New Research on Fatigue and Heavy Bleeding in Perimenopause

And some info on a vaginal ring for MHT in development

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A new study is out, published in the journal Menopause, that looks at the correlation between abnormal menstrual bleeding in the menopause transition (a.k.a. perimenopause) and fatigue. It’s not exactly revelatory–spoiler alert, women who report heavier or prolonged bleeding are more likely to also report fatigue. To be clear, I am not being snarky here–we need to study things that feel intuitive because “vibes” isn’t science. Also, all studies contribute something, we could find things we didn’t expect, and, of course, we might even have our minds blown as medicine is filled with hypotheses that seemed bang on at first, but fell apart when studied. This study is worth looking at because there are some interesting tidbits regarding the scope of the problem that might be useful for you if you have fatigue and are in the menopause transition.

The paper is an analysis of data from the Study of Women’s Health Across the Nation (SWAN). Data was collected about menstrual periods; prolonged menstrual bleeding was defined as bleeding for 8 days or longer and a heavy period was defined as a heavy flow for three or more days. Fatigue was scored based on answers to questions about feeling worn out, tired, full of pep, and having energy.

It turns out that heavy and prolonged bleeding are common in the menopause transition. This is something we’ve known, but I didn’t think we had good numbers to describe the scope of the problem. In this study, over a six month time frame, 20.7% of women reported at least one episode of heavy menstrual bleeding and 5.0% reported three episodes. And just under a quarter (24.4%) of women reported prolonged menstrual bleeding, with 4.6% reporting at least three episodes of prolonged bleeding in six months.

It turns out that fatigue is also a common concern in the menopause transition. In the previous two weeks, 26.6% or women reported feeling tired and 24.2% reported feeling worn out. When it came to having energy or being full of pep, those experiences were reported by 50.2% and 50.0% of women respectively. That’s a lot of women with an energy deficit, so it’s important that we try to understand the cause or causes.

After adjusting for several factors, three or more episodes of heavy bleeding in the previous six months was associated with feeling tired (about a 60% increase in likelihood of feeling tired) and a 44% increased risk for feeling worn out. Prolonged menstrual bleeding three or more times in the previous six months was associated with a 32% lower chance of being full of pep. I mean, yes, I can see that.

This study has a lot of limitations. For example, the cause of the fatigue can’t be known for sure. Also, I am curious to know what percentage of age matched men with the same social responsibilities at work and home feel they have energy or are full of pep. I am not discounting any findings here at all, I am riffing a bit, and am genuinely curious about what the baseline experience might be for someone age 48 or 49, especially considering there is a lot in the world that is leaving a lot of people feeling worn out right now. And of course, I think it would be interesting to look at energy levels as they relate to household tasks and responsibilities.

As the answers to the questions about heavy or prolonged bleeding and fatigue aren’t matched with blood work, we can’t say much, but it isn’t unreasonable, as the authors suggest, to link heavy or prolonged bleeding with fatigue. This is because a staggering 33% of women ages 19-49 have iron deficiency, and it’s primarily due to menstruation, and fatigue is a common symptom of iron deficiency. Other symptoms of iron deficiency include depression, hair loss, and brain fog, which are also reported in the menopause transition. It’s not a big leap to think that some or a lot of this fatigue experienced by women with heavy or prolonged periods could be related to iron deficiency. After all, some women with heavy periods can lose 5-6 times more iron with each period.

Why is this important? Raising awareness about heavy bleeding matters because only 6% of women with heavy periods get care from a healthcare provider. This is a staggering indictment of the health care system as well as a stunning display of the impact of the patriarchy, which not only belittles women and downplays their experiences, but denies them the education to know if they have heavy periods or not. I pick up a lot of iron deficiency in the office, and when I say a lot, I mean probably one-third of my patients, which fits with the data. I ask every woman first if she has heavy periods, and uniformly I hear “Not really” or even “No” as a response. And then I ask specifics, such as:

• Do you bleed for longer than seven days?

• Are your clots bigger than the size of a quarter?

• Do you ever soak through your menstrual products onto your clothes?

• Do you have a sensation of gushing when you stand?

• Do you need to double up on menstrual products?

I would guess that nine out of ten times the answer is yes to one or more of those questions, and so my patient has medically heavy periods but had bee socialized to believe her bleeding was normal. In a society where talking specifically about menstruation is discouraged and women are routinely labeled as complainers, not knowing these specifics about what constitutes heavy bleeding is obviously understandable. And of course, even if someone can talk with their mother or another woman about their periods (and that is not always the case), chances are that person in whom they are confiding may not know what heavy periods are either. I was sixteen years old and soaking through my pads two nights out of every period and had every one of those signs of heavy bleeding listed above, and yet my own mother never said a word. She knew my bedsheets and clothes were bloody and how many boxes of pads I went through. When I tried to give blood at age 18, I was turned away for, you guessed it, anemia, and so the nurse at the Red Cross advised me to see my doctor, who simply said that heavy bleeding and iron deficiency and anemia were normal. I didn’t know I had heavy periods until my OB/GYN rotation in medical school!

