Composition comprising estradiol and progesterone for use for preventing a major adverse cardiovascular event in a woman

Abstract

The present invention relates to the use of compositions comprising estradiol and progesterone. The compositions are for use in preventing a major adverse cardiovascular event (MACE) in a woman, or decreasing the risk of MACE associated with combined hormone replacement therapy (HRT). The compositions may be used in combined HRT and / or methods of treating menopause related symptoms.

Description

[0001] COMPOSITION COMPRISING ESTRADIOL AND PROGESTERONE FOR USE FOR PREVENTING A MAJOR

[0002] ADVERSE CARDIOVASCULAR EVENT IN A WOMAN

[0003] FIELD OF THE INVENTION

[0004] 5 The present invention relates to the use of compositions comprising estradiol and progesterone. The compositions are for use in preventing a major adverse cardiovascular event (MACE) in a woman, or decreasing the risk of MACE associated with combined hormone replacement therapy (HRT). The compositions may be used in combined HRT or methods of treating menopause related symptoms.

[0005] BACKGROUND

[0006] Menopause is a process in which a woman’s menstrual period stops typically due to reduced hormone (such as estrogen and / or progesterone) production levels by the ovaries. The reduction in hormone levels that take place before, during and after menopause can lead to a variety of

[0007] 15 wide-ranging symptoms in women such as anxiety, mood changes, brain fog, hot flushes (or hot flashes), night sweats, irregular menstrual bleeding, vaginal dryness, atrophic vaginitis and irregular periods.

[0008] Most women experience hot flushes (or hot flashes) and night sweats in the perimenopausal

[0009] 20 period as well as during and after menopause, which can significantly impair their quality of life. Hot flushes and night sweats are often described as vasomotor symptoms. Hormonal replacement therapy (HRT) is the mainstay treatment for such vasomotor symptoms. Estrogen- only HRT is prescribed to women without a uterus. In women with an intact uterus, a combination of estrogen and progestogen (combined HRT) is recommended, with progestogen added to

[0010] 25 ensure endometrial protection (The NAMS 2017 Hormone Therapy Position Statement Advisory Panel 2017 Menopause 24(7):728-753).

[0011] A commonly prescribed combined HRT is an oral combination of conjugated equine estrogens and the synthetic progestin, medroxyprogesterone acetate (CEE / MPA or Prempro®). However, combined HRT remains underutilized due to safety concerns raised in the landmark Women’s Health Initiative (WHI) study showing an increased risk of breast cancer and cardiovascular diseases (including stroke) for women treated with CEE / MPA compared to placebo (Rossouw et al. 2002 JAMA. 288(3) :321 -333).

[0012] 35 Bijuva® is the first HRT product that combines two bioidentical compounds, 17 -estradiol (also referred to as E2 or estradiol) and progesterone (also referred to as P4) in a single oral capsule. Bijuva® was approved by the FDA in 2018 for the treatment of moderate to severe vasomotor symptoms due to menopause. The cardiovascular effect of newer combined hormone therapies, such as Bijuva®, is of foremost importance given the adverse events associated with older combined HRT such as CEE / MPA. Furthermore, menopausal women are at increased risk of cardiovascular disease independently of HRT, due to older age and menopause-related metabolic changes that are known risk factors of cardiovascular disease e.g., increased visceral adiposity, increased insulin resistance, hypercholesterolemia (Maas et al. 2021 Eur. Heart J. 42(10):967-84).

[0013] There are no randomized clinical trials, nor real-world observational studies comparing rates of Major Adverse Cardiovascular Events (MACE including stroke, acute myocardial infarction and heart failure) for combined HRT of estradiol and progesterone (such as E2 / P4) vs conjugated estrogen and progestin (in particular CEE / MPA).

[0014] SUMMARY OF INVENTION

[0015] An object of the invention is to compare the incidence of Major Adverse Cardiovascular Events (MACE) between women treated with estradiol and progesterone (such as E2 / P4) vs placebo.

[0016] Unexpectedly, it has been demonstrated that compositions comprising estradiol and progesterone have a cardioprotective effect in perimenopausal, menopausal and postmenopausal women, decreasing the risk of a major adverse cardiovascular event (MACE) versus placebo (a proxy for the general female population). Perimenopausal, menopausal and postmenopausal women are at an increased risk of cardiovascular disease independently of any hormone replacement therapy. Advantageously therefore, the composition comprising estradiol and progesterone can offset the increased risk of MACE among perimenopausal, menopausal and postmenopausal women. Moreover, the composition has a dual benefit in treating menopause related symptoms due to perimenopause, menopause and postmenopause while also preventing a MACE (i.e. reducing MACE incidence).

[0017] It follows that, in a first aspect, the invention provides a method of preventing a MACE in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone (e.g. E2 / P4).

[0018] In a related aspect, the invention provides a method of decreasing the risk of a MACE in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone (e.g. E2 / P4). In some embodiments, the risk of a MACE is decreased compared to a placebo. As explained above, this reflects a prophylactic effect in preventing a MACE, or more broadly in preventing cardiovascular disease. This prophylactic effect is of particular benefit to perimenopausal, menopausal and postmenopausal women to offset their increased risk of MACE.

[0019] The only published head-to-head comparison of E2 / P4 and CEE / MPA is with respect to risk of venous thromboembolism (VTE) (Panay et al. 2023 Maturitas. 172:23-31 ). However, VTE risk is not indicative of a major adverse cardiovascular event (MACE) risk.

[0020] Other studies have indirectly compared the adverse events of synthetic progestogens (Kaemmle etal. 2022 Climacteric 25(4): 327-336) or different estrogens (Graham et al. 2022 Gynecol. Endocrinol. 38(11 ):891 -910) individually rather than a direct comparison of combined hormone replacement therapies. As such, the risk profile of a combined HRT cannot be ascertained from such studies.

[0021] Another object of the present invention is to compare the safety profile (in particular the incidence of MACE) of a composition comprising estradiol and progesterone (such as E2 / P4) vs conjugated estrogen and progestin (in particular CEE / MPA) when used in clinical practice (i.e. the real-world outcomes).

[0022] Another unexpected discovery reported herein is that a combined hormone replacement therapy (HRT) comprising estradiol and progesterone is associated with a significantly decreased risk of acute myocardial infarction (Ml), stroke and heart failure in perimenopausal, menopausal and postmenopausal women as compared to other combined HRTs. This finding is of particular benefit to patients and medical professionals when assessing the benefit-risk profile of the combined HRT. In particular, menopause related symptoms can be treated while minimizing adverse side effects.

[0023] It follows that, in a second aspect, the invention provides a method of decreasing the risk of a MACE associated with combined HRT in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone. In a related aspect, the invention provides a composition for use in decreasing the risk of a MACE associated with combined HRT, wherein the composition for use comprises estradiol and progesterone.

[0024] In some embodiments, the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). Combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) is commonly prescribed to menopausal women, and therefore the decreased risk profile is of particular benefit to medical professionals and patients in weighing up the benefit-risk profile of different combined HRT options. In another aspect, the present invention provides a method of combined HRT in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a related aspect, the invention provides a composition for use in a method of combined HRT in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for combined HRT, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA).

[0025] Since the composition for use according to the invention comprises both the estrogen and progestogen components required for combined HRT in a single product, patient compliance is expected to be better than other combined hormone replacement therapies that require taking the two hormone components separately.

[0026] In another aspect, the present invention provides a method of selecting a combined HRT, comprising (i) identifying a woman as suitable for combined HRT; (ii) selecting a combined HRT, wherein the selected combined HRT has been identified as a combined HRT associated with a decreased risk of a MACE compared to combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA), wherein the selected combined HRT is a composition comprising estradiol and progesterone. Previously, selection of a combined HRT may be driven by an alleged risk of other adverse effects, such as risk of breast cancer, endometrial cancer or ovarian cancer.

[0027] Combined HRT remains the most effective treatment for menopause related symptoms.

[0028] Thus, in another aspect, the present invention provides a method of treating menopause related symptoms in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a related aspect, the invention provides a composition for use in a method of treating menopause related symptoms in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for menopause related symptoms, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA).

[0029] In some embodiments, the menopause related symptoms are associated with estrogen deficiency. In some embodiments, the menopause related symptoms comprise vasomotor symptoms, preferably moderate to severe vasomotor symptoms. Several existing combined hormone replacement therapies (such as Bijuva®) are approved for the treatment of vasomotor symptoms due to menopause.

[0030] In some embodiments the MACE is selected from at least one of acute myocardial infarction (Ml), stroke and heart failure. The present Examples identify a decreased risk profile for each of acute Ml, stroke and heart failure in women receiving a composition comprising estradiol and progesterone, showing that the composition is well tolerated.

[0031] The woman may be a perimenopausal, menopausal or postmenopausal woman. In preferred embodiments, the woman has not had a period for at least 12 months (i.e. is a menopausal or postmenopausal woman). Combined HRT is beneficial to women regardless of the menopausal stage, or whether the menopause was surgically- or medically- induced or early menopause (under the age of 45).

[0032] Preferably, the woman has an intact uterus. Combined HRT is recommended for such women as the progestogen provides endometrial protection.

[0033] The woman may be aged 40-79 years. In further embodiments, the woman is aged 50-79 years.

[0034] In some embodiments, the woman is aged 40-59 years. In some embodiments, the woman is aged 60-79 years. As demonstrated herein, women aged 60-79 are at an increased risk of MACE as compared to those aged 40-59 years, and the composition comprising estradiol and progesterone can offset this increased MACE risk.

[0035] In some embodiments, the woman is aged 50-59 years. More than 60% of the women studied in the present examples were in this age category. Based on an average age of 51 years for menopause onset, women in this age are <10 years from menopause onset. Without wishing to be bound by theory, it is expected that a better decrease in MACE may be achieved if the combined HRT of the invention is started in this window of opportunity (the “timing hypothesis”). In some embodiments, the decreased risk of a MACE comprises a lower number of MACE per 10,000 women-years. The present Examples reflect an accurate number of events per 10,000 women-years due to the large number of women in each cohort, and sufficient duration of the observation period of the study.

[0036] In some embodiments, the decreased risk of the MACE comprises an Incident Rate Ratio of 0.17-0.45, or of about 0.28. In women aged 40-59 years, the decreased risk of the MACE may comprise an Incident Rate Ratio of 0.23-0.65, or of about 0.39. In women aged 60-79, the decreased risk of the MACE may comprise an Incident Rate Ratio of 0.09-0.79, or of about 0.27.

[0037] In some embodiments, the MACE is acute Ml, and the decreased risk of acute Ml comprises an Incident Rate Ratio of 0.08-0.63, or of about 0.20-0.25, or of about 0.23 or about 0.22. In some embodiments, the MACE is heart failure, and the decreased risk of heart failure comprises an Incident Rate Ratio of 0.11 -0.51 , or of about 0.24. In some embodiments, the MACE is stroke, and the decreased risk of stroke comprises an Incident Rate Ratio of 0.15-0.70, or of about 0.32.

