Diagnosis and treatment of pelvic disorders

Abstract

To provide a system for determining a state of a pelvic condition in a subject characterized by abnormal contractile activity in a target pelvic structure.SOLUTION: The system includes a sensing module configured to measure electrical activity in a pelvis of a subject at a plurality of time points during a hormonal cycle of the subject, a signal processing module configured to receive measurements of the electrical activity from the sensing module and to isolate a measurement of an electrical contractility parameter representative of a pelvic structure of interest from the measurements of the electrical activity, and a processor module operatively connected to the signal processing module. The system is configured to receive as input a measurement of an electrical contractility parameter representing a pelvic structure of a subject, generate a data profile of the subject including the measurement of the electrical contractility parameter representing the pelvic structure of the subject, compare the data profile to a reference database including different pelvic disease states, and output a pelvic disease state in the subject based on the comparison.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to methods and devices for diagnosing pelvic conditions such as endometriosis, prostatitis, or benign prostatic hyperplasia. The present invention also relates to methods and devices for treating pelvic conditions. [Background technology]

[0002] Endocrine hormones (e.g., cortisol, thyroid hormone, sex steroids, GH) are regulated by complex reciprocal interactions between the hypothalamus, anterior pituitary, and adrenal glands, i.e., the hypothalamic-pituitary-adrenal axis. This central control mechanism is involved in the circulation of gonadal sex steroid hormones, estrogens in women, and testosterone in men after puberty. Disturbances in this mechanism can occur as a result of environmental changes (stress, estrogen-like pollutants, endocrine-disrupting compounds in the diet), aging, or disease, either by directly affecting the hypothalamic-pituitary-adrenal axis or by altering the local hormonal milieu within tissues. Loss of hormonal balance can lead to diseases such as depression and inflammatory disorders. Tissues whose injury, inflammation, and motility are affected by sex steroid hormones, such as estrogen, include the brain, endocrine glands, endocrine system, immune system, lungs, cardiovascular system, genitor-urinary, and reproductive systems.

[0003] The process of maintaining a suitable environment for pelvic function is complex, involving local and central control mechanisms and the interplay of the endocrine and immune systems. While the role of estrogen in the gonadal organ is well understood, many studies have emphasized a role for local estrogen production in regulating smooth muscle tone in the visceral organ of the pelvic cavity, with or without dependence on circulating estrogen. In women with disorders such as endometriosis and adenomyosis, estradiol concentrations in menstrual blood are higher than in healthy women, although peripheral levels of each are similar (Takahashi et al., 1989). In men, conditions such as benign prostate hyperplasia are associated with increased serum estrogen levels and urinary estrogen content (Sodani, 2018). Therefore, autocrine and paracrine systems function under these pelvic disorders and are regulated, at least in part, by sex steroids. Reciprocal interactions between cytokines and other components of the immune system interact with the endocrine system. These interactions between these two systems contribute to many pelvic disorders in men and women. Inflammation is a fundamental process by which bodily tissues respond to injury. Different hormonal exposures in men and women potentially contribute to different injury rates.Furthermore, different hormonal milieus at different stages in a man's or woman's life may alter injury risk levels to pelvic organs and structures (Bowmin-Colin et al., 2016).

[0004] Patterns of sex-steroid exposure vary throughout the day and lifespan in both men and women, and even cyclically for women during their reproductive years. After puberty, increases in gonadal steroids in both men and women activate the reproductive organs in the pelvic cavity. Female ovaries and uteruses are exposed to cyclical patterns of estradiol, the primary gonadal steroid, during certain periods of adult life until levels decline sharply at reproductive senescence or menopause. In contrast, male testes and prostates are exposed to relatively stable levels of testosterone, the primary gonadal steroid, during most of adult life. However, as men age, the amount of active testosterone in their blood decreases, and the proportion of estrogen increases.

[0005] These gonadal-derived hormones are released into the general circulation and target distal hormone-responsive visceral organs in the pelvic cavity. This greater estrogen dominance in aging men increases smooth muscle tone in the prostate. In women, cyclical patterns throughout the reproductive years exert more complex effects on the visceral organs, particularly the uterus. The amplitude, frequency, basal tone, and direction of uterine contractions (UC) correlate with the various phases of the hormonal cyclic.

[0006] However, injury to the internal organs can lead to increased inflammation and contractility resulting in pathological pelvic conditions. For example, abnormal uterine contractility has been associated with endometriosis (Bulletti et al., 1997) (Kido et al., 2007), polycystic ovary syndrome (Sajadi et al., 2018), endometritis (Pinto et al., 2015), uterine leiomyoma (Kido et al., 2014), and ovarian cancer (Modzelewska et al., 2017), and may underlie other common and important disorders such as infertility, implantation failure, dysmenorrhea (spontaneous miscarriage), or preterm birth (Aguilar et al., 2010). In men, prostate smooth muscle contractility plays a role in the pathophysiology of pelvic diseases such as lower urinary tract symptoms (LUTS) (Hennenberg et al., 2018), benign prostatic hyperplasia (BPH) (Kugler et al., 2017), and prostatitis.

[0007] However, increased contractility in one organ, such as the uterus, can contribute to changes in tone in other pelvic structures (this region of the body includes the uterus, ovaries, cervix, vagina and clitoris along the five pelvic bones, muscles, ligaments, nerves, blood vessels, bladder, urethra, colon, and rectum) through paracrine changes, such as altered hormonal and inflammatory milieu. In the case of endometriosis, where uterine contractility is elevated, this manifests as an inflammatory disorder of the pelvic viscera that induces noxious stimuli to the sacral cord, causing pelvic floor muscle dysfunction with sacral nerve hypersensitivity and sacral cord wind-up. The guarding reflex is a viscero-muscular reflex activated to increase pelvic floor tone during routine daytime activities. In these patients, there is an afferent autonomic bombardment that can strengthen and maintain the guarding reflex, which manifests as pelvic floor hypertonia. Other pain disorders such as irritable bowel syndrome, inflammatory bowel disease, interstitial cystitis, fibromyalgia, and vulvodynia are all known to have pelvic hypertonia.Chronic pelvic pain (CPP) is often characterized by the overlap of these distinct disorders. Similarly in men, prostatic inflammation affects other pelvic structures, such as bladder sensation and function.

[0008] Changes in the contractility of any of the organs or structures within the pelvis, whether caused directly by injury or indirectly from cross talk from another organ, contribute to many pelvic disorders, including: Endometriosis, adenomyosis, endometritis, chronic pelvic pain, benign prostatic hyperplasia, prostatitis, interstitial cystitis, pelvic inflammatory disease, irritable bowel syndrome, inflammatory bowel disease, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent cancers of the pelvic (ovarian, uterine, endometrial, prostate, testicular, bladder), polycystic ovary syndrome, follicular maturation arrest, anovulation, dysmenorrhea, infertility, uterine leiomyoma, precocious puberty, endometritis, erectile dysfunction, incontinence (fecal incontinence) incontinence), stress urinary incontinence, urge incontinence, mixed incontinence), pelvic floor myalgia, pelvic floor dysfunction, interstitial cystitis, dysuria (painful urinary urination), dyspareunia (pain during intercourse), dyschezia (painful defaecation), and dysorgasmia (painful ejaculation).WO 2019 / 016759 describes a system for monitoring uterine activity in a pregnant woman, which includes monitoring uterine electrical activity, extracting uterine electrical activity characteristics, and analyzing the electrical activity characteristics to classify the uterine activity as one of several labor conditions, including pre-term labor contraction and labor. Uterine contractions associated with pregnant women are typically measured in the frequency range of 0.3-5 Hz.

[0009] SUMMARY OF THE INVENTION It is an object of the present invention to overcome at least one of the above-referenced problems. Summary of the Invention

[0010] Applicants have discovered that contractility parameters of pelvic structures in non-pregnant subjects, mapped over a period of time, such as a hormonal cycle (e.g., the menstrual cycle in non-pregnant women) or a specific phase of the hormonal cycle, differ between subjects with and without pelvic disorder and can therefore be used to determine the status of pelvic disorder in a subject. Applicants have also discovered that wearable sensors can be used to measure contractility parameters non-invasively, allowing for measurement of contractility parameters over long periods of time. In specific embodiments, the systems and methods of the present invention isolate slow waves characteristic of pelvic organs of interest and use the slow wave signals, or features extracted from the slow waves, as diagnostic variables for pelvic disorder. An example of a slow wave signal used in one embodiment of the systems and methods of the present invention is uterine myometrial motility having a frequency in the range 0.00-0.05 Hz. Applicant can use an externally worn sensor to isolate, process, and compare this slow wave signal to reference signals to identify endocrine conditions, such as endometriosis and related disorders. In a related aspect, Applicant has discovered that electrical stimulation of target structures during specific phases of the hormonal cycle can be used to normalize abnormal contractile activity of pelvic structures, thereby treating or preventing pelvic disorders. For example, in the case of a female subject with endometriosis, Applicant has discovered that applying electrostimulation therapy specifically during the follicular stage of the subject's hormonal cycle normalizes uterine contractile activity.

