Perimenopausal abnormal uterine bleeding

Introduction

Case Vignettes

1. 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.

2. 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.’¹

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).² 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.² Perimenopausal women may experience menstrual irregularities consisting of shortened menstrual cycles and cycles with or without ovulation.³ 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.⁴ 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.

POLYPS. In a cohort of 64 asymptomatic women with a mean age of 44, 16% were observed to have polyps.⁵ Another sample of 112 reproductive-aged women with endometrial polyps followed over almost 2 years indicated that 15% developed AUB.⁶ 

ADENOMYOSIS. 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.⁷ 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.⁸ However, AUB attributed to adenomyosis is usually not amenable to medical management and often requires surgical treatment.

LEIOMYOMATA. 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 45-49.⁹ 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.

MALIGNANCY. The average age at diagnosis for endometrial cancer is 60, and cases are relatively uncommon prior to age 45.¹⁰ 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.

THE OTHER SIDE OF THE COEIN. 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.¹¹ Platelet dysfunction can be present in vWD and immune thrombocytopenia, which has an overall prevalence of 1/10,000, increases in prevalence with age.¹¹ Ovulatory disorders, described above, are relatively common in perimenopausal women. Up to 7% of women have polycystic ovary syndrome (PCOS) and are chronically anovulatory.¹² 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.

Clinical Management

Evaluation and Workup

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.^13,14 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.¹

Figure 3. 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.^15,16

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.^17,18

Treatment

Surveillance

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.¹³

Medical Management

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.¹⁹

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.²⁰ 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.^21,22

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.

Drawbacks include lack of efficacy for hypoestrogenic menopausal symptoms and an increased risk of irregular bleeding patterns.^19,23

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.²² 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.^25,27

Hysteroscopy

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.⁵

Ablation

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.²⁸

However, approximately 20% of women who undergo endometrial ablation will later have a hysterectomy.²⁹ 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.³⁰

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,³² 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.³¹

A recent, randomized, controlled trial of UAE versus MR-focused ultrasound reported similar outcomes, although UAE had a lower rate of reintervention.³³

Hysterectomy

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.³⁴

Case-Based Management Considerations

Case 1

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.

Case 2

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.³⁰

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References

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.

29. Soini T, Rantanen M, Paavonen J, Grénman S, Mäenpää J, Pukkala E, et al. Long-term Follow-up After Endometrial Ablation in Finland: Cancer Risks and Later Hysterectomies. Obstet Gynecol 2017 Sep;130(3):554-60.

30. Endometrial Ablation and Postmenopausal Bleeding. In: Sokol RJ, editor. ACOG Update; 2018; 2018.

31. de Bruijn AM, Ankum WM, Reekers JA, Birnie E, van der Kooij SM, Volkers NA, et al. Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 10-year outcomes from the randomized EMMY trial. Am J Obstet Gynecol 2016 Dec;215(6):745.e1-.e12.

32. Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2014 Dec 26(12):Cd005073.

33. Laughlin-Tommaso S, Barnard EP, AbdElmagied AM, Vaughan LE, Weaver AL, Hesley GK, et al. FIRSTT study: randomized controlled trial of uterine artery embolization vs focused ultrasound surgery. Am J Obstet Gynecol 2019 Feb;220(2):174.e1-.e13.

34. Louie M, Strassle PD, Moulder JK, Dizon AM, Schiff LD, Carey ET. Uterine weight and complications after abdominal, laparoscopic, and vaginal hysterectomy. Am J Obstet Gynecol 2018 Nov;219(5):480.e1-.e8.