Uterine bleeding with hormone therapies in menopausal women: a systematic review

Abstract

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17β-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18–54%), ethinyl estradiol/NETA (31–61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9–27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

摘要

子宫出血是妇女中断绝经激素治疗（HT）的常见原因。本系统性综述比较了北美和欧洲批准的有子宫的绝经后女性中重度血管舒缩症状连续联合HT治疗药物在研究中报道的出血情况。非面对面的研究表明, 子宫出血因制剂和给药途径的不同而不同, 口服比经皮制剂更容易出血。闭经超过一年的人中, 大约为18%-61%采用口服HT, 9%-27%采用经皮HT治疗。据报道采用的连续联合HT治疗有17β-雌二醇（E2）/孕酮（P4）（56%）, E2/醋酸炔诺酮（NETA）（49%）、E2/屈螺酮（45%）、马结合雌激素/醋酸甲羟孕酮（18-54%）、炔雌醇/NETA（31%-61%）、E2/左炔诺孕酮贴片（16%）和E2/NETA贴片（9-27%)。闭经率和和平均出血/点滴出血天数随时间而改善。口服E2/P4组合是出血率较低的一组药物之一, 可能对于追求HT的女性和/或其他HT引起出血的女性的合适的选择。

Keywords:

• Amenorrhea
• bleeding
• continuous-combined hormone therapy
• hormone therapy
• menopause
• uterine bleeding
• vasomotor symptoms
• bioidentical

Introduction

Menopausal hormone therapy (HT) is used to treat postmenopausal hot flushes, to treat symptoms associated with vulvovaginal atrophy, and to prevent bone loss. While therapy with estrogen alone is effective in relieving these symptoms, addition of a progestogen is necessary for women with an intact uterus to counteract estrogen-induced endometrial stimulation, protecting the endometrium¹. However, endometrial breakthrough bleeding with HT often occurs in postmenopausal women due to the addition of a progestogen².

Undesired uterine bleeding can interfere with women’s daily activities and negatively impact their physiological well-being, reducing their quality of life³. Uterine bleeding is also one of the major contributors to the discontinuation of HT⁴. In a large, 1-year, international study assessing the effects of combined HT on health-related quality of life, uterine bleeding was the most common reason for discontinuation, accounting for 32% of women who prematurely withdrew from the study⁵. Postmenopausal women presenting with uterine bleeding ≥6 months after initiating combined HT should also be assessed¹. However, this often necessitates endometrial evaluation, as well as other clinical assessments⁶, increasing the use of health-care resources and causing anxiety in women. Tolerability of an HT with regard to uterine bleeding is thus important, as adherence to the treatment is crucial for taking full advantage of HT benefits⁷.

A variety of continuous-combined HT preparations with different formulations, progestogens, and dosages has been developed to treat postmenopausal symptoms with acceptable tolerability to improve compliance. This systematic review evaluated uterine bleeding profiles of oral and transdermal continuous-combined HT products that are available in North America and Europe for treating moderate to severe vasomotor symptoms in postmenopausal women with a uterus.

Methods

A list of continuous-combined, estrogen-progestogen HT products approved in North America and in Europe with indications for the treatment of moderate to severe vasomotor symptoms or estrogen deficiency symptoms in postmenopausal women with an intact uterus was compiled. Prescribing information or summaries of product characteristics for these approved products were obtained. A systematic literature search generally following the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed (Figure 1). English-language studies were identified using the Medline database (PubMed) with the keywords of menopause and bleeding combined with conjugated estrogen or estradiol. Interventional studies, including randomized controlled and non-comparative trials, of approved formulations were included in this review.

Figure 1. Flow chart of article selection for the systemic review. HT, hormone therapy.

Bleeding data collected over 1 year (≥48 weeks, or 12–13 cycles of 28–30 days) from comparative or separate studies of continuous-combined oral or transdermal HT (estrogen plus progestogen) with at least 25 women per treatment group were summarized. Cumulative amenorrhea and other bleeding data were also collected from relevant prescribing information or summaries of product characteristics. Amenorrhea was defined as no bleeding or spotting. Spotting was defined as not requiring sanitary protection, while bleeding required sanitary protection. The primary goal of this review was to compare cumulative amenorrhea rates (proportions of women remaining amenorrheic) from cycle 1 to cycle 12/13 and during the last cycle or quarter of 1 year as reported in comparative studies or separate studies for different HT products. Other data reviewed included the mean number of bleeding/spotting days and discontinuation rates due to irregular bleeding.

