Nanette Santoro, MD is professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado School of Medicine in Aurora, Colo.

Nanette Santoro, MD

Perimenopausal bleeding can be due to structural causes (polyps, adenomyosis, leiomyomas, malignancy) or non-structural causes (coagulopathy, ovulatory dysfunction, endometrial factors, iatrogenic, or “not otherwise classified”.) Malignancy and ovulatory dysfunction in particular are more common in this population.

Initial evaluation includes history & physical, ultrasound, and possible saline infusion sonohysterography or endometrial biopsy.

Hormonal treatments can be used, just as with premenopausal women, but more frequent comorbidities and a possible need to transition to hormone replacement therapy may influence the choice of treatment. Newer oral GnRH analogues may be useful as well.

Procedures such as hysteroscopic polypectomy, endometrial ablation, and uterine artery embolization can be considered when hormones are not helpful or contraindicated, though ablation in particular can make later evaluation of the endometrium challenging.

Hysterectomy remains a reasonable choice for women who have failed more conservative management.

 A 48-year-old woman reports that her menstrual cycles have gone from a mean of 30 days to 25 days, and her menstrual periods have lengthened to 10 days from 5 days, with intermittent very heavy bleeding (more than 2 pads or tampons per hour for more than 4 hours) and staining of her bedsheets with blood. She does not report cramping in association with bleeding. On examination, her uterus is irregular and 10 weeks’ size. A pelvic ultrasound indicates 2 fibroids, both 4-5 cm in mean diameter. One is clearly intramural and the second fibroid appears to be encroaching on the endometrial stripe, which is irregular and 8mm in largest thickness. Ovaries appear normal-sized with an antral follicle count of 7.

A 52-year-old woman who had an endometrial ablation at age 45 for menorrhagia presents with irregular spotting for the past 3 months. She reports some cramping in association with her spotting, along with a dull ache in her left lower quadrant. Her pelvic examination is negative and an ultrasound indicates an irregular endometrium with ‘skip areas’. The thickest portion of the endometrium that can be identified in sagittal section is 3mm. The remainder of her ultrasound examination is within normal limits.

Prevalence and causes of abnormal uterine bleeding

Perimenopausal bleeding is challenging to define because distinguishing normal from abnormal uterine bleeding (AUB) during a time in life when a woman’s menstrual cycles are dynamically changing requires an extra degree of clinical acumen and attention. The American College of Obstetricians and Gynecologists (ACOG) defines AUB as: ‘bleeding from the uterine corpus that is abnormal in its regularity, volume, frequency or duration and is not associated with pregnancy.’

This entity is further separated into acute AUB, which requires immediate assessment of the patient’s hemodynamic stability and consideration of acute management modalities, and chronic AUB, which is defined as AUB that is present for most of the past 6 months. Regardless of acute or chronic nature, the differential diagnosis is the same and the PALM-COEIN diagnostic has been adopted by ACOG as a preferred classification system (Figure 1).

 The ‘PALM’ refers to uterine structural abnormalities and the ‘COEIN’ refers to conditions unrelated to structural abnormalities of the uterus. It is assumed that pregnancy has been excluded once PALM-COEIN has been invoked as a diagnostic tool.

Figure 1. The PALM-COEIN system is used to classify causes of abnormal bleeding in nonpregnant premenopausal women. 

First described in FIGO Working Group on Menstrual Disorders. Int J Gynaecol Obstet 2011; 113:3-13.

The prevalence of AUB is 3-30%, with higher prevalences clustering at the extremes of reproductive life—perimenarche and perimenopause.

Perimenopausal women may experience menstrual irregularities consisting of shortened menstrual cycles and cycles with or without ovulation.

 Both short (<21 days) and long (>36 days) cycles are associated with anovulatory patterns of progesterone secretion. Anovulatory cycles are more likely to be associated with spotting. Some shortened menstrual cycles are the result of the so-called LOOP—luteal-out-of-phase phenomenon, in which folliculogenesis begins during the luteal phase preceding menses.

