Dr. Sara Gottfried Links Estrogen Loss to Perimenopausal Brain Hypometabolism

Sara Gottfried 博士指出雌激素流失与围绝经期大脑代谢减退存在关联 围绝经期雌激素缺乏会导致女性大脑葡萄糖代谢下降20%，从而增加认知能力下降和阿尔茨海默病的长期风险。 Sara Gottfried 博士与 Andrew Huberman 探讨了在女性各个生命阶段优化激素与代谢健康的综合策略。对话重点探讨了代际创伤的影响、微量营养素与激素检测，以及降低主观感知压力等个性化压力管理策略。Gottfried 博士还深入分析了 PCOS（多囊卵巢综合征）的诊断细节、口服避孕药的益处及常被忽视的风险、围绝经期大脑葡萄糖代谢的变化，以及持续葡萄糖监测（CGM）和冠状动脉钙化（CAC）扫描等关键的长寿筛查工具。 Sara Gottfried 博士强调，了解母亲和外祖母的健康史（包括代际创伤以及子宫内膜异位症、子宫肌瘤和 PCOS 等疾病）对于评估内分泌与激素健康至关重要。 (0:00) 建立基线激素追踪理想情况下应始于女性的20多岁或30多岁，青春期应优先关注皮质醇模式，成年早期则应评估性激素、微量营养素及肠道微生物组的健康状况。 (1:31) 在标准的28天月经周期中，为确保激素检测的最佳准确性，检测应在第21至22天进行（月经周期较短者在第19至20天），且干尿检测比血液检测能提供更全面的评估图景。 (3:35) 每天饮用加入冷冻熟蔬菜或果蔬粉的冰沙，是一种改善微生物组健康并填补营养缺口的实用行为策略。 (5:40) 普遍存在的镁缺乏（影响70%至80%的美国人）会严重阻碍雌激素解毒，这使得红细胞（RBC）镁检测和针对性补充成为关键的干预措施。 (6:39)

Dr. Sara Gottfried argues that female vitality and longevity depend on proactive, decade-by-decade endocrine tracking, addressing metabolic root causes, stress-induced autonomic dysfunction, and hormonal transitions long before overt disease develops. Proactive Biomarker Tracking and Endocrine Baselines (1:31) Dr. Gottfried advocates establishing a hormonal baseline—termed "base-casing"—in a woman's 20s or 30s, accounting for family health history and intergenerational trauma that alter cortisol signaling. For cycling women, she identifies days 21–22 of a standard 28-day cycle (or days 19–20 for shorter cycles) as the optimal testing window, favoring dried urine metabolomic profiles over single blood draws to assess estrogen metabolites and androgen pathways. Precision medicine also prioritizes identifying cellular micronutrient deficiencies early. In particular, evaluating red blood cell magnesium is essential for supporting estrogen clearance pathways, yet Dr. Gottfried estimates that 70% to 80% of Americans are deficient. Correcting dietary and micronutrient shortfalls during youth serves as a high-leverage intervention to reduce long-term disease risks decades later. Stress Dysregulation, Gastrointestinal Motility, and Adaptive Exercise (8:01) Female physiology carries disproportionate systemic vulnerability to stress: women experience twice the rates of depression and insomnia and five to eight times the risk of thyroid dysfunction compared to men. Dr. Gottfried observes that roughly 80% of her female patients suffer from chronic constipation. She attributes this to an anatomical GI tract roughly 10 feet longer than men's combined with elevated perceived stress, which slows GI motility through the hypothalamic-pituitary-adrenal-gut axis. To manage stress without exacerbating endocrine dysfunction, Dr. Gottfried cautions against high-volume endurance running ("chronic cardio"), which can elevate fasting cortisol and insulin while depressing progesterone. Instead, she recommends personalized adaptive exercise, such as Pilates and yoga, alongside an evolving "à la carte menu" of stress-reduction tools including breathwork, meditation, and interpersonal connection. Metabolic Underpinnings of PCOS and Testosterone Dynamics (13:18) Polycystic Ovary Syndrome (PCOS) requires meeting at least two of three criteria: polycystic ovaries on ultrasound, ovulatory dysfunction (cycles exceeding 35 days), or clinical hyperandrogenism. Dr. Gottfried explains that hyperinsulinemia is the core physiological engine across several PCOS subtypes, directly stimulating ovarian theca cells to overproduce testosterone. Continuous glucose monitors (CGMs) provide immediate biofeedback to modify glycemic variability and lower insulin before clinical pre-diabetes emerges. In women without PCOS, testosterone naturally declines by approximately 1% per year beginning as early as age 28. Dr. Gottfried targets maintaining testosterone in the upper half of the normal reference range to sustain mood, muscle mass, and agency, warning that elevated androgens in PCOS shift from reproductive complications in young adulthood to significant cardiometabolic threats after menopause. Oral Contraceptive Trade-Offs: Oncology and Endocrine Health (20:00) Oral contraceptives provide proven oncologic protection: by suppressing "incessant ovulation," five years of usage cuts a woman's lifetime risk of ovarian cancer by 50%. This benefit is clinically valuable because early detection tools for ovarian cancer remain unreliable, with early signs frequently masked as benign abdominal bloating. However, Dr. Gottfried expresses concern regarding routine pill usage for non-contraceptive complaints. Synthetic progestins differ structurally from native progesterone, and oral formulations can double to triple inflammatory markers like hs-CRP, deplete B vitamins, alter the gut microbiome, and drastically raise sex hormone-binding globulin (SHBG). High SHBG sequesters free testosterone, often precipitating persistent low libido, vaginal dryness, and up to a 20% reduction in clitoral volume. For menstrual pain, she recommends addressing baseline inflammation with fish oil, specialized pro-resolving mediators (SPMs), and low-dose aspirin instead of hormonal suppression. Perimenopausal Cerebral Hypometabolism and Cardiovascular Screening (28:11) Citing neuroimaging research from Dr. Lisa Mosconi, Dr. Gottfried explains that the perimenopausal transition triggers an average 20% decline in cerebral glucose metabolism due to falling estrogen levels. Vasomotor symptoms like hot flashes and night sweats should not be dismissed as mere nuisances; they act as clinical biomarkers for accelerated neurometabolic decline, cardiovascular strain, and heightened risk for Alzheimer's disease. Because cardiovascular disease remains the primary killer of women post-menopause, Dr. Gottfried recommends obtaining a Coronary Artery Calcium (CAC) scan via low-dose CT by age 45, or earlier with a family history of premature heart disease. Directly measuring calcified arterial plaque establishes an objective baseline to guide preventive interventions and assess the safety of hormone restoration strategies. While Dr. Gottfried offers a comprehensive framework combining advanced diagnostics and functional interventions, the clinical adoption of modalities like dried urine metabolomics and continuous glucose monitors remains limited by out-of-pocket costs and conventional primary care constraints.

