WO2023214285A1 - Compositions comprising female reproductive hormones and methods for using thereof - Google Patents

Abstract

The disclosure presented herein provides methods for treating a subject suffering from a pathological condition. The method is based on a fast desensitization protocol comprising intradermal injection of female sexual hormones. Further disclosed herein are composition comprising said female sexual hormones.

Description

COMPOSITIONS COMPRISING FEMALE REPRODUCTIVE HORMONES AND METHODS FOR USING THEREOF

RELATED APPLICATION

The present application gains priority from US provisional patent application US 63/337,738 filed 3 May 2022 which is included by reference as if fully set-forth herein.

FIELD AND BACKGROUND OF THE INVENTION

The disclosure presented herein provides methods for treating a subject suffering from a pathological condition. The method is based on a fast de sensitization protocol comprising intradermal/epicutaneous injection of female sexual hormones. Further disclosed herein are composition comprising said female sexual hormones.

Desensitization, also known as allergen immunotherapy, is a medical treatment in which the patient is exposed to an allergen or antigen, in an attempt to induce the immune system to tolerate the allergen, thus preventing future allergic reactions. Desensitization has been proved useful for treating skin atopic dermatitis, allergic rhinitis, respiratory allergies, allergic conjunctivitis, asthma, and others.

While not fully elucidated, the desensitization mechanism seems to redirect the immune response from humoral immunity towards cellular immunity, thereby encouraging the body to produce more CD4+ T regulatory cells, which secrete IL-10 and TGF-P, and inhibit IgE production. The treatment usually consists of an initial phase, in which the allergen is administered subcutaneously in increasing doses; followed by a maintenance phase, in which the maximal dose is administered monthly for a number of years. Other forms of desensitization, such as sublingual, oral, and transdermal immunotherapy, are also used.

A number of clinical observations suggest that intolerance to female sex hormones, such as estradiol, estrone, estriol, progesterone, and testosterone, are involved in diverse autoimmune pathologies. Clinical studies indicate, for example, a higher incidence of autoimmune diseases in woman compared to man. Further, an improvement or worsening of autoimmune diseases was correlated with increases or decreases of hormone levels, as during puberty, pregnancy and menopause. Clinical studies further revealed higher levels of estrogen and progesterone specific immunoglobulins in patients with menstruation cycle dependent disorders. Finally, androgens and estrogens were shown to promote autoimmune diseases with a profile of type 1 cytokines, or a type 2 cytokine profile, respectively, in animal models. Sex-hormone induced autoimmune disorders are treated with systemic corticosteroids, conjugated estrogen, the anti-estrogen Tamoxifen and oral contraceptives, among others. While these approaches are efficient at addressing the symptoms, they do not offer a cure for the disease. Among others, these methods may cause systemic and skin local impaired lymphatic drainage and interstitial inflammatory stasis, lower levels of Mg, vitamin Bl, vitamin D, and tissue acidosis. Further, these methods require from the patient to attend a praxis a number of times per week for years, therefore the compliance is very low. Desensitization protocols have been proposed, including oral, intradermal and intravaginal application of the hormones found as immune triggers.

Other desensitization protocols were reported in the literature, as Itsekson AM et al. 2013 Gynecol Endocrinol, 29:2 pp. 169-172, and Foer D et al. 2016, J Allergy Clin Immunol Pract, 4:4 pp. 723-729. Despite the general advances in the field, the diverse desensitization methods can only be considered as experimental approaches, and they are rarely applied in clinical routine.

Herein is disclosed a desensitization method to treat diverse hormone-induced disorders. The methods disclosed herein were proven to be very efficient in treating autoimmune disorders, even after a single therapy session.

SUMMARY OF THE INVENTION

In some aspects, disclosed herein is a method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment, wherein said area of treatment comprises an adipose depot.

In some related aspects, the area of treatment comprises the abdomen, the hip, or the forearm. In some related aspects, the method further comprising intradermally injecting lidocaine, bupivacaine, magnesium, mannitol, or a combination thereof to said area of treatment, before step (e).

In some related aspects, the female reproductive hormone comprises estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof. In some related aspects, the female reproductive hormone comprises estradiol, estrone, progesterone, or testosterone and is injected in a 20 nmol dose; or wherein said female reproductive hormone comprises estriol and is injected in a 60 nmol dose. In some related aspects, the female reproductive hormones are injected at 37°C. In some related aspects, the pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, a hormonal disorder, premenstrual dysphoric disorder (PMDD), fibromyalgia, post-traumatic brain injury, cerebrovascular accident (CVA), a viral infection, COVID-19, cytomegalovirus infection, optic neuritis, Hashimoto disease, post-vaccination syndrome, multifocal pain disorder, hormonal dependence skin disease, psoriasis, atopic dermatitis, metabolic syndrome, postappendectomy syndrome, Alzheimer’s disease, anorexia, or any combination thereof.

In some related aspects, the pathological condition comprises menstrual migraine, and said female reproductive hormones comprise estriol and progesterone. In some related aspects, the pathological condition comprises mastalgia and said female reproductive hormones comprise estradiol and progesterone.

In some related aspects, the pathological condition comprises red eyes or runny nose, and said female reproductive hormones comprise progesterone and testosterone. In some related aspects, the pathological condition comprises depression or anxiety, and said female reproductive hormones comprise progesterone.

In some related aspects, the pathological conditions comprise intrauterine-device (IUD) related side effects, and said female reproductive hormones comprise progesterone. In some related aspects, the mechanical impulse is applied by a chiropractic activator. In some related aspects, the mild electrical current is applied by a transcutaneous electrical nerve stimulation (TENS) device.

In some related aspects, the method further comprises applying red light or infrared light stimulation to said area of treatment, previous to step (e). In some related aspects, the subject is provided with supplements of magnesium, vitamin D, vitamin Bl, melatonin, or probiotic supplements, previous to step (a).

In some aspects, disclosed herein is a method for preventing a pathological condition in a subject, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment, wherein said area of treatment comprises an adipose depot.

In some aspects, disclosed herein is a composition comprising at least one female reproductive hormone for use in a method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment, wherein said area of treatment comprises an adipose depot.

In some related aspects, the female reproductive hormones comprise estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof. In some related aspects, the female reproductive hormone comprises estradiol, estrone, progesterone, or testosterone and is injected in a 20 nmol dose; or wherein said female reproductive hormone comprises estriol and is injected in a 60 nmol dose.

In some related aspects, the pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, or a hormonal disorder. In some related aspects, the pathological condition comprises menstrual migraine, and said female reproductive hormones comprise estriol and progesterone.

In some related aspects, the pathological condition comprises mastalgia and said female reproductive hormones comprise estradiol and progesterone. In some related aspects, the pathological condition comprises red eyes or runny nose, and said female reproductive hormones comprise progesterone and testosterone.

