Poor ovarian reserve

Impaired ovarian reserve (aka poor ovarian reserve or declining ovarian reserve) is a condition of low fertility characterized by low numbers of remaining oocytes in the ovaries. Quality of the eggs (oocytes) may also be impaired as a 1989 study by Scott et al. of 758 IVF cycles showed a dramatic decline in implantation rates between high (> 25 mIU/mL) and low day three FSH (<15 mIU/mL) women even though the ages of the women were equivalent between the two groups (mean age 35 years). [Gardner, David K; Weissman, Ariel; Howles, Colin M.; Shoham, Zeev, 2001. "Textbook of Assisted Reproductive Techniques: Laboratory and Clinical Perspectives". Taylor & Francis. ISBN 1853178705. (See page 528.)] [Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z, 1989. "Follicle-stimulation hormone levels on cycle day 3 are predictive of in vitro fertilization outcome." Fertility and Sterility 51(4):651-4. PMID: 2494082.] 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. [Thum, Meen-You, et al., 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.] [Abdulla H, Thum MY, 2004. An elevated basal FSH reflects a quantitative rather than a qualitative decline of the ovarian reserve. "Human Reproduction", 19(4): 893-898]

Etiology

* Natural decline of ovarian reserve due to age.

* 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). [ [http://www.fragilex.org/html/menopause.htm The National Fragile X Foundation] ]

* 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. (The primordial follicles are located in the thin outer one-millimeter layer of the ovary.) [Silber, Sherman J., 2005. "How to Get Pregnant". Little Brown and Company, New York. ISBN 0-316-06650-8. Pages 47 and 71.]

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. [Broekmans FJ, et al. 2006. "A systematic review of tests predicting ovarian reserve and IVF outcome." "Hum. Reprod. Update," 12(6):685-718. PMID: 16891297.] Also Centers for Disease Control and Prevention statistics show that the success rates for IVF with diminished ovarian reserve vary widely between IVF centers. [ [http://www.cdc.gov/ART/ Centers for Disease Control and Prevention - Assisted Reproduction Technology] ]

* 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. [Ghumman, Surveen, 2006. "Step by Step Ovulation Induction". Anshan Ltd, Kent, United Kingdom. ISBN 1-904798-96-9. Page 134.]

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%). [Navot D, Rosenwaks Z, Margalioth EJ., 1987. "Prognostic assessment of female fecundity." "Lancet" 1987;2:645–7.]

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.Fact|date=June 2007

* 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).

* Transvaginal ultrasonography 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. [Klinkert, Ellen R, et al.,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.] This method of determining ovarian reserve is recommended by Dr. Sherman J. Silber, author and medical director of the Infertility Center of St. Louis. [Silber, Sherman J., 2005. "How to Get Pregnant". Little Brown and Company, New York. ISBN 0-316-06650-8.]

Values in a row with unlike letters indicate significant difference at P<0.05.
SE = Standard Error of Mean

* Homeopathy plus herbs, vitamins and lifestyle changes may possibly help. An article by Liz Lalor titled "Fertility Success using homeopathy" outlines a protocol that she states has been successful in forty out of fifty cases of infertilty. Of note is that two of the ten that failed later conceived in one IVF cycle and she writes: "it was reported back to me that the doctors were very surprised at the quality and numbers of eggs as well as the health of the endometrium." [URL:.]

Related Animal Research

* Recently, two publications have reported the renewal of ovarian follicles from germline stem cells [cite journal | author = Johnson J, Bagley J, Skaznik-Wikiel M, Lee H, Adams G, Niikura Y, Tschudy K, Tilly J, Cortes M, Forkert R, Spitzer T, Iacomini J, Scadden D, Tilly J | title = Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. | journal = Cell | volume = 122 | issue = 2 | pages = 303–15 | year = 2005 | pmid = 16051153 | doi = 10.1016/j.cell.2005.06.031 ] [cite journal | author = Johnson J, Canning J, Kaneko T, Pru J, Tilly J | title = Germline stem cells and follicular renewal in the postnatal mammalian ovary. | journal = Nature | volume = 428 | issue = 6979 | pages = 145–50 | year = 2004 | pmid = 15014492 | doi = 10.1038/nature02316] . Prior to these papers it was believed that the number of oocytes was fixed.
* 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. [Brann, Darrel W. and Mahesh, Virenda B., 2005. "The aging reproductive neuroendocrine axis." "Steroids" 70, pages 273-283.]

Related Conditions

* Premature ovarian failure: Defined as no menses for six months before the age of forty due to any cause. Another term for premature menopause. Often diagnosed by elevated gonadotropin (Follicle Stimulating Hormone and LH) levels. In some cases (more so in younger women) ovarian function and ovulation can spontaneously resume.

* Premature menopause: A synonym for premature ovarian failure. The term encompasses early menopause due to any cause, including surgical removal of the ovaries for any reason.

Cross References

* Ovarian reserve

* Follicle-stimulating hormone

References