哈佛医学院背景的内科医生 Sara Gottfried 指出，女性荷尔蒙健康受代际遗传、神经内分泌压力反应与糖脂代谢共同调节；通过在二三十岁尽早测定生物标志物基线、纠正高胰岛素血症与微量营养素缺口，并严密监测围绝经期脑代谢及心血管病变，能够有效阻断晚年严重慢性退行性疾病的发生。 荷尔蒙基线评估与微量营养素筛查 (3:35) Gottfried 建议女性在20至30岁期间启动荷尔蒙“基线测定”（base-casing），重点评估雌激素、孕酮与睾酮的动态平衡。在标准28天周期中，检测时间应选在黄体期的第21至22天（周期较短者提前至19至20天）。相较于单次抽血提供的瞬时快照，她更推荐干尿检测（如 DUTCH 测试）以获取全面的代谢物图谱，从而辨别具有保护性或潜在致病风险的雌激素代谢物。 在微量营养素层面，Gottfried 主张检测B族维生素（结合 MTHFR 突变评估甲基化途径）、谷胱甘肽与抗氧化物。她指出全美有70%至80%的人群存在镁缺乏，检测红细胞镁（RBC magnesium）对评估体内雌激素代谢酶的活性至关重要。由于年轻时期蔬菜多酚摄入不足与数十年后的乳腺癌风险直接相关，她建议使用冷冻西兰花与果蔬粉制作全食物奶昔，作为低门槛改善肠道菌群与弥补微量营养素缺口的实用干预手段。 神经内分泌压力超载与消化道异常 (8:01) 临床就诊者中约有80%的女性患有慢性便秘。Gottfried 指出，这既与女性胃肠道平均比男性长约10英尺且更易迂曲的解剖特点有关，也与神经内分泌压力密切相连。数据显示，60%的中年女性报告有童年不良经历（ACE），且女性在抑郁、失眠（为男性的2倍）及甲状腺功能减退（为男性的5至8倍）上面临更高风险，潜伏的甲状腺失调与心理压力共同减缓了胃肠蠕动速度。 针对下丘脑-垂体-肾上腺（HPA）轴超载，Gottfried 强调干预关键在于降低“主观感知压力”（perceived stress）。长期进行高容量中长跑等过度耐力运动会进一步推高皮质醇，恶化腹部脂肪堆积和糖代谢异常。她提倡依据个人状态制定减压清单（涵盖超觉静坐、正念呼吸、瑜伽及深层人际连接），并转向普拉提等自适应运动以维护神经内分泌平衡。 睾酮失衡、PCOS与高胰岛素血症 (11:58) 睾酮是女性体内最丰富的性甾体激素，但通常自28岁起即以每年约1%的速度下降。Gottfried 建议将25岁以上女性的睾酮水平维持在正常参考区间的上半部分，以保护认知、肌肉量与代谢活力。相反，雄激素异常过高则是多囊卵巢综合征（PCOS）的关键表征，临床需结合超声多囊表征、高雄体征（如多毛症、痤疮）以及周期超过35天的排卵障碍进行诊断。PCOS 不仅影响育龄期生育，更是绝经后心血管与代谢疾病的重大诱因。 高胰岛素血症是驱动 PCOS 的核心机制：过高的胰岛素会直接刺激卵巢卵泡膜细胞过量合成睾酮。引用白厅研究（Whitehall study）证据，空腹及餐后胰岛素异常可在血糖达标诊断前数年甚至数十年出现。Gottfried 极力推崇使用持续葡萄糖监测仪（CGM）获取即时反馈，帮助女性主动通过生活方式干预控制血糖波动与胰岛素过量分泌。 口服避孕药权衡与SHBG激增风险 (20:00) 口服复方避孕药的核心价值在于保障生育自主权，且连续服用5年可因阻断“持续不间断排卵”而将女性卵巢癌终身患病风险降低50%。鉴于卵巢癌早期常表现为腹胀和盆腔压迫等非特异性症状且缺乏常规早筛手段，避孕药在流行病学上具有显著的肿瘤防护效益。 然而，Gottfried 反对将避孕药盲目用于治疗痤疮或痛经。合成孕激素不同于人体天然孕酮，长期服药会耗竭B族维生素与镁，使超敏C反应蛋白（hs-CRP）升高两至三倍。更为关键的是，口服雌激素会刺激肝脏合成大量性激素结合球蛋白（SHBG），强力结合游离睾酮与游离雌激素。易感女性可能出现持续性欲减退、阴道干涩乃至阴蒂萎缩（体积缩小可达20%），且停药后 SHBG 仍可能维持高位长达一年。因此，针对原发性痛经，她更推荐高品质鱼油、专一性促消退介质（SPMs）及经期低剂量阿司匹林等抗炎替代方案。 围绝经期脑代谢减退与CAC钙化筛查 (28:11) 引用 Lisa Mosconi 等人的脑部正电子发射断层扫描（PET）研究，Gottfried 指出女性在围绝经期至绝经后过渡阶段，大脑葡萄糖代谢率平均下降20%。中枢神经系统雌激素缺乏导致的“脑能量减缓”是脑雾和记忆力衰退的生物学诱因，也将阿尔茨海默病与中年代谢改变紧密挂钩。严重的血管舒缩症状（如潮热、盗汗）绝非普通不适，而是中枢神经与心血管系统承受代谢压力的生理指标。 针对绝经后女性首要死因心血管疾病，Gottfried 建议女性在45岁前接受低剂量心脏 CT 扫描以获取冠状动脉钙化（CAC）积分。CAC 积分为零代表目前冠状动脉无钙化斑块，而任何非零积分则是心血管风险管理的分水岭，提示应立即采取针对性预防措施，并为后续评估个体化荷尔蒙疗法的安全性提供明确的生理参考。 Gottfried 强调女性健康管理应转向以患者为中心、依靠早期客观数据驱动的主动预防模式。然而，干尿代谢物检测与持续血糖监测等新兴精准医疗工具的实际应用，仍需结合个体的具体临床表征、遗传风险及心血管基线进行综合权衡，避免盲目依赖单一指标或进行过度干预。

[0:00] Welcome to Huberman Lab Essentials, [0:02] where we revisit past episodes for the [0:04] most potent and actionable science-based [0:06] tools for mental health, physical [0:08] health, and performance. [0:11] I'm Andrew Huberman and I'm a professor [0:13] of neurobiology and opthalmology at [0:15] Stamford School of Medicine. And now for [0:17] my discussion with Dr. Sarah Gotfrieded. [0:20] Dr. Gotfrieded. Sarah, welcome. [0:22] >> Thank you. So happy to be here. [0:24] >> Yeah, I'm delighted and very excited to [0:26] ask you about an enormous number of [0:28] topics. You are expert in so many [0:29] things, female hormones in particular. [0:31] Is it ever informative for a woman, [0:34] regardless of age, to know something [0:36] about her mother's, perhaps even her [0:39] grandmother's experience visav hormones? [0:42] What sorts of conversations should women [0:44] be having with themselves and with [0:47] family members to get a window into what [0:49] their specific needs might be? [0:51] >> So, my work is really at the interface [0:54] between genetics and environment. And I [0:56] think it's essential that you understand [0:59] what your grandmother went through and [1:02] especially your mother. So I would [1:06] probably start first with trauma and [1:09] intergenerational trauma because I think [1:11] that affects the endocrine system so [1:13] hugely especially cortisol signaling. [1:16] And then there's certain female [1:18] conditions that have a very strong [1:21] component genetically, most of which run [1:24] in my family. So that includes [1:26] endometriosis, fibroids, and polycystic [1:30] ovarian syndrome. [1:31] >> Maybe we could march through and just [1:32] say for a woman in her teens who's [1:35] already hit puberty, what sorts of [1:37] biomarkers should those young women be [1:40] paying attention to? Likewise for women [1:41] in their 20s, 30s, maybe we could take [1:43] it more or less by by decade at starting [1:46] at puberty. [1:46] >> In your teenage years, what I think is [1:48] really interesting is to look at [1:50] cortisol, to look at the dance between [1:53] estrogen and progesterone in those years [1:55] is less helpful because I think there's [1:58] a lot of variability due to the [1:59] immaturity of the system. If you've got [2:01] someone who's got really regular [2:03] periods, it's probably better to do some [2:05] benchmarking at that age. But generally, [2:07] I find that benchmarking is best [2:09] performed in your 20s or 30s. [2:11] >> Are periods not that regular in terms of [2:14] duration of the menstrual cycle? When [2:17] the menstrual cycle first sets in? [2:19] >> For a lot of women, they're not regular. [2:22] And then there's the whole piece of oral [2:24] contraceptives and other forms of [2:26] contraception where you have no idea [2:28] what the normal cycle is. But getting [2:31] back to your original question, which is [2:32] about biomarkers per decade, in your [2:35] 20s, that's when you want to do some [2:37] base casing with estrogen, progesterone, [2:40] and testosterone. What happens a lot of [2:42] the time is that estrogen dominates in [2:45] that tango. And when that happens, it [2:48] sets you up for greater risk of [2:51] fibroids, endometriosis. [2:53] I'd want to know about DHEA and sort of [2:55] the whole androgen pathway. I'd want to [2:57] know about the metabolites of estrogen [3:00] because some of them are protective and [3:03] very helpful. Others are a bit like [3:07] Homer Simpson. I mean, they are just [3:09] like causing all kinds of problems in [3:11] your body. I'd also like to know about [3:13] their stool. So, I want to know about [3:15] the microbiome. [3:16] >> In terms of