 Anovulatory cycles have been associated with heavier bleeding that is typically sporadic but may be acute. Thus, some AUB in the perimenopause may be physiologic. Structural lesions of the uterus (PALM) such as polyps, adenomyosis, leiomyomata, and malignancy are not uncommon in women in the perimenopausal years.

 In a cohort of 64 asymptomatic women with a mean age of 44, 16% were observed to have polyps.

 Another sample of 112 reproductive-aged women with endometrial polyps followed over almost 2 years indicated that 15% developed AUB.

 Adenomyosis has a prevalence ranging from 5-70%; however, 70-80% of women who undergo hysterectomy for adenomyosis are in the 4th-5th decade of life.

 Thus, adenomyosis appears to cause the most symptoms around perimenopause. Some argue that adenomyosis, present in 48% of hysterectomy specimens, is not necessarily associated with bleeding and may be a normal variant and not a disease.

 However, AUB attributed to adenomyosis is usually not amenable to medical management and often requires surgical treatment.

 In a population-based sample of 650,000 U.S. women age 18-65 in the Kaiser Permanente Washington system, 15.9% of women aged 50-54 had leiomyomata, the highest prevalence in the sample; peak incidence rates were at ages 45-49.

 These numbers align with the sample of de Waay, et al, in which 23% of women had leiomyomata by ultrasound.5 The growth rate of leiomyomata was faster in premenopausal women and slower in women who were closer to their final menstrual period.

 The average age at diagnosis for endometrial cancer is 60, and cases are relatively uncommon prior to age 45.

 Clinically, it is recommended that perimenopausal women with AUB be screened with endometrial sampling to rule out cancer (see below). Since bleeding patterns are inherently irregular for perimenopausal women, and dysfunctional uterine bleeding due to anovulation can cause isolated episodes of heavy bleeding, many women undergo endometrial sampling but very few will actually have hyperplasia or cancer. Risk factors for endometrial cancer are provided in Table 1.

 Coagulopathies are usually diagnosed earlier in life; however, perimenopausal women can acquire them. Von Willebrand’s Disease (vWD) is present in 1% of women, and 95% of women with vWD report heavy menstrual bleeding.

 Platelet dysfunction can be present in vWD and immune thrombocytopenia, which has an overall prevalence of 1/10,000, increases in prevalence with age.

Ovulatory disorders, described above, are relatively common in perimenopausal women. Up to 7% of women have polycystic ovary syndrome (PCOS) and are chronically anovulatory.

 Endometrial causes include chronic endometritis. 

Figure 2. Ovarian Follicles at Various Stages of Development.

Primordial follicles are the reserve pool from which all other follicles are derived. Preantral follicles are unresponsive to follicle-stimulating hormone (FSH) and do not produce appreciable amounts of inhibin or estradiol and therefore do not exert negative feedback upon FSH. When follicles reach the antral stage, they are visible on ultrasonography. This is the beginning of follicular negative feedback upon FSH, which influences the number of follicles that grow to achieve preovulatory status. Beyond the use of ultrasonography to quantify antral follicles, serum estradiol and (less commonly) inhibin levels can be measured. FSH can also be used as an indirect measure of the number of large follicles; here, elevated FSH results when antral follicles are diminished in number, and negative feedback is reduced. Because cycle-to-cycle variation in the number of antral follicles present in the ovary can occur, FSH levels vary cycle-to-cycle (depending on the number of antral follicles). Measurement of circulating serum antimüllerian hormone (AMH) is used to estimate the population of small growing preantral follicles. AMH levels also reflect the largest fraction of the follicle pool that can currently be measured. From Diagnosing the Onset of Menopause, JAMA 2019; 32(8):775-776. Reprinted with permission from JAMA.

The true prevalence of chronic endometritis and its histologic definition are not well established, but the diagnosis should be suspected in women with intermenstrual bleeding and overall mild symptoms. Other forms of endometrial dysfunction and failure of the normal hemostatic mechanisms that allow menses to stop are poorly understood but seem to be responsible for some cases of AUB in the perimenopause. 

