Norethindrone dosing for adequate menstrual suppression in adolescents

Introduction

The majority of menstrual irregularities in adolescents originate from anovulatory cycles leading to dysfunctional endometrial shedding [1]. Studies have shown that 60–80 % of adolescents report dysmenorrhea, 20–30 % describe irregular menstrual bleeding, and 15–20 % have heavy menstrual bleeding [2], [3], [4], [5], [6]. Adolescents may desire menstrual suppression for a myriad of reasons including those listed above, as well as for management of medical conditions such as menstrual migraines, catamenial seizures, irritable bowel syndrome, or rheumatoid arthritis [7, 8]. Additionally, adolescents with disabilities and their caregivers may desire menstrual suppression to aid with menstrual hygiene, caregiver burden, or menstrual symptoms [9]. Menstrual suppression can reduce heavy blood loss and anemia in addition to improving menstrual-related pelvic pain [10].

Combined hormonal contraceptives (CHCs) such as combined oral contraceptive pills (OCPs), the vaginal ring, and the transdermal patch are among the most common methods for menstrual suppression, yet many adolescents are unable to utilize these options due to having contraindications to estrogen [11]. Absolute contraindications to estrogen include a history of deep vein thrombosis (DVT), pulmonary embolism, or stroke [12]. Other contraindications include inherited thrombophilias such as factor V Leiden, migraines with aura, and liver or renal disease [12, 13]. Estrogen may also interact with several drug classes including anti-epileptic drugs and psychotropic medications [12]. Options for menstrual suppression without estrogen include levonorgestrel intrauterine devices, the etonogestrel implant, depot medroxyprogesterone acetate (DMPA), and progestin-only pills (POPs). Previous studies demonstrate 76 % amenorrhea rates with POPs [8, 14]. Compared to other progestin-only methods, POPs such as norethindrone, norethindrone acetate (NA), medroxyprogesterone acetate, or megestrol acetate have the benefit of both easy cessation of therapy and easy escalation of dosage for improved pharmacologic effect [15].

Among progestins, norethindrone is the only method available in a low-dose formulation (0.35 mg) [16]. This formulation has the additional benefit of being an FDA-approved contraceptive [17]. NA is biosimilar and can also be prescribed in higher doses, up to 15 mg daily, which may allow for dose titration to help adolescents achieve amenorrhea [18]. Previous studies have shown that NA tapers are effective in the setting of acute menstrual bleeding [19]. While amenorrhea rates as low as 10 % for norethindrone POPs have been reported, norethindrone is commonly used for menstrual suppression, particularly for patients seeking non-estrogen-containing methods or low-dose formulations of hormones [20]. However, there is a paucity of literature investigating the effectiveness of norethindrone 0.35 mg for menstrual suppression in adolescents. The aim of this study is to determine patient characteristics associated with achieving menstrual suppression using norethindrone 0.35 mg. Secondary outcomes include evaluating patient characteristics that make providers more or less likely to prescribe varying doses of norethindrone or NA and evaluating patient satisfaction with norethindrone 0.35 mg for menstrual management.

Materials and methods

A retrospective study of adolescents desiring menstrual suppression was performed at an academic medical center. The study was reviewed by the University of Michigan Institutional Review Board and deemed to be exempt. Informed consent was waived, as this is a retrospective review of existing data included in the standard care of patients. Patients who presented for care at Pediatric and Adolescent Gynecology (PAG) clinics from January 2010-June 2022 were included. Inclusion criteria were females <18 years not previously on hormone therapy. Participants were identified in the institutional medical record search engine according to International Classification of Diseases (ICD) 9 and 10 codes for heavy menstrual bleeding and irregular bleeding and for receiving a norethindrone or NA prescription [21]. Providers included four board-certified obstetrician-gynecologists with additional training in PAG.

Patients’ initial visit was defined as the date on which norethindrone or NA was initiated. Patients were prescribed either 0.35 mg norethindrone or 2.5 , 5, or 10 mg of NA. Follow-up care was measured at one, three, and 12 months after initiation of norethindrone or NA. Follow-up care was considered subsequent office visits, virtual visits, or portal messages reporting menstrual patterns or requesting change in treatment plan. Data collected at initial visits included demographics, past medical history, current medications, menstrual history and bleeding pattern, hemoglobin value within one month of presentation, and norethindrone or NA dose prescribed. Follow-up visit data included body mass index (BMI), bleeding pattern, satisfaction with treatment, side effects, and changes in treatment plan.

Regularity of menstrual cycles was defined as 21–45 days if within two years of menarche and 21–35 day cycles thereafter [22]. Amenorrhea was defined as no menstrual bleeding or spotting in the previous three months [22]. Light or heavy bleeding was classified based on patient perception of bleeding. Prolonged bleeding was defined as >7 days, normal bleeding as 5–7 days, and light as <5 days [22]. Menstrual suppression was defined as amenorrhea or light bleeding. Satisfaction was based on reported patient satisfaction unless patients were nonverbal or significantly developmentally delayed, in which case caregiver satisfaction served as a proxy.