blood testing or various [3:18] tests for these other biomarkers, [3:19] getting estrogen, testosterone, and [3:22] other ratios, women will need to do it [3:23] at different stages of their menstrual [3:24] cycle. if they had to pick one either in [3:27] the follicular phase and or in the [3:30] ludial stage of their ovulatory [3:32] menstrual cycle, when would you suggest [3:34] they do that? [3:35] >> So, if you forced me to pick one, I [3:37] would say probably day 21 to 22 for [3:42] someone in her 20s. So, for most women, [3:45] they've got a menstrual cycle date that [3:47] averages out at 28 days. So, this is [3:49] about a week before they start their [3:51] period. For women who are more [3:53] irregular, it's harder to do that. As [3:55] women get older, usually the cycle gets [3:57] a little shorter. So, as they start to [4:00] decline in their progesterone [4:01] production, their period gets a little [4:03] closer together. At that point, you want [4:05] to test sooner, like day 19, 20. Blood [4:08] test is the cheapest thing. It's usually [4:10] what's covered by insurance. But my [4:12] preference would be to do dried urine so [4:14] that I get metabolomics in addition to [4:16] the levels of these hormones. And if I'm [4:19] forced to, I'll use blood testing. It's [4:21] not as comprehensive and as you know [4:23] it's a quick little snapshot while the [4:25] needle's in your vein for you know 30 [4:27] seconds. Let me go back and say one [4:29] other thing about biomarkers. A big part [4:31] of the testing that I do in phenotyping [4:33] my patients I practice precision [4:35] medicine. I like to almost start with [4:38] nutritional testing. That would be [4:40] potentially a helpful thing to do in [4:42] your 20s. Becomes less important as you [4:44] get older and you develop more [4:45] micronutrient deficiencies. But [4:48] micronutrients play a huge role in terms [4:50] of hormone production. Magnesium is [4:52] hugely involved in the way that you get [4:54] rid of estrogen as an example. So [4:57] micronutrient testing, what I usually do [4:59] is a combination of blood and urine. And [5:01] so I'm looking at all of the [5:02] micronutrients that we can measure that [5:05] have some clinical scientific basis [5:08] behind them. intake of vegetables, [5:11] polyphenols, is such an important [5:13] predictor of future risk of breast [5:16] cancer, like when you're 50, 60 plus. [5:18] And the most important time is when [5:20] you're a teenager. If you have evidence [5:24] that you could show a 17-year-old that [5:27] they've got micronutrient gaps, I think [5:30] that would be a motivator for them to [5:32] eat differently at a time when it's so [5:34] critical, even though it's 25 years in [5:36] the future, that it's going to [5:38] potentially change this arc that they're [5:39] on. What do you do for a young woman who [5:43] doesn't like vegetables is or is not [5:46] somehow able or willing to to get those [5:49] five colors a day of vegetable to help [5:52] support the microbiome? What other sorts [5:54] of tools, behavioral or otherwise, are [5:56] useful? [5:57] >> What I try to get them to do is to have [5:58] a smoothie. If I could get them to have [6:00] a smoothie three times a week and to [6:02] throw some of these vegetables in, that [6:04] makes a huge difference. I mean, we know [6:06] that makes a difference in terms of [6:07] microbiome change. Like I have them do [6:10] steamed broccoli that's in the freezer [6:12] because it's got very little taste. They [6:14] could do that in a chocolate smoothie. [6:15] They could add some greens. I like [6:17] greens powders are super convenient. So [6:21] that with you know kind of a a taste [6:23] that they like whether that's chocolate [6:25] which is what most of my clients want or [6:28] you know vanilla with berries and that [6:30] sort of thing. So that can go a long way [6:32] if you don't like vegetables. And short [6:34] of that, I would say some supplements, [6:36] but I would say that's a distant second [6:38] to making a smoothie. [6:39] >> What is going to be the best way to test [6:41] the microbiome? [6:42] >> What I like to do with nutritional [6:44] testing is run a panel that's looking at [6:50] antioxidants. So like vitamin A, vitamin [6:52] C, alpha lipoic acid, plant-based [6:55] antioxidants, because you can measure [6:56] that in the blood. I like to look at [6:59] some of the key vitamins, especially the [7:02] B vitamin range, because as you probably [7:05] know, if you've got particular genetic [7:07] polymorphisms, you might be less likely [7:10] to be absorbing the right level of [7:12] vitamin B9, folate, vitamin B12, etc. [7:15] I'm also looking going back to the [7:16] antioxidants at glutathione because I [7:18] think that's such an important lever. [7:20] And then I'm looking at some of the [7:21] minerals. Magnesium is really the most [7:23] important and we know that somewhere [7:25] around 70 to 80% of Americans are [7:27] deficient in magnesium. That's like the [7:28] the lowest hanging fruit. [7:30] >> I would be curious for instance like [7:32] with magnesium if that number of people [7:34] are deficient does that mean that that [7:36] number of people should be targeting [7:38] their nutrition towards foods that [7:39] contain magnesium andor supplementing [7:41] with magnesium? And if so what forms of [7:43] magnesium? You have to measure red blood [7:46] cell magnesium like whole blood. And [7:49] with deficiency, it's interesting with [7:53] supplementation [7:55] for my patients who tend toward [7:57] constipation, and that's frankly about [7:59] 80% of the women that I take care of. [8:01] >> Really? [8:02] >> Yes. [8:03] >> Wow. I'd be curious as to why that that [8:05] is. [8:06] >> Patriarchy, [8:07] rage, the pine system, [8:09] >> right? psychology, immunology, neural [8:12] and endocrine factors combined. Is that [8:14] >> Yes. And then I would say there's [8:16] another factor. Being female is a health [8:18] hazard. So we have twice the rate of [8:21] depression, insomnia. We've got 3 to 4x [8:25] increased risk of multiple sclerosis. [8:28] We've got 5 to eight times the risk of [8:31] thyroid dysfunction. So if you just look [8:33] at that and you look at subtle [8:35] preclinical thyroid dysfunction, a large [8:38] number of the women that I take care of [8:40] have thyroid dysfunction that's [8:42] contributing to constipation. And if we [8:45] go back to that control system, the [8:47] hypothalamic pituitary, adrenal, [8:48] thyroid, canatal, gut axis, and they [8:51] have a lot of perceived stress together [8:54] with this borderline thyroid function [8:56] that no mainstream medicine doctor has [8:59] told her is a problem. And then she's [9:01] got a problem with the tango between [9:03] estrogen and progesterone. She's going [9:05] to tend toward constipation. Women have [9:06] a lot more constipation than men. The [9:09] gut is about 10 ft longer in women [9:11] compared to men. And they are much more [9:13] likely to have a torturous colon. And [9:17] the way you know that is you get a [9:18] colonoscopy. Women experience more [9:20] trauma than men. This is well [9:21] established. If you look at the ACE [9:23] studies that were done by the CDC and [9:26] Kaiser in 1998, we know that men for the [9:29] most part, middle-aged men have about [9:31] about 50% of them experience significant [9:34] trauma as defined by the ACE [9:36] questionnaire. Women are at 60%. And [9:39] that's pretty durable since 1998. They [9:41] have different forms of abuse, much more [9:44] likely to have sexual abuse. They have a [9:47] different HPA response than men. [9:50] their perceived stress tends to be [9:53] higher. And I'm generalizing for a [9:54] population. And so if you look at the [9:57] physiology of a female, I think that um [10:01] constipation and that need to like [10:04] control and restrain and hold things in, [10:07] I think that's part of the physiology. [10:09] So I'm veering away from the science, [10:11] but I do think that it is a really [10:14] important signal to pay a lot of [10:16] attention to. What sorts of tools do you [10:19] recommend people use to relieve [10:21] constipation? Sounds like reducing [10:23] stress is going to be a huge one. [10:25] >> Yes. [10:26] >> What are your favorite stress reduction [10:27] tools? Things that can really lower the [10:29] baseline. [10:30] >> So, I'm not a fan of lowering stress. [10:34] I'm a fan of lowering perceived stress. [10:36] I think all of us need an allocart menu [10:39] of what is most effective. [10:42] So what works for me now at my age is [10:45] different than the TM I did as a college [10:47] student transcendental meditation. I [10:49] became a certified yoga teacher when I [10:50] was in my 30s. That is very effective [10:53] for a lot of people. I do holotropic [10:55] breath work. [10:56] >> I think people are starting to [10:57] appreciate that there are ways that they [10:58] can relieve their stress that that don't [11:01] all only fall under the categories of [11:03] vacation, [11:04] >> right, [11:04] >> and meditation. But I want to say that [11:06] meditation is obviously a wonderful [11:08] tool. Well, certainly it's a great tool [11:10] and it's got such a scientific basis [11:11] behind it, but there's so many things on [11:14] this allocart menu. Sex, orgasm, [11:17] um, connection, feeling heard and seen [11:20] and loved. I want to use this as an [11:23] opportunity to a keep this in mind as a [11:26] return to a a question that I didn't uh [11:29] close the hatch on earlier and it's my [11:30] fault which is I'm now clear on the fact [11:33] that a woman in her late teens early 20s [11:37] ought to know something about her [11:38] testosterone estrogen thyroid cortisol [11:40] levels should start at least thinking [11:41] about her microbiome [11:43] should be thinking about how many bowel [11:45] movements and the timing of those bowel [11:46] movements per day and I'm assuming that [11:49] what I just described is also true for [11:52] women in their 20s, 30s, 40s, 50s on up [11:56] to hundreds. Is that correct? [11:58] >> That's correct. But I would say that [11:59] there are differential opportunities by [12:02] decade. So, I'm glad you circled it back [12:05] to teenagers and testosterone because I [12:09] think if you know, for instance, in your [12:12] teenage years that you have high [12:15] androgens and that you've got this [12:17] potential phenotype way into the future [12:20] that you may not even notice. I mean, [12:21] maybe you notice you got a few extra [12:23] hairs on your chin or something. If you [12:26] know that your testosterone is elevated [12:27] or some other androgen, it might change [12:30] the arc of how you take care of [12:32] yourself. So I think that could be very [12:33] helpful in your teenage years. In your [12:36] 20s for people who are a stress case [12:39] like me, so age 27 on the wards at UCSF, [12:43] if I had known that I was such a high [12:45] cortisol person, I think I would have [12:47] done things differently. I would have [12:48] changed my behavior. Your testosterone [12:51] can decline starting in your 20s, kind [12:54] of depending on how much stress your [12:56] matrix is under. So for women, that can [12:59] start as early as 28. Usually your [13:01] testosterone declines by about 1% per [13:04] year. [13:05] >> What level of testosterone do you like [13:06] to see in a woman once she's sort of [13:08] post let's say after age 25. [13:11] >> So the way I tend to describe this on [13:12] podcasts is the top half of the normal [13:15] range. [13:16] >> I get a lot of questions about PCOS. [13:18] >> Yeah. So PCOS is one of those really [13:21] poorly understood conditions. It kind of [13:24] flies