WO2016064997A1 - Compositions and methods for treating fatigue and depression - Google Patents

Abstract

Provided are methods for treating fatigue or depression in a subject that has a neurodegenerative disease, such as multiple sclerosis, and/or treating a neurodegenerative disease patient (e.g., a multiple sclerosis patient) presenting with fatigue or depression using a continuous regimen of estrogen in combination with periodic administration of a progestogen.

Description

COMPOSITIONS AND METHODS FOR TREATING FATIGUE

AND DEPRESSION

PRIORITY CLAIM

This application claims priority U.S. Provisional Patent Application No. 62/067,264, filed October 22, 2014, and U.S. Provisional Patent Application No. 62/068,162, filed October 24, 2014, each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is a chronic, often debilitating disease affecting the central nervous system (brain and spinal cord). MS affects more than 1 million people worldwide and is the most common neurological disease among young adults, particularly women. The exact cause of MS is still unknown. MS is an autoimmune disease in which myelin sheaths surrounding neuronal axons are destroyed. This condition can cause weakness, impaired vision, loss of balance, and poor muscle coordination.

MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or bui lding up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.

In 1996, the United States National Multiple Sclerosis Society described four clinical subtypes of MS: (i) relapsing-remitting; (ii) secondary -progressive; (iii) primary- progressive; and (iv) progressive-relapsing.

Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave sequelae, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign MS, although people will still build up some degree of disability in the long term. On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period of time. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination but does not fulfil l the criteria for multiple sclerosis; 30 to 70% of persons experiencing CIS go on to develop MS.

Secondary-progressive MS occurs in around 65% of those with initial relapsing- remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The median length of time between disease onset and conversion from relapsing- remitting to secondary progressive MS is 19 years.

Primary-progressive MS occurs in approximately 10-20% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype, but similar to the age that secondary-progressive MS usually begins in relapsing-remitting MS, around 40 years of age.

Progressive-relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also have clear superimposed attacks. This is the least common of all subtypes.

Depression is a common and frequently disabling symptom of MS, which occurs at some point in approximately half of all MS patients. Similarly, fatigue is also a common and frequently disabling symptom of MS. In individuals with MS, fatigue and depression can significantly impair the ability to function in day-to-day activities.

Currently the following agents are approved by the U.S. Food and Drug

Administration (FDA) to reduce disease activity and disease progression for many people with relapsing forms of MS, including relapsing-remitting MS, as well as secondary- progressive and progressive-relapsing MS in those people who continue to have relapses: dimethyl fumarate (Tecfidera®; BG-12), fmgolimod (Gilenya®), glatiramer acetate (Copaxone®), interferon beta- la ( Avonex® and Rebif®), interferon beta-! b (Betaseron® and Extavia®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), and teriflunomide ( Aubagio®). However, many of these therapies fail to successfully treat all patients or all symptoms in treated patients, and many of these therapies are associated with undesirable side effects. None of the current therapies have been shown to significantly help treat depression in MS. Accordingly, alternative therapies are needed. SUMMARY OF THE INVENTION

An aspect of the invention is a method of treating fatigue or depression in a subject that has multiple sclerosis (and/or treating a multiple sclerosis patient presenting with fatigue or depression), comprising administering to a subject in need thereof, on a continuous basis throughout one or more (preferably at least two) consecutive treatment periods, a therapeutically effective amount of an estrogen; and administering to the subject, for only a portion of each treatment period, a therapeutically effective amount of a progestogen.

In certain embodiments, the estrogen is selected from estriol (E3), estradiol (E2), estrone (El ), pharmaceutically acceptable salts of any of the foregoing, and any

combination thereof.

In certain embodiments, the estrogen is estriol.

In certain embodiments, the progestogen is selected from chlormadmone acetate, cyproterone acetate, desogestrel, dienogest, 5a~dihydroprogesterone, drospirenone

(Yasmin®), ethinodiol acetate, ethynodiol diacetate, etonogestrel (Nexplanon©), gestodene, 17-hydroxyprogesterone, levonorgestrel (Aiesse®), medroxyprogesterone acetate (17a- hydroxy-6a-methylprogesterone acetate; Provera®), megestrol, megestrol acetate (17a- acetoxy-6-dehydro-6-methylprogesterone), nestorone, nomegestrol acetate, norethindrone, norethmdrone acetate (also known as norethisterone acetate), norethynodrel (Enovid®), norgestimate, norgestrel, progesterone, tanaproget, trimegestone, pharmaceutically acceptable salts of any of the foregoing, and any combination thereof.

In certain embodiments, the progestogen is progesterone.

In certain embodiments, the progestogen is norethmdrone.

In certain embodiments, the estrogen is administered orally in a dose equal or equivalent to about 8 mg of estriol daily.

In certain embodiments, the progestogen is administered oral ly in a dose equal or equivalent to about 700 g of norethindrone daily.

An aspect of the invention is a method of treating fatigue or depression in a subject that has multiple sclerosis (and/or treating a multiple sclerosis patient presenting with fatigue or depression), comprising administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), 8 mg of estriol daily; and

administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), 0.7 mg of norethindrone daily. In certain embodiments, the method further comprises administering to the subject a pl acebo in place of the norethindrone on each of the days the norethmdrone is not administered to the subject.

In certain embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis.

In certain embodiments, the multiple sclerosis is secondary-progressive multiple sclerosis.

in certain embodiments, the multiple sclerosis is primary-progressive multiple sclerosis.

In certain embodiments, the multiple sclerosis is progressive -relapsing multiple sclerosis.

In certain embodiments, the multiple sclerosis is clinically isolated syndrome (CIS). In certain embodiments, the method further comprises administering to the subject an immunotherapeutic agent, wherein the immunotherapeutic agent is neither an estrogen nor a progestogen, e.g., an immunotherapeutic agent selected from interferon-beta la, interferon-beta lb, glatiramer acetate, natalizumab, mitoxantrone, flngolimod,

terifiunomide, and dimethyl fumarate.

In certain embodiments, the subject is a subject being treated with an

immunotherapeutic agent yet experiencing a relapse and/or progression of the multiple sclerosis.

Although the methods disclosed throughout the specification and claims are useful for treating multiple sclerosis in its various forms and stages, these methods can also be applied the treatment of other neurodegenerative diseases, such as, by way of illustration, Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, cerebellar ataxia, frontotemporal dementia, prion disease, Huntington's Disease, cerebral ischemia, idiopathic Morbus Parkinson, Parkinson syndrome, Morbus Alzheimers, cerebral dementia syndrome, infection-induced neurodegeneration disorders (e.g., AIDS-encephalopathy, Creutzfeid- Jakob disease, encephalopathies induced by rubiola and herpes viruses and borrelioses), metabolic-toxic neurodegenerative disorders (such as hepatic-, alcoholic-, hypoxic-, hypo- or hyperglycemically-induced encephalopathies), encephalopathies induced by solvents or pharmaceuticals, degenerative retina disorders, trauma-induced brain damage, trauma-induced bone marrow damage, cerebral hyperexcitability symptoms, cerebral hyperexcitability states ( e.g., of varying origin, such as after the addition of and/or withdrawal of medicaments, toxins, noxae and drugs), neurodegenerative syndromes of the peripheral nervous system, peripheral nerve injury, and spinal cord injury. In certain preferred embodiments, the neurodegenerative disease is multiple sclerosis. In preferred embodiments, the patient is a woman. In some embodiments, the patient is a

premenopausal or perimenopausal woman. In other embodiments, the patient is a postmenopausal woman.

In certain embodiments, the method comprises measuring a fatigue or depression score for the subject. The fatigue or depression score may be measured prior to

administering the estrogen and the measurement may be repeated after one or more treatment periods. For example, an initial depression score may be measured immediately prior to administering the estrogen, such as during the same day or preceding week that the subject is first administered the estrogen. In other embodiments, the depression score is first measured shortly after administering the estrogen, such as within a day or week after the subject is first administered the estrogen. A subsequent measurement may be obtained after one, two, three, four, five, six, seven, eight, nine, ten, or more treatment periods, such as three, six, nine, twelve, fifteen, eighteen, twenty-one, twenty-four, twenty-seven, or thirty months after the subject is first administered the estrogen. The depression score may be measured, for example, using the Beck Depression Inventory. In some embodiments, the patient has an initial Beck Depression Inventory score of at least 9, such as at least 10, at least 1 1 , or at least 12.

