Addressing the perimenopause: what’s blood got to do with it?

Abstract

A state of the art lecture titled, “Addressing the Perimenopause: What’s Blood Got to Do with It?” was presented at the International Society on Haemostasis and Thrombosis (ISTH) Congress in 2024. Perimenopause is when fluctuations of previously cyclically regulated hormones occur prior to menopause, resulting in a number of symptoms that can negatively impact a woman’s quality of life. Thrombosis and hemostasis experts are often approached to help investigate and manage clinical issues associated with perimenopause. This includes the safety of using menopause hormonal therapy in a past history or family history of venous thromboembolism, arterial thrombosis or thrombophilia, heavy menstrual bleeding, and iron deficiency anemia. A review of recent literature and clinical practice guidelines was undertaken to help determine the role of iron deficiency anemia in perimenopause, thrombotic risk in the setting of using menopause hormonal therapy, and indications for thrombophilia testing prior to commencing menopause hormonal therapy. Finally, we summarize relevant new data on this topic presented during the ISTH 2024 Congress.

1. Introduction

Perimenopause is the time when a woman transitions to menopause. Menopause is defined as not having a menstrual period for 12 months and marks the end of a woman’s reproductive years [1]. It usually commences when women are in their mid to late forties and can last a few months up to 10 years in duration. The Stages of Reproductive Workshop nomenclature describes the beginning of perimenopause when there are persistently different cycle lengths of 7 or more days between consecutive cycles until 12 months after the last menstrual period [2]. This means that perimenopausal women can have normal to elevated follicular stimulating hormone (FSH) levels but fluctuations of estrogen, progesterone, and testosterone, causing multiorgan effects. These effects include irregular heavy menstrual cycles, brain fog, impaired cognitive function, hot flashes, mood changes (including depressed mood and anxiety), insomnia, fatigue, low libido, vaginal dryness, and dyspareunia (Figure 1) [3,4]. These symptoms are experienced by 75% of women during perimenopause and menopause and can impact heavily on a woman’s quality of life. Brain fog impacts women’s function in the workplace and causes reduced ability to undertake everyday tasks. Irritability and mood swings negatively impact personal relationships. Weight gain and fatigue impact energy levels, self-esteem, and mood. Vaginal dryness and dyspareunia can impact libido and intimacy [1]. There is a perception that as women enter menopause and stop reproducing, their place and status in society diminish [5]. Research to date has focused on menopausal women. There is growing recognition that perimenopause can be fraught for many women. Symptom overlap with menopause is common, and treating perimenopausal symptoms can significantly improve quality of life.

Figure 1.

Hormone fluctuations in perimenopause. Women transition from having a regular menstrual period with cyclical fluctuations of estrogen, progesterone, and follicle-stimulating hormone to irregular hormonal fluctuations where menstrual periods become irregular. Over time, a reduction in follicles needing stimulation results in estrogen levels declining. Reduced estrogen levels result in an increase in FSH as there is not enough estrogen production to “switch off” FSH production. Menopause is defined as no menstrual period for 12 months and is characterized by low estrogen levels and elevated FSH levels.

In perimenopause, the follicle pool and ovarian reserve decrease. This causes a reduced production of inhibin B by follicular granulosa cells. This results in a gradual increase in FSH. These hormones are controlled by regulatory feedback mechanisms within the hypothalamus and pituitary. Research undertaken has shown that as women transition to menopause, their brains go through a “renovation” process. A shift in function occurs away from monthly preparation for potential conception and pregnancy [6]. Why, then, do hemostasis and thrombosis experts get asked to help manage these women?

Perimenopausal women can present with clinical dilemmas requiring hemostasis and thrombosis expertise. We present a clinical case highlighting management issues, including (i) investigating and managing heavy menstrual bleeding, (ii) iron deficiency anemia and symptom overlap with perimenopause, (iii) thrombotic risk with menopause hormonal therapy (MHT), and (iv) managing women at increased risk of venous thromboembolism (VTE) wishing to control perimenopause symptoms with MHT. In this article, the term “women” refers to cisgender women. Trans- and gender-diverse people can also experience perimenopausal symptoms and may benefit from appropriately tailored health services.