[0011] Accordingly, applicant provides a system for determining a state of pelvic disease in a subject that uses a non-invasive sensor to measure contractility parameters of a pelvic structure of interest (such as a female uterus or a male prostate) at time points during a hormonal cycle (e.g., the menstrual system in a non-pregnant woman) and a connected processor configured to compile the measurements into a data profile and correlate the data profile with a state of pelvic disease, e.g., using a computational classification model generated using reference data profiles. The system, in one aspect, may also include a non-invasive pelvic structure stimulation model, and the processor may be configured to activate the stimulation model upon detection of a pelvic disease. The processor may also be configured to monitor the hormonal cycle in the subject and activate a stimulation module during specific phases in the hormonal cycle. In one embodiment, the processor is configured to activate the stimulation module (typically via a controller) during specific phases in the subject's hormonal cycle when abnormal contractility parameter activity is detected by the processor (a closed-loop system illustrated in FIGS. 18 and 19 ).

[0012] In a first aspect, the present invention provides a system for determining a pelvic disease state in a subject, generally a non-pregnant subject, characterized by abnormal contractile activity in the subject's pelvic structures, comprising: a sensing module for measuring electrical activity in the subject's pelvis at multiple time points during the subject's hormonal cycle; a signal processing module configured to receive the electrical activity measurements from the sensing module and to separate from the electrical activity measurements measurements of electrical contractility parameters representative of the subject's pelvic structure; a processor module operatively connected to the signal processing module and configured to: receiving as input a measurement of an electrical contractility parameter representative of a pelvic structure of interest; generating a data profile for the subject including measurements of electrical contractility parameters representative of a pelvic structure of interest; and comparing the data profile to a database of reference data profiles; Outputting a pelvic disease status in the subject based on the comparison.

[0013] In any embodiment, the signal processing module is configured to separate measurements of slow wave electrical contractility parameters representative of the subject's pelvic structures from measurements of electrical activity.

[0014] In one embodiment, the processor module is configured to receive as additional input a plurality of measurements of at least one non-electrical hormonal cycle parameter obtained at a plurality of time points during the subject's hormonal cycle, and the generated data profile includes measurements of the electrical contractility parameter representative of the subject's pelvic structure and measurements of the non-electrical hormonal cycle parameter.

[0015] In one embodiment, the signal processing module includes a filter corresponding to a characteristic frequency in the target pelvic structure. In one embodiment, the signal processing module includes a filter corresponding to a characteristic frequency range of slow-wave motility in the target pelvic structure. Slow-wave motility in the target pelvic organ is motility of the inner smooth muscle layer, such as the sub-endometrial layer of the myometrium in the uterus or myogenic smooth muscle activity in the prostate gland in men. Thus, the filter can be configured to isolate slow-wave contractile signals in the target pelvic organ. The filter can be configured to isolate slow waves in the frequency range 0.00-0.05 Hz.

[0016] In any embodiment, the electrical contractility parameter is a signal that includes or consists of a slow wave contractility frequency.

[0017] In any embodiment, the at least one isolated electrical activity measurement comprises an electrical signal measurement for a signal arising from the inner smooth muscle layer of the pelvic organs, the signal including or consisting of a low frequency component.

[0018] In any embodiment, when the pelvic organ is a uterus, the electrical contractility parameter is a signal arising from the subendometrial layer of the myometrium.

[0019] In any embodiment, the processor is configured to analyze the generated profile and provide an estimate or calculate a predictive value of whether the underlying health condition (pelvic disorder) is likely to develop based on the generated data profile.

[0020] In any embodiment, the signal processing module includes a filter configured to isolate measurements of one or more electrical contractility parameters corresponding to a characteristic frequency range of slow wave motility in the pelvic structure of interest.

[0021] In one embodiment, the signal processing module is configured to amplify and digitize the signal.

[0022] In one embodiment, the signal processing module is configured to separate signals representing the pelvic structures of interest from the overall signal (e.g., pelvic EMG signal) by transforming the signal into the frequency domain, typically by dividing the frequency spectrum of the signal into segments corresponding to characteristic frequencies of each pelvic structure.

[0023] In one embodiment, the non-electrical hormone cycle parameters are selected from pain location, pain intensity, pain onset, bleeding onset, urinary habits (nocturia, urgency, onset or "stop-start"), onset of prostate erectile dysfunction, abdominal bloating, appetite changes due to ovarian cancer (poor appetite, feeling full quickly). In one embodiment, the processor is configured to record the non-electrical parameters on a time basis and compare them with the contractility parameters over time.

[0024] In one embodiment, the pelvic disorder is an endocrine disorder.

[0025] In one embodiment, the subject is a female, typically a non-pregnant female, hi one embodiment, the female subject is an adult or pubescent female from menarche.

[0026] In any embodiment, the subject is a woman undergoing in vitro fertilization treatment. In this regard, the systems and methods of the present invention can be used to monitor the effects of ovarian stimulation and identify optimal timing and uterine receptivity for embryo transfer. To determine the optimal ovarian stimulation protocol, the systems and methods of the present invention can be used to monitor the uterine response to ovarian stimulation medications. Successful embryo implantation requires proper timing so that the embryo is present in the uterus during the 8-10 day window of implantation after ovulation and the uterus is optimally prepared to receive the embryo. Therefore, the systems and methods of the present invention can be used during IVF treatment to identify a uterine receptive for embryo implantation. In any embodiment, the methods and systems can be configured to stimulate the uterus to prepare it to receive the embryo.

[0027] In one embodiment, the subject is a female (typically a non-pregnant female), the pelvic structure of interest is the uterus or pelvic floor, and the pelvic disorder is an endocrine disorder such as endometriosis. The hormonal cycle is typically the menstrual cycle.

[0028] In any embodiment, the systems and methods of the present invention are for detecting irritable bowel syndrome in a subject. In one embodiment, the subject is a non-pregnant female.

[0029] In any embodiment, the systems and methods of the present invention are for detecting the risk of miscarriage, usually early miscarriage, in pregnant women. Early miscarriage refers to miscarriage within 13 weeks of gestation. In any embodiment, the systems and methods comprise measuring uterine contractions before conception, during early pregnancy, or both. In any embodiment, increased uterine motility (e.g., on or about day 14 of the menstrual cycle) correlates with the risk of subsequent miscarriage if the subject is pregnant. The systems and methods of the present invention may comprise treating subjects identified as at risk for early miscarriage with uterine electrical stimulation to normalize uterine contractions, usually on or about day 14 of the subject's menstrual cycle. See FIG. 27.

[0030] In some embodiments, the systems and methods of the present invention are for detecting women with fertility issues (e.g., infertility or subfertility). In some embodiments, the systems and methods comprise measuring uterine contractions during the subject's menstrual cycle. In some embodiments, decreased uterine motility on or around day 14 of the menstrual cycle correlates with fertility issues. See FIG. 28.

[0031] In any embodiment, the systems and methods of the present invention are directed to ovulation in a non-pregnant female subject, and therefore may be used to help a woman conceive or to prevent conception.

[0032] In some embodiments, the systems and methods of the present invention detect the optimal time to collect eggs from a subject undergoing in vitro fertilization (IVF) therapy. In some embodiments, maximum uterine motility during the cycle correlates with final egg maturation and indicates the optimal time for egg collection during IVF treatment. See Figure 29.

[0033] In some embodiments, the systems and methods of the present invention are for monitoring treatment of endometriosis. In some embodiments, the systems and methods include measuring uterine contractions during treatment. In some embodiments, a decrease in uterine motility over one or more time points during treatment correlates with a decrease in endometriotic lesions and / or treatment efficacy. See FIG. 30.

[0034] In any embodiment, the subject is male.

[0035] In some embodiments, the subject is male, the pelvic structure of interest is the prostate, and the pelvic disease is an endocrine disorder selected from prostatitis, benign prostatic hyperplasia, and prostate cancer. In some embodiments, the at least one isolated electrical activity measurement comprises an electrical signal measurement related to a signal arising from myogenic smooth muscle of the prostate, the signal comprising or consisting of a low frequency component.

[0036] In any embodiment, the processor module is configured to receive at least one non-electrical non-hormonal cycle parameter as an additional input, and the generated data profile includes a measurement of an electrical contractility parameter representative of a pelvic structure of the subject, a measurement of a non-electrical non-hormonal cycle parameter, and optionally a measurement of a non-electrical non-hormonal cycle parameter.

[0037] In any embodiment, the non-electrical non-hormonal cycle parameters are selected from gender, age, reproductive status, hormonal cycle status, previous diagnoses or diseases, family history, medical records, medical images, body mass index (BMI), and medications.

[0038] In one embodiment, the electrical contractility parameters used in the data profile are extracted from the time domain signal and selected from frequency, amplitude, strength and basal tone of the contractility of the structure of interest.

[0039] In one embodiment, the processor is configured to convert the filtered electrical signal into a frequency domain signal, for example, using a fast Fourier transform. In one embodiment, the electrical contractility parameter used in the data profile is selected from power spectrum density, DWT mean, maximum power, and peak frequency. Maximum power refers to the maximum power spectral density of the signal.

[0040] In one embodiment, the electrical contractility parameters are extracted based on independent component analysis.