Therapeutic anticoagulation and chemotherapy-associated thrombocytopenia are potential iatrogenic causes of AUB, as are any type of exogenous hormone therapy that can cause breakthrough bleeding. Some medications also can interfere with normal menstrual cycling, such as dopamine antagonists, and result in acyclic, anovulatory bleeding (but more often cause oligomenorrhea). 

Finally, a category of ‘Not Otherwise Classified’ disorders are responsible for the remainder of cases. These latter conditions are rare but can include bleeding from Cesarean scar related uterine diverticula, which accumulate blood and sporadically cause spotting.

Discussion of patient history should include review of the patient’s bleeding pattern, contraceptive use, risk factors for endometrial cancer, medical problems, personal or family history of underlying bleeding disorders, and current medications. 

Physical exam should include speculum and bimanual exams and thyroid exam. Laboratory testing may include a complete blood count, pregnancy testing, coagulation studies, assessment for bleeding disorders such as vWD, and thyroid screening.

Patients with acute bleeding who are hemodynamically unstable require surgical management or high-dose estrogen treatment and will not be discussed further in this review.

 Approach to management of abnormal uterine bleeding in perimenopausal patients. After ruling out underlying medical disorders and pathology requiring surgical intervention, management should incorporate need for contraception and patient preferences.

Structural causes of bleeding are best assessed with ultrasound, which may also guide the need for endometrial sampling to evaluate for hyperplasia or malignancy. If possible, ultrasound performed 4-6 days after onset of bleeding will yield maximum information about the endometrium. If the endometrial stripe is irregular or not clearly identified, sonohysterography can help distinguish between global and focal changes. 

Generally, endometrial sampling should be performed in women over 45 years old with AUB, and those younger than 45 with a history of unopposed estrogen exposure, risk factors for endometrial cancer, or failed medical management. Significant focal pathology, such as polyps or submucosal myomas, will likely be missed by a blind endometrial biopsy. Hysteroscopy may be indicated in selected cases when focal disease is strongly suspected or visualized on ultrasound; however, it is more expensive and invasive.

Evaluation of the likely time until menopause can be helpful when discussing treatment options. Women who are close to menopause may prefer temporizing medical management to avoid surgery, while those for whom menopause is more distant may prioritize efficacy over limiting invasive procedures. 

An anti-Mullerian hormone (AMH) level >200 ng/mL makes menopause highly unlikely within the next five years, regardless of a woman’s age, whereas a very low AMH level predicts menopause in next year with a positive predictive value ranging from 51% at <48 years of age to 79% at ³51 years of age.

If hyperplasia and malignancy have been ruled out, and the patient is not anemic, reassurance and surveillance are sufficient if the bleeding pattern is not too bothersome.

Hormonal treatments are the mainstay of medical management for AUB, and many simultaneously provide reliable contraception.

Combined hormonal contraceptives (including pills, vaginal ring, and patches) are effective for managing many etiologies of AUB and will alleviate vasomotor symptoms and vaginal dryness associated with perimenopause, particularly with extended or continuous dosing.

Furthermore, they reduce the risk of endometrial and ovarian cancers and can maintain or improve bone mineral density. 

However, estrogen-containing hormonal contraceptives increase risk of thrombotic stroke and myocardial infarction, both of which increase in terms of background risk with age.

 Older reproductive-aged women are also more likely to have medical comorbidities including hypertension, obesity, diabetes, and cardiac disease that may contraindicate the use of contraceptive doses of estrogen.

Progestin-only methods have fewer contraindications and risks than estrogen-containing methods while still providing excellent contraception. 

These include progestin-only pills, injectables (depot medroxyprogesterone acetate), etonogestrel-containing implants, and the levonorgestrel intrauterine system (LNG-IUS). The LNG-IUS and POPs can also be continued into menopause to provide endometrial protection for women using estrogen to treat menopausal symptoms. 

Early age at menarche and late age at menopause

Estrogen secreting tumors of the ovary (granulosa tumors)

Personal prior history of epithelial cancers of breast or ovary

Family history of endometrial or epithelial cancers of the colon, breast, or ovary

Unopposed estrogen or certain SERM use (i.e., tamoxifen)

www.cancer.org/cancer/endometrial-cancer/about/key-statistics

Drawbacks include lack of efficacy for hypoestrogenic menopausal symptoms and an increased risk of irregular bleeding patterns.