2. Case Presentation

A 47-year-old woman with 2 previous pregnancies via in vitro fertilization was referred by her general practitioner with refractory iron deficiency anemia despite oral iron therapy (Ferro-grad-C) 1 tablet daily for 3 months. She complains of fatigue, shortness of breath, palpitations, muscle aches, hot flashes, insomnia, brain fog, and depressed mood. She has 2 further frozen embryos, but she and her husband are uncertain if they have completed their family. Her fertility specialist undertook thrombophilia testing; however, the indication for testing was unclear. She is known to be heterozygous for factor (F)V Leiden and has no family history of VTE. She has been on an oral contraceptive pill for 10 years prior to undertaking in vitro fertilization. In both pregnancies, she birthed via cesarean section, and both were complicated by postpartum hemorrhage. She has had no other previous surgery. Her menses were previously “ok,” but over the past 12 months, they have become “erratic,” with her cycles changing from 21 to 32 days in length and are much heavier, requiring her to change a sanitary napkin every 1 to 2 hours. She is passing clots 2 to 3 cm in diameter and occasionally flooding overnight. She is not vegetarian and does not have any other history of blood loss. Subsequent investigations undertaken show a full blood examination with hemoglobin of 105 g/L (range, 115-135 g/L) and ferritin of 7 mcg/L (range, 30-160 mcg/L) with changes consistent with marked iron deficiency anemia. Her other parameters are within the normal range. A pelvic ultrasound reveals a previously undiagnosed large 8 cm submucosal fibroid.

3. Investigating and Managing Heavy Menstrual Bleeding in Perimenopausal Patients

Women who present with heavy menstrual bleeding in perimenopause require the following considerations: (i) determining an etiology, (ii) managing symptoms of heavy menstrual bleeding, and (iii) treating the underlying etiology. Investigating an etiology should happen in parallel to managing symptoms of heavy menstrual bleeding. Once hemodynamically stable, etiologies that may be causing heavy menstrual bleeding need to be investigated. The PALM–COEIN acronym (Polyps, Adenomyosis, Leiomyoma [uterine fibroids], Malignancy—Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not otherwise specified, eg, atriovenous malformation) offers a systematic approach (see Table) to exclude structural and nonstructural pathology for abnormal uterine bleeding [7]. The most common reason for heavy menstrual bleeding in this age bracket of women is leiomyomas—fibroids. By the age of 50, 70% of Caucasian women and >80% of African American women will have developed at least 1 fibroid [8]. Studies show that fibroids have a systemic effect on the endometrium as opposed to the localized effect that was once postulated [8]. When greater than 10 cm in size, fibroids also significantly increase the risk of VTE through localized pelvic venous compression and increased stasis [9]. It is also postulated that the increased risk of VTE in women with large fibroids occurs due to a prothrombotic state created by secondary effects from significant blood loss with associated anemia and reactive thrombocytosis [10]. To determine the presence, location, and size of fibroids, pelvic ultrasound has excellent specificity and sensitivity. It can be ordered prior to review by a gynecologist if it has not been previously undertaken. If a fibroid is found, a referral to a gynecologist for management is required [7].

Table.

▪.

	Structural causes of abnormal uterine bleeding: “PALM”
P	Polyps
A	Adenomyosis
L	Leiomyoma (fibroids)
M	Malignancy and hyperplasia

	Nonstructural causes of abnormal uterine bleeding:“COIEN”
C	Coagulopathy
O	Ovarian dysfunction
E	Endometrium
I	Iatrogenic
N	Not otherwise classified

Heavy menstrual bleeding can significantly impact the quality of life and, in its severest form, render women housebound. Using tranexamic acid (TXA) as a simple first line of therapy to help manage heavy menstrual bleeding in this cohort of women can be used safely. Prescribing a dose of 1000 mg every 6 to 8 hours orally to see if this helps reduce blood loss can be offered on the heavier days of a woman’s menstrual cycle. The use of fibrinolytic agents to decrease bleeding has often raised concerns about concomitant thrombotic risk. A large population study by Meaidi et al. [11] examined the incidence of women diagnosed with venous and arterial thrombosis after filling a prescription for TXA. The use of oral TXA had an increased incidence rate ratio for both venous thrombosis of 4.0 (95% CI, 1.8-8.8) and arterial thrombosis of 1.3 (95% CI, 0.4-4.2). However, the number needed to harm per 5 days of treatment with TXA was 78,549 women; thus, the authors concluded that TXA could be used safely to help manage heavy menstrual bleeding [11]. TXA has also been used during other prothrombotic states in large randomized controlled trials to reduce bleeding, such as postpartum hemorrhage in the World Maternal Antifibrinolytic (WOMAN) trial and posttrauma bleeding in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2) trial. Both trials did not see increased rates of VTE with use [12,13].