In some related aspects, the pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, a hormonal disorder, premenstrual dysphoric disorder (PMDD), fibromyalgia, post-traumatic brain injury, cerebrovascular accident (CVA), a viral infection, COVID-19, cytomegalovirus infection, optic neuritis, Hashimoto disease, post-vaccination syndrome, multifocal pain disorder, hormonal dependence skin disease, psoriasis, atopic dermatitis, metabolic syndrome, postappendectomy syndrome, Alzheimer’s disease, anorexia, or any combination thereof.

In some related aspects, the pathological conditions comprise intrauterine-device (IUD) related side effects, and said female reproductive hormones comprise progesterone. In some related aspects, the method further comprises applying red light or infrared light stimulation to said area of treatment, previous to step (d). In some related aspects, the subject is provided with supplements of Mg, vitamin D, vitamin Bl, melatonin, or probiotic supplements, previous to step (a).

In some aspects, disclosed herein is a composition comprising a female reproductive hormone, mannitol, hyaluronic acid, and vitamin D. In some related aspects, the female reproductive hormone comprises estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof. In some aspects, disclosed herein is a kit comprising a composition comprising at least one female reproductive hormone, for use in a method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment, wherein said area of treatment comprises an adipose depot.

In some aspects, disclosed herein is a kit comprising a composition comprising at least one female reproductive hormone, an intradermal injector, intradermal injector needles, a device for applying a mechanic impulse, and a device for applying a mild electrical current.

DESCRIPTION OF SOME EMBODIMENTS OF THE INVENTION

The present subject matter may be understood more readily by reference to the following detailed description, which forms a part of this disclosure. It is to be understood that this disclosure is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed disclosure.

Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

In the present disclosure the singular forms "a," "an," and "the" include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. The term "plurality", as used herein, means more than one. When values are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable. In some embodiments, the term “about”, refers to a deviance of between 0.0001-10% from the indicated number or range of numbers. In some embodiments, the term “about”, refers to a deviance of up to 25% from the indicated number or range of numbers. The term “comprises” means encompasses all the elements listed, but may also include additional, unnamed elements, and it may be used interchangeably with the terms “encompasses”, “includes”, or “contains” having all the same qualities and meanings. The term "consisting of' means being composed of the recited elements or steps, and it may be used interchangeably with the terms “composed of’ having all the same qualities and meanings.

The present disclosure relates to method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to an area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment; wherein said area of treatment comprises an adipose depot.

A skilled artisan would appreciate that “female reproductive hormone” refers to any hormone involved in female fertility, sexuality, the menstrual cycle, or pregnancy. Female reproductive hormones may refer to a hormone secreted by or acting on the female reproduction system, such as hormones secreted by the ovaries, fatty tissue, adrenal glands, and placenta. In some embodiments, a female reproductive hormone comprises an estrogen steroid hormone. In some embodiments, a female reproductive hormone comprises estradiol. A skilled artisan would appreciate that estradiol can be termed also “oestradiol”, “E2”, “170- estradiol”, “estra-l,3,5(lO)-triene-3,170-diol”, or “170-oestradiol”.

In some embodiments, a female reproductive hormone comprises estrone, which can be also termed “oestrone”, “El”, or “3-hydroxyestra-l,3,5(10)-trien-17-one”. In some embodiments, a female reproductive hormone comprises estriol, which can be also termed “oestriol”, “E3”, “estratriol”, “theelol”, “trihydroxyestrin”, “trihydroxy oestrin”, “16a- hydroxyestradiol”, “estra-l,3,5(lO)-triene-3,16a,170-triol”. In some embodiments, a female reproductive hormone comprises progesterone, which can be also termed “P4”, “pregnenedione”, “pregn-4-ene-3, 20-dione”.

In some embodiments, a female sex hormone comprises testosterone, which can be also termed “androst-4-en-170-ol-3-one”. While testosterone is the primary sex hormone in males, it is present to lower extents also in females, in which it is secreted by the ovaries and has been associated with sexual arousal. In some embodiments, a female reproductive hormone can be a naturally occurring hormone.

In some embodiments, a female reproductive hormone comprises a synthetic hormone, or a derivative thereof. Synthetic hormones are provided as part of hormonal therapies for diverse medical treatments, such as hormone replacement therapy, hormonal therapy for cancer, contraceptive therapies, and others. These therapies gave rise to a number FDA-approved products comprising bioidentical hormones, synthetic hormones, hormones agonists, hormone precursors, and their derivates. Any of these can be used in the methods and compositions disclosed herein.

In some embodiments, bioidentical sex hormones comprise progestogens, pregnenolone, progesterone, allopregnanedione, allopregnanolone, 17a- hydroxypregnenolone, 17a-hydroxyprogesterone, androgens, dehydroepiandrosterone, androstenedione, androstanedione, androsterone, androstenediol, testosterone, dihydrotestosterone, androstanediol, estrogens, 2-hydroxyestrone, estrone, 16a- hydroxyestrone, 2-hydroxyestradiol, estradiol, estriol, estetrol.

In some embodiments, synthetic estrogen comprises 17P -estradiol, di ethylstilbestrol (DES), ethinylestradiol, N-acetyl-p-aminophenol.

In some embodiments, the female sex hormone is injected in a 0.1 nmol, 0.5 nmol, 1 nmol, 2 nmol, 3 nmol, 4 nmol, 5 nmol, 6 nmol, 7 nmol, 8 nmol, 9 nmol, 10 nmol, 11 nmol, 12 nmol, 13 nmol, 14 nmol, 15 nmol, 16 nmol, 17 nmol, 18 nmol, 19 nmol, 20 nmol, 21 nmol, 22 nmol, 23 nmol, 24 nmol, 25 nmol, 26 nmol, 27 nmol, 28 nmol, 29 nmol, 30 nmol, 31 nmol, 32 nmol, 33 nmol, 34 nmol, 35 nmol, 36 nmol, 37 nmol, 38 nmol, 39 nmol, 40 nmol, 50 nmol, 60 nmol, 70 nmol, 80 nmol, 90 nmol, or 100 nmol dose.

In some embodiments, the female sex hormone is injected in a dosage range from 0.1 to 1 nmol, from 1 to 2.5 nmol, from 2.5 to 5 nmol, from 5 to 7.5 nmol, from 7.5 to 10 nmol, from 10 to 12.5 nmol, from 12.5 to 15 nmol, from 15 to 17.5 nmol, from 17.5 to 20 nmol, from 20 to 22.5 nmol, from 22.5 to 25 nmol, from 25 to 27.5 nmol, from 27.5 to 30 nmol, from 30 to 35 nmol, from 35 to 40 nmol, from 40 to 50 nmol, from 50 to 60 nmol, from 60 to 70 nmol, from 70 to 80 nmol, from 80 to 90 nmol, from 90 to 100 nmol, from 100 to 150 nmol, or from 150 to 200 nmol. In some embodiments the female sex hormone is injected in a dosage lower than 0.1 nmol. In some embodiments the female sex hormone is injected in a dosage higher than 200 nmol.