[0038] In some embodiments, the decreased risk of the MACE comprises a decrease in the number of MACE within 3 months, 4 months, 6 months, 9 months, 1 year or 2 years from the start of treatment. In some embodiments, the decreased risk of MACE comprises a decrease in the number of MACE within 2 years from the start of treatment, and wherein the decreased risk of a MACE within 2 years comprises a Hazard Ratio of 0.27-0.50, or of about 0.37. In some embodiments, the decreased risk of MACE comprises a decrease in the number of MACE within 1 year from the start of treatment, and wherein the decreased risk of a MACE within 1 year comprises an Incident Rate Ratio of 0.23-0.65, or of about 0.39. In some embodiments, the decreased risk of the MACE comprises a decrease in the number of MACE within 4 months from the start of treatment, optionally wherein the decreased risk of a MACE within 4 months comprises a Hazard Ratio of 0.14-0.84, or of about 0.34.

[0039] In some embodiments, the MACE is acute Ml and the decreased risk of acute Ml within 1 year comprises an Incident Rate Ratio of 0.08-0.77, or of about 0.24. In some embodiments, the MACE is heart failure, and the decreased risk of heart failure within 1 year comprises an Incident Rate Ratio of 0.18-0.82, or of about 0.38. In some embodiments, the MACE is stroke, wherein the decreased risk of stroke within 1 year comprises an Incident Rate Ratio of about 0.47.

[0040] The composition of estradiol and progesterone may be administered orally. Women typically prefer oral treatment, since it is more convenient, particularly women with skin sensitivity. In some embodiments, the progestin is medroxyprogesterone or medroxyprogesterone acetate (MPA). In some embodiments, the conjugated estrogen is conjugated equine estrogen (CEE). In some embodiments, the progestin and conjugated estrogen are administered orally. In some embodiments, the comparator combined HRT is an oral capsule comprising CEE / MPA (such as Prempro®).

[0041] In some embodiments, the composition comprises 0.5 mg or 1 mg estradiol. The estradiol may be estradiol hemihydrate.

[0042] In some embodiments, the composition comprises 100 mg progesterone. The progesterone may preferably be bio-identical progesterone. In some embodiments, the progesterone is micronized progesterone. Advantageously, micronized progesterone is efficiently absorbed in the body.

[0043] In some embodiments, the composition comprises 1 mg estradiol and 100 mg progesterone. Bijuva® is an FDA approved drug comprising 1 mg estradiol and 100 mg micronized progesterone.

[0044] In some embodiments, the estradiol and progesterone are co-formulated, optionally as a soft capsule. Soft capsules readily dissolve in the gastric juices of the stomach, and so typically work faster than other capsules.

[0045] BRIEF DESCRIPTION OF FIGURES

[0046] FIG. 1A is a schematic of the study design; MACE = major adverse cardiovascular events. The first prescription fill for E2 / P4 or CEE / MPA was used to identify the index date. The baseline period spanned from the first medical or pharmacy claim in the data to the index date. The observation period spanned from the index date to the earliest of (a) the day before a treatment switch (i.e. initiation of CEE / MPA for women in the E2 / P4 cohort, or initiation of E2 / P4 for women in the CEE / MPA cohort); (b) the data cut-off date (i.e., June 2021 ); or (c) the end of clinical activity (i.e. the date of the last pharmacy claim before the first gap of >12 months without any pharmacy claim, or the date of the last medical visit claim before the first gap of >12 months without any medical visit claim).

[0047] FIG. 1 B shows the sample selection flowchart for the study described in Example 1

[0048] FIG. 2 shows the post-IPT-weighted MACE in E2 / P4 v CEE / MPA cohorts of Example 1 . FIG. 3A shows the IPT-weighted MACE rates in E2 / P4 v CEE / MPA cohorts of Example 1 in all women aged > 40 years, women aged 40-59 years, and women aged 60-79 years.

[0049] FIG. 3B shows the IPT-weighted MACE rates in E2 / P4 v CEE / MPA cohorts of Example 1 stratified by MACE event subtypes.

[0050] FIG. 4 shows the distribution of the propensity score (PS) before and after inverse probability of treatment (1 I PS) weighting.

[0051] DETAILED DESCRIPTION

[0052] A. Definitions

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art in the technical field of the invention.

[0054] “Combined hormone replacement therapy” or “combined HRT” as used herein refers to a hormone replacement therapy that includes both an estrogen and a progestogen (as opposed to estrogen-only HRT), which is typically used to treat menopause related symptoms. Combined HRT has a decreased risk of endometrial cancer as compared to estrogen-only HRT, and is therefore prescribed to perimenopausal, menopausal and postmenopausal women with an intact uterus (i.e. who have not had a hysterectomy). The therapy is beneficial to women regardless of the menopausal stage, or whether the menopause was surgically- or medically- induced or early menopause (under the age of 45). A variety of different combinations of estrogens and progestogens are known to be used in different combined hormone replacement therapies.

[0055] Typically, menopausal and postmenopausal women are prescribed “continuous combined HRT”, wherein estrogen and progestogen are taken daily. Perimenopausal women (with menopausal symptoms but still having periods) are instead typically prescribed “cyclical HRT” (also known as “sequential HRT”), wherein estrogen is taken daily while progestogen is taken for only part of the month. Cyclical HRT encompasses, but is not limited to, monthly HRT (typically the progestogen is taken for the last 10-14 days of the menstrual cycle every month) and 3-monthly HRT (typically the progestogen is taken for 10-14 days every 3 months). As used herein the term “combined HRT” encompasses continuous combined HRT and cyclical HRT. A “major adverse cardiovascular event” or “MACE” as used herein encompasses, but is not limited to, acute myocardial infarction (Ml), stroke or heart failure. A MACE may be diagnosed, for example, during or on the day before hospitalization, or indicated by medical claims (e.g. revascularization procedures indicative of Ml i.e. , coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI]). The term may encompass both non-fatal and fatal events. Diagnosis and procedure codes to identify different types of MACE are set out in Table 2.

[0056] “Acute myocardial infarction” or “acute Ml” is used herein to refer to myocardial necrosis resulting from acute obstruction of a coronary artery, and includes both non-ST-segment-elevation myocardial infarction (NSTEMI) and ST-segment-elevation myocardial infarction (STEMI). Acute Ml encompasses, but is not limited to, ICD-10 diagnostic codes: 121 .x or I22.x; CPT procedure codes: 33510 - 33516, 33517 - 33521 , 33533 - 33536, 92920, 92921 , 92924, 92925, 92928, 92929, 92933, 92934, 92937, 92938, 92941 , 92943, 92944, 92980, 92981 , 92982, 92984, 92995, 92996, C9600, C9601 , C9602, C9603, C9604, C9605, C9606, C9607, C9608, G0290, G0291 (see Table 2); revascularization procedures indicative of Ml (such as CABG or PCI); or silent Ml determined from serial electrocardiogram.

[0057] “Stroke” as used herein refers to a condition in which poor blood flow to the brain causes cell death. The term stroke encompasses ischemic stroke (such as ICD-10 diagnostic codes I63.x, 164.x), haemorrhagic stroke (such as ICD-10 diagnostic codes 161 .x, I62.x) or rapid onset of neurological deficit lasting >24 hours. The term "stroke” therefore encompasses ischemic stroke and haemorrhagic stroke.

[0058] “Heart failure” or “HF” as used herein refers to an inability of the heart to pump sufficient blood around the body. Heart failure encompasses, but is not limited to, ICD-10 diagnostic code 150.x excluding l50.x2 and l50.8x, i.e. excluding chronic heart failure (see Table 2).

[0059] “Estrogen” or “oestrogen” as used herein refers to any form of naturally-occurring (i.e. endogenous) or synthetic (i.e. non-endogenous) estrogen, including but not limited to estrone (E1 ), estradiol (E2), estriol (E3) and estetrol (E4), and conjugated estrogen (e.g. conjugated equine estrogens). Endogenous estrogens perform a multitude of functions within the human body including regulation of the menstrual cycle, ovulation and fertility.

[0060] “Estradiol” or “E2” as used herein refers to bioidentical estrogen, i.e. estrogen that is chemically and biologically identical to endogenous human estrogen, as represented by the formula below:

[0061] This compound is also known as “17p-estradiol”, “beta-estradiol” or“estra-1 ,3,5 (10)-trience-3- 17p-diol”, has a molecular weight of 272.38, and chemical formula C18H24O2. The term encompasses synthetically produced 17p-estradiol.

[0062] “Conjugated estrogen” as used herein refer to estrogen conjugates and salt derivatives thereof. Example conjugate estrogens include estrone sulfate, sodium estrone sulfate, equilin sulfate and sodium equilin sulfate. Estrogen conjugates found in horses are referred to herein as “conjugated equine estrogens” or “CEE”, and encompass both natural preparations manufactured from the urine of pregnant mares (such as Premarin), and fully synthetic replications of the natural preparations (such as Cenestin and Enjuvia). Conjugated estrogen medication (such as Premarin) typically includes a mixture of estrogens.

[0063] “Progestogen” as used herein refers to both naturally occurring and synthetic steroid hormones that bind to and activate the progesterone receptor. The progestogen can be structurally identical to naturally occurring (i.e. endogenous) forms of progestogens. One example of a naturally occurring progestogen is progesterone. As used herein the tern “progesterone” encompasses naturally occurring progesterone as well as synthetically derived forms that are structurally identical to naturally occurring form. As noted above, the term progestogen also encompasses non-naturally (i.e. non-endogenous) occurring forms of steroid hormones, which are typically referred to as progestins (defined below). Progestogens generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen.

[0064] In the context of hormone replacement therapy, in women with an intact uterus, combinations of estrogens with progestogens are typically recommended. This is because estrogen use that is unopposed by a progestogen has been implicated in increased risk of endometrial cancer. However, studies have also shown that progestogens have androgenic activity and may interact with aldosterone and androgen receptors resulting in fluid retention and other androgenic adverse events, thus increasing the patient’s risk of cardiovascular disease. “Progesterone” or“P4” as used herein refers to progesterone that is chemically and biologically identical to endogenous human progesterone, as represented by the formula:

[0065] The above compound is also known as “pregn-4-ene-3, 20-dione”, has a molecular weight of 314.47, and chemical formula C21H30O2. Progesterone encompasses all forms of the molecule, including synthetically produced forms. By way of non-limiting example progesterone encompasses micronized progesterone. Also encompassed within this term is micronized and partially solubilised progesterone. Also encompassed within this term is micronized progesterone that is partially suspended as well as partially solubilised.

[0066] As used herein, “progestin” refers to a class of synthetic progestagens that are not chemically identical to progestagens which are found in the body (such as progesterone) but produce similar effects. Progestins include, but are not limited to, medroxyprogesterone, medroxyprogesterone acetate, dydrogesterone, norethisterone, norethisterone acetate, norethisterone enanthate, chlormadinone acetate, cyproterone acetate, desogestrel, drospirenone, ethynodiol diacetate, gestodene, levonorgestrel, lynestrenol, megestrol acetate, norethynodrel, norgestimate or norgestrel, as well as derivatives or metabolites thereof.

[0067] A “bio-identical” or “body identical” hormone as used herein refers to hormones that are identical to naturally occurring (i.e. endogenous) hormones produced by the human body. Whilst a bioidentical hormone can be synthetically produced, they nevertheless are considered a bioidentical hormone provided that the synthetically produced hormone is chemically identical to an endogenous human hormone. Examples of bio-identical (also referred to as body-identical) hormones in the context of the invention are estradiol and progesterone (e.g. micronized progesterone).

