Conservative Modalities for Management of AUB: Role of Norethisterone

Overview

Abnormal uterine bleeding (AUB) is a clinical condition characterized by excessive, prolonged, or irregular uterine bleeding in women in the absence of an evident pelvic organ disease or a systemic disorder. A glance through the epidemiological data suggests a high prevalence of AUB across clinical settings. It accounts for 10-15% of patient referrals to gynecologist, half of which are perimenopausal; 20% are perimenarchal and the remaining are in the reproductive age group.¹   While a woman experiences around 400 menstrual cycles during her reproductive lifespan, it is assumed that up to 20% of women will have excessive menstrual bleeding.²

AUB is largely accepted as a broad term which encompasses all kinds of menstrual disturbances except amenorrhea. Nevertheless, the clinical variety of bleeding and the underlying pathology hardly show any significant association. Some authors suggest that AUB mostly occurs during the two extremes of the reproductive lifespan of a woman, with about three-fourth of the cases occurring in the over-35-years age group.³   The two ends of the reproductive life are more likely to be affected as these are times at which irregular ovulation is often encountered.²

In premenopausal women, AUB is usually identified when there is a noteworthy change in frequency, duration, or amount of bleeding during or between the menstrual cycles. In postmenopausal women, any vaginal bleeding 12 months after attaining menopause is labeled as abnormal and warrants prompt diagnostic intervention.⁴

Anovulatory and ovulatory AUB

AUB that occurs from adolescence through perimenopause can be classified as either anovulatory or ovulatory. Anovulatory bleeding is marked by irregular or infrequent periods, with flow that can be either light or excessively heavy. With anovulation there is absence of a corpus luteum follicle and hence absence of progesterone. As a result, there is multiple follicle development in the ovaries and failure of the midcycle surge of LH. Concentrations of FSH are mildly decreased, but the frequency of LH pulses is adequate to trigger the estradiol release from the ovary. The concentrations of estrogen in the preovulation phase of the cycle are comparable in ovulatory and anovulatory cycles, but in the latter there is a failure of the positive feedback effect of the estriol, which occurs without an LH surge. The multiple follicles continue to grow until spontaneous inhibition of the new follicles occurs. Estrogen strengthens the endometrium lining by increasing both vascularity and the number of endometrial glands, at the expense of stroma. Consequently, there is an unorchestrated development of stroma, glands, and blood vessels due to unopposed estrogen stimulation. This leads to abnormal endometrial shedding.

Ovulatory AUB, also referred to as menorrhagia, occurs at regular intervals (every 24 to 35 days), but with excessive volume or duration of more than seven days.^3,5   The pathophysiology of ovulatory bleeding is far from completely understood. Some authors have indicated that local factors play a key role in the process of endometrial shedding. Lysosomal enzyme activity in ovulatory DUB is believed to be increased, providing grounds for the proposal that hydrolytic enzymes may play a part in the process. Furthermore, endothelins causing local vasoconstriction, migratory leukocytes, and disturbances in the endometrial repair mechanisms may all collaborate in increasing the risk of bleeding in ovulatory AUB.²

Diagnosis and evaluation of abnormal uterine bleeding

Before initiating investigations, clinicians must first rule out a gravid context through a meticulous history taking. They must also conduct urine/serum assay for the presence of the β-subunit of human chorionic gonadotropin. The next step is to rule out a structural (or organic) etiology (belonging to the PALM group of PALM-COEIN classification). The spectrum of organic causes encompasses polyps, adenomyosis, leiomyoma, and malignant/pre-malignant conditions. In such a scenario, it is worthwile to examine the uterine cavity using a transvaginal ultrasound. When there are intrauterine abnormalities, hysteroscopy or saline hydrosonography can be undertaken. The non-structural causes include coagulopathy, ovulatory dysfunction, iatrogenic causes, endometrial disorders and other non-deined causes. The PALM-COEIN classification is depicted in figure 1.

The summary of first-line laboratory tests for AUB and age-based differential diagnosis are provided in box 1 and table 1, repectively.⁶

PALM-COEIN classification system

Polyps

For the basic classification system, polyps are classified as being either present or absent, as observed on ultrasonographic and hysteroscopic imaging with or without histopathology.