In certain embodiments, the method comprises administering to the subject an agent to treat depression, wherein the agent to treat depression is not an estrogen or a

progestogen. For example, the method may comprise administering to the subject an agent to treat depression, wherein the agent to treat depression is a tricyclic antidepressant, monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, or a serotonin- norepinephrine reuptake inhibitor. In some embodiments, the agent to treat depression is a tricyclic antidepressant and the tricyclic antidepressant is clomipramine, imipramine, desipramine, fibenzepin, lofepramine, nortriptyline, protriptyline, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, demexiptiline, dimetacrme, dosulepin, doxepin, imipraminoxide, melitracen, metapramine, nitroxazepine, noxiptiline, pipofezine, propizepine, quinupramine, amineptine, iprindole, opipramol, tianeptine, or trimipramine. In some embodiments, the tricyclic antidepressant is amitriptyline, desipramine, or nortriptyline. In certain embodiments, the agent to treat depression is a monoamine oxidase inhibitor (MAOI) and the MAOI is isocarboxazid, isoniazid, nialamide, phenelzine, procarbazine, hydracarbazine, tranylcypromine, moelohemide, pirlindole, toloxatone, rasagiline, selegiline, imez.ol.id, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, or minaprine. In certain embodiments, the agent to treat depression is a selective serotonin reuptake inhibitor (SSRI) and the SSRI is citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, or zimelidine. For example, the SSRI may be fluoxetine, paroxetine, or sertraline. In certain embodiments, the agent to treat depression is a serotonin-norepinephrine reuptake inhibitor (SNRI) and the SNRI is venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, or sibutramine. For example, the SNRI may be venlafaxine or duloxetine.

In certain embodiments, the method comprises measuring a fatigue or depression score for the subject. The fatigue or depression score may be measured prior to

administering the estrogen and the measurement may be repeated after one or more treatment periods. For example, an initial fatigue score may be measured immediately prior to administering the estrogen, such as during the same day or preceding week that the subject is first administered the estrogen. In other embodiments, the fatigue score is first measured shortly after administering the estrogen, such as within a day or week after the subject is first administered the estrogen. A. subsequent measurement may be obtained after one, two, three, four, five, six, seven, eight, nine, ten, or more treatment periods, such as three, six, nine, twelve, fifteen, eighteen, twenty-one, twenty-four, twenty-seven, or thirty months after the subject is first administered the estrogen. The fatigue score may be measured, for example, using the Modified Fatigue Impact Scale. In some embodiments, the patient has an initial fatigue score of at least 25, such as at least 28 or at least 30.

In certain embodiments, the method comprises administering to the subject an agent to treat fatigue or an agent to increase wakefulness, wherein neither the agent to treat fatigue nor the agent to increase wakefulness is an estrogen or a progestogen. For example, the method may comprise administering to the subject an agent to treat fatigue, wherein the agent to treat fatigue is amantadine. In some embodiments, the method comprises administering to the subject modafinil, armodafinil, pemoline, or methylphenidate. The amount of the agent to treat fatigue or the agent to increase wakefulness may be less than a therapeutically effective amount when the agent is administered in the absence of the estrogen. In some embodiments, the method further comprises reducing the dosage of the agent to treat fatigue and/or the agent to increase wakefulness over a period of 1 -6 weeks after initiation of treatment with the estrogen and progestogen. In certain embodiments, the subject does not receive conjoint therapy with an agent to treat fatigue or an agent to increase wakefulness other than the estrogen.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a line graph depicting a change from baseline (0) of Beck Depression Inventory (BDI) scores for MS subjects who received Estrio! and Copaxone therapy versus MS subjects who received placebo and Copaxone therapy. Confidence intervals depict standard error.

Figure 2 is a line graph depicting a change from baseline (0) of scores on the Modified Fatigue Impact Scale for MS subjects who received Estriol and Copaxone therapy versus MS subjects who received placebo and Copaxone therapy. Confidence intervals depict standard error.

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the in vention is a method of treating fatigue or depression in a subject that has multiple sclerosis (and/or treating a multiple sclerosis patient presenting with fatigue or depression). The method includes the steps of administering to a subject in need thereof, on a continuous basis throughout two or more consecutive treatment periods, a therapeutically effective amount of an estrogen; and administering to the subject, for only a portion of each treatment period, a therapeutically effective amount of a progestogen.

Estrogen treatment may be neuroprotective in preventing structural neuropathological changes in the brain that lead to the development and worsening of depression in MS, thus, estrogen treatment may not merely treat depressive symptoms, but it may slow their development and potentially repair such neuropathology. Further, standard anti -depressive treatments cany with them considerable side effects that can be more problematic in the MS population than in the general population at large without MS.

The term "estrogen" as used herein refers to any biologically active form of estrogen or precursor thereof. The term "estrogen" thus embraces naturally occurring, synthetic, and semi-synthetic forms of estrogen, and biologically active, pharmaceutically acceptable salts and esters thereof. In certain embodiments, estrogen is selected from estriol (E3), estradiol (E2), estrone (El ), an ester thereof, a pharmaceutically acceptable salt of an ester thereof, and any combination of the foregoing. In certain embodiments, estrogen is estriol (E3) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof. For example, the estrogen can be estriol, estriol succinate, estriol dihexanoate, or estriol sulfate. In other embodiments, estrogen is estradiol (E2) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof, while in yet other embodiments, estrogen is estrone (EI) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof. In certain preferred embodiments, estrogen is estriol (E3). In certain

embodiments, estrogen is estradiol (E2). In certain embodiments, estrogen is estrone (El ).

In certain embodiments, the estrogen is administered in a dose equal or equivalent to about 200 ,ug to about 20 mg estriol daily. For example, a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1.25 mg of conjugated estrogens or estrone. In certain embodiments, the estrogen is administered in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily. In most preferred embodiments, the estrogen is estriol administered in a dose of about 8 mg estriol daily.

In certain embodiments, the estrogen is formulated for oral administration, e.g., in a dose equal or equivalent to about 200 g to about 20 mg estriol daily. For example, a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1.25 mg of conjugated estrogens or estrone. In certain embodiments, the estrogen is formulated for oral administration in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily. In most preferred embodiments, the estrogen is estriol formulated for oral administration in a dose of about 8 mg estriol daily.

In certain embodiments, the estrogen is orally administered in a dose equal or equivalent to about 200 }ig to about 20 mg estriol daily. For example, a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1 .25 mg of conjugated estrogens or estrone. In certain embodiments, the estrogen is orally administered in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily. In most preferred embodiments, the estrogen is estriol orally administered in a dose of about 8 mg estriol daily.

An "effective amount", as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A "therapeutically effective amount", as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve a symptom of fatigue, which may be measured by an improvement in the Modified Fatigue Impact Scale (MFIS), such as by an improvement by three points. Similarly, a

therapeutically effective amount can refer to an amount that is sufficient to improve a symptom of depression, which may be measured by an improvement in the Beck

Depression Inventory (BDI), such as by an improvement by two points. Additional ly, a therapeutically effective amount can refer to an amount that is sufficient to improve a symptom of depression as measured by an improvement by Diagnostic Criteria and

Statistical Manual (e.g., DSM-IV or DSM-5) criteria, such as improvement in three or more of the nine DSM-IV criteria for the diagnosis of depression.

A therapeutically effective dose of the estrogen is, in some embodiments, one sufficient to raise the serum concentration above basal levels, and preferably to pregnancy levels or above pregnancy levels. In certain embodiments, the therapeutically effective dose of the estrogen is selected to result in serum levels in a patient equivalent to the steroid hormone level of that agent in women in the second or third trimester of pregnancy.

For example, during the normal female menstrual cycle estradiol levels are in the range of about 350 pg/ml serum. During pregnancy, there is about a 100-fold increase in the level of estradiol to about 10,000 to about 35,000 pg/ml serum. Correaie et ai., J Immunol 161 :3365-74 (1998) and Gilmore et al., J Immunol 158:446-51 (1997). In contrast, estriol levels are undetectable during the menstrual cycle in the non-pregnant state. Estradiol levels rise progressively during pregnancy to levels from 3,000 to 30,000 pg/ml (3 to 30 ng/ml).

In one embodiment, where the estrogen is estriol, the dose is from about 4 to 16 milligrams daily, and more specifically, about 8 milligrams daily. In this embodiment, blood serum levels preferably reach at least about 2 ng/ml, may reach about 10 to about 35 ng/ml, or most preferably about 10-15 ng/ml. Sicotte et al. Neurology 56:A75 (2001). In some embodiments, estradiol (E2) levels would preferably reach at least about 2 ng ml and most preferably about to 10-35 ng/ml. In some embodiments, estrone (El) levels would preferably reach at least about 2 ng/ml and most preferably about 5-18 ng/ml. DeGroot et al., Endocrinology' 3(9):2171-223 (1994). In some embodiments, a therapeutically effective amount of estriol is an amount of an estriol sufficient to increase the serum estriol concentration in the blood of a subject about 20-30 ng/rnL. The dosage of the estrogen may be selected for an individual patient depending upon the route of administration, severity of disease, age and weight of the patient, other medications the patient is taking and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected. In vitro or in vivo assays can be employed to help identify optimal dosage ranges.