The timing of discontinuing hormonal contraception in perimenopausal women is not straightforward. Women using LNG-IUS or etonogestrel-containing implants may experience amenorrhea prior to menopause, and women using combined hormonal contraception can experience withdrawal bleeding even after menopause. 

Discontinuing hormonal treatment to assess for 12 months of amenorrhea, which defines a woman as menopausal, leaves that woman at risk of unwanted pregnancy. 

For women using combined hormonal contraceptives, an age-based shared decision on when to stop can be used, taking into account the woman’s family history. Use of AMH17, 24 or FSH (³30 IU/l on two occasions 6-8 weeks apart, measured 7-14 days after discontinuation of hormones) have been described, but these biochemical methods have not been validated in large, diverse populations of women and therefore cannot be considered definitive.

 Women using LNG-IUS can start hormone replacement therapy (HRT) as needed while continuing use of the IUS.

Gonadotropin-releasing hormone (GnRH) analogues can induce a hypogonadal state that leads to endometrial atrophy. 

Agonists are available in injectable form (leuprolide acetate) and newer, orally active antagonists (elagolix) have recently been FDA approved for use in women with endometriosis. Long-term use of these compounds is limited by hypoestrogenic side effects including bone loss, vasomotor symptoms, and vaginal atrophy, but they can be useful in bridging women to menopause. 

“Add-back” therapy with low-dose norethindrone and estrogen can minimize side effects and bone demineralization. Elagolix is now available in a combined capsule with estradiol 1mg and norethindrone acetate 0.5mg.25,26 It is FDA approved for women with uterine fibroids who have excessively heavy bleeding.

For women with contraindications or objections to hormonal therapy, scheduled NSAIDs or tranexamic acid can significantly reduce menstrual blood loss.

Uterine polyps and submucosal fibroids can usually be effectively and efficiently treated with hysteroscopic removal. Incomplete removal and regrowth can cause recurrent bleeding. 

Polyps have been reported to have a cumulative incidence rate as high as 12% per year; thus, recurrent AUB in a woman previously treated for polyps should be managed proactively.

Endometrial ablation or resection provides a significant reduction in bleeding for many women, with a shorter recovery time and quicker return to work than hysterectomy, and comparable patient satisfaction rates.

However, approximately 20% of women who undergo endometrial ablation will later have a hysterectomy.

 Ablation makes later evaluation of the endometrium challenging and sometimes impossible, leaving women at risk of postmenopausal bleeding that cannot be adequately evaluated as well as endometrial cancers that present late due to lack of bleeding.

Uterine Artery Embolization (UAE) and Focused Ultrasound

UAE is an interventional radiology procedure by which the uterine arteries are occluded, with the aim of causing fibroid necrosis. UAE is associated with a shorter hospital stay and quicker return to full activity, but an increased risk of minor complications compared to hysterectomy,

 and had comparable satisfaction and quality of life scores in a randomized study. 

Among those who underwent UAE, 24% had a hysterectomy by the 5th postoperative year and 35% by the 10th.

A recent, randomized, controlled trial of UAE versus MR-focused ultrasound reported similar outcomes, although UAE had a lower rate of reintervention.

While hysterectomy is the definitive treatment for abnormal bleeding, it carries an approximately 8% risk of complications, so it is best reserved for patients who have failed conservative management.

This patient’s changing bleeding pattern may be partially attributed to her perimenopausal status, but there is likely a contribution from her fibroids. Progesterone-only pills such as norethindrone may decrease her bleeding, although fibroids may grow and she is at risk of both hypoestrogenism with menopausal symptoms and an irregular bleeding pattern. 

DMPA or etonogestrel implant would offer contraception but could have more pronounced hypoestrogenic side effects and irregular bleeding than pills. 

Combined estrogen-progesterone methods may have a better bleeding profile, providing she has no contraindications. If her uterine cavity is not significantly distorted, an LNG-IUD can offer bleeding control and contraception with less risk of hypoestrogenism. 

