Method of preventing progesterone contraceptive-induced abnormal uterine bleeding (AUB)

Abstract

The present disclosure provides for a method of treating or preventing progesterone contraceptive-induced abnormal uterine bleeding (AUB) in a subject, comprising: administering to the subject an effective amount of a composition comprising 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2).

Description

[0001]Attorney Docket No.11001-207WO1 METHOD OF PREVENTING PROGESTERONE CONTRACEPTIVE-INDUCED ABNORMAL UTERINE BLEEDING (AUB) CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 599,560 filed on November 16, 2023, the disclosure of which is hereby expressly incorporated by reference herein in its entirety. BACKGROUND Unintended pregnancy is a public health issue in the United States. An unintended pregnancy is one that occurs when a woman is not actively seeking pregnancy. Approximately half of pregnancies in the U.S. each year are unintended, a rate much higher than in other developed nations. An estimated 1.2 million live births in the U.S. are unplanned and are a critical public health challenge because they are associated with adverse health outcomes for the mother-child dyad, including preterm birth, low birth weight, and maternal and perinatal morbidity and mortality. The annual direct medical costs of unintended pregnancy in the U.S. were conservatively estimated to be at least $5.5 billion in 2018. When considering childcare and indirect costs, the actual economic impact is likely much higher, with historical estimates between $12–$21 billion annually. More than half of unintended pregnancies in the U.S. occur in women, who are not using any form of contraception. Therefore, enhancing contraceptive use, efficacy, and acceptability is a crucial strategy to address this problem. Abnormal uterine bleeding (AUB) limits broad adoption of progestin-only long- acting, reversible contraceptives (pLARCs). pLARC methods are highly effective, with a success rate of over 99% in preventing unintended pregnancy. They are also reversible and convenient, eliminating the need for daily compliance. pLARC products include DEPO- PROVERATM(injectable medroxyprogesterone acetate; MPA), Nexplanon™ (implanted etonogestrel; ETO), and MIRENATMor SKYLATM(intrauterine levonorgestrel; LNG). pLARCs are particularly useful for adolescents, who face the highest risk of unintended pregnancy and preterm birth. However, a key deterrent to pLARC use and / or discontinuation is AUB characterized by unpredictable bleeding causing inconvenience. There is considerable intra- and inter-individual variability in the occurrence and severity of AUB, complicating counseling and management strategies, and AUB is the leading cause of pLARC discontinuation. In the Contraceptive Choice Project, an extensive study focused on Attorney Docket No.11001-207WO1 increasing the use of long-acting reversible contraception and reducing unintended pregnancies, AUB was the primary reason participants discontinued pLARC. This includes 19% of LNG users, 46% of ETO users, and 26% of MPA users. Treatments like supplemental estrogen, oral contraceptives, anti-inflammatories, vitamins, and / or doxycycline have been tried for AUB, but none provides a lasting solution. Therefore, effective treatments are needed to improve user satisfaction and continuation of pLARC. The methods disclosed herein address these and other needs. SUMMARY In accordance with the purposes of the disclosed materials and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to pLARC- induced AUB and methods of treating thereof. Thus, in one example, a method of treating or preventing progesterone contraceptive- induced abnormal uterine bleeding (AUB) in a subject is provided, including administering to the subject an effective amount of a composition comprising 15-deoxy-^12,14- prostaglandin J2 (15dPGJ2). Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. Figures 1A-1C show 15dPGJ2 inhibits FKBP5 and IL1B and PTGS2 levels in primary cultured human endometrial stromal cells (HESCs). Figure 1A shows FKBP5 levels in HESCs (n=3) treated with 10-8M estradiol (E) or E+ 10-7M MPA (EM) ± 10 or 15 ^M 15dPGJ2 for 6h. Bars represent mean ± SEM; ***P<0.001 vs. E, EM+10 or EM+15 ^M 15dPGJ2,++P<0.01 vs. EM, and#P<0.05 vs. 10 ^M 15dPGJ2; Figure 1B shows IL1B and C) PTGS2 levels in HESCs (n=3) treated with 10 ng / ml recombinant human IL-1^ or 1 U / ml thrombin (THR) + 10 ^M 15dPGJ2 (J2) for 6h. Bars represent mean ± SEM; *P<0.05 vs. Attorney Docket No.11001-207WO1 control in graph B. graph C. Figure 2 shows 15dPGJ2 inhibits proliferation of primary human endometrial endothelial cell (HEEC) cultures. HEECs (5x103) were seeded in 96-well plates. Primary HEEC cultures treated with 10 µM MPA ± 1 or 5 or 10 µM 15dPGJ2 for 48 and 96 h and followed by XTT cell viability assay. Bars represent mean ± SEM from experimental triplicate for each treatment. Figure 3 shows molecular mechanisms underpinning pLARC-induced AUB proposed strategies to counter them (left, via 15dPGJ2; right, via rCCL2). Figures 4A-4D show progestin treatment increases FKBP51 levels in endometrial cells of humans and guinea pigs. FKBP51 immunostaining (brown) in stromal (arrowheads) and epithelial (arrows) cells of paired human (A-B) and guinea pig (C-D) endometria. A and C are representative images corresponding to pre-treatment (Pre) representing endometrial tissue specimens taken from women in the secretory phase of the menstrual cycle before pLARC administration; and B and D are corresponding to post MPA treatment (post). Graphs show endometrial FKBP51 HSCOREs; mean± SEM; n=6; ** or++P<0.01 vs. Post. Negative controls used normal IgG isotypes at the same primary antibody concentrations (not shown). Original Magnification: x40. Figure 5 shows progestin treatment increases FKBP5 mRNA in cultured HESCs treated with 10−8M estradiol (E2) ± 10−7M ETO, LNG or MPA for 7d by qPCR. Graph represents mean± SEM; n=3. Figures 6A-6B show FKBP51 augments thrombin induced inflammation in cultured HESCs. (A) Basal IL-1^ levels in HESCs treated with 10−8M estradiol (E) or E + 10−7M MPA (EM) at 44 h post-transfection with either a control (Cont-v) or FKBP5 (FKBP5-v) vectors (n=3). (B) Thrombin (TH) induced IL-1^ levels in EM treated HESCs transfected with Cont-v or FKBP5-v (n=2 and 3 replicates / group). Bars represent mean± SEM. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiments. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that Attorney Docket No.11001-207WO1 modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. As can be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Attorney Docket No.11001-207WO1 Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.” As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound”, “a composition”, or “a disorder”, includes, but is not limited to, two or more such compounds, compositions, or disorders, and the like. It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Attorney Docket No.11001-207WO1 Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “substantially free,” when used in the context of a composition or component of a composition that is substantially absent, is intended to refer to an amount that is then about 1 % by weight or less, e.g., less than about 0.5 % by weight, less than about 0.1 % by weight, less than about 0.05 % by weight, or less than about 0.01 % by weight of the stated material, based on the total weight of the composition. Attorney Docket No.11001-207WO1 The term “subject” preferably refers to a human in need of treatment with an anti- cancer agent or treatment for any purpose, and more preferably a human in need of such a treatment to treat cancer, or a precancerous condition or lesion. However, the term “patient” can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with an anti- cancer agent or treatment. The term “treating” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms. The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. Attorney Docket No.11001-207WO1 Method Method of Treating or Preventing Progesterone Contraceptive-Induced Abnormal Uterine Bleeding (AUB) The present disclosure, in one aspect, provides for a method of treating or preventing progesterone contraceptive-induced abnormal uterine bleeding (AUB) in a subject, comprising administering to the subject an effective amount of a composition comprising 15- deoxy-^12,14-prostaglandin J2 (15dPGJ2). 15-deoxy-^12,14-prostaglandin J2 (15dPGJ2) is an FKBP51 inhibitor. The compound 15-deoxy-^12,14-prostaglandin J2 is an endogenously produced anti- inflammatory prostaglandin, which reduces inflammation by blocking NF-^B signaling in human myocytes and amnion epithelial cells. As demonstrated herein, 15dPGJ2 may completely block glucocorticoid (e.g., dexamethasone (DEX) or medroxyprogesterone acetate (MPA) induced FKBP51 expression. The inhibiting FK506 binding protein 51 (FKBP51), as used herein, refers to any molecule, compound, or substance that prevents, blocks, or impairs the function or activity of FKBP51. For example, an FKBP51 inhibitor may prevent or block expression of the gene encoding FKBP5. Alternatively, an FKBP51 inhibitor may prevent or block production of the FKBP51 protein following gene expression. In other embodiments, an FKBP51 inhibitor may prevent, block, or impair a function of the FKBP51 protein (e.g., inhibition of glucocorticoid or progesterone receptor function). Any suitable inhibitor of FKBP51 may be used in the methods described herein. Suitable FKBP51 inhibitors include, but are not limited to, non- coding RNA (e.g., RNA that does not encode protein), such as small interfering RNAs (siRNAs), microRNAs (miRNAs), and short hairpin RNAs (shRNAs). siRNAs and miRNAs are central to RNA interference (RNAi), which is a biological process in which RNA molecules inhibit gene expression or translation by neutralizing targeted mRNA molecules. siRNA, also known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules 20-25 base pairs in length, which interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation (Agrawal et al., Microbiol. Mol. Biol. Rev., 67(4): 657-668 (2003). shRNAs are artificial RNA molecules with a tight hairpin turn that can be used to silence target gene expression via RNAi. miRNAs are small non-coding RNA molecules about 22 base pairs in length, which are found in plants, animals, and some viruses and function in RNA silencing and post-transcriptional regulation of gene expression (see, e.g., Ambros, V., Nature, 431 (7006): 350-355 (2004); and Bartel, D.P., Cell, 116(2): 281-297 (2004)). While Attorney Docket No.11001-207WO1 the majority of miRNAs are located within a cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, have also been found in extracellular environment, including various biological fluids and cell culture media. miRNAs differ from siRNAs in that miRNAs are derived from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of double- stranded RNA. The composition may comprise any suitable dose of 15dPGJ2. A suitable dose will be determined, at least in part, by the particular method used to administer the composition. Therapeutic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment can be repeated until a desired outcome occurs. However, other dosage regimens may be useful and are within the scope of the disclosure. The compositions may also comprise an additional FKBP51 inhibitor, as described herein. Compositions suitable for use herein include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, an “effective amount” means an amount of active ingredients (e.g., 15dPGJ2) effective to prevent, delay onset of, alleviate, or ameliorate symptoms of a disorder (e.g., AUB), e.g., by partially or fully reversing pLARC-inducedAUB via: 1) inhibiting FKBP51 levels and