While it is unusual for women to be diagnosed with a new bleeding disorder in perimenopause, it is not impossible, and a bleeding history should be undertaken [8]. Globally, women are underdiagnosed with bleeding disorders, and a presentation such as this provides an opportunity in clinical care to exclude a bleeding disorder [14]. The International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool shows that women with a bleeding score of ≥6 have good sensitivity and specificity for determining if a woman has a bleeding disorder. A score of ≥6 should prompt investigation of a bleeding disorder and acknowledgment that this may be the cause and path for treating heavy menstrual bleeding [15]. The ISTH bleeding assessment tool can be found here: https://bleedingscore.certe.nl.

4. Iron Deficiency Anemia and Perimenopause Symptom Overlap

Perimenopausal symptoms can be debilitating; however, in this patient, it is worth considering that she also has significant iron deficiency anemia. While many of her symptoms are typical for perimenopause, there is also a potential overlap with iron deficiency anemia (see Figure 2) [16]. Iron’s vital role in the synthesis of hemoglobin and tissue oxygen delivery is well-established. There is a growing body of evidence that the role of ferritin goes beyond this. Ferritin is essential for the synthesis of cofactors and enzymes necessary for cellular respiration and oxygen delivery in multiple tissues. Skeletal muscle, cardiac myocytes, and the brain are the most sensitive to iron deficiency, so symptoms of iron deficiency, including myalgias, increased fatigue, reduced exercise tolerance, shortness of breath, poor concentration, reduced cognitive function, and headache, can be reflective of iron deficiency [17]. Importantly, ferritin is an important cofactor in the synthesis of dopamine and serotonin and may play a role in glutamate and γ-aminobutyric acid homeostasis [18,19]. Impairment in synthesis and an imbalance in the homeostasis of serotonin and dopamine can result in depression and anxiety. Treating iron deficiency anemia can potentially reverse these symptoms [20].

Figure 2.

Perimenopause symptoms overlap with symptoms of iron deficiency anemia. Overlap of symptoms with perimenopause and iron deficiency anemia can occur, including fatigue, depressed mood, impaired cognition, sleep disturbance, and headaches.

While heavy menstrual bleeding likely accounts for this patient’s iron deficiency anemia, if it were to persist despite the reduction in her heavy menstrual bleeding, other etiologies (such as gastrointestinal blood loss) need to be investigated. Ongoing symptoms of muscle aches, depressed mood, and brain fog despite iron repletion and correction of anemia would indicate that these symptoms are perimenopausal due to hormonal fluctuations, and other treatments such as MHT may be beneficial.

5. MHT in Perimenopausal Patients

Estrogen, as a means to help manage menopausal symptoms, has existed since the early 20th century. Over time, it became apparent that while estrogen could assist in alleviating menopausal symptoms, it also had adverse effects, including a 2- to 4-fold increased risk of developing VTE [21]. These findings, along with similar detrimental effects seen in patients prescribed the oral contraceptive pill, led to the evaluation of the effects of estrogen on thrombosis formation [22]. We are now aware that estrogen exerts its thrombotic effect through a number of mechanisms. First, estrogen elevates von Willebrand factor levels through stimulation of endothelial cells, as well as platelet activation and adhesion. Second, it increases thrombin generation and fibrin clot formation by increasing hepatically synthesized clotting factors, including FVII, FVIII, FX, FXIII, fibrinogen, and activated protein C. Finally, it decreases plasma levels of naturally occurring inhibitors of hemostasis, such as tissue factor pathway inhibitor, protein S, and antithrombin (see Figure 3) [23]. Importantly, oral estrogen is metabolized during the first pass effect through the liver, and it is during this process that it “switches on” these prothrombotic effects [24].

Figure 3.

Effects of estrogen on thrombosis and hemostasis. Estrogen can cause an increase and decrease in a number of factors that play a role in thrombosis. vWF, von Willebrand factor.

