Diagnosis and treatment of pelvic disorders

Abstract

This invention describes a system for determining the state of a pelvic disorder in a subject, characterized by abnormal contractile activity of a target pelvic structure. The system includes a sensing module for measuring electrical activity of the subject's pelvis at multiple time points during the subject's hormonal cycle; a signal processing module configured to receive electrical activity measurements from the sensing module and separate electrocontraction parameter measurements representing the target pelvic structure from the electrical activity measurements; and a processor module operatively connected to the signal processing module. The processor is configured to receive the electrocontraction parameter measurements representing the target pelvic structure as input; generate a data profile of the subject containing the electrocontraction parameter measurements representing the target pelvic structure; compare the data profile with the database of reference data profiles containing reference data profiles of subjects with different pelvic disorder states; and output the state of the subject's pelvic disorder based on the comparison. In any embodiment, the signal processing module is configured to separate slow-wave electrocontraction parameter measurements representing the target pelvic structure from the electrical activity measurements. The present invention also describes systems and methods for treating pelvic disorders, including stimulating pelvic structures to normalize their contraction.

Description

Technical Field

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

[0002] Endocrine hormones (e.g., cortisol, thyroid hormones, sex steroids, GH) are regulated by complex interactions between the hypothalamus, anterior pituitary, and adrenal glands (hypothalamic-pituitary-adrenal axis). This central control mechanism is responsible for the circulation of sex steroid hormones, estrogen in women, and testosterone in men after puberty. Disruptions to this mechanism can be caused by environmental changes (stress, estrogen-like pollutants, endocrine disruptors in the diet), aging, or disease, directly affecting the central hypothalamic-pituitary-adrenal axis or altering the local hormonal environment in tissues. Hormonal imbalances can lead to conditions such as depression and inflammatory disorders. Tissues affected by damage, inflammation, and activity levels associated with sex steroid hormones (e.g., estrogen) may include the brain, endocrine glands, endocrine system, immune system, lungs, cardiovascular system, genitourinary system, or reproductive system.

[0003] Maintaining a suitable environment for pelvic function is a complex process involving local and central control mechanisms, as well as interactions between the endocrine and immune systems. While the role of estrogen in gonadal organs is well-known, many studies have highlighted the role of local estrogen production in regulating smooth muscle tone in pelvic visceral organs, regardless of its dependence on circulating estrogen. In women with conditions such as endometriosis and adenomyosis, menstrual blood estradiol concentrations are higher than in healthy women, while peripheral blood levels are similar (Takahashi et al., 1989). In men, conditions such as benign prostatic hyperplasia are associated with elevated serum and urinary estrogen levels (Sodani 2018). Therefore, autocrine and paracrine functions are the underlying basis for these pelvic conditions and are at least partially regulated by sex hormones. The interaction of cytokines and other components of the immune system with the endocrine system is also a contributing factor to many pelvic conditions in both men and women. Inflammation is a fundamental process by which the body's tissues respond to damage. Different hormone exposures in men and women may lead to different rates of damage. Furthermore, due to different hormonal environments, the risk level of damage to pelvic organs and structures changes at different life stages in men or women (Bowmin Coline et al., 2016).

[0004] Sex steroid exposure patterns differ between the sexes throughout the day and throughout life, and women also experience cyclical exposure during their reproductive years. After puberty, increases in male and female sex hormones activate the reproductive organs within the pelvic cavity. A woman's ovaries and uterus are exposed to a cyclical pattern of the primary sex hormone, estradiol, for a period after adulthood until levels drop sharply at reproductive aging or menopause. In contrast, a man's testes and prostate are exposed to relatively stable levels of the primary sex hormone, testosterone, for most of adulthood. However, as men age, the amount of active testosterone in their blood decreases, resulting in a higher proportion of estrogen.

[0005] These gonadal-derived hormones are released into the systemic circulation and target distal hormone-responsive visceral organs in the pelvic cavity. This estrogen dominance in older men increases smooth muscle tone in the prostate. In women, the cyclical patterns of the reproductive year have more complex effects on visceral organs, particularly the uterus. The amplitude, frequency, basal tone, and direction of uterine contractions (UC) are associated with different phases of the hormonal cycle.

[0006] However, damage to internal organs can lead to increased inflammation and contractions, resulting in pathological pelvic conditions. For example, abnormal uterine contractions are associated with endometriosis (Bulletti et al., 1997), (Kido et al., 2007), polycystic ovary syndrome (Sajadi et al., 2018), endometritis (Pinto et al., 2015), uterine leiomyomas (Kito et al., 2014), and ovarian cancer (Modzelewska et al., 2017), and may also be a cause of other common and important conditions such as infertility, implantation failure, dysmenorrhea, miscarriage, or premature birth (Aguilar et al., 2010).

