HoldsUp

Dr. Tyna Moore · 2026-02-10 · Tyna Moore (host)

Weight Gain on HRT For Middle Aged Women: What’s Really Causing It (And How To Avoid It) | Ep. 247

27 research-tied claims examined: 1 contradicted 3 overstated 3 context 18 supported 2 unverified

1

Contradicted by research

0:30:23Tyna Moore (host)contradictedmoderate

Topical hormone creams can accumulate in adipose tissue, resulting in erratic or aberrant release into the bloodstream.

"creams can get It can get messy with creams, because they can really um they just kind of glom up in your fat, if you will. And so, you get aberrant release into your bloodstream when you start glomming up and increasing levels in the adipose tissue and it's not necessarily getting into the blood" (said at 0:30:23)

Pharmacokinetic evidence contradicts the claim that topical or transdermal hormone creams accumulate in adipose tissue to cause erratic or aberrant release into the bloodstream. Transdermal administration of steroid hormones (such as estrogens and progestogens) is specifically utilized in clinical medicine because bypassing first-pass hepatic metabolism yields more stable and consistent serum hormone levels compared to oral administration. While lipophilic hormones traverse the stratum corneum and local dermal layers, clinical pharmacokinetic studies show that transdermal delivery provides predictable, steady systemic release rather than erratic dumping from subcutaneous adipose depots.

3

Overstated

0:06:13Tyna Moore (host)overstatedmoderate

Excessive doses of testosterone in women can lead to increased aromatase activity, converting excess testosterone into estrogen.

"the one thing that has made me gain weight the most quickly and just kind of out of nowhere has been when I have used uh testosterone at too high a dose. All of a sudden my body likes to do the aromatization process of my aromatase enzyme kicks up and I convert all my testosterone into estrogen." (said at 0:06:13)

While testosterone can be converted into estradiol by the enzyme aromatase, the claim that high doses of testosterone induce aromatase enzyme activity and convert all exogenous testosterone into estrogen is exaggerated. A meta-analysis of clinical trials examining androgen replacement therapy in postmenopausal women found that direct testosterone administration significantly increases serum testosterone levels without significantly raising circulating estradiol (E2) or estrone (E1) levels (PMID 32016915). Increases in estrogen levels were observed following DHEA administration, but not with direct testosterone therapy.

0:23:37Tyna Moore (host)overstatedhigh

Low progesterone levels are a primary cause of miscarriage.

"Low progesterone is a massive reason for miscarriage." (said at 0:23:37)

Low progesterone is predominantly a downstream marker of a failing or non-viable pregnancy rather than a primary causal driver of miscarriage. Approximately 50% to 70% of early miscarriages are caused by embryonic chromosomal abnormalities. When an embryo is genetically abnormal or implantation fails, insufficient human chorionic gonadotropin (hCG) signaling leads to corpus luteum failure, resulting in secondary low serum progesterone. Furthermore, large randomized controlled trials (such as the PRISM trial) and Cochrane meta-analyses demonstrate that routine progesterone supplementation does not significantly improve live birth rates in unselected women with early pregnancy bleeding, though a modest benefit is observed in specific subgroups with both bleeding and a history of recurrent pregnancy loss.

0:33:19Tyna Moore (host)overstatedvery low

Loss of estrogen in the brain causes a drop in dopamine levels.

"You have this incredible drop in dopamine as the estrogen leaves your brain and you just want to stop moving." (said at 0:33:19)

Preclinical evidence demonstrates that 17β-estradiol modulates central dopaminergic pathways—enhancing striatal dopamine release, turnover, and receptor sensitivity—and that estrogen depletion can alter dopamine signaling related to motor and reward circuitry. However, describing this as an "incredible drop in dopamine" as estrogen declines is an exaggeration of the literature. Rodent models comparing surgical and gradual menopausal depletion show complex, region-specific, and transient monoamine changes rather than a generalized, severe deficit in total brain dopamine, and human clinical evidence on dopamine depletion during menopause remains sparse and indirect.