Hormonal replacement therapy (HRT), consisting of oral estrogen therapy in combination with progestin, had rapid uptake in clinical practice in the 1990s. The aim was to reduce debilitating hot flashes and reduce the risk of chronic diseases such as osteoporosis in menopausal women [21]. This form of HRT was an improvement to previous HRT that had used unopposed estrogen with a resultant increased risk of endometrial cancer [25]. Subsequent studies (such as the The Heart and Estrogen/progestin Replacement Study (HERS) randomized controlled trial), found an increased risk of nonfatal myocardial infarction and death from coronary artery disease in those on HRT [26]. The Women’s Health Initiative demonstrated an increased risk of pulmonary embolism, myocardial infarction, stroke, and breast cancer in women on oral estrogen alone [27]. These studies resulted in a subsequent dramatic decline in HRT use globally in the early 2000s [21]. The aftermath effect is still present in clinical practice today. Many patients, especially those with a past history, family history, or risk factors for VTE, cardiovascular, and cerebrovascular disease, are often denied access to HRT due to concerns that the risk outweighs the benefit.

The nomenclature for HRT has also changed to MHT over recent times. There is an acknowledgment that HRT indicates significant hormone deficiency with higher doses of estrogen replacement required. The levels of estrogen required to manage perimenopause and menopause symptoms are lower. The new terminology of MHT has been adapted to reflect clinical practice [28].

The negative press and need to advocate for women with perimenopausal and menopausal symptoms has driven research to find MHT that treats symptoms without the same detrimental side effects. This has led to the development of alternative delivery methods for HRT, such as transdermal estrogen. Transdermal estrogen is absorbed through the skin, directly enters the bloodstream, and avoids the reduced bioavailability that occurs with oral estrogen. This means transdermal estrogen avoids the first pass hepatic metabolism, which reduces estrogen exposure to clotting factors within the liver. It is postulated that this is the mechanism that makes transdermal estrogen less thrombotic [24].

In perimenopausal patients, MHT can be offered to help manage vasomotor symptoms such as hot flashes, sleep deprivation and the associated negative impact on quality of life. If women have not had a hysterectomy, they require the addition of progestin, as unopposed estrogen increases the risk of endometrial cancer [29]. Oral estrogen has been shown to increase the risk of VTE, with multiple studies showing the risk to be highest in the first 12 months of therapy [30]. Since the advent of transdermal estrogen, further studies have been monitoring for adverse effects, including VTE. Two recent studies, including a meta-analysis by Scarabin [31] and 2 nested case-control studies by Vinogradova et al. [32], have shown compelling evidence that transdermal estrogen, compared with oral estrogen, does not increase the risk of VTE. In Scarabin’s [31] paper, 26,471 VTE cases were included, of which 735 women used a transdermal estrogen preparation. The relative risk of transdermal estrogen compared with women not taking MHT was 0.97 (95% CI, 0.87-1.09). Combination therapy with transdermal estradiol and micronized progesterone also did not increase VTE risk (relative risk, 0.93; 95% CI, 0.65-1.33) [31]. Vinogradova et al. [32] reported no increased risk of VTE with transdermal estrogen. However, the type and dose of oral estrogen, as well as which type of progestogen estrogen it was combined with, did impact rates of VTE: conjugated equine estrogen and medroxyprogesterone acetate conferred the highest risk [32]. Why certain types of progestogen interacting with estrogen enhance thrombosis is not known. Transdermal estrogen also does not appear to increase the risk of stroke [29].

The thrombotic effects of the combination of transdermal estrogen with locally delivered progestogens to the endometrium, such as the levonorgestrel intrauterine system (Mirena), are not known. This combination would be worth researching, given that it would provide contraception, has a low risk of causing VTE, and is often used to help control heavy menstrual bleeding, all of which are considerations in perimenopausal women [33,34].

6. MHT in Patients at Risk of VTE

If patients and clinicians wish to use MHT to help manage symptoms in the context of an increased risk of VTE, based on the above data, transdermal estrogen can be used safely as first-line therapy [29].

Risk factors such as inherited thrombophilias require consideration. The American Society of Hematology has recently published guidelines to suggest when and if testing for thrombophilias should be undertaken prior to commencing MHT. It recommends testing prior to initiating MHT if there is a family history of VTE and an intermediate- or high-risk thrombophilia is present in the family, including protein C and S or antithrombin deficiency. If patients are positive for one of the above thrombophilias, the risk of VTE is high, and ideally, MHT is avoided [35].

