The Pregnancy Lab

Assessing Ovarian Reserve

Women in their mid to late 30s and early 40s with infertility constitute the largest portion of the total infertility population. These women are also at an increased risk for pregnancy loss. This reflects a decline in oocyte quality and a diminished ovarian reserve as a result of follicular depletion. Ovarian reserve is a term that is used to describe the capacity of the ovary to provide eggs that are capable of fertilization resulting in a healthy and successful pregnancy.

While there is no gold standard for assessing the ovarian reserve of individual women, its indirect determination has been used to help direct infertility treatment.

Serum concentrations of follicle-stimulating hormone (FSH) and estradiol on day 3 of the menstrual cycle have been the tests of choice for assessing ovarian reserve. Cycle day 3 is chosen because at this time the estrogen concentration is expected to be low, a critical feature, as FSH concentrations are subject to negative feedback from estradiol. In general, day 3 FSH concentrations >20 to 25 IU/L are considered to be elevated and associated with poor reproductive outcome.   FSH concentrations are expected to be below 10 IU/L in women with reproductive potential.  Concomitant measurement of serum estradiol adds to the predictive power of an isolated FSH determination. Basal estradiol concentrations >75-80 pg/mL are associated with poor outcome. 

Inhibin B is produced by the developing follicles and concentrations peak during the follicular phase. Concentrations of inhibin B can be used in conjunction with serum FSH and estradiol to assess ovarian function. As women age, serum FSH concentrations in the early follicular phase begin to increase. It has been suggested that this is due to a decline in the number of small follicles secreting inhibin B.  Because inhibin is produced by the ovaries, it is thought to be a more direct marker of ovarian activity and ovarian reserve than FSH. In addition, cycle day 3 inhibin B concentrations may demonstrate a decrease before day 3 FSH concentrations. 

Seifer et al reported that women undergoing in vitro fertilization (IVF) with day 3 inhibin B concentration <45 pg/mL had a pregnancy rate of 7% and a spontaneous abortion rate of 33% as compared to pregnancy rate of 26% and abortion rate of 3% in women with day 3 inhibin B concentrations of > 45 pg/mL. 

In recent years, anti-Mullerian Hormone (AMH) has been suggested to be a more useful predictor of ovarian reserve. AMH is expressed by the granulosa cells of the ovary during the reproductive years, and controls the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. In 2005 Tremellen reported that plasma AMH concentrations start to drop rapidly by age 30, and are ~10 pmol/L by the age of 37. David has blogged previously about the use of AMH as a predictor of IVF outcome.   

Using a cut off value of 8.1 pmol/L, plasma AMH could predict poor ovarian reserve on a subsequent IVF cycle with a sensitivity of 80% and a specificity of 85%.     In 2008, Riggs and colleagues confirmed that AMH concentrations correlated the best with the number of retrieved oocytes relative to age, FSH, inhibin B, LH, and estradiol. 

High concentrations of AMH can also be present in women with polycystic ovarian syndrome (PCOS), a cause of female infertility.  Therefore, in PCOS patientsAMH should not be used alone, but should be combined with transvaginal ultrasound to count the number of follicles.

Women who are diagnosed with diminished ovarian reserve should be counseled regarding options such as oocyte donation or adoption.

Anti-müllerian hormone as a predictor of IVF outcome

Investigators at Brown University have reported that the serum concentration of a hormone made by the ovaries can predict the success of in vitro fertilization (IVF). Specifically, the higher amounts of the hormone were correlated to a greater number of eggs retrieved and the probability of achieving pregnancy.

The study measured blood concentrations of anti-müllerian hormone, or AMH. This is a rather interesting hormone. It plays an important role in both males and females but at different stages of human development.

• In fetal development, AMH is synthesized by the testes of a male fetus and it functions to suppress the transformation of the müllerian ducts into the uterus and fallopian tubes. In the absence of AMH (i.e. a female fetus), the wolffian ducts fail to develop into ejaculatory ducts of the male reproductive system while the müllerian ducts complete their development.

• AMH is synthesized by the female ovary but only after birth when it does not affect the development or maturation of the female reproductive tract. It increases slightly at puberty because of it functions to regulate the formation of ovarian follicles (eggs) by opposing the action of another hormone, follicle-stimulating hormone (FSH).

Because of its role in follicle development, AMH can be useful as a marker of ovarian function. In particular it seems to be a good indicator of the growing pool of follicles in the ovary and so reflects the number of eggs in the ovary. That’s exactly what the scientists at Brown University reported.

In 190 women undergoing IVF to achieve pregnancy, the concentration of AMH in a blood sample collected on the first day of ovarian stimulation with FSH was a strong predictor of favorable outcome. Women with the lowest concentrations of AMH had fewer eggs retrieved than those with higher concentrations. Also, the probability of achieving pregnancy was 2.5 times greater in the women with the higher AMH concentrations.

What might these results mean from a practical perspective? The authors of the study comment that IVF patients could be better counseled and IVF management strategies modified by the AMH results. IVF is expensive. Women who seek to achieve a pregnancy by this route are highly motivated to obtain a positive outcome and so they may undergo several IVF cycles in an effort to become pregnant. Those with a low AMH concentration may opt for only a single IVF cycle or seek adoption or other routes of parenthood rather than invest thousands of dollars into what may be an unachievable biological goal.