[0041] In one embodiment, the signal processing module is configured to amplify and digitize the electrical signal before extracting the parameter measurement.

[0042] In one embodiment, the sensing module is a wearable, non-invasive sensor.

[0043] In one embodiment, the sensor or signal processing module includes a wireless communication module configured to wirelessly transmit the contractility parameter measurements to the processor, optionally via a communication device.

[0044] In one embodiment, the system includes downloadable software for the mobile communication device configured to cause the mobile communication device to: receiving a contractility parameter measurement from the signal processing module; communicating the measured contractility parameter to a processor module; receiving a pelvic disease status from the processor module; and Displaying received pelvic disease status.

[0045] In one embodiment, the downloadable software is configured to enable a subject to input non-electrical hormonal cycle parameter measurements and / or non-electrical non-hormonal cycle parameter measurements using a user interface on the mobile communication device and to communicate the input measurements to the processor module.

[0046] In one embodiment, the pelvic disease status is selected from a positive diagnosis of pelvic disease, a negative diagnosis of pelvic disease, a diagnosis of developing or being at risk of developing pelvic disease, and a subject's response to treatment for pelvic disease.

[0047] In another aspect, the present invention provides a system for treating or preventing a pelvic disorder in a subject, comprising: A system for determining the state of a pelvic disease in a subject according to the present invention; and A pelvic structure stimulation module for applying stimulation therapy to pelvic structures.

[0048] In one embodiment, the pelvic structure stimulation module is non-invasive.

[0049] In one embodiment, the pelvic structure stimulation module is wearable.

[0050] In one embodiment, the processor is operably connected to the wearable pelvic structure stimulation module and configured to activate the pelvic structure stimulation module when a pelvic disease condition in the subject is determined as a positive diagnosis of pelvic disease or a risk of developing pelvic disease.

[0051] In one embodiment, the processor is configured to activate the pelvic structure stimulation module to normalize pelvic organ contractility.

[0052] In one embodiment, the processor: monitoring the subject's hormonal cycle using the contractility parameter measurements received from the signal processing module and / or additional subject data obtained at multiple time points during the subject's hormonal cycle; and Temporarily activating the pelvic structure stimulation module during a particular phase of the subject's hormonal cycle, e.g., to normalize pelvic organ contractility. The device is configured to:

[0053] In one embodiment, the additional subject data is selected from one or more subject data parameters selected from body temperature, date of last menstrual period, and cervical discharge status.

[0054] In one embodiment, the processor is configured to activate (typically via a controller) the stimulation module during a phase in the subject's hormonal cycle when abnormal contractile parameter activity is detected by the processor (a closed-loop system as illustrated in Figures 18 and 19).

[0055] In one embodiment, the processor is configured to measure a contractility parameter for the target pelvic structure after it has been stimulated, and to re-activate the pelvic structure stimulation module if the contractility parameter for the pelvic structure is determined to be abnormal. The processor may be configured to repeat these steps until it is determined that the contractility parameter sensed by the sensing module has normalized.

[0056] In one embodiment, the sensing module includes a subject temperature sensor operably connected to the processor.

[0057] In one embodiment, the pelvic structure stimulation module is an electrical stimulation module.

[0058] In one embodiment, the system comprises a wearable device including a sensing module and a wearable pelvic structure stimulation module.

[0059] In one embodiment, the wearable device includes a signal processing module.

[0060] In one embodiment, the downloadable software is configured to cause the mobile communications device to: receiving activation instructions for the pelvic structure stimulation module from the processor module; and Activate the pelvic structure stimulation module as instructed.

[0061] In one embodiment, the downloadable software is configured to display, on the mobile communication device, information regarding the operation of the wearable pelvic structure stimulation module.

[0062] In one embodiment, the pelvic disease is endometriosis, where the pelvic structure of interest is the subject's uterus or an adjacent pelvic structure.

[0063] In one embodiment, the pelvic disorder is endometriosis, where the target pelvic structure is the subject's uterus or an adjacent pelvic structure, and the processor is configured to activate the pelvic structure stimulation module during a follicular phase of the subject's hormonal cycle.

[0064] In one embodiment, the system comprises a controller configured to control output parameters of the pelvic structure stimulation module.

[0065] In one embodiment, the controller is configured to cause the stimulation module to emit electrical pulses of 0.1 to 20 mA.

[0066] In one embodiment, the controller is configured to cause the stimulation module to emit electrical pulses having a pulse width of 500 μs to 20 ms.

[0067] In one embodiment, the controller is configured to cause the stimulation module to emit electrical pulses at a frequency between 0.1 and 50 Hz.

[0068] In one embodiment, the controller is configured to activate the stimulation module for a treatment time of 30 to 60 minutes.

[0069] In one embodiment, the controller is configured to activate the stimulation module to emit constant current square wave pulses.

[0070] In one embodiment, the controller is configured to activate the stimulation module to emit constant current square wave pulses of about 1-2 mA, about 2 milliseconds per pulse, at an AC frequency of about 2 / 15 Hz.

[0071] In another aspect, the present invention provides a computer-implemented method comprising a processor module operatively connected to a signal processing module, the method comprising: receiving measurements of electrical contractility parameters of an input representative of a pelvic structure of a subject; generating a data profile for the subject including measurements of electrical contractility parameters representative of a pelvic structure of interest; comparing the data profile to a database of reference data profiles, the database including reference data profiles of subjects having different pelvic disease conditions; and and outputting a pelvic disease status for the particular subject based on the comparison. Equipped with.

[0072] In another aspect, the present invention provides a method for determining a pelvic disease status in a subject, comprising: measuring contractility parameters for a pelvic structure of a subject at multiple time points during a hormonal cycle; preparing a data profile including measurements of contractility parameters; comparing the data profile with one or more reference data profiles; and Determining pelvic disease status based on the comparison.

[0073] In any embodiment, the contractility parameter is a slow wave electrical contractility parameter.

[0074] In one embodiment, the method includes measuring at least one non-electrical hormonal cycle parameter at multiple time points during the subject's hormonal cycle, and the data profile includes measurements of an electrical contractility parameter representative of the subject's pelvic structure and measurements of the non-electrical hormonal cycle parameter.

[0075] In one embodiment, the pelvic disorder is an endocrine disorder.

[0076] In any embodiment, the slow wave electrical contractility parameter is frequency, typically contractility frequency in the range 0.00 to 0.05 Hz.

[0077] In one embodiment, the pelvic structure of interest is selected from the uterus, the pelvic floor, and the prostate.

[0078] In one embodiment, the subject is a female, the pelvic structure of interest is the uterus or pelvic floor, and the pelvic disorder is an endocrine disorder such as endometriosis.

[0079] In one embodiment, the subject is male, the pelvic structure of interest is the prostate, and the pelvic disease is a disease of the prostate selected from prostatitis, benign prostatic hyperplasia, and prostate cancer.

[0080] In one embodiment, the method comprises determining at least one non-electrical non-hormonal cycle parameter, wherein the data profile includes a measurement of an electrical contractility parameter representative of a pelvic structure of the subject, a measurement of a non-electrical non-hormonal cycle parameter, and optionally a measurement of a non-electrical non-hormonal cycle parameter.

[0081] In one embodiment, the non-electrical non-hormonal cycle parameters are selected from gender, age, reproductive status, hormonal cycle status, previous diagnoses or diseases, family history, medical records, medical images, BMI, and medications.

[0082] In one embodiment, the electrical contractility parameter is selected from frequency, amplitude, and basal tone of contractions of the target structure.

[0083] In one embodiment, the electrical contractility parameter is measured using a sensing module that is a wearable, non-invasive sensor.

[0084] In another aspect, the present invention provides a method of treating a pelvic disorder in a subject, comprising stimulating a pelvic structure of the subject with a stimulation module.

[0085] In one embodiment, the stimulator is an electrical stimulator.

[0086] In one embodiment, the method includes stimulating a pelvic structure of the subject with an electrical pulse of 0.1-20 mA.

[0087] In one embodiment, the method includes stimulating a pelvic structure of a subject with electrical pulses having a pulse width of 500 μs to 20 ms.

[0088] In one embodiment, the method comprises stimulating the pelvic organs of the subject with electrical pulses having a frequency of 0.1 to 50 Hz.

[0089] In one embodiment, the method comprises stimulating the subject's pelvic organs for a treatment time of 30 to 60 minutes.

[0090] In one embodiment, the method includes stimulating with constant current square wave pulses.

[0091] In one embodiment, the method includes stimulating the subject's pelvic structures with constant current square wave pulses of about 1-2 mA, about 2 milliseconds per pulse, at an alternating current frequency of about 2 / 15 Hz.

[0092] In one embodiment, the subject's pelvic structures are stimulated using a non-invasive stimulation module.

[0093] In one embodiment, the stimulation is performed during a particular phase of the hormone cycle.

[0094] In one embodiment, the stimulation is performed during the follicular phase of the hormone cycle.

[0095] In one embodiment, the contractility parameter of the target pelvic structure is determined after stimulation, and if the contractility parameter of the target pelvic structure remains abnormal, further stimulation therapy is performed. These steps may be repeated until the contractility parameter for the target pelvic structure is determined to be normalized.