Adenomyosis

Data on the association between adenomyosis and the genesis of AUB is sparse. Diagnosis of adenomyosis was traditionally based on histopathologic evaluation of the depth of “endometrial” tissue beneath the endometrial– myometrial interface. However, the histopathologic criteria vary substantially, serving as a major clinical limitation. In PALM-COEIN system, diagnosis is based on uterine imaging with either ultrasound or MRI.

Leiomyoma

Benign fibromuscular tumors of the myometrium are also referred to as “leiomyoma,” “myoma,” and the frequently used “fibroid.” Many cases of leiomyomas present with no symptoms, just like polyps and adenomyosis. More often than not, their presence is not the cause of AUB.

The primary classification system includes only the presence or absence of 1 or more leiomyomas, irrespective of the site, number, and size of the lesion. The secondary system, on the other hand differentiates leiomyomas invading the endometrial cavity (submucosal [SM]) from others (O) because it is proven that submucosal lesions are the most likely to contribute to the genesis of AUB.

The leiomyoma category (L) is subdivided into those patients who have at least one submucosal myoma (Lsm) and those with myomas that do not impact the endometrial cavity (Lo).

Malignancy and hyperplasia (AUB-M)

This category included both pre-malignant and malignant lesions. Albeit less common, atypical hyperplasia and malignancy are count worthy causes of, or findings associated with AUB and should be evaluated in women of reproductive age. When a premalignant hyperplastic or malignant lesion is diagnosed during AUB investigation, it would be categorized as AUB-M and then subclassified using the appropriate WHO or FIGO system.

Coagulopathy (AUB-C)

“Coagulopathy” is an umbrella term which includes several systemic disorders of hemostasis that may be related to AUB. Estimates suggest 13% of women with heavy menstrual bleeding have biochemical evidence of systemic disorders of hemostasis, among which von Willebrand disease is the most common. Consideration of such disorders appears essential in light of the evidence favoring their potential contribution to some cases of AUB.

Ovulatory dysfunction (AUB-O)

Ovulatory dysfunction can play a role in the occurrence of AUB, usually manifesting as unpredictable timing of bleeding with variable quantity of flow, which in a fraction of patients leads to HMB. Albeit the etiology of ovulatory dysfunction is far from completely understood, some authors suggest that endocrinopathies (e.g. polycystic ovary syndrome (PCOS), hypothyroidism, hyperprolactinemia) may have a role. Besides, in some cases, the disorder may also be iatrogenic, and the cause may be traced to the use of gonadal steroids.

Iatrogenic (AUB-I)

Certain medical procedures or devices can potentially cause or contribute to the occurrence of AUB. These include medicated or inert intrauterine systems and therapeutic agents which directly affect the endometrium, perturb the blood clotting mechanisms, or alter the systemic control of ovulation. As previously mentioned, use of gonadal steroid therapy is an important cause of iatrogenic AUB. It usually results in what is called as “breakthrough bleeding”.

Endometrial (AUB-E)

Endometrial disorders are considered after exclusion of other abnormalities in the presence of normal ovulatory function. In such as scenario a primary disorder is found within the endometrium, which may or may not manifest as heavy menstrual bleeding. Currently, specific tests for these disorders are lacking, due to which AUB-E can only be ascertained by ruling out other identifiable abnormalities in women of reproductive age with a normal status of ovulatory function.

Not yet classified (AUB-N)

Some uterine entities such as chronic endometritis, arteriovenous malformations, and myometrial hypertrophy, although improperly defined and/or inadequately examined, may be contributory factors in AUB. Besides, there are few disorders, not yet recognized, and can be defined only by biochemical or molecular biological methods. Together, these entities come under the “not yet classified” category.^7,8