inflammatory mediators in human endometrial stromal cell; and 2) blocking proliferation of human endometrial endothelial cells, thereby contributing to the prevention of pLARC-induced aberrant endometrial angiogenesis. Thus, 15dPGJ2 promotes pLARC responsiveness, prevents pLARC-induced endometrial inflammation and aberrant angiogenesis, supporting the therapeutic use of 15dPGJ2 alone or in combination with any pLARC formulation to prevent pLARC-induced AUB. s Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any preparation used in these methods, the dosage or the effective amount can be estimated initially from in vitro and cell culture assays (e.g., proliferation assay as further described herein below). For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans. Compositions as discussed herein may be formulated using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate Attorney Docket No.11001-207WO1 processing of the active ingredients into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Progesterone, as used herein, includes progesterone, progesterone derivatives, progestin, progestin derivates, progestogens, or progestogen derivatives. This includes both natural and synthetic compounds. Abnormal uterine bleeding (also referred to as oligomenorrhea, menorrhagia, and dysfunctional uterine bleeding) refers to irregularities in the menstrual cycle involving frequency, regularity, duration, and volume of flow outside of pregnancy. A normal menstrual cycle has a frequency of 24 to 38 days and lasts 2 to 7 days, with 5 to 80 milliliters of blood loss. Variations in these parameters constitutes AUB. In some examples, the subject used a progesterone contraceptive from 0 to 120 days before administration of the composition. In further examples, the progesterone contraceptive is a progesterone long-active reversible contraceptive (pLARC). In specific examples, the pLARC comprises medroxyprogesterone acetate (MPA), etonogestrel (ETO), or levonorgestrel (LNG). MPA is a progesterone derivative that has an increased resistance to metabolism and therefore has improved pharmacokinetic properties. ETO is a 3-ketodesogestrel or 19-nortestosterone, which is a synthetic biologically active metabolite of progestin desogestrel. LNG is a synthetic progestogen, and in some examples, is administered along with estrogen. In certain examples, the pLARC is administered orally, via injection, transdermally, via implant, or via intrauterine device (IUD). In some examples, the MPA is administered via injection. In further examples, the ETO is administered via implant. In specific examples, the LNG is administered intrauterineally. In certain examples, the composition comprising 15dPGJ2 is administered orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously, intravenously, intraperitoneally, intranasally, intravaginally, intrauterineally, or intraocularly. In some examples, the composition comprising the 15dPGJ2 is administered intrauterineally or intravaginally. In further examples, the composition comprising 15dPGJ2 is administered via a patch, implant, intrauterine device, or vaginal ring. In specific examples, the composition comprising 15dPGJ2 is administered via an intrauterine device (IUD). In certain examples, the IUD is inserted intrauterineally into the subject and remains in the subject for no more than 6 months. Attorney Docket No.11001-207WO1 In some examples, the composition comprising 15dPGJ2 is administered via a vaginal suppository. In further examples, the vaginal suppository is repeatedly administered to the subject for from 1 day to 6 months. In some examples, the composition comprising 15dPGJ2 is administered locally. In further examples, the composition comprising 15dPGJ2 is a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension. In specific examples, the subject has AUB at the time of administration of the composition comprising 15dPGJ2. In certain examples, the subject does not have AUB at the time of administration of the composition comprising 15dPGJ2. Intrauterine devices typically include a frame and retention elements for retaining the frame within the uterus. Such devices are often “T”-shaped. For injection, the active ingredients of the composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation. Such penetrants are generally known in the art. For oral administration, the composition can be formulated readily by combining the active ingredient(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee Attorney Docket No.11001-207WO1 coatings for identification or to characterize different combinations of active compound doses. Compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration are in dosages suitable for the chosen route of administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by nasal inhalation, the active ingredients for use herein are delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, or carbon dioxide. In the case of a pressurized aerosol, the dosage may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch. The composition described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with, optionally, an added preservative. The compositions may be suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water-based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the active ingredients, to allow for the preparation of highly concentrated solutions. Attorney Docket No.11001-207WO1 Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use. As used herein, a suppository is a small piece of solid material, such as cocoa butter or glycerin, that comprises a composition (e.g., 15dPGJ2) and melts at body temperature. In some examples, a suppository is administered via insertion into the rectum, vagina, or urethra. In further examples, the medicine is absorbed into the bloodstream. A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. Example 1: Prevention of Progestin-only Long-Acting, Reversible Contraceptive (pLARC) induced Abnormal Uterine Bleeding (AUB) via therapeutic inhibition of FKBP51 by 15-deoxy-ll.12,14-prostaglandin J2 (15dPGJ2) Background pLARCs induce AUB by triggering endometrial aberrant angiogenesis, inflammation and increasing levels of FKBP51, which inhibit progesterone and glucocorticoid receptor transcriptional activity. FKBP51 overexpression blocks anti-inflammatory action of pLARCs in human endometrial stromal cells (HESCs), causing functional progesterone withdrawal Attorney Docket No.11001-207WO1 and inflammation in endometrium, contributing to AUB pathogenesis. 