Executive Summary of the Stages of Reproductive Aging
STRAW +10 retained the criteria for an ideal staging system used by the 2001 Workshop. Therefore, a staging system should
1. rely primarily on objective data;
2. use widely available, reliable, noninvasive, and inexpensive tests;
3. allow for prospective classification of women; and
4. permit unambiguous classification of women into a unique stage.
In addition, it was concluded that the modified staging system should
5. retain the same widely accepted nomenclature;
6. consider menstrual cycle criteria to remain the most important criteria given the continuing lack of international standardization of biomarker assays as well as their cost and/or invasiveness, particularly in the context of resource-poor countries;
7. consider biomarker criteria as supportive criteria given the lack of assay standardization (supportive criteria are to be used only as necessary and should not be interpreted as required for diagnosis); and
8. use criteria that are independent of age, symptoms, and pathology (because no universal menopausal syndrome has been established across ethnic groups, two key symptoms are incorporated only as descriptive additional information that may support other criteria in assessing stage).
The revised STRAW + 10 Staging System is presented in Figure 2. STRAW + 10 recommended the acceptance of the ReSTAGE Collaboration's more precise and simplified specification of the menstrual cycle criteria for the early and late menopausal transition and concurred with ReSTAGE recommendations that the quantification of the FSH criteria in Stage -1 is possible given the improved standardization of this assay and additional population-based data. In addition, STRAW + 10 recommended modifications to the criteria for the late reproductive stage (Stage -3) as well as the early postmenopause stage (Stage +1) and provided information on the duration of the late transition (Stage -1) and early post-menopause (Stage +1) stages. Although additional biomarkers, especially AMH and AFC, have considerable promise, the lack of standardized assays and data from noninfertility populations remain important limitations to their incorporation into the STRAW staging system and their utility as clinical tools for staging reproductive aging. Nonetheless, the revised STRAW + 10 Staging System includes qualitative criteria for these biomarkers during the late reproductive life when relative changes in these parameters have important consequences for fertility potential.
(Enlarge Image)
Figure 2.
The Stages of Reproductive Aging Workshop + 10 staging system for reproductive aging in women.
Late Reproductive Stage (Stage -3). The late reproductive stage marks the time when fecundability begins to decline and during which a woman may begin to notice changes in her menstrual cycles. Given that critical endocrine parameters begin to change before overt changes in menstrual cyclicity and that these endocrine changes are important to fertility assessments, STRAW + 10 recommended that the late reproductive stage be subdivided into two substages (-3b and -3a). In Stage -3b, menstrual cycles remain regular without change in length or early follicular phase FSH levels; however, AMH and antral follicle counts are low. Most but not all studies suggest that inhibin-B is also low. In Stage -3a, subtle changes in menstrual cycle characteristics, specifically shorter cycles, begin. Early follicular phase (cycle days 2-5) FSH increases and becomes more variable, with the other three markers of ovarian aging being low. The lack of standardized AMH assays prevented the development of quantitative recommendations for this biomarker.
Early Menopausal Transition (Stage -2). Early menopausal transition is marked by increased variability in menstrual cycle length, defined as a persistent difference of 7 days or more in the length of consecutive cycles. Persistence is defined as recurrence within 10 cycles of the first variable length cycle. Cycles in the early menopausal transition are also characterized by elevated but variable early follicular phase FSH levels and low AMH levels and AFC.