[0068] “Menopause related symptoms” as used herein encompasses a range of physical and mental symptoms associated with reduced hormone levels (in particular estrogen levels) that occur during perimenopause, menopause and postmenopause. Symptoms include but are not limited to hot flushes (also known as hot flashes), night sweats, vaginal dryness, atrophic vaginitis, recurrent urinary tract infections (UTIs), low mood or anxiety, problems with memory or concentration (or “brain fog”), hair loss, weight gain, insomnia, urogenital atrophy, and low sex drive.

[0069] “Vasomotor symptoms” as used herein encompasses, but is not limited to, hot flushes (also known as hot flashes) and night sweats. Vasomotor symptoms are experienced by the majority of perimenopausal, menopausal and postmenopausal women due to dilatation of blood vessels in the skin that can lead to a sudden increase in blood flow to allow heat loss. Vasomotor symptoms may be graded mild, moderate or severe according to any measurement scales known in the art, and can have a major impact on activities of daily living.

[0070] “Urogenital atrophy” as used herein refers to thinning and shrinking of the tissues of the vulva, vagina, urethra and bladder caused by estrogen deficiency. This results in multiple symptoms such as vaginal dryness and urinary tract infections.

[0071] “Woman” as used herein refers to an adult female human. The women treated in the context of the present invention are typically perimenopausal, menopausal or postmenopausal women with an intact uterus. The plural of woman is women. All aspects and embodiments described herein in the context of a “woman” are equally applicable to “women” and vice versa.

[0072] “Menopausal” as used herein refers to a woman who has not had a natural menstrual period for 12 consecutive months. Menopause typically occurs in a woman between ages 40 and 58 years and includes surgically- or medically-induced menopause or early menopause (under the age of 45 years). The average age of menopause in the UK is around 51 years.

[0073] “Postmenopausal” as used herein encompasses a woman who has not had a natural menstrual period for greater than 12 consecutive months. The term therefore encompasses a woman in which menopause (as defined above) has already occurred.

[0074] “Perimenopausal” as used herein refers to a woman in the transitional period before the menopause when levels of hormones (particularly estrogen) start to decrease and the woman experiences irregular or skipped periods (the “perimenopause”). Perimenopausal women may experience menopause related symptoms, such as hot flushes (also known as hot flashes) and mood changes. Suitable tests to diagnose the perimenopause are known to a person skilled in the art, including follicle stimulating hormone (FSH) tests. The average length of perimenopause is around 4 to 8 years, and perimenopausal women are typically aged around 45-55 years. “Women-years” or “WY” is a measure of time that takes into account both the number of women in a study and the amount of time each woman spends in the study. As used herein, the women- years of a particular cohort (e.g. estradiol and progesterone cohort) is calculated by multiplying the number of women in the cohort by the total number of years that the women are in the study. For example, a study that follows 1 ,000 women for one year would contain 1 ,000 women-years of data.

[0075] “Incident Rate Ratio” (IRR) as used herein is the ratio of incident rate per 10,000 women-years in a first group of subjects versus the incident rate per 10,000 women-years in a second group of subjects. Said IRR can be referred to as an unadjusted (i.e. raw) IRR. By way of example, an unadjusted MACE IRR can be determined taking the MACE incident rate per 10,000 women- years in women receiving E2 / P4 and dividing by the MACE incident rate per 10,000 women- years in women receiving CEE / MPA.

[0076] IRRs may also be calculated and expressed in an adjusted form, whereby the IRR is adjusted to take into account other known MACE risk factors such as age, medical insurance, hormonal therapies dispensed prior to start of treatment with the composition or comparator combined HRT (including oral contraceptives) and comorbidity burden (including cardiovascular disease, hypercholesterolemia, diabetes) in the two groups of subjects. IRRs that are adjusted to take into account other known MACE risk factors are typically referred to herein as IPT-weighted IRRs.

[0077] “Hazard Ratio” (HR) as used herein is the ratio of risk of a MACE in a first group of subjects versus the risk of a MACE in a second group of subjects at a specific time point. Hazard Ratios may be calculated using any suitable methods known in the art, such as Kaplan-Meir analysis. The HR as described herein typically represents the risk of a MACE associated with women receiving compositions as described herein (comprising E2 / P4) as compared with the risk of a MACE associated with women receiving a composition comprising CEE / MPA. HRs may be calculated and expressed in an unadjusted (i.e. raw) form - by simply comparing the risk of a MACE between two groups of subjects.

[0078] HRs may also be calculated and expressed in an adjusted form, whereby the HR is adjusted to take into account other known MACE risk factors such as age, medical insurance, hormonal therapies dispensed prior to start of treatment with the composition or comparator combined HRT (including oral contraceptives) and comorbidity burden (including cardiovascular disease, hypercholesterolemia, diabetes), in the two groups of subjects. HRs that are adjusted to take into account other known MACE risk factors are typically referred to herein as weighted or post-IPT weighted HRs. "Oral administration" or “administered orally” as used herein means that the composition is taken by mouth and is thereby delivered into the gastrointestinal tract.

[0079] “Soft capsule” as used herein refers to a dosage form in which a liquid, semi-solid (e.g. paste or powder) centre is encapsulated by a film or shell of defined shape (such as a gelatin-based shell in soft gelatin capsules).

[0080] “Pill” as used herein refers to any solid form of medication. “Tablet” as used herein refers to a solid composition that is compressed or otherwise formed into a defined shape. A tablet may by plain or encapsulated by a polymer-based coating (“film-coated”), or by a mono-, di-, oligo- or poly-saccharide coating (“sugar-coated”)

[0081] “Excipient” - as used herein this term refers to a compound that is generally safe, non-toxic and neither biologically nor otherwise undesirable. The excipient is substantially inert.

[0082] “Placebo” as used herein refers to a dosage form containing no active ingredient. As described elsewhere herein, the placebo arm of a clinical study can be used as a proxy for the general population since patients in the placebo arm receive no active ingredients throughout the duration of the clinical study.

[0083] B. Methods for preventing MACE or decreasing risk of MACE

[0084] Cardiovascular disease (CVD) refers to a broad range of conditions affecting the heart and blood vessels, including but not limited to myocardial infarction (Ml), angina, heart failure, hypertension, cardiomyopathy, stroke and vascular dementia. CVD is the leading cause of death in women worldwide and results in more than twice as many deaths of women in the UK as breast cancer.

[0085] Perimenopausal, menopausal and postmenopausal women are at an increased risk of CVD. Before menopause, estrogen helps to keep arteries smooth and flexible, and also regulates cholesterol levels and body fat distribution. However, once endogenous estrogen levels decline, the arteries become more prone to developing fatty plaque(s), and narrowing of the arteries. Overall the decline in estrogen levels increases the risk of acute Ml, stroke and heart failure.

[0086] As used herein a MACE encompasses a sub-set of CVD conditions including but not limited to acute Ml, stroke and heart failure. Unexpectedly, this application reports for the first time that a composition comprising estradiol and progesterone (i.e. bio-identical or body-identical hormones) significantly decreases the risk of a MACE versus placebo (a proxy for the general female population) and therefore has a cardioprotective effect in perimenopausal, menopausal and postmenopausal women.

[0087] In further detail, the rates of acute Ml observed in women treated with E2 / P4 were consistently lower than the rates observed in a placebo arm even after inverse probability of treatment (IPT) weighting to control for confounding factors was applied. Specifically, the rates of acute Ml when measured over the entire observation period were 3.5 vs. 23 acute Ml events per 10,000 women- years) and in the first-year post-treatment (4.8 vs. 23 acute Ml events per 10,000 women-years).

[0088] The rates of stroke observed in women treated with E2 / P4 were also consistently lower than the rates observed in a placebo arm when measured over the entire observation period (9.4 vs 14-21 stroke events per 10,000 women-years) and in the first-year post-treatment (13.1 vs 21 stroke events per 10,000 women-years).

[0089] Thus, in a first aspect, the invention provides a method preventing a MACE in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone. In the context of this aspect of the invention in some embodiments the MACE is acute Ml, stroke and / or heart failure. In some embodiments, the MACE is acute Ml and / or stroke. In a related aspect, the invention provides a composition for use in a method of preventing a MACE in a woman, wherein the composition comprises estradiol and progesterone. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for preventing a MACE in a woman, wherein the composition comprises estradiol and progesterone. In these related aspects, in some embodiments the MACE is acute Ml, stroke and / or heart failure. In some embodiments, the MACE is acute Ml and / or stroke.

[0090] In a further aspect, the invention provides a method of reducing the risk of a MACE in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone. In the context of this aspect of the invention in some embodiments the MACE is acute Ml, stroke and / or heart failure. In some embodiments, the MACE is acute Ml and / or stroke. In a related aspect, the invention provides a composition for use in a method of reducing the risk of a MACE in a woman, wherein the composition comprises estradiol and progesterone. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for reducing the risk of a MACE in a woman, wherein the composition comprises estradiol and progesterone. In these related aspects, in some embodiments the MACE is acute Ml, stroke and / or heart failure. In some embodiments, the MACE is acute Ml and / or stroke. In the context of these aspects of the invention, the risk of a MACE can be decreased as compared to a placebo.

[0091] The observations for MACE can be extrapolated more broadly to cardiovascular disease (CVD) overall. Without wishing to be bound by theory, it is thought that estradiol can act as an antioxidant and / or can inhibit vascular inflammation. This means that compositions comprising estradiol and progesterone may prevent CVD.

[0092] The invention therefore also provides a method of preventing cardiovascular disease (CVD), in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone. In a related aspect, the invention provides a composition for use in a method of preventing cardiovascular disease in a woman, wherein the composition comprises estradiol and progesterone. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for preventing cardiovascular disease in a woman, wherein the composition comprises estradiol and progesterone.

[0093] Moreover, this prevention of MACE was seen at a dose of the composition which is therapeutically effective for treating menopause related symptoms. Thus, the composition of the invention has a dual benefit in treating menopause related symptoms while also preventing a MACE.

[0094] The use of combined hormone replacement therapy (HRT) in a woman has been associated with an increased risk of CVD. Indeed, the primary outcome of the landmark WHI study comparing CEE / MPA vs placebo was coronary heart disease (CHD) events (defined as nonfatal Ml, silent Ml or CHD death). The study identified inter alia the following increased risks attributable to CEE / MPA: 7 more CHD events (41 vs 34) and 8 more strokes (45 vs 33) per 10,000 women- years, in women 50-79 years of age. The increase in risk was demonstrated after the first year and persisted.

[0095] It has however unexpectedly been found that women taking a combined HRT containing estradiol and progesterone (i.e. body-identical hormones) exhibit a significantly decreased risk of a MACE such as acute Ml, stroke and heart failure. This decreased risk was first identified relative to women taking combined HRT containing different forms of estrogen and progestogen (i.e. forms of hormones that are not body-identical).

[0096] Thus, in a further aspect, the invention provides a method of decreasing the risk of a MACE associated with combined HRT in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone. In a related aspect, the invention provides a composition for use in decreasing the risk of a MACE associated with combined HRT, wherein the composition comprises estradiol and progesterone.