15dPGJ2 inhibits levels of FKBP51 and pro-inflammatory markers in HESCs and proliferation of HEECs in pLARC-treated cultures, supporting therapeutic 15dPGJ2 use to prevent AUB. pLARCs are among the most effective contraceptive method but pLARC induced AUB in users causes about half of pLARC users to discontinue treatment within the first year due to AUB. Thus, prevention of AUB will increase pLARC adherence in users. pLARC induces AUB by triggering aberrant endometrial angiogenesis, inflammation, and expression of FKBP51, which inhibits transcriptional activity of progesterone and glucocorticoid receptors. FKBP51 overexpression causes functional progesterone withdrawal and induces inflammation in HESC to promote AUB. Contraceptive properties include inhibition of ovulation, changes in cervical mucus and tubal motility that impair sperm migration, and hostile endometrial environment preventing blastocyst implantation (Birgisson et al., J Womens Health (Larchmt). 2015;24:349-53). A large prospective cohort study in which 75% of teenage participants that received pLARCs found reduction in mean annual rates of pregnancy, birth, and abortion compared with overall pool of sexually experienced US teens (Secura et al., N Engl J Med. 2014;371:1316-1323). However, 3-year discontinuation rates are high, 47% and 27% for implant and IUD users, respectively (Weisberg et al., Eur J Contracept Reprod Health Care. 2014;19:5-14). The major reason for discontinuation of pLARCs was AUB occurring in most users. pLARC-formulations Unintended pregnancies can be prevented with > 99% efficacy in women using pLARCs. pLARCs include DEPO-PROVERATM, an injectable form of medroxyprogesterone acetate (MPA), NEXPLANON™, a subdermal implanted rod that releases etonogestrel (ETO), and MIRENATMor SKYLATM, intrauterine devices releasing levonorgestrel (LNG). Mechanisms of pLARC-associated abnormal bleeding pLARCs markedly reduce endometrial perfusion, as measured by laser Doppler fluxmetry, within a month of insertion (Hickey et al. J Clin Endocrinol Metab. 2006;91: 3633-8) and pLARC treated endometria displayed evidence of hypoxia / reperfusion injury and increased immunostaining for phosphorylated forms of stress and inflammation activated kinases SAPK / JNK and p38 MAPK (Krikun et al., Am J Pathol. 2002; 161:979-86). This oxidative stress causes aberrant endometrial angiogenesis resulting in abnormal endometrial vasculature consisting of thin-walled, hyper-dilated fragile micro-vessels deficient in vascular smooth muscle cell support, which are prone to bleeding (Runic et al., J Clin Endocrinol Attorney Docket No.11001-207WO1 Metab. 2000; 85:3853-9; Lockwood CJ. Menopause. 2011;18:408- 11; Schatz et al. Hum Reprod Update.2016;22:497-515; Kayisli et al. Proc Natl Acad Sci U S A. 2015;112:5153- 8.; Shapiro et al. Contraception.2017;95:592-601). FKBP51, a co-chaperone protein that inhibits PR and GR-mediated transcriptional activity FKBP51 protein is encoded by FKBP5 gene. FKBP5 gene promoter and introns contain several progesterone or glucocorticoid response elements (PREs or GREs), which mediate transcriptional induction of FKBP51 by progesterone receptor (PR) and glucocorticoid receptor (GR). FKBP52 positively regulates PR and GR-mediated transcriptional activity while FKBP51 is a negative regulator of these receptors (Riggs et al., Mol Cell Biol. 2007;27:8658-69; Cioffi et al., Curr Opin Pharmacol. 2011;11:308-13.; Sanchez ER, Biochim Biophys Acta.2012;1823:722-9). Overexpression of human or squirrel monkey FKBP5: 1) requires a 3- or 11-fold, respectively, higher progesterone EC50 for PR activation in HepG2 cells; and 2) reduces cortisol induced GR activity by 2- or 12-fold, respectively in COS7 cells, indicating reduced progesterone and glucocorticoid responses by increased FKBP51 levels. (Hubler et al., Endocrinology.2003;144:2380-7; Denny, W.B., et al Endocrinology 2005;146, 3194-320). Since pLARCs do not decrease PR expression in human endometrial stromal cells (HESCs) it was hypothesized that they increased HESC FKBP51 expression, creating a negative feedback loop impairing responsiveness of crucial genes to progestin. In immuno-stained sections, FKBP51 HSCOREs were significantly higher in human endometrial stromal and glandular cells from post-DMPA vs. pre-DMPA. In guinea pigs, estradiol (E2)+MPA significantly increased FKBP51 immuno-reactivity in endometrial stromal and glandular cells vs. E2 alone (Guzeloglu-Kayisli et al., PLoS One. 2015;10:e0137855). Ingenuity pathway analysis of microarray results from HESC cultures treated with MPA or ETO identified GR activation as an upstream regulator of both MPA and ETO- specific differentially regulated genes, including significant enhancement of FKBP51 (Guzeloglu-Kayisli et al., PLoS One.2015;10:e0137855). FKBP51 overexpression in HESC cultures reverses the anti-inflammatory action of pLARC MPA Previous in vitro analysis revealed that MPA fails to inhibit IL-1B mRNA levels following overexpression of FKBP5 in HESC cultures, indicating that elevated FKBP51 levels block the anti-inflammatory action of MPA (Guzeloglu-Kayisli et al., PLoS One. 2015;10:e0137855). Attorney Docket No.11001-207WO1 In parallel incubations, FKBP51 overexpression increased thrombin induced IL-1B mRNA levels in E2+MPA treated HESC cultures compared to control transfected cultures (Guzeloglu-Kayisli et al., PLoS One.2015;10:e0137855). Collectively, these results indicate that pLARC induced endometrial FKBP51 expression inhibits PR and GR-mediated transcriptional activity, thereby contributing to pLARC associated endometrial inflammation, aberrant angiogenesis, and abnormal uterine bleeding. Methods and Discussion Progestin contraceptive combination with 15PGJ2 to prevent AUB in pLARC users 15-deoxy-ll.12,14-prostaglandin J2 (15dPGJ2) inhibits progestin induced FKBP51 levels and inflammatory mediators in HESC cultures, thereby enhancing effect of progestin to block inflammation. 