Late Menopausal Transition (Stage -1). The late menopausal transition is marked by the occurrence of amenorrhea of 60 days or longer. Menstrual cycles in the late menopausal transition are characterized by increased variability in cycle length, extreme fluctuations in hormonal levels, and increased prevalence of anovulation. In this stage, FSH levels are sometimes elevated into the menopausal range and sometimes within the range characteristic of the earlier reproductive years, particularly in association with high estradiol levels. The development of international standards and the availability of substantive population-based data now permit the definition of quantitative FSH criteria, with levels greater than 25 IU/L in a random blood draw characteristic of being in late transition, based on current international pituitary standards that approximate more than 40 IU/L in the previously used urine-based gonadotropin standards. Empirical analyses should be undertaken to confirm this recommendation, and researchers and clinicians should carefully evaluate the appropriate FSH value, depending on the assay they use. Based on studies of menstrual calendars and on changes in FSH and estradiol, this stage is estimated to last, on average, 1 to 3 years. Symptoms, most notably vasomotor symptoms, are likely to occur during this stage.
Early Postmenopause (Stage +1a, +1b, +1c). New data on the trajectories of change in mean levels of FSH and estradiol indicate that FSH continues to increase and that estradiol continues to decrease until approximately 2 years after the FMP, after which the levels of each of these hormones stabilize. Therefore, STRAW + 10 recommended that early postmenopause be subdivided into three substages (+1a, +1b, and +1c).
Stages +1a and +1b each last 1 year and end at the time point at which FSH and estradiol levels stabilize. Stage +1a marks the end of the 12- month period of amenorrhea required to define that the FMP has occurred. It corresponds to the end of "perimenopause," a term still in common usage that means the time around menopause and begins at Stage -2 and ends 12 months after the FMP. Stage +1b includes the remainder of the period of rapid changes in mean FSH and estradiol levels. Based on studies of hormonal changes, Stages +1a and +1b together are estimated to last, on average, 2 years. Symptoms, most notably vasomotor symptoms, are most likely to occur during this stage.
Stage +1c represents the period of stabilization of high FSH levels and low estradiol values that is estimated to last 3 to 6 years; therefore, the entire early postmenopause lasts approximately 5 to 8 years. Further specification of this stage will require additional studies of trajectories of change in FSH and estradiol from the FMP through the late postmenopause.
Late Postmenopause (Stage +2). Stage +2 represents the period in which further changes in reproductive endocrine function are more limited and processes of somatic aging become of paramount concern. Symptoms of vaginal dryness and urogenital atrophy become increasingly prevalent at this time. However, many years after menopause, it has been observed that there may be a further decline in levels of FSH in very old persons; future studies will be needed to determine whether an additional stage is warranted near the end of life.
Evidence now supports the applicability of the STRAW + 10 recommendations for most women. Epidemiologic and clinical studies have documented that the process of reproductive aging, although influenced by demographic factors, lifestyle, and BMI, follows a robust and predictable pattern. Although smoking and BMI influence hormonal levels and the timing of transition, these factors do not alter the trajectory of change in bleeding patterns or hormonal levels with reproductive aging. Therefore, the STRAW + 10 staging system is applicable to women regardless of age, demographic, BMI, or lifestyle characteristics.
The STRAW + 10 model does not use age as a criterion for determining reproductive staging. However, women meeting the criteria for POI/premature ovarian failure (age <40 y with 4 mo of amenorrhea and two serum FSH levels [at least a month apart] in the menopausal range) do not easily fit into this model. The course of reproductive aging in women with POI/premature ovarian failure seems to be considerably more variable than that of women with normal reproductive aging. Not only are there several potential etiologies but also a substantial proportion of women have spontaneous resumption of menstrual function once the diagnosis has been confirmed, including ovulation and successful spontaneous pregnancy. Additional research is needed to better document the process of ovarian aging in these women and whether the course of ovarian aging differs by etiology of POI. Studies of reproductive aging in POI are considered to be a research priority.
Women who have undergone hysterectomy or endometrial ablation cannot be staged by menstrual bleeding criteria.Reproductive stage in these women can only be assessed using the supportive criteria, that is, the endocrine markers of ovarian aging. It is recommended that clinicians and researchers wait at least 3 months after surgery to assess endocrine status, given emerging evidence that pelvic surgeries may transiently raise FSH levels. Further research on the nature and duration of alterations in biomarkers of ovarian aging secondary to pelvic surgery is warranted. In most cases, staging will be limited to the classification of whether such women are premenopausal or postmenopausal. A single sample for measurement of FSH and estradiol may be ambiguous or misleading, and at least one repeated measurement is often required.