3

Needs context

0:34:50Tyna Moore (host)needs contextlow

Excessively high estradiol levels suppress lipolysis and promote insulin resistance and energy storage.

"And then if you take too much estradiol, it starts to promote energy storage and we get back to insulin resistance. So it's like this U-shaped curve on a graph. There's like we don't want to be over here, we don't want to be over here. And we get this rising insulin tone, it suppresses lipolysis, which is the breakdown of fat." (said at 0:34:50)

Physiological estradiol generally enhances insulin sensitivity, protects against metabolic dysfunction, and supports lipid homeostasis. However, evidence from cellular models supports a biphasic (inverted U-shaped) dose-response curve, where low/physiological estradiol concentrations stimulate insulin signaling and glucose transport, whereas supraphysiological/excessive concentrations impair insulin receptor substrate-1 (IRS-1) phosphorylation, inducing insulin resistance and favoring lipid storage. Insulin itself is the primary anti-lipolytic hormone that suppresses lipolysis in adipose tissue. While this mechanism is well-documented in vitro, robust clinical trial evidence demonstrating that clinical estradiol overdose causes insulin resistance and lipolytic suppression in humans remains limited.

0:41:30Tyna Moore (host)needs contextmoderate

Excessively high estradiol levels can disrupt thyroid binding sites, impair cortisol signaling, and stimulate autoimmune disease, while progesterone protects against autoimmune disease.

"too high of estradiol can mess up thyroid site binding. Too high of estradiol can mess up cortisol signaling. Too high of estradiol can drive autoimmune disease. The very simplistic version of that is progesterone protects against autoimmune disease and estrogen may drive it." (said at 0:41:30)

The statement captures broad endocrine and immunomodulatory concepts but oversimplifies complex mechanisms. Elevated estrogens (particularly oral formulations via hepatic first-pass metabolism) stimulate the hepatic synthesis of thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG), altering total and free circulating thyroid and cortisol hormone levels rather than damaging cellular binding sites or receptor signaling. In immunology, estrogen exerts nuanced, dose- and context-dependent biphasic effects: while it can enhance B-cell activation and humoral immunity (frequently exacerbating antibody-mediated diseases like systemic lupus erythematosus), it can also suppress cell-mediated inflammation and improve conditions like rheumatoid arthritis. Progesterone generally exerts immunosuppressive effects, but neither hormone functions simply as a universal driver or protector against all autoimmune diseases.

0:54:45Tyna Moore (host)needs contextlow

Progesterone induces hyperinsulinemia, acts on the pancreas and liver, and antagonizes GLUT4 receptor translocation in skeletal muscle to deposit body fat.

"progesterone has important effects on carbohydrate, lipid, and protein metabolism. Um it induces this sort of roundabout hyperinsulinemia, which is increased insulin. It has some direct action on our pancreas and our liver. Um but and it has this antagonizing effect on our muscle getting that GLUT4 receptor up to bring in the the glucose. But basically just understand that its job is to deposit body fat so that we can have a baby." (said at 0:54:45)

Preclinical and animal studies show that progesterone and progestins can impair insulin sensitivity, reduce skeletal muscle GLUT4 protein content, and contribute to pregnancy-associated metabolic shifts that favor maternal adipose deposition. For example, in ovariectomized rats, progesterone treatment reduced skeletal muscle GLUT4 protein content by 21% and impaired exercise-induced glucose uptake, and progestin therapy in non-human primates significantly reduced skeletal muscle GLUT4 expression. However, framing progesterone's primary metabolic role simply as blocking GLUT4 translocation to deposit body fat oversimplifies complex endocrine interactions, and direct evidence demonstrating specific translocation antagonism in human skeletal muscle is limited compared to animal models.

18

Supported by research

0:03:07Tyna Moore (host)supportedmoderate

Depo-Provera use has been associated with an increased risk of brain tumors, leading to lawsuits.

