Evaluation of ovarian function after breast cancer treatment

  Breast cancer is the most common malignant tumor in women. Currently, the treatment of breast cancer adopts a comprehensive treatment based on surgery and supplemented by other treatments, among which endocrine therapy plays a very important role in the adjuvant. The choice of endocrine therapy is closely related to the functional status of ovaries, and various adjuvant treatments for breast cancer may have certain impact on the assessment of ovarian function, therefore, the assessment of ovarian function is clinically important for the treatment of breast cancer, but sometimes it becomes a difficult point. This article will review the assessment of ovarian function in the treatment of breast cancer from the perspective of a gynecologic endocrinologist.  Determination of menopause in physiological status and assessment of ovarian function Ovarian function is mainly evaluated by testing the ovarian reserve function of the patient. Ovarian reserve function is the ability of follicles in the cortical region of the ovary to grow and develop to form fertilizable oocytes, and usually includes both the number of follicles retained in the ovary and the quality of oocytes. It is an important indicator of ovarian function and fertility in women. Menopause occurs when follicles are depleted.  Menopause is a retrospective concept and is usually confirmed 12 months after the last menstrual period. The average age of menopause does not vary much around the world, mostly around 50 years old. The average age of menopause for women in China is around 49.5 years and 51.4 years for women in the U.S. Menopause before the age of 40 is called premature ovarian failure. There are no studies on the age distribution of menopause in women with large samples. According to a survey involving a total of 1641 women in 14 hospitals nationwide, the majority of women were menopausal between the ages of 45 and 55, accounting for 90.2% of the women surveyed; 8.6% were menopausal before the age of 45; and only 1.2% were not yet menopausal at the age of 55. In this survey, the maximum age of menopause was 57 years old. From the point of view of certainty, it is reliable to consider women over 60 years old as postmenopausal.  The determination of menopause in the physiological state is relatively easy. A woman of appropriate age with more than 12 months of amenorrhea can be considered clinically menopausal; in combination with characteristic endocrine changes, the diagnosis of menopause can be made. Menopause is the result of the failure of the ovaries, the unique female gonads, themselves, so that the estrogen secreted by the ovaries declines; while the hypothalamus and pituitary gland, the superiors that direct the ovaries, are still functioning normally, due to negative feedback, thus manifesting as follicle stimulating hormone (FSH) and follicle stimulating hormone (FSH) secreted by the pituitary gland. hormone (FSH) and luteinizinghormone (LH) are elevated, with FSH predominantly elevated. Because estrogen has extraglandular conversion in addition to ovarian sources, and is affected by many factors, such as the relatively high estrogen levels in obese postmenopausal women, FSH levels have become a more reliable indicator of menopause. Ovarian failure (menopause) is usually judged as FSH > 40 IU/L.  The significance of amenorrhea or menstrual disorders in women of different ages varies. In women over 45 years of age, if amenorrhea has been present for 12 months with symptoms associated with menopause such as hot flashes and sweats, insomnia, or mood disorders, it is likely that menopause is the cause rather than other diseases, and therefore no more diagnostic evaluation is recommended. For women between 40 and 45 years of age, the same endocrine tests such as blood beta HCG to rule out pregnancy, serum prolactin to rule out hyperprolactinemia, and blood thyroid stimulating hormone to rule out hyperthyroidism are recommended as for any woman with scanty menstruation and amenorrhea. For women under 40 years of age, a complete screening for the cause of menstrual abnormalities is recommended.  Such stringent criteria for menopause were used in the first AI adjuvant study, ATAC: for women over 60 years of age, they are considered directly postmenopausal; for women under 60 years of age, they need to meet the criteria for menopause in terms of both time of menopause and hormone levels to be considered menopausal.  