Results

A list of continuous-combined HT products approved for treatment of postmenopausal symptoms in North America and Europe is summarized in Table 1. Estrogens in these products include 17β-estradiol (E2), conjugated equine estrogens (CEE), ethinyl estradiol (EE), and estradiol valerate (E2V), while progestogens include progesterone (P4), norethindrone acetate or norethisterone acetate (NETA), dydrogesterone (DYD), drospirenone, medroxyprogesterone acetate (MPA), levonorgestrel, and dienogest. The majority of the products are oral HT formulations (Table 1). All continuous-combined formulations reviewed contain synthetic progestogens (progestins) except for one product containing E2/P4.

Table 1. Approved, continuous-combined hormone therapy products for the treatment of vasomotor symptoms in North America and Europe.

Active ingredients	Product name	Daily dosage (mg/mg)	Administration
E2/P4	Bijuva	1/100	Oral
E2/NETA	Activella, Activelle, Elleste Duet Conti, Kliofem, Kliogest, Kliovance	0.5/0.1 1/0.5 2/1	Oral
E2/DRSP	Angeliq	0.5/0.25 1/0.5 1/1 1/2	Oral
E2/DYD	Femoston-conti	0.5/2.5 1/5	Oral
CEE/MPA	Prempro, Premique	0.3/1.5 0.45/1.5 0.625/2.5 0.625/5	Oral
EE/NETA	femHRT	0.005/1 0.0025/0.5	Oral
E2V/DNG	Climodien	2/2	Oral
E2V/MPA	Indivina	1/2.5 1/5 2/5	Oral
E2/LNG	Climara Pro	0.045/0.015	Transdermal
E2/NETA	CombiPatch, Estalis, Evorel Conti	0.025/0.125 0.05/0.14 0.05/0.17 0.05/0.25	Transdermal

CEE, conjugated equine estrogens; DNG, dienogest; DRSP, drospirenone; DYD, dydrogesterone; E2, 17β-estradiol; E2V, estradiol valerate; EE, ethinyl estradiol; LNG, levonorgestrel; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate or norethisterone acetate; P4, progesterone.

Forty-five studies met the inclusion criteria and were included in the review (Figure 1)^8–52. Most of them were randomized trials with an active control (n = 25)^8–32, followed by placebo-controlled studies (n = 14)^33–46 and non-comparative studies (n = 6)^47–52. The majority were not head-to-head studies of the HT combinations compared in this review. Bleeding data reported in the included studies and product prescribing information/summaries of product characteristics (Table 2)^8–63 were reviewed.

Table 2. Summary of bleeding data with approved continuous-combined hormone therapy.