below the radar until a woman [13:26] wants to get pregnant or she's got some [13:28] other issue that drives her to a [13:30] physician. The problem is that it is a [13:33] syndrome, right? So, polycystic ovary [13:36] syndrome, sometimes polycystic ovarian [13:39] syndrome and syndromes don't necessarily [13:42] fit together into a really clear [13:45] diagnostic criteria. So, in this [13:48] instance, there are three different [13:50] criteria that we look for. cysts on the [13:52] ovaries having clinical manifestations [13:55] of hyper androgenism. So that could be [13:58] hercetism, acne, other things and then [14:01] usually irregular periods and the way [14:03] that that's defined at least by the [14:05] latest criteria is having a period every [14:08] 35 days or less. So typical cycle length [14:11] 28 days, 35 days, you know, you're [14:13] skipping a period here and there. So [14:14] those are the criteria that we use to [14:16] diagnose PCOS. There are about four [14:19] different systems out there in the [14:21] literature for diagnosing PCOS, which is [14:23] where it starts to get confusing. So [14:26] there's some women who have no cyst on [14:29] their ovaries, but they've got heretism [14:32] and they've got irregular periods. [14:34] >> Could you define heretism? [14:35] >> Here is increased hair growth, usually [14:38] in places that you don't want it. So for [14:40] women, it can be, you know, kind of male [14:42] pattern. They might notice it on their [14:43] breasts, on their chest. What we know is [14:46] that PCOS is not just a problem in terms [14:49] of irregular periods and then difficulty [14:52] getting pregnant. So those are mostly [14:54] problems in your 20s, 30s, early 40s. [14:57] But it is a massive risk factor for [15:01] cardioabolic disease as you get older. [15:04] So many people tend to pigeonhole PCOS [15:07] as a problem of reproductive age. We [15:09] have to be thinking of it over the [15:11] entire female life cycle. And I would [15:14] say it's even more important to consider [15:16] it over the age of 50. You know, average [15:19] age of menopause is 51 to 52 because we [15:22] know that that elevated testosterone, [15:24] the high androgens [15:26] are probably the greatest card metabolic [15:30] driver of disease for women with PCOS. [15:33] The thread we haven't talked about is [15:35] the role of insulin and glucose. [15:38] So for some of the phenotypes of PCOS, [15:42] the problem is hyperinsulinemia, [15:45] high insulin in the blood is driving [15:47] those theta cells in the ovaries to [15:48] overproduce testosterone. [15:50] >> Are you a fan of continuous glucose [15:52] monitors? [15:53] >> The hugest, most gigantic fan of CGMs. [15:55] I've never seen any tool that I've ever [15:57] used in medicine change behavior the way [16:00] that CGMs do. Like I think really [16:02] understanding what the mediators are of [16:05] your glucose control is essential. Now [16:07] that said, it's also kind of a later [16:10] effect. I mean, I'd rather know your [16:12] insulin and we know from uh the [16:15] Whitehead White Hall study that insulin, [16:18] especially postprandial insulin, fasting [16:20] insulin too, can change years and years [16:23] before you get a change in glucose. So, [16:27] um that's more for pre-diabetes and [16:29] diabetes. Third thing is it democratizes [16:32] data. One of the most hopeful and [16:35] exciting things that I'm seeing right [16:37] now in the health space is that we're [16:41] going from this patriarchal relationship [16:45] where doctors hold the power and are the [16:47] gatekeepers of data to patients and [16:51] clients having much more access to that [16:55] enchantment about their own chemistry [16:58] and their own biology. teaching the [17:00] patient to be their own clinician. To [17:04] me, that is a loop of benevolence and [17:07] integrity that I think is essential to [17:10] creating health. We've got a disease [17:12] care system. We need the democratization [17:15] of data to become a health-based system. [17:19] If you had a magic wand and you could [17:21] give like two or three don'ts to [17:24] maximize vitality and longevity. Let's [17:28] focus first on female patients, but if [17:30] it extends to male patients as well, [17:31] what would you like to see them not do? [17:33] >> So, I would say sleep, alcohol, high [17:36] perceived stress, eating the wrong [17:38] foods, toxic relationships, and [17:41] isolation. And then number six, not [17:44] moving enough or not moving and [17:46] exercising in a way that really fits [17:48] with your body. [17:49] >> Can we start with that one actually just [17:50] cuz it's such a and then work backwards? [17:52] >> Yeah. Well, I think for me, because I [17:55] have a phenotype that produces a lot of [17:57] insulin, kind of depending on how I'm on [18:00] my game, I have a lot of glucose. So, I [18:03] have to exercise a lot more to dispose [18:05] that glucose. So, I think you then have [18:08] to move from medicine for the population [18:11] or prescriptions for the population to [18:14] what works for the individual. One of [18:16] the mediators that I think is important, [18:18] especially for people who do what I call [18:20] chronic cardio, which is what I did, [18:23] is cortisol. So, we know that runners, [18:26] especially marathon runners, people who [18:28] do a lot of cardio and don't do much [18:31] resistance training, they tend to have [18:32] much high cortisol levels. And you can [18:34] buffer that with vitamin C. Vitamin C [18:36] can decrease the effect. But chronic [18:40] cardio doesn't always serve people. When [18:42] I first started measuring hormone panels [18:45] in myself, I went to my physician and I [18:48] said, "I'm 35. I've never been so [18:51] exhausted in my life. I just feel like [18:52] I'm pushing a rock up the hill. I've got [18:55] this belly fat that