Our understanding of the high-incidence, low-risk thrombophilia FV Leiden and prothrombin gene mutation heterozygosity has evolved. We now know that the risk of venous and/or arterial thrombosis associated with these mutations is low. However, many women who are perimenopausal or menopausal have been tested for these mutations in the past for indications we now view as inappropriate. It is important that these patients are counseled about their low risk of thrombosis and, importantly, reassured that they can safely be prescribed transdermal estrogen.

If there is a past history of VTE, oral MHT can potentially be given, provided there is a discussion and communication with the patient and their healthcare team on the risks and benefits of hormonal therapy [36]. In women with a moderate to high risk of VTE, using anticoagulation with a direct oral anticoagulant in conjunction with oral MHT may be an option that helps offset the risk of VTE and enables MHT to be still given. In patients with a moderate to high risk of having a VTE without a past history, education of signs and symptoms of VTE and what action to take if they have concerns about VTE is essential. It is important to inform these women of when they will be at higher risk of VTE (such as in the postoperative setting or significant immobility) so that appropriate thromboprophylaxis can be given during these times.

In patients where MHT is considered a significant risk or not a desirable treatment option, other management options exist and can be further explored with a woman’s healthcare team. Lifestyle modifications such as regular exercise, weight optimization, and decreasing alcohol intake can make symptoms more manageable. Cognitive behavioral therapy has been shown to help reduce hot flashes and associated sleep disturbance. Other pharmacologic management may be explored depending on symptoms, eg, selective serotonin reuptake inhibitors can be efficacious for depressed mood and sleep disturbance and may improve vasomotor symptoms without the same thrombotic risk.

7. The Multidisciplinary Team and Patient-Centered Care

Successfully helping women address perimenopausal issues will require a patient-centered approach. Discussion requires defining her specific goals of care. Open communication between herself and her healthcare professionals can then ensue so that each member of the team can play their appropriate role in helping improve quality of life and deliver on these goals.

8. Conclusion

Perimenopause is a time that can be fraught and require intervention to manage symptomology that can negatively impact quality of life. Ensuring research in perimenopause moves forward and addresses knowledge gaps in the future is paramount. Research should ideally be international and collaborative. It should focus on issues such as managing concurrent iron deficiency anemia, exploring thrombotic risk with different estrogen and progestogen combinations, and determining if VTE risk can be mitigated using direct oral anticoagulants in high-risk patients taking MHT. Understanding the benefits and risks of evolving MHT will enable optimal management to be possible during what can be an extremely challenging time in women’s lives.

9. ISTH 2024 Congress Report

At the ISTH 2024 Congress, other abstracts that examined the use of hormonal therapy and venous thromboembolic risk included Smith et al. [37], who undertook an environment case-only meta-analysis to identify a potential genetic predisposition to VTE in hormonal therapy users but found a stronger association in oral contraceptive pill users compared with hormonal therapy users.

10. Future Directions

Addressing the role perimenopause plays in women’s health and how this impacts the management of hematological issues is evolving. There are a number of important questions that require answers to help optimize care in this patient group and improve quality of life. Specifically, we do not know the prevalence of iron deficiency in perimenopausal women and if management has a positive impact on symptoms. Determining the ongoing risks and adverse events of patients who are perimenopausal and receive MHT in the era of low-risk transdermal estrogen usage needs ongoing gathering of data. How different progestogens interact with estrogen to increase thrombosis is unanswered, and exploring if using locally delivered progesterone systems such as the levonorgestrel intrauterine system has a lower thrombotic risk compared with micronized progestogen is also unknown. A prediction model for VTE for patients at moderate to high risk who wish to take MHT would be beneficial. This would help clinicians counsel women better and help inform patient care choices in regard to whether they would or would not benefit from concomitant thromboprophylaxis. Ongoing gathering of data on the usage of thromboprophylaxis in the era of direct oral anticoagulants is pertinent. Finally, and importantly, transgender and gender-diverse individuals who are born with ovaries have a distinct lack of research to help guide management around the same issues encountered in perimenopause. Ensuring future research is inclusive and examines best patient-centered management along with international collaboration to standardize care will assist in managing patients during this transition in their lives.