The takeaway from this study is that women in the menopause transition (and of course, at any age) should discuss heavy and/or prolonged periods with their health care practitioners. And the corollary is that any woman with fatigue in the menopause transition should be asked about heavy or prolonged periods. Anyone with heavy or prolonged bleeding or fatigue (or hair loss or restless leg syndrome or migraines or any other unexplained symptom) should have their iron level tested, which is a ferritin level. It’s also important to check the hemoglobin level, which is how we diagnose anemia., But it’s crucial that women and their health care professionals know that iron deficiency by itself, in the absence of anemia, is a medical condition that requires treatment. A ferritin level of < 30 ng/ml is considered iron deficiency, and the best treatment (oral vs intravenous iron) and any other evaluation that may be needed will depend on the individual circumstance.

New Menopause Hormone Therapy Likely to Enter Phase 3 Testing

There isn’t a new product ready to go here, but I thought it would be interesting to do a short review of what we know about a product that is under investigation. I stumbled across the data awhile back when I was writing about what we know and don’t know about using progesterone vaginally (you can read more about that here).

The product is a vaginal ring with estradiol and progesterone that is changed every 28 days, called DARE-HRT1, and it is under investigation for symptoms of menopause, including genitourinary syndrome of menopause. It’s made by Dare Bioscience Inc. Two different doses of the ring have been studied in phase 1 and phase 1/2 trials: 80 mcg of estradiol with 4 mg of progesterone/day versus 160 mcg estradiol and 8 mg of progesterone/day.

The initial studies show that both rings treat genitourinary syndrome of menopause and improve quality of life, including reducing hot flashes, but the studies are very small and not placebo-controlled, so it’s not really possible to comment on effectiveness, just that it’s worth further study. The lower dose ring produced average estradiol levels of 20.73 pg/ml, which is just in the normal range for the early part of the cycle, although some women had levels that remained below 20 pg/ml (menopause range), and it’s unclear given the study size how that might affect effectiveness. The progesterone levels were 1.19 ng/ml and the paper reports that the average progesterone level in the luteal phase of > 1 ng/ml is associated with ovulation, and so the hypothesis is this level would be sufficient for endometrial protection. The higher dose ring resulted in an average estradiol level of 38.16 pg/ml, and every participant had estradiol levels > 20 pg/ml. Average progesterone levels were 1.89 ng/ml.

The investigators evaluated endometrial thickness with ultrasound to evaluate how the lining of the uterus responded. While the results were reassuring (the thickness of the endometrium was ≤ 4.8 mm for all participants), the studies were short (12 weeks) and endometrial biopsies are needed for safety evaluation.

In 2024 in a Quarter 1 call with investors, Dare Bioscience Inc stated they were preparing for their phase 3 trial, so hopefully that is underway or will be shortly and in a couple of years we can get some higher quality data about this delivery method for progesterone. This is the path of science, and while I probably have beaten this idea to a pulp, this is not the kind of scientific progression we see with supplements for menopause.

I am really interested to see where this goes as more options are good, and given the mood side effects that some women report with progesterone or progestins, it would be great to have a vaginal route where the product is formulated for absorption from the vagina and has been appropriately tested.

References

Harlow, Siobán D. PhD1; Gold, Ellen B. PhD2; Hood, Michelle M. MSc1; Mukwege, Alain A. MD, MSc1; Randolph, John F. MD3; Greendale, Gail A. MD4. Abnormal uterine bleeding is associated with fatigue during the menopause transition. Menopause ():10.1097/GME.0000000000002525, March 11, 2025. | DOI: 10.1097/GME.0000000000002525

Tawfik YMK, Billingsley H, Bhatt AS, Aboelsaad I, Al-Khezi OS, Lutsey PL, Buckley LF. Absolute and Functional Iron Deficiency in the US, 2017-2020. JAMA Netw Open. 2024 Sep 3;7(9):e2433126. doi: 10.1001/jamanetworkopen.2024.33126. Erratum in: JAMA Netw Open. 2024 Oct 1;7(10):e2445802. doi: 10.1001/jamanetworkopen.2024.45802. PMID: 39316402; PMCID: PMC11423176.

Napolitano M, Dolce A, Celenza G, Grandone E, Perilli MG, Siragusa S, Carta G, Orecchioni A, Mariani G. Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses. Ann Hematol. 2014 Apr;93(4):557-63. doi: 10.1007/s00277-013-1901-3. Epub 2013 Sep 19. PMID: 24048634.

Thurman A, Hull ML, Stuckey B, Hatheway J, Zack N, Mauck C, Friend D. A phase 1/2, open-label, parallel group study to evaluate the safety and pharmacokinetics of DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal rings) over 12 weeks in healthy postmenopausal women. Menopause. 2023 Aug 1;30(8):817-823. doi: 10.1097/GME.0000000000002210. Epub 2023 Jun 20. PMID: 37339390; PMCID: PMC10389193.

Thurman A, Hull ML, Stuckey B, Hatheway J, Zack N, Mauck C, Friend D. A phase 1/2, open-label, parallel group study to evaluate the preliminary efficacy and usability DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal RinGSM) over 12 weeks in healthy postmenopausal women. Menopause. 2023 Sep 1;30(9):940-946. doi: 10.1097/GME.0000000000002230. Epub 2023 Aug 7. PMID: 37625088; PMCID: PMC10487358.