		Amenorrhea (% women)			Mean number of bleeding/spotting days
Type of hormone or reference	Dose (mg/mg)	Cumulative (cycle 1 to cycle 12/13)	At cycle 12/13	Over 1 year^a	Cycle 1 to cycle 12/13	Quarter 1 to quarter 4	Over 1 year	Withdrawal due to bleeding (% women)
E2/P4 (oral)
Bijuva PI^53	1/100 Placebo	56 79
REPLENISH^54	1/100 Placebo				1.2 to 0.7 0.4 to 0.1	4.2 to 2.6 0.8 to 0.2
Mirkin et al. 2020^45	1/100 Placebo	56 79	90 98					1.4 0
E2/NETA (oral)
Mattsson et al. 2015^51	0.5/0.1		88
Activella PI^55	1/0.5	49	86
Kliovance SPC^56	1/0.5		90 (Q4)
Archer et al. 1999^8	1/0.5		90^b					1.7
Yildirim et al. 2006^9	1/0.5		88 (Q4)
Hammar et al. 2007^10	1/0.5		86 (Q4)					1.9^c
Samsioe et al. 2007^11	1/0.5		97			4.9 to 1.8		1.8
Genazzani et al. 2013^12	1/0.5		85					3.5
Bouchard et al. 2005^13	1/0.5 2/1		75 78		6.5 (cy13)^d 8.6 (cy13)^d
Kliofem SPC^57	2/1		94 (Q4)
Haines et al. 1997^47	2/1		84 (Q4)^b
Hammar et al. 1998^14	2/1		92				12.6	12.8
Mattsson et al. 1999^15	2/1		79 (Q4)	36				0.7
Doren et al. 1999^16	2/1		74^b	41			35.6
Graser et al. 2000^17	2/1						31.7^d
Rozenberg et al. 2001^18	2/1		84					7.0
Odmark et al. 2001^19	2/1		82	32	4.2 to 1.8^b			13.5
Jirapinyo et al. 2003^34	2/1 Placebo		68 (Q4) 100 (Q4)			11.5 to 4.7 0.1 to 0
Bassol et al. 2005^48	2/1		87–100					1.7–6.1
Limpaphayom and Bunyavejchevin 2000^44	2/1 Placebo		74 100			10.3 to 8.5^b 0
Rozenberg et al. 2009^46	2/1 Placebo		72 (wk36–52) 97 (wk36–52)	28 62
E2/DRSP (oral)
Genazzani et al. 2013^12	0.5/0.25		85					1.0
Angeliq PI^58	1/0.5	45	74
Archer et al. 2005^20	1/0.5 1/1 1/2		83^b 88^b 88^b
Angeliq SPC^59	1/2		73 (Q4)
E2/DYD (oral)
Bergeron et al. 2010^52	0.5/2.5		88 (Q4)	68	0.6 to 0.2		5.8	0.2
Stevenson et al. 2010^21	0.5/2.5 1/5		91 (Q4) 88 (Q4)	81 75	0.1 to 0.5 0.6 to 0.2
Stevenson et al. 2001^31	1/5		76
Quereux et al. 2006^49	1/5		77	41	1.5 to 1.5			2.4
CEE/MPA (oral)
Prempro PI^60	0.3/1.5 0.45/1.5 0.625/2.5 0.625/5	45 42 23, 24 26	88 80 78, 79 86
Archer et al. 2001^35	0.3/1.5 0.45/1.5 0.625/2.5 Placebo	45 44 22 68	89 82 76 96
Mirkin et al. 2013^36	0.45/1.5 Placebo	49 82	83 95
Pinkerton et al. 2014^37	0.45/1.5 Placebo	54 90	91 95					2.3 0.2
Kagan et al. 2018^38	0.45/1.5 Placebo		86 97			5.0 to 4.0 1.0 to 1.0
Simon et al. 2003^39	0.625/2.5 Placebo	18 65	65 91		3.9 to 2 0.2 to 0.4
Yildirim et al. 2006^9	0.625/2.5		82
Kazerooni and Zolghadri 2004^40	0.625/2.5 Placebo	18 67	70 93					17.5 11.8
Barnabei et al. 2005^41	0.625/2.5 Placebo		68 97					2.8 0.1
AinMelk 1996^32	0.625/2.5		93					7.4
Archer et al. 1994^33	0.625/2.5 0.625/5 Placebo						9.8^b 8.0^b 11.2^b
Pickar et al. 1998^22	0.625/2.5 0.625/5	24 22	79 85
Archer and Pickar 2000^23	0.625/2.5 0.625/5		90^b 94^b
Baracat et al. 2002^24	0.625/5		90					2.2
Odmark et al. 2001^19	0.625/5		92	33	3.8 to 0.4^b			5.3
EE/NETA (oral)
Rowan et al. 2006^42	0.0025/0.5 0.005/1 Placebo	61 36 80	90 82 93
Simon et al. 2003^39	0.005/1 Placebo	31 65	87 91		2.6 to 0.9 0.2 to 0.4
E2V/DNG (oral)
Climodien SPC^61	2/2		83–86 (Q4)
Graser et al. 2000^17	2/2						40.8^d
Grase et al. r 2001^50	2/2		86				31.1^d	7.5
E2V/MPA (oral)
Heikkinen et al. 2004^25	1/2.5 1/5 2.5		98 97 91		1.4 to 0.1 0.9 to 0 1.8 to 0.5
Mattsson et al. 2007^26	1/2.5 1/5 2/5		94^b 88^b 90^b		1.9 to 0.5 2.2 to 0.5 3.5 to 0.9
E2/LNG (TD)
Climara Pro PI^62	0.045/0.015	16	40
Shulman et al. 2002^27	0.045/0.015		41		3.6 (cy13)^b			12.3
E2/NETA (TD)
Brynhildsen and Hammar 2002^43	0.025/0.125 Placebo		92 (Q4) 90 (Q4)	50 73				1.7
Samsioe et al. 2007^11	0.025/0.125		86			5.8 to 2.4		3.6
Mattsson et al. 1999^15	0.025/0.125 0.05/0.25		86 (Q4) 65 (Q4)	60 28				1.4 12.0
Archer et al. 1999^28	0.05/0.14 0.05/0.25	27 9	65 54
Evorel Conti SPC^63	0.05/0.17		63 (Q4)^b
Ylikorkala and Rozenberg 2000^29	0.05/0.17		47 (Q4)	∼20		15 to 11–14
Oosterbaan et al. 1995^30	0.05/0.25		88	24	3.6 to 0.2			30