The new combination of elagolix and low dose estradiol with norethindrone may provide bleeding control and bridge the patient to menopause. Prior to considering a hysterectomy, UAE is another potential non-surgical option.

A crucial first step for this patient is assessing her menopausal status. If she is not yet menopausal, it is reasonable to observe her. 

However, if she is postmenopausal or menopausal status is unclear, an endometrial evaluation is needed. There is no “normal” endometrial thickness for a post-ablation uterus, therefore ultrasound alone is not sufficient. 

Endometrial biopsy via Pipelle catheter can be attempted, but is often unsuccessful, and may not evaluate the whole uterine cavity. Hysteroscopy with directed biopsies is the best choice for sampling but may be difficult due to obstructive scarring. If the entire cavity cannot be visualized, a hysterectomy must be considered.

1. ACOG. Committee Opinion 557: Management of Acute Abnormal Uterine Bleeding in Nonpregnant Reproductive-Aged Women. Obstet Gynecol 2013 Apr;121(4):891-6.

2. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet 2011 Apr;113(1):3-13.

3. Van Voorhis BJ, Santoro N, Harlow S, Crawford SL, Randolph J. The relationship of bleeding patterns to daily reproductive hormones in women approaching menopause. Obstet Gynecol 2008 Jul;112(1):101-8.

4. Hale GE, Hughes CL, Burger HG, Robertson DM, Fraser IS. Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition. Menopause 2009 Jan-Feb;16(1):50-9.

5. DeWaay DJ, Syrop CH, Nygaard IE, Davis WA, Van Voorhis BJ. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002 Jul;100(1):3-7.

6. Wong M, Crnobrnja B, Liberale V, Dharmarajah K, Widschwendter M, Jurkovic D. The natural history of endometrial polyps. Hum Reprod 2017 Feb;32(2):340-5.

7. Taran FA, Stewart EA, Brucker S. Adenomyosis: Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy. Geburtshilfe Frauenheilkd 2013 Sep;73(9):924-31.

8. Weiss G, Maseelall P, Schott LL, Brockwell SE, Schocken M, Johnston JM. Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN). Fertil Steril 2009 Jan;91(1):201-6.

9. Yu O, Scholes D, Schulze-Rath R, Grafton J, Hansen K, Reed SD. A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014. Am J Obstet Gynecol 2018 Dec;219(6):591.e1-.e8.

10. American Cancer Society. Facts & Figures 2020. https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics. Accessed August 2020.

11. Centers for Disease Control and Prevention. Data and Statistics on von Willebrand Disease. https://www.cdc.gov/ncbddd/vwd/data.html. Accessed August 2020.

12. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004 Jun;89(6):2745-9.

13. Goldstein SR, Lumsden MA. Abnormal uterine bleeding in perimenopause. Climacteric 2017 Oct;20(5):414-20.

14. Delamater L, Santoro N. Management of the Perimenopause. Clin Obstet Gynecol 2018 Sep;61(3):419-32.

15. Goldstein SR, Zeltser I, Horan CK, Snyder JR, Schwartz LB. Ultrasonography-based triage for perimenopausal patients with abnormal uterine bleeding. Am J Obstet Gynecol 1997 Jul;177(1):102-8.

16. ACOG. Practice Bulletin 128: Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women. Obstet Gynecol 2012 Jul;120(1):197-206.

17. Finkelstein JS, Lee H, Karlamangla A, Neer RM, Sluss PM, Burnett-Bowie SM, et al. Antimullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women's Health Across the Nation. J Clin Endocrinol Metab 2020 Apr 1;105(4):e1862-71.

18. Santoro N. Using Antimüllerian Hormone to Predict Fertility. Jama 2017 Oct 10;318(14):1333-4.

19. Long ME, Faubion SS, MacLaughlin KL, Pruthi S, Casey PM. Contraception and hormonal management in the perimenopause. J Womens Health (Larchmt) 2015 Jan;24(1):3-10.

20. Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012 Jun 14;366(24):2257-66.