[0007] In men, prostate smooth muscle contraction plays a role in the pathophysiology of pelvic disorders such as lower urinary tract symptoms (LUTS) (Hennenberg et al, 2018), benign prostatic hyperplasia (BPH) (Kugler et al, 2017), and prostatitis.

[0008] However, due to paracrine changes, such as alterations in hormones and the inflammatory environment, increased contraction of one organ (e.g., the uterus) can lead to changes in tone in other pelvic structures (this region of the body includes the uterus, ovaries, cervix, vagina, and clitoris, as well as the five pelvic bones, muscles, ligaments, nerves, blood vessels, bladder, urethra, colon, and rectum). In an embodiment of endometriosis, with increased uterine contractions, this manifests as an inflammatory disorder of the pelvic viscera, causing nociceptive stimulation of the sacral spinal cord, resulting in pelvic floor muscle dysfunction, accompanied by sacral hypersensitivity and sacral spinal cord elevation. The protective reflex is a visceral muscle reflex activated to increase pelvic floor tone during daily activities. In these patients, there is an afferent autonomic nerve bombardment that enhances and maintains the protective reflex, manifesting as hypertonia in the pelvic floor muscles. Other pain disorders, such as irritable bowel syndrome, inflammatory bowel disease, interstitial cystitis, fibromyalgia, and vulvar pain, have also been found to present with hypertonia in the pelvic muscles. Typically, chronic pelvic pain (CPP) is characterized by an overlay of these different conditions. Similarly, in men, prostatitis can affect other pelvic structures, such as bladder sensation and function.

[0009] Any contractile changes in pelvic organs or structures, whether directly caused by injury or indirectly by the interaction of another organ, can lead to a variety of pelvic conditions, including: endometriosis, adenomyosis, endometritis, chronic pelvic pain, benign prostatic hyperplasia, prostatitis, interstitial cystitis, inflammatory pelvic diseases, irritable bowel syndrome, inflammatory bowel disease, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent pelvic (ovarian, uterine, endometrial, prostate, testicular, bladder) cancer, polycystic ovary syndrome, follicular arrest, anovulation, dysmenorrhea, infertility, uterine leiomyomas, precocious puberty, endometritis, erectile dysfunction, incontinence (fecal incontinence, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence), pelvic floor muscle pain, pelvic floor dysfunction, interstitial cystitis (dysuria), dyspareunia (painful intercourse), dysdefecation (painful defecation), and orgasmic disorder (painful ejaculation).

[0010] WO2019 / 016759 describes a system for monitoring uterine activity in pregnant women, including monitoring uterine electrical activity, extracting uterine electrical activity characteristics, and analyzing the electrical activity characteristics to classify uterine activity into one of several labor disorders, including preterm labor contractions and labor contractions. Uterine contractions associated with pregnant women are generally measured in the frequency range of 0.3 Hz to 5 Hz.

[0011] The object of this invention is to overcome at least one of the above-mentioned problems. Summary of the Invention

[0012] The applicant discovered that contraction parameters of the pelvic structures of non-pregnant subjects mapped during a specific time period, such as a hormonal cycle (e.g., the menstrual cycle of a non-pregnant woman), differ between subjects with and without pelvic disorders. Therefore, these contraction parameters can be used to determine the status of a subject's pelvic disorder. The applicant also discovered that contraction parameters can be measured non-invasively using wearable sensors, allowing for measurement over extended time periods. In a specific aspect, the systems and methods of the present invention isolate slow-wave features of target pelvic organs and employ the slow-wave signal or features extracted from the slow waves as diagnostic variables for pelvic disorders. An example of the slow-wave signal used in one aspect of the systems and methods of the present invention is uterine myometrial activity with a frequency in the range of 0.00 Hz to 0.05 Hz. The applicant demonstrates herein that this slow-wave signal can be isolated, processed, and compared with a reference signal using an external wearable sensor to identify endocrine disorders, such as endometriosis and related conditions. In this regard, the applicant found 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 female subjects with endometriosis, the applicant found that applying electrical stimulation therapy, particularly during the follicular phase of the subject's hormonal cycle, could normalize uterine contractile activity.

[0013] Therefore, the applicant provides a system for determining the state of a subject's pelvic disorder, which employs a non-invasive sensor to measure contraction parameters of a target pelvic structure (e.g., the uterus in women or the prostate in men) at time points during a hormonal cycle (e.g., the menstrual system in non-pregnant women), and employs a connected processor configured to compile the measurements into a data profile and correlate the data profile with the state of the pelvic disorder using, for example, a computational classification model generated from a reference data profile. In one aspect, the system may further include: a pelvic structure stimulation model, which is non-invasive; and a processor configured to actuate the stimulation model upon detection of a pelvic disorder. The processor may also be configured to monitor the subject's hormonal cycle and actuate the stimulation module during specific phases of the hormonal cycle. In one embodiment, when the processor detects abnormal contraction parameter activity (… Figure 18 and Figure 19 In the closed-loop system illustrated, the processor is configured to actuate the stimulation module (typically via a controller) at a certain stage of the subject's hormone cycle.