The therapeutically effective dose of the estrogen included in the dosage form is selected at least by considering the type of estrogen selected and the mode of

administration. The dosage form may include the estrogen in combination with other inert ingredients, including adjuvants and pharmaceutically acceptable carriers for the facilitation of dosage to the patient as known to those skilled in the pharmaceutical arts. The dosage form may be any form suitable to cause the estrogen to enter into the tissues of the patient.

Pharmaceutically acceptable earners can optionally comprise a suitable amount of a pharmaceutically acceptable excipie t so as to provide the form for proper admmistration. Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can include, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. In one embodiment, the dosage form of the estrogen is an oral preparation (liquid, tablet, capsule, caplet, gelcap, or the like) which when consumed results in elevated serum estrogen levels. The oral preparation may comprise conventional carriers including diluents, binders, time-release agents, lubricants, and disintegrants.

In other embodiments of the invention, the dosage form of the estrogen may be provided in a topical preparation (lotion, cream, ointment, patch, or the like) for

transdermal application.

Alternati ve!)', the dosage form may be provided as a suppository or the like for transvaginal or transrectal application.

However, in other embodiments, the dosage form may also allow for preparations to be applied subeutaneously, intravenously, intramuscularly, or via the respiratory system.

The term "progestogen" (also known as "gestagen") as used herein refers to any steroid hormone that binds to and activates a progesterone receptor, or a precursor thereof. The term "progestogen" thus embraces naturally occurring, synthetic, and semi -synthetic forms of progestogen, and biologically active, pharmaceutically acceptable salts and esters thereof.

in certain embodiments, the progestogen is selected from chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, 5a-dihydroprogesterone, drospirenone

(Yasmin®), ethinodiol acetate, ethynodiol diacetate, etonogestrel (Nexplanon®), gestodene, 17-hydroxyprogesterone, levonorgestrel (Alesse®), medroxyprogesterone acetate (17a- hydroxy-6a-methylprogesterone acetate; Provera®), megestrol, megestrol acetate (17a- acetoxy-6-dehydro-6-methylprogesterone), nestorone, nomegestrol acetate, norethindrone, norethindrone acetate (also known as norethisterone acetate), norethynodrel (Enovid®), norgestirnate, norgestrel, progesterone, tanaproget, trimegestone, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

In certain embodiments, progestogen is a progestin. The term "progestin" as used herein refers to a synthetic progestogen as defined herein. Examples of progestins include desogestrel, dienogest, drospirenone (Yasmin®), ethinodiol acetate, etonogestrel

(Nexplanon®), gestodene, levonorgestrel (Alesse®), medroxyprogesterone acetate

(Provera®), nestorone, nomegestrol acetate, norethindrone, norethindrone acetate, norethynodrel (Enovid®), norgestirnate, norgestrel, and trimegestone. In certain embodiments, the progestogen is selected from progesterone, 17- hydroxyprogesterone, 5a-dihydroprogesterone, norethmdrone, norethmdrone acetate (also known as norethisterone acetate), medroxyprogesterone acetate ( 17ct-hy droxy-6a- methylprogesterone acetate), megestrol acetate (17a-acetoxy-6-dehydro-6- methylprogesterone), desogestrel, ievonorgestrei, chloroiadinoiie acetate, and cyproterone acetate, pharmaceutically acceptable salts of any of the foregoing, and any combination thereof. In certain embodiments, progestogen is selected from progesterone, 17- hydroxyprogesterone, 5a-dihydroprogesterone, norethmdrone, norethmdrone acetate (also known as norethisterone acetate), desogestrel, Ievonorgestrei, chlorrnadinone acetate, and cyproterone acetate, pharmaceutically acceptable salts and esters of any of the foregoing, and any combination thereof. In certain embodiments, progestogen is norethmdrone or an ester thereof, or a pharmaceutical ly acceptable salt of an ester thereof, preferably norethmdrone. In certain embodiments, progestogen is progesterone or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof.

In certain embodiments, the progestogen is administered in a dose equal or equivalent to about 70 p.g to about 7 mg norethmdrone daily, such as about 100 g to about 1 mg norethmdrone daily, most preferably in a dose equal or equivalent to about 0.7 mg norethmdrone daily. In certain preferred embodiments, the progestogen is norethmdrone administered in a dose of 0.7 mg norethmdrone daily.

In certain embodiments, the progestogen is formulated for oral administration, e.g., in a dose equal or equivalent to about 70 ig to about 7 mg norethmdrone daily, such as about 100 tig to about 1 mg norethmdrone daily, most preferably in a dose equal or equivalent to about 0.7 mg norethmdrone daily. In certain preferred embodiments, the progestogen is norethmdrone formulated for oral administration in a dose of 0.7 mg norethmdrone daily.

In certain embodiments, the progestogen is orally administered in a dose equal or equivalent to about 70 g to about 7 mg norethmdrone daily, such as about 100 ig to about 1 mg norethmdrone daily, most preferably in a dose equal or equivalent to about 0.7 mg (i.e., 700 ,ug) norethmdrone daily. In certain preferred embodiments, the progestogen is norethmdrone orally administered in a dose of 0.7 mg (i.e., 700_,u.g) norethmdrone daily.

The therapeutically effective dose of the progestogen included in the dosage form can be selected at least by considering the type of progestogen selected and the mode of administration. The dosage form may include the progestogen in combination with other inert ingredients, including adjuvants and pharmaceutically acceptable earners for the facilitation of dosage to the patient as known to those skilled in the pharmaceutical arts. The dosage form may be any form suitable to cause the progestogen to enter into the tissues of the pati ent.

In one embodiment, the dosage form of the progestogen is an oral preparation

(liquid, tablet, capsule, caplet, gelcap, or the like) which when consumed results in elevated serum progestogen levels. The oral preparation may comprise conventional carriers including diluents, binders, time-release agents, lubricants, and disintegrants.

In other embodiments of the invention, the dosage form of the progestogen may be provided in a topical preparation (lotion, cream, ointment, patch, or the like) for

transdermal application.

Alternatively, the dosage form may be provided as a suppository or the like for transvaginal or transrectal application.

The estrogen is administered to the subject on a continuous basis throughout two or more consecutive treatment periods, in certain embodiments a continuous basis means daily, i.e., on consecutive days. For example, estrogen administered orally to a subject on a daily basis throughout two or more consecutive treatment periods is deemed to be estrogen administered to the subject on a continuous basis throughout two or more consecutive treatment periods. Alternatively, estrogen administered transdermally to a subject on a daily basis throughout two or more consecutive treatment periods is deemed to be estrogen administered to the subject on a continuous basis throughout two or more consecutive treatment periods.

As used herein, a "treatment period" refers to a period of time during which a subject is receiving, on a continuous or daily basis, at least one therapeutic agent administered for the purpose of treating MS in the subject. In certain embodiments, each treatment period is at least 28 consecutive days. In certain embodiments, each treatment period is at least 56 consecutive days. In certain embodiments, each treatment period is at least 84 consecutive days. In certain embodiments, each treatment period is at least 112 consecutive days. In certain embodiments, each treatment period is at least 140 consecutive days. In certain embodiments, each treatment period is at least 168 consecutive days.

In certain embodiments, each treatment period is at least 4 consecutive weeks. In certain embodiments, each treatment period is at least 8 consecutive weeks. In certain embodiments, each treatment period is at least 12 consecutive weeks. In certain embodiments, each treatment period is at least 16 consecutive weeks. In certain

embodiments, each treatment period is at least 20 consecutive weeks. In certain

embodiments, each treatment period is at least 24 consecutive weeks.

In certain embodiments, each treatment period is at least one month. In certain embodiments, each treatment period is at least two consecutive months. In certain embodiments, each treatment period is at least three consecutive months. In certain embodiments, each treatment period is at least four consecutive months. In certain embodiments, each treatment period is at least five consecutive months. In certain embodiments, each treatment period is at least six consecutive months,

The progestogen is administered to the subject for only a portion of each treatment period. As used herein, "for only a portion of each treatment period" refers generally to a period of time that occurs during but is at least one day shorter than a treatment period. In a preferred embodiment, the phrase "for only a portion of each treatment period" refers generally to a period of consecutive days that occurs during but is at least one day shorter than a treatment period.

In certain embodiments, the portion of each treatment period is daily for ail but at least 7 consecutive days of each treatment period. For example, if the treatment period is 28 days, in various embodiments the portion of such treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 consecutive days. For convenience, such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 or days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 1 1, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, or I to 21.

In certain embodiments, the portion of each treatment period is daily for all but at least 14 consecutive days of each treatment period. For example, if the treatment period is 28 days, in various embodiments the portion of such treatment period can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days. For convenience, such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 or days 1 to 2, I to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 1 1, 1 to 12, I to 13, or 1 to 14.