21. Curtis KM, Jatlaoui TC, Tepper NK, Zapata LB, Horton LG, Jamieson DJ, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 2016 Jul 29;65(4):1-66.

22. Baldwin MK, Jensen JT. Contraception during the perimenopause. Maturitas 2013 Nov;76(3):235-42.

23. Sitruk-Ware R. The levonorgestrel intrauterine system for use in peri- and postmenopausal women. Contraception 2007 Jun;75(6 Suppl):S155-60.

24. Santoro N, Johnson J. Diagnosing the Onset of Menopause. Jama 2019 Jul 22.

25. Bradley LD, Gueye NA. The medical management of abnormal uterine bleeding in reproductive-aged women. Am J Obstet Gynecol 2016 Jan;214(1):31-44.

26. Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, Barnhart KT, Bradley LD, et al. Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids. N Engl J Med 2020 Jan 23;382(4):328-40.

27. Bofill Rodriguez M, Lethaby A, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2019 Sep 19;9(9):Cd000400.

28. Fergusson RJ, Bofill Rodriguez M, Lethaby A, Farquhar C. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev 2019 Aug 29;8(8):Cd000329.

Articles

The challenge of diagnosis occurs in distinguishing “normal” from “abnormal” in a time of rapid and dynamic change.  

Perimenopausal abnormal uterine bleeding

The path that led to American women favoring compounded bioidentical hormone therapy (cBHT) is rooted in several important historical factors. The Dietary Supplement Health and Education Act of 1994 specifically exempted compounded hormones from being considered pharmaceuticals; instead, they were put into the same category as dietary supplements. 

This designation requires far less rigor in terms of quality control, no need for adverse event reporting, and carries no requirements for potential conflicts of interest disclosures. Penalties for false advertising are rare.

In 2002, the Women’s Health Initiative (WHI) showed that estrogen and progesterone were ineffective as preventives for cardiovascular disease for women and confirmed that ‘conventional’, FDA-approved forms of hormone therapy carried health risks. 

Overall, hormone therapy caused net harm or gave no benefit to most of the women who had been taking it for treatment other than for symptoms.

 As a result, millions of women abruptly abandoned their hormone therapy. Many doctors who had prescribed it for preventive purposes were loath to accept the WHI data. 

The information gap was filled by cBHT. Because cBHT products were now dietary supplements, they were not subject to FDA approval; they had no restraints on proof of claim or efficacy and had no adverse event reporting requirements. 

Moreover, the claim that cBHT, which contained ‘natural’ –as opposed to ‘synthetic’ hormones used in research trials such as the WHI—developed great resonance in the consumer sphere. 

The concept that naturally occurring hormones were harmless began to be promulgated and provided women with a new, alternative treatment that seemed to be superior.

Although many naturally occurring hormone products got approved by the FDA during and immediately after the WHI and rapidly became widely available, 

the cBHT industry effectively used internet-based marketing and repetition of partial truths to garner a significant portion of the dwindling hormone therapy market. 

The mythology that the hormones used in the WHI were simply the 

hormones, and alternative cBHT products had no such side effects or risks and would, indeed, prevent aging, was widely and successfully marketed such that current estimates are that one-third to half of the national use of menopausal hormone therapy is cBHT.

‘Natural’ hormones have become highly desired by consumers, and are incorrectly viewed as without risk, in comparison to FDA-approved ‘synthetics’ used in many research trials.

Many cBHT prescribers and compounders have financial interest in prescribing and continuing therapy. 

Consumers may be recommended to use a proprietary cBHT formulation as well as a panel of ‘customized’ proprietary blood or saliva tests to follow hormone levels, with no requirement for patient disclosure. Prescribing proprietary cBHT preparations for a profit creates an overt conflict of interest and may violate professional ethics.

Due to several concerns raised by these ongoing practices, the National Academies of Sciences, Engineering, and Medicine (NASEM)

 of the field, gathering data and taking in-person testimony from pharmacists, practitioners, and patients. 

Their recommendations recently have been released and are supported by the North American Menopause Society (NAMS).

The chief recommendations relevant to many ob/gyns are summarized below and offer an excellent starting point to rein in potentially harmful medical practice in our field.