In some embodiments, the female sex hormone is injected in a dosage lower than 0.1 nmol. In some embodiments the female sex hormone is injected in a dosage higher than 200 nmol.

In some embodiments, estradiol, estrone, progesterone, or testosterone are injected in a 20 nmol dose. In some embodiments, estriol is injected in a 60 nmol dose. In some embodiments, the dose of the female reproductive hormone which is administered into the skin of the subject is selected such that is induces a reaction on the skin of the subject. As used herein “a reaction” refers to a change of color, texture or swelling of the skin.

As disclosed in the Examples section, the inventor realized that the temperature at which the female reproductive hormones are injected has a major effect on the therapy outcome. In some embodiments, the female reproductive hormones are injected in a temperature range of between 34°C and 40°C, more preferably between 35°C and 39°C, and more preferably between 36°C and 38°C. In some embodiments, the female reproductive hormones are injected at 37°C.

In some embodiments, the female sex hormones are diluted in a diluent. Such diluent is biocompatible, thus, when in contact with cells, tissues or body fluid of a subject does not induce adverse effects such as a pronounced immunological reaction. Non-limiting examples of biocompatible diluents include saline, a biocompatible oil, alcohol and the like.

In some embodiments, the diluent comprises an oil such as a synthetic oil, mineral oil, ethyl oleate, a vegetable or fruit oil such as Soy-bean oil, groundnut oil, sesame oil, peach oil, peanut oil, almond oil and the like, an animal oil or a combination thereof.

In some embodiments, the diluent comprises an alcohol or an alcohol solution. Nonlimiting examples of suitable diluents include ethyl alcohol, and benzyl alcohol. In some embodiments, the diluent comprises ethyl oleate.

In some embodiments, the diluent further comprises an enhancer for increasing permeabilization of the skin to the female reproductive hormone. In some embodiments, the diluent's viscosity at room temperature, or at body temperature, is selected for smooth intradermal introduction. Adjustment of the viscosity can be performed by adding a solvent such as ethyl or benzyl alcohol to the hormone's diluent. In some embodiments, the final concentration of the solvent (e.g., benzyl alcohol, ethyl alcohol) within the diluent is in the range of about 5-45%.

In some embodiments, the active agent is formulated with a vehicle designed to increase delivery to the epidermis or the dermis layers. Such vehicles include, but are not limited to liposomes, dendrimers, noisome, transfersome, microemulsion and solid lipid nanoparticles. In some embodiments, the active agent is mixed with chemical enhancers such as sulphoxides, azones, glycols, alkanols and terpenes which enhance delivery of active agents into the skin.

In some embodiments, the hormones are injected intradermally to an area of treatment. An intradermal injection, as used herein, refers to a shallow or superficial injection into the dermis, which is the region between the epidermis and the hypodermis. A skilled artisan would appreciate that this route of administration is the preferred route for allergy tests, as it induces strong immune responses and allows an easy observation of the body's reaction to the injected substance.

In a preferred embodiment, intradermal injection comprises epicutaneous injection. A skilled artisan would appreciate that the term “epicutaneous” refers to the introduction of biologic material or drugs into the skin by shallow, bloodless piercing with small-gauge needles through drops of solution. In some embodiments, the terms “intradermal” and “epicutaneous”, are used herein interchangeably, having all the same limitations and meanings.

In some embodiments, the female reproductive hormone is injected using a 0.5-ml or 1.0 ml tuberculin syringe through a 26-gauge or 27-gauge needle. The syringe can be placed at an angle of 45 degrees to the skin, and the bevel of the needle is angled downward, facing the skin, and penetrating entirely but not deeper than the superficial layers of the skin.

In some embodiments, an area of treatment comprises an adipose depot. Adipose depots may comprise any connective tissue composed mostly of adipocytes. In some embodiments, an adipose depot comprises at least 60%, at least 70%, at least 80%, or at least 90% of adipocytes. Adipose tissues are found in different locations in the body, as under the skin (subcutaneous fat), between muscles, and around internal organs. Most non-visceral fat is found below the skin, and is usually found around the hips, thighs, and buttocks. In some embodiments, the female reproductive hormone is administered to the buttock, the abdomen, upper outer arm, upper torso, or the thigh of the subject. In a preferred embodiment, the female reproductive hormone is administered to the abdomen. In a preferred embodiment, the female reproductive hormone is administered to the leg of a patient. As shown in the Examples section, injections to adipose depots, particularly to the abdomen or to the hip induce particularly efficient therapeutic effects. In a preferred embodiment, the female hormones are administered to subcutaneous brown adipose tissue.

In some embodiments, an area of treatment comprises a size of from about 0.5 cm² to about 10 cm², e.g., about 0.6 cm² to about 8 cm², e.g., about 0.8 cm² to about 6 cm², e.g., about 1 cm² to about 5 cm², e.g., about 1 cm² to about 4 cm², e.g., about 1 cm² to about 2 cm².

In some embodiments, the methods disclosed herein are useful for treating a subject suffering from a pathological condition. In some embodiments, the condition is pain. In some embodiments, the condition is neuropathic pain. In some embodiments, the neuropathic pain is associated with a damage or a disease affecting the somatosensory nervous system. Neuropathic pain may comprise dysesthesia and/or allodynia. Neuropathic pain may have continuous and/or episodic (paroxysmal) components. In some embodiments, the condition is post-vaccination syndrome. In some embodiments, the condition is multifocal pain disorder.

In some embodiments, the condition is an autoimmune disorder. Autoimmune disorders comprise at least 80 types of diseases, in which nearly any body part is involved. An autoimmune disorder may comprise celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. In some embodiments, the condition is Hashimoto disease. In some cases, an exact diagnosis can be difficult to establish. In some embodiments, the autoimmune disorder comprises comorbidity with chronic pain syndrome.

In some embodiments, the condition is an allergy. In some embodiments, the condition is a psychiatric disorder.

In some embodiments, the condition is a hormonal disorder. In some embodiments, the condition is premenstrual dysphoric disorder (PMDD). The diagnosis of PMDD is based on a patient reporting at least 5 specific symptoms including physical symptoms, such as breast tenderness, joint pain; and mood symptoms, such as marked anxiety, persistent irritability, or feelings of hopelessness.