In certain embodiments, the portion of each treatment period is daily for up to 7 consecutive days of each treatment period. For example, if the treatment period is 28 days, in various embodiments the portion of such treatment period can be 1, 2, 3, 4, 5, 6, or 7 consecutive days. For convenience, such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 or days 1 to 2, 1 to 3, 1 to 4, 1 to 5, ! to 6, or ! to 7.

In certain embodiments, the portion of each treatment period is daily for up to 14 consecutive days of each treatment period. For example, if the treatment period is 28 days, in various embodiments the portion of such treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9,

10, 11, 12, 13, or 14 consecutive days. For convenience, such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 or days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, or 1 to 14.

In certain embodiments, the portion of each treatment period is daily for all but at least half of each treatment period. For example, if the treatment period is 28 days, in various embodiments the portion of such treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

11 , 12, 13, or 14 consecutive days. For convenience, such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day I or days 1 to

2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, or 1 to 14.

Preferably the progestogen is administered to the subject for only a portion of each treatment period. During the remainder of the treatment period, in certain embodiments the subject can receive estrogen but neither progestogen nor a placebo in place of the progestogen. Alternatively, during the remainder of the treatment period, in certain embodiments the subject can receive both estrogen and a placebo in place of the

progestogen.

An aspect of the invention is a method of treating fatigue or depression in a subject that has multiple sclerosis (and/or treating a multiple sclerosis patient presenting with fatigue or depression). The method includes the steps of administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), about 8 mg of estriol daily; and administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), about 0.7 mg of progestogen daily, in certain embodiments, the 14 consecutive days (2 weeks) are the first 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks). That is, if the 84 consecutive days of estrogen administration are deemed to start on day 1, the progestogen is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14, and then stopped. In certain embodiments, the subject may then continue to receive estrogen but neither progestogen nor a placebo in place of the progestogen for the remaining 70 days. In other embodiments, the method further includes the step of administering to the subject a pl acebo in place of the

progestogen on each of the days the progestogen is not administered to the subject. That is, the subject may then receive both estrogen and a placebo in place of the progestogen for the remaining 70 days.

An aspect of the invention is a method of treating fatigue or depression in a subject that has multiple sclerosis (and/or treating a multiple sclerosis patient presenting with fatigue or depression). The method includes the steps of administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), about 8 mg of estriol daily; and administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), about 0.7 mg of norethindrone daily. In certain embodiments, the 14 consecutive days (2 weeks) are the first 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks). That is, if the 84 consecutive days of estrogen administration are deemed to start on day 1 , the norethindrone is administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, I I, 12, 13, and 14, and then stopped. In certain embodiments, the subject may then continue to receive estrogen but neither norethindrone nor a placebo in place of the norethindrone for the remaining 70 days. In other embodiments, the method further includes the step of administering to the subject a placebo in pl ace of the

norethindrone on each of the days the norethindrone is not administered to the subject. That is, the subject may then receive both estrogen and a placebo in place of the

norethindrone for the remaining 70 days.

The term ''subject" as used herein refers to a living mammal and may be

interchangeably used with the term "patient". In certain embodiments, the subject is a human. Preferably, the human subject is female, such as a woman. In certain

embodiments, the subject is a premenopausal or perimenopausai woman. In certain embodiments, the subject is a premenopausal woman. In certain embodiments, the subject is a perimenopausai woman. In certain embodiments, the subject is a postmenopausal woman.

In certain embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis. In certain embodiments, the multiple sclerosis is secondary-progressive multiple sclerosis. In certain embodiments, the multiple sclerosis is primary-progressive multiple sclerosis. In certain embodiments, the multiple sclerosis is progressive -relapsing multiple sclerosis. In certain embodiments, the subject has a mild form of any one of the foregoing subtypes of MS. In certain embodiments, the subject has a moderate form of any one of the foregoing subtypes of MS. In certain embodiments, the subject has an aggressive form of any one of the foregoing subtypes of MS.

In certain embodiments, the multiple sclerosis is, more accurately, so-called clinicalty isolated syndrome (CIS). Estriol can be used, in accordance with the invention, to prevent or delay the onset of relapsing-remitting MS in subjects having CIS.

While the various methods disclosed herein are typically efficacious when administered without additional therapeutics, in certain embodiments, any of these methods further includes the step of administering to the subject an immunotherapeutic agent, wherein the immunotherapeutic agent is neither an estrogen nor a progestogen. That is, in certain embodiments the subject is administered, in addition to the estrogen and

progestogen (or placebo), a third agent useful in the treatment of MS. Such agents useful in the treatment of MS are, in general, immunotherapeutic agents. At least in connection with MS, such agents are sometimes referred to as disease-modifying therapies or disease- modifying therapeutics (DMTs).

The term "immunotherapeutic agent" as used herein refers to a compound with an objectively measurable effect on at least one aspect of the immune system or an immune response. In certain embodiments, the immunotherapeutic agent is immunosuppressive, i.e., it exerts an objectively measurable inhibitory effect on at least one aspect of the immune system or an immune response. In certain embodiments, the immunotherapeutic agent is anti-inflammatory. In certain embodiments, the immunotherapeutic agent is a small molecule (molecular weight less than or equal to about 1.5 kDa) pharmaceutical compound or composition. In certain embodiments, the immunotherapeutic agent is a biological compound or composition, e.g., an antibody, peptide, nucleic acid, etc.

In certain embodiments, the immunotherapeutic agent is not an estrogen. In certain embodiments, the immunotherapeutic agent is not a progestogen. Preferably, the immunotherapeutic agent is neither an estrogen nor a progestogen.

In certain embodiments, the immunotherapeutic agent is selected from dimethyl fumarate (Tec fid era®; BG-12), fingolimod (Gilenya®), glatiramer acetate (Copaxone®, for example "longer-lasting" 40 mg/ml or 20 mg/ml versions), interferon beta- la (Avonex® or Rebif®), interferon beta-lb (Betaseron® or Extavia®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), and teriflunomide (Aubagio®), mycophenoiate mofetil, paclitaxel, eyelosporme, corticosteroids (e.g., prednisone, methylprenisoione), azathioprine, cyclophosphamide, methotrexate, cladribine, 4-aminopyridine, and tizanidine. In certain embodiments, the immunotherapeutic agent is selected from dimethyl fumarate

(Teefidera®; BG-12), fingolimod (Gilenya®), glatiramer acetate (Copaxone®), interferon beta- la (Avonex® or Rebif®), interferon beta- lb (Betaseron® or Extavia®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), and teriflunomide (Aubagio®).

The immunotherapeutic may be selected from the group comprising β-interferon compounds. Examples include as β-interferon (e.g., Avonex® (interfero -beta la), Rebiff® (by Serono); Extavia®, Betaseron® (interferon-beta lb; Berlex, Schering), PLEGRIDY™ (peginterferon beta-la; Biogen)). Optionally, the following agents may be used: dimethyl fumarate (Teefidera®; BG-12), fingolimod (Gilenya®), glatiramer acetate (Copaxone®), interferon beta-l a (e.g., Avonex® or Rebif®), pegylated interferon-beta- la (PLEGRIDY™; Biogen) mitoxantrone (Novantrone®; Lederle Labs), natalizumab (Tysabri®), anti-LINGO- 1 antibody (BIIBQ33, Biogen-Idec), Antegren® (Elan Corp.), teriflunomide (Aubagio®), mycophenolate mofetil (CellCept® Hoffman-LaRoche inc.), paclitaxel (Taxol®; Bristol- Meyers Oncology), cyclosporine (such as cyclosporin A), corticosteroids (e.g., prednisone, methylprenisoione), azathioprine, cyclophosphamide, methotrexate, cladribine, 4- aminopyridine, and tizanidine.

In certain embodiments, the immunotherapeutic agent is dimethyl fumarate

(Teefidera®; BG-12). In certain embodiments, the immunotherapeutic agent is fingolimod (Gilenya®). In certain embodiments, the immunotherapeutic agent is glatiramer acetate (Copaxone®). In certain embodiments, the immunotherapeutic agent is interferon beta- la (Avonex® or Rebif®), In certain embodiments, the immunotherapeutic agent is interferon beta- lb (Betaseron® or Extavia®). In certain embodiments, the immunotherapeutic agent is mitoxantrone (Novantrone®). In certain embodiments, the immunotherapeutic agent is natalizumab (Tysabri®). in certain embodiments, the immunotherapeutic agent is teriflunomide (Aubagio®).