Women with PCOS frequently experience oligomenorrhea that is not attributable to ovarian aging. Therefore, the current menstrual cycle criteria used to stage reproductive aging are not applicable to this population. Understanding of the changes occurring before menopause in this group of women is limited. Some data suggest that women with PCOS may experience a later age at menopause, as well as more regular cycles with reproductive aging; however, the experience of reproductive aging in PCOS is not well understood. Similarly, menstrual cycle criteria are not applicable in women with hypothalamic amenorrhea. Studies of reproductive aging in these subgroups of women are considered to be a research priority.
Many medications and loss of body fat can cause amenorrhea, which can make the staging of the menopausal transition difficult. Several important subgroups remain difficult to stage yet deserve attention in any staging system. Depending on the age at treatment and cancer treatment type, a significant proportion of women who undergo cancer treatment, particularly with alkylating agents, may experience transient increases in FSH and decreases in AMH and AFC with return of bleeding even after 12 months or more of amenorrhea. In these women, resumption of menstrual cycles may not indicate a return of normal menstrual function. Women undergoing treatment with tamoxifen pose an additional problem because FSH and estradiol levels may be altered by this treatment and may therefore be misleading and cause abnormal bleeding. Women with chronic illnesses such as HIV-AIDS also pose a problem in the staging of reproductive aging because of the lack of reliability of bleeding patterns and hormonal markers. Staging in these women will require assessment with menstrual cycle criteria, the supportive criteria using relevant biomarkers, and age to better characterize their ovarian function. Large prospective cohort studies are needed to better characterize the trajectories of ovarian aging in these populations.
Results
STRAW +10 retained the criteria for an ideal staging system used by the 2001 Workshop. Therefore, a staging system should
1. rely primarily on objective data;
2. use widely available, reliable, noninvasive, and inexpensive tests;
3. allow for prospective classification of women; and
4. permit unambiguous classification of women into a unique stage.
In addition, it was concluded that the modified staging system should
5. retain the same widely accepted nomenclature;
6. consider menstrual cycle criteria to remain the most important criteria given the continuing lack of international standardization of biomarker assays as well as their cost and/or invasiveness, particularly in the context of resource-poor countries;
7. consider biomarker criteria as supportive criteria given the lack of assay standardization (supportive criteria are to be used only as necessary and should not be interpreted as required for diagnosis); and
8. use criteria that are independent of age, symptoms, and pathology (because no universal menopausal syndrome has been established across ethnic groups, two key symptoms are incorporated only as descriptive additional information that may support other criteria in assessing stage).
The revised STRAW + 10 Staging System is presented in Figure 2. STRAW + 10 recommended the acceptance of the ReSTAGE Collaboration's more precise and simplified specification of the menstrual cycle criteria for the early and late menopausal transition and concurred with ReSTAGE recommendations that the quantification of the FSH criteria in Stage -1 is possible given the improved standardization of this assay and additional population-based data. In addition, STRAW + 10 recommended modifications to the criteria for the late reproductive stage (Stage -3) as well as the early postmenopause stage (Stage +1) and provided information on the duration of the late transition (Stage -1) and early post-menopause (Stage +1) stages. Although additional biomarkers, especially AMH and AFC, have considerable promise, the lack of standardized assays and data from noninfertility populations remain important limitations to their incorporation into the STRAW staging system and their utility as clinical tools for staging reproductive aging. Nonetheless, the revised STRAW + 10 Staging System includes qualitative criteria for these biomarkers during the late reproductive life when relative changes in these parameters have important consequences for fertility potential.
(Enlarge Image)
Figure 2.
The Stages of Reproductive Aging Workshop + 10 staging system for reproductive aging in women.
