Poor ovarian reserve

Poor ovarian reserve
Other names	Impaired ovarian reserve, premature ovarian aging, declining ovarian reserve
Specialty	Gynecology

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 (aka primary ovarian insufficiency) may represent a continuum of premature ovarian senescence. ^[1] It is usually accompanied by high FSH (follicle stimulating hormone) levels.

Quality of the eggs may also be impaired. ^{[2] [3]} However, other studies show no association with elevated FSH levels and genetic quality of embryos after adjusting for age. The decline in quality was age related, not FSH related as the younger women with high day three FSH levels had higher live birth rates than the older women with high FSH. There was no significant difference in genetic embryo quality between same aged women regardless of FSH levels. ^{[4] [5]} A 2008 study concluded that diminished reserve did not affect the quality of oocytes and any reduction in quality in diminished reserve women was age related. ^[6] One expert concluded: in young women with poor reserve when eggs are obtained they have near normal rates of implantation and pregnancy rates, but they are at high risk for IVF cancellation; if eggs are obtained, pregnancy rates are typically better than in older woman with normal reserve. However, if the FSH level is extremely elevated these conclusions are likely not applicable. ^[7]

Presentation

Related conditions

• Premature ovarian failure: Defined as no menses for six months before the age of forty due to any cause. Often diagnosed by elevated gonadotropin (Follicle-stimulating hormone (FSH) and LH) levels. In some cases (more so in younger women) ovarian function and ovulation can spontaneously resume. With POF up to 50% of women may ovulate once in any given year and 5–10% may become pregnant. POF is often associated with autoimmune diseases.^{[ citation needed ]}
• Premature menopause: An outdated synonym for premature ovarian failure. The term encompasses premature menopause due to any cause, including surgical removal of the ovaries for any reason. Early menopause and premature ovarian failure are no longer considered to be the same condition.^{[ citation needed ]}

Cause

• Natural decline of ovarian reserve due to age. ^[8]
• Idiopathic.
• Genetic factors, such as fragile x syndrome. Approximately 20–28% of women with an FMR1 premutation (55–200 CGG repeats) experience fragile x primary ovarian insufficiency (POI) and another 23% experience early menopause (i.e., menopause before the age of forty five). ^[9]
• Autoimmune disorders.
• Adrenal gland impairment.
• Iatrogenic, e.g., due to radiation, chemotherapy or surgery, such as laserization of the surface of the ovary to treat endometriosis. Excessive laparoscopic ovarian drilling has been reported to cause premature ovarian failure. ^{[10] [11]} (The primordial follicles are located in the thin outer one-millimeter layer of the ovary.) ^[12]

Diagnosis

There is some controversy as the accuracy of the tests used to predict poor ovarian reserve. One systematic review concluded that the accuracy of predicting the occurrence of pregnancy is very limited. When a high threshold is used, to prevent couples from wrongly being refused IVF, only approximately 3% of IVF-indicated cases are identified as having unfavourable prospects in an IVF treatment cycle. Also, the review concluded the use of any ORT (Ovarian Reserve Testing) for outcome prediction cannot be supported. ^[13] Also Centers for Disease Control and Prevention statistics show that the success rates for IVF with diminished ovarian reserve vary widely between IVF centers. ^[14]

Follicle stimulating hormone

Elevated serum follicle stimulating hormone (FSH) level measured on day three of the menstrual cycle. (First day of period flow is counted as day one. Spotting is not considered start of period.) If a lower value occurs from later testing, the highest value is considered the most predictive. FSH assays can differ somewhat so reference ranges as to what is normal, premenopausal or menopausal should be based on ranges provided by the laboratory doing the testing. Estradiol (E2) should also be measured as women who ovulate early may have elevated E2 levels above 80 pg/mL (due to early follicle recruitment, possibly due to a low serum inhibin B level) which will mask an elevated FSH level and give a false negative result. ^[15]