In certain embodiments, the subject is already receiving a disease-modifying therapeutic. In this circumstance, the subject can continue to receive the disease-modifying therapeutic while taking the estrogen, with and without the progestogen. Significantly, however, the dose of the disease-modifying therapeutic may be decreased when used in combination with the estrogen, with and without the progestogen. For example, a current standard dose for glatiramer acetate (Copaxone®) is 40 mg subcutaneous!)' (s.c.) three times a week, or 20 mg s.c. daily. In conjunction with estrogen and progestogen in accordance with the invention, the dose for glatiramer acetate (Copaxone©) may be reduced by up to 50 percent or more, e.g., to 20 mg s.c. three times a week.

As another example, a current standard dose for fingolimod (Gilenya®) is 0.5 mg by mouth (p.o.) daily. In conjunction with estrogen and progestogen in accordance with the invention, the dose for fingolimod (Gilenya®) may be reduced by up to 50 percent or more, e.g., to 0.25 mg p.o. daily.

As another example, a current standard dose for dimethyl fumarate (Tecfidera®) is 240 mg p.o. daily. In conjunction with estrogen and progestogen in accordance with the invention, the dose for dimethyl fumarate (Tecfidera®) may be reduced by up to 50 percent or more, e.g., to 120 mg p.o. daily.

As yet another example, a current standard dose for interferon beta- la (Avonex® or Rebif®) is 30 tig intramuscularly (i.m.) weekly (Avonex®) or 44 iig s.c. three days a week (Rebif®). In conjunction with estrogen and progestogen in accordance with the invention, the dose for Avonex® may be reduced to 15 ig i.m. weekly, and the dose for Rebif® may be reduced to 22 μ& s.c. three days a week.

As yet another example, a current standard dose for interferon beta- lb (Betaseron® or Extavia®) is 0.25 mg s.c. every other day (Betaseron® or Extavia®). In conjunction with estrogen and progestogen in accordance with the invention, the dose for interferon beta- lb (Betaseron® or Extavia®) may be reduced to 0.125 mg s.c. ever other day.

In certain embodiments, the subject is receiving an immunotherapeutic agent and experiencing fatigue or depression (e.g., fatigue or depression associated with a

neurodegenerative disease, such as multiple sclerosis).

The subject may begin concurrent treatment with estrogen in accordance with a method of the present invention, e.g., to reduce reported symptoms of fatigue either or to improve a fatigue score, for example, as measured on the Modified Fatigue Impact Scale (MFIS). In certain embodiments, the subject is treated with estrogen in accordance with a method of the present invention to improve a fatigue score as measured on the Fatigue Severity Scale or the MS Quality of Life-54.

The subject may begin concurrent treatment with estrogen in accordance with a method of the present invention, e.g., to reduce reported symptoms of depression either or to improve a depression score, for example, as measured on the Beck Depression Inventory. In certain embodiments, the subject is treated with estrogen in accordance with a method of the present invention to improve depression as assessed by the Beck Depression Inventory (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Coraell Scale for Depression in Dementia (CSDD), Geriatric Depression Scale (GDS), Hamilton Rating Scale for Depression (HAM-D), Hospital Anxiety and Depression Scale, utcher Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ), Clinical Global Impression scale (CGI, e.g., CGI severity scale and/or CGI improvement scale), or Zung Self-Rating Depression Scale. In certain embodiments, the subject is treated with estrogen in accordance with a method of the present invention to improve depression as assessed by the Diagnostic and Statistical Manual of Mental Disorders (DSM), such depression as assessed using the DSM-IV criteria or the DSM-5 criteria. The nine DSM-IV categories include: depressed mood or irritable most of the day or most days, decreased pleasure or interest, weight or appetite change, change in sleep, change in activity level, fatigue, guilt, poor concentration, and suicidal ideation.

In certain embodiments, the subject is receiving an immunotherapeutic agent selected from interferon-beta la, interferon-beta lb, glatiramer acetate, natalizumab, mitoxantrone, fmgolimod, teriflunomi.de, and dimethyl fumarate during a ramp-up period for dose of the immunotherapeutic agent, e.g., the patient begins receiving the

immunotherapeutic and the estrogen therapy at the same time or at about the same time (such as for patients who have not previously received treatments for their disease).

Advantageously, estrogen induces a rapid onset of therapeutic effect on MS, while commonly an immunotherapeutic agent such as interferon-beta la, interferon-beta lb, glatiramer acetate, natalizumab, mitoxantrone, fmgolimod, teriflunomide, or dimethyl fumarate may take weeks to months to induce observable improvements on some or all symptoms.

In certain embodiments, the subject is receiving glatiramer acetate during a ramp-up period for dose of the glatiramer acetate. In other certain embodiments, the subject is not already receiving a disease-modifying therapeutic.

In certain embodiments, the estrogen and the progestogen are formulated separately from one another, e.g., the subject receives the estrogen as a single formulation and the progestogen as a separate formulation. For oral administration, a given dose of each formulation can comprise one or more pills, tablets, capsules, geicaps, or the like (i.e., unit doses). For example, an 8 mg dose of estriol can be administered as four 2 mg capsules, and a 0.7 mg dose of norethindrone can be administered as a single capsule, though preferably each dose is administered in a single unit dose (e.g., one unit dose each for the estrogen and the progestogen).

In certain embodiments, e.g., where a placebo is administered with the estrogen on days when progestogen is not administered, the estrogen and the placebo are formulated separately from one another. For example, the subject is administered the estrogen as a single formulation and the placebo as a separate formulation. For oral administration, a given dose of each formulation can comprise one or more pills, tablets, capsules, gelcaps, or the like (i.e., unit doses). For example, an 8 mg dose of estriol can be administered as four 2 mg capsules, and a placebo can be administered as a single capsule.

When a given dose of any agent involves administration of more than a single unit dose, e.g., four 2 mg capsules of estriol, the individual unit doses can be administered at essentially the same time, or they can be administered at different times on a given day, provided the entire daily dose is administered within a single day. For example, four 2 mg capsules of estriol can be taken together essential ly once a day, or they may be taken two at a time twice a day, or they may be taken one at a time four times a day. Additional schedules are contemplated by the invention, again provided the entire daily dose is administered within a single day. While it may be preferable that the subject follow the same schedule from one day to the next, such is not required, once again provided the entire daily dose is administered within a single day.

When the estrogen and the progestogen are formulated separately, they can be administered essentially simultaneously, or they can be administered sequentially with respect to each other. For example, in one embodiment the subject is administered four 2 mg capsules of estriol and one 0.7 mg capsule of norethindrone essentially simultaneously. In another embodiment, the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice dai ly, and the progestogen is administered essential ly simultaneously with one of the divided doses of estriol. In yet another embodiment, the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the progestogen is administered at a separate time from either one of the divided doses of estriol.

Similarly, when the estrogen and the placebo are formulated separately, they can be administered essentially simultaneously, or they can be administered sequentially with respect to each other. For example, in one embodiment the subject is administered four 2 mg capsules of estriol and one placebo essential ly simultaneous!)'. In another embodiment, the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the placebo is administered essentially simultaneously with one of the divided doses of estriol. In yet another embodiment, the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the placebo is administered at a separate time from either one of the divided doses of estriol.

In certain embodiments, the estrogen and the progestogen are formulated together. For oral administration, a given dose of each component, formulated together, can comprise one or more pills, tablets, capsules, gelcaps, or the like (i.e., unit doses). For example, an 8 mg dose of estriol and a 0.7 mg dose of norethindrone can be coformulated and

administered as four capsules, each containing 2 mg estriol and 0.0875 mg norethindrone, though preferably, where applicable, they are coformulated as one unit dose comprising both the estrogen and the progestogen.

In certain embodiments, e.g., where a placebo is administered with the estrogen on days when progestogen is not administered, the estrogen and the placebo are formulated together. For oral administration, a given dose of each component, formulated together, can comprise one or more pills, tablets, capsules, gelcaps, or the like (i.e., unit doses). For example, an 8 mg dose of estriol and a placebo can be coformulated and administered as four capsules, each containing 2 mg estriol and a suitable amount of placebo.

When a given dose of any coformulation of estriol and progestogen (or placebo) involves administration of more than a single unit dose, e.g., four capsules, each containing 2 mg estriol and 0.0875 mg norethindrone, the individual unit doses can be administered at essentially the same time, or they can be administered at different times on a given day, provided the entire daily dose is administered within a single day. For example, four capsules, each containing estriol and progestogen (or placebo) can be taken together essentially once a day, or they may be taken two at a time twice a day, or they may be taken one at a time four times a day. Additional schedules are contemplated by the invention, again provided the entire daily dose is administered within a single day. While it may be preferable that the subject follow the same schedule from one day to the next, such is not required, once again provided the entire daily dose is administered within a single day.