[0014] In a first aspect, the present invention provides a system for determining a state of pelvic disorder characterized by abnormal contractile activity of a target pelvic structure in a subject, generally a non-pregnant subject, the system comprising:

[0015] A sensing module for measuring the electrical activity of the subject's pelvis at multiple time points during the subject's hormone cycle;

[0016] A signal processing module configured to receive electrical activity measurements from a sensing module and separate electrocontraction parameter measurements representing the target pelvic structure from the electrical activity measurements; and

[0017] A processor module, operatively connected to a signal processing module, is configured to:

[0018] Receives measurements of electroconstriction parameters representing the target pelvic structure as input;

[0019] Generate a subject's data profile containing measurements of electroconstriction parameters representing the target pelvic structure;

[0020] Compare the data configuration file with the database of the reference data configuration file; and

[0021] The output is based on the status of the subject's pelvic condition.

[0022] In any implementation, the signal processing module is configured to separate slow-wave electroconstriction parameter measurements representing the target pelvic structure from the electrical activity measurements.

[0023] In one implementation, the processor module is configured to receive multiple measurements of at least one non-electrical hormone cycle parameter received at multiple time points during the subject's hormone cycle as additional input, wherein the generated data profile includes measurements of electrical contractile parameters and non-electrical hormone cycle parameters representing the target pelvic structure.

[0024] In one embodiment, the signal processing module includes a filter with characteristic frequencies corresponding to the target pelvic structure. In another embodiment, the signal processing module includes a filter corresponding to a characteristic frequency range of slow-wave activity in the target pelvic structure. Slow-wave activity in the target pelvic organ refers to the activity of the internal smooth muscle layer, such as the subendometrial layer of the myometrium in the uterus or myogenic smooth muscle activity in the male prostate. Therefore, the filter can be configured to separate slow-wave contraction signals of the target pelvic organ. The filter can be configured to separate slow waves in the frequency range of 0.00 Hz to 0.05 Hz.

[0025] In any implementation, the electrocontraction parameter is a signal that includes or consists of the slow-wave contraction frequency.

[0026] In any implementation, at least one separate electrical activity measurement includes an electrical signal measurement of a signal originating from the internal smooth muscle layer of the pelvic organ, which contains or is composed of low-frequency content.

[0027] In any implementation, when the pelvic organ is the uterus, the electroconstriction parameters are signals derived from the subendometrial layer of the myometrium.

[0028] In any implementation, the processor is configured to analyze the generated profile and, based on the generated data profile, provide an estimate or calculation of a predictive value regarding the likelihood of a health condition (pelvic dysplasia) developing.

[0029] In any implementation, the signal processing module includes a filter, wherein the filter is configured to separate one or more electroconstriction parameter measurements corresponding to the characteristic frequency range of slow-wave activity of the target pelvic structure.

[0030] In one implementation, the signal processing module is configured to amplify and digitize the signal.

[0031] In one implementation, the signal processing module is configured to transform the signal into the frequency domain and typically separate the signal representing the target pelvic structure from the global signal (e.g., the pelvic EMG signal) by dividing the spectrum of the signal into frequency bands corresponding to the characteristic frequencies of each pelvic structure.

[0032] In one implementation, non-electrical hormone cycle parameters are selected from pain location, pain intensity, pain incidence, bleeding incidence, urination habits (nocturia, urgency, initiation of urination, or intermittent urination), occurrence of erectile dysfunction, abdominal distension, and changes in appetite due to ovarian cancer (loss of appetite, feeling full quickly). In one implementation, the processor is configured to record the relationship between non-electrical parameters and time and compare them with contraction parameters that change over time.

[0033] In one implementation scheme, pelvic dysplasia is defined as an endocrine disorder.

[0034] In one implementation, the subjects are female, and typically non-pregnant women. In another implementation, the female subjects are adult women or adolescent women who have started menstruating.

[0035] In any embodiment, the subject is a woman undergoing in vitro fertilization (IVF) treatment. In this case, the system and method of the present invention can be used to monitor the effects of ovarian stimulation and identify the optimal timing for embryo transfer and uterine receptivity. To determine the optimal ovarian stimulation protocol, the system and method of the present invention are used to monitor the uterine response to ovarian stimulation medication. Successful embryo implantation requires appropriate timing so that the embryo is in the uterus during the implantation window of 8–10 days post-ovulation and the uterus is optimally prepared to receive the embryo. Therefore, the system and method of the present invention can be used during IVF treatment to identify uteri receptive to embryo implantation. In any embodiment, the method and system can be configured to stimulate the uterus to prepare it for embryo transfer.

