Poor ovarian reserve
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.
Quality of the eggs may also be impaired. 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. 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. 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.
Cause
- 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 experience fragile x primary ovarian insufficiency and another 23% experience early menopause.
- 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.
Diagnosis
Follicle stimulating hormone
Elevated serum follicle stimulating hormone level measured on day three of the menstrual cycle. 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 should also be measured as women who ovulate early may have elevated E2 levels above 80 pg/mL which will mask an elevated FSH level and give a false negative result.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.
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.
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.
Antral follicle count
Transvaginal ultrasonography can be used to determine antral follicle count. This is an easy-to-perform and noninvasive method. Several studies show this test to be more accurate than basal FSH testing for older women in predicting IVF outcome. This method of determining ovarian reserve is recommended by Dr. Sherman J. Silber, author and medical director of the Infertility Center of St. Louis.AFC and Median Fertile Years Remaining
| Antral Follicle Count | 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. 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
| Antral Follicle Count | 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 |
AFC and FSH Stimulation Recommendations for Cycles Using Assisted Reproduction Technology
| 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 fertility in measuring age related decline in ovarian reserve.
- 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.
- Ultrasound measurement of ovarian volume. Lass and Brinsden report that the correlation between ovarian volume and follicular density appears to only hold in women ≥ 35 years of age.
- Dynamic Assessment Following GnRH-a Administration. 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 gonadatropin 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.
- 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.
Treatment
- 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.
- Natural or Mini-IVF, but without the use of hCG to trigger ovulation, instead the GnRH agonist Synarel in a diluted form is taken as a nasal spray to trigger ovulation. Human chorionic gonadotropin has a long half life and may stimulate 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.
- 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. 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 and FSH levels greater or equal than 40 mIU/mL. The researchers believe this protocol would work for women in early post menopause as well.
- Ethinylestradiol or other synthetic estrogens along with luteal phase progesterone 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 oral estradiol. Since conception may have occurred estradiol is used instead of the synthetic ethinylestradiol.
- Cyclical hormone replacement therapy.
- The following protocols have shown promise: high dose gonadoropins, flare up GnRH-a protocol, stop protocols, short protocol, natural cycle or modified natural cycle and low dose hCG during the beginning of the stimulation protocol.
- Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming protocol. Fisch, Keskintepe and Sher report 35% ongoing gestation in women with elevated FSH levels ; among women aged 41–42 the ongoing gestation rate was 19%.
- DHEA: Recent clinical trial by the Center for Human Reproduction in New York showed significant effectiveness. Leonidas and Eudoxia Mamas report six cases of premature ovarian failure. After two to six months of treatment with DHEA 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. In addition, there is strong evidence that continuous micronized DHEA 25 mg TID reduces miscarriage and aneuploidy rates, especially above age 35.
- Glucocorticoid therapy. A recent randomized double blind study done in Egypt reported a statistically significant theurapeutic effect with dexamethasone pretreatment. Fifty-eight women with idiopathic premature ovarian failure and normal karyotype were divided into two groups of twenty-nine. The control group received placebo for twenty-eight days and then GnRH agonists plus gonadotropin therapy. The treatment group received dexamethasone for twenty-eight days and then GnRH agonists plus gonadotropin therapy. The treatment group had six ovulations and two pregnancies. The control group had three ovulations and no pregnancies.
- A combined pentoxifylline-tocopherol treatment has been reported effective in improving uterine parameters in women with POF undergoing IVF with donor oocytes. Three women with uterine hormonoresistance despite high estradiol plasma levels received treatment with 800 mg pentoxifylline and 1000 IU of vitamin E for at least nine months. Three frozen-thawed embryo transfers resulted in two viable pregnancies. Mean endometrial thickness increased from 4.9 mm to 7.4 mm with nice uterine crosses. This treatment protocol has also reversed some cases of iatrogenic POF caused by full body radiation treatment.
Research
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 levels. In some cases 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.
- Premature menopause: A 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.