[0097] All embodiments described herein below are equally applicable to the compositions for use and methods of decreasing the risk of MACE associated with combined HRT or methods of preventing a MACE in a woman.

[0098] (i) Decreased risk of a major adverse cardiovascular event (MACE)

[0099] The major adverse cardiovascular event (MACE) may be selected from at least one of acute myocardial infarction (Ml), stroke and heart failure. In some embodiments, the MACE comprises or consists of acute Ml and heart failure. In some embodiments, the MACE comprises or consists of acute Ml, stroke and heart failure. It follows that, the decreased risk of a MACE may be a decreased risk of acute Ml and / or stroke and / or heart failure. In some embodiments, the stroke is ischemic and / or haemorrhagic stroke.

[0100] In some embodiments of any aspects of the invention, the risk of a MACE is decreased compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA). In some embodiments, the risk of a MACE is decreased compared to a placebo.

[0101] In some embodiments, the decreased risk of a MACE comprises a lower number of MACE per 10,000 women-years. As defined elsewhere herein, women-years is a measure of time that takes into account both the number of women in a particular cohort of the study and the amount of time each woman in that cohort spends in the study. Thus, in the present context, there is a decrease in the number of MACE per 10,000 women-years among women receiving the composition for the use according of the invention (comprising estradiol and progesterone) as compared to a combined HRT comprising progestin and a conjugated estrogen, or as compared to a placebo.

[0102] As described herein, the risk of a MACE may be adjusted to take into account other known MACE risk factors. These risk factors include, for example, age, comorbidities (such as cardiovascular disease, diabetes, hypercholesterolemia, smoking, obesity) and hormonal therapies (such as oral contraceptives) dispensed prior to start of treatment with the composition or comparator combined HRT. In some embodiments, the risk of a MACE is IPT-weighted using one or more of the following covariates: age; census region; healthcare insurance plan type; comorbidities, the number of comorbidities and comorbidity burden (Elixhauser comorbidity index category); hip or pelvis fracture; inpatient surgery; drug classes and distinct non-topical agents dispensed prior to the combined HRT, and month and year of beginning the combined HRT. In some embodiments, the risk of a MACE (e.g. acute Ml, stroke and / or heart failure) is decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% or at least 85%, before or after any IPT-weighting (or other adjustment to take into account other known MACE risk factors).

[0103] In some embodiments, the risk of MACE may be decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 55-65 MACE events per 10,000 women-years, or about 61 .9 MACE events per 10,000 women-years. In women aged 40-59 years, the risk of MACE may be decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 30-40 MACE events per 10,000 women-years, or about 37.7 MACE events per 10,000 women-years. In women aged 60-79 years, the risk of MACE may be decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 100-110 MACE events per 10,000 women-years, or about 106.3 MACE events per 10,000 women-years.

[0104] In some embodiments, the risk of heart failure (HF) is decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 25-35 HF events per 10,000 women-years, or about 30.9 HF events per 10,000 women-years. In some embodiments, the risk of acute Ml is decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 15-25 acute Ml events per 10,000 women-years, or about 19.4 acute Ml events per 10,000 women-years. In some embodiments, the risk of stroke decreased as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) by about 15-25 stroke events per 10,000 women-years, or about 19.9 stroke events per 10,000 women-years.

[0105] The decreased risk of a MACE may be expressed as an Incident Rate Ratio (IRR). As defined elsewhere herein, IRR is a measure of the ratio of the incident rate per 10,000 women-years in women receiving the composition for use according of the invention (comprising estradiol and progesterone) versus the incident rate per 10,000 women-years for women receiving combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), or versus the incident rate per 10,000 women-years for women receiving a placebo. The IRR may be calculated and expressed pre- or post- adjustment (e.g. IPT weighted) to take into account other known MACE risk factors. In some embodiments, the decreased risk of a MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), comprises an adjusted (e.g. IPT weighted) IRR of about 0.17-0.45, or of about 0.28. In some embodiments, the decreased risk of a MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), comprises an unadjusted IRR of about 0.22. Thus, the risk of a MACE may be decreased by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA).

[0106] In women aged 40-59 years, the decreased risk of a MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), may comprise an adjusted (e.g. IPT weighted) IRR of 0.23-0.65, or of about 0.39. Thus, the risk of a MACE in a woman aged 40-59 years may be decreased by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA).

[0107] In women aged 60-79, the decreased risk of a MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), may comprise an adjusted (e.g. IPT weighted) IRR of 0.09-0.79, or of about 0.27. Thus, the risk of a MACE in a woman aged 60-79 years may be decreased by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, or at least 70% as compared with combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA).

[0108] In embodiments wherein the MACE is or comprises acute Ml, the decreased risk of acute Ml as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) may comprise an adjusted (e.g. IPT weighted) IRR of about 0.08-0.63, or of about 0.20-0.25, or of about 0.23 or about 0.22. In some embodiments, the decreased risk of acute Ml as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), comprises an unadjusted IRR of about 0.24. Thus, the decreased risk of acute Ml may be decreased by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70% or at least 75% as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA).

[0109] In embodiments wherein the MACE is or comprises heart failure, the decreased risk of heart failure as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) may comprise an adjusted (e.g. IPT weighted) IRR of about 0.11 -0.51 , or of about 0.24. In some embodiments, the decreased risk of heart failure as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), comprises an unadjusted IRR of about 0.14. Thus, the decreased risk of heart failure may be decreased by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75%, at least 80% or at least 85% as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA).

[0110] In embodiments wherein the MACE is or comprises stroke, the decreased risk of stroke as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) may comprise an adjusted (e.g. IPT weighted) IRR of about 0.15-0.70, or of about 0.32. In some embodiments, the decreased risk of stroke as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), comprises an unadjusted IRR of about 0.28. In some embodiments, the decreased risk of stroke as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA), may be decreased by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 70%.

[0111] Alternatively, or in addition, the decreased risk of a MACE associated with compositions used in accordance with the invention may be expressed as a Hazard Ratio (HR). In the context of the present invention, the HR is the risk of MACE in women receiving the composition for use according of the invention (comprising estradiol and progesterone) versus the risk of a MACE in women receiving combined HRT comprising progestin and a conjugated estrogen and / or a placebo, at a specific time point. A Hazard Ratio may be calculated, for example, by Kaplan-Meier analysis. The HR may be calculated and expressed pre- or post- adjustment (e.g. IPT weighted) to take into account other known MACE risk factors.

[0112] In some embodiments, the decreased risk of MACE comprises a lower number of MACE within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 2 years from the start of treatment. In certain embodiments, the decreased risk of a MACE is or comprises a lower number of MACE within 1 or 2 years.

[0113] In embodiments wherein the decreased risk of a MACE is or comprises a decrease in the number of MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 2 years from the start of treatment, the decreased risk of a MACE within 2 years may comprise an adjusted (e.g. IPT weighted) Hazard Ratio of about 0.27- 0.50, or of about 0.37. Thus, the decreased risk of a MACE within the 2 years may be at least at least 45%, at least 50%, at least 55% or at least 60%.

[0114] In embodiments wherein the decreased risk of a MACE is or comprises a decrease in the number of MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year from the start of treatment, the decreased risk of a MACE within 1 year may comprise an adjusted (e.g. IPT weighted) Incident Rate Ratio of about 0.23- 0.65, or of about 0.39. In some embodiments, the decreased risk of a MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year, may comprise an unadjusted Incident Rate Ratio of about 0.30. Thus, the decreased risk of a MACE within the 1 year may be at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% at least 60%, at least 65% or at least 70%.

[0115] In some embodiments, the decreased risk of a MACE is or comprises a decrease in the number of MACE as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 4 months from the start of treatment, optionally wherein the decreased risk of a MACE within 4 months comprises an adjusted (e.g. IPT weighted) Hazard Ratio of about 0.14- 0.84, or of about 0.34. Thus, the decreased risk of a MACE within the 4 months may be at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% at least 60%, at least 65%, at least 70% or at least 75%.

[0116] In embodiments wherein the MACE is or comprises acute Ml, the decreased risk of acute Ml as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year may comprise an adjusted (e.g. IPT weighted) Incident Rate Ratio of about 0.08- 0.77, or of about 0.24. In some embodiments, the decreased risk of acute Ml as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year, may comprise an unadjusted Incident Rate Ratio of about 0.26. Thus, the decreased risk of acute Ml within the 1 year may be at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% at least 60%, at least 65%, at least 70% or at least 75%.

[0117] In embodiments wherein the MACE is or comprises heart failure, the decreased risk of heart failure as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year may comprise an adjusted (e.g. IPT weighted) Incident Rate Ratio of about 0.18-0.82, or of about 0.38. In some embodiments, the decreased risk of heart failure as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year, may comprise an unadjusted Incident Rate Ratio of about 0.21 . Thus, the decreased risk of heart failure within the 1 year may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25% at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% at least 60%, at least 65%, at least 70% or at least 75%.

[0118] In embodiments wherein the MACE is or comprises stroke, the decreased risk of stroke as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year may comprise an adjusted (e.g. IPT weighted) Incident Rate Ratio of about 0.47. In some embodiments, the decreased risk of stroke as compared to a combined HRT comprising progestin and a conjugated estrogen (e.g. CEE / MPA) within 1 year, may comprise an unadjusted Incident Rate Ratio of about 0.40. Thus, the decreased risk of stroke within the 1 year may be at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60%.

[0119] In embodiments wherein the risk of a MACE is decreased compared to placebo, the decreased risk of MACE (e.g. acute Ml, stroke and / or heart failure) may be in woman aged 50-79 years. The risk of MACE compared to placebo (e.g. in woman aged 50-79 years) may be decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% or at least 80% before or after any IPT-weighting (or other adjustment to take into account other known MACE risk factors). In some embodiments, the unadjusted MACE rate per 10,000 women-years may be decreased as compared to placebo.

[0120] In embodiments wherein the MACE is or comprises acute Ml, the unadjusted rate of acute Ml per 10,000 women years of may be decreased as compared to placebo, for example by at least at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% or at least 80% (particularly in women aged 50-79).

[0121] In embodiments wherein the MACE is or comprises stroke, the unadjusted rate of stroke per 10,000 women years of may be decreased as compared to placebo, for example by at least at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% at least 50%, at least 55%, at least 60%, at least 65%, or at least 70% (particularly in women aged 50-79).

[0122] (ii) Administration to a woman or women

[0123] The current invention is concerned with the use of compositions comprising an estrogen (estradiol) and a progestogen (progesterone) in a woman or women. As described herein, combined HRT (i.e. estrogen and progestogen) is beneficial for the treatment of menopause related symptoms (in particular symptoms related to estrogen deficiency). It follows that, the woman administered the composition for use according to the invention may be a perimenopausal, menopausal or postmenopausal woman, preferably a postmenopausal woman. As defined elsewhere herein, a menopausal woman is a woman who has not had a menstrual period for 12 consecutive months, and is typically aged 50 years or over. Further defined elsewhere herein, a postmenopausal woman is a woman who has not had a menstrual period for greater than 12 consecutive months. Also defined elsewhere herein, a perimenopausal woman is a woman experiencing menopause related symptoms before menopause, and is typically aged between 45-55 years. In preferred embodiments, the woman administered the compositions for use according to the invention has not had a period for at least 12 months (i.e. is a menopausal or postmenopausal woman). Nonetheless, perimenopausal, menopausal or postmenopausal women may be younger than 45 years, for example due to surgically- or medically- induced menopause or early menopause.