[0036] In one implementation, the subject is a woman (typically a non-pregnant woman), the target pelvic structure is the uterus or pelvic floor, and the pelvic condition is an endocrine disorder, such as endometriosis. The hormonal cycle is generally the menstrual cycle.

[0037] In any embodiment, the system and method of the present invention are used to detect irritable bowel syndrome in a subject. In one embodiment, the subject is a non-pregnant woman.

[0038] In any embodiment, the system and method of the present invention are used to detect the risk of miscarriage in pregnant women, typically early miscarriage. Early miscarriage is defined as miscarriage within 13 weeks of pregnancy. In any embodiment, the system and method include measuring uterine contractions before conception or during early pregnancy or both. In any embodiment, if the subject is pregnant, increased uterine activity (e.g., on or around day 14 of the menstrual cycle) is associated with a subsequent risk of miscarriage. The system and method of the present invention may include treating a subject identified as having a risk of early miscarriage by electrically stimulating the uterus to normalize uterine contractions, typically on or around day 14 of the subject's menstrual cycle. Figure 27 .

[0039] In any embodiment, the system and method of the present invention are used to detect women with fertility problems (e.g., infertility or low fertility). In any embodiment, the system and method include measuring uterine contractions during the subject's menstrual cycle. In any embodiment, decreased uterine motility on or around day 14 of the menstrual cycle is associated with fertility problems. Figure 28 .

[0040] In any implementation, the system and method of the present invention are used to induce ovulation in non-pregnant female subjects. Therefore, the present invention can be used to assist women in becoming pregnant or to prevent pregnancy.

[0041] In any embodiment, the system and method of the present invention are used to determine the optimal time to retrieve oocytes from a subject undergoing in vitro fertilization (IVF) treatment. In any embodiment, maximum uterine motility during the cycle is correlated with the final maturation of the oocytes and indicates the optimal time to retrieve oocytes during IVF treatment. Figure 29 .

[0042] In any embodiment, the system and method of the present invention are used to monitor treatment for endometriosis. In any embodiment, the system and method include measuring uterine contractions during the treatment period. In any embodiment, decreased uterine motility at one or more time points during the treatment period is associated with reduced endometriotic lesions and / or decreased treatment effectiveness. Figure 30 .

[0043] In any implementation, the subject is male.

[0044] In any embodiment, the subject is male, the target pelvic structure is the prostate, and the pelvic condition is an endocrine disorder selected from prostatitis, benign prostatic hyperplasia, and prostate cancer. In any embodiment, the at least one separate electrical activity measurement includes an electrical signal measurement of a signal originating from myogenic smooth muscle of the prostate, which contains or is composed of low-frequency content.

[0045] In any implementation, the processor module is configured to receive at least one non-electrical, non-hormonal cycle parameter as additional input, wherein the generated data profile includes measurements of electrical contractile parameters representing the target pelvic structure, measurements of non-electrical, non-hormonal cycle parameters, and optional measurements of non-electrical hormonal cycle parameters.

[0046] In any implementation, non-electrical, non-hormonal cycle parameters are selected from sex, age, reproductive status, hormonal cycle status, previous diagnosis or condition, family history, medical records, medical imaging, body mass index (BMI), and medications.

[0047] In one implementation, the electrical shrinkage parameters used for the data profile are extracted from the time-domain signal and selected from the frequency, amplitude, intensity, and base tension of the target structure shrinkage.

[0048] In one implementation, the processor is configured to convert the filtered electrical signal into a frequency domain signal using, for example, a Fast Fourier Transform. In one implementation, the electrical shrinkage parameter used for the data profile is selected from power spectral density, DWT average value, MaxPower, and peak frequency. MaxPower refers to the maximum power spectral density of the signal.

[0049] In one implementation, the electroshrinkage parameter is extracted based on independent component analysis.

[0050] In one implementation, the signal processing module is configured to amplify and digitize the electrical signal before extracting the parameter measurements.

[0051] In one implementation, the sensing module is a wearable, non-invasive sensor.

[0052] In one embodiment, the sensor or signal processing module includes a wireless communication module configured to optionally wirelessly transmit contraction parameter measurements to a processor via a communication device.

[0053] In one embodiment, the system includes downloadable software for a mobile communication device, the downloadable software being configured to enable the mobile communication device to:

[0054] Receive contraction parameter measurements from the signal processing module;

[0055] The measured values ​​of the contraction parameters are transmitted to the processor module;

[0056] Receive pelvic condition status from the processor module; and

[0057] Displays the received pelvic condition status.

[0058] In one implementation, the downloadable software is configured to allow subjects to input non-electrical hormone cycle parameter measurements and / or non-electrical non-hormonal cycle parameters using a user interface on a mobile communication device, and to transmit the input measurements to a processor module.

[0059] In one implementation, the status of pelvic disorder is selected from a positive diagnosis of pelvic disorder, a negative diagnosis of pelvic disorder, a diagnosis of the risk of developing or occurring pelvic disorder, and the subject's response to treatment for pelvic disorder.

