Predicting Age of Menopause Onset

Current methods of predicting final menstrual period are not very accurate. They can only predict final menstrual period to within four years. These methods include measuring menstrual bleeding patterns and follicle stimulating hormone (FSH). Measuring FSH indirectly measures ovarian reserve; but levels vary widely across the menstrual cycle, and even within a given day.

Anti-mullerian hormone (AMH), produced in the ovarian follicles, slowly but continuously decreases as the number of follicles declines. AMH generally stays stable and is also increasingly being used although previous tests have not been very precise; however, a new ultrasensitive AMH test that is providing a much lower detection limit is considered more accurate (1.85 pg/mL, compared with 50 to 100 pg/mL).

Lower serum AMH levels, high serum FSH levels, and low antral follicle count (AFC) are associated with the onset of menopause; but it is unclear which of these measures or combination of measures best predicts menopause. In the updated 2011 STRAW + 10 analysis of newer studies, the authors deemed cycle day 3 FSH levels greater than 25 IU/L characteristic of the late menopause transition and are associated with onset of menopause within one to three years.

In the 2013 analysis of the CARDIA women’s study showed that an antral follicle count of 4 or lower independently predicted menopause within seven years.

In another study, Nair and colleagues showed that an AMH of less than 0.5 ng/dL was independently associated with natural menopause.

The AMH test is one of the most common hormones used in estimating a woman’s fertility and is often used during fertility treatments like in-vitro fertilization (IVF). The level of AMH measured for that purpose (measured in ng/mL) is often 1000-fold higher than the levels measured by the ultrasensitive test in order to determine the time to final menstrual period.

It took the SWAN study (Study of Women’s Health Across the Nation), which followed the same women year after year from well before menopause until well after, to get the data necessary to be able to demonstrate the predictive value of AMH. Results showed that the ultrasensitive AMH test had significantly better accuracy for predicting final menstrual period within the next two years compared to FSH, as well as the next three years.

For women with an AMH <10 pg/mL, the probability of having a final menstrual period in the next 12 months ranged from 51% for those younger than 48 years to 79% for those aged 51 years or older.

If AMH <10 pg/mL, the probability of having a final menstrual period (FMP) in the next 12 months ranged from 51% for those <48 years old to 79% for those aged 51 years or older.

For 36% of samples, AMH levels were <10 pg/mL. The sensitivities for having a FMP with an AMH <10 pg/mL ranged from 71% for women younger than 48 years old to 82% for women aged 51 years or older. For these age groups, positive predictive values ranged from 51% to 79%.

For 38% of samples, AMH levels were >100 pg/mL: 65% for women younger than 48 and 27% for women aged 51 or older. The specifics for not having a FMP in the next 12 months ranged from 65% for women <48 years old to 27% for women 51 or older. For these aged groups, the negative predictive values ranged from 97% to 90%.

The level of AMH fluctuates much less over the course of menstruation than FSH, LH, estrogen, and progesterone, so it won’t change much based on which day you took this test. This chart below shows typical changes in AMH levels with age.

Does Screening Mammography Reduce Breast Cancer Mortality??

According to this Australian study covering the last three decades, it looks like the answer is “no.” Rather, it is adjuvant therapy for breast cancer patients that reduces mortality. Breast cancer screening’s primary goal is to identify women with early breast cancers, stages I or II. The principle is based on the assertion that early detection and thus early treatment results in reduced incidence of advanced malignancies and thus, saves lives. The results of this study seriously challenge that paradigm. In addition, other studies in the last few years, have resulted in changes in screening guidelines as well as confusion and differences in recommendations amongst different organizations.

The current study assessed the relative influences of screening mammography and adjuvant therapy on breast cancer mortality trends by analyzing data from cancer registries and mammographic results for 76,630 women with invasive breast cancer in an Australian region that offers screening every two years for women ages 50-69 over a period from 1982 through 2013. In that age group, screening rates increased from 48% in 1994 to 57% in 2012. By 1999, they report that 74% of women with early stage breast cancers were receiving tamoxifen and the use of adjuvant chemotherapy was 72% for premenopausal women and 29% for postmenopausal women. In the time period of the study, breast cancer mortality fell from 32 per 100,000 in 1982 to 24 per 100,000 in 2013. Unfortunately, the incidence of advanced breast cancer rose from 12 per 100,000 in 1986 to 24 per 100,000 in 2013.