High FSH strongly predicts poor IVF response in older women, less so in younger women. One study showed an elevated basal day-three FSH is correlated with diminished ovarian reserve in women aged over 35 years and is associated with poor pregnancy rates after treatment of ovulation induction (6% versus 42%). ^[16]

The rates for spontaneous pregnancy in older women with elevated FSH levels have not been studied very well and the spontaneous pregnancy success rate, while low, may be underestimated due to non reporting bias, as most infertility clinics will not accept women over the age of forty with FSH levels in the premenopausal range or higher.^{[ citation needed ]}

A woman can have a normal day-three FSH level yet still respond poorly to ovarian stimulation and hence can be considered to have poor reserve. Thus, another FSH-based test is often used to detect poor ovarian reserve: the clomid challenge test, also known as CCCT (clomiphene citrate challenge test).^{[ citation needed ]}

Antral follicle count

Transvaginal ultrasonography can be used to determine antral follicle count (AFC). This is an easy-to-perform and noninvasive method (but there may be some discomfort). Several studies show this test to be more accurate than basal FSH testing for older women (< 44 years of age) in predicting IVF outcome. ^[17] This method of determining ovarian reserve is recommended by Dr. Sherman J. Silber, author and medical director of the Infertility Center of St. Louis. ^[18]

AFC and Median Fertile Years Remaining ^{[19] [20]}

Antral Follicle Count (Per Ovary [See comment below as these figures are under dispute.])	Median Years to Last Child	Median Years to Menopause
5	__	7.3
10	4.2	12.9
15	9.3	18.4
20	14.8	24.0

Note, the above table from Silber's book may be in error as it has no basis in any scientific study, and contradicts data from Broekmans, et al. 2004 study. ^[21] The above table closely matches Broekmans' data only if interpreted as the total AFC of both ovaries. Only antral follicles that were 2–10 mm in size were counted in Broekmans' study.

Age and AFC and Age of Loss of Natural Fertility (See Broekmans, et al. [2004])

Antral Follicle Count (Both Ovaries)	Age at Time of Count	Age of Loss of Natural Fertility
6	30	29–33
6	35	33–38
6	40	38–41
10	30	33–38
10	35	38–41
15	30	38–41 (closer to 41)

AFC and FSH Stimulation Recommendations for Cycles Using Assisted Reproduction Technology ^[22]

Further information: Controlled ovarian hyperstimulation § Response prediction

Antral Follicle Count	Significance
< 4	Poor reserve
4–7	Low count, high dosage of FSH required
8–12	Slightly reduced reserve
> 12	Normal

Other

• Declining serum levels of anti-müllerian hormone. Recent studies have validated the use of serum AMH levels as a marker for the quantitative aspect of ovarian reserve. Because of the lack of cycle variations in serum levels of AMH, this marker has been proposed to be used as part of the standard diagnostic procedures to assess ovarian dysfunctions, such as premature ovarian failure. One study has shown AMH to be a better marker than basal FSH for women with proven (prior) fertility in measuring age related decline in ovarian reserve. ^[23]
• Inhibin B blood level. Inhibin B levels tend to decline in advanced reproductive aged women due to both fewer follicles and decreased secretion by the granulosa cells. Inhibin B levels start to rise around day zero and low day three levels are associated with poor IVF outcome. ^{[24] [25]}
• Ultrasound measurement of ovarian volume. Lass and Brinsden (1999) report that the correlation between ovarian volume and follicular density appears to only hold in women ≥ 35 years of age. ^[26]
• Dynamic Assessment Following GnRH-a Administration (GAST). This test measures the change in serum estradiol levels between cycle day two and three after administration of one mg of subcutaneous leuprolide acetate, a gonadotropin releasing hormone agonist. Patients with estradiol elevations by day two followed by a decline by day three had improved implantation and pregnancy rates than those patients with either no rise in estradiol or persistently elevated estradiol levels. ^[27]
• Home testing of FSH urine concentration to alert a woman to possible impaired ovarian reserve became possible in June 2007 with the introduction of Fertell in the United States and UK, which claims a 95% equivalence to standard serum marker results. ^[28]

Treatment

Variable success rate with treatment, very few controlled studies, mostly case reports. Treatment success strongly tends to diminish with age and degree of elevation of FSH.