1. Review select bioidentical hormone therapies and dosage forms as candidates for the FDA Difficult to Compound list.

Drugs considered ‘difficult to compound’ are defined as “drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs.”

The NASEM report suggests the Pharmacy Compounding Advisory Committee (PCAC) review the following cBHT hormones as candidates for this list: estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, testosterone cypionate, and testosterone propionate. They also recommend that all cBHT in pellet form be added to this list.

The six criteria presented to the PCAC for evaluating whether a drug product or category of drug products is demonstrably difficult to compound are complexity of the:

The ‘difficult to compound’ designation prevents compounding pharmacies from making cBHT products unless they are listed as a manufacturer. 

This recommendation is the first step towards improved quality control

, which is important for cBHT as these commonly used preparations have a dearth of data specifically related to bioavailability and product-to-product variability given drug formulations differ and quality control varies from formulation to formulation in currently unknown ways.

2. Improve education for prescribers and pharmacists who market, prescribe, compound, and dispense cBHT preparations.

NASEM recommends that State medical boards and professional medical societies advocate for state-level certification for those who want to begin or continue prescribing. 

Additionally, professional societies (AMA, NAMS) that are not-for-profit could help establish evidence-based recommendations and guidelines. Education from industry is discouraged. Education would include identification of safe formulations and contraindications to treatment, description of conflicts of interest, and reasoning for when to consider cBHT over FDA-approved products.

Related: Hear from Dr. Santoro as she discusses highlights from the 2020 North American Menopause Society (NAMS) Annual Meeting.

Although prescribers are responding to patient demand, this does not supersede practice informed by evidence. Given this breach in obligation to patient safety, it is possible that prescribers could face consequences including invalidation of malpractice insurance, personal liability, or possible criminal charges.

3. Additional federal and state-level oversight should be implemented to better ad

dress public health and clinical concerns regarding the safety and effectiveness of compounded cBHT.

The report calls on the National Association of Boards of Pharmacy (NABP) and state boards of pharmacy to expand and improve oversight and standardization. 

Among the most significant suggested measure is that cBHT products include an insert containing critical details about the preparation, including active ingredients and a statement that the preparation is not FDA approved and therefore lacks the rigorous dosage, safety and efficacy data required by the FDA. 

Pharmacies are called upon to disclose their good manufacturing practices or United States Pharmacopeia (USP) designation and to include contact information for the pharmacy and those responsible for quality and safety.

Boxed warnings for adverse effects identical to that required for FDA-approved estrogens, androgens and progestins was recommended. Pharmacies providing cBHT were also called upon to create a robust methodology for 

 of adverse events, as well as make that information available to the public. 

There is no current insight into the prevalence of such events as they are not reported or available to the consumer. NASEM calls for required adverse event reporting of cBHT to state boards of pharmacy as well as to MedWatch and the FDA Adverse Event Reporting System. 

This would allow states to respond to these issues locally.

Lastly, all states should adopt USP standards to meet minimum quality standards for sterile and non-sterile cBHT preparations.

4. Collect and disclose conflicts of interest.

cBHT is often sold directly by the prescriber, which violates professional ethical conduct and is a clear example of a conflict of interest (COI).

Many providers of cBHT are physicians and advanced practice providers with credentials that patients believe to mean that they are well informed and practicing safe medicine. 

Disclosures of COI should be publicly available and disclosed to patients at the point of care. 

NASEM also recommends that state licensing boards collect and make public financial relationships so that these COIs are easily accessible to all consumers.

5. Strengthen and expand the evidence base on the safety, effectiveness, and use of cBHT preparations.

NASEM calls for increased engagement in research to generate a comprehensive evidence base for cBHT use. Assuming patient interest is here to stay, we need to provide consumers with the 

same breadth of safety data and industry accountability 

This goal will require funding and clinical research with high-quality trials, generation of bioavailability data of active ingredients, and adverse event reporting. These trials should be approved and registered by the Institutional Review Board (IRB).