[0124] The woman administered the composition for use according to the invention may be aged 40-79 years. The present Examples show a decreased risk of a MACE in woman aged 40-79 receiving a composition comprising estradiol and progesterone compared to other combined HRTs. The Examples demonstrate a decreased risk of a MACE in woman aged 40-79 receiving a composition comprising estradiol and progesterone compared to a placebo.

[0125] The woman may be aged at least 40 years, at least 45 years, at least 50 years, at least 55 years, at least 60 years, at least 65 years, at least 70 years or at least 75 years. The woman may be aged 79 years or less, 74 years or less, 69 years or less, 64 years or less, 59 years or less, 54 years or less, 49 years or less or 45 years or less. Thus, in some embodiments, the woman may be aged 45-79 years, 50-79 years, 40-59 years or 60-79 years. In some embodiments, the woman is be aged 40-59 years. In some embodiments, the woman is aged 60-79 years.

[0126] The present Examples show a decreased risk of a MACE in woman aged 40-59 years or 60-79 years receiving a composition comprising estradiol and progesterone compared to other combined HRTs (e.g. CEE / MPA).

[0127] The present Examples show a decreased risk of a MACE in women aged 50-79 years receiving a composition comprising estradiol and progesterone compared to the general female population, not receiving combined HRT.

[0128] In some embodiments, the woman is aged 50-59 years. More than 60% of the women studied in the present Examples were in this age category. Based on an average age of 51 years for menopause onset, women in this age category are typically <10 years from menopause onset. Without wishing to be bound by theory, a better decrease in MACE is expected to be achieved if the composition for use according to the invention is first administered in this window of opportunity (the “timing hypothesis”).

[0129] Preferably, the woman has an intact uterus. Combined HRT is recommended for such woman as the progestogen provides endometrial protection.

[0130] (Hi) Comparator combined HR T

[0131] As noted elsewhere, the compositions for use in accordance with the invention comprise the hormones estradiol and progesterone, which are bio-identical. Said compositions have been found to decrease the risk of a MACE compared to other combined HRTs. The risk of a MACE in some embodiments, is decreased as compared to a combined HRT comprising synthetic (i.e. non-endogenous or non-bio-identical) hormones.

[0132] In some embodiments, the risk of a MACE is decreased compared to a combined HRT comprising a progestin and / or conjugated estrogen. In some embodiments, the risk is decreased compared to a combined HRT comprising progestin and a conjugated estrogen (referred to herein as the “comparator combined HRT”), such as CEE / MPA.

[0133] In some embodiments, the progestin is selected from the group consisting of medroxyprogesterone, medroxyprogesterone acetate, dydrogesterone, norethisterone, norethisterone acetate, norethisterone enanthate, chlormadinone acetate, cyproterone acetate, desogestrel, drospirenone, ethynodiol diacetate, gestodene, levonorgestrel, lynestrenol, megestrol acetate, norethynodrel, norgestimate or norgestrel. In some embodiments, the progesitn is medroxyprogesterone, medroxyprogesterone acetate (MPA) or a derivative or metabolite thereof. In preferred embodiments, the progestin is medroxyprogesterone acetate (MPA).

[0134] In preferred embodiments, the conjugated estrogen is conjugated equine estrogen (CEE) or a derivative or metabolite thereof. In some embodiments the conjugated equine estrogen is selected from estrone sulfate, equilin sulfate or a derivative or metabolite thereof.

[0135] Thus, in some embodiments, the comparator combined HRT comprises medroxyprogesterone acetate (MPA) or a derivative or metabolite thereof, and a conjugated equine estrogen (CEE) or a derivative or metabolite thereof. Preferably, the comparator combined HRT comprises or consists of medroxyprogesterone acetate (MPA) and conjugated equine estrogen (CEE). In some embodiments, the comparator combined HRT comprises synthetic CEE / MPA.

[0136] In some embodiments, the progestin and conjugated estrogen (e.g. MPA / CEE) are coadministered (e.g. co-formulated). In other words, the progestin (e.g. medroxyprogesterone acetate (MPA)) and conjugated estrogen (e.g. conjugated equine estrogen CEE) may be coformulated together in a single dosage form (e.g. as a fixed dose combination). In alternative embodiments, the progestin and conjugated estrogen of the comparator combined HRT are separately administered. The comparator combined HRT may be continuous combined HRT or cyclical HRT (defined elsewhere herein).

[0137] The comparator combined HRT may be administered orally, transdermally (e.g. in a patch, gel or spray) or vaginally (e.g. vaginal ring, pessary, Mirena coil, cream). For example, the estrogen (e.g. conjugated estrogen) and / or the progestogen (e.g. medroxyprogesterone acetate) of the comparator combined HRT may be administered orally.

[0138] In preferred embodiments, the comparator combined HRT is administered via the same route of administration as the composition comprising estradiol and progesterone (e.g. orally). Studies analysing the risk profile of transdermally administered combined HRT may not be reflective of the risk profile of orally administered combined HRT given that transdermal administration and oral administration lead to differences in metabolic processing of the combined HRT. By way of example, transdermal administration may bypass the first-pass hepatic effect (i.e. bypassing the liver).

[0139] In some embodiments, the comparator combined HRT is administered for the treatment of menopause related symptoms. In some embodiments, the comparator combined HRT is administered at an effective dose (or therapeutically effective amount) for the treatment of menopause related symptoms. In some embodiments, the comparator combined HRT comprises around 0.3 - 0.625mg CEE and around 1 .5 - 5 mg MPA, optionally 0.625mg CEE and 2.5 mg MPA. In some embodiments, the comparator combined HRT is Prempro®.

[0140] C. Compositions comprising estradiol and progesterone

[0141] As described elsewhere, the composition for use according to the invention comprises estradiol (i.e. 17p-estradiol (structure shown elsewhere herein). In some embodiments, the estradiol is in a hemihydrate form (i.e. estradiol hemihydrate). In preferred embodiments, the progesterone in the composition for use according to the invention is micronized progesterone (structure shown elsewhere herein). Thus, in a further preferred embodiment, the composition for use according to the invention comprises estradiol (i.e. 17p- estradiol) and micronized progesterone. In specific examples, the composition for use according to the invention is Bijuva® / Bijuve®.

[0142] In other embodiments, the progesterone in the composition for use according to the invention may comprise micronized and partially solubilised progesterone. In further embodiments, the progesterone in the composition for use according to the invention may comprise micronized progesterone that is partially suspended and also partially solubilised progesterone.

[0143] As noted elsewhere, the composition for use according to the invention preferably comprise bioidentical (or body-identical) hormones such as estradiol and progesterone.

[0144] In some embodiments, the composition for use according to the invention comprises 0.5 mg - 4mg of estradiol, optionally 0.5 mg or 1 mg estradiol. In preferred embodiments, the composition for use according to the invention comprises 0.5 mg or 1 mg estradiol. In some embodiments, the composition for use according to the invention comprises 100 mg - 300 mg of progesterone (e.g. micronized progesterone), optionally 100 mg or 200 mg progesterone (e.g. micronized progesterone). It is particularly preferred that the composition for use according to the invention comprises 100 mg progesterone. In some embodiments, the progesterone is micronized.

[0145] Thus, in some embodiments, the weight ratio of estradiol (e.g. 17p-estradiol) to progesterone (e.g. micronized progesterone) in the composition for use according to the invention is between around 1 :25 to around 1 :600. For example, the weight ratio of estradiol (e.g. 17p-estradiol) to progesterone (e.g. micronized progesterone) in the composition for use according to the invention may be around 1 :100, around 1 :200, or around 1 :400.

[0146] The compositions that are described herein comprise an effective amount (e.g. therapeutically effective amount) of estradiol and progesterone. In particularly preferred embodiments, the composition for use according to the invention comprises 1 mg estradiol and 100 mg progesterone (e.g. micronized progesterone). In some embodiments, the composition for use according to the invention comprises 0.5 mg estradiol and 100 mg progesterone (e.g. micronized progesterone).

[0147] In preferred embodiments, the estradiol (e.g. 17 -estradiol) and progesterone (e.g. micronized progesterone) are co-formulated. In other words, estradiol and progesterone can be formulated into a single dosage form (e.g. as a fixed dose combination). In said embodiments, estradiol and progesterone are co-administered.

[0148] In alternative embodiments, the estradiol (e.g. 17p-estradiol) and progesterone (e.g. micronized progesterone) are separately formulated.

[0149] In any aspect of the present invention, the estradiol and progesterone (e.g. a composition of estradiol and progesterone) may be administered orally, transdermally (e.g. in a patch, gel or spray) and / or vaginally (e.g. vaginal ring, pessary, cream, Mirena coil). Oral administration is preferred, particularly for women with skin sensitivity. Typically, women prefer oral treatment since it is more convenient.

[0150] The compositions for use according to the invention may be formulated so as to comprise one or more pharmaceutically acceptable carriers or excipients. Alternatively or in addition, the compositions for use according to the invention may be formulated as to comprise one or more additional agents selected from but not limited to: binding agents; disintegrants; lubricants; glidants; fillers; and / or diluents. In some embodiments, the composition for use according to the invention may be formulated so as to comprise medium chain mono- and di-glycerides and optionally lauroyl polyoxyl-32 glycerides.

[0151] Glycerides are esters formed from glycerol and at least one fatty acid. Glycerol has three hydroxyl functional groups. One, two or three (i.e. all) of the hydroxyl functional groups can be esterified to one or more fatty acids. An esterified glycerol in which only a single hydroxyl functional group has been esterified to a fatty acid is referred to as a mono-glyceride (or monoglyceride). An esterified glycerol in which two of the hydroxyl functional groups have been esterified to two fatty acids is referred to as a di-glyceride (or diglyceride). An esterified glycerol in which all three of the hydroxyl functional groups have been esterified to three fatty acids are referred to as a tri-glyceride (or triglyceride).

[0152] As noted above, in some embodiments the compositions for use comprise medium chain monoglycerides and di-glycerides and optionally tri-glycerides. In this context “medium chain” relates to the fatty acid component of the glyceride. Specifically, “medium chain” is used in the context of the number of carbon atoms possessed by the fatty acid(s) in the glyceride. In some embodiments, a medium chain mono-, di- or tri- glyceride comprises a fatty acid with 6-12 carbon atoms. In further embodiments, a medium chain mono-, di-, or tri- glyceride comprises a fatty acid with an aliphatic tail of 6-12 carbon atoms. Thus in some embodiments, the compositions for use comprise mono-, di-, or tri- glycerides with C6-C12 fatty acids. In some embodiments, the mono-, di-, or tri- glycerides comprise at least one fatty acid selected from: caproic acid (hexanoic acid), caprylic acid (octanoic acid), capric acid (decanoic acid), lauric acid (dodecanoic acid) and combinations thereof. Further, the mono-, di, or tri- glycerides may comprise salts and / or esters of the fatty acids. Therefore, in other embodiments, the glycerides comprise at least one salt / ester selected from: caproate (hexanoate), caprylate (octanoate), caprate (decanoate), laurate (dodecanoate) and combinations thereof.