15dPGJ2, an endogenous prostaglandin, exerts anti-inflammatory effects by inhibiting NF-KB signaling in human myocytes and amnion epithelial cells. 15dPGJ2 blocks glucocorticoid induced FKBP51 expression in term decidual cell cultures. In animal models, 15dPGJ2 delays LPS or thrombin or stress-induced preterm birth and improves pup survival. Thus, it was evaluated whether 15dPGJ2: 1) inhibits pLARC-induced FKBP51; and 2) exhibits anti-inflammatory effects in HESC cultures. These data demonstrated that: 1) 15dPGJ2 significantly inhibited MPA-induced FKBP5 levels in a dose dependent manner (Fig. 1A); 2) both IL-1^ and thrombin significantly increased expression of IL- 1^ by ~26- and 4-fold, respectively and PTGS2 (COX2) by ~16- and 4-fold, respectively vs. control; and 4) 15dPGJ2 significantly reversed IL-1^ or thrombin induced IL-1^ and PTGS2 levels (Fig.1B, C). Progestin contraceptive combination with 15dPGJ2 to prevent AUB in pLARC users 15dPGJ2 blocks proliferation of human endometrial endothelial cells, thereby contributes to prevention of pLARC- induced aberrant endometrial angiogenesis. The impact of 15dPGJ2 on HEEC proliferation was investigated, a first step of angiogenesis. HEEC cultures were treated with 10 µM MPA ± 1 or 5 or 10 µM 15dPGJ2 for either 48 or 96 h. XTT cell viability assay (Cell Signaling Technology, Danvers, MA) were performed to determine HEEC proliferation. This analysis revealed that that 15dPGJ2 significantly inhibited HEEC number in dose dependent manner after 48 and 96 h (Fig.2). Collectively, the data indicate that 15dPGJ2 inhibits FKBP51 and pro-inflammatory markers in HESCs, and proliferation in HEECs in pLARC treated cultures. Thus, 15dPGJ2 promotes progestin responsiveness, prevents pLARC-induced inflammation as well as aberrant angiogenesis in endometrial cells, supporting therapeutic use of 15dPGJ2 alone or Attorney Docket No.11001-207WO1 in combination with any pLARC formulation to prevent pLARC-induced AUB. Example 2: Treating abnormal uterine bleeding (AUB) associated with progestin-only, long-acting, reversible contraceptives (pLARCs) The research herein validated a therapeutic approach to mitigate abnormal uterine bleeding (AUB) induced by progestin-only long-acting reversible contraceptives (pLARCs). AUB is a significant factor leading to the discontinuation of pLARC use, despite their effectiveness and safety profile. The disclosed strategy involves the use of 15-deoxy-^12,14- prostaglandin J2 (15dPGJ2) to mitigate the underlying causes of AUB, such as hypoxia, inflammation, and impaired vascular maturation, all of which compromise vascular integrity. Discussed herein is the demonstration of the biological efficacy of 15dPGJ2 in preventing pLARC-induced AUB using an established guinea pig model, with endpoints that include uterine bleeding, hemorrhagic areas, and blood vessel count. Abnormal uterine bleeding (AUB) associated with progestin-only, long-acting, reversible contraceptives (pLARCs) is much more than an inconvenient and uncomfortable side effect—it is the most common reason for stopping use of these highly effective contraceptives. An aim herein was to demonstrate the feasibility of a novel therapeutic strategy to reduce contraceptive-induced AUB. Unintended pregnancy poses significant health risks, including maternal mortality and preterm birth. In the U.S., the rate of unintended pregnancy has remained unacceptably high (45-50%) over the past two decades and is notably higher in some groups when disaggregated by age, race / ethnicity, income, and education level. Progestin-only long-acting, reversible contraceptives (pLARCs) are not only highly effective, but are also safe for women at high risk for a variety of medical complications including thromboembolism. Despite this, up to half of users stop using pLARCs within a year due to unpredictable AUB that can last up to six months. Addressing AUB is useful for wider pLARC adoption and continued use, with the goal to improve user satisfaction without compromising efficacy or safety. AUB in pLARC users is distinct from normal menstrual bleeding because it is initiated by decreased endometrial blood flow. This condition leads to low oxygen, inflammation, and abnormal development of blood vessels, which along with the loss of vascular smooth muscle cells and pericytes, weakens the endometrial microvasculature structure. Consequently, this results in focal vascular damage and tissue breakdown, leading to irregular and unpredictable bleeding. Prior work identified two distinct molecular pathways through which pLARCs cause AUB and suggests the potential of treatments to counter these effects. First, pLARCs are linked to an increase in endometrial FKBP51, a stress response protein that impairs the Attorney Docket No.11001-207WO1 transcriptional activity of glucocorticoid and progesterone receptors, leading to endometrial inflammation. It was demonstrated that 15-deoxy-^12,14-prostaglandin J2 (15dPGJ2), an endogenous prostaglandin, inhibits pLARC induced FKBP51 expression in endometrial stromal cells and significantly blunts inflammation. Secondly, pLARCs hinder the growth and migration of vascular smooth muscle cells (VSMCs) by blocking chemokine (C-C motif) ligand 2 (CCL2), disrupting maturation of newly formed blood vessels and causing hemorrhage. It showed that CCL2 treatment blunts pLARC effects by improving VSMC proliferation and migration. Building on these data, a goal was to conduct proof-of-concept studies to confirm whether 15dPGJ2 and / or recombinant CCL2 (rCCL2) can effectively prevent or mitigate AUB caused by pLARCs using the validated guinea pig model of progestin-induced AUB. Demonstrate the biological activity of 15dPGJ2 on the prevention of pLARC induced AUB The established guinea pig model for studying AUB induced by progestins use implants of 49-day release subcutaneous pellets of medroxyprogesterone acetate (MPA, 120 µg / day) in female guinea pigs during their diestrus phase. Animals will be randomized to three treatment groups (n=6 / group) receiving MPA, MPA+15dPGJ2 (20 µg / day), or vehicle control. The primary endpoints for evaluating AUB severity are: (1) uterine bleeding score, as measured by a vaginal smear; (2) number and size of hemorrhagic areas by H+E staining in endometrial sections; and (3) number of blood vessels, measured by CD31 (endothelial cells) immunohistochemistry. As above, AUB will be measured in the three treatment groups (n=6 / group): MPA, MPA+rCCL2 (i.p. injection of 0.6 ^g / kg / day), or vehicle control. The primary endpoints for evaluating AUB severity are: (1) uterine bleeding score and (2) endometrial hemorrhagic areas (both as in Aim 1) and (3) number of blood vessels expressing CD31 and alpha-smooth muscle actin (^SMA). Introduction Menstrual bleeding from uterine spiral arterioles occurs when declining late luteal phase progesterone levels lead to a reduction in blood clotting factors in endometrial stromal cells and augmented production of proteases, angiogenic factors, and vasoconstrictors. In con- trast, pLARC-associated progestin delivery causes AUB which occurs intermittently and focally from irregularly distributed, superficial, thin-walled, hyper dilated microvessels. Briefly, pLARCs reduce uterine blood flow, causing hypoxia, inflammation, abnormal angiogenesis, and upregulation of molecular cascades that compromise the stability of Attorney Docket No.11001-207WO1 existing vascular smooth muscle cells (VSMCs), leading to formation of pathological microvessels. pLARC induced human endometrial cell expressed tissue factor generates excess thrombin from prothrombin extravagated from these fragile thinned walled vessels, thereby exacerbating endothelial permeability and endometrial inflammation, resulting a pathological cycle of focal hemorrhage characteristic of pLARC-induced AUB (FIG.3). Therapeutic rationale for targeting the pathophysiology of AUB in pLARC users. Discussion herein supports the proposed strategy to develop a therapeutic that could be administered to pLARC users to reduce AUB. As shown in Fig.3, using a combination of in vitro studies on human endometrial tissues and in vivo studies in a guinea pig (GP) model of pLARC-induced AUB, it was demonstrated that: (1) progestins induce FKBP51 expression. FKBP51 is an immunophilin stress response protein that impairs transcriptional activity of glucocorticoid and progesterone receptor, that in turn promotes endometrial inflammation; (2) 15-deoxy-^12,14-prostaglandin J2 (15dPGJ2), an exogenous prostaglandin, inhibits FKBP51 expression and reduces markers of inflammation in vitro; (3) pLARCs block VSMC proliferation and migration by inhibiting chemokine (C-C motif) ligand 2 (CCL2) expression; and (4) exogenous recombinant (r) CCL2 improves VSMC proliferation and migration. Outcomes The discovery of the pLARC-mediated molecular pathways linking AUB associated inflammation and defective angiogenesis to an increase in FKBP51 and a decrease in CCL2, respectively, paves the way for targeting those pathways to develop a novel therapeutic. The demonstration that 15dPGJ2 targets and inhibits FKBP51—safely and effectively—as well as that CCL2 improves vascular integrity has great potential for enhancing pLARC user satisfaction and continuation rates, thereby contributing to the broader objective of reducing unintended pregnancies in the U.S. pLARCs upregulate FKBP51 expression Changes in FKBP51 expression in paired endometrial tissue specimens taken from women in the secretory phase of the menstrual cycle [Pre] and three months after MPA treatment [Post] (Figs. 4A, 4B) were investigated. Immunostaining demonstrated that FKBP51 protein levels increased after MPA treatment. This finding was also observed in endometrial cells of GPs treated with estradiol [Pre] and estradiol plus MPA [Post] (Figs.4C, 4D). Human endometrial stromal cells (HESCs) were cultured and treated with estradiol alone or combined with various progestins (ETO, LNG, or MPA) for 7 days. Analysis of these cells by qPCR revealed that all the progestins, not just MPA, increased levels of FKBP5, the Attorney Docket No.11001-207WO1 gene that codes for FKBP51 protein, confirming and extending the in-situ results (Fig.5; P<0.01). FKBP51 augments thrombin induced inflammation in cultured HESCs Fig. 3 demonstrates that pLARCs boost tissue factor (TF) expression in HESC cultures, leads to an increase in thrombin, which in turn raises levels of proteins and enzymes involved in blood vessel formation (VEGF), protein breakdown (MMP-1), and inflammation (IL-8), highlighting thrombin’s role in pLARC-induced AUB. High FKBP51 levels are linked to stress-related disorders, inflammation, and hormonal imbalances, prompting us to explore pLARCs’ role in inflammation through FKBP51 upregulation. First, the change in IL1^ mRNA (a proxy for inflammation) in HESCs transfected with a control or FKBP5 vector and treated with estradiol alone or estradiol plus MPA was evaluated. It was found that combining estradiol with MPA decreases IL1^ levels, versus estradiol alone (Fig. 6A). However, introducing FKBP5 increases IL1^ levels, negating MPA’s initial benefit. Additional tests confirmed that adding thrombin with FKBP5 further heightens IL1^ levels (Fig.6B). 