Clinically, depression in MS (or another neurodegenerative disease) may be assessed using the Beck Depression Inventoiy (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Cornell Scale for Depression in Dementia (CSDD), Geriatric Depression Scale (GDS), Hamilton Rating Scale for Depression (HAM-D), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PFIQ), Clinical Global Impression scale (CGI, e.g. , CGI severity scale and/or CGI improvement scale), Zung Self- Rating Depression Scale, or Diagnostic and Statistical Manual of Mental Disorders (DSM; such as D8M-IV or DSM-5), or other such instruments.

Clinically, fatigue in MS (or another neurodegenerative disease) may be assessed using the Modified Fatigue Impact Scale (MFIS), the Fatigue Severity Scale, the MS Quality of Life-54, or other such instruments.

A randomized, double-blind, placebo-controlled clinical trial was designed to ascertain whether, in women, treatment with an estrogen pill (estriol), used in combination with major FDA-approved standard treatments for MS (Betaseron©, Extavia©, Rebif®, Avonex®, Copaxone®, Gilenya®, Aubagio®, or Tecfidera®) for one year, can improve cognitive testing as compared to treatment with a placebo pill in combination with the same major FDA-approved standard treatments for MS,

With respect to the estriol intervention, the study design includes continuous treatment with estriol, part of the time with norethindrone, and part of the time without norethindrone. That is, again with respect to the estriol intervention, the study can be understood as a series of consecutive periods, wherein for each period the subject continuously receives estriol and, for only a portion of each period, the subject also receives norethindrone.

In the experimental group, subjects receive standard MS treatment plus estriol 8 mg by mouth daily (continuously) plus norethindrone 0.7 mg by mouth daily for two weeks starting at month 6 and at months 9 and 12.

In the control group, subjects receive standard MS treatment plus estriol placebo by mouth daily (continuously) plus norethindrone placebo by mouth daily for two weeks starting at month 6 and at months 9 and 12,

Study subjects are 18- to 50-year-old women with diagnosis of clinically definite or

MacDonald criteria relapsing-remitting MS, secondary-progressive MS, or primary- progressive MS; on a stable dose of Copaxone®, Betaseron®, Extavia®, Rebif®,

Avonex®, Gilenya®, Aubagio®, or Tecfidera® for a minimum of 3 months duration prior to enrollment; and with no relapse within 30 days before trial enrollment. Excluded from the study are women on oral contraceptives (QCP), hormone replacement therapy (HRT), progesterone intrauterine devices (IUDs), or other sex hormones.

The primary outcome measure for this study is change from baseline in cognitive function (processing speed), assessed by Paced Serial Addition Test (PAS AT). Numerical test scores (ranging from 0-60) are acquired, then percent change for each subject at trial conclusion as compared to baseline is determined. A primary goal is to determine whether greater improvement as expressed as percent change occurs in the estriol group as compared to the placebo group.

Secondary outcome measures include change from baseline in cognitive function as assessed by cognitive evoked potentials, measured in milliseconds; change from baseline in standard MS outcome measures (relapses, expanded disability status score (EDSS), 25-foot walk test, 9-hole peg test, low contrast visual acuity, MS Quality of Life, Modified Fatigue Impact Scale, and Beck Depression Inventory); change from baseline in cognitive function as assessed by a brief battery of cognitive tests; and safety.

Cognitive evoked potentials are recorded in msecs for each subject at baseline and conclusion. The percent improvement at conclusion as compared to baseline for each subject is determined. Group comparisons will reveal whether the percent improvement is greater in the estriol treated group as compared to the placebo treated group.

A brief batteiy of cognitive tests is administered, including: Processing speed: symbol digit modalities test (SDMT); Visual memory: 7/24 Spatial Recall Test, Benton Forms F & G; Verbal memory: Buschke Selective Reminding Test, Verbal Paired

Associates; and Language: Word List Generation. Each subject is tested at baseline, month 6, and conclusion. Percent change at conclusion as compared to baseline is determined in each subject. Group comparisons will reveal which cognitive test within the batter}' had greater improvement in the estriol treated group as compared to the placebo treated group.

Safety is measured based on neurologic exams, laboratory tests (chemistries, complete blood count (CBC)), and breast and gynecologic exams.

Fatigue is measured, for example, with the Modified Fatigue Impact Scale (MFIS), The Modified Fatigue Impact Scale is based on items derived from interviews with MS patients concerning how fatigue affects their lives. The MFIS focuses on the ways in which MS-related fatigue affects everyday life. The MFIS consists of 21 items on a Likert scale. The MFIS has the three subscales: Physical, Cognitive, and Psychosocial functioning. These subscales examine the effect of particular interventions on fatigue as it relates to these different functional areas.

Depression is assessed, for example, with the Beck Depression Inventory (BDI), The Beck Depression Inventory is a questionnaire developed to measure the presence and severity of depression. This test provides an exemplary method of measuring depression over the course of treatment according to certain embodiments of the present invention. The test may also be used for reassessing a patient during treatment. An assessment may be used, for example, to determine choice and dosage of an agent to treat depression.

The second edition of the Beck Depression Inventor}' is a 21 -item questionnaire with each item rated on a four-point Likert scale (0-3) with total scores ranging from 0 to 63. A higher score indicates a more severe level of depression. Generally, a total score below 10 indicates no depression; a score from 10-16 indicates mild depression; 17-29 indicates moderate depression; and 30-63 indicates severe depression.

Eleven items of the BDI specifically identify how a depressed person thinks and feels about himself or herself. These items were found to be unique and distinctive for the experience of depression and unrelated to the experience of dissociation. In paraphrased form they are: feeling disappointment in oneself; critical of oneself; suicidal thoughts; sadness; discouraged about the future; feelings of being punished; guilty; feeling like a failure; feeling a lack of satisfaction; feeling old/unattractive/ugly; and loss of interest in people.

Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to limit the invention. EXAMPLES

Example I - Use of Copaxone® and Estriol for the Treatment of Multiple Sclerosis

This example describes a randomized, double-blind, placebo-controlled human clinical trial for the treatment of multiple sclerosis using Copaxone© and estriol.

Enrollment Criteria

Eligible patients were female, between ages 18 and 50, had active relapsing disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial. Study Conduct, and Monitoring Schedule

Patients were randomized to Copaxone® (glatiramer acetate) injections (20 mg/day) and oral estriol (8 mg/day) or to Copaxone® injections and placebo for a 24-month treatment duration. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants' estriol levels, and assessed for MS relapses and MS-related disabilities.

A total of 82 patients received Copaxone® plus estriol, and 76 patients received Copaxone® plus placebo. Baseline characteristics were similar in both patient groups. Participants' mean age at entry was approximately 38, and their mean EDSS score at entry was 2.2. Estriol levels in serum were in a mid-pregnancy range in the estriol-treated group. To ensure breast and uterus safety, every three months the patients took norethindrone 0.7 mg once a day for 14 days. This hormone regimen was found to be safe and well tolerated with regard to serious adverse events, adverse events, general exams, blood chemistries, and hematological studies, as well as for gynecological outcomes (see Table 1).

Table 1 - Safety aed Tolerability Data

Patients received Copaxone® with either estriol or placebo

Depression Assessment

Depression scores were measured for subjects at 0, 3, 6, 12, 18, and 24 months after beginning Estriol therapy using the Beck Depression Inventor}'. Subjects displayed signs of depression as assessed using the Beck Depression Inventory. Estriol-treated subjects had significantly less depression, while the placebo-treated group displayed no change. Results are shown in Figure 1 and in Tables 2 and 3 below:

2^ Table 2: Beck Depression Iiiventon (Raw Scores):

Estriol

Month N Mean Std Dev Median 25th Pc l 75th Pctl

0 82 11.3 9.2 10.0 4.0 17.0

3 80 10.1 9.7 7.5 3.0 13.5

6 77 S.7 8.7 6.0 2.G 12.0

12 70 S.3 8.2 7.0 2.1 16.0

18 63 8.5 7.7 7.0 2.0 14.0

24 59 7.4 7.2 6.0 1.0 12.0

Placebo

Month N Mean Std Dev Median 25th Pctl 75t Pctl

0 76 10.9 10.0 9.0 5.0 14.0

3 75 9.2. 8.7 7.0 3.0 13.0

6 72 9.6 9.3 8.0 2.1 13.0

12 S2 9.4 9.1 7.0 3.0 14.0

18 55 8.9 8.9 6.0 2.0 12.0

24 56 8.1 8.1 5.5 2.0 12.5

The mean Beck Depression Inventory score decreased significantly in the estriol group (slope = -1 ,06 ± 0.49, p=0.0320, units = points per month), whereas, in the placebo group, the mean Beck Depression Inventory score did not decrease significantly (slope =^;: - 0.35 ± 0.52, p=0.5068).