[0096] In one embodiment, the subject is a woman of reproductive age who has an endocrine disorder (such as endometriosis).

[0097] In one embodiment, the subject is a male with a prostate disease such as prostatitis, prostate cancer, or benign prostatic hyperplasia.

[0098] In one embodiment, stimulation of the subject's pelvic structures is configured to normalize contractile activity of the abnormal pelvic structures.

[0099] In another aspect, the present invention provides a method of treating endometriosis in a subject, comprising administering electrical stimulation therapy to the subject's uterus during the follicular phase of the subject's hormonal cycle, but not during the ovulatory stage.

[0100] In another aspect, the present invention provides a wearable device comprising: a sensing module for measuring electrical activity in the subject's pelvis at multiple time points during the subject's hormonal cycle; a signal processing module configured to receive the electrical activity measurements from the sensing module and to isolate measurements of electrical contractility parameters representative of the subject's pelvic structure from the electrical activity measurements; a pelvic structure stimulation module for applying a stimulation treatment to a pelvic structure; and Optionally, a controller configured to actuate output parameters of the pelvic structure stimulation module in a pattern configured to normalize electrical contractility parameters for the subject's pelvic structure.

[0101] In any embodiment, the signal processing module is configured to separate slow wave electrical contractility parameters from measures of electrical activity.

[0102] The system may be an electrical medical system. The system may include a real-time operating system. The system may include an embedded platform for automation. The system may include firmware and software components. The system may also include an application specific integrated circuit (ASIC), a programmable logic device (PLD) that may include digital circuitry, a digital signal processor, a microcontroller or microprocessor, memory components, and control circuitry.

[0103] The system may include analog interfaces (digital-to-analog, analog-to-digital). The system may include voltage or current regulators and power management circuits. The system may further include timing sources.

[0104] Other aspects and preferred embodiments of the present invention are defined and described in the other claims set out below. [Brief explanation of the drawings]

[0105] [Figure 1]Figure 1 shows uterine contractions in rats with endometriosis (n=8) and without endometriosis (n=8) during all phases of the rat hormonal cycle. Uterine contractions were measured using electrical sensors and displayed as electrohysterograms (EHG) converted to the frequency domain using a fast Fourier transform (FFT). [Figure 2] Figure 1 shows uterine contractions in rats with endometriosis (n=3) and without endometriosis (n=5) during the diestrus stage of the rat hormonal cycle. Uterine contractions were measured using electrical sensors and electrohysterograms (EHGs) converted to the frequency domain using a fast Fourier transform (FFT). [Figure 3] Figure 1 shows uterine contractions in rats with endometriosis (n=3) and without endometriosis (n=1) during the proestrus stage of the rat hormonal cycle. Uterine contractions were measured using electrical sensors and electrohysterograms (EHGs) converted to the frequency domain using a fast Fourier transform (FFT). [Figure 4] Figure 1 shows uterine contractions in rats with endometriosis (n=2) and without endometriosis (n=2) during the estrus stage of the rat hormonal cycle. Uterine contractions were measured using electrical sensors and displayed as electrohysterograms (EHGs) transformed into the frequency domain using a fast Fourier transform (FFT). [Figure 5] Figure 1 shows that electrical stimulation of the uterus using non-invasive electrical stimulation electrodes can reduce uterine contractions in rats. Uterine contractions are measured using electrical sensors and displayed as electrohysterograms (EHGs) converted to the frequency domain using a fast Fourier transform (FFT). [Figure 6]

[0023] Figure 10 illustrates the effect of electrical stimulation on uterine contractions in control rats (without endometriosis) during the estrus, proestrus, and diestrus phases of the rat's hormonal cycle. Uterine contractions were recorded for 20 minutes, electrical stimulation was applied for 20 minutes, and then uterine contractions were recorded for another 20 minutes. The graph illustrates that in rats without endometriosis, electrical stimulation during the estrus and proestrus phases of the hormonal cycle caused an increase in the amplitude of contractions, while electrical stimulation during the diestrus phase of the hormonal cycle caused a decrease in the amplitude of contractions. [Figure 7A]

[0023] Figure 10 illustrates the effect of electrical stimulation on uterine contractions in rats with endometriosis during the estrus and proestrus phases, and diestrus phase of the rat's hormonal cycle. Uterine contractions were recorded for 20 minutes, electrical stimulation was applied for 20 minutes, and then uterine contractions were recorded for another 20 minutes. The graph illustrates that in rats with endometriosis, electrical stimulation during the estrus and proestrus phases of the hormonal cycle caused a decrease in contraction amplitude, while electrical stimulation during the diestrus phase of the hormonal cycle did not have the same effect. [Figure 7B] FIG. 10 demonstrates the effect of electrical stimulation on uterine contractions in rats with endometriosis during estrus, proestrus and diestrus phases of the rat hormonal cycle. [Figure 8] 1 is a flow chart illustrating a method of diagnosing a pelvic disorder according to the present invention. [Figure 9] FIG. 1 illustrates an example of a subject's data profile generated using two contractility parameters (contraction frequency, basal tone) and three non-electrical hormonal cycle parameters (fatigue, pain intensity, bleeding) matched over the subject's 28-day hormonal cycle. [Figure 10] FIG. 10 illustrates another example of a subject's data profile generated using two contractility parameters (contraction frequency and basal tone) and one non-electrical hormonal cycle parameter (pain intensity) matched across the subject's 24-hour hormonal cycle. [Figure 11]FIG. 1 illustrates a system for diagnosing pelvic disorders according to one embodiment of the present invention, showing the flow of data from sensors placed on the pelvic surface to a mobile application on the user's phone, a remote server, and a clinician's personal device. [Figure 12] FIG. 1 illustrates summary data accessed from a remote server and presented to patients and clinicians on their personal computing devices. [Figure 13] 1 is a flow chart illustrating a method of treating or preventing a pelvic disorder according to the present invention. [Figure 14] 1 is a diagram illustrating a system for treating or preventing pelvic disorders according to an embodiment of the present invention, showing the flow of sensed data from sensors placed on the pelvic surface to a mobile application on a user's phone, to a remote server including a processor that determines a state of pelvic disorder in a subject, calculates specific phases of a hormonal cycle to apply stimulation, monitors the progression of the hormonal cycle in the subject, and activates an electrical stimulation device to apply electrical stimulation at the calculated phases. [Figure 15] FIG. 1 illustrates a treatment protocol for a female subject determined to have endometriosis. [Figure 16] Top panel: Extraction of contractility parameters from electrical activity using a signal processing module to convert electrical signals from the time domain to the frequency domain (peak frequency or power spectral density). Bottom panel: Non-electrical hormone cycle parameters (pain) that form part of the subject's data profile. [Figure 17] Top: Illustrates the placement of non-invasive skin sensor electrodes relative to the target organ in a female subject. Bottom: Illustrates the placement of non-invasive skin sensor electrodes relative to the target organ in a male subject. Electrodes can be placed anteriorly or posteriorly. [Figure 18] FIG. 1 illustrates a closed-loop sensing and stimulation system based on hormone cycles. [Figure 19]

[0023] Figure 1 illustrates the comparison function in the system and process of the present invention. Software embedded in the controller receives electrical contractility parameters from the sensors and compares them to a healthy population template in relation to that hormonal cycle phase (i.e., menstrual cycle day). An algorithm assesses whether the subject's reading is within normal limits at that time. Based on this, the controller sends instructions to the electrical stimulator to stimulate or not stimulate the target pelvic structure on that day. [Figure 20] 1 illustrates a wearable sensing and stimulation module forming part of the system of the present invention, configured for application to the skin in the pelvic region, and including electrodes and a central housing incorporating a battery, PCB, and SD card, the PCB including a microcontroller, current control module, and Bluetooth antenna. [Figure 21] FIG. 1 shows the total recorded signal (days 1, 7, 14, 21) for a volunteer with endometriosis. [Figure 22] FIG. 21 shows the total recorded signal (days 1, 7, 14, 21) for a volunteer with endometriosis. This is the same volunteer as for FIG. 21. [Figure 23] FIG. 1 shows the signals recorded on days 14 and 15 in a healthy volunteer (top panel) and their power spectra (bottom panel). [Figure 24] FIG. 1 shows boxplots and statistical summaries of mean DWT on day 14 for healthy, no medication (n=11) and endometriosis, no medication (n=15) volunteers. [Figure 25] Average daily "peak power" (days 1, 7, 14, 21) and signal modulation by hormonal intervention for volunteers with endometriosis and no medication (n=15), healthy and no medication (n=11), endometriosis and medication (n=7), and healthy and medication (n=2). [Figure 26A]Scatter plots of volunteers (n=39) with IBS (red) and without IBS (blue) using features in (a) spectral falloff and mean frequency, and (b) DWT standard deviation (Std) and autocorrelation. [Figure 26B] Scatter plots of volunteers (n=39) with IBS (red) and without IBS (blue) using features in (a) spectral falloff and mean frequency, and (b) DWT standard deviation (Std) and autocorrelation. [Figure 27] A comparison of maximum power at day 14 of the volunteers: pregnant woman with miscarriage (n=1), endometriosis, no medication (n=15), healthy, no medication (n=11), endometriosis, medication (n=7), healthy, medication (n=2). Looking at the maximum power of the pregnant woman with miscarriage at day 14 of pregnancy, the maximum power is elevated compared to all other volunteers. This means that she has much higher uterine motility, which can interfere with implantation. [Figure 28] Figure 1 shows the maximum power at various time points in volunteers: women with endometriosis surgically diagnosed for pain (n=11), healthy volunteers (n=15), and women with endometriosis surgically diagnosed for infertility problems (n=4). Those with infertility problems show significantly reduced uterine motility on day 14. [Figure 29] Figure showing maximum power at various time points in volunteers: Infertility / No IVF (n=4), Health / No medication (n=11), Infertility / IVF (n=1). The ovarian stimulation protocol in volunteers undergoing IVF promotes ovulation compared to volunteers with infertility problems not undergoing fertility treatment. [Figure 30] Maximum power at various time points in volunteers: endometriosis, no medication (n=15), healthy, no medication (n=11), hysterectomy (n=1). The ability to detect signals from endometriotic lesions means that this technique will make it possible to monitor the effectiveness of treatments (surgery and medication) in terms of lesion removal / regression. [Figure 31]FIG. 1 is a block diagram illustrating one method of diagnosing endometriosis according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0106] [Detailed Description of the Invention]