"And now we've got lawsuits coming out around Depo-Provera and I you know, brain tumors." (said at 0:03:07)

Epidemiological studies and meta-analyses show that prolonged use of depot medroxyprogesterone acetate (DMPA, commonly known under the brand name Depo-Provera) is associated with a significantly increased risk of intracranial meningioma (a primary brain and central nervous system tumor). A landmark 2024 French national case-control study (BMJ) found that prolonged use of injectable medroxyprogesterone acetate was associated with an odds ratio of 5.55 (95% CI: 2.27 to 13.56) for intracranial meningioma requiring surgery. Subsequent large-scale cohort studies and systematic reviews have confirmed this association (with pooled odds ratios typically ranging between 2.4 and 2.7, particularly with exposures exceeding 1 to 4 years), which has led to high-profile product liability litigation.

0:06:44Tyna Moore (host)supportedmoderate

A transient state of insulin resistance occurs in the week prior to menstruation (the late luteal phase).

"This is similar to those of you who are menstruating of whatever age and you find yourself that week before your bleed, right before your period starts... It was insulin resistance. You become transiently insulin resistant." (said at 0:06:44)

Clinical studies demonstrate that insulin sensitivity significantly fluctuates across the menstrual cycle, with a transient decrease in insulin sensitivity (and a corresponding increase in insulin resistance) occurring during the luteal phase compared to the follicular phase. A 2023 mechanistic study evaluating brain and whole-body insulin action found that hypothalamic responsivity to insulin is present during the follicular phase but absent during the luteal phase, concluding that transient brain insulin resistance contributes to whole-body insulin resistance during the luteal phase. Similar variations in insulin sensitivity and glycemic control across cycle phases have been observed in clinical populations, including women with type 1 diabetes.

0:11:20Tyna Moore (host)supportedmoderate

A type of diabetes occurring in malnourished individuals is being categorized as type 5 diabetes.

"there is a type of diabetes that they're discussing now in malnourished folks and they're calling it type five" (said at 0:11:20)

Malnutrition-related diabetes mellitus, historically recognized in undernourished individuals in low- and middle-income regions, has recently been categorized and discussed in the literature and by the International Diabetes Federation as type 5 diabetes mellitus (T5DM). It is characterized by severe insulin deficiency, low body mass index, preserved insulin sensitivity, absence of autoimmune markers, and resistance to ketosis.

0:21:01Tyna Moore (host)supportedmoderate

Progesterone antagonizes insulin action by impairing insulin-mediated glucose uptake and reducing GLUT4 receptor translocation, as well as altering hepatic glucose handling.

"progesterone induces a state of physiologic insulin antagonism. So it antagonizes insulin to go by impairing insulin-mediated glucose uptake and altering hepatic glucose handling... normally when insulin binds a cell that's if it's healthy... the cell will translocate a a GLUT4 um receptor basically and that that GLUT4 translocation is what allows glucose to come in the cell and be used as fuel. In a nutshell. And that's normal, but progesterone reduces that mechanism from happening." (said at 0:21:01)

Progesterone is well established as a physiological antagonist of insulin action, particularly during states of elevated levels such as pregnancy. Mechanistic studies show that progesterone impairs insulin signaling (including reduction of IRS-1 expression and downstream Akt phosphorylation), leading directly to decreased insulin-stimulated GLUT4 translocation to the plasma membrane and marked inhibition of glucose uptake.

0:25:35Tyna Moore (host)supportedhigh

Pregnancy induces a state of transient, adaptive insulin resistance.

"And so, for the pregnant woman, she's going to have a transient insulin resistance throughout her pregnancy. That is part of a natural, normal part of pregnancy is this sort of transient insulin resistance." (said at 0:25:35)

The speaker's claim is supported by standard maternal physiology literature. Normal pregnancy naturally induces a state of transient, reversible peripheral insulin resistance that increases across gestation. This adaptive metabolic shift shunts glucose and nutrients toward the placenta to sustain fetal growth, while maternal pancreatic beta-cells typically compensate by increasing insulin secretion to maintain glycemic control until delivery, after which insulin sensitivity rapidly restores.