In some embodiments, the condition is fibromyalgia. In some embodiments, the condition is post-traumatic brain injury. In some embodiments, the condition is cerebrovascular accident (CVA). In some embodiments, the condition is a viral infection. In some embodiments, the condition is COVID-19.

In some embodiments, the condition is cytomegalovirus infection. In some embodiments, the condition is optic neuritis. In some embodiments, the condition is hormonal dependent skin disease.

In some embodiments, the condition is psoriasis. In some embodiments, the condition is atopic dermatitis. In some embodiments, the condition is metabolic syndrome. In some embodiments, the condition is post-appendectomy syndrome. In some embodiments, the condition is dementia. In some embodiments, the condition is Alzheimer’s disease. In some embodiments, the condition is anorexia.

In some embodiments, a series of stimuli are applied to the area of treatment before the injection of the female reproductive hormones. The application of said stimuli were surprisingly found to predispose the immune system to respond to the hormones. While the mechanism of action of said stimuli is not yet elucidated, it is clear from the data disclosed in the Examples section that said stimuli significantly increase the effectiveness of the clinical treatment. In some embodiments, cryostimulation is applied to an area of treatment before injecting the female hormones. A skilled artisan would appreciate that cryostimulation refers to the local application of low temperatures for medical purposes. In some embodiments, cryostimulation comprises applying an element at a temperature between 0°C to -5°C for about 10 sec. In some embodiments, cryostimulation comprises applying an element at a temperature between 0°C to -5°C until a cold wound is formed.

In some embodiments, a mechanic impulse is applied to an area of treatment before injecting the female hormones. In some embodiments, a mechanic impulse is applied by using a chiropractic activator. As used herein, a chiropractic activator refers to a handheld instrument which delivers a controlled and reproducible mechanical impulse to an area of treatment. The mechanical impulse can be generated by different means, as for example a spring, or an electronic tool that delivers mechanical force. In some embodiments, a chiropractic activator delivers around 0.3 J of kinetic energy in a 3-millisecond pulse.

In some embodiments, an electrical current is applied to an area of treatment before injecting the female hormones. In some embodiments, the electrical current is applied by a transcutaneous electrical nerve stimulation, TENS, or TNS device. A skilled artisan would appreciate that TENS is a device that electrically stimulate the nerves for therapeutic purposes. In some embodiments, the device is connected to the area of treatment by using two or more electrodes, as conductive gel pads. In some embodiments, TENS is applied at frequencies above 50 Hz, with an intensity below motor contraction. In some embodiments, TENS is applied at frequencies below 10 Hz, with an intensity that produces motor contraction. In some embodiments, TENS is applied at mixed frequency mode.

In some embodiments, red light stimulation is applied to an area of treatment before injecting the female hormones. In some embodiments, infrared light stimulation is applied to an area of treatment after injecting the female hormones. These types of light stimulation comprises the application of low-level wavelengths of light to an area of treatment on the skin. Red or infrared light stimulation is known also as photobiomodulation (PBM), low level light therapy (LLLT), low level light therapy, soft laser therapy, cold laser therapy, photonic stimulation, and low-power laser therapy (LPLT).

A number of commercial devices are available to apply light stimulation, and any of these can be used to implement the methods disclosed herein. In some embodiments, a Celluma PRO device (Celluma, US) is used to apply red light stimulation.

In some embodiments, cryostimulation and a mechanic impulse are applied to an area of treatment before injecting the hormones, and a mild electrical current is applied during the injection of the hormones. In some embodiments, cryostimulation, a mechanic impulse, a mild electrical current are applied to an area of treatment before injecting the hormones. In some embodiments, cryostimulation and a mechanic impulse are applied to an area of treatment. In some embodiments, cryostimulation and a mild electrical current are applied to an area of treatment.

In some embodiments, a mechanic impulse and a mild electrical current are applied to an area of treatment before injecting the hormones. In some embodiments, a mechanic impulse, a mild electrical current are applied to an area of treatment before injecting the hormones. In some embodiments, a mechanic impulse and a red or infrared light stimulus are applied to an area of treatment after injecting the hormones.

In some embodiments, the method further comprises intradermally injecting lidocaine before injecting the female reproductive hormones. In some embodiments, the method further comprises intradermally (epicutaneous) injecting bupivacaine before injecting the female reproductive hormones.

In some embodiments, the method further comprises intradermally (epicutaneous) injecting magnesium (Mg), or a magnesium salt, before injecting the female reproductive hormones. A magnesium salt may comprise magnesium sulphate or magnesium chloride. In some embodiments, magnesium is administered in a concentration ranging from about 0.9% to about 0.7%.

In some embodiments, the method further comprises intradermally injecting mannitol before injecting the female reproductive hormones.

In some embodiments, the method further comprises intradermally injecting lidocaine before injecting the female reproductive hormones. In some embodiments, the method further comprises intradermally injecting lidocaine before injecting the female reproductive hormones.

In some embodiments, the method comprises injecting lidocaine, bupivacaine, magnesium, and mannitol before injecting the hormones. In some embodiments, the method comprises injecting lidocaine and bupivacaine before injecting the hormones. In some embodiments, the method comprises injecting lidocaine and bupivacaine before injecting the hormones. In some embodiments, the method comprises injecting lidocaine and magnesium before injecting the hormones. In some embodiments, the method comprises injecting lidocaine and mannitol before injecting the hormones.

In some embodiments, the method comprises injecting lidocaine, bupivacaine, and magnesium before injecting the hormones. In some embodiments, the method comprises injecting lidocaine, bupivacaine, and mannitol before injecting the hormones. In some embodiments, the method comprises injecting lidocaine, magnesium, and mannitol before injecting the hormones.

In some embodiments, the method comprises injecting bupivacaine, and magnesium before injecting the hormones. In some embodiments, the method comprises injecting bupivacaine, and mannitol before injecting the hormones. In some embodiments, the method comprises injecting bupivacaine, magnesium, and mannitol before injecting the hormones. In some embodiments, the method comprises injecting magnesium, and mannitol before injecting the hormones.

In some embodiments, at least one supplement is provided to the subject before applying cryostimulation to an area of treatment. As used herein, the term “supplement” refers to a concentrated sources of nutrients or other substances with a nutritional or physiological effect. In some embodiments, a nutrient comprises a mineral, a vitamin, an amino acid, an essential fatty acid, a fibre, or any combination thereof.

Usually nutrients are marketed in “dose” form, as pills, tablets, capsules, or liquids in measured doses. In some embodiments, a supplement can be administered as part of a food, or a food supplement. In some embodiments, supplements are intended to correct nutritional deficiencies, maintain an adequate intake of certain nutrients, or to support specific physiological functions.