[0107] All publications, patents, patent applications, and other references mentioned herein are incorporated by reference in their entirety for all purposes as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference and the contents of which were set forth in full.

[0108] (Definitions and general settings) As used herein, unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meaning that the terms may enjoy in the art.

[0109] Unless the context otherwise requires, the use of the singular herein shall be construed to include the plural and vice versa. The term "a" or "an" when used in reference to an entity shall be construed to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0110] As used herein, the term "comprise," or variations thereof, such as "comprises" or "comprising," should be interpreted to indicate the inclusion of any listed integer (e.g., feature, element, property, attribute, method or process step, or limitation) or group of integers (e.g., feature, element, property, attribute, method or process step, or limitation), but not the exclusion of any other integers or group of integers. Thus, as used herein, the term "comprising" is inclusive or open-ended and does not exclude additional, unlisted integers or method or process steps.

[0111] As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. This term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, regardless of the nature of the etiology (or whether an etiological basis for the disease has actually been established). Thus, diseases resulting from infection, trauma, injury, surgery, radiological ablation, age, poisoning, or nutritional deficiencies are included.

[0112] As used herein, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that cures, ameliorates, or lessens the symptoms of a disease or eliminates its cause (or lessens its effects) (e.g., a reduction in the accumulation of pathological levels of lysosomal enzymes). In this context, the term is used interchangeably with the term "therapy."

[0113] Additionally, the terms "treatment" or "treating" refer to an intervention (e.g., administration of a drug to a subject) that prevents or delays the onset or progression of a disease, or reduces its incidence (or eradicates) within a treated population. In this context, the term treatment is used interchangeably with the term "prophylaxis."

[0114] As used herein, an effective amount or therapeutically effective amount of an agent defines an amount that can be administered to a subject without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, but sufficient to provide the desired effect, e.g., treatment or prophylaxis as manifested by permanent or temporary improvement in the subject's disease. This dosage will vary from subject to subject, depending on the individual's age and general disease, the method of administration, and other factors. Therefore, it is not always possible to identify an exact effective amount, but one of ordinary skill in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and general background knowledge. Therapeutic results in this context include eradication or alleviation of symptoms, relief from pain or discomfort, prolonged survival, improved mobility, and other markers of clinical improvement. Therapeutic results need not be a complete cure. Improvement may be observed through biological or molecular markers, clinical improvement, or observational improvement. In preferred embodiments, the methods of the present invention are applicable to humans, large sports animals (horses, camels, dogs), and domestic animals (cats and dogs).

[0115] As defined above, in the context of treatment and effective amounts, the term subject (which shall be interpreted as including "individual," "animal," "patient," or "mammal," where the context permits) defines any subject, particularly a mammalian subject, for which treatment is indicated. Mammalian subjects include humans, domestic animals, farm animals, zoo animals, sport animals, dogs, cats, guinea pigs, and the like. pet animals such as pigs, rabbits, rats, mice, horses, camels, bison, cattle, and cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; cats, lions, and tigers Examples of animals that may be used include, but are not limited to, felids such as igers, equids such as horses, donkeys, and zebras, food animals such as cows, pigs, and sheep, ungulates such as deer and giraffes, and rodents such as mice, rats, hamsters, and guinea pigs. In a preferred embodiment, the subject is a human. As used herein, the term "equine" refers to mammals of the family Equidae, which includes horses, donkeys, asses, kiang, and zebras.

[0116] "Pelvic structure" is intended to include structures within the pelvic cavity with their muscular components, including the pelvic floor, bladder, rectum and descending colon, caecum, uterus, fallopian tubes, clitoris, vagina, cervix, and ovaries in women, and the prostate, penis, and testes in men. In one embodiment, the pelvic structure is a pelvic organ.

[0117] "Pelvic condition" refers to endocrine and reproductive disorders associated with altered contractility in one or more pelvic structures. "Reproductive conditions" can be pathological or non-pathological reproductive diseases or events, including infertility, implantation failure (either natural or during assisted reproduction), spontaneous miscarriage, or premature birth. The methods and systems of the present invention can be used or configured to treat or prevent infertility and prevent or reduce the risk of undesirable reproductive events, such as implantation failure, spontaneous miscarriage, or premature birth, in women.

[0118] An "endocrine disorder" or "endocrine condition" refers to a disease associated with the body's endocrine glands, usually resulting in a hormonal imbalance. Examples of conditions originating from the glands in the pelvic cavity include endometriosis, adenomyosis, endometritis, chronic pelvic pain, benign prostatic hyperplasia, prostatitis, interstitial cystitis, pelvic inflammatory disease, irritable bowel syndrome, inflammatory bowel disease, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent pelvic cancer (ovary, uterus, endometrium, prostate, testes, bladder), polycystic ovary syndrome, arrested follicular maturation, anovulation, dysmenorrhea, anovulation, infertility, uterine leiomyoma, precocious puberty, endometritis, erectile dysfunction, incontinence (fecal incontinence, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence), pelvic floor muscle pain, pelvic floor dysfunction, dysuria (painful urination), dyspareunia (painful intercourse), difficulty with defecation (painful defecation), and difficulty with ejaculation (painful ejaculation).

[0119] A "contractility parameter" as applied to a pelvic structure is intended to mean the motility, tone, occurrence, frequency, amplitude, intensity, direction, power, power density, pattern, duration, periodicity, dominant frequency, peak to peak, or area under the curve of contractions in a pelvic structure. Preferably, the contractility parameter is selected from frequency, amplitude, and basal tone.

[0120] "Slow wave electrical contractility." In any embodiment, the contractility parameter can be a slow wave electrical contractility parameter, such as slow wave electrical contractility frequency. Slow wave contractility is generally caused by the inner smooth muscle layer in the organ of interest, e.g., the inner endometrial SM layer in the uterus or the myogenic SM layer in the prostate. Slow wave contractility in the uterus and cecum is generally measured in the range 0.00-0.05 Hz.

[0121] "Status" as applied to a pelvic disorder in a subject should be understood to mean a positive or negative diagnosis of the pelvic disorder, the risk of development or occurrence of the pelvic disorder, the response of the pelvic disorder to treatment, the severity of the pelvic disorder, or any other clinically useful information related to the pelvic disorder. Specific examples include endometriosis, IBD, risk of miscarriage or infertility in women (generally non-pregnant women), and a diagnosis of a prostate endocrine disorder (e.g., prostate cancer or BPH) in men.

[0122] "Sensing module" refers to a sensor capable of detecting contractility parameters in a pelvic structure of interest. The sensing module is typically an external sensor. The sensing module may take the form of a patch configured for skin attachment to a subject. The sensing module may be wearable. The sensing module may be configured for subcutaneous application. The sensing module may be an electrical sensor configured to detect electrical activity in the pelvic region. The sensing module may be configured to transmit sensing data wirelessly, for example, to a mobile device or computer. The sensing module may include one or more sensing electrodes, which may be spaced apart. The sensing module may be placed on the subject's abdomen in proximity to the target structure. Examples of suitable electrical sensing modules include the Biosignalsplux Solo kit and the Biosignalsplux Electrogastrography (EGG) sensor, both manufactured by Wireless Signals SA.

[0123] "Plurality of time points during the subjects' hormonal cycle" means at least two time points, typically at least 5, 10, 15, 20, or 25 time points. The time points are generally spaced apart during the hormonal cycle. Typically, at least one time point occurs during each phase of the hormonal cycle, e.g., at least 2, 3, 4, 5, or 6 time points per stage of the hormonal cycle. Measurements taken at multiple time points map a variable measured over the course of the cycle. This variable can be a contractile parameter (frequency or intensity) or a non-contractile hormonal cycle parameter (bleeding, pain, or fatigue). Data collected at each time point can be processed into representative data summaries. Time points can be evenly spaced over an extended recording period, e.g., daily. After recording is complete, signals over the hormonal cycle can be represented by mapping the summary data generated (electronically and user-entered) at each time point to create a data profile for the subject. For non-pregnant women, the time points may be days 1, 7, 14, and 21 (+ / - 1 or 2 days) of the menstrual cycle. For women with irregular hormonal cycles, measurements may be taken on days 13, 14, and 15 and compared, with one of the measurements (e.g., the one with the highest maximum power) being used. Measurements of electrical activity (e.g., signal, etc.) are typically recorded for at least 10, 15, 20, or 25 minutes.