Commentary: It has been generally presumed for decades that screening mammography and early detection of breast cancer plays an essential role in the declining mortality of breast cancer. However, important studies in the US in 2012 (NEJM  2012 Nov 22; 367:1998, and NEJM 2012;367:1998) and in the Netherlands (BMJ 2017;359:j5224) actually found that the incidence of advanced breast cancer was stable or increased after screening mammography was introduced. The researchers of the current Australian study concluded that the reduced mortality from breast cancer in women in that region can be entirely due to the increased utilization of adjuvant therapy and that the increase in the incidence of advanced breast cancer rules out a direct association of mammography screening with a decline in mortality. They then proposed a radical shift in medical practice and that government-sponsored programs for screening mammography be discontinued.

This evolving story of the value of screening mammography and resulting guidelines will continue to slowly change based on a more individualized approach, taking into account age and other distinguishing, known breast cancer risk factors such as first degree relative of history of breast cancer, pregnancy/birthing history, hormone therapy, alcohol, exercise and weight history…. and maybe eventually, even nutrition.

Reference: Burton R, Stevenson C. Assessment of breast cancer mortality trends associated with mammography mortality trends associated with mammographic screening and adjuvant therapy from 1986 to 2013 in the State of Victoria, Australia. JAMA NetwOpen 2020 June 1;3:e208249.

Diagnosis of Subclinical Hypothyroidism in Pregnancy

The threshold for diagnosing subclinical hypothyroidism in pregnancy during the first trimester is thought to be a thyroid stimulating hormone (TSH) value of >2.5 mIU/L (with a normal T4 level) by most organizations, although not all.

Investigators in Poland wanted to know if this approach and thus prescribing of prescription T4 was inaccurate. Baseline serum levels of free T4, free T3 and TSH every 30 minutes for a two-hour period during the morning time was conducted in 110 pregnant women, with an average gestation of 9.9 weeks, and 19 non-pregnant women of a similar age and body mass index.

TSH levels in the pregnant women averaged 1.6 mIU/L but varied by about 40%. The mean TSH levels and variation were similar in the pregnant vs the nonpregnant women. The number of pregnant woman with a TSH >2.5 ranged from 12.7% (based on the lowest of 5 consecutive TSH measurements) to 20.9% (the highest of 5 consecutive measurements).

Commentary: While we do not know about the assays being used, the results are an important reminder that the secretion of TSH is pulsatile and using diagnostic cutoff values can be misleading. None the less, untreated hypothyroidism during the first and third trimester in particular, is potentially harmful to the fetus and resulting child. I would refer people to clinical guidelines in managing subclinical hypothyroidism with special attention to the recurring need and timing of f/u TSH testing. In addition, low dose prescribing of T4 to pregnant women with suspected subclinical hypothyroid carries very little risk as long as testing and adjusting of dose is scrutinized. At the same time, it should be pointed out that thyrotoxicosis as well as subclinical hypothyroid during pregnancy can have adverse pregnancy outcomes and adverse effects on infants and children born to mothers with unmanaged or poorly managed thyroid disorders

Lewandowski K, et al. Subclinical thyroid dysfunction in the first trimester of pregnancy: Disease versus physiological (pulsatile) variation in TSH concentrations. Clin endocrinol (Oxf) 2020; May 19; e-pub.

Colposcopy and Cervical Pathology Guideline Changes

In 2019, the American Society for Colposcopy and Cervical Pathology (ASCCP) revised their prior guidelines moving from result based to risk-based management recommendations for HPV and cervical dysplasia. Below is a summary of these changes as published in the Perkins, et al paper of April 2020. The purpose of the updated management guidelines are the following:

• Allow for a more complete and precise estimation of risk
• Provide more appropriate intervention for high-risk individuals
• Recommend less intervention for low-risk individuals
• Allow for additions of new risk modifiers, screening and management technologies in the future
• The summary that I share here does not address primary natural treatment methods or adjunct natural treatment methods.

Essential Changes from Prior Management Guidelines

1. Recommendations are based on risk, not results.

• Recommendations of colposcopy, treatment, or surveillance will be based on a patient’s risk of CIN3+ determined by a combination of current results and past history (including unknown history). The same current test results may yield different management recommendations depending on the history of recent past test results.

2. Colposcopy can be deferred for certain patients.

• Repeat HPV testing or co-testing at one year is recommended for patients with minor screening abnormalities indicating HPV infection with low risk of underlying CIN 3+ (e.g., HPV-positive, low-grade cytologic abnormalities after a documented negative screening HPV test or co-test).