Data were analyzed with Stata 16 (College Station, TX). Descriptive statistics were used to summarize the data. Bivariate analysis was conducted on four outcome variables: 1) those who were started on norethindrone 0.35 mg, 2) those who stayed on this dose, 3) those who achieved menstrual suppression, and 4) those who reported satisfaction with their bleeding pattern. Factors associated with the outcome variables at the p<0.05 level bivariately were included in multivariate analysis. Due to data limitations, starting hemoglobin level was not included in the final analysis, as this data was absent in over half of the cases. The margins command was used to determine marginal effects of each of the statistically significant findings after completing regression models [23].

Results

A total of 262 patients met inclusion criteria; of these, 219 had at least one follow-up visit. Participants were mainly non-Hispanic white with normal BMI (average 24.8). Average age at menarche was 11.5 years (range 7–17 years), while average age at initial visit was 13.5 years (range 9–18 years). Very few participants reported being sexually active. Nearly one-quarter of patients had a documented cognitive or physical disability (53/216, 24.5 %). Approximately 28 % of patients achieved menstrual suppression on norethindrone 0.35 mg (47/170, 27.6 %). See Table 1 for the full demographic data and other characteristics of the sample.

In bivariate logistic regression with initiating norethindrone 0.35 mg as the outcome variable, all 262 participants were included. However, less than half (125/262, 47.7 %) of the patients had an initial hemoglobin level documented. While starting hemoglobin level was highly significantly associated with three of our outcomes (starting norethindrone 0.35 mg, staying on norethindrone 0.35 mg, and achieving menstrual suppression), it was removed from multivariate analysis due to the missing data. Starting hemoglobin level was also negatively associated with prolonged bleeding.

Multivariate logistic regressions were performed on four outcomes of interest: norethindrone initiation, continuation, menstrual suppression, and patient satisfaction (Figure 1). Providers were more likely to prescribe norethindrone 0.35 mg to patients who were younger, had a lower BMI, were older at menarche, or had estrogen contraindications for migraines with aura or risk of venous thromboembolism (VTE). Those with prolonged bleeding were significantly less likely to be started on norethindrone 0.35 mg. See Table 2 for full results.

Figure 1:

Patient characteristics associated with main outcome measures. (A) Initiating norethindrone 0.35 mg. (B) Continuing norethindrone 0.35 mg. (C) Achieving menstrual suppression. (D) Satisfaction on norethindrone 0.35 mg *p<0.1, **p<0.05, ***p<0.001.

In multivariate logistic regression with continuing norethindrone 0.35 mg as the outcome variable, prolonged bleeding and age at menarche are significantly negatively associated with the outcome. Patients with prolonged bleeding were 13.1 % less likely to continue norethindrone 0.35 mg, while for each year of age older at menarche, patients were 2.6 % less likely to stay on the lowest dose. See Table 2 for full results.

In a multivariate logistic regression analysis of patients likely to achieve menstrual suppression, those who initiated norethindrone 0.35 mg (compared to a higher dose), were younger at their first visit, had an overweight or obese BMI (≥25 kg/m²), and had heavy bleeding were significantly less likely to achieve menstrual suppression. See Table 3 for a complete list of characteristics associated with achieving menstrual suppression.

When analyzing patient satisfaction among those started on norethindrone 0.35 mg, age at first visit was negatively associated with satisfaction. For each year younger at initiation, patients were 6 % less likely to be satisfied with their bleeding. However, for each year older at menarche, patients were nearly 10 % more likely to report satisfaction. See Table 4 for details of the analysis.

Satisfaction was also analyzed in patients with a documented disability, who were significantly more likely to continue norethindrone 0.35 mg at three and twelve months compared to those without a disability (p=0.031, p=0.044).

The number of follow-up visits was compared according to reported side effects (irregular bleeding, weight gain, mood changes) to further analyze patient satisfaction. In Chi-square analysis, irregular bleeding was significantly associated with the number of follow-up visits (p<0.001), whereas weight gain (p=0.149) and mood changes (p=0.653) had no significant association. Compared to those with one follow-up, patients with two follow-ups were 26 % more likely to report irregular bleeding (p=0.001), and those with three follow-ups were 37 % more likely to report irregular bleeding (p<0.001).

Discussion

This study elucidates several opportunities to improve prescribing patterns by identifying patient characteristics predictive of achieving menstrual suppression and satisfaction on norethindrone 0.35 mg. In summary, we found that those who were younger, overweight, or reported heavy bleeding were less likely to achieve menstrual suppression on norethindrone. However, providers were most likely to prescribe norethindrone 0.35 mg for those who were younger or who had estrogen contraindications for migraines with aura or risk of VTE. Those who were older at initiation or menarche were more likely to report satisfaction on norethindrone 0.35 mg. Additionally, patients with disabilities were more likely to continue with low-dose norethindrone, suggesting greater satisfaction among this population. Patients who experienced irregular bleeding as a side effect were more likely to present for additional follow-up visits, which may indicate lower satisfaction as a result of this side effect.

Providers are more likely to prescribe the low-dose norethindrone formulation for younger patients. Interestingly, however, these patients are less likely to achieve light bleeding or amenorrhea with this dose. Younger patients—particularly those within two years of menarche—are more likely to have anovulatory cycles due to hypothalamic–pituitary–ovarian axis immaturity, which contributes to menstrual irregularity [24]. It may be postulated that norethindrone 0.35 mg is less effective in controlling anovulatory cycles than other options used for menstrual suppression such as CHCs. Alternatively, norethindrone has a short half-life, which requires patients to take the medication at the same time each day to avoid breakthrough bleeding [17]. Younger patients may be less accustomed to taking daily medication and therefore miss pills, causing irregular bleeding. Furthermore, in line with other literature, our study shows that younger patients often present with a more acute need for treatment as manifested by lower starting hemoglobin values and heavier bleeding [25]. Younger adolescents are even more likely to be admitted to the emergency department for heavy vaginal bleeding compared to older adolescents [25]. These patients may require higher doses of NA when trying to decrease heavy bleeding in order for menstrual regulation to be achieved.

When analyzing prescribing patterns, starting hemoglobin was significantly predictive of initiating norethindrone 0.35 mg. Patients with low starting hemoglobin levels were significantly less likely to be started on norethindrone 0.35 mg compared to higher doses of NA. Understandably, providers are likely concerned that heavy menstrual bleeding could lead to critically-low hemoglobin levels in patients with low starting levels. Studies demonstrate that higher doses of NA (5–10 mg) are effective in achieving menstrual suppression in patients with heavy menstrual bleeding [26, 27]. Thus, providers may be more inclined to start these patients on higher doses of NA to stop heavy bleeding and achieve menstrual suppression.

Previous studies demonstrate amenorrhea rates as low as 10 % with norethindrone POPs [20]. This study similarly demonstrates a menstrual suppression rate of 28 % (47/170, 27.6 %). As we defined menstrual suppression to include both amenorrhea and light bleeding, this is likely why our study describes a slightly higher percentage.

Patients with an overweight or obese BMI (≥25 kg/m²) were less likely to achieve menstrual suppression with norethindrone 0.35 mg when compared to normal weight individuals. Previous studies demonstrate that obesity contributes to heavy menstrual bleeding due to hyperandrogenism, decreased sex hormone binding globulin concentrations, increased aromatization, hyperinsulinemia, and endometrial hyperplasia [28], [29], [30], [31]. It is therefore possible that norethindrone 0.35 mg does not work as well in this cohort of adolescents, as they are more likely to have heavier bleeding than individuals with a normal BMI.

Side effects are an important consideration for medication adherence and therapy continuation. The side effects of norethindrone 0.35 mg are well known from previous studies and include, but are not limited to, irregular bleeding, weight gain, and mood changes [17]. This study found that patients reporting irregular bleeding on norethindrone had significantly more follow-up visits and, subsequently, adjustments in norethindrone or NA dosage compared to those who reported weight gain or mood changes, which is consistent with prior studies [19]. Timely dose adjustments for patients with irregular bleeding may increase patient satisfaction by helping them achieve adequate menstrual suppression.

This study shows that patients with disabilities were significantly more likely to be satisfied with norethindrone 0.35 mg, as evidenced by their higher likelihood of continuing norethindrone 0.35 mg at three and 12 months. This is similar to literature reporting high rates (82.5 %) of satisfaction among adolescents with disabilities on oral progestins [32]. For non-ambulatory adolescents, often the lowest dose method is prescribed due to the risk of VTE and medication interactions.

This study represents a large cohort seeking menstrual suppression with progestin-only pills, which makes the study design unique. However, there are a few limitations. First, the study is retrospective in nature and relies on provider documentation. Patients who did not have specific variables documented were unable to be included in parts of the analysis. For example, approximately half of the patients had a documented starting hemoglobin level, which limited our ability to include the full sample when analyzing the influence of hemoglobin level on prescribing patterns. Furthermore, patient and caregiver reporting of bleeding patterns is subjective and may lead to skewing of data. Lastly, obesity was measured using BMI. However, waist circumference and waist-to-hip ratios may better measure obesity in adolescents [31]. Future studies could evaluate obesity and menstrual suppression with greater granularity by using these other metrics.

While providers correctly predicted that patients with prolonged bleeding were less likely to continue on low-dose norethindrone or achieve menstrual suppression, they were more likely to prescribe norethindrone 0.35 mg to younger patients, who had a lower likelihood of achieving menstrual suppression at this low dose. Additionally, patients who were overweight or had heavy menstrual bleeding were less likely to achieve menstrual suppression on norethindrone 0.35 mg. These patients may benefit from a higher starting dose of NA. Monitoring for irregular bleeding side effects, and adjusting norethindrone or NA dose accordingly, may improve patient satisfaction.

Conclusions

This study highlights several opportunities to improve norethindrone prescribing patterns for adolescents seeking adequate menstrual suppression.