[0124] "Subject's hormonal cycle," as applied to a female subject, refers to the cyclical changes in the female body during the reproductive years caused by the complex interplay of the following hormones: luteinizing hormone, follicle-stimulating hormone, and the female hormones estrogen and progesterone. The phases of the female hormonal cycle are the follicular phase, the ovulatory phase, and the luteal phase. In animals with estrus cycles, the proestrus stage corresponds to the follicular phase, the estrus stage corresponds to the ovulatory phase, and the estrus stage corresponds to the luteal phase. When applied to male mammals, the term refers to cyclical hormonal changes over a period of time (e.g., 24 hours) and changes that occur as males age (i.e., andropause). In one embodiment, the invention comprises stimulating a subject's pelvic structures at a particular phase in the subject's hormonal cycle for the purpose of normalizing contractions of the pelvic structures. In women of reproductive age with an endocrine disorder, such as endometriosis, stimulation is usually performed during the follicular phase.

[0125] A "signal processing module" refers to a device configured to receive and process electrical activity signals from the sensing module. The signals may be processed to amplify and / or digitize the signals. The digitization of the signals may be performed by an analog-to-digital converter. The signals may be processed to extract signals representative of the pelvic structures of interest (e.g., electrical contractility parameters). In some embodiments, this is accomplished by applying a digital filter corresponding to the dominant or characteristic frequency of that structure. Alternatively, the digitized signals may be converted to the frequency domain, where contractile structures are separated from the overall pelvic EMG signal, e.g., by dividing the frequency spectrum into segments corresponding to the characteristic frequencies of each pelvic structure. In some embodiments, signals representing the uterus, colon, bladder, prostate, and pelvic floor are separated within the frequency ranges of 0-0.05 Hz, 0.2-0.4 Hz, 0.1-5 Hz, 0.06-0.11 Hz, and 20-500 Hz, respectively. In some embodiments, the signals are processed to isolate characteristics of slow-wave electrical contractions in the target organ. In many pelvic organs of interest, slow-wave activity has frequencies in the range 0.00-0.05 Hz, typically 0.01-0.03 Hz or 0.01-0.02 Hz. Slow-wave signals are characteristic of the internal smooth muscle of the target organ, e.g., the endometrial SM layer in the uterus and the myogenic SM layer in the prostate. In some cases, the methods and systems of the present invention may include algorithmic processing of the isolated signals to compensate for body location and artifacts from other parts of the body (e.g., heart, GI tract, respiration, skeletal muscle) and to extract further relevant parameters (e.g., frequency, basal tone, amplitude). These methods include linear modeling, digital filtering, spectral analysis, and statistical analysis. Signal quality can be further improved by recording the signal for an extended period of time, e.g., 30 minutes, at each time point and averaging the signal to reduce the signal-to-noise ratio.

[0126] A "data profile" refers to multiple measurements of one or more contractility parameters that are correlated over a defined period of time, e.g., an interval of a hormonal cycle (e.g., a menstrual cycle in a non-pregnant woman). A data profile may include one or more non-electrical hormonal cycle parameters correlated over the same period of time; examples include hormonal cycle parameters such as bleeding, fatigue, pain intensity, and pain occurrence. Generally, a data profile that includes more than one variable will correlate different variables to the same time point. Examples of data profiles are provided in FIGS. 9 and 10. Generally, a data profile includes at least one contractility parameter (e.g., 1, 2, or 3) and, optionally, at least one non-electrical hormonal cycle parameter (e.g., at least 1, 2, 3, 4, or 5). In one embodiment, the contractility parameters are transformed from the time domain to the frequency domain.

[0127] "Reference data profiles" refer to data profiles of subjects with known pelvic disease conditions. For example, if the system or method is for detecting endometriosis in a subject, the reference data profile may be a data profile from a subject who is positive for the disease or a subject who is negative for the disease. Generally, a subject's data profile is associated with a pelvic disease condition by using a classification model generated using reference data profiles from a population of subjects with known pelvic disease conditions, such as positive disease, negative disease, risk of developing the disease, and disease severity. Generally, if a subject's data profile includes one or more variables mapped over time, the reference data profiles to which the subject's data profile is compared all include the same variables mapped over time. Comparing a subject's data profile to a reference data profile or profiles generally involves a computational model, which may be multiple linear computational models. Various methods, including mathematical modeling and pattern recognition, may be used to match a subject's data profile to one of the reference data profiles. In one embodiment, this comparing step may be performed by mathematical modeling using "Linear discriminant analysis" and "nearest neighbor Euclidian distance minimization" using a subset of the chemical growth responses. Other methods for matching or correlating a query data profile with one or more reference data profiles include simple Euclidian matching, or hierarchical cluster analysis. In one embodiment, the reference data profiles are from the same subject obtained previously, e.g., before treatment.This allows a subject or physician to monitor pelvic disease over time and determine changes in pelvic disease in a subject (e.g., before or after treatment). In the context of determining fertility and in IVF-related applications, reference data profiles are typically obtained from one or more healthy, fertile women. The systems and methods of the present invention can also be used to determine pelvic disease status in a subject in the context of a population defined by any cohort of people, such as age, geography, habits (e.g., alcohol use, smoking, etc.), ethnicity, race, sex, number of pregnancies, or any combination thereof (e.g., women in the 20-30 age group).

[0128] "Non-electrical hormonal cycle parameter" refers to a non-electrical parameter of a hormonal cycle in a subject. Examples include pain intensity, pain location, pain type, bleeding, urination pattern, bowel pattern, mood, bloating, fatigue, weakness, or impact on daily life. Pain may include pelvic pain, back pain, upper abdominal pain, vaginal pain, labia pain, perineum pain, breast pain, pain during intercourse, pain after intercourse, pain during ejaculation, pain during urination or defecation, chills, fever, or lack of energy. Bleeding patterns include menstrual bleeding, spotting, blood in semen, or blood in urine. Urinary patterns include an increase or decrease in urination frequency, flow rate, or need to urinate. Bowel patterns include constipation, diarrhea, increased frequency, or decreased frequency. Impact on daily life includes missed work or school, inability to exercise, or inability to perform household chores. Measurements of these parameters can be entered by the subject, for example, using a mobile phone or computer user interface.

[0129] "Non-electrical, non-hormonal cycle parameters." The data profile may also include non-electrical, non-hormonal cycle parameters. These parameters are phenotype parameters of the subject, such as age, sex, reproductive status, hormonal cycle status, previous diagnoses or diseases, family history, medical records, medical images, BMI, symptoms, and medications. The use of one or more of these variables in the data profile can be used to provide information for a reference data profile used in determining a pelvic disease status in the subject. For example, if the subject is female and 35 years old, a particular classification model can be used to determine a pelvic disease status and provide an output.

[0130] A "pelvic structure stimulating module" is a device configured to stimulate a subject's pelvic structures to modulate at least one contractility parameter in the pelvic structures. In the embodiments described herein, an electrical stimulation device is used. The device can be configured to emit electrical pulses of 0.1 to 20 mA. The device can be configured to emit electrical pulses having a pulse width of 500 μs to 20 ms. The device can be configured to emit electrical pulses at a frequency of 0.1 to 50 Hz. Stimulation can be applied for 30 to 60 minutes at a time. The device can include one or more electrodes or an electrode array. The module can be configured for application to the skin and stimulation of the pelvic structures from the surface of the subject's body. The stimulation module can be configured to receive signals wirelessly from a remote location, such as a mobile communication device or computer. The signals can include instructions regarding the type and intensity of electrical stimulation and the timing of the electrical stimulation. Alternatively, stimulation of the subject's pelvic structures may be achieved using magnetic waves, high-intensity light waves, shock waves, high-energy laser radiation, or electroacupuncture. Typically, the stimulation module is configured to apply stimulation configured to normalize the contractility of the pelvic structures (e.g., adjust contractility parameters to resemble corresponding contractility parameters from a disease-negative individual). Generally, this includes stimulation configured to normalize contractions or reduce the frequency, amplitude, intensity, or basal tone of contractions.

[0131] "Monitor the subject's hormonal cycle." In one embodiment, the systems and methods of the present invention include monitoring the subject's hormonal cycle, thereby allowing treatment of the subject during one or more specific phases of the hormonal cycle. The monitoring includes taking measurements during the hormonal cycle of at least one contractility parameter or another variable related to the hormonal cycle, such as body temperature, date of last menstrual period, or cervical secretion status. The contractility parameter may be sensed by a sensing module, and other variables may be input by a user, and the processor may be configured to monitor the progression of the hormonal cycle from the received measurements and subsequently operate the simulation module at specific phases during the hormonal cycle.

