Ovarian Aging May Be Missed as Infertility Cause


ASHEVILLE, N.C. — Ovarian aging is often overlooked as a cause of infertility and should be considered even in younger women, Dr. Tamer M. Yalcinkaya said at the Southern Obstetric and Gynecologic Seminar.

Dr. Yalcinkaya, medical director of the in vitro fertilization program at Wake Forest University, Winston-Salem, N.C., said that ovarian aging is an evolving concept. It encompasses age-related infertility, diminished ovarian reserve, and early ovarian aging.

Ovarian aging often is hidden among the “unexplained” causes of infertility, but it is as common as many of the factors usually examined and is more severe and less treatable, said Dr. Yalcinkaya.

Ovarian aging is usually a result of progressive follicular depletion and/or abnormalities in the oocyte/follicle. Oocytes are continually declining from birth to menopause, but the decrease accelerates starting at age 38, he said, citing a 2005 study (N. Engl. J. Med. 2005;353:64–73). At the same time, there is an increase in basal follicle-stimulating hormone (FSH) levels, a decrease in fecundity, and an increase in aneuploidy. While endocrine and menstrual functions remain relatively unchanged for the next 6–8 years, menstrual irregularities generally begin at 45. By menopause, there are 1,000 or fewer follicles. The mean age of menopause is 51, though it ranges from 40 to 60. The age of onset is primarily determined by genetic factors but is slightly influenced by lifestyle, environmental, and parity factors.

Ten percent of the population will have early menopause—that is, by age 45—and another 10% will show early ovarian aging, when they are aged 27–32, said Dr. Yalcinkaya. Women in the normal range of reproductive age can experience ovarian aging, he said. However, women with diminished ovarian reserve still have the potential to conceive, and it is important to identify these women early so that various assisted reproductive techniques can be attempted, said Dr. Yalcinkaya.

Diagnostics include baseline hormone measures, including early follicular phase FSH, estradiol, inhibin B, and antimüllerian hormone. Ultrasound can be used to count the number of antral follicles if the technician is experienced; it can also measure ovarian volume. A threshold of 3 cm

Hormone tests should be challenged with clomiphene citrate, exogenous FSH reserve, and gonadotropin-releasing hormone agonist stimulation.

The clomiphene citrate challenge may be better at detecting diminished ovarian reserve than the FSH test but can only be used in patients over age 35, he said. Often, patients who have an abnormal clomiphene citrate test are told they have “ovulatory disorder” or “unexplained infertility,” but clinicians should investigate further as to whether the cause is ovarian aging, Dr. Yalcinkaya said.

The inhibin B test is new and evolving, with divergent data on its utility, he said.

Most of these tests have a low positive predictive value; good results mean the clinician can't guarantee that the patient will become pregnant. But they also have a high negative predictive value; abnormal results generally mean a pregnancy is highly unlikely, Dr. Yalcinkaya said.

Ovarian aging can't be stopped, but physicians can counsel women to maintain healthy lifestyles that promote fertility, including quitting smoking. Physicians can also consider liberal testing of ovarian reserve in all infertile women who are over age 35 or who have a single ovary; in women with a history of ovarian surgery; and in women who smoke or have unexplained infertility, recurrent unexplained early pregnancy losses, irregular periods, or a family history of early menopause, he said. Patients with mild to moderate ovarian aging should be referred to a reproductive endocrinologist for aggressive treatment with exogenous gonadotropin and intrauterine insemination or in vitro fertilization, he said.

Dr. Yalcinkaya had no conflicts of interest to disclose.

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