I don't like and I [18:58] don't want to have sex with my husband. [18:59] What can we do about this?" And he [19:01] offered a birth control pill and an [19:04] anti-depressant. [19:05] >> Oh, goodness. So, I left him and I went [19:08] to the lab and I ran a hormone panel and [19:10] my cortisol was three times what it [19:12] should have been. My insulin was in the [19:14] 20s. I was fasting. My glucose was 105. [19:18] My thyroid was mildly abnormal. My [19:22] progesterone was low. And that set me on [19:25] this course of realizing that what I was [19:29] doing as a physician, taking care [19:31] especially of women, was not getting to [19:34] some of these root causes that are so [19:36] essential. And I would say I had to [19:38] start first with cortisol. [19:40] At that time, I was running four miles [19:42] three times a week, four times a week. [19:44] That was just raising my cortisol [19:46] further. So that was not the right [19:47] exercise for me. I needed more adaptive [19:49] exercise. I started doing Pilates, more [19:51] yoga. That helped to lower my cortisol. [19:54] I mean, it started me on changing the [19:56] way I was managing perceived stress and [19:58] it also changed my supplement regimen. [20:00] >> I'd like to make sure that we circle [20:02] back to birth control in particular oral [20:05] contraceptive birth control. What are [20:07] your concerns? What do you like about [20:08] oral contraceptives? What do you dislike [20:10] about them? [20:11] >> In terms of benefit, I think that [20:13] especially when they first came out and [20:15] even now, it gives women reproductive [20:17] choice and that's essential. So I'm a [20:19] big fan in that regard and we've got a [20:21] lot of data to show both the risks and [20:24] also the benefits of it. So I'll speak [20:27] first into the benefits because I'm [20:29] going to get on a soap box a little bit [20:30] about the risks. So we know that it [20:33] reduces the risk of ovarian cancer. So [20:36] there's something about this idea of [20:38] incessant ovulation that is not good for [20:41] the female body. So if you look at for [20:43] instance women who are nuns who don't [20:48] take oral contraceptives and they have a [20:50] period every single month of their [20:52] reproductive lives, they have a greater [20:54] risk of ovarian cancer. So if you look [20:57] then at women who have several babies [21:00] and they've got a period of time when [21:02] they're pregnant that they're not [21:03] ovulating and then they breastfeed for [21:04] some period of time, they have a lower [21:06] risk of ovarian cancer. So oral contra [21:09] contraceptives help with reducing [21:12] ovulation and reducing risk. We know [21:15] that if you take the oral contraceptive [21:18] for about 5 years, it reduced your risk [21:19] of ovarian cancer by 50%. And that's [21:22] significant because [21:24] we're so poor at diagnosing ovarian [21:27] cancer early. There's really no method [21:30] that's really effective. We use CA125 [21:33] and ultrasound screening, especially in [21:35] women who are at greater genetic risk. [21:37] But even that often we diagnose it you [21:39] know in a later stage. [21:41] >> Maybe just because that statement is [21:43] going to highlight for a number of [21:44] people um the question of what are some [21:46] of the earliest symptoms that people can [21:49] recognize without a blood test. So is o [21:51] ovarian cancer is it going to be pain? [21:54] >> So the problem is the symptoms are so [21:56] vague and they're so non-specific. [21:59] One of the most common symptoms is [22:00] bloating. And we've already talked about [22:03] constipation. We've talked about how [22:04] women have this longer track, GI track, [22:07] and so bloating is a really common [22:09] experience for most women. You can have [22:11] bulk symptoms, you know, feeling like [22:13] your your lower belly is kind of pressed [22:16] out. The way that we inform women in [22:19] terms of watching for this is to get [22:22] regular gynecologic exams for women who [22:25] are at high risk where they have, for [22:26] instance, an ultrasound for some reason [22:28] and it shows a mass that we're concerned [22:30] about. there's a way to triage that in [22:32] terms of what kind of evaluation that [22:33] they need and that's a situation where [22:36] you might get a blood test called the [22:37] CA125. [22:38] >> Taking estrogen and thereby reducing the [22:42] frequency of ovulation [22:44] lowers the risk of ovarian cancer. [22:46] Should women that are even women who are [22:49] not sexually active, so they're they're [22:50] not actively trying to get pregnant or [22:52] avoid getting pregnant, but if they're [22:54] not sexually active, would they be wise [22:56] to suppress ovulation for periodically [22:59] using hormone-based contraception just [23:01] so that they can offset the risk of [23:03] ovarian cancer? That's a very rational [23:06] question and I would say that's what [23:07] mainstream medicine has had at its back [23:11] to recommend oral contraceptives not [23:14] just for women who are seeking [23:15] contraception but for acne for painful [23:18] periods for really kind of the drop of a [23:22] hat. They're prescribing oral [23:23] contraceptives. That's what I was taught [23:25] to do. And I think a lot of that is [23:26] pharmaceutical influence. The oral [23:28] contraceptive is two hormones. It's [23:31] ethanol estradile and it's a [23:34] progesterine. So it's not the normal uh [23:38] progesterone that your body makes that [23:40] your ovaries make and your adrenals [23:41] make. It is a synthetic form of [23:45] progesterone and it is the same [23:48] progesterine similar same class that was [23:51] shown to be dangerous and provocative in [23:53] the women's health initiative. So I'm [23:55] not a fan of progesterines. [23:58] I do not recommend