Conservative management of AUB

The goals of AUB management are to prevent short and long term complications (acute or chronic anemia, long-term consequences of anovulation), and to return to a pattern of normal menstrual cycles. The choice management depends on age, past history, bleeding amount & fertility desire of the patient.⁹   American College of Obstetricians and Gynecologists (ACOG) recommends that a combination of oral contraceptives or cyclic progestin be used for such cases. Progestin therapy and oral contraceptives induce routine withdrawal bleeding, mitigate the risk of hyperplasia or cancer, and keep excessive menstrual bleeding under check.^5,9   The FDA has approved use of oral contraceptives in women up to the time of menopause provided there is no contraindication such as smoking, elevated blood pressure, coagulation disorders or hyperlipidemia.¹   There are also nonhormonal treatment options which include NSAIDs and tranexamic acid. Endometrial ablation and hysterectomy are the two main surgical procedure undertaken in AUB.⁶   Progestogens are first-line treatment for AUB, particularly a drug of choice in anovulatory AUB due to the following:^10,11

• Progestins inhibit estrogen receptor replenishment and stimulate 17-OHsteroid dehydrogenase activity in endometrial cells, converting estradiol to the less active estrone
• They suppress estrogen-mediated transcription of oncogens
• Synthetic progestins have an antimitotic effect, allowing the endometrium to become atrophic if administered continuously (effective in cases of endometrial hyperplasia)
• They stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal.

In anovulatory women with episodic AUB, orderly, predictable, withdrawal bleeding can be induced by cyclic treatment with oral progestin. Occasional anovulatory bleeding that is not profuse or prolonged can be treated successfully with progestins. Norethisterone acetate (NETA) is a synthetic progestin first synthesized nearly 60 years ago in a search for an orally active progestational agent.

Role of Norethisterone Acetate

Norethisterone Acetate (or Norethindrone Acetate) is the acetic acid ester of Norethisterone (NET). On a weight basis, it is twice as potent as Norethisterone. NETA is completely and rapidly deacetylated to NET after oral administration, and the disposition of NETA is indistinguishable from that of orally administered NET. Research suggests that NETA binds to progesterone receptors in the endometrium and brings synchronous secretory changes in estrogen primed endometrium. It further promotes regrowth of the endometrium over irregularly denuded surfaces due to its weak estrogenic action. It also has a styptic effect on uterine hemorrhage and is beneficial in both ovulatory and anovulatory AUB.¹²

Apart from oral contraceptive action; it is used to treat secondary amenorrhea and menstrual irregularities.¹³   It is commonly prescribed especially in menorrhagia by many healthcare practitioners, because the other treatment options such as tranexamic acid have poor tolerability; Norethisterone is therefore considered as a safer alternative to these drugs.¹⁴   Several clinical trials are evident of its efficacy in the management of AUB. A randomized controlled study¹⁵   conducted on 22 female patients with menorrhagia showed that oral

Norethisterone reduced menstrual blood loss by 87% (median reduction 95 ml; range 56 to 212 ml) (figure 2). The authors concluded oral Norethisterone to be an efficient treatment for reducing menstrual blood loss to within normal limits. To delve further, a group of investigators16 compared the effects of Norethisterone progestogens and dydrogesterone in the treatment of 200 women with AUB. The participants were equally divided into a study group and a control group. In the study group 75 patients had regular cycle, while 25 patients still had irregular cycle with no control of bleeding. In the control group, 46 patients had regular cycle with arrested bleeding, while 54 patients still had irregular cycle with no control of bleeding. Norethisterone progestogen was concluded to be more effective in the treatment of AUB than dydrogesterone. The micronized controlled release formulation of Norethisterone has particularly received attention due to its several advantages over conventional formulations. The advantages of micronization are enlisted in box 1. Controlled oral drug delivery ensures a predetermined rate, for a specified period of time leading to predictability and reproducibility in the drug release kinetics, which implies that the release of ingredient from the system occurs at a rate profile that is not only predictable kinetically, but also reproducible from one unit to another. The advantages of controlled-release drug delivery are summarized in box 2.

Other treatment options

In addition to progesterone formulations, estrogen therapy can also be administered in acute and heavy bleeding when the endometrium is grossly denuded. Combined estrogen and progestogen is considered as second-line therapy in cases where progestogen alone does not result in a sufficient response. Some authors suggest that an initial estrogen therapy should be followed by NETA 5-10 mg and must be continued until the 21st day of therapy in order to generate a withdrawal bleeding. This approach has been found to be effective in restoring menstrual bleeding in most cases of AUB whether anovulatory or ovulatory.