0:27:15Tyna Moore (host)supportedhigh

Oral micronized progesterone undergoes extensive first-pass hepatic metabolism where a significant amount is converted into allopregnanolone, which exerts neural calming and sedative effects.

"When you take oral micronized progesterone, it goes through first pass in your liver, meaning your liver metabolizes it first. It doesn't just end up in the bloodstream. And in that process, progesterone, a huge amount of it gets turned into allopregnanolone. And allopregnanolone is that neural calming agent." (said at 0:27:15)

Oral administration of micronized progesterone is subject to extensive first-pass metabolism in the digestive tract and liver, leading to significant conversion into 5-alpha and 5-beta reduced metabolites, notably allopregnanolone (3-alpha,5-alpha-tetrahydroprogesterone). Allopregnanolone is a potent positive allosteric modulator of gamma-aminobutyric acid type A (GABA-A) receptors in the central nervous system, responsible for the sedative, anxiolytic, and hypnotic ('neural calming') effects observed after oral progesterone administration.

0:27:41Tyna Moore (host)supportedlow

Allopregnanolone, a neuroactive metabolite of progesterone, stimulates appetite and triggers carbohydrate cravings.

"And in that process, progesterone, a huge amount of it gets turned into allopregnanolone... It makes you crave carbs. It creates a carb-driven response." (said at 0:27:41)

Preclinical studies and neuroendocrinology reviews support the finding that allopregnanolone—a neuroactive metabolite of progesterone and positive GABAA receptor modulator—stimulates food intake (hyperphagia) and preferentially drives consumption of palatable, energy-dense foods. In animal models, acute administration of allopregnanolone significantly increases food intake and preference for energy-rich foods (such as cookies/carbohydrates). In human observational studies, elevated allopregnanolone concentrations (such as during the luteal phase, pregnancy, or in conditions like PCOS) are linked to uncontrolled eating and increased appetite. The evidence is rated low certainty because the direct causal link between allopregnanolone and selective carbohydrate cravings is primarily established in animal models and observational human data.

0:30:45Tyna Moore (host)supportedhigh

Allopregnanolone binds to GABA receptors in the brain.

"allopregnanolone sits on those GABA receptors in the brain and it's lovely, but it also can make you really crave carbohydrates." (said at 0:30:45)

Allopregnanolone is an endogenous neuroactive steroid that acts as a potent positive allosteric modulator of type A gamma-aminobutyric acid (GABA_A) receptors in the central nervous system. Activation and positive modulation of central GABA_A receptors by allopregnanolone has been shown in human and animal studies to increase appetite, stimulate hyperphagia, and promote a preference for energy-rich foods and sweet/carbohydrate intake.

0:31:46Tyna Moore (host)supportedhigh

When ovaries stop producing estradiol, adipose tissue produces estrone.

"when your ovaries go offline and you stop producing estradiol out of the ovaries, your fat will take over and your fat produces estrone, which is a different type of estrogen." (said at 0:31:46)

The speaker's statement accurately reflects established human endocrinology. Prior to menopause, the ovaries are the primary source of circulating estrogens, predominantly producing 17β-estradiol (E2). Following the cessation of ovarian function at menopause, white adipose tissue becomes the principal site of estrogen biosynthesis. In adipose stromal cells, the aromatase enzyme (CYP19A1) converts circulating adrenal and ovarian androgens—primarily androstenedione—into estrone (E1), making estrone the predominant circulating estrogen in postmenopausal women.

0:32:48Tyna Moore (host)supportedmoderate

Estradiol supports muscle satellite cells to help maintain and build skeletal muscle.