15dPGJ2 inhibits MPA induced FKBP5 levels and prevents IL-1^ or thrombin induced inflammation. 15dPGJ2 is an endogenous prostaglandin that reduces inflammation by blocking NF- ^B signaling in human myocytes and amnion epithelial cells. It was demonstrated that 15dPGJ2: (1) lowers FKBP51 levels in term decidual cell cultures; and (2) prevents stress induced preterm birth in mice. Moreover, others have shown that 15dPGJ2 lessens premature birth caused by lipopolysaccharide or thrombin, enhancing pup survival. Relevant to this proposal, 15dPGJ2 significantly reduces FKBP5 expression and counteracts the upregulation of both IL1^ and PTGS2 (COX2) caused by IL-1^ and thrombin in HESC cultures (Figs.7A- 7C). MPA decreases endometrial VSMC proliferation. the number of VSMCs (as measured by alpha-smooth muscle actin; ^SMA) were evaluated and the percent of proliferating VSMCs (as measured by proliferating cell nuclear antigen; PCNA) in paired endometrial tissue specimens taken from women pre- and post- MPA treatment and in GPs treated with estradiol and estradiol plus MPA. This data demonstrate that MPA treatment significantly reduces both the number of VSMCs and the number of proliferating VSMCs in both humans and GPs. pLARC inhibited VSMC proliferation is reversed by rCCL2. The global microarray analysis of VSMC cultures identified CCL2 as a gene that is the most significantly inhibited by progestin (MPA and ETO) treatment. CCL2 plays a role by enhancing VSMC proliferation Attorney Docket No.11001-207WO1 and migration to remodel vessels and by promoting immune defense in physiological conditions. To confirm the microarray data, the cell proliferation index (BrdU incorporation) of MPA or ETO treated VSMC cultures was measured. Compared to control, both MPA and ETO significantly reduced BrdU incorporation (P< 0.001) but not apoptosis (data not shown). VSMCs were also treated with vehicle or MPA or ETO ± 1 and 10 ng / ml rCCL2. Relative to controls, rCCL2 elicited a concentration dependent increase in BrdU incorporation (P< 0.05) and addition of 10 ng / mL rCCL2 reversed the inhibitory effects of MPA or ETO (P<0.001). Female GPs and humans have comparable endometrial histology, ovarian cycle patterns, and reproductive hormones. They also share similar placentation types, steroid receptor profiles, and nearly identical molecular, histological, and clinical responses to progestins. The objective is to demonstrate 15dPGJ2’s potential to lessen AUB caused by pLARC. Study Design Female Hartley GPs aged 2-4 months and weighing 450–650 grams, will have their estrous cycles monitored daily by checking the vaginal membrane. Those in diestrus, indicated by a closed vaginal membrane, will be given subcutaneous silastic pellets with a 49- day sustained release period and assigned to one of three groups (Table 3): 1) Control with sham pellet; 2) MPA pellet (5.9 mg with a release of 120 µg / day); 3) MPA pellet plus 15dPGJ2 pellet (0.98 mg with a release of 20 µg / day). Following implantation of pellets, vaginal fluid will be collected every two days to assess uterine bleeding. After 49 days, the guinea pigs will be weighed and then euthanized to collect uterine tissues. Data Collection and Analysis Uterine bleeding: Vaginal fluid will be collected by vaginal smear every two days using 100 µl PBS. Slides containing dried vaginal fluid will be fixed by cold methanol for 30 min and stained with 0.1% Crystal violet. Slides will be scored under light microscopy using an established 5-point Likert scale of bleeding intensity: 1 = few erythrocytes; 2 = evenly scattered erythrocytes; 3 = frequent occurrence of erythrocytes with little cluster formation; 4 = very frequent occurrence of erythrocytes, strong cluster formation; 5 = massive accumulations and clustering of erythrocytes. Gross morphological and histopathological analysis: 5-µm transverse and longitudinal sections from 4% paraformaldehyde fixed and paraffin embedded uterine specimens of each horn will be stained with H+E to identify focal hemorrhagic area. Evaluation of angiogenesis: Uterine sections will be immunolabeled with endothelial cell marker CD31 and be quantified for blood vessel diameter and density as described. Attorney Docket No.11001-207WO1 Pilot studies suggest the potential of rCCL2 therapy in reducing pLARC-induced AUB (Figs.7A-7C and 8A-8M). The objective is to demonstrate rCCL2’s potential to lessen AUB caused by pLARC. As detailed above, female GPs will be given subcutaneous silastic pellets with a 49- day sustained-release capacity and randomized into treatment groups (Table 5): 1) sham pellet+ daily i.p. injection of placebo; 2) MPA pellet (5.9 mg; 120 µg / d release) + daily intraperitoneal (i.p.) injection of placebo and 3) MPA pellet+ daily i.p. injection of 0.6 µg / kg rCCL2. Following implantation of pellets, vaginal fluid will be collected every two days to assess uterine bleeding. After 49 days, the guinea pigs will be weighed and then euthanized to collect uterine tissues. Uterine bleeding and Gross morphological and histopathological analysis was evaluated as described herein. To evaluate blood vessel diameter, density, and mature vessel quantitation, uterine sections was double-immunostained with antibodies against endothelial cell marker CD31 and VSMC marker ^SMA and analyzed as described. Other advantages which are obvious, and which are inherent to the invention, will be evident to one skilled in the art. It will be understood that certain features and sub- combinations are of utility and may be employed without reference to other features and sub- combinations. This is contemplated by and is within the scope of the claims. Since many possible embodiments may be made of the invention without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense.