[0060] In another aspect, the present invention provides a system for treating or preventing pelvic disorders in a subject, the system comprising:

[0061] A system for determining the pelvic symptom status of a subject according to the present invention; and

[0062] A pelvic structure stimulation module for applying stimulation therapy to the pelvic structure.

[0063] In one implementation, the pelvic structure stimulation module is non-invasive.

[0064] In one implementation, the pelvic structure stimulation module is wearable.

[0065] In one implementation, the processor is operatively connected to the wearable pelvic structure stimulation module and is configured to actuate the pelvic structure stimulation module when the subject's pelvic condition is determined to be a positive diagnosis of pelvic condition or a risk of developing pelvic condition.

[0066] In one implementation, the processor is configured to actuate the pelvic structure stimulation module to normalize the contraction of the pelvic organs.

[0067] In one implementation, the processor is configured as follows:

[0068] The subject's hormone cycle is monitored using contraction parameter measurements received from the signal processing module and / or additional subject data obtained at multiple time points during the subject's hormone cycle; and

[0069] The pelvic structure stimulation module is transiently actuated during a specific phase of the subject's hormone cycle to normalize, for example, the contraction of pelvic organs.

[0070] In one implementation, the additional subject data is selected from one or more subject data parameters, which are selected from temperature, date of last menstrual period, and cervical secretion status.

[0071] In one implementation, when the processor detects abnormal contraction parameter activity ( Figure 18 and Figure 19 In the closed-loop system illustrated, the processor is configured to actuate the stimulation module (typically via a controller) at a certain stage of the subject's hormone cycle.

[0072] In one implementation, the processor is configured to measure the contraction parameters of the target pelvic structure after stimulation, and to re-actuate the pelvic structure stimulation module if the contraction parameters of the pelvic structure are determined to be abnormal. The processor may be configured to repeat these steps until the contraction parameters sensed by the sensing module are determined to be normal.

[0073] In one implementation, the sensing module includes a subject temperature sensor operatively connected to the processor.

[0074] In one implementation, the pelvic structure stimulation module is an electrical stimulation module.

[0075] In one embodiment, the system includes a wearable device that includes a sensing module and a wearable pelvic structure stimulation module.

[0076] In one embodiment, the wearable device includes a signal processing module.

[0077] In one implementation, the downloadable software is configured to enable the mobile communication device to:

[0078] Receive actuation instructions for the pelvic structure stimulation module from the processor module; and

[0079] The pelvic structure stimulation module is activated according to the instructions.

[0080] In one implementation, the downloadable software is configured to enable a mobile communication device to display information related to the actuation of the wearable pelvic structure stimulation module.

[0081] In one implementation, the pelvic condition is endometriosis, in which the target pelvic structure is the subject's uterus or an adjacent pelvic structure.

[0082] In one implementation, the pelvic condition is endometriosis, in which the target pelvic structure is the subject's uterus or an adjacent pelvic structure, and wherein the processor is configured to actuate the pelvic structure stimulation module during the follicular phase of the subject's hormonal cycle.

[0083] In one implementation, the system includes a controller configured to control the output parameters of the pelvic structure stimulation module.

[0084] In one embodiment, the controller is configured to cause the stimulation module to emit electrical pulses ranging from 0.1 mA to 20 mA.

[0085] In one implementation, the controller is configured to cause the stimulation module to emit electrical pulses with a pulse width of 500 μs to 20 ms.

[0086] In one embodiment, the controller is configured to cause the stimulation module to emit electrical pulses at a frequency of 0.1 Hz to 50 Hz.

[0087] In one implementation, the controller is configured to actuate the stimulation module during a treatment period of 30-60 minutes.

[0088] In one implementation, the controller is configured to actuate the stimulation module to emit a constant current square wave pulse.

[0089] In one implementation, the controller is configured to actuate the stimulation module to emit a constant current square wave pulse of about 1-2 mA, about 2 milliseconds / pulse, and an alternating frequency of about 2 / 15 Hz.

[0090] In another aspect, the present invention provides a computer-implemented method including a processor module operatively connected to a signal processing module, the method comprising the following steps:

[0091] Receives measurements of electroconstriction parameters representing the target pelvic structure as input;

[0092] Generate a subject's data profile containing measurements of electroconstriction parameters representing the target pelvic structure;

[0093] The data profiles were compared with a database of reference data profiles containing reference data profiles for subjects with different pelvic condition states; and

[0094] The output is based on the status of the subject's pelvic condition.

[0095] In another aspect, the present invention provides a method for determining the pelvic disease status of a subject, the method comprising the following steps:

[0096] Contraction parameters of the target pelvic structure were measured at multiple time points during the hormone cycle;

[0097] Prepare a data configuration file containing the measured values ​​of this contraction parameter;

[0098] Compare the data configuration file with one or more reference data configuration files; and

[0099] The condition of pelvic diseases is determined based on comparison.