"estradiol helps with those satellite cells of your muscle and so it helps with maintaining and building muscle to some degree, not necessarily anabolic like testosterone, but really is necessary to maintain that healthy muscle." (said at 0:32:48)

Preclinical models and human muscle biopsy studies demonstrate that 17β-estradiol signaling via estrogen receptors (primarily estrogen receptor alpha) is essential for maintaining the skeletal muscle stem cell (satellite cell) pool. Estrogen deficiency leads to satellite cell apoptosis, impaired cell-cycle progression, and diminished self-renewal and differentiation, while estradiol preservation or replacement helps maintain the satellite cell pool and supports muscle regeneration and maintenance.

0:33:50Tyna Moore (host)supportedvery low

Ovariectomized rodents exhibit reduced physical activity, cage hiding, and visceral fat accumulation.

"when they take the ovaries out of rodents, they go in the corner of the cage and they hide and they get fat. That's what happens. They get a bunch of visceral fat and they hide." (said at 0:33:50)

Animal literature supports the statement that ovariectomy (surgical removal of the ovaries) in rodents leads to increased body weight, marked accumulation of visceral adipose tissue, and reductions in physical activity. Multiple controlled rodent studies demonstrate that estrogen deficiency induced by ovariectomy significantly expands visceral fat depots and adipocyte size, effects that are reversed or attenuated by 17β-estradiol replacement and exercise training. Because the evidence is derived entirely from animal models, the GRADE certainty is very low.

0:34:20Tyna Moore (host)supportedhigh

Loss of estrogen leads to increasing insulin resistance.

"your insulin sensitivity dials in because you become insulin [clears throat] resistant as your estrogen's leaving. You become more and more insulin resistant." (said at 0:34:20)

Extensive clinical and mechanistic evidence demonstrates that estrogen loss (such as during the menopausal transition) impairs glucose homeostasis and increases insulin resistance. Meta-analyses of randomized controlled trials show that estrogen replacement significantly improves insulin sensitivity and reduces HOMA-IR in postmenopausal women.

0:35:21Tyna Moore (host)supportedmoderate

Studies demonstrate that metabolism does not slow down during menopause.

"Well, the studies show that, you know, your metabolism doesn't slow down. And that's true. I have said that myself and I've shared those studies." (said at 0:35:21)

Large-scale metabolic studies using doubly labeled water (such as the global DLW database analysis by Pontzer et al.) have demonstrated that total daily energy expenditure, adjusted for fat-free mass, remains stable throughout adulthood from ages 20 to 60, with no distinct drop during the typical menopausal transition ages. Furthermore, studies evaluating resting and postprandial energy expenditure across pre-, peri-, and postmenopausal women show that menopausal status itself does not reduce metabolic rate when controlling for fat-free mass and activity levels.

0:37:53Tyna Moore (host)supportedmoderate

Studies show starting hormone replacement therapy earlier in perimenopause rather than waiting until well after menopause provides better outcomes.

"there are good studies coming out showing that getting to this sooner than later is better. There's a window. There's a magic window for sure." (said at 0:37:53)

Published randomized clinical trials and systematic reviews support the 'timing hypothesis' (or 'window of opportunity' hypothesis) for menopausal hormone therapy. A Cochrane systematic review of randomized controlled trials found that women initiating hormone therapy within 10 years of menopause had significantly lower all-cause mortality (RR 0.70, 95% CI 0.52–0.95) and coronary heart disease events (RR 0.52, 95% CI 0.29–0.96) compared to placebo or no treatment, whereas initiation more than 10 years post-menopause conferred no cardiovascular mortality benefit and was associated with increased risks of stroke and venous thromboembolism.

0:45:36Tyna Moore (host)supportedhigh

Steroid hormone biosynthesis takes place inside the mitochondria.