Definition and Rationale for Key Revisions to the Staging Criteria
Late Reproductive Stage (Stage -3). The late reproductive stage marks the time when fecundability begins to decline and during which a woman may begin to notice changes in her menstrual cycles. Given that critical endocrine parameters begin to change before overt changes in menstrual cyclicity and that these endocrine changes are important to fertility assessments, STRAW + 10 recommended that the late reproductive stage be subdivided into two substages (-3b and -3a). In Stage -3b, menstrual cycles remain regular without change in length or early follicular phase FSH levels; however, AMH and antral follicle counts are low. Most but not all studies suggest that inhibin-B is also low. In Stage -3a, subtle changes in menstrual cycle characteristics, specifically shorter cycles, begin. Early follicular phase (cycle days 2-5) FSH increases and becomes more variable, with the other three markers of ovarian aging being low. The lack of standardized AMH assays prevented the development of quantitative recommendations for this biomarker.
Early Menopausal Transition (Stage -2). Early menopausal transition is marked by increased variability in menstrual cycle length, defined as a persistent difference of 7 days or more in the length of consecutive cycles. Persistence is defined as recurrence within 10 cycles of the first variable length cycle. Cycles in the early menopausal transition are also characterized by elevated but variable early follicular phase FSH levels and low AMH levels and AFC.
Late Menopausal Transition (Stage -1). The late menopausal transition is marked by the occurrence of amenorrhea of 60 days or longer. Menstrual cycles in the late menopausal transition are characterized by increased variability in cycle length, extreme fluctuations in hormonal levels, and increased prevalence of anovulation. In this stage, FSH levels are sometimes elevated into the menopausal range and sometimes within the range characteristic of the earlier reproductive years, particularly in association with high estradiol levels. The development of international standards and the availability of substantive population-based data now permit the definition of quantitative FSH criteria, with levels greater than 25 IU/L in a random blood draw characteristic of being in late transition, based on current international pituitary standards that approximate more than 40 IU/L in the previously used urine-based gonadotropin standards. Empirical analyses should be undertaken to confirm this recommendation, and researchers and clinicians should carefully evaluate the appropriate FSH value, depending on the assay they use. Based on studies of menstrual calendars and on changes in FSH and estradiol, this stage is estimated to last, on average, 1 to 3 years. Symptoms, most notably vasomotor symptoms, are likely to occur during this stage.
Early Postmenopause (Stage +1a, +1b, +1c). New data on the trajectories of change in mean levels of FSH and estradiol indicate that FSH continues to increase and that estradiol continues to decrease until approximately 2 years after the FMP, after which the levels of each of these hormones stabilize. Therefore, STRAW + 10 recommended that early postmenopause be subdivided into three substages (+1a, +1b, and +1c).
Stages +1a and +1b each last 1 year and end at the time point at which FSH and estradiol levels stabilize. Stage +1a marks the end of the 12- month period of amenorrhea required to define that the FMP has occurred. It corresponds to the end of "perimenopause," a term still in common usage that means the time around menopause and begins at Stage -2 and ends 12 months after the FMP. Stage +1b includes the remainder of the period of rapid changes in mean FSH and estradiol levels. Based on studies of hormonal changes, Stages +1a and +1b together are estimated to last, on average, 2 years. Symptoms, most notably vasomotor symptoms, are most likely to occur during this stage.
Stage +1c represents the period of stabilization of high FSH levels and low estradiol values that is estimated to last 3 to 6 years; therefore, the entire early postmenopause lasts approximately 5 to 8 years. Further specification of this stage will require additional studies of trajectories of change in FSH and estradiol from the FMP through the late postmenopause.
Late Postmenopause (Stage +2). Stage +2 represents the period in which further changes in reproductive endocrine function are more limited and processes of somatic aging become of paramount concern. Symptoms of vaginal dryness and urogenital atrophy become increasingly prevalent at this time. However, many years after menopause, it has been observed that there may be a further decline in levels of FSH in very old persons; future studies will be needed to determine whether an additional stage is warranted near the end of life.