[0100] In any implementation, the contraction parameter is the slow-wave electrical contraction parameter.

[0101] In one embodiment, the method includes measuring at least one non-electrical hormone cycle parameter at multiple time points during the subject's hormone cycle, wherein the data profile includes measurements of electrical contractile parameters representing the target pelvic structure and measurements of the non-electrical hormone cycle parameter.

[0102] In one implementation scheme, pelvic dysplasia is defined as an endocrine disorder.

[0103] In any implementation, the slow-wave electrical contraction parameter is the frequency, typically in the range of 0.00 Hz to 0.05 Hz.

[0104] In one implementation, the target pelvic structures are selected from the uterus, pelvic floor, and prostate.

[0105] In one implementation, the subject is female and the target pelvic structure is the uterus or pelvic floor, and the pelvic condition is an endocrine disorder, such as endometriosis.

[0106] In one implementation, the subject is male, the target pelvic structure is the prostate, and the pelvic condition is a prostate condition selected from prostatitis, benign prostatic hyperplasia, and prostate cancer.

[0107] In one embodiment, the method includes the step of determining at least one non-electro-hormonal cycle parameter, wherein the data profile includes measurements of electro-contraction parameters representing the target pelvic structure, measurements of non-electro-hormonal cycle parameters, and optional measurements of non-electro-hormonal cycle parameters.

[0108] In one implementation, non-electrical, non-hormonal cycle parameters are selected from sex, age, reproductive status, hormonal cycle status, previous diagnosis or condition, family history, medical records, medical imaging, BMI, and medications.

[0109] In one implementation, the electroshrinkage parameters are selected from the frequency, amplitude, and base tension of the target structure shrinkage.

[0110] In one implementation, the electroconstriction parameter is measured using a sensing module, which is a wearable, non-invasive sensor.

[0111] In another aspect, the present invention provides a method for treating pelvic disorders in a subject, the method comprising the step of stimulating a target pelvic structure with a stimulation module.

[0112] In one implementation, the stimulation device is an electrical stimulation device.

[0113] In one embodiment, the method includes stimulating a target pelvic structure with electrical pulses ranging from 0.1 mA to 20 mA.

[0114] In one implementation, the method includes stimulating a target pelvic structure with electrical pulses of 500 μs to 20 ms in width.

[0115] In one embodiment, the method includes stimulating a target pelvic organ with electrical pulses of a frequency of 0.1 Hz to 50 Hz.

[0116] In one implementation, the method includes stimulating the target pelvic organ over a treatment period of 30-60 minutes.

[0117] In one implementation, the method includes constant current square wave pulse stimulation.

[0118] In one implementation, the method includes stimulating a target pelvic structure with a constant current square wave pulse of about 1-2 mA, about 2 milliseconds / pulse, and an alternating frequency of about 2 / 15 Hz.

[0119] In one implementation, the target pelvic structure is stimulated using a non-invasive stimulation module.

[0120] In one implementation, stimulation occurs at a specific phase of the hormone cycle.

[0121] In one implementation, stimulation is performed during the follicular phase of the hormone cycle.

[0122] In one implementation, the contraction parameters of the target pelvic structure are determined after stimulation, and if the contraction parameters of the target pelvic structure remain abnormal, further stimulation treatment is performed. These steps can be repeated until the contraction parameters of the target pelvic structure are determined to be normalized.

[0123] In one implementation, the subjects are women of childbearing age with an endocrine disorder (such as endometriosis).

[0124] In one implementation, the subjects are men suffering from prostate conditions such as prostatitis, prostate cancer, or benign prostatic hyperplasia.

[0125] In one implementation, stimulation of the target pelvic structure is configured to normalize abnormal pelvic structure contraction activity.

[0126] In another aspect, the present invention provides a method for treating endometriosis in a subject, the method comprising the step of applying electrical stimulation therapy to the subject's uterus during the follicular phase of the subject's hormone cycle, rather than the ovulation phase.

[0127] In another aspect, the present invention provides a wearable device comprising:

[0128] A sensing module for measuring the electrical activity of the subject's pelvis at multiple time points during the subject's hormone cycle;

[0129] A signal processing module is configured to receive electrical activity measurements from a sensing module and separate electrical contraction parameter measurements representing the target pelvic structure from the electrical activity measurements.

[0130] A pelvic structure stimulation module for applying stimulation therapy to the pelvic structure; and

[0131] Optionally, the controller is configured to actuate the output parameters of the pelvic structure stimulation module in a mode configured to normalize the electrocontraction parameters of the target pelvic structure.

[0132] In any implementation, the signal processing module is configured to separate the slow-wave electrical contraction parameter from the electrical activity measurement.

