What are the concerns for a 70-year-old woman taking 0.5mg of Estradiol (estrogen) and 100mg of Progesterone, who previously switched from Levothyroxine (T4) to Thyromin (a thyroid supplement containing Parsley leaf powder, Bovine thyroid powder, L-Tyrosine, and other ingredients) without issues, and now wants to add Cortstop (a supplement containing Pregnenolone, Phosphatidylserine, Phosphatidylcholine, and other ingredients)?

From the Guidelines

I strongly advise against adding CortiStop to this 70-year-old woman's regimen without consulting a healthcare provider due to potential interactions and adverse effects. The main concern is the interaction between the multiple hormonal compounds she's already taking (Estradiol, Progesterone, and Thyromin which contains thyroid hormones) and CortiStop's ingredients like pregnenolone and DHEA, which are hormone precursors that could disrupt her current hormonal balance 1. Additionally, black cohosh in CortiStop may interact with her estrogen therapy, potentially increasing side effects, as estrogen plus progestin has been shown to increase the risk for breast cancer and probable dementia 1. The supplement also contains multiple herbal ingredients with unknown effects when combined with her current medications.

At her age of 70, there's an increased risk of adverse effects from multiple supplements due to potential changes in metabolism and kidney function. The switch from a regulated medication (LevoThyroxine) to a supplement (Thyromin) already represents a significant change, and adding another complex supplement could further complicate monitoring her thyroid function. The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women, citing substantial harms and small benefits 1.

Key concerns include:

• Potential interactions between CortiStop's ingredients and her current hormonal therapy
• Increased risk of adverse effects due to age-related changes in metabolism and kidney function
• Lack of FDA approval and standardization for CortiStop, making its effects unpredictable
• Complexity of monitoring thyroid function with multiple supplements
• Substantial harms associated with hormone therapy in postmenopausal women, as noted by the USPSTF 1. Therefore, it is crucial to consult with a healthcare provider before adding CortiStop to her regimen to weigh the potential benefits against the risks and to ensure safe and effective management of her health.

From the FDA Drug Label

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66. 7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4. 1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6. 8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b Venous thromboembolism (VTE) In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI, a 2­fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women­years in the CE/MPA group compared to 16 per 10,000 women­years in the placebo group. The increase in VTE risk was observed during the first year and persisted If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more and this risk persists for 8 to over 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important (see PRECAUTIONS) Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5. 6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1. 24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1. 86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1. 09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2. 5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0. 625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0. 80]. Consistent with the Women’s Health Initiative (WHI clinical trials), observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy and a smaller, but still increased risk, for estrogen-alone therapy after several years of use One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy

The biggest concerns for a 70-year-old woman taking 0.5mg of Estradiol and 100mg of Progesterone who had no issues in the last few years when she switched from LevoThyroxine to Thyromin and wants to add Cortstop are:

• Increased risk of stroke and venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, associated with estrogen plus progestin therapy 2
• Increased risk of breast cancer associated with estrogen plus progestin therapy, with a relative risk of 1.24 and an absolute risk of 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo 2
• Increased risk of endometrial cancer associated with unopposed estrogen use, although the addition of progestin to estrogen therapy has been shown to reduce this risk 2
• Potential interactions between Cortstop and her current hormone replacement therapy, although the FDA drug label does not provide information on this specific interaction
• Potential effects of Cortstop on her cardiovascular risk profile, although the FDA drug label does not provide information on this specific topic It is essential to weigh these risks against the potential benefits of adding Cortstop to her regimen and to closely monitor her for any adverse effects.

From the Research

Concerns with Adding Cortstop to Existing Medication Regimen

• The patient is already taking a complex medication regimen, including Estradiol, Progesterone, and Thyromin, which may increase the risk of adverse drug events or interactions 3.
• The addition of Cortstop, which contains multiple ingredients, may further increase the complexity of the medication regimen and potentially lead to errors in administration or adverse interactions 3, 4.
• There is limited research on the specific interactions between Cortstop and the patient's existing medications, including Estradiol and Progesterone, which may affect the efficacy or safety of the treatment regimen 5, 6.

Potential Effects on Hormone Levels

• The patient's hormone levels, including thyroid hormones and sex hormones, may be affected by the addition of Cortstop, particularly due to the presence of ingredients such as DHEA and Black cohosh 5, 6.
• The study on oral versus transdermal estrogen therapy found that oral estrogen therapy can affect thyroid hormone levels, which may be relevant to the patient's use of Thyromin 5.

Importance of Medication Regimen Simplification

• Simplifying the patient's medication regimen may be beneficial in reducing the risk of adverse drug events and improving adherence to the treatment plan 3, 4.
• A study on medication regimen simplification found that simplifying the regimen can improve medication adherence, but may not necessarily improve clinical outcomes 4.