In some embodiments, a supplement comprises magnesium. In some embodiments, a supplement comprises vitamin D. In some embodiments, a supplement comprises vitamin Bl. In some embodiments, a supplement comprises melatonin. In some embodiments, a supplement comprises a probiotic supplement. In some embodiments, a supplement comprises sodium bicarbonate.

In some embodiments, a supplement is provided at least 24h, preferably 48h, preferably 72h before the application of the hormones. In some embodiments, a supplement is provided at least 1 week before the application of the hormones. In some embodiments, a supplement is provided at least 1 month before the application of the hormones. In some embodiments, a supplement is provided during and following the application of the hormones.

In some embodiments, a supplement is provided when the subject has a deficit of said nutrient, or of any other metabolically related nutrient or molecule. In some embodiments, a supplement is provided until said deficit is corrected. In some embodiments, the method further comprises applying low level light therapy to the area of treatment. In some embodiments, said therapy is provided by a commercially available device, as for example Celluma LED Light Therapy device. In some embodiments, the applied light therapy is in a range of 660 to 840 nm.

As shown in the Examples section below, some specific hormone treatments are particularly efficient for specific pathological conditions. In some embodiments, disclosed herein is a method for treating menstrual migraine in a subject in need thereof, said method comprising injecting estriol and progesterone to said subject.

In some embodiments, disclosed herein is a method for treating mastalgia in a subject in need thereof, said method comprising injecting estradiol and progesterone to said subject. In some embodiments, disclosed herein is a method for treating red eyes or runny nose in a subject in need thereof, said method comprising injecting progesterone and testosterone to said subject.

In some embodiments, disclosed herein is a method for treating depression in a subject in need thereof, said method comprising injecting progesterone to said subject. In some embodiments, disclosed herein is a method for treating anxiety, said method comprising injecting progesterone to said subject.

In some embodiments, disclosed herein is a method for treating intrauterine-device (IUD) related side effects in a subject in need thereof, said method comprising injecting progesterone to said subject.

In some embodiments, the term “treatment” refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly. In another embodiment, the term “treating” refers to reducing incidence, or alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis or combinations thereof.

In some embodiments, the treating a pathological condition comprises the amelioration of an existing condition. The skilled artisan would understand that treatment does not necessarily result in the complete absence or removal of symptoms. Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition. The alleviation of a condition that results in a more serious condition is also encompassed by this term. As used herein, “subject” refers in one embodiment, to a human. In some embodiments, the term subject refers to a mammal. In some embodiments, the treatment comprises a first treatment session, before injecting the female reproductive hormones. In said session objective and subjective tests of pain are carried. In some embodiments, the subject is requested to fill pain-scale questionnaires. In some embodiments, an algometer is used to determine the sensitivity to pain-inducing stimuli.

In some embodiments, an immune profile of the subject is determined. A skilled artisan would appreciate that immune profile, as used herein, comprises determining the blood concentration of immune cells, immune suppressive cells, natural killer cells, inflammatory markers, or a combination thereof. In case a hormonal treatment is provided to the subject, the subject is requested to discontinue said hormonal treatment.

In some embodiments, the blood concentration of different nutrients, including magnesium, vitamin D, vitamin Bl, and melatonin, is evaluated. In case of a nutrient deficit, the subject is provided with said nutrient. In some embodiments, the microbiota homeostasis of the subject is evaluated, for example by a dysbiosis test. In case of dysbiosis, the subject is provided with a treatment for correcting said dysbiosis, as for example probiotics treatments. In some embodiments, a dysbiosis can be corrected after finishing an antibiotics treatment.

Following said first session, a second treatment session is held. The second session is preferably held after any nutrient deficit or dysbiosis, as detected in the first session, is corrected. In some embodiments, the second treatment session is held 1 month following the first treatment session. When the subject is female, the second treatment should be held during the second stage, or follicular phase of the menstrual cycle.

In some embodiments, during the second treatment session female reproductive hormones are intradermally (epicutaneous) injected to the subject. In some embodiments, the injection of female reproductive hormones is preceded by a number of steps, including applying cryostimulation, and/or applying a mechanic impulse.

In some embodiments, a lidocaine, bupivacaine, magnesium, mannitol, or a combination thereof, are injected to the area of treatment before injecting the female reproductive hormones.

The inventors are surprisingly found that following the second treatment session, i.e., after a single injection of at least one female reproductive hormone, there is a significant improvement in the condition of the subject. In some embodiments, further treatment sessions are needed to further ameliorate the condition.

In some embodiments, a third treatment session is held, about 1 month following the second session. In some embodiments, said third session is essentially similar to the second session, i.e., cryostimulation, a mechanic impulse, and a mild electrical current are applied to an area of treatment, before injecting to said area at least one female reproductive hormone.

In some embodiments, a fourth or further additional sessions are recommended when that can further ameliorate the subjects condition. In some embodiments, female subjects receive additional sessions 1 time a week for 3 consecutive weeks. In some embodiments, a male subject receives additional session monthly.

In some embodiments, the reaction to the female reproductive hormone is monitored, and according to it a course of treatment is decided. In some embodiments, the reaction to the female reproductive hormone is performed by evaluating the presence and/or the size of a wheal formed in response to the hormone. The reaction can be characterized by a change of skin color, texture and/or by swelling of the skin.

In some embodiments, when hypersensitivity to the female reproductive hormone is reduced following a treatment session, no further treatment sessions are required. In some embodiments, when the subject is essentially free of symptoms of the medical condition, no further desensitization administrations are required.

In some embodiments, when hypersensitivity to the female reproductive hormone is moderately or not reduced following a treatment session, then further treatment sessions are required. In some embodiments, when hypersensitivity to the female reproductive hormone is increased or not changed, subsequent treatment sessions might not be recommended.

In some embodiments, disclosed herein is a method for preventing a pathological condition in a subject, said method comprising:

1) selecting an area of treatment

2) applying cryostimulation to said area of treatment,

3) applying a mechanic impulse to said area of treatment,

4) applying a mild electrical current to said area of treatment, and

5) intradermally injecting at least one female reproductive hormone to said area of treatment; wherein said area of treatment comprises an adipose depot.

A skilled artisan would appreciate that preventing a pathological condition refers to to reducing the likelihood of a pathological condition to occur, reducing the likelihood of symptoms to occur, preventing the recurrence of symptoms, improving prognosis or combinations thereof. The skilled artisan would understand that prevention does not necessarily result in the complete avoidance of a potential pathological condition. In some embodiments, a preventive treatment is provided to a subject having a predisposition to a pathological condition. In some embodiments, a predisposition comprises a genetic predisposition. In some embodiments, a predisposition comprises having one of more relatives suffering from a disease. In some embodiments, a predisposition comprises having been exposed to a pathogen, as a virus or bacteria. In some embodiments, a predisposition comprises a physical or psychological traumatic event. In some embodiments, a predisposition comprising a traumatic injury to the central nervous system and/or the peripheral nervous system.

