. doi:10.1097/GCO.0000000000000370. PMC   5551049 . PMID   28538003.
  29. ↑ Rudant J, Amigou A, Orsi L, Althaus T, Leverger G, Baruchel A, et al. (February 2013). "Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE)". Pediatric Blood & Cancer. 60 (2): 301–308. doi:10.1002/pbc.24192. PMID   22610722. S2CID   26010916.
  30. ↑ Banker M, Garcia-Velasco JA (2015). "Revisiting ovarian hyper stimulation syndrome: Towards OHSS free clinic". J Hum Reprod Sci. 8 (1): 13–7. doi: 10.4103/0974-1208.153120 . PMC   4381376 . PMID   25838743.
  31. ↑ Gameiro S, Boivin J, Peronace L, Verhaak CM (August 2012). "Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation in fertility treatment". Human Reproduction Update. 18 (6): 652–69. doi:10.1093/humupd/dms031. PMC   3461967 . PMID   22869759.
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