Inclusiveness of the STRAW + 10 Criteria
Evidence now supports the applicability of the STRAW + 10 recommendations for most women. Epidemiologic and clinical studies have documented that the process of reproductive aging, although influenced by demographic factors, lifestyle, and BMI, follows a robust and predictable pattern. Although smoking and BMI influence hormonal levels and the timing of transition, these factors do not alter the trajectory of change in bleeding patterns or hormonal levels with reproductive aging. Therefore, the STRAW + 10 staging system is applicable to women regardless of age, demographic, BMI, or lifestyle characteristics.
The STRAW + 10 model does not use age as a criterion for determining reproductive staging. However, women meeting the criteria for POI/premature ovarian failure (age <40 y with 4 mo of amenorrhea and two serum FSH levels [at least a month apart] in the menopausal range) do not easily fit into this model. The course of reproductive aging in women with POI/premature ovarian failure seems to be considerably more variable than that of women with normal reproductive aging. Not only are there several potential etiologies but also a substantial proportion of women have spontaneous resumption of menstrual function once the diagnosis has been confirmed, including ovulation and successful spontaneous pregnancy. Additional research is needed to better document the process of ovarian aging in these women and whether the course of ovarian aging differs by etiology of POI. Studies of reproductive aging in POI are considered to be a research priority.
Hysterectomy and Endometrial Ablation
Women who have undergone hysterectomy or endometrial ablation cannot be staged by menstrual bleeding criteria.Reproductive stage in these women can only be assessed using the supportive criteria, that is, the endocrine markers of ovarian aging. It is recommended that clinicians and researchers wait at least 3 months after surgery to assess endocrine status, given emerging evidence that pelvic surgeries may transiently raise FSH levels. Further research on the nature and duration of alterations in biomarkers of ovarian aging secondary to pelvic surgery is warranted. In most cases, staging will be limited to the classification of whether such women are premenopausal or postmenopausal. A single sample for measurement of FSH and estradiol may be ambiguous or misleading, and at least one repeated measurement is often required.
Polycystic Ovary Syndrome
Women with PCOS frequently experience oligomenorrhea that is not attributable to ovarian aging. Therefore, the current menstrual cycle criteria used to stage reproductive aging are not applicable to this population. Understanding of the changes occurring before menopause in this group of women is limited. Some data suggest that women with PCOS may experience a later age at menopause, as well as more regular cycles with reproductive aging; however, the experience of reproductive aging in PCOS is not well understood. Similarly, menstrual cycle criteria are not applicable in women with hypothalamic amenorrhea. Studies of reproductive aging in these subgroups of women are considered to be a research priority.
Women With Chronic Illness Undergoing Chemotherapy
Many medications and loss of body fat can cause amenorrhea, which can make the staging of the menopausal transition difficult. Several important subgroups remain difficult to stage yet deserve attention in any staging system. Depending on the age at treatment and cancer treatment type, a significant proportion of women who undergo cancer treatment, particularly with alkylating agents, may experience transient increases in FSH and decreases in AMH and AFC with return of bleeding even after 12 months or more of amenorrhea. In these women, resumption of menstrual cycles may not indicate a return of normal menstrual function. Women undergoing treatment with tamoxifen pose an additional problem because FSH and estradiol levels may be altered by this treatment and may therefore be misleading and cause abnormal bleeding. Women with chronic illnesses such as HIV-AIDS also pose a problem in the staging of reproductive aging because of the lack of reliability of bleeding patterns and hormonal markers. Staging in these women will require assessment with menstrual cycle criteria, the supportive criteria using relevant biomarkers, and age to better characterize their ovarian function. Large prospective cohort studies are needed to better characterize the trajectories of ovarian aging in these populations.
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