In some embodiments, a predisposition comprises having an allergy or sensitivity to a female reproductive hormone. In some embodiments, sensitiveness to a female reproductive hormone can be detected by an allergen test, for example using the methods and compositions disclosed herein. In brief, an allergen test comprises placing small amounts of the potential allergen, in this case female reproductive hormones on the skin. The hormones can be applied according to the usual practice, i.e., applying a small amount of the hormone on the skin and then making a small scratch or prick on the skin. The allergy can also be carried according to the methods disclosed herein, i.e.: a) selecting a skin area, b) applying cryostimulation to said area, c) applying a mechanic impulse to said area, d) applying a mild electrical current to said area, and e) intradermally injecting at least one female reproductive hormone to said area of skin, wherein said area of treatment comprises an adipose depot.

In some embodiments, disclosed herein is a composition comprising at least one female reproductive hormone for use in a method for treating a subject suffering from a pathological condition, said method comprising: a) applying cryostimulation to an area of treatment, b) applying a mechanic impulse to said area of treatment, c) applying a mild electrical current to said area of treatment, and d) intradermally injecting at least one female reproductive hormone to said area of treatment; wherein said area of treatment comprises an adipose depot. In some embodiments, said composition comprises estradiol, estrone, estriol, progesterone, or testosterone. In some embodiments, said composition comprises any combination of estradiol, estrone, estriol, progesterone, or testosterone.

In some embodiments, disclosed herein is a composition comprising a female reproductive hormone, and one of mannitol, hyaluronic acid, and vitamin D. In some embodiments, disclosed herein is a composition comprising a female reproductive hormone, mannitol, hyaluronic acid, and vitamin D.

In some embodiments, disclosed herein is the use of a composition comprising at least one female reproductive hormone for the treatment of a pathological condition in a subject. In some embodiments, disclosed herein is the use of a composition comprising at least one female reproductive hormone in a method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area, c) applying a mechanic impulse to said area, d) applying a mild electrical current to said area, and e) intradermally injecting said composition to said area; wherein said area of treatment comprises an adipose depot.

In some embodiments, the methods for treating and/or preventing disclosed herein, are executed in the following order: first, an area of treatment is selected; then cryostimulation is applied to said area; then a mechanic impulse is applied to said area; then a mild electrical current is applied to said area, then the female reproductive hormones are intradermally injected to said area.

In some embodiments, disclosed herein is the use of a composition comprising at least one female reproductive hormone for the manufacture of a medicament for treating a pathological condition in a subject. In some embodiments, disclosed herein is the use of a composition comprising at least one female reproductive hormone for the manufacture of a medicament to be used in a method for treating a subject suffering from a pathological condition, the method comprising: a) selecting and area of treatment, b) applying cryostimulation to said area, c) applying a mechanic impulse to said area, d) applying a mild electrical current to said area, and e) intradermally injecting said composition to said area; wherein said area of treatment comprises an adipose depot.

In some embodiments, disclosed herein is a kit comprising the compounds and elements needed to carry the clinical protocols herein disclosed. In some embodiments, a kit comprises at least one female reproductive hormone and instructions of using thereof, according to the methods herein disclosed. In some embodiments, a kit further discloses nondisposable devices to carry the clinical protocols disclosed herein. In some embodiments, these devices comprise a device for applying a mechanic impulse, a device for applying a mild electrical current, a device for red light or infrared light stimulation, or any combination thereof.

In some embodiments, the kit comprises dispensable devices to carry the clinical protocols herein described. In some embodiments, said dispensable devices an intradermal injector, intradermal injector needles, or a combination thereof. In some embodiments, all the kits disclosed herein comprise instructions describing the clinical procedures herein disclosed.

EXAMPLES

The following examples are presented in order to more fully illustrate some embodiments of the methods and compositions disclosed herein. They should in no way be construed, however, as limiting the scope of the invention.

The following examples show the unexpected amelioration of symptoms from diverse disease, following a single intradermal injection of female sex hormones, according to the protocol disclosed herein.

EXAMPLE 1 - Clinical Protocol

In all the examples disclosed below, patients underwent a clinical protocol comprising: applying to an adipose depot in the leg: a) cryostimulation; b) mechanic impulses with a chiropractic activator; c) electrical impulses with a transcutaneous electrical nerve stimulation (TENS) device; and d) intradermal injections of female reproductive hormones.

Female patients were treated in the luteal phase of the menstruation cycle (days 16- 20).

The injected female reproductive hormones comprised estradiol, estrone, estriol, progesterone, and testosterone. Hormones were dissolved in a saline solution comprising 10% ethyl oleate, and were then heated to body temperature before injection. Estradiol, estrone, progesterone, and testosterone were injected in a 20 nmol dose. Estriol was injected in a 60 nmol dose. Each hormone was intradermanlly injected in a 0.02 ml volume, at a distance of at least 2.5 cm from each other.

In the indicated cases, low level light therapy was applied to the area of treatment before the hormone injection. Further, in the indicated cases, supplements consisting of magnesium sulphate, mannitol, trental, calcitonin, vitamin Bl, vitamin B6, vitamin Bl 2, lidocaine 1%, bipuvicaine, and sodium bicarbonate were epicutaneously applied. For brevity considerations, the supplements listed above are referred to as “the supplements” in the following examples.

Skin reactions were evaluated 20 minutes after injection. Diameter (mm) of intradermal wheal (not erythema) was considered for evaluation as a skin cellular reaction.

EXAMPLE 2

A 64-year-old woman, mother of two children, obese, with psychological traumatic experiences came for a consultation for dysmenorrhea and premenstrual syndrome (PMS). The patient presented pruritus vulvae complains, and migraine. The patient had a family history of Alzheimer’s disease and dementia.

The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 15 mm to estriol, and of about 5 mm to progesterone. No skin reaction was detected for other hormones.

Subsequently, the patient received 3 further intradermal injections of estriol and progesterone in the following 20 years.

Following the first treatment, the patient showed clinical improvement in migraine, pruritus vulvae, and less arthritis symptoms, as assessed by clinical evaluation and by the patients’ self-report.

The patient did not present dementia symptoms until she passed away at the age of 92.

EXAMPLE 3

An 84-year-old man, presented with symptoms of allergic rhinitis. The patient suffered from chronic ischemic heart disease, chronic atrial fibrillation, and Alzheimer’s disease. The patient further exhibited hypertension. The patient served in the army and received a bullet in the vertebral spine with contusion and showed post-traumatic stress disorder (PTSD) symptoms. The patient passed an appendectomy surgery 40 years before the first consultation. The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 15 mm to progesterone. No skin reaction was detected for other hormones.