them for any woman [24:01] unless it it gives them some freedom in [24:03] some way. So like with almost any [24:06] pharmaceutical, the oral contraceptive [24:08] depletes certain micronutrients, [24:10] magnesium, there's certain vitamin B's [24:12] that are depleted. It also affects the [24:15] microbiome. That data is not as strong, [24:18] but there seems to be some effect. And [24:20] there's also an increased risk of [24:21] inflammatory bowel disease and [24:23] autoimmune condition. It increases [24:25] inflammatory tone. So the studies that [24:28] I've seen increase one of the markers of [24:32] inflammatory tone high sensitivity CRP [24:34] by about two to 3x. It seems to make the [24:37] hypothalamic pituitary adrenal axis more [24:41] rigid so that you can't kind of roll [24:44] with the punches and wax and wayne in [24:46] terms of cortisol production the way [24:48] that you can off the birth control pill. [24:50] It can affect thyroid function. Anytime [24:53] you take oral estrogen, it raises sex [24:56] hormone binding gabbulin. And you've [24:58] talked to other podcast guests about [24:59] this, Kyle. I think [25:01] >> sex hormone binding globulin I think of [25:03] as a sponge that soaks up free estrogen [25:07] and free testosterone. So when you go on [25:10] the birth control pill, you raise your [25:12] sex hormone binding globulin. It soaks [25:14] up especially free testosterone. [25:17] And for some women, it's not a big deal. [25:20] they don't notice much of a difference. [25:22] But then there's a phenotype maybe [25:24] related to CAG repeats on the androgen [25:27] receptor who are exquisitly sensitive to [25:31] that decline in free testosterone. So [25:34] this then opens the portal of talking a [25:36] little bit about testosterone in women. [25:38] It's the most abundant biologically the [25:41] most abundant hormone in the female [25:43] system. It is so important for women. It [25:46] is essential to so many things, not just [25:48] sex drive and muscle mass and seeing a [25:50] response to resistance training, but [25:53] also confidence and agency. And so those [25:56] women who are so sensitive to their [25:59] testosterone level, they've got this [26:00] high sex hormone binding gabbulin, their [26:02] testosterone declines. [26:04] What they describe is vaginal dryness, [26:08] maybe a decline in sex drive. But [26:11] there's also this bigger issue related [26:13] to confidence and agency, even [26:15] risk-taking from studies that we've done [26:17] with MBA students that I think is a [26:19] serious problem. [26:21] Maybe the most important out of all of [26:23] these things, is that it can shrink the [26:25] clitoris by up to 20%. 20%. And if I've [26:28] got a woman that I think should not be [26:30] on the birth control pill, maybe she's [26:32] taking it for acne or she's taking it [26:33] cuz her periods were a little painful. [26:35] What I'm going to do is say, let's [26:38] leverage these other ways of making your [26:40] period less painful. Let's take the [26:42] message of your painful periods and [26:46] figure out, okay, is it your [26:47] inflammatory tone and we give you some [26:49] fish oil and SPMs, maybe a little [26:51] aspirin when you've got your period? [26:52] like let's find some other ways to deal [26:54] with it than to take the oral [26:56] contraceptive which you have not [26:58] received informed consent about because [27:01] it can trick your by up to 20%. Now [27:03] that usually convinces most people to [27:05] come. The data that we have is limited. [27:08] There's one woman who uh Claudia [27:11] something something who looked at sex [27:13] hormone binding globulin a year out from [27:16] stopping the birth control pill and it [27:18] was still elevated. It wasn't as high as [27:20] it was when they were on the pill, but [27:22] it was still elevated. So, your question [27:24] about reversibility, I don't know if we [27:26] know the answer to that. [27:28] >> What are your thoughts on menopause? [27:29] When should people start thinking about [27:31] it? And I'm guessing based on everything [27:33] you've told me today that there are [27:35] women in their 30s that while they may [27:37] be 20 years out from menopause, probably [27:40] should be doing things now in [27:41] anticipation of that. The more you know [27:43] about your phenotype, your hormonal [27:45] phenotype when you're in your 30s, [27:47] you're set up in terms of what to do in [27:50] the future, especially things like your [27:52] thyroid, your estrogen and progesterone [27:54] levels cuz you can replace to a state of [27:57] you thyroid. I don't usually go exactly [27:59] back to where the estrogen and [28:01] progesterone levels were were, but we [28:03] can get pretty close. So, in your 30s, [28:05] having a base case, I think, is really [28:07] essential. What's more interesting is to [28:09] talk about pmenopause. [28:11] So pmenopause is the the period of time [28:15] before your final menstrual cycle. And [28:17] for most women, depending on how attuned [28:20] you are to the symptoms, it can last for [28:23] 10 years. So I'm still in period [28:25] menopause. It's been like 20 years [28:28] because I've been tracking it so [28:29] carefully. It usually gets kicked off by [28:31] having your cycle get closer together. [28:33] So that can happen in your 30s or your [28:35] 40s. you go from 28 days to 25 days, [28:38] that sort of thing. You may notice it as [28:40] more anxiety, difficulty sleeping, and [28:42] that probably is related to the estrogen [28:45] receptor. So, there's this whole period [28:47] of permenopause. And what's most [28:49] fascinating to me is that there is this [28:52] massive, massive change that happens in [28:54] the female brain that people are not [28:56] talking about enough. And so looking at [29:00] the work of Lisa Mosonei at Cornell, [29:02] starting