• Donor oocyte. Oocyte donation is the most successful method for producing pregnancy in perimenopausal women. In the UK the use of donor oocytes after natural menopause is controversial. ^[29] A 1995 study reported that women age fifty or higher experience similar pregnancy rates after oocyte donation as younger women. They are at equal risk for multiple gestation as younger women. In addition, antenatal complications were experienced by the majority of patients, and that high risk obstetric surveillance and care is vital. ^[30]
• Natural or Mini-IVF, but without the use of hCG to trigger ovulation, instead the GnRH agonist Synarel (nafarelin acetate) in a diluted form is taken as a nasal spray to trigger ovulation. Human chorionic gonadotropin (hCG) has a long half life and may stimulate (luteinize) small follicles prematurely and cause them to become cysts. Whereas nafarelin acetate in a nasal spray induces a short lived LH surge that is high enough to induce ovulation in large follicles, but too short lived to adversely affect small follicles. This increases the likelihood of the small follicles and oocytes therein developing normally for upcoming cycles and also allows the woman to cycle without taking a break and consequently increases the probability of conception in poor ovarian reserve women and advanced reproductive aged women. ^[31]
• Pretreatment with 50 mcg ethinylestradiol three times a day for two weeks, followed by recombinant FSH 200 IU/day subcutaneously. Ethinylestradiol treatment was maintained during FSH stimulation. When at least one follicle reached 18mm in diameter and serum estradiol was greater or equal to 150 pg/ML ovulation was induced with an intramuscular injection of 10,000 IU of hCG (human chorionic gonadotropin hormone). For luteal phase support 5,000 IU of hCG was administered every 72 hours. Out of 25 patients 8 ovulated and 4 became pregnant. In the control group there were no ovulations. The patients ranged in age between 24 and 39 years with an average age of 32.7. All women had amenorrhea for at least 6 months (average 16.75 months) and FSH levels greater or equal than 40 mIU/mL (average FSH 68 mIU/ML). The researchers believe this protocol would work for women in early post menopause as well. ^[32]
• Ethinylestradiol or other synthetic estrogens along with luteal phase progesterone (twice daily 200 mg vaginal suppositories) and estradiol support. Ethinylestradiol lowers high FSH levels which then, it is theorized, up regulates FSH receptor sites and restores sensitivity to FSH. Ethinylestradiol also has the advantage that it does not interfere with the measurement of serum levels of endogenous estradiol. During the luteal phase the FSH levels should be kept low for subsequent cycles, thus the phase is supplemented with 4 mg ^[33] oral estradiol. Since conception may have occurred estradiol is used instead of the synthetic ethinylestradiol. ^{[34] [35] [36] [37] [38]}
• Cyclical hormone replacement therapy. ^[39]
• The following protocols have shown promise: high dose gonadoropins, flare up GnRH-a protocol (standard or microdose), stop protocols, short protocol, natural cycle or modified natural cycle and low dose hCG during the beginning of the stimulation protocol. ^[40]
• Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming (AACEP) protocol. Fisch, Keskintepe and Sher report 35% (14 out of 40) ongoing gestation in women with elevated FSH levels (all women had prior IVF and poor quality embryos); among women aged 41–42 the ongoing gestation rate was 19% (5 out of 26). ^[41]
• DHEA: Recent clinical trial by the Center for Human Reproduction in New York showed significant effectiveness. ^{[42] [43]} Leonidas and Eudoxia Mamas report six cases of premature ovarian failure. After two to six months of treatment with DHEA (Two 25 mg capsules daily in five cases and three 25 mg capsules daily in one case.) all women conceived. One delivered via C-section, one aborted at 7 weeks and the remaining four were reported at 11 to 27 weeks gestation. Ages were from 37 to 40. FSH levels were from 30 to 112 mIU/mL. Ammenorhea ranged from 9 to 13 months. ^[44] In addition, there is strong evidence that continuous micronized DHEA 25 mg TID reduces miscarriage and aneuploidy rates, especially above age 35. ^[45]
• A combined pentoxifylline-tocopherol treatment has been reported effective in improving uterine parameters in women with POF undergoing IVF with donor oocytes (IVF-OD). Three women with uterine hormonoresistance despite high estradiol (E2) plasma levels received treatment with 800 mg pentoxifylline and 1000 IU of vitamin E for at least nine months. Three frozen-thawed embryo transfers (ETs) resulted in two viable pregnancies. Mean endometrial thickness increased from 4.9 mm (with thin uterine crosses) to 7.4 mm with nice uterine crosses. ^{[46] [47]} This treatment protocol has also reversed some cases of iatrogenic POF caused by full body radiation treatment. ^[48]