Following the first treatment, the patient showed cognitive clinical improvement and in PTSD symptoms, as assessed by clinical evaluation and by the patients’ self-report. The improvements persisted for about 2 months.

EXAMPLE 4

A 37-year-old man, presented with symptoms of allergic rhinitis. The patient suffered from multiple myeloma. Additionally, the patient had an history of diabetes mellitus and hypertriglyceridemia, and hypertensions. The patient was previously diagnosed with PTSD. The patient passed an appendectomy surgery 20 years before the consultation.

The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 15 mm to progesterone. No skin reaction was detected for other hormones.

Following the first treatment, the patient showed immediate clinical improvement in allergic rhinitis symptoms.

EXAMPLE 5

A 64-year-old man, presented with symptoms of allergic rhinitis. The patient suffered from a head contusion in his childhood, passed appendectomy 41 years before the consultation.

The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 10 mm to progesterone and testosterone, and a reaction of about 5 mm to estriol. No skin reaction was detected for other hormones.

Following the first treatment, the patient showed immediate clinical improvement in allergic rhinitis symptoms.

The treatment was continued once a month according to the same clinical protocol and remained symptom free.

EXAMPLE 6

A 36-year-old woman, with a history of post-partum depression, presented with symptoms of fatigue syndrome, post cytomegalovirus (CMV) infection, and dysmenorrhea. The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 15 mm to progesterone. No skin reaction was detected for other hormones.

Following the first treatment, the patient showed immediate clinical improvement in dysmenorrhea and fatigue syndrome.

The treatment was continued once in 3 to 6 months.

EXAMPLE 7

A 15-year-old man, born preterm with a weight of 2.3 kg, presented with symptoms of anorexia, from which she suffered for around one year.

The patient was initially treated according to the clinical protocol disclosed in Example 1. The patient showed a skin reaction of about 10 mm to progesterone. No skin reaction was detected for other hormones.

Following the first treatment, the patient showed immediate clinical improvement in anorexia symptoms.

The treatment was continued once a month.

EXAMPLE 8

A 46-year-old woman, presented with dysmenorrhea complaints, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multifocal myofascial pain syndrome (VAS 9/10) Carnet’s test ++, headache tension and menstrual migraine. The patient reported use of contraceptive pills from age 10 to 20. The patient suffered 3 traumatic brain injuries 5, 4, and 2 years before consultation. The patient had early menopause (FSH 36) and reported 3 in vitro fertilization failures. The patient further reported allergy to nickel.

The patient was initially treated according to the clinical protocol disclosed in Example 1, including light therapy and administration of the supplements listed. The patient showed a skin reaction of about 10 mm to estrone, estradiol, and estriol; and a skin reaction of about 5 mm to progesterone. No skin reaction was detected for other hormones.

A test 48 hours following hormones injection showed a late skin reaction of about 15 mm to estriol.

Following the first treatment, the patient showed clinical remission of arthritic psoriasis and IBS. Patient underwent IVF with 2 successful embryo implants simultaneously (twins). The children were delivered in week 36 week. The patient showed gestation diabetes. During and after pregnancy the patent exhibited arthritis relapse. EXAMPLE 9

A 26-year-old woman, presented with dysmenorrhea complaints, psoriasis, headache tension, menstrual migraine, multifocal myofascial pain syndrome (Carnett’s test ++), mastalgia, anxiety. The patient was a heavy smoker and reported allergy to milk.

The patient had a periodic menstrual cycle from age 10 and used contraceptive pills for 8 years.

The patient was initially treated according to the clinical protocol disclosed in Example 1, including light therapy and administration of the supplements listed. The patient showed a skin reaction of about 7 mm to estrone, of about 8 mm to estradiol, of about 8 mm to estriol, of about 4 mm to progesterone. No skin reaction was detected for other hormones.

A test 48 hours following hormones injection showed a late skin reaction of about 10 mm to estriol and progesterone.

Following the first treatment, the patient showed clinical remission of arthritic psoriasis, IBS, and multifocal pain syndrome for 6 years.

EXAMPLE 10

A 47-year-old woman, mother of one child, presented with menstrual migraine. The patient suffered from post-traumatic brain injury (whiplash), contact dermatitis, and multifocal myofascial pain syndrome (Carnett’s test ++). The patient presented sensitivity to bronopol, (chlor) Methylisothiazolon, musk mix.

The patient had a periodic menstrual cycle from age 14.

The patient was initially treated according to the clinical protocol disclosed in Example 1, including light therapy and administration of the supplements listed. The patient showed a skin reaction of about 5 mm to estrone, of about 5 mm to estradiol, of about 10 mm to estriol, of about 6 mm to progesterone. No skin reaction was detected for other hormones.

A test 48 hours following hormones injection showed a late skin reaction of about 5 mm to estrone, estradiol, estriol and progesterone.

.Following the first treatment, the patient showed clinical remission of contact dermatitis, multifocal myofascial pain syndrome, and menstrual migraines for 3 years.

EXAMPLE 11

A 55-year-old woman, mother of two children, presented with fibromyalgia; allergic rhinitis; multifocal myofascial pain syndrome (Carnett’s test +++); severe premenstrual syndrome including chills, fatigue, abdominal pain, and diarrhea; uterine leomyoma; cholelithiasis; pruritus ani; irritable bowel syndrome. An irregular growth of the thyroid gland (goiter) was suspected.

The patient suffered a car accident 3 years before the consultation which caused brain injury, and suffered from PTSD symptoms since then. The patient presented a family clinical history which includes breast cancer (mother), cholelithiasis (mother), artherosclerosis (father), and tuberculosis (father).

The patient had a periodic menstrual cycle from age 13. The patient was implanted with a Mirena® intra uterine device for 5 years before the consultation.

The patient was initially treated according to the clinical protocol disclosed in Example 1, including light therapy and administration of the supplements listed. The patient showed a skin reaction of about 11 mm to estrone, of about 11 mm to estradiol, of about 8 mm to estriol, of about 7 mm to progesterone. No skin reaction was detected for other hormones.

A test 48 hours following hormones injection showed a late skin reaction of about 15 mm to estriol and progesterone.

Following the first treatment, the patient showed clinical remission of fibromyalgia, premenstrual syndrome, and pruritus ani for 5 years.

EXAMPLE 12

A 47-year-old woman, mother of one child, presented with menstrual migraine. The patient suffered from post-traumatic brain injury (whiplash), contact dermatitis, and multifocal myofascial pain syndrome (Camett’s test ++). The patient presented sensitivity to bronopol, (chlor)Methylisothiazolon, musk mix.

The patient had a periodic menstrual cycle from age 14.

