Poor ovarian reserve

Impaired ovarian reserve (aka poor ovarian reserve) is a condition of low fertility characterized by low numbers of remaining oocytes in the ovaries. Quality of the eggs (oocytes) is not necessarily impaired. Quality of eggs is more a function of age, unless the eggs, for example, have been damaged by radiation or chemotherapy or other toxins.

Etiology

 * Natural decline of ovarian reserve due to age.


 * Idiopathic.


 * Genetic factors.


 * Autoimmune disorders.


 * Adrenal gland impairment.


 * Iatrogenic, e.g., due to radiation or chemotherapy.

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.


 * 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.  It should be understood that almost all the research on elevated FSH levels and pregnancy rates has been done in the context of assisted reproduction technology (ART), especially in vitro fertilization (IVF).

Elevated 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%).

However, the success rates for all categories of diminished ovarian reserve vary across IVF centers. 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 very low, may be underestimated due to non reporting bias, as most IVF centers will not accept women over the age of forty with FSH levels in the premenopausal range or higher.


 * 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). One study showed this test to be more accurate than basal FSH testing for older women (< 44 years of age) in predicting IVF outcome.  However, in this study a very specific IVF protocol was followed to achieve the results reported.


 * 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.


 * Inhibin B blood level.


 * Ultrasound measurement of ovarian volume.


 * Home testing of FSH urine concentration to alert a woman to possible impaired ovarian reserve became possible in June of 2007 with the introduction of Fertell in the United States and UK, which claims a 95% equivalence to standard serum marker results.

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. 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.


 * Ethinyl estradiol or other synthetic estrogens along with luteal phase progesterone support. Ethinyl estradiol lowers high FSH levels which then it is theorized up regulates FSH receptor sites and restores sensitivity to FSH. Ethinyl estradiol also has the advantage that it does not interfere with the measurement of serum levels of endogenous estrogens.


 * Modifications to standard IVF protocols, such as High-Stim[ulation] Protocols, Minimal-Stim Protocols and Natural Cycle with Controlled Ovulation Protocols.


 * DHEA: Recent clinical trial by the Center for Human Reproduction in New York showed significant effectiveness..

Unproven Treatments with Possible Merit

 * Melatonin: One double blind study showed that extended treatment with melatonin lowered FSH levels (only in woman with low initial nocturnal melatonin levels) and in some cases restored normal menstruation in early menopausal women. The authors claimed fertility was restored in the women with resumption of normal menstruation, however, no ultrasonography was done to verify follicular development.


 * Homeopathy plus herbs 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."

Related Animal Research

 * Recently, two publications have reported the renewal of ovarian follicles from germline stem cells .  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.

Related Conditions

 * Premature ovarian failure: Defined as ovarian failure 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.


 * 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.