[0153] In some embodiments, the mono-, di, or tri- glycerides comprise a combination of medium chain fatty acids. In a preferred embodiment, the composition comprises medium chain mono- and diglycerides that are predominantly caprylic (octanoic) acid and capric (decanoic) acid. As used herein “predominantly” refers to greater than 90% by weight. Therefore, in a further preferred embodiment the medium chain mono- and di- glycerides comprise greater than 90% by weight of caprylic (octanoic) acid and capric (decanoic) acid.

[0154] As noted above, the compositions for use according to the invention may be formulated so as to comprise one or more pharmaceutically acceptable carriers or excipients in addition to estradiol and progesterone an example being lauroyl polyoxyl-32 glycerides. Lauroyl polyoxyl-32 glycerides are also known as lauroyl macrgolglycerides 32 or lauroyl macrogol-32 glycerides. As such, the terms lauroyl polyoxyl-32 glycerides, lauroyl macrgolglycerides 32 and lauroyl macrogol-32 glycerides can be used interchangeably.

[0155] Therefore, in a further embodiment, the composition for use according to the invention may be formulated so as to comprise medium chain mono- and di-glycerides and optionally lauroyl macrgolglycerides 32. As noted above, in some embodiments, the composition for use according to the invention may further comprise medium chain tri-glycerides. In some embodiments, the composition for use according to the invention comprises or consists of solubilised estradiol and micronized progesterone that is suspended in a mixture of medium chain mono- and diglycerides and lauroyl polyoxyl-32 glycerides. In some embodiments, the composition for use according to the invention comprises or consists of solubilised estradiol and micronized progesterone that is suspended in a mixture of medium chain mono- and di-glycerides and lauroyl macrgolglycerides 32. In some embodiments, the composition for use according to the invention comprises or consists of solubilised estradiol and micronized progesterone that is suspended in a mixture of medium chain mono- and di-glycerides and lauroyl macrogol-32 glycerides.

[0156] In some embodiments, the composition for use comprises estradiol, progesterone, mono-, diglycerides predominantly comprising caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl macrgolglycerides 32. In a further embodiment, the composition for use comprises estradiol, progesterone, mono-, di- glycerides predominantly comprising caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl polyoxyl-32 glycerides. In a further embodiment, the composition for use comprises estradiol, progesterone, mono-, di- glycerides predominantly comprising caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl macrogol-32 glycerides.

[0157] In some embodiments, the composition for use comprises estradiol, progesterone, mono-, diglycerides comprising greater than 90% by weight of caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl macrgolglycerides 32. In a further embodiment, the composition for use comprises estradiol, progesterone, mono-, di- glycerides comprising greater than 90% by weight of caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl polyoxyl-32 glycerides. In a further embodiment, the composition for use comprises estradiol, progesterone, mono-, di- glycerides comprising greater than 90% by weight of caprylic (octanoic) acid and capric (decanoic) acid as well as lauroyl macrogol-32 glycerides.

[0158] In preferred embodiments, the composition for use according to the invention may be formulated for oral administration. In some embodiments, the composition is in the form of a pill, tablet (e.g. a film coated, plain or sugar-coated tablet), or preferably soft capsule (e.g. soft gelatin capsule). Alternatively, the composition for use according to the invention may be formulated for transdermal administration, for example in the form of a patch, gel or spray. In other embodiments, the composition for use according to the invention may be formulated for vaginal administration.

[0159] In some embodiments, the composition for use is formulated as a capsule, wherein the capsule comprises a centre and a shell. Thus, in certain embodiments the composition for use is formulated as a capsule comprising estradiol, progesterone, medium chain mono- and diglycerides and lauroyl polyoxyl-32 glycerides in the centre. In certain embodiments the composition for use is formulated as a capsule comprising estradiol, progesterone, medium chain mono- and di-glycerides and lauroyl macrgolglycerides 32 in the centre. In some embodiments, the composition for use is formulated as a capsule comprising estradiol, progesterone, medium chain mono-glycerides, di-glycerides and lauroyl macrogol-32 glycerides in the centre. In such embodiments, the capsule shell may contain one or more, or preferably all, of gelatin 200 Bloom, hydrolysed gelatin, glycerine (E422), allura red (E129), and titanium dioxide (E171 ). The capsule may shell may also comprise printing ink, such as Opacode® White WB (containing propylene glycol (E1520), titanium dioxide (E171 ), polyvinyl acetate phthalate, polyethylene glycol (E1521 ) and ammonium hydroxide (E527)). Thus, in certain embodiments the composition for use is formulated as a soft capsule comprising medium chain mono- and di-glycerides and lauroyl polyoxyl-32 glycerides in the centre; gelatin 200 Bloom, hydrolysed gelatin, glycerine (E422), allura red (E129) and titanium dioxide (E171 ) in the capsule shell; and optionally Opacode® White WB printing ink (containing propylene glycol (E1520), titanium dioxide (E171 ) polyvinyl acetate phthalate, polyethylene glycol (E1521 ) and ammonium hydroxide (E527)).

[0160] In some embodiments, the compositions for use according to the invention, are provided in the form of pharmaceutical kits, optionally wherein the kits contain instructions for use. A pharmaceutical kit may comprise a plurality of dosage units of compositions as described herein, for example 28 or 84 oral capsules.

[0161] In some embodiments, the compositions for use according to the invention may be coadministered or co-formulated with testosterone. Testosterone levels also fall during perimenopause, menopause and postmenopause. When testosterone levels fall, it can manifest as loss of libido, fatigue and brain sharpness.

[0162] In embodiments of any aspect of the invention, the composition comprising estradiol and progesterone may be administered at an effective dose (or therapeutically effective amount) for treating menopause related symptoms in perimenopausal, menopausal and postmenopausal women. In preferred embodiments, the composition comprising estradiol and progesterone are administered at an effective dose (or therapeutically effective amount) for treating estrogen deficiency symptoms in perimenopausal, menopausal and postmenopausal women.

[0163] In embodiments of any aspect of the invention, the composition comprising estradiol and progesterone may be administered at a prophylactically effective dose for preventing a MACE (e.g. acute Ml, stroke or heart failure). In embodiments of any aspect of the invention, the composition comprising estradiol and progesterone may be administered at a prophylactically effective dose for preventing cardiovascular disease (CVD).

[0164] D. Methods of combined HRT and treating menopause related symptoms

[0165] In another aspect, the present invention provides a method of combined HRT in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a related aspect, the invention provides a composition for use in a method of combined HRT in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for combined HRT, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen.

[0166] In any aspects of the invention, the compositions for use (comprising estradiol and progesterone) are preferably administered as continuous combined HRT. Alternatively, the compositions for use (comprising estradiol and progesterone separately) may be administered as cyclical HRT, for example monthly HRT or 3-monthly HRT. Methods of continuous combined HRT and cyclical HRT are known to a person skilled in the art and described elsewhere herein.

[0167] In another aspect, the present invention provides a method of selecting a combined HRT, comprising (i) identifying a woman as suitable for combined HRT; (ii) selecting a combined HRT, wherein the selected combined HRT has been identified as a combined HRT associated with a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen, wherein the selected combined HRT is a composition comprising estradiol and progesterone. In some embodiments, the method of selecting a combined HRT, further comprises administering to the woman an effective amount (or therapeutically effective amount) of the selected combined HRT (i.e. combined HRT comprising estradiol and progesterone).

[0168] Combined HRT can be used to treat menopause related symptoms associated with perimenopause, menopause and postmenopause. In a preferred embodiment, the combined HRT is used to treat menopause related symptoms. As noted elsewhere estradiol is the main active ingredient in the compositions for use in accordance with the invention, with progesterone added as a second active ingredient to ensure endometrial protection.

[0169] Thus, in another aspect, the present invention provides a method of treating menopause related symptoms in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a related aspect, the invention provides a composition for use in a method of treating menopause related symptoms in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA). In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for menopause related symptoms, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen (e.g. CEE / MPA).

[0170] In some embodiments, the menopause related symptoms comprise one or more of the following symptoms: vasomotor symptoms, vaginal dryness, atrophic vaginitis, urinary tract infections (e.g. recurrent UTIs), low mood or anxiety, problems with memory or concentration (e.g. “brain fog”), hair loss, weight gain, insomnia, urogenital atrophy and low sex drive.

[0171] In some embodiments, the menopause related symptoms comprise or consist of vasomotor symptoms, preferably moderate to severe vasomotor symptoms. As described elsewhere, the intensity of vasomotor symptoms can be graded according to any measurement scales known in the art. By way of non-limiting example vasomotor symptoms can be graded as mild (sensation of heat without sweating), moderate (sensation of heat with sweating but able to continue activity), or severe (sensation of heat with sweating, causing cessation of activity). Several existing combined hormone replacement therapies (such as Bijuva® / Bijuve®, Prempro®) are approved for the treatment of vasomotor symptoms due to menopause. Non-limiting examples of vasomotor symptoms include hot flushes (or hot flashes) and night sweats.

[0172] The menopause related symptoms described herein can be associated with hormone deficiency that occurs during perimenopause, menopause and postmenopause. Therefore, the present invention also provides methods of treating hormone deficiency in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a related aspect, the invention provides a composition for use in a method of treating hormone deficiency in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for hormone deficiency, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen.

[0173] In some embodiments, the hormone deficiency is estrogen deficiency. In other embodiments, the hormone deficiency is progesterone deficiency. Treatment of hormone deficiency encompasses treatment of symptoms associated with hormone deficiency, preferably symptoms associated with estrogen deficiency. Therefore, the present invention also provides methods of treating estrogen deficiency symptoms in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a related aspect, the invention provides a composition for use in a method of treating estrogen deficiency symptoms in a woman, wherein the composition comprises estradiol and progesterone, and wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen. In a further related aspect, the invention provides uses of a composition for the manufacture of a medicament for estrogen deficiency symptoms, wherein the composition comprises estradiol and progesterone, and wherein the combined HRT has a decreased risk of a MACE compared to a combined HRT comprising a progestin and a conjugated estrogen.

[0174] In some embodiments, the methods described herein comprise concurrent administration of testosterone to the woman. As described elsewhere herein, testosterone levels also fall during perimenopause, menopause and postmenopause and can manifest as loss of libido. Testosterone is typically formulated as a gel.

[0175] All embodiments described herein relating to the composition for use according to the preceding aspects of the invention (see in particular, Sections B and C) are equally applicable to these further aspects of the invention.

[0176] Incorporation by reference

[0177] Various publications are cited in the foregoing description and throughout the following examples, each of which is incorporated by reference herein in its entirety.

[0178] EXAMPLES

[0179] The invention will be further understood with reference to the following non-limiting examples.