The patient was initially treated according to the clinical protocol disclosed in Example 1, including light therapy and administration of the supplements listed. The patient showed a skin reaction of about 5 mm to estrone, of about 5 mm to estradiol, of about 10 mm to estriol, of about 6 mm to progesterone. No skin reaction was detected for other hormones.

A test 48 hours following hormones injection showed a late skin reaction of about 5 mm to estrone, estradiol, estriol and progesterone.

Following the first treatment, the patient showed clinical remission of contact dermatitis, multifocal myofascial pain syndrome, and menstrual migraines for 3 years.

Claims

1. A method for treating a subject suffering from a pathological condition, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment, wherein said area of treatment comprises an adipose depot.

2. The method of claim 1, wherein said area of treatment comprises the abdomen, the hip, or the forearm.

3. The method of any one of claims 1 to 2, further comprising intradermally injecting lidocaine, bupivacaine, magnesium, mannitol, or a combination thereof to said area of treatment, before step (e).

4. The method of any one of claims 1 to 3, wherein said female reproductive hormone comprises estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof.

5. The method of any one of claims 1 to 4, wherein said female reproductive hormone comprises estradiol, estrone, progesterone, or testosterone and is injected in a 20 nmol dose; or wherein said female reproductive hormone comprises estriol and is injected in a 60 nmol dose.

6. The method of any one of claims 1 to 5, wherein said female reproductive hormones are injected at 37°C.

7. The method of any one of claims 1 to 6, wherein said pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, a hormonal disorder, premenstrual dysphoric disorder (PMDD), fibromyalgia, post-traumatic brain injury, cerebrovascular accident (CVA), a viral infection, COVID-19, cytomegalovirus infection, optic neuritis, Hashimoto disease, post-vaccination syndrome, multifocal pain disorder, hormonal dependence skin disease, psoriasis, atopic dermatitis, metabolic syndrome, post-appendectomy syndrome, Alzheimer’s disease, anorexia, or any combination thereof.

8. The method of any one of claims 1 to 7, wherein said pathological condition comprises menstrual migraine, and said female reproductive hormones comprise estriol and progesterone.

9. The method of any one of claims 1 to 7, wherein said pathological condition comprises mastalgia and said female reproductive hormones comprise estradiol and progesterone.

10. The method of any one of claims 1 to 7, wherein said pathological condition comprises red eyes or runny nose, and said female reproductive hormones comprise progesterone and testosterone.

11. The method of any one of claims 1 to 7, wherein said pathological condition comprises depression or anxiety, and said female reproductive hormones comprise progesterone.

12. The method of any one of claims 1 to 7, wherein said pathological conditions comprise intrauterine-device (IUD) related side effects, and said female reproductive hormones comprise progesterone.

13. The method of any one of claims 1 to 12, wherein said mechanical impulse is applied by a chiropractic activator.

14. The method of any one of claims 1 to 13, wherein said mild electrical current is applied by a transcutaneous electrical nerve stimulation (TENS) device.

15. The method of any one of claims 1 to 14, further comprising applying red light or infrared light stimulation to said area of treatment, previous to step (e).

16. The method of any one of claims 1 to 15, wherein said subject is provided with supplements of magnesium, vitamin D, vitamin Bl, melatonin, or probiotic supplements, previous to step (a).

17. A method for preventing a pathological condition in a subject, said method comprising: a) selecting an area of treatment, b) applying cryostimulation to said area of treatment, c) applying a mechanic impulse to said area of treatment, d) applying a mild electrical current to said area of treatment, and e) intradermally injecting at least one female reproductive hormone to said area of treatment; wherein said area of treatment comprises an adipose depot.

18. A composition comprising at least one female reproductive hormone for use in a method for treating a subject suffering from a pathological condition, said method comprising: a) applying cryostimulation to an area of treatment, b) applying a mechanic impulse to said area of treatment, c) applying a mild electrical current to said area of treatment, and d) intradermally injecting said composition to said area of treatment; wherein said area of treatment comprises an adipose depot.

19. The composition of any one of claim 18, wherein said female reproductive hormones comprise estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof.

20. The composition of any one of claims 18 to 19, wherein said female reproductive hormone comprises estradiol, estrone, progesterone, or testosterone and is injected in a 20 nmol dose; or wherein said female reproductive hormone comprises estriol and is injected in a 60 nmol dose.

21. The composition of any one of claims 18 to 20, wherein said pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, or a hormonal disorder.

22. The composition of any one of claims 18 to 21, wherein said pathological condition comprises menstrual migraine, and said female reproductive hormones comprise estriol and progesterone.

23. The composition of any one of claims 18 to 22, wherein said pathological condition comprises mastalgia and said female reproductive hormones comprise estradiol and progesterone.

24. The composition of any one of claims 18 to 23, wherein said pathological condition comprises red eyes or runny nose, and said female reproductive hormones comprise progesterone and testosterone.

25. The composition of any one of claims 18 to 24, wherein said pathological condition comprises pain, neuropathic pain, an autoimmune disorder, an allergy, a psychiatric disorder, a hormonal disorder, premenstrual dysphoric disorder (PMDD), fibromyalgia, post-traumatic brain injury, cerebrovascular accident (CVA), a viral infection, COVID-19, cytomegalovirus infection, optic neuritis, Hashimoto disease, post-vaccination syndrome, multifocal pain disorder, hormonal dependence skin disease, psoriasis, atopic dermatitis, metabolic syndrome, post-appendectomy syndrome, Alzheimer’s disease, anorexia, or any combination thereof.

26. The composition of any one of claims 18 to 25, wherein said pathological conditions comprise intrauterine-device (IUD) related side effects, and said female reproductive hormones comprise progesterone.

27. The composition of any one of claims 18 to 26, wherein said method further comprises applying red light or infrared light stimulation to said area of treatment, previous to step (d).

28. The composition of any one of claims 18 to 27, wherein said subject is provided with supplements of Mg, vitamin D, vitamin Bl, melatonin, or probiotic supplements, previous to step (a).

29. A composition comprising a female reproductive hormone, mannitol, hyaluronic acid, and vitamin D.

30. The composition of claim 29, wherein said female reproductive hormone comprises estradiol, estrone, estriol, progesterone, testosterone, or a combination thereof.

31. A kit comprising a composition comprising at least one female reproductive hormone, for use in a method for treating a subject suffering from a pathological condition, said method comprising: a) applying cryostimulation to an area of treatment, b) applying a mechanic impulse to said area of treatment, c) applying a mild electrical current to said area of treatment, and d)' intradermally injecting said composition to said area of treatment; wherein said area of treatment comprises an adipose depot.

32. A kit comprising a composition comprising at least one female reproductive hormone, an intradermal injector, intradermal injector needles, a device for applying a mechanic impulse, and a device for applying a mild electrical current.