Age at menopause is influenced by genetics and a number of other factors (e.g., smoking), and a 2013 study found that carriers of BCRA mutations are more likely to experience early menopause, a strong indicator of low ovarian reserve function. In patients receiving chemotherapy, which will cause oocyte damage, women with BCRA mutations may be more susceptible to apoptosis as a result of chemotherapy, suggesting that BCRA mutations may be a more sensitive indicator of ovarian reserve function. BRCA mutation carriers over 35 years of age who develop amenorrhea after breast cancer chemotherapy are at higher risk of developing permanent amenorrhea, but BRCA mutation does not increase the chance of chemotherapy-induced amenorrhea.  2. Evaluation of ovarian reserve function Physiologically, the evaluation of ovarian reserve function includes the following indicators: (1) Age: There is a consensus that ovarian function decreases with age. The number of oocytes in adolescence is about 300,000, which decreases to about 25,000 by the age of 35 years. However, due to individual variability and the influence of many factors, the rate of ovarian aging varies and the age of menopause is highly variable and unpredictable. Age can only be used as a crude indicator to predict the evaluation of ovarian reserve function and needs to be assessed in combination with other predictive indicators.  (2) Basal state index testing: including FSH, LH, estradiol (E2), FSH/LH values and inhibin B (INHB). Each sex hormone secreted by the ovary and its superordinate, gonadotropin secreted by the pituitary gland, are cyclic, and the hormone levels on days 2-4 of the menstrual cycle are generally referred to as the basal state. Basal FSH>10 IU/L is generally considered as the criterion to determine the decline of ovarian reserve, and assisted reproduction is no longer performed when basal FSH>20 IU/L. In the process of declining ovarian reserve, basal E2 elevation precedes basal FSH elevation, but the specific criteria for basal E2 elevation are not uniform. Some studies suggest that elevated FSH/LH values are more sensitive than basal FSH, but there are also differing opinions. These indicators often need to be considered together.  INHB is secreted and synthesized by small sinusoidal follicular granulosa cells in the ovary, is regulated by FSH, and feedback inhibits FSH. women with diminished ovarian reserve capacity first show a decrease in INHB and then an increase in FSH. Therefore, INHB is considered to be a direct predictor of ovarian reserve. However, INHB measurement has not been performed for a long time and there is no accepted standard.  (3) Anti-Mullerian hormone (AMH): AMH is a member of the transforming growth factor β superfamily, which is expressed only in the ovary in women and is most strongly secreted by granulosa cells in the antral follicles and small sinusoidal follicles. AMH levels are not affected by the feedback regulation of the hypothalamic-pituitary-ovarian axis and are stable during the menstrual cycle and remain constant during pregnancy and contraceptive use. Compared to the aforementioned indicators, AMH measurement is not limited by the menstrual cycle and is more sensitive and accurate because it occurs earlier than changes in hormone levels such as FSH during the decline of ovarian reserve. Unfortunately, it is still not widely used in clinical practice.  (4) Ovarian ultrasonography: including sinus follicle count (antral folliclecount, AFC), ovarian volume, mean ovarian diameter and ovarian stromal blood flow, of which AFC is most commonly used. The basal AFC is the number of sinus follicles of 2-9 mm in diameter detected on vaginal ultrasound during the early follicular phase. Sinus follicles are precursors to mature follicles and their number can indirectly reflect the number of primordial follicles remaining in the follicular pool. Theoretically, AFC obtained by transvaginal ultrasound can reflect ovarian reserve function relatively accurately, but AFC only reflects the number of follicles, not the quality of follicles, and the patient’s pregnancy outcome may depend more on the quality of follicles. Moreover, the error of the AFC test is often large due to the technical level of the examining physician and the pelvic environment of different women, and it is often not widely used in clinical practice.  (5) Ovarian stimulation tests: such as clomiphene stimulation test (CCCT), exogenous FSH ovarian reserve test (EFORT) or FSH stimulation test (FCT), and gonadotropin-releasing hormone agonist stimulation test (GAST). The various ovarian stimulation tests are superior to single basal hormone assays, but the tests are time-consuming and more expensive.