[0180] Example 1 - Observational study of MACE in E2 / P4 vs CEE / MPA cohorts

[0181] A first observational study to directly compare risk of major adverse cardiovascular events (MACE) between women receiving E2 / P4 and those receiving CEE / MPA was conducted using real-world claims data from Symphony Health Solutions’ Integrated Dataverse® for the period of April 2019 - June 2021 . The Symphony database is a large US claims database that includes pharmacy and medical claims from >317 million active patients in the US. The size of the database makes it particularly well suited for detecting MACE events in women receiving combined HRT.

[0182] Study Design, Patient Selection and Statistical Analysis

[0183] The study design is illustrated in Figures 1A and 1 B. Women were classified into E2 / P4 or CEE / MPA cohorts based on their first dispensing claim for E2 / P4 or CEE / MPA. Evidence of medical and pharmacy clinical activity was required to ensure that the women were active in the Symphony database when the baseline patient characteristics were measured. The duration of the baseline period (from first medical or pharmacy claim in the data to first dispensing claim for E2 / P4 or CEE / MPA) was allowed to vary to maximize the sample size and was controlled for in the analyses.

[0184] Eligible women were those:

[0185] Aged >40 years

[0186] Having >1 prescription fill for E2 / P4 or CEE / MPA

[0187] Having >1 medical claim and >1 pharmacy claim before the index date, with continuous clinical activity (i.e. no gap >12 months between two medical- or prescription- claims for hormone therapy or any other drug) for > 6 months after the index date;

[0188] No hospitalization with diagnosis of MACE before or on index date (MACE = acute myocardial infarction [Ml], ischemic or hemorrhagic stroke, or heart failure, identified using the ICD10 codes and CPT procedure codes in Table 2 below).

[0189] Of the 132,567 women aged >40 years with >1 dispensing claim for E2 / P4 or CEE / MPA between April 2019 and June 2021 in the Symphony Database, 6,520 and 29,426 were respectively identified in the E2 / P4 cohort and the CEE / MPA cohort based on the sample selection criteria above.

[0190] Patient characteristics including demographics, comorbidities and potential risk factors for MACE were assessed (see Table 1 below). Inverse probability of treatment (IPT) weighting methodology was applied to control for confounding when comparing the study cohorts. IPT weights were estimated from a propensity score model that included the following baseline covariates: age category; census region; healthcare insurance plan type; comorbidity burden (Elixhauser comorbidity index category [Gagne et al, 2011 J Clin Epidemiol. 64(7): 749-759]); hip or pelvis fracture; inpatient surgery; selected comorbidities, dispensing of selected drug classes (selected based on their frequency and clinical relevance for menopause management or MACE risk); the number of comorbidities; the number of distinct non-topical agents dispensed during the baseline period; month and year of the index date, and duration of the baseline period. To reduce the influence of large weights, the IPT weights were stabilized and truncated at the 99.5 percentile to reduce the influence of large weights.

[0191] Standardized differences were used to compare the distribution of baseline patient characteristics before and after IPT weighting. To align with the literature, a standardized mean difference threshold of >|0.15| was used to identify imbalanced covariates (indicated by a * in Table 1 below).

[0192] Table 1 : Women Baseline Characteristics Post-IPT Weighting; * = statistically significant

[0193]

[0194]

[0195] dx, diagnosis codes; HT, hormonal therapy; Ml, myocardial infarction; STDIFF, standardized differences; tx, drug dispensing.aThe symbol * is used to indicates imbalanced covariates (i.e., STDIFF > / O. 151).bThe Elixhauser Comorbidity Index assigns integer values to 20 comorbidities identified on the basis of diagnosis codes. Lower scores indicate lesser disease burden while higher scores indicate greater disease burden (15). Underlying comorbidities were identified over a maximum period of six months before the index date.cAnti-arrhythmic drug classes included sodium-channel blockers and potassium-channel blockers.dWomen with MACE events (defined as hospitalization for heart failure, acute myocardial infarction, or stroke) in the baseline period were excluded from the sample based on sample inclusion / exclusion criteria.eDrug classes used to identify cardiovascular diseases include ACE inhibitors, adenosine receptor antagonists, angiotensin II antagonists, anti-arrhythmia agents, antihypertensives, betablockers, calcium channel blockers, digoxin, direct renin inhibitors, diuretics, IF channel inhibitors, and nitrites.fDispensing of bisphosphonates were used to identify osteoporosis.

[0196] 9Categories of comorbidities include cardiovascular, diabetes, hypercholesterolemia, obesity, and osteoporosis identified by diagnosis codes.

[0197] IPT weighting resulted in well-balanced cohorts with respect to most covariates (Table 1 ), thus the IPT weighting controlled for confounding. The distribution of the propensity score was similar between the two cohorts post-weighting, also indicating successful weighting (Figure 4).

[0198] Outcomes and Measurements

[0199] Outcomes were measured during the observation period (see Figure 1), which was an average of 1 .2 years for the E2 / P4 cohort, and an average of 1 .4 years for the CEE / MPA cohort.

[0200] The primary study outcome was the first MACE after the initiation of E2 / P4 or CEE / MPA. MACE included diagnosis of acute Ml, ischemic or haemorrhagic stroke, or heart failure (identified using the ICD-10 codes and CPT procedure codes in Table 2 below) observed during or on the day before hospitalization, as well as medical claims for revascularization procedures indicative of Ml (i.e., coronary artery bypass grafting, percutaneous coronary intervention).

[0201] Table 2: MACE classification codes

[0202] Incidence rate ratios (IRRs) were estimated using unadjusted Poisson / negative binomial regression models. IPT-weighted IRRs were also estimated using IPT weights from a propensity score model that included the following covariates: age category, region, healthcare insurance plan type, comorbidity burden (Elixhauser comorbidity index category), hip or pelvis fracture anytime before the index date, surgery in an inpatient setting anytime before the index date, selected comorbidities anytime before the index date, selected drug classes dispensed anytime before the index date, the number of distinct non-topical agents dispensed anytime before the index date, month / year of index date, and time from first claim until index date. The IPT weights were stabilized and truncated at the 99.5 percentile to reduce the influence of large weights. Because the covariates were balanced in the IPT-weighted cohorts, IPT weighting controlled for confounding.

[0203] The time to the first MACE event was compared between the IPT-weighted cohorts using Kaplan-Meier plots and Cox proportional hazard regression models. An IPT-weighted Poisson regression model (or, when overdispersion was detected, a negative binomial regression model) was also used to compare the occurrence of a first MACE event between the two study cohorts.

[0204] Results & Discussion

[0205] During the observation period, 16 out of 6,520 (0.25%) women receiving E2 / P4 and 375 out of 29,426 (1 .27%) women receiving CEE / MPA experienced a MACE event. IRRs were estimated using unadjusted Poisson / negative binomial regression models.

[0206] Table 3: MACE rates for eligible women (40-79 years) over the entire observation period; an IRR <1 indicates a lower incidence of events among the E2 / P4 cohort; * = statistically significant at p < 0.05 Table 4: MACE rates for eligible women (40-79 years) over the first year following the index date; an IRR <1 indicates a lower incidence of events among the E2 / P4 cohort; * = statistically significant at p < 0.05 Table 5: IPT-weighted rates of MACE for eligible women (40-79 years); WY = women years;

[0207] = statistically significant at p < 0.05 After controlling for potential confounding, the probability of experiencing a MACE was significantly lower for women aged 40-79 receiving E2 / P4 than for those receiving CEE / MPA (72% decrease; incidence rate ratio 0.28, 95% Cl: 0.17 - 0.45; hazard ratio 0.37, 95% Cl 0.27 - 0.50; Figure 2).

[0208] In IPT-weighted time to event analyses, the probability of experiencing a MACE event was also significantly lower for women receiving E2 / P4 than for those receiving CEE / MPA (IPT-weighted hazard ratio [HR] 0.37, 95% Cl 0.27 - 0.50; Figure 2), with a significant difference being detected at month four after treatment initiation (IPT-weighted HR 0.34, 95% Cl 0.14 - 0.84, p= 0.020).

[0209] IPT-weighted analyses stratified by age showed higher MACE event rates in women aged 60-79 years than those aged 40-59 years (MACE events per 10,000 women-years: 39.5 vs 23.9 for E2 / P4 and 145.8 vs 61 .6 for CEE / MPA, respectively) with a strong relative risk reduction for E2 / P4 as compared CEE / MPA in both age groups (40- 59 years: IPT-weighted IRR 0.39, 95% Cl 0.23-0.65; 60-79 years: 0.27, 0.09 — 0.79; Figure 3A).

[0210] In analyses stratified by type of MACE event, all three MACE event types were associated with significantly lower relative risks for E2 / P4 as compared CEE / MPA (heart failure: IPT-weighted IRR 0.24, 95% Cl 0.11 -0.51 ; acute Ml: 0.22, 0.08 - 0.63; stroke: 0.32, 0.15-0.70; Figure 3B).

[0211] Summary

[0212] The data presented herein demonstrates that women receiving E2 / P4 had a significantly lower risk of experiencing a MACE event than those receiving CEE / MPA, after controlling for potential confounding variables.

[0213] Example 2 - Comparison of CEE / MPA cohort with WHI study

[0214] The MACE event rates estimated in the study of Example for the CEE / MPA cohort were juxtaposed with those estimated in the Women Health Initiative (WHI) trial for the CEE / MPA arm (Rossouw etal. 2002 JAMA. 288(3) :321 -333) by restricting the population of women included in our study to the age range of WHI participants (50-79 years) and the MACE events to stroke and acute Ml.

[0215] A sensitivity analysis was carried out in which the analyses in Example 1 was replicated for the subset of women in the study cohorts aged 50-79 years, both over the entire observation period as well as over the first year after the treatment initiation. IPT-weighted rates were reported overall as well as stratified by MACE event type. Consistent with Example 1 , the sensitivity analysis found a significantly lower risk of experiencing a MACE event for women receiving E2 / P4 compared to those receiving CEE / MPA (75% risk decrease over the entire observation period; 62% over the first year after the treatment initiation; p<0.05; Table 6).

[0216] Table 6: Sensitivity analysis - MACE rates in women aged 50-79 yrs

[0217] More importantly, despite having different MACE event definitions in the current study (based on diagnosis codes in claims) and the WHI study (clinical definitions), the event rates for the CEE / MPA-treated patients in the sensitivity analysis (Table 6) were generally aligned to those of the CEE / MPA-treated patients in the WHI.

[0218] Specifically, in the sensitivity analysis of the current study, the acute Ml event rates per 10,000 women-years in the CEE / MPA cohort were 28.0 over the entire observation period and 27.2 in the first year after the treatment initiation in the current sensitivity analysis; in the WHI trial, the acute Ml event rates per 10,000 women-years in the CEE / MPA arm in the corresponding periods were 30 and 30, respectively; for stroke, the event rates were 32 and 31 in the current sensitivity analysis versus 21 -29 (depending on definition) and 20 in the WHI trial, respectively. Example 3 - observational study of MACE in E2 / P4 vs placebo cohorts

[0219] Given MACE event rates were comparable between the current study and WHI trial for the common comparator group CEE / MPA, an indirect comparison between the E2 / P4 cohort in the current study and the placebo arm in the WHI study (proxy for the general female population) was conducted.