CEE, conjugated equine estrogens; cy, cycle; DNG, dienogest; DRSP, drospirenone; DYD, dydrogesterone; E2, 17β-estradiol; E2V, estradiol valerate; EE, ethinyl estradiol; LNG, levonorgestrel; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate or norethisterone acetate; P4, progesterone; PI, prescribing information; Q1, Month 1–3 or Cycle 1–3; Q4, month 10–12 or cycle 10–12; SPC, summary of product characteristics; TD, transdermal; wk, week.

^aReported as percentage of women having amenorrhea throughout the year; not clearly defined in the published studies.

^bData on spotting only were excluded.

^cDiscontinuation within the first 6 months.

^dData calculated in women with bleeding/spotting.

Cumulative amenorrhea rates from cycle 1 to cycle 12/13

Cumulative amenorrhea rates over 1 year were reported for 12 HT combinations (Table 2)^{22,28,35–40,42,45,55,58,60,62}. The rates were generally lower with transdermal HT (9−27%) than oral HT (18−61%) in non-head-to-head studies. The highest cumulative amenorrhea rates were reported for oral 1 mg/100 mg E2/P4⁴⁵ and 0.0025 mg/0.5 mg EE/NETA⁴² (Figure 2(A)). In addition, women using lower doses of hormones had higher rates of cumulative amenorrhea (Figure 2(A)), as observed in studies comparing different doses of CEE/MPA^35,60, EE/NETA⁴², and transdermal E2/NETA²⁸. Cumulative amenorrhea rates with continuous-combined HT started to improve as early as cycle 2 or 3, and continued to increase over time, with the highest rates observed in the last cycle or quarter^{22,28,35–37,39,40,42,45,55,58,60,62}.

Figure 2. Non-head-to-head trial comparison of reported (A) cumulative amenorrhea rates from cycle 1 to cycle 12/13 and (B) amenorrhea rates at cycle 12/13 with continuous-combined hormone therapy (HT). Numbers labeled above bars indicate the minimum (lower) and maximum (upper) reported by different studies, with a single number indicating only one percentage being reported. CEE, conjugated equine estrogens; DRSP, drospirenone; E2, 17β-estradiol; EE, ethinyl estradiol; LNG, levonorgestrel; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate or norethisterone acetate; P4, progesterone.

Amenorrhea rates at cycle 12/13

Oral HT showed a better bleeding profile than most of the transdermal HT formulations. In studies reporting cumulative amenorrhea, the observed amenorrhea rates at cycle 12/13 ranged from 65 to 91% for oral HT and from 40 to 65% for transdermal HT (Figure 2(B)). High amenorrhea rates (≥90%) at cycle 12/13 were achieved with oral HT of 1 mg/100 mg E2/P4⁴⁵, 0.45 mg/1.5 mg CEE/MPA³⁷, and 0.0025 mg/0.5 mg EE/NETA⁴², close to the rates observed with placebo in the same studies (Table 2).