around age 40, there is this [29:05] massive change in cerebral metabolism. [29:08] So you can do FDG PET scans, you can [29:10] look at glucose uptake, and there's [29:12] about on average a 20% decline from [29:16] premenopause up to like age 35 to [29:19] pmenopause to postmenopause. [29:23] The women who are having the most [29:25] symptoms in pmenopause and menopause, [29:27] the hot flashes, the night sweats, the [29:28] difficulty sleeping, those are the ones [29:30] who have the most significant cerebral [29:33] hypom metabolism. [29:35] >> So, it's almost like a um I don't I [29:38] don't want to scare people with this [29:39] language, but it's it's a low-level or [29:42] let's call it pseudo dementia of sorts. [29:45] Yes, it it seems to be a phenotype that [29:48] you can then map to Alzheimer's disease [29:51] because that's Lisa Muscone's work. [29:53] She's looking at, okay, Alzheimer's [29:56] disease is not a disease of old age. It [29:58] is disease of middle age. What are some [30:00] of the biomarkers that we can define [30:02] that can tell you what your risk is? [30:05] I've got a mother and a grandmother with [30:07] Alzheimer's disease. You can believe I [30:09] am all over this data. [30:10] >> And insulin resistance, insulin [30:13] sensitivity, as we talked about before. [30:15] um seems to be somewhere in there which [30:17] I think when that first when that idea [30:20] first surfaced a few people are like [30:21] really but then of course right I mean [30:22] the brain is this incredibly [30:24] metabolically demanding organ you [30:26] deprive neurons of fuel sources they or [30:29] you make them less sensitive to fuel [30:31] sources they start dying they they [30:33] certainly start firing less it makes [30:35] perfect sense and I think now it's [30:37] thanks to Lisa's work work that you've [30:38] you've done and have talked about quite [30:40] a lot is um in your books and elsewhere [30:42] I think has really you [30:44] highlighted for people that metabolism [30:47] and metabolomics is going to be as [30:50] important as genes and genomics when it [30:52] comes to that's right [30:53] >> dementia [30:55] >> perhaps especially in women is it safe [30:57] to say that [30:58] >> I think so because we believe that this [31:01] system is regulated by estrogen [31:04] so the decline in estrogen starting [31:06] around age 40 43 is kind of the average [31:10] seems to be the driver behind cerebral [31:12] hypom metabolism the I describe it to my [31:14] patients is it's like slow brain energy. [31:18] So you walk into a room, you can't [31:20] remember why. Like you just notice that [31:22] you can't manage all the tasks the way [31:24] that you once could. Like things are [31:26] just a little slower. And I say that to [31:29] women and they're like, I have that like [31:31] help me. We've got all of these women [31:33] that are marching toward potentially a [31:36] greater risk of Alzheimer's disease. And [31:38] they have this opportunity in their 40s [31:40] and their 50s to take hormone therapy. [31:43] and they may not be offered it because [31:45] the typical conventional approach based [31:48] on whi is to say unless you're having [31:51] hot flashes and night sweats that are [31:52] severe, I'm not going to give you [31:54] hormone therapy. And I I just want to [31:56] call that out. I would say no, that is [31:58] not the way to approach it. The concept [32:00] right now in conventional medicine is [32:02] that hot flashes and night sweats are [32:03] these nuisance symptoms that we will [32:06] take care of temporarily. Doesn't matter [32:08] that you're not sleeping anymore. Turn [32:09] down the temperature in your room. And [32:11] that's not right because hot flashes and [32:14] night sweats are a biomarker [32:17] of cardioabolic disease. They are a [32:19] biomarker of increased bone loss. They [32:22] are a biomarker of changes in the brain. [32:24] So many of these symptoms that occur in [32:26] pmenopause are not driven by the [32:28] ovaries. They are driven by the brain. [32:30] >> I just want to say you've taught me a [32:33] tremendous amount. the amount of [32:34] knowledge that you shared is is immense [32:37] and is going to be very useful and [32:40] actionable for women in particular. [32:42] >> Can I just add one last thing because I [32:44] didn't talk about it since we didn't get [32:46] to the 40s and the 50s in this list of [32:48] biomarkers. [32:49] >> Please do. [32:49] >> If women went away with one thing today, [32:52] >> it would be to do a coronary artery [32:54] calcium score [32:56] >> by age 45 and sooner if you've got [32:58] premature heart disease. [33:00] >> How is that taken? So, it's a CT scan of [33:02] the chest. You can self-order it. It [33:05] almost gives you this fork in the road [33:08] in terms of how much you need to pay [33:09] attention to cardio metabolic health as [33:11] a woman. It's so fascinating because, [33:14] you know, there's some women who have a [33:15] zero. So, my score is zero. But if [33:17] you're 45 and you're starting to be [33:20] elevated or you've got, you know, maybe [33:22] you've got PCOS or you've got some other [33:24] biomarkers tending you in this direction [33:27] toward the number one killer that allows [33:29] you to really start to make changes. And [33:31] I I think it's essential to know that [33:33] data. Most conventional doctors are not [33:35] going to do it. [33:36] >> So if I were to go to my doctor and I [33:37] just say I want a a cardiac calcium [33:39] score. That's what people [33:40] >> coronary artery calcium score. [33:44] >> Okay. There are certain people they are [33:45] exceedingly rare but you are one such [33:48] person that when they speak knowledge [33:49] just comes out of them and it's [33:51] incredibly useful and helpful knowledge. [33:53] So [33:53] >> thank you. [33:54] >> Thank you.