Claims

Attorney Docket No.11001-207WO1 CLAIMS What is claimed is:

1. A method of treating or preventing progesterone contraceptive-induced abnormal uterine bleeding (AUB) in a subject, comprising: administering to the subject an effective amount of a composition comprising 15-deoxy-^12,14-prostaglandin J2 (15dPGJ2).

2. The method of claim 1, wherein the subject used a progesterone contraceptive from 0 to 120 days before administration of the composition.

3. The method of any one of claims 1-2, wherein the progesterone contraceptive is a progesterone long-active reversible contraceptive (pLARC).

4. The method of claim 3, wherein the pLARC is medroxyprogesterone acetate (MPA), etonogestrel (ETO), or levonorgestrel (LNG).

5. The method of any one of claims 3-4, wherein the pLARC is administered orally, via injection, transdermally, via implant, or via intrauterine device (IUD).

6. The method of any one of claims 4-5, wherein the MPA is administered via injection.

7. The method of any one of claims 4-5, wherein the ETO is administered via implant.

8. The method of any one of claims 4-5, wherein the LNG is administered intrauterineally.

9. The method of any one of claims 1-8, wherein the composition comprising 15dPGJ2 is administered orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously, intravenously, intraperitoneally, intranasally, intravaginally, intrauterineally, or intraocularly.

10. The method of claim 9, wherein the composition comprising the 15dPGJ2 is administered intrauterineally or intravaginally.

11. The method of any one of claims 1-10, wherein the composition comprising 15dPGJ2 is administered via a patch, implant, intrauterine device, or vaginal ring.

12. The method of claim 11, wherein the composition comprising 15dPGJ2 is administered via an intrauterine device (IUD).Attorney Docket No.11001-207WO1 13. The method of claim 12, wherein the IUD is inserted intrauterineally into the subject and remains in the subject for no more than 6 months.

14. The method of claim 10, wherein the composition comprising 15dPGJ2 is administered via a vaginal suppository.

15. The method of claim 14, wherein the vaginal suppository is repeatedly administered to the subject for from 1 day to 6 months.

16. The method of any one of claims 1-15, wherein the composition comprising 15dPGJ2 is administered locally.

17. The method of any one of claims 1-16, wherein the composition comprising 15dPGJ2 is a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.

18. The method of any one of claims 1-17, wherein the subject has AUB at the time of administration of the composition comprising 15dPGJ2.

19. The method of any one of claims 1-17, wherein the subject does not have AUB at the time of administration of the composition comprising 15dPGJ2.

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