[0133] The system may be an electromedical system. The system may include a real-time operating system. The system may include an embedded platform for automation. The system may include firmware software components. The system may also include application-specific integrated circuits (ASICs), programmable logic devices (PLDs) that may include digital circuitry, digital signal processors, microcontrollers or microprocessors, memory components, and controller circuitry.

[0134] The system may include an analog interface (digital-to-analog, analog-to-digital). The system may include voltage or current regulators and power management circuitry. The system may also include a timing source.

[0135] Other aspects and preferred embodiments of the invention are defined and described in the other claims listed below. Attached Figure Description

[0136] Figure 1 Uterine contractions were shown in rats with endometriosis (n=8) and rats without endometriosis (n=8) at all stages of the rat hormonal cycle. Uterine contractions were measured using an electrical sensor and represented as electromyography (EHG) of the uterus converted to the frequency domain using a fast Fourier transform (FFT).

[0137] Figure 2 Uterine contractions during the interestrus phase of the rat hormonal cycle are shown in rats with endometriosis (n=3) and rats without endometriosis (n=5). Uterine contractions were measured using an electromyography (EMG) sensor and converted to the frequency domain using a fast Fourier transform (FFT).

[0138] Figure 3 Uterine contractions during the preestrus phase of the rat hormonal cycle are shown in rats with endometriosis (n=3) and rats without endometriosis (n=1). Uterine contractions were measured using an electromyography (EMG) sensor and converted to the frequency domain using a Fast Fourier Transform (FFT).

[0139] Figure 4 Uterine contractions during the estrus phase of the rat hormonal cycle are shown in rats with endometriosis (n=2) and rats without endometriosis (n=2). Uterine contractions were measured using an electromyography (EMG) sensor and represented as electromyography (EHG) of the uterus converted to the frequency domain using a fast Fourier transform (FFT).

[0140] Figure 5 This study demonstrates that uterine contractions in rats can be reduced by using non-invasive electrical stimulation electrodes. Uterine contractions were measured using electrical sensors and represented as electromyography (EHG) of the uterus converted to the frequency domain using Fast Fourier Transform (FFT).

[0141] Figure 6This study demonstrates the effect of electrical stimulation on uterine contractions in control rats (without endometriosis) during the estrus, preestrus, and diaestrus phases of the rat hormonal cycle. Uterine contractions were recorded for 20 minutes, followed by 20 minutes of electrical stimulation, and then another 20 minutes of recording. The graphs show that in rats without endometriosis, electrical stimulation increased the amplitude of contractions during the estrus and preestrus phases of the hormonal cycle, while decreasing the amplitude of contractions during the diaestrus phase.

[0142] Figure 7 This study demonstrates the effect of electrical stimulation on uterine contractions in rats with endometriosis during the estrus and preestrus phases of the hormonal cycle. Uterine contractions were recorded for 20 minutes, followed by 20 minutes of electrical stimulation, and then another 20 minutes of recording. The graphs show that in rats with endometriosis, electrical stimulation reduced the amplitude of contractions during the estrus and preestrus phases of the hormonal cycle, but did not show the same effect during the estrus phase.

[0143] Figure 8 This is a flowchart illustrating a method for diagnosing pelvic disorders according to the present invention.

[0144] Figure 9 An example of a subject's data profile generated by mapping two contraction parameters (contraction frequency, base tension) and three non-electrical hormone cycle parameters (fatigue, pain intensity, bleeding) over a subject's 28-day hormone cycle is shown.

[0145] Figure 10 Another example of a subject's data profile is shown, generated by mapping two contraction parameters (contraction frequency and base tension) and one non-electric hormone cycle parameter (pain intensity) over the subject's 24-hour hormone cycle.

[0146] Figure 11 A system for diagnosing pelvic disorders according to one embodiment of the invention is shown, illustrating the data flow from sensors placed on the surface of the pelvis to a mobile application on the user's phone, and then to a remote server and the clinician's personal device.

[0147] Figure 12 It is a diagram of summary data accessed from a remote server and presented to patients and clinicians on their respective personal computing devices.

[0148] Figure 13 It is a flowchart illustrating a method for treating or preventing pelvic disorders according to the present invention.

[0149] Figure 14A system for treating or preventing pelvic disorders according to one embodiment of the invention is shown, illustrating a flow of sensed data from a sensor placed on the surface of the pelvis to a mobile application on a user's phone, and then to a remote server including a processor. The processor determines the state of the subject's pelvic disorder, calculates a specific phase of the hormonal cycle for which stimulation is applied, monitors the progress of the subject's hormonal cycle, and actuates an electrical stimulation device to apply electrical stimulation during the calculation phase.

[0150] Figure 15 The treatment options for female subjects diagnosed with endometriosis were presented.

[0151] Figure 16 The top section shows the contraction parameters extracted from electrical activity, which was converted from the time domain to the frequency domain (power spectral density and peak frequency) using a signal processing module. The bottom section shows the non-electrical hormone cycle parameters (pain) that form part of the subject's data profile.