"if we're not supporting the mitochondria, which is where hormonal biosynthesis takes place, and we are driving pathways too hard, and our redox modulation's all screwed up, we're going to have a hard time processing and handling those hormones." (said at 0:45:36)

Steroid hormone biosynthesis critically takes place within the mitochondria. The initial and rate-limiting step of steroidogenesis—the transport of cholesterol into the inner mitochondrial membrane and its subsequent cleavage by cytochrome P450scc (CYP11A1) to form pregnenolone—occurs inside the mitochondria. While downstream enzymatic steps in steroid pathways also involve the smooth endoplasmic reticulum, mitochondria host several key steroidogenic enzymes (such as P450scc, 11β-hydroxylase, and aldosterone synthase) and are universally recognized as essential sites for steroid hormone synthesis.

0:55:46Tyna Moore (host)supportedhigh

Aromatase enzyme in visceral and abdominal fat converts testosterone into estrogen.

"if you've got visceral fat or belly fat or you just happen to be built, you know, this is just how your system drives, it can turn itself through the aromatase enzyme into, which is present in your visceral and belly fat, that aromatase enzyme will convert it into estrogen." (said at 0:55:46)

The host's claim that the aromatase enzyme present in visceral and abdominal fat converts testosterone into estrogen is fully supported by established endocrine and adipose biology research. Aromatase (encoded by CYP19A1) is expressed in adipose tissue—including visceral (intra-abdominal) and subcutaneous abdominal depots—where it catalyzes the irreversible aromatization of androgens, predominantly converting testosterone into estradiol (and androstenedione into estrone). Increased adipose tissue mass, particularly intra-abdominal/visceral fat, correlates with increased aromatase expression and activity, leading to higher peripheral conversion of testosterone to estrogen.

0:59:51Tyna Moore (host)supportedmoderate

Estrogen depletion causes the diameter of the hair shaft to shrink.

"I will tell you that estrogen leaving the body causes the hair shaft itself to become thinner. So, it's just the diameter shrinks." (said at 0:59:51)

Clinical research investigating menopausal hair changes confirms that menopausal status—characterized by marked estrogen decline—significantly affects scalp hair parameters, including causing reductions in hair shaft diameter and altering hair diameter distribution, particularly on the frontal scalp. Pre- and postmenopausal comparative studies demonstrate that the reduction in estrogen availability contributes to follicular miniaturization and decreased hair fiber thickness.

0:56:16Tyna Moore (host)supportedmoderate

The 4-hydroxyestrogen (4-OH) metabolic pathway is carcinogenic and associated with cancer development.

"If you're going down the 4-OH pathway, that's not good. That's That's the cancer pathway." (said at 0:56:16)

Estrogen metabolism proceeds through several major hydroxylated pathways. The 4-hydroxyestrogen (4-OHE) pathway, catalyzed predominantly by CYP1B1, is well-established in toxicological and biochemical literature as a genotoxic and carcinogenic pathway. 4-hydroxyestrogens (such as 4-hydroxyestradiol and 4-hydroxyestrone) can be oxidized into reactive catechol estrogen quinones (estrogen-3,4-quinones) and generate reactive oxygen species, leading to depurinating DNA adducts, mutagenesis, and neoplastic transformation, in contrast to the generally non-toxic 2-hydroxyestrogen pathway.

2

No source found (not proven false)

0:00:10Tyna Moore (host)unverifiedvery low

Both abnormally low and excessively high sex hormone levels can induce insulin resistance.

"Because the mechanisms where HRT can actually induce some level of insulin resistance. That's right. Low hormones can induce insulin resistance. Too high of hormones can induce insulin resistance." (said at 0:00:10)

No published record matching the claim that both abnormally low and excessively high sex hormone levels can induce insulin resistance was located; this does not prove the claim false.

0:46:36Tyna Moore (host)unverifiedvery low

Skeletal muscle is the primary target tissue for insulin action.

"And then lastly, your muscle. So, your muscle is the primary target tissue of insulin. And we want as much muscle there to hear it as we can, right? We want to build that meat suit so that we have that sink. We have that glucose sink." (said at 0:46:36)

No published record matching the claim that skeletal muscle is the primary target tissue of insulin was located; this does not prove the claim false.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.