6. Restrict the use of cBHT preparations.

There are select scenarios in which compounding is helpful. Some people may have an allergy to an active ingredient in all possible appropriate FDA approved formulations, and this is the most common reason to use compounded drugs in all categories. 

Other users may also require a dosage unavailable via FDA approved formulation. cBHT use should be limited to these select scenarios. 

, it should be made clear that compounded formulations are not FDA approved and thus have limited safety and efficacy data. 

patient preference alone should not be a reason to prescribe cBHT

. We understand there is patient demand, but educated decision making and doing no harm must take precedence.

The 350-page NASEM report recommends long-overdue measures that will protect consumers from unsafe health outcomes. 

Prescribers and pharmacies alike have a duty to provide the safest treatments, and to do so requires significantly more data and regulation than is currently present. 

Without evidence, oversight, and reporting systems in place,

 patients are poorly equipped to make informed and safe decisions. “When statements about cBHT are inaccurate or misleading, informed consent cannot take place.”

All healthcare providers take an oath to do no harm, but without more education, data, oversight, and patient education, harm is not only possible but likely. 

 and NASEM provides excellent recommendations to help us to take steps in the right direction.

DR. LISS is an assistant professor of obstetrics and gynecology at the University of Colorado Denver School of Medicine. She also is the OB/GYN Clerkship Director.

DR. SANTORO is professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado School of Medicine in Aurora, Colo.

Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. 

Rosenthal, MS. Ethical problems with bioidentical hormone therapy. 

National Academies of Sciences, Engineering, and Medicine 2020. 

The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. 

Washington, DC: The National Academies Press. https://doi.org/10.17226/25791.

The North American Menopause Society. NAMS Applauds NASEM Efforts on Compounded Bioidentical Hormone Therapy. Accessed July 13, 2020. Menopause.org

Federal Register. Public docket on Drug Products That Present Demonstrable Difficulties for Compounding Under the Federal Food, Drug and Cosmetic Act. Accessed Sept. 11, 2020. 

The compounded bioidentical hormone industry needs major changes in oversight to keep consumers safe.

Stand firm with science

Most women who traverse menopause experience significant symptoms and many require at least temporary pharmacological treatment for maintenance of quality of life. Despite the controversy surrounding it, hormone therapy (HT) with either estrogen alone (E) or estrogen plus progestin (E+P) remains the most effective treatment for menopausal symptoms. This article provides a brief history of menopausal hormone therapy (HT) and discusses practical aspects of treatment and discontinuation.


	HT has had a cyclical history of high acceptance and uptake, followed by reduced use related to emergence of risk. Its efficacy for symptoms was recognized in the 1950s and 1960s.

 Shortly thereafter, increased risk of endometrial cancer associated with E preparations was followed by the addition of progestin to regimens for women with a uterus, and a transient reduction in enthusiasm for HT.

In the 1980s, the strong observational association between hormone use and reduced risk of coronary heart disease (CHD)

 led to exploration of systemic benefits of HT beyond symptom relief, which triggered another surge in use. However, when the effectiveness of HT as a preventive medication was tested in a randomized clinical trial, the 

(WHI), there was no observed reduction in CHD in women with or without a uterus, and a small signal for initial harm emerged, with differential risks depending upon whether a woman had a uterus and was randomized to E+P or had a hysterectomy and therefore took E Alone (Table 1).

 Differences in treatment with E+P compared to E alone reveal an elevated risk of CHD, venous thromboembolism (VTE), breast cancer in the E+P arm and no risk for breast cancer in the E-only arm (Table 1). The association between breast cancer in the E+P arm was further corroborated by an 11-year follow-up study among participants of the WHI study, which demonstrated a small increase in breast cancer incidence (HR, 1.25 [95%CI 1.07-1.46; 

 = 0.004]) and mortality (HR, 1.96 [95%CI: 1.00-4.04, 

 After publication of these findings, HT prescriptions dropped by 32% overall with a > 60% drop in prescriptions for conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA).

Based upon these findings, HT is not recommended for preventive use by 

The American College of Obstetricians and Gynecologists

Hormonal therapy is not without controversy but it is still one of the most effective treatments for patients with symptoms.

Nanette Santoro, MD

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