[0152] Figure 17 The top shows the placement of the non-invasive skin sensor electrode relative to the target organ in a female subject. The bottom shows the placement of the non-invasive skin sensor electrode relative to the target organ in a male subject. The electrodes can be placed anteriorly or posteriorly.

[0153] Figure 18 A closed-loop sensing and stimulation system based on the hormone cycle was demonstrated.

[0154] Figure 19 The comparative functionality of the system and process of this invention is demonstrated. Software embedded in the controller receives electroconstriction parameters from sensors and compares them with a template of healthy individuals relative to that hormonal cycle phase (i.e., menstrual cycle day). The algorithm assesses whether the subject's readings are within the normal range at that time point. Based on this, the controller sends instructions to the electrostimulator to stimulate or de-stimulate the target pelvic structure on that day.

[0155] Figure 20 A wearable sensing and stimulation module that forms part of the system of the present invention is shown. The module is configured for skin application in the pelvic region and includes electrodes and a central housing that integrates a battery, a PCB including a microcontroller, a current control module and a Bluetooth antenna, and an SD card.

[0156] Figure 21 —All recorded signals from volunteers with endometriosis (days 1, 7, 14, and 21).

[0157] Figure 22 —All recorded signals from volunteers with endometriosis (days 1, 7, 14, and 21). This is consistent with... Figure 21The volunteers were the same.

[0158] Figure 23 —Recorded signals (top) and their power spectra (bottom) of healthy volunteers on days 14 and 15.

[0159] Figure 24 —Box plots and statistical summaries of the mean DWT on day 14 for healthy, medication-free volunteers (n=11) and medication-free volunteers with endometriosis (n=15).

[0160] Figure 25 —The mean “MaxPower” and signal modulation with hormone intervention in volunteers with endometriosis but no medication (n=15), healthy but no medication (n=11), with endometriosis and medication (n=7), and healthy but medication (n=2) on days 1, 7, 14, and 21.

[0161] Figure 26: Usage characteristics (a) spectral reduction and mean frequency and (b) scatter plots of DWTStd and autocorrelation for volunteers (n=39) with (red) and without (blue) IBS.

[0162] Figure 27 —Compare the MaxPower of volunteers on day 14. The groups included those with pregnancy and miscarriage (n=1), those with endometriosis but not using medication (n=15), healthy and not using medication (n=11), those with endometriosis and using medication (n=7), and healthy but using medication (n=2). When we observed the MaxPower of the pregnant + miscarried volunteer on day 14, it was elevated relative to all other volunteers—her uterine activity was much greater, which could hinder implantation.

[0163] Figure 28 —MaxPower of volunteers at different time points. Women diagnosed with endometriosis surgically due to pain (n=11), healthy volunteers (n=15), and women diagnosed with endometriosis surgically due to fertility problems (n=4). Patients with fertility problems showed significantly reduced uterine motility on day 14.

[0164] Figure 29 —MaxPower at different time points for volunteers with fertility problems but not undergoing IVF (n=4), healthy volunteers not using medication (n=11), and volunteers with fertility problems undergoing IVF (n=1). The ovarian stimulation protocol in volunteers undergoing IVF enhanced ovulation compared to those with fertility problems but not receiving fertility treatment.

[0165] Figure 30—MaxPower volunteers at different time points. Those with endometriosis but not using medication (n=15), healthy and not using medication (n=11), and those who had undergone hysterectomy (n=1). The ability to detect signals generated by endometriotic lesions means that this technology will be able to monitor the effectiveness of treatments (surgery and medication) in lesion removal / regression.

[0166] Figure 31 —A block diagram of a method for diagnosing endometriosis according to the present invention. Detailed Implementation

[0167] All published documents, patents, patent applications and other references mentioned herein are incorporated herein by reference in their entirety for all purposes, just as each individual published document, patent or patent application is specifically and individually identified and incorporated by reference, and their contents are fully described.

[0168] Definition and general preference

[0169] As used herein, and unless otherwise specified, the following terms shall have the following meanings, in addition to having any broader (or narrower) meaning that may be enjoyed in the art:

[0170] Unless the context otherwise requires, the singular as used herein shall be understood to include the plural, and vice versa. The terms “a” or “an” as used with respect to entities shall be understood to refer to one or more of those entities. Therefore, the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably herein.

[0171] As used herein, the term “comprise” or variations thereof (e.g., “comprises” or “comprising”) should be understood to indicate inclusion of any of the listed wholes (e.g., features, elements, characteristics, properties, methods / process steps, or limitations) or groups of wholes (e.g., features, elements, characteristics, properties, methods / process steps, or limitations), but does not exclude any other wholes or groups of wholes. Therefore, the term “comprising” as used herein is inclusive or open