Research

While the primary cause of the end to menstrual cycles is the exhaustion of ovarian follicles, there is some evidence that a defect in the hypothalamus is critical in the transition from regular to irregular cycles. This is supported by at least one study in which transplantation of ovaries from old rats to young ovariectomized rats resulted in follicular development and ovulation. Also, electrical stimulation of the hypothalamus is capable of restoring reproductive function in aged animals. Due to the complex interrelationship among the hypothalamus, pituitary and ovaries (HPO axis) defects in the functioning of one level can cause defects on the other levels. ^[49]

References

1. Gleicher N, Weghofer A, Oktay K, Barad D (October 2009). "Do etiologies of premature ovarian aging (POA) mimic those of premature ovarian failure (POF)?". Human Reproduction. 24 (10): 2395–2400. doi: 10.1093/humrep/dep256 . PMID   19617205.
2. Gardner DK, Weissman A, Howles CM, Shoham Z (2001). Textbook of Assisted Reproductive Techniques: Laboratory and Clinical Perspectives. Taylor & Francis. p. 528. ISBN   978-1-85317-870-2.
3. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z (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.
4. Thum MY, Abdalla HI, Taylor D (August 2008). "Relationship between women's age and basal follicle-stimulating hormone levels with aneuploidy risk in in vitro fertilization treatment". Fertility and Sterility. 90 (2): 315–321. doi: 10.1016/j.fertnstert.2007.06.063 . PMID   17953958.
5. Abdalla H, Thum MY (April 2004). "An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve". Human Reproduction. 19 (4): 893–898. doi: 10.1093/humrep/deh141 . PMID   15016786.
6. Rosen MP, Shen S, Huddleston HG, Fujimoto VY, Cedars MI (September 2008). "What is diminished ovarian reserve (DOR) – reduced quantity vs. reduced quality?". Fertil. Steril. 90 (Supplement): S258. doi: 10.1016/j.fertnstert.2008.07.1283 .
7. Toner JP (March 2003). "Age = egg quality, FSH level = egg quantity". Fertility and Sterility. 79 (3): 491. doi: 10.1016/S0015-0282(02)04840-9 . PMID   12620427.
8. Wallace WH, Kelsey TW (January 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.
9. "Facts about Primary Ovarian Insufficiency (POI)". The National Fragile X Foundation. Archived from the original on 2008-11-06.
10. Seow KM, Juan CC, Hwang JL, Ho LT (January 2008). "Laparoscopic surgery in polycystic ovary syndrome: reproductive and metabolic effects". Seminars in Reproductive Medicine. 26 (1): 101–110. doi:10.1055/s-2007-992930. PMID   18181088. S2CID   260316693.
11. Bordewijk EM, Ng KY, Rakic L, Mol BW, Brown J, Crawford TJ, et al. (2020-02-11). "Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 2 (2): CD001122. doi:10.1002/14651858.CD001122.pub5. ISSN   1469-493X. PMC   7013239 . PMID   32048270.
12. Silber 2005 , pp. 47, 71
13. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB (2006). "A systematic review of tests predicting ovarian reserve and IVF outcome". Human Reproduction Update. 12 (6): 685–718. doi: 10.1093/humupd/dml034 . PMID   16891297.
14. "Assisted Reproduction Technology". Centers for Disease Control and Prevention. U.S. Department of Health & Human Services. 17 December 2021.
15. Ghumman S (2006). Step by Step Ovulation Induction. Kent UK: Anshan. p. 134. ISBN   978-1-904798-96-5.