[0132] A "system" related to determining a pelvic disease status comprises a sensing module, optionally a signal processing module, and a processor. The system may also include software for a computing device, particularly downloadable software suitable for use with a mobile communication device such as a mobile phone. The sensing module or signal processing module may be configured to wirelessly transmit data to the computing device. The software may be configured to cause the communication device to receive data from the sensing module or signal processing module, optionally store the data, transmit the data to a processor (e.g., a processor at a remote location), receive data from the processor related to the pelvic disease status in the subject, and display some or all of the data. The processor may be configured to transmit data related to the pelvic disease status to another location, such as a computing device at a hospital or clinic.

[0133] A "system" related to the treatment or prevention of pelvic disorders further includes a pelvic structure stimulation module, e.g., an electrical stimulation device. This module may be configured to receive treatment instructions from a remote location, e.g., a mobile communication device. The processor may be configured to generate treatment instructions when treatment should be applied, including treatment parameters including interval, intensity, and stage of a hormone cycle. Software may be configured to cause the mobile phone to receive the treatment parameters from the processor and transmit the treatment parameters to the stimulation module.

[0134] A "wearable device" refers to a device that includes a sensing module, optionally a signal processing module, and a pelvic structure stimulation module. The device is wearable and may be provided in the form of a patch that can be applied to the subject's skin. The device generally includes a wireless communication module configured to transmit data to and receive data from a remote location. The device may include one or more sensing or treatment electrodes. The device may include a power source (e.g., a battery, etc.) operably connected to any of the device's modules. The device may include a pelvic structure stimulation module and, optionally, a controller (e.g., a microcontroller) operably connected to the power source.

[0135] [Example] The present invention will now be described with reference to specific examples. These are merely exemplary and are for illustrative purposes only and are not intended to limit the scope of the claimed monopoly or the invention described. These examples constitute the best mode presently contemplated for carrying out the invention.

[0136] (material and method) (Animal model) Female Sprague-Dawley rats weighing 200–250 g were housed at 23°C with a 12-h light / dark cycle and free access to food and water. They were randomly assigned to endometriosis or sham groups, eight rats per group. The Animal Care and Research Ethics Committee (ACREC) at the National University of Ireland, Galway, approved all procedures. Animals were handled (5 min / day) for 7 days prior to the start of the experiment to reduce handling stress, and vaginal cytological smears were performed to confirm reproductive cycle status.

[0137] (Introduction of endometriosis) Endometriosis was surgically induced under isoflurane anesthesia according to the method of Vernon and Wilson (1985). The distal 2 cm of the right uterine horn was removed and immersed in warm (37°C) sterile saline. The endometrium was exposed by opening the horn longitudinally with sterile scissors. A biopsy punch was used to remove a 5 mm section of the uterine horn. 2Four sections of the uterus were excised. The implants were sutured to the serosal surface adjacent to the mesenteric vessels of the small intestine and to the endometrial surface exposed to the peritoneum. In the sham-operated groups, the right uterine horn was explanted and attached to the mesenteric intestine with four sutures without a uterine implant. The peritoneal cavity was kept moist with copious amounts of saline solution throughout the procedure to reduce adhesions. Endometriosis was allowed to progress for 56 days after the induction surgery before electrohysterogram (EHG) recordings and electrical stimulation studies were completed.

[0138] (Electrohysterogram (EHG) recording) Laparotomy was performed under isoflurane anesthesia. For direct measurements, bipolar needle electrodes (AD Instruments) were inserted into the myometrium (the distance between the two electrodes was 8 mm). For noninvasive measurements, an abdominal skin incision was made, and a bipolar disk electrode pair (MDE GmbH Walldorf, Germany) was placed subcutaneously over the uterus (the distance between the two electrodes was 20 mm). Basal uterine contractility was detected for 60 min. Electrical signals were recorded and analyzed by an online computer and amplifier system (AD Instruments PowerLab and Quad BioAmplifier). All analog signals were converted to digital signals at a sampling rate of 1000 Hz.

[0139] During recording, animals were maintained under isoflurane anesthesia. Upon completion of the experiment, animals were sacrificed in accordance with Directive 2010 / 63 / EU. A digital filter (low-pass 0.1 Hz) was applied to the recorded signals. To compare EHG between the groups (endometriosis and sham), exploratory statistical analyses were calculated on the raw signals (see Table 1). They were further analyzed by fast Fourier transform (FFT), where the frequency of electrical activity was characterized in Hz and the magnitude of activity was described as the power spectral density (see Figures 1–4).

[0140] (Electrical stimulation test) A second bipolar electrode made of Teflon-insulated multistranded stainless steel was inserted into the myometrium, 10 mm away from the sensing electrode. For noninvasive electrical stimulation, a bipolar disk electrode pair (MDE GmbH, Walldorf, Germany) was placed subcutaneously over the uterus (the distance between the two electrodes was 20 mm). Baseline EHG was recorded for 20 min (as previously described). The electrodes were connected to a pulse generator (Multichannel System: Stimulus Generator 4002) preprogrammed with constant-current square-wave pulses of 1–2 mA, 2 ms / pulse, and 2–15 Hz. After 20 min of electrical stimulation, the electrodes were removed from the pulse generator, and recovery EHG was recorded for another 20 min.

[0141] During recording, animals were maintained under isoflurane anesthesia. Upon completion of the experiment, animals were sacrificed in accordance with Directive 2010 / 63 / EU. A digital filter (low-pass 0.1 Hz) was applied to the recorded signals. Results were analyzed by fast Fourier transform (FFT), where the frequency of electrical activity was characterized in Hz and the magnitude of activity was expressed as power spectral density (Figure 5). Raw signals are compared in Figures 6-7 to demonstrate the effect of electrical stimulation at various times during the hormonal cycle.

[0142] (result) Figure 1 illustrates that uterine contraction parameters measured using electrical sensors across the entire hormonal cycle can be used to distinguish rats with and without endometriosis. Uterine contractions are represented by the power spectral density at the peak frequency.

[0143] Figures 2 and 3 illustrate that the difference in uterine contractions between rats with and without endometriosis is particularly pronounced during the proestrus and estrus phases of the hormonal cycle.

[0144] Endometriotic and sham animals can also be distinguished using other contractility parameters, as shown in Table 1 below.

[0145] [Table 1]

[0146] Table 2 shows the subject's data profile, including electrical contractility parameters determined at four time points, T1 through T4, and non-electrical hormonal cycle parameters (pain location, pain intensity, pain type, and bleeding intensity) determined at the same time points.

[0147] [Table 2]

[0148] Figures 5-7 demonstrate that uterine contractions in mammals can be regulated using electrical stimulation, and that the effects of electrical stimulation are informed by the hormonal state of the animal. For example, in Figure 6, application of electrical stimulation to control rats (without endometriosis) during proestrus (corresponding to the follicular phase of the hormonal cycle in humans) increased contractile activity, whereas application of electrical stimulation to rats with endometriosis during proestrus reduced or normalized contractile activity, as shown in Figure 7. This is summarized in Table 3 below.

[0149] Summary of the effects of electrical stimulation of instruction execution synchronization (SiSync) across the hormonal cycle

[0150] [Table 3]

[0151] (Clinical data) (Data Source) The following data were collected from volunteers who consented to the study. 1. Uterine signals: These are electrohysterogram (EHG) signals recorded via a CE marked "Biosignalplux solo" device for research purposes. These are numerical and time-ordered data. 2. Self-reported symptoms: This data is collected through a daily questionnaire completed by each volunteer. The questions touch on a variety of topics, such as pain, bleeding patterns, general health, medications, etc. This is primarily ordinal and categorical data. 3. Other patient data: This data will be collected through a pre-study questionnaire and will include information such as height, weight, age, nationality, etc. This is primarily numerical and categorical data.

[0152] (research recruitment) In the first study, data were collected from 39 volunteers. All volunteers were divided into four groups, defined as follows: Each group was further divided according to whether the volunteer was receiving hormonal intervention or not. 1. Healthy: Self-selected volunteers with regular menstrual cycles and no pain throughout the cycle. 2. Endometriosis (Endo): Volunteers who have been surgically diagnosed with endometriosis and experience pain throughout their cycle. 3. Others: Volunteers who have been medically diagnosed with endometriosis or who believe they have endometriosis and experience pain throughout their cycle. 4. Hysterectomy: Candidates who do not have a uterus.

[0153] Thirteen women were healthy and 22 women had endometriosis, as detailed in Table 4. Three women were classified as "Others" for various reasons listed in Table 5.

[0154] [Table 4]

[0155] All volunteers (n=39) by group and hormone intervention *Medications refer to hormonal interventions, including Mirena, progesterone pills, combined contraceptive pills, and GnRH agonists. Some women received more than one hormonal intervention.

[0156] [Table 5]

[0157] Applicants classified as "other" (n=3), and related reasons.

[0158] The volunteers with endometriosis were recruited with the support of the Endometriosis Society of Ireland and EndoAware, and were mostly Irish and British. The healthy volunteers were of various nationalities, reflecting the diversity of the research team, who asked family and friends to volunteer for the study. The groups were well matched for age (29-33 years) and well represented in terms of weight distribution.