Table 3: Beck Depression Inventory, absolute change from baseline

Estriol

Month N Me Std Dev Medi n Pr > It}

3 80 -1.2 7.2 -1.0 0.1385

6 77 -2.2 6.8 -2.0 0.0062

12 70 -1.6 7.1 -2.0 0.0666

18 63 -2.1 7.8 -2.0 0.0364

24 59 -2.6 6.0 -3.0 0.0019

Placebo

Month N Me n Std Dev Median Pr > It}

3 75 -1.6 7.6 -1.0 0.0702.

6 72 -0.6 7.2 -1.0 0.5080

12 62 -0.6 9.3 -0.5 0.6365

18 55 -0.3 S .8 0.0 0.7869

24 56 -1.2 6.8 -2.0 0.1743 Fatigue Assessment

Fatigue scores were measured for subjects at 0, 3, 6, 12, 18, and 24 months after beginning Estrioi therapy using the Modified Fatigue Impact Scale. Results are shown in Figure 2 and in Tables 4 and 5 below:

Table 4: Total Raw Scores

Estrioi group

Month N Mean Std Dev Median 25th Pctl 75th Pctl

0 82 33.7 19.5 32.0 17.0 50.0

3 80 31.1 19.0 30.5 17.0 46,0

6 77 28.3 20.1 26.0 10.0 42.0

12 70 2.9.4 20.0 29.5 10.0 45 , 0

18 63 27.2. 20.7 2.5.0 8.0 45.0

24 58 25.9 19.4 22.0 10.0 45.0

Placebo g oup

Month N Mean Std Dev Median 25th Pctl 75 th Pctl

0 76 31.1 19.0 28.5 17.0 44 , 5

3 75 28.5 19.4 2.7.0 12.0 42.0

6 72 2.9.3 20.3 28.7 11.5 44 , 5

12 62 30.3 18.3 29.5 16.0 45.0

18 55 27.6 18.0 26.0 11.0 39.0

24 56 30.2 18.7 28.5 17.0 42,0

Table 5: Absolute change from baseline

Estrioi group

Month N Mean Std Dev Median 25th Pctl 75th Pctl Pr > !t!

3 80 -2 , .4 11.2 -2.0 -10.0 4.0 0 .0556

6 77 -4 , ,0 11.0 -4.0 -11,0 4.0 0. .0022

12 70 -3. .4 13.4 -3.0 -10.0 5.0 0. .0386

18 63 -4. .0 13.7 -5.0 -11.0 3.6 0. .0257

24 58 -5. .0 1 .0 -3.0 -10.0 4.0 0. .0091

Placebo group

MOD th N Mean Std Dev Median 25th Pctl 75th Pctl Pr > !t!

3 75 _ o , 4 11.8 -2.0 -10,0 2.0 0. .0784

6 72 -1. .3 13.5 -2.0 -9.5 6.5 0. .4179

12 62 --0. .6 15.1 -0.5 -8.0 9.0 0. .7561

18 55 _ 0 , 4 12.3 -1.0 -9.0 5.0 0. .1453

24 56 0 , .5 12.8 1.0 -6.0 7.0 0 .7841 In the estrioi group, the absolute di ff erence for the mean score on the Modified

Fatigue Impact Scale was significantly lower than baseline for every month except month 3, which demonuStrates an improvement. In the placebo group, the absolute difference for the mean score on the Modified Fatigue Impact Scale was not significantly different at any time point, which demonstrates no improvement. The total fatigue score dropped 5 points in the estriol group, indicating an improvement, but increased 0.5 point in the Placebo group, indicating no improvement, p=0.0337 (Wilcoxon rank sum test) (Table 4 and Figure 2).

I NC ORPORATION BY REFERENCE

All patents, published patent applications, and other publications mentioned in the description above are incorporated by reference herein in their entirety.

EQU I VALENTS

Having now fully described the present invention in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious to one of ordinary skill in the art that the same can be performed by modifying or changing the invention within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any specific embodiment thereof, and that such modifications or changes are intended to be encompassed within the scope of the appended claims.

Claims

CLAIMS I claim:

1. A method of treating fatigue in a subject that has a neurodegenerative disease, such as multiple sclerosis, comprising:

administering to a subject in need thereof, on a continuous basis throughout one or more consecutive treatment periods, a therapeutically effective amount of an estrogen; and administering to the subject, for only a portion of each treatment period, a therapeutically effective amount of a progestogen.

2. A method of treating fatigue in a subject that has a neurodegenerative disease, such as multiple sclerosis, comprising:

administering to a subject in need thereof, on a continuous basis throughout one or more consecutive treatment periods, a therapeutically effective amount of an estrogen; wherein the subject, for only a portion of each treatment period, receives a therapeutically effective amount of a progestogen.

3. A method of treating depression in a subject that has a neurodegenerative disease, such as multiple sclerosis, comprising:

administering to a subject in need thereof, on a continuous basis throughout one or more consecutive treatment periods, a therapeutically effective amount of an estrogen; and administering to the subject, for only a portion of each treatment period, a therapeutically effective amount of a progestogen.

4. A method of treating depression in a subject that has a neurodegenerative disease, such as multiple sclerosis, comprising:

administering to a subject in need thereof, on a continuous basis throughout one or more consecutive treatment periods, a therapeutically effective amount of an estrogen; wherein the subject, for only a portion of each treatment period, receives a therapeutically effective amount of a progestogen.

5. The method of any one of the preceding claims, wherein the method continues for at least two treatment periods.

6. The method of any one of the preceding claims, wherein the estrogen is selected from estriol (E3), estradiol (E2), estrone (El ), pharmaceutically acceptable salts of any of the foregoing, and any combination thereof,

7. The method of claim 6, wherein the estrogen is estriol,

8. The method of any one of the preceding claims, wherein the progestogen is selected from chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, 5a- dihydroprogesterone, drospirenone, ethinodiol acetate, ethynodio! diacetate, etonogestrel, gestodene, 17-hydroxyprogesterone, Ievonorgestrel, medroxyprogesterone acetate (17a- hydroxy-6a-methyiprogesterone acetate), megestrol, megestroi acetate (17a-acetoxy-6- dehydro-6-rnethylprogesterone), nestoroiie, nomegestrol acetate, iiorethiiidrone, norethindrone acetate, norethynodrei, norgestimate, norgestrel, progesterone, tanaproget, trimegestone, pharmaceutically acceptable salts of any of the foregoing, and any combination thereof.

9. The method of claim 8, wherein the progestogen is progesterone.

10. The method of claim 8„ wherein the progestogen is norethindrone.

11. The method of any one of the preceding claims, wherein each treatment period is at least 28 consecutive days.

12. The method of claim 11, wherein each treatment period is at least 56 consecutive days.

13. The method of claim 12, wherein each treatment period is at least 84 consecutive days.

14. The method of claim 13, wherein each treatment period is at least 112 consecutive days.

15. The method of any one of the preceding claims, wherein each treatment period is at least 4 consecutive weeks.

16. The method of claim 15, wherein each treatment period is at least 8 consecutive weeks.

17. The method of claim 16, wherein each treatment period is at least 12 consecutive weeks.

18. The method of claim 17, wherein each treatment period is at least 16 consecutive weeks.

19. The method of any one of the preceding claims, wherein each treatment period is at least one month.

20. The method of claim 19, wherein each treatment period is at least two consecutive months.

21. The method of claim 20, wherein each treatment period is at least three consecutive months.

22. The method of claim 21 , wherein each treatment period is at least four consecutive months.

23. The method of any one of the preceding claims, wherein the continuous basis is daily.

24. The method of any one of the preceding cl aims, wherein the portion of each treatment period is daily for all but at least 7 consecutive days of each treatment period.

25. The method of claim 24, wherein the portion of each treatment period is daily for all but at least 14 consecutive days of each treatment period.

26. The method of any one of the preceding claims, wherein the portion of each treatment period is daily for up to 14 consecutive days of each treatment period.

27. The method of claim 26, wherein the portion of each treatment period is daily for up to 7 consecutive days of each treatment period.

28. The method of any one of claims 1 -23 , wherein the portion of each treatment period is daily for all but at least half of each treatment period,

29. The method of any one of the preceding cl aims, wherein the estrogen is

administered orally in a dose equal or equivalent to about 200 μg to about 20 mg of estriol daily.

30. The method of claim 29 wherein the estrogen is administered orally in a dose equal or equivalent to about 1 mg to about 10 mg of estriol daily.

31. The method of claim 30, wherein the estrogen is administered orally in a dose equal or equivalent to about 8 mg of estriol dai ly.

32. The method of any one of the preceding claims, wherein the progestogen is administered orally in a dose equal or equivalent to about 70 tig to about 7 mg of norethindrone daily.

33. The method of claim 32, wherein the progestogen is administered orally in a dose equal or equivalent to about 100 ,ug to about 1 mg of norethindrone daily.

34. The method of claim 33, wherein the progestogen is administered orally in a dose equal or equivalent to about 700 ,ug of norethindrone daily.