16. Navot D, Rosenwaks Z, Margalioth EJ (September 1987). "Prognostic assessment of female fecundity". Lancet. 2 (8560): 645–647. doi:10.1016/s0140-6736(87)92439-1. PMID   2887939. S2CID   13959528.
17. Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER (March 2005). "The antral follicle count is a better marker than basal follicle-stimulating hormone for the selection of older patients with acceptable pregnancy prospects after in vitro fertilization". Fertility and Sterility. 83 (3): 811–814. doi:10.1016/j.fertnstert.2004.11.005. hdl: 1874/10690 . PMID   15749527. S2CID   44442128.
18. Silber SJ (2005). How to Get Pregnant . New York: Little Brown and Company. ISBN   978-0-316-06650-1.
19. Silber 2005 , p. 66
20. Silber SJ (2006). "Treating Infertility" (PDF). St. Louis, Missouri: Infertility Center of St. Louis.
21. Broekmans FJ, Faddy MJ, Scheffer G, te Velde ER (2004). "Antral follicle counts are related to age at natural fertility loss and age at menopause". Menopause. 11 (6 Pt 1): 607–614. doi:10.1097/01.gme.0000123643.76105.27. hdl: 1874/10681 . PMID   15545788. S2CID   23142876.
22. Ghumman 2006 , p. 135
23. van Rooij IA, Broekmans FJ, Scheffer GJ, Looman CW, Habbema JD, de Jong FH, et al. (April 2005). "Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study". Fertility and Sterility. 83 (4): 979–987. doi:10.1016/j.fertnstert.2004.11.029. hdl: 1765/73139 . PMID   15820810. S2CID   2579891.
24. Ghumman 2006 , pp. 134–5
25. Speroff L, Fritz MA (2005). Clinical Gynecologic Endocrinology and Infertility (7th ed.). Philadelphia PA: Lippincott Williams & Wilkins. ISBN   978-0-7817-4795-0.
26. Lass A, Brinsden P (1999). "The role of ovarian volume in reproductive medicine". Human Reproduction Update. 5 (3): 256–266. doi: 10.1093/humupd/5.3.256 . PMID   10438110.
27. Ghumman 2006 , pp. 136–7
28. "Fertell Clinical Results". Fertell.com. Archived from the original on 2 February 2007.
29. "Clinical Guideline, February 2004: Fertility assessment and treatment for people with fertility problems." National Collaborating Centre for Women's and Children's Health.
30. Sauer MV, Paulson RJ, Lobo RA (July 1995). "Pregnancy in women 50 or more years of age: outcomes of 22 consecutively established pregnancies from oocyte donation". Fertility and Sterility. 64 (1): 111–115. doi: 10.1016/S0015-0282(16)57665-1 . PMID   7789544.
31. "IVF Message Boards". www.newhopefertility.com. Archived from the original on 2008-03-12.
32. Tartagni M, Cicinelli E, De Pergola G, De Salvia MA, Lavopa C, Loverro G (April 2007). "Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial". Fertility and Sterility. 87 (4): 858–861. doi: 10.1016/j.fertnstert.2006.08.086 . PMID   17261285.
33. Check JH, Check ML, Katsoff D (August 2000). "Three pregnancies despite elevated serum FSH and advanced age: case report". Human Reproduction. 15 (8): 1709–1712. doi: 10.1093/humrep/15.8.1709 . PMID   10920090.
34. Check ML, Check JH, Choe JK, Berger GS (2002). "Successful pregnancy in a 42-year-old woman with imminent ovarian failure following ovulation induction with ethinyl estradiol without gonadotropins and in vitro fertilization". Clinical and Experimental Obstetrics & Gynecology. 29 (1): 11–14. PMID   12013081.
35. Check ML, Check JH, Kaplan H (2004). "Pregnancy despite imminent ovarian failure and extremely high endogenous gonadotropins and therapeutic strategies: case report and review". Clinical and Experimental Obstetrics & Gynecology. 31 (4): 299–301. PMID   15672973.