[0220] Table 7: Pre-IPT weighted MACE rates in women aged 50-79 Table 8: Post-IPT weighting MACE rates in women aged 50-79

[0221] Noteworthily, Table 7 and Table 8 show that the observed rates of acute Ml and stroke among women aged 50-79 treated with E2 / P4 in the sensitivity analysis of the current study were consistently lower than the rates observed in the placebo arm of the WHI trial. Specifically, this observation was made when measured over the entire observation period (pre-IPT weighted 4.7 vs. 23 acute Ml events per 10,000 women-years and 9.3 vs 14-21 (depending on definition) stroke events per 10,000 women-years; post-IPT weighting 3.5 vs. 23 acute Ml events per 10,000 women-years and 9.4 vs 14-21 (depending on definition) stroke events per 10,000 women-years). The lower rates were also observed when only data in respect of the first year post-treatment was taken into account (pre-IPT weighted 6.3 vs. 23 acute Ml events per 10,000 women-years and 12.6 vs 21 stroke events per 10,000 women-years; post-IPT weighting 4.8 vs. 23 acute Ml events per 10,000 women-years and 13.1 vs 21 stroke events per 10,000 women- years). The current study therefore demonstrates a cardioprotective effect of E2 / P4 in the general population of women at a perimenopausal, menopausal and post-menopausal age.

[0222] References

[0223] 1 . Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005; 118(12): 14-24.

[0224] 2. Williams RE, Levine KB, Kalilani L, Lewis J, Clark R V. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health- related quality of life. Maturitas. 2009;62(2): 153-9.

[0225] 3. ACOG Practice Bulletin No. 141 : management of menopausal symptoms. Obstetrics and gynecology. 2014; 123(1 ):202-16.

[0226] 4. Hauk L. ACOG Releases Clinical Guidelines on Management of Menopausal Symptoms. Am Fam Physician. 2014;90(5):338-40.

[0227] 5. Mehta J, Kling JM, Manson JAE. Risks, Benefits, and Treatment Modalities of Menopausal Hormone Therapy: Current Concepts. Front Endocrinol (Lausanne) .

[0228] 2021 ;12:564781.

[0229] 6. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291 (1):47-53.

[0230] 7. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321- 33.

[0231] 8. Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women’s Health Initiative trials of menopausal hormone therapy. Obstetrics and gynecology.

[0232] 2013;121 (1):172-6.

[0233] 9. FDA, CDER. Highlights of prescribing information full prescribing information. 2018 [cited 2023 Jun 12]; Available from: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 210132s000lbl.pdf 10. Piette PCM. The pharmacodynamics and safety of progesterone. Best Pract Res Clin Obstet Gynaecol. 2020;69:13-29.

[0234] 11 . Lobo RA, Liu J, Stanczyk FZ, Constantine GD, Pickar JH, Shadiack AM, et al. Estradiol and progesterone bioavailability for moderate to severe vasomotor symptom treatment and endometrial protection with the continuous-combined regimen of TX-001 HR (oral estradiol and progesterone capsules). Menopause. 2019;26(7):720-7.

[0235] 12. Lobo RA, Archer DF, Kagan R, Kaunitz AM, Constantine GD, Pickar JH, et al. A 17p- Estradiol-Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial. Obstetrics and gynecology. 2018; 132(1): 161 -70.

[0236] 13. Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric. 2018;21 (4):346-54.

[0237] 14. Panay N, Nappi RE, Stute P, Palacios S, Paszkowski T, Kagan R, et al. Oral estradiol / micronized progesterone may be associated with lower risk of venous thromboembolism compared with conjugated equine estrogens / medroxyprogesterone acetate in real-world practice. Maturitas. 2023;172:23-31.

[0238] 15. Gagne J J , Glynn RJ, Avorn J, Levin R, Schneeweiss S. A combined comorbidity score predicted mortality in elderly patients better than existing scores. J Clin Epidemiol.

[0239] 2011 ;64(7):749-59.

[0240] 16. Austin P. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083-107.

[0241] 17. Yang D, Dalton JE. A unified approach to measuring the effect size between two groups using SAS ®. :335-2012.

[0242] 18. Austin PC. Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research. Commun Stat Simul Comput. 2009 Jun;38(6):1228-34.

[0243] 19. Nguyen TL, Collins GS, Spence J, Daures JP, Devereaux PJ, Landais P, et al. Doubleadjustment in propensity score matching analysis: choosing a threshold for considering residual imbalance. BMC Med Res Methodol. 2017;17(1 ).

[0244] 20. Anagnostis P, Goulis DG. Menopause and its Cardiometabolic Consequences: Current Perspectives. Curr Vase Pharmacol. 2019;17(6):543-5.

[0245] 21 . Miller VT, LaRosa J, Barnabei V, Kessler C, Levin G, Smith-Roth A, et al. Effects of Estrogen or Estrogen / Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women: The Postmenopausal Estrogen / Progestin Interventions (PEPI) Trial. JAMA. 1995;273(3): 199-208.

[0246] 22. Coquoz A, Gruetter C, Stute P. Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review. Climacteric. 2019;22(2): 148-61 . 23. Lee DY, Kim JY, Kim JH, Choi DS, Kim DK, Koh KK, et al. Effects of hormone therapy on ambulatory blood pressure in postmenopausal Korean women. Climacteric. 2011 ; 14(1 ):92— 9.

[0247] 24. Yoon BK, Sung J, Song YM, Kim SM, Son KA, Yoo JH, et al. Effects of menopausal hormone therapy on ambulatory blood pressure and arterial stiffness in postmenopausal Korean women with grade 1 hypertension: a randomized, placebo-controlled trial. Clinical hypertension.

[0248] 2021 ;27(1):18.

[0249] 25. Louw-du Toit R, Perkins MS, Hapgood JP, Africander D. Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy. Biochem Biophys Res Commun. 2017;491 (1 ): 140— 6. 26. Graham S, Archer DF, Simon JA, Ohleth KM, Bernick B. Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins. Gynecol Endocrinol. 2022;38(11):891-910.

[0250] 27. Maas AHEM, Rosano G, Cifkova R, Chieffo A, Van Dijken D, Hamoda H, et al.

[0251] Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: a consensus document from European cardiologists, gynaecologists, and endocrinologists. Eur Heart J. 2021 ;42(10):967-84.

Claims

CLAIMS1 . A method of preventing a major adverse cardiovascular event (MACE) in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone.

2. A method of decreasing the risk of a MACE associated with combined hormone replacement therapy (HRT) in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone.

3. The method of claim 2, wherein the risk of a MACE is decreased compared to a placebo.

4. The method of claim 2, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen.

5. A method of combined HRT in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to a combined HRT comprising a progestin and a conjugated estrogen.

6. A method of selecting a combined HRT, comprising(i) identifying a woman as suitable for combined HRT ;(ii) selecting a combined HRT, wherein the selected combined HRT has been identified as a combined HRT associated with a decreased risk of a MACE compared to combined HRT comprising a progestin and a conjugated estrogen, wherein the selected combined HRT is a composition comprising estradiol and progesterone.

7. A method of treating menopause related symptoms in a woman, the method comprising administering to the woman a composition comprising estradiol and progesterone, wherein the risk of a MACE is decreased compared to combined HRT comprising a progestin and a conjugated estrogen.

8. The method of claim 7, wherein the menopause related symptoms comprise vasomotor symptoms, preferably moderate to severe vasomotor symptoms.

9. The method of any one of claims 1 -8, wherein the MACE is selected from at least one of acute myocardial infarction (Ml), stroke and heart failure.

10. The method of any one of claims 1 -9, wherein the woman is a perimenopausal, menopausal or postmenopausal woman.11 . The method of any one of claims 1 -10, wherein the woman has an intact uterus.

12. The method of any one of claims 1 -11 , wherein the woman is aged 40-79 years, optionally 50-79 years.

13. The method of claim 12, wherein the woman is aged 50-59 years.

14. The method of claim 12, wherein the woman is aged 40-59 years or 60-79 years.

15. The method of any one of claims 2-14, wherein the decreased risk of a MACE comprises a lower number of MACE per 10,000 women-years.

16. The method of any one of claims 2-15, wherein the decreased risk of the MACE comprises an Incident Rate Ratio of 0.17-0.45, or of about 0.28, optionally wherein:(i) the MACE is acute Ml, and the decreased risk of acute Ml comprises an Incident Rate Ratio of 0.08-0.63, or of about 0.23 or about 0.22;(ii) the MACE is heart failure, and the decreased risk of heart failure comprises an Incident Rate Ratio of 0.11 -0.51 , or of about 0.24; and / or(iii) the MACE is stroke, and the decreased risk of stroke comprises an Incident Rate Ratio of 0.15-0.70, or of about 0.32.

17. The method of any one of claims 2-16, wherein:(i) the woman is aged 40-59 years, and the decreased risk of the MACE comprises an Incident Rate Ratio of 0.23-0.65, or of about 0.39; or(ii) the woman is aged 60-79 years, and the decreased risk of the MACE comprises an Incident Rate Ratio of 0.09-0.79, or of about 0.27.

18. The method of any one of claims 2-17, wherein the decreased risk of the MACE comprises a lower number of MACE within 3 months, 4 months, 6 months, 9 months, 1 year or 2 years from the start of treatment, optionally wherein:(i) the decreased risk of MACE comprises a lower number of MACE within 2 years from the start of treatment, and wherein the decreased risk of a MACE within 2 years comprises a Hazard Ratio of 0.27-0.50, or of about 0.37;(ii) the decreased risk of MACE comprises a lower number of MACE within 1 year from the start of treatment, and wherein the decreased risk of a MACE within 1 year comprises an Incident Rate Ratio of 0.23-0.65, or of about 0.39; and / or(iii) the decreased risk of MACE comprises a lower number of MACE within 4 months from the start of treatment, and wherein the decreased risk of a MACE within 4 months comprises a Hazard Ratio of 0.14-0.84, or of about 0.34.

19. The method of claim 18, wherein:(i) the MACE is acute Ml and the decreased risk of acute Ml within 1 year comprises an Incident Rate Ratio of 0.08-0.77, or of about 0.24; and / or(ii) the MACE is heart failure and, and the decreased risk of heart failure within 1 year comprises an Incident Rate Ratio of 0.18-0.82, or of about 0.38; and / or(iii) the MACE is stroke, wherein the decreased risk of stroke within 1 year comprises an Incident Rate Ratio of about 0.47.

20. The method of any one of claims 1 -19, wherein the composition is administered orally.21 . The method of any one of claims 4-20, wherein:(i) the progestin is medroxyprogesterone or medroxyprogesterone acetate; and / or(ii) the conjugated estrogen is conjugated equine estrogen; and / or(iii) the progestin and conjugated estrogen are administered orally.

22. The method of any one of the preceding claims, wherein the composition comprises 0.5 mg or 1 mg estradiol.

23. The method of any one of the preceding claims, wherein the estradiol is estradiol hemihydrate.

24. The method of any one of the preceding claims, wherein the composition comprises 100 mg progesterone.

25. The method of any one of the preceding claims, wherein the composition comprises 1 mg estradiol and 100 mg progesterone.

26. The method of any one of the preceding claims, wherein the progesterone is bio-identical progesterone and / or micronized progesterone.

27. The method according to any one of the preceding claims, wherein the estradiol and progesterone are co-formulated, optionally as a soft capsule.

Images