35. The method of any one of the preceding claims, wherein the subject is a

premenopausal female.

36. The method of any one of claims 1-34, wherein the subject is a perimenopausal female.

37. The method of any one of the preceding claims, wherein the estrogen and the progestogen are formulated together,

38. A method of treating fatigue in a subject that has multiple sclerosis, comprising administering oral ly to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), 8 mg of estriol daily; and

administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), 0.7 mg of norethindrone daily.

39. A method of treating depression in a subject that has multiple sclerosis, comprising administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), 8 mg of estriol daily; and

administering orally to the subject, for 1 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), 0.7 mg of norethindrone daily.

40. The method of claim 38 or 39, wherein the 14 consecutive days (2 weeks) are the first 14 consecutive days (2 weeks) of the 84 consecutive days ( 12 weeks).

41. The method of any one of claims 38-40, further comprising administering to the subject a placebo in place of the norethindrone on each of the days the norethindrone is not administered to the subject.

42. The method of any one of the preceding claims, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis, secondary-progressive multiple sclerosis, primary- progressive multiple sclerosis, or progressive-relapsing multiple sclerosis.

43. The method of any one of the preceding claims, wherein the subject is not being treated with another immunotherapeutic agent (besides the estrogen and progestogen).

44. The method of any one of claims 1-42, further comprising administering to the subject an immunotherapeutic agent, wherein the immunotherapeutic agent is neither an estrogen nor a progestogen.

45. The method of claim 44, wherein treatment with the immunotherapeutic agent is initiated at the same time or about the same time as initiation of treatment with the estrogen and progestogen.

46. The method of any claim 44 or 45, wherein the immunotherapeutic agent is selected from i terferon-beta l a, interferon-beta l b, glatiramer acetate, nataiizumab, mitoxantrone, fmgolimod, teriflunomide, dimethyl fumarate, mycophenolate mofetil, paclitaxel, cyclosporine, corticosteroids, azathioprine, cyclophosphamide, methotrexate, cladribine, 4- aminopyridine, and tizanidine.

47. The method of claim 46, wherein the immunotherapeutic agent is selected from interferon-beta la, interferon-beta lb, glatiramer acetate, nataiizumab, mitoxantrone, fingolimod, teriflunomide, and dimethyl fumarate.

48. The method of claim 47, wherein the immunotherapeutic agent is glatiramer acetate.

49. The method of any one of claims 44-48, wherein the amount of the

immunotherapeutic agent administered in combination with the estrogen and the

progestogen is less than a therapeutically effective amount when the immunotherapeutic agent is administered alone (e.g., 20 mg glatiramer three times a week instead of 40 mg three times a week or 20 mg daily; 0.25 mg fmgolimod daily instead of 0.5 mg daily; 120 mg dimethyl fumarate daily instead of 240 mg daily; or 0.125 mg interferon beta- lb ever}' other day instead of 0.25 mg every other day).

50. The method of any one of the preceding claims, wherein the subject is experiencing progression of the multiple sclerosis.

51. The method of any one of the preceding claims, wherein the subject is experiencing a relapse of the multiple sclerosis.

52. The method of any one of the preceding claims, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, amyotrophic lateral sclerosis, cerebellar ataxia, frontotemporal dementia, prion disease, Huntington's Disease, cerebral ischaemia, idiopathic Morbus Parkinson, Parkinson syndrome, Morbus Alzheimers, cerebral dementia syndrome, infection-induced iieurodegeiieration disorders (e.g., AlDS-encephalopathy, Creutzfeld- Jakob disease, encephalopathies induced by rubioia and herpes viruses and borrelioses), metabolic-toxic neurodegenerative disorders (such as hepatic-, alcoholic-, hypoxic-, hypo- or hyperglycemicaily-induced encephalopathies), encephalopathies induced by solvents or pharmaceuticals, degenerative retina disorders, trauma-induced brain damage, trauma-induced bone marrow damage, cerebral

hyperexcitability symptoms, cerebral hyperexcitability states (e.g., of varying origin, such as after the addition of and/or withdrawal of medicaments, toxins, noxae and drugs), neurodegenerative syndromes of the peripheral nervous system, peripheral nerve injury, or spina] cord injury.

53. The method of any one of the preceding claims, further comprising measuring a depression score for the subject.

54. The method of claim 53, wherein an initial depression score is measured prior to administering the estrogen and the measurement is repeated after one or more treatment periods.

55. The method of claim 53 or 54, wherein the depression score is measured using the Beck Depression Inventory .

56. The method of claim 55, wherein the patient has an initial depression score of at least 9.

57. The method of claim 56, wherein the patient has an initial depression score of at least 10.

58. The method of claim 57, wherein the patient has an initial depression score of at least 1 1.

59. The method of any one of the preceding claims, further comprising administering to the subject an agent to treat depression, wherein the agent to treat depression is not an estrogen or a progestogen,

60. The method of claim 59, comprising administering to the subject an agent to treat depression, wherein the agent to treat depression is a tricyclic antidepressant, monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, or serotonin-norepinephrine reuptake inhibitor.

61. The method of claim 60, wherein the agent to treat depression is a tricyclic antidepressant, and the tricyclic antidepressant is clomipramine, imipramine, desipramine, fibenzepm, lofepramine, nortriptyline, protriptyline, amitriptyline, amitriptyl.inoxi.de, amoxapine, butriptyline, demexiptiline, dimetacrme, dosulepin, doxepin, imipraminoxide, meiitracen, metapramine, nitroxazepine, noxiptiline, pipofezine, propizepine,

quinupramine, ammeptine, iprindole, opipramol, tianeptine, or trimipramine.

62. The method of claim 6.1 , wherein the tricyclic antidepressant is amitriptyline, desipramine, or nortriptyline,

63. The method of claim 60, wherein the agent to treat depression is a monoamine oxidase inhibitor (MAO!), and the MA.OI is isocarboxazid, isoniazid, nialamide, phenelzine, procarbazine, hydracarbazine, tranylcypromine, mociobemide, pirlindole, toloxatone, rasagiline, selegiline, iinezolid, iproclozide, iproiiiazid, mebaiiazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, or minaprine.

64. The method of claim 60, wherein the agent to treat depression is a selective serotonin reuptake inhibitor (SSRI), and the SSRI is citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, or zimelidine.

The method of claim 64, wherein the SSRI is fluoxetine, paroxetine, or sertraline.

66. The method of claim 60, wherein the agent to treat depression is a serotonin- norepinephrine reuptake inhibitor (SNRI), and the SNR1 is venlafaxine, desvenlafaxine, duioxetine, milnacipran, ievomihiaeipran, or sibutramine.

67. The method of claim 66, wherein the SNRI is venlafaxine or duioxetine.

68. The method of any one of claims 59-67, wherein the amount of the agent to treat depression is less than a therapeutically effective amount when the agent is administered in the absence of the estrogen,

69. The method of any one of claims 59-68, further comprising reducing the dosage of the agent to treat depression over a period of 2-12 weeks after initiation of treatment with the estrogen and progestogen.

70. The method of any one of claims 1-58, wherein the subject does not receive conjoint therapy with an agent to treat depression other than the estrogen.

71. The method of any one of the preceding claims, further comprising measuring a fatigue score for the subject.

72. The method of claim 71 , wherein an initial fatigue score is measured prior to administering the estrogen and the measurement is repeated after one or more treatment periods.

73. The method of claim 71 or 72, wherein the fatigue score is measured using the Modified Fatigue Impact Scale.

74. The method of claim 73, wherein the patient has an initial fatigue score of at least 25.

75. The method of claim 74, wherein the patient has an initial fatigue score of at least 28.

76. The method of claim 75, wherein the patient has an initial fatigue score of at least 30.

77. The method of any one of the preceding claims, further comprising administering to the subject an agent to treat fatigue or an agent to increase wakefulness, wherein neither the agent to treat fatigue nor the agent to increase wakefulness is an estrogen or a progestogen,

78. The method of claim 77, comprising administering to the subject an agent to treat fatigue, wherein the agent to treat fatigue is amantadine.

79. The method of claim 77, comprising administering to the subject modafmi!, armodafmil, pemoline, or methylphenidate.

80. The method of any one of claims 77-79, wherein the amount of the agent to treat fatigue or the agent to increase wakefulness is less than a therapeutically effective amount when the agent is administered in the absence of the estrogen.

81. The method of any one of claims 77-80, further comprising reducing the dosage of the agent to treat fatigue and/or the agent to increase wakefulness over a period of 1 ~6 weeks after initiation of treatment with the estrogen and progestogen.

82. The method of any one of claims 1-76, wherein the subject does not receive conjoint therapy with an agent to treat fatigue or an agent to increase wakefulness other than the estrogen.