36. Katsoff B, Check JH (2005). "Successful pregnancy in a 45-year-old woman with elevated day 3 serum follicle stimulating hormone and a short follicular phase". Clinical and Experimental Obstetrics & Gynecology. 32 (2): 97–98. PMID   16108390.
37. Check JH (2006). "Pharmacological options in resistent[sic] ovary syndrome and premature ovarian failure". Clinical and Experimental Obstetrics & Gynecology. 33 (2): 71–77. PMID   16903240.
38. Check JH (December 2007). "Mild ovarian stimulation". Journal of Assisted Reproduction and Genetics. 24 (12): 621–627. doi:10.1007/s10815-007-9179-9. PMC   3454994 . PMID   18058016.
39. Dragojević-Dikić S, Rakić S, Nikolić B, Popovac S (December 2009). "Hormone replacement therapy and successful pregnancy in a patient with premature ovarian failure". Gynecological Endocrinology. 25 (12): 769–772. doi:10.3109/09513590903004126. PMID   19905994. S2CID   32319689.
40. Loutradis D, Drakakis P, Vomvolaki E, Antsaklis A (December 2007). "Different ovarian stimulation protocols for women with diminished ovarian reserve". Journal of Assisted Reproduction and Genetics. 24 (12): 597–611. doi:10.1007/s10815-007-9181-2. PMC   3455002 . PMID   18034299.
41. Fisch JD, Keskintepe L, Sher G (February 2008). "Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming in low responders with prior in vitro fertilization failure". Fertility and Sterility. 89 (2): 342–347. doi:10.1016/j.fertnstert.2007.03.004. PMID   17562336.
42. Barad D, Gleicher N (November 2006). "Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF". Human Reproduction. 21 (11): 2845–2849. doi: 10.1093/humrep/del254 . PMID   16997936.
43. Barad DH, Gleicher N (September 2005). "Increased oocyte production after treatment with dehydroepiandrosterone". Fertility and Sterility. 84 (3): 756.e1–756.e3. doi:10.1016/j.fertnstert.2005.02.049. PMID   16169414.
44. Mamas L, Mamas E (February 2009). "Premature ovarian failure and dehydroepiandrosterone". Fertility and Sterility. 91 (2): 644–646. doi: 10.1016/j.fertnstert.2007.11.055 . PMID   18321501.
45. Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH (October 2009). "Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study". Reproductive Biology and Endocrinology. 7: 108. doi: 10.1186/1477-7827-7-108 . PMC   2764711 . PMID   19811650.
46. Letur-Konirsch H, Delanian S (February 2003). "Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with premature ovarian failure who are resistant to hormone replacement therapy". Fertility and Sterility. 79 (2): 439–441. doi: 10.1016/S0015-0282(02)04579-X . PMID   12568863.
47. Letur-Könirsch H, Guis F, Delanian S (June 2002). "Uterine restoration by radiation sequelae regression with combined pentoxifylline-tocopherol: a phase II study". Fertility and Sterility. 77 (6): 1219–1226. doi: 10.1016/s0015-0282(02)03120-5 . PMID   12057732.
48. Lédée-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S (May 2002). "Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme". Human Reproduction. 17 (5): 1249–1253. doi: 10.1093/humrep/17.5.1249 . PMID   11980747.
49. Brann DW, Mahesh VB (April 2005). "The aging reproductive neuroendocrine axis". Steroids. 70 (4): 273–283. doi:10.1016/j.steroids.2004.12.008. PMID   16080236. S2CID   54300307.