[0159] [Table 6]

[0160] Healthy (n=13) and endometriosis (n=22) demographics: (a) nationality, (b) age, and (c) weight. The extension study recruited five more volunteers with endometriosis who had been diagnosed because of fertility issues (rather than chronic pelvic pain), one of whom was undergoing ovarian stimulation for IVF treatment.

[0161] (Data collection, preprocessing, and filtering) Data Collection: Uterine signals will be collected for research purposes via a CE-marked portable device, Biosignalplux solo. Volunteers will be asked to record signals on four key days of their menstrual cycle (days 1, 7, 14, and 21). Signals will be recorded for 30 minutes. Volunteers will be asked to lie quietly during each recording session and, if possible, to collect signals at the same time during each recording session. An example of the four signals recorded for a particular volunteer is shown in Figure 22.

[0162] Preprocessing: The signal is preprocessed in several steps before analysis. First, the signal is transformed using a "transfer function" that adjusts the signal to fall within the range ±0.25 millivolts. Next, the first and last 30 seconds of the signal are deleted. Finally, the signal is cut off at 20 minutes. Signals that are less than 20 minutes long are discarded.

[0163] Filtering: The Biosignalplux Solo device (and EMG sensor) collects signals between 0.01591 and 0.1591 Hz (-0.96 cpm to 9.5 cpm; cpm = contractions per minute). For all analyses performed in this report, the raw signals were filtered using a Butterworth low-pass filter with a cutoff frequency equal to 0.03 Hz. The rationale is that we are interested in the contractile activity of the non-pregnant uterus, which is best described by slow waves. This approach has been validated in pre-clinical studies.

[0164] Data Labeling: Regarding key days in the menstrual cycle, the first day of menstrual bleeding is considered day 1 of the cycle, when estrogen levels are low and bleeding is typically heavy. By day 7, bleeding usually stops, estrogen levels rise, and the dominant follicle containing the egg develops. Day 14 is the day the egg is released from the ovary and is called ovulation. Day 21 is when the egg combines with sperm as it travels through the fallopian tube, and after fertilization, the resulting embryo implants in the uterine wall. However, if pregnancy does not occur, estrogen levels drop again, preparing the uterine lining for shedding.

[0165] However, menstrual cycles vary widely among individuals and can be longer or shorter than the canonical 28-day cycle. Therefore, ovulation can occur earlier or later than day 14 of the cycle. For this reason, women who describe their cycles as irregular are asked to record signals during days 13, 14, and 15 of their cycle. These signals are compared, and the signal with the highest maximum power (MaxPower) is retained. Two example recordings (days 14 and 15) from a healthy volunteer are shown in Figure 23.

[0166] (signal feature analysis) The DWT mean (the mean value of the coefficients in the discrete wavelet transform calculated using the Haar wavelet) showed a statistically significant difference between healthy volunteers and women with endometriosis at day 14.

[0167] Plotting the average maximum power values ​​at four time points for healthy women and women with endometriosis reveals patterns in uterine motility across the hormonal or menstrual cycle. The signal for women with endometriosis increases around ovulation compared to healthy volunteers. Hormonal intervention reduces the signal for both healthy volunteers and women with endometriosis. This demonstrates the utility of this signal as a non-invasive digital marker for uterine motility.

[0168] It will be appreciated that many different filtering and mathematical techniques can be used to separate and identify measurements of one or more electrical contractility parameters to generate a subject data profile including the separated electrical contractility parameter measurements representative of the pelvic structures of interest. The systems and methods of the present invention take advantage of the fact that electrical contractility parameters are signals that include measurements of electrical signals at slow-wave contractile frequencies originating from smooth muscle or organs characterized by low-frequency components. The low-frequency components in the uterus and cecum can be characterized by a frequency range of 0.00 to 0.05 Hz. The system separates and identifies these low-frequency signals to create a subject profile that can be compared with other profiles to provide a diagnosis of the health of organs in the pelvic region. Furthermore, the generated profile can detect disease in a subject who was previously asymptomatic of that disease in a simple and non-invasive manner. The system can be further configured to provide an estimate or calculate a predictive value of whether an underlying disease is likely to develop based on the generated profile.

[0169] (For use by overweight people) One challenge in developing a non-invasive device to be placed in the abdomen is the ability to detect signals relevant to overweight individuals. For those volunteers (n=33) who reported their weight and height, BMI was calculated as outlined in Table 3. From a data analysis perspective, there was no correlation between the extracted features and BMI, confirming that digital biomarkers can be detected in all individuals, including those who were overweight. This was established for both DWT mean and maximum power.

[0170] [equivalents] The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in its practice are expected to occur to those skilled in the art in light of these descriptions. These modifications and variations are intended to be included within the scope of the claims appended hereto.

Claims

1. A system for determining the state of prostate disease in a male subject characterized by abnormal contractile activity of the prostate, comprising: a sensing module configured to measure electrical activity in the subject's prostate at multiple spaced time points over a 24-hour period, the sensing module being a wearable, non-invasive sensor; a signal processing module configured to receive electrical activity measurements from the sensing module and to isolate from each electrical activity measurement a signal containing a contractile frequency representative of the prostate; operatively connected to the signal processing module; receiving as input a plurality of said signals including contractile frequencies representative of said prostate; generating a data profile for the subject, the data profile including a plurality of the signals representing the contractile frequencies in the subject's prostate gland associated with the plurality of spaced time points over the 24 hour period; correlating the subject's data profile to the state of the prostate disease in the subject using a classification model generated from a database of reference data profiles, the reference data profiles including reference data profiles in reference subjects with and without the prostate disease and reference prostate disease, each reference data profile including a plurality of signals representing the contractile frequencies in the prostate of the reference subject mapped over a 24 hour period; outputting a calculated state of the prostate disease in the subject based on the correlation; and a processor module configured to: A system comprising:

2. 10. The system of claim 1, wherein the signal processing module is configured to isolate signals containing contractile frequencies between 0.06 and 0.11 Hz from each measurement of electrical activity.

3. 3. The system of claim 1 or 2, wherein the prostate disease is prostatitis, prostate cancer, or benign prostatic hyperplasia (BPH).

4. The system described in claim 1, characterized in that the separated signal is a signal derived from myogenic smooth muscle of the prostate that includes low frequency components.

5. The system according to any one of claims 1 to 4, wherein the processor module is configured to receive as an additional input a plurality of measured values ​​of at least one non-electrical parameter acquired at a plurality of points in time during the 24-hour period, and the generated data profile includes a plurality of IF signals and the measured values ​​of the non-electrical parameter.

6. 6. The system of claim 5, wherein the non-electrical parameters are selected from pain location, pain intensity, pain type, and bleeding occurrence.

7. A mobile communication device comprising downloadable software for the mobile communication device, the mobile communication device comprising: receiving a measurement of an electrical contractility parameter from the signal processing module; transmitting the electrical contractility parameter measurements to the processor module; receiving a pelvic disorder status from the processor module; displaying the received pelvic disease status; and 7. A system according to claim 1, which is adapted to:

8. The system according to claim 7, characterized in that the downloadable software is configured to enable the subject to input measurements of non-electrical hormonal cycle parameters and / or non-electrical non-hormonal cycle parameters using the user interface of the mobile communication device, and to transmit the input measurements to the processor module.

9. A system described in any one of claims 1 to 8, characterized in that the signal processing module is configured to amplify and digitize the signal.

10. A system described in any one of claims 1 to 9, characterized in that the signal processing module is configured to convert the signal into the frequency domain.

11. The system according to claim 10, wherein the signal processing module is configured to separate the signal including the contractile frequency representing the prostate from the received electrical activity measurement by dividing the frequency spectrum of the received electrical activity measurement into segments corresponding to the characteristic frequencies of each pelvic structure.

12. A system for treating or preventing prostate disease in a subject, comprising: A system for determining the state of prostate disease in a subject, as described in any one of claims 1 to 11, a wearable prostate stimulation module for applying stimulation therapy to the prostate to normalize contractility of the prostate; A system comprising:

13. The system according to claim 12, wherein the processor module is operably connected to the wearable prostate stimulation module and is configured to activate the wearable prostate stimulation module when the state of the prostate disease in the subject is determined to be a positive diagnosis of the prostate disease or a risk of developing the prostate disease.

14. The processor module is monitoring the subject's hormonal cycle using contractility parameter measurements received from the signal processing module and / or additional subject data acquired at multiple time points during the 24 hour period; temporarily activating the prostate stimulation module during a particular phase of the subject's hormonal cycle to normalize contractility of pelvic structures; 14. The system according to claim 12 or 13, characterized in that it is configured to perform the following.

15. A system as described in any one of claims 12 to 14, comprising a wearable device, the wearable device comprising the detection module, the wearable prostate stimulation module, and optionally, the signal processing module.

16. A mobile communication device, receiving operation instructions for a prostate stimulation module from the processor module; Activate the prostate stimulation module in accordance with the above instructions.

16. A system according to any one of claims 12 to 15, comprising downloadable software adapted to:

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