In some cases where hormonal therapy is contraindicated, the use of non-hormonal drugs such as diosmin can be considered. Diosmin is prescribed for correction of basic abnormalities seen in AUB such as increased capillary fragility, PGE₂ overproduction, and impaired lymphatic drainage.¹²   In a study¹⁷  , outpatients with a history of untreated menorrhagia over 3 previous cycles were prescribed diosmin 5 days prior to the expected onset of menstruation and up to the end of bleeding for 3 consecutive cycles. The results demonstrated 50% reduction in the total amount of bleeding in 70% of the patients. Moreover, the duration of bleeding decreased by 33% and there was about 50% improvement in associated dysmenorrhea in 75% of the cases. These findings were confirmed in another study on a population with hypermenorrhea and menometrorrhagias, wherein 82% of patients got their cycle normalized with the use of diosmin. These data provide convincing evidence in favor of the high efficacy of diosmin in the treatment of bleeding problems such as AUB.

Conclusion

AUB mostly occurs during the two extremes of the reproductive lifespan of a woman, with about threefourth of the cases occurring in the over-35-years age group. Before initiating investigations, clinicians must first rule out a gravid context through a meticulous history taking. There is lack of consensus on specific treatment regimens for anovulatory AUB. Medical therapy is the main tenet of treatment, and surgical therapy is considered only when there is no response to medical therapy. Norethisterone or Norethindrone Acetate is a synthetic progesterone that has both estrogenic and androgenic effects is indeed a potent and fruitful therapy for patients with AUB. In cases where hormones are contraindicated, non-hormonal drugs such as Diosmin can be used.

References

1. Dysfunctional uterine bleeding. Available at http://www.eric. vcu.edu/home/resources/whh/VIIIbDYSFUNCTIONAL_ UTERINE_BLEEDING.pdf Accessed on 6.5.16.
2. Chen BH, Giudice LC. Dysfunctional uterine bleeding. Western Journal of Medicine. 1998;169(5):280-284.
3. Livingstone VH. Dysfunctional Uterine Bleeding. Canadian Family Physician. 1987;33:2563-2566.
4. Telner DE, Jakubovicz D. Approach to diagnosis and management of abnormal uterine bleeding. Canadian Family Physician. 2007;53(1): 58-64.

.

5. Sweet MG, Shmidt-dalton TA, Weiss PM. Evaluation and Management of Abnormal Uterine Bleeding in Premenopausal Women. Available at www.aafp.org/afp. Accessed on 6.5.2106.
6. Khrouf M, Terras K. Diagnosis and Management of Formerly Called “Dysfunctional Uterine Bleeding” According to PALMCOEIN FIGO Classification and the New Guidelines. Journal of Obstetrics and Gynaecology of India. 2014;64(6):388-393.
7. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011 Jun;95(7):2204-8, 2208.e1-3.
8. Munro MG, Critchley HO, Broder MS, Fraser IS; FIGO Working Group on Menstrual Disorders. 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.
9. Casablanca Y. Management of dysfunctional uterine bleeding. Obstet Gynecol Clin North Am. 2008 Jun;35(2):219-34, viii.
10. Speroff L, Fritz M, eds. Dysfunctional uterine bleeding. In: Clinical gynecologic endocrinology and infertility. 8th ed.
11. Joan Pitkin. BMJ Best Practice Dysfunctional Uterine Bleeding. BMJ 2007;334:1110.
12. Data on file 13. Muneyyirci-Delale O, Chandrareddy A, Mankame S, Osei-Tutu N, von Gizycki H. Norethindrone Acetate in the Medical Management of Adenomyosis. Pharmaceuticals. 2012;5(10):1120-1127.
13. Prentice A. Medical management of menorrhagia. Western Journal of Medicine. 2000;172(4):253-255.
14. Irvine GA, Campbell-Brown MB, Lumsden MA, Heikkilä A, Walker JJ, Cameron IT. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol. 1998 Jun;105(6):592-8.
15. Yaaqoub nk. A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding. American Medical Journal. 2010;1(1):23-26.
16. Mukherjee GG, Gajaraj AJ, Mathias J, Marya D. Treatment of abnormal uterine bleeding with micronized flavonoids. Int J Gynaecol Obstet. 2005 May;89(2):156-7.