3. Guidance for expedited treatment is expanded (i.e., treatment without colposcopic biopsy).

• Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines; this guidance is now better defined.
• For non-pregnant patients 25 years or older, expedited treatment, defined as treatment without preceding colposcopic biopsy demonstrating CIN 2+, is preferred when the immediate risk of CIN 3+ is ≥60%, and is acceptable for those with risks between 25% and 60%. Expedited treatment is preferred for nonpregnant patients 25 years or older with high-grade squamous intraepithelial lesion (HSIL) cytology and concurrent positive testing for HPV genotype 16 (HPV 16) (i.e., HPV 16–positive HSIL cytology) and never or rarely screened patients with HPV-positive HSIL cytology regardless of HPV genotype.
• Shared decision-making should be used when considering expedited treatment, especially for patients with concerns about the potential impact of treatment on pregnancy outcomes.

4. Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or CIN 3) in the United States. Excision is recommended for adenocarcinoma in situ (AIS).

5. Observation is preferred to treatment for CIN 1.

6. Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO) recommendations for reporting histologic HSIL should include CIN 2 or CIN 3 qualifiers, i.e., HSIL (CIN 2) and HSIL (CIN 3).

7. All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (e.g., reflex cytology).

• Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, those HPV-16 positive HSIL cytology qualify for expedited treatment.
• HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (e.g., colposcopy with biopsy) is necessary even when cytology results are negative.
• If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy.

8. Continued surveillance with HPV testing or co-testing at three-year intervals for at least 25 years is recommended after treatment and initial post-treatment management of histologic HSIL, CIN 2, CIN 3, or AIS. Continued surveillance at three-year intervals beyond 25 years is acceptable for as long as the patient’s life expectancy and ability to be screened are not significantly compromised by serious health issues.

• The 2012 guidelines recommended return to five-year screening intervals and did not specify when screening should cease. New evidence indicates that risk remains elevated for at least 25 years, with no evidence that treated patients ever return to risk levels compatible with five-year intervals.

9. Surveillance with cytology alone is acceptable only if testing with HPV or co-testing is not feasible. Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often. Cytology is recommended at 6-month intervals when HPV testing or co-testing is recommended annually. Cytology is recommended annually when 3-year intervals are recommended for HPV or co-testing.

10. Human papillomavirus assays that are Food and Drug Administration (FDA)-approved for screening should be used for management according to their regulatory approval in the United States. (Note: all HPV testing in this document refers to testing for high-risk HPV types only).

• For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a cotest with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management.

Perkins, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors, Journal of Lower Genital Tract Disease: April 2020 – Volume 24 – Issue 2 – p 102-131. doi:10.1097/LGT.0000000000000525

Glossary and Definitions

• Atypical glandular cells (AGC)
• Atypical squamous cells of undetermined significance (ASC-US)
• Atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H)
• Cervical intraepithelial neoplasia (CIN)
• CIN 2+: CIN 2, CIN 3, AIS, and cancer
• CIN 3+: CIN 3, AIS, and cancer
• Co-testing: screening or surveillance performed with the evaluation of both cytology and testing for HPV
• Excisional treatment: procedure to remove transformation zone and produce tissue sample for histologic evaluation. Excisional treatment options may include: lip electrosurgical excision procedure (LEEP), large loop excision of the transformation zone (LLETZ), laser cone biopsy, or cold knife conization.
• High-grade squamous intraepithelial lesion or worse (HSIL)
• Human papillomavirus (HPV). While there are over 100 varieties of HPV, those with oncogenic potential are of primary concern and at present include the following: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.
• Low-grade squamous intraepithelial lesion (LSIL)
• Negative for Intraepithelial lesion or malignancy (NILM)
• Primary HPV testing: screening or surveillance performed with HPV testing only
• Reflex testing: ASCCP defines reflex testing to mean “that laboratories should perform a specific additional triage test in the setting of a positive screening test to inform the next steps in management. For example, an ASC-US cytology should trigger a reflex HPV test. New for these guidelines, a positive primary HPV screening test should trigger both a reflex genotyping test (to determine the presence/absence of HPV 16/18 if that information is not included in the initial primary test result) and also a reflex cytology test to determine whether the patient would be a candidate for expedited management.”
• Surveillance: ASCCP defines surveillance as “repeat testing (HPV primary screening, co-testing, or cytology alone) that occurs at shorter intervals than those recommended for routine screening. For example, HPV primary testing or co-testing at intervals of less than 5 years, or cytology alone at intervals of less than 3 years.”