Overall amenorrhea

Several studies reported percentages of women who had no bleeding or spotting over a year (overall amenorrhea); however, overall, amenorrhea was not clearly defined in the studies and could not be assumed to be cumulative amenorrhea. Relatively high percentages of women reported overall amenorrhea with 0.5 mg/2.5 mg E2/DYD^21,52, 1 mg/5 mg E2/DYD²¹, and 0.025 mg/0.125 mg E2/NETA patch^15,43 (Table 2). The study comparing different doses of transdermal E2/NETA also showed a higher rate of overall amenorrhea with the lower dose¹⁵.

Mean number of bleeding/spotting days

The majority of studies reported a reduction in the mean number of bleeding/spotting days over time with HT (Table 2). Most of the reported numbers were ≤2 during the last cycle^{19,21,25,26,30,39,49,52,54} or ≤5 during the last quarter^11,34,38,54, while longer durations were observed for doses of both oral E2/NETA¹³ and transdermal 0.05 mg/0.17 mg E2/NETA²⁹. Less than 1 day of bleeding/spotting at the end of 1 year was reported for 1 mg/100 mg E2/P4⁵⁴, 0.5 mg/2.5 mg E2/DYD^21,52, 1 mg/5 mg E2/DYD²¹, 0.005 mg/1 mg EE/NETA³⁹, all three doses of E2V/MPA^25,26, and transdermal 0.05 mg/2.5 mg E2/NETA³⁰.

Discontinuation due to bleeding

Study discontinuation rates due to irregular bleeding were in the range of 0.2–30% for 14 HT combinations in separate studies (Table 2). Some studies reported a <2% rate of discontinuation due to bleeding for six HT combinations, including oral 1 mg/100 mg E2/P4⁴⁵, 1 mg/0.5 and 2 mg/1 mg E2/NETA^{8,10,11,15,48}, 0.5 mg/0.25 mg E2/drospirenone¹², 0.5 mg/2.5 mg E2/DYD⁵², and transdermal 0.025 mg/0.125 mg E2/NETA^15,43.

Discussion

This systematic review of uterine bleeding data reported over 1 year shows that bleeding improves over time with HT use, and that oral HT provides better bleeding control than transdermal HT. In non-head-to-head studies, oral 1 mg/100 mg E2/P4 and 0.0025 mg/0.5 mg EE/NETA were found to be associated with a better bleeding profile as compared with some of the other oral combined HT or transdermal HT formulations containing progestin. Uterine bleeding begins to decrease after two or three cycles of HT use and the number of women remaining amenorrheic gradually increases over time.

Non-head-to-head trial comparisons revealed that generally more women stayed amenorrheic throughout 1 year with oral HT compared with transdermal HT. While cumulative amenorrhea rates with oral HT ranged from 18 to 61%, all of the reported rates with transdermal HT were less than 30%. Higher incidence of uterine bleeding with most of the transdermal formulations would possibly limit the choices of a transdermal HT with acceptable tolerability with regard to bleeding. Even with the low-dose transdermal E2/NETA (0.025 mg/0.125 mg), a somewhat higher discontinuation rate versus oral 1 mg/0.5 mg E2/NETA was reported when compared directly in a randomized trial (3.6% vs. 1.8%)¹¹.

A combination of transdermal estrogen and oral P4, although not regulatory approved, is commonly prescribed in some countries⁶⁴. However, no studies properly addressing the bleeding profile or endometrial safety of continuous-combined transdermal estrogen and oral P4 were identified in our search.

Incidence of bleeding varies by HT formulation⁶⁵. In non-head-to-head studies, oral E2/P4 was associated with a better bleeding profile compared with most of the other oral or transdermal HT formulations containing progestin. Although the exact mechanism remains unclear, it has been suggested that some progestogens induce changes in the structure of the microvasculature of the endometrium causing endometrial bleeding^2,66. In vitro studies demonstrated that P4 has less impact on the delicate ratio among angiogenic/anti-angiogenic factors in the endometrial glands and stroma compared with progestins^67,68. Several studies included in this review also demonstrated more favorable bleeding profiles with lower doses of hormones^15,35,42,60, despite similar ratios of estrogen/progestogen being used in some studies^15,42.

The incidence of uterine bleeding usually decreased over time with continuous-combined HT. HT discontinuation due to bleeding also occurred more often within the first 6 months of use^10,15,25. Additionally, bleeding during the early cycles of treatment could be predictive of bleeding in subsequent cycles, as it was shown that the majority of women with bleeding earlier in studies were more likely to report bleeding during subsequent cycles^29,69.

Time since menopause was another factor associated with uterine bleeding incidence. Studies found that bleeding was less frequently reported in postmenopausal than perimenopausal women^70,71. Cumulative amenorrhea rates were generally higher in women further from menopause than in those closer to menopause³⁵. Significant associations of amenorrhea with age and time since menopause were also found for the E2/P4 formulation, showing less bleeding in older women or for women with a longer time from menopause⁴⁵.

The present review has some limitations as it is a cross-study comparison. Methodologies adopted for bleeding data analysis in each study were not consistent. Not all studies calculated a cumulative amenorrhea rate over 1 year and some of the oral HT formulations (0.5 mg/0.1 mg E2/NETA, E2V/dienogest, and all doses of E2V/MPA) were therefore excluded from the comparisons of amenorrhea rates. Amenorrhea rates were evaluated in differently defined populations, such as intent-to-treat, safety, completer, or efficacy-evaluable populations among studies. The mean number of bleeding/spotting days was analyzed in women reporting bleeding/spotting events in some studies, while this was measured in all women in other studies. Such inconsistencies between studies could limit data interpretations in this review. In addition, bleeding data with transdermal HT were limited as the majority of the approved products were oral HT and fewer studies were on transdermal than oral combinations. Strengths of this review include the fact that it provides a comprehensive overview of irregular bleeding with continuous-combined HT. Moreover, this review provides value with comparisons among non-head-to-head trials from different publications.

Conclusion

Comparison of published bleeding data with various continuous-combined HT in separate studies shows that oral HT formulations in general result in higher amenorrhea rates than most transdermal HT formulations. Additionally, amenorrhea rates were mostly higher with lower doses of hormones within the same hormone combinations. Lastly, uterine bleeding decreased over time as shown by an increase in amenorrhea rates and a decrease in the mean numbers of bleeding/spotting days over time, demonstrating improvements with persistent use of continuous-combined HT. The oral E2/P4 combination was amongst those with the lowest bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

Potential conflict of interest

J.H.P. has served as a consultant to Pfizer, Shionogi, Sojournix, and TherapeuticsMD; and has stock options with TherapeuticsMD. D.F.A. has served as a consultant to AbbVie, Actavis, Agile Therapeutics, Bayer Healthcare, Endoceutics, Exeltis, InnovaGyn, Merck, Pfizer, Radius Health, Sermonix, Shionogi, Teva Women’s Healthcare, and TherapeuticsMD; and has received research support from Actavis, Bayer Healthcare, Endoceutics, Glenmark, Merck, Radius Health, Shionogi, and TherapeuticsMD. S.R.G. has served as a consultant to Cook ObGyn, Cooper Surgical, and IBSA; is on the advisory board of AbbVie, AMAG, and TherapeuticsMD; and has also served on the speaker’s bureau of AMAG, Duchesnay, and TherapeuticsMD. R.K. has served as a consultant to Amgen, Astellas, Cooper Surgical, Jazz Pharma, Lupin, Radius Health and TherapeuticsMD; and also serves on the speaker’s bureau of AMAG, Cooper Surgical, and TherapeuticsMD. B.B. and S.M. are employees of TherapeuticsMD with stock/stock options.

Acknowledgements

The authors would like to acknowledge the medical writing assistance of H. Zhang, PhD, D. Verlaan, PhD, and K. Ohleth, PhD, of Precise Publications, LLC.

Additional information

Funding

Medical writing assistance provided by H. Zhang, D. Verlaan, and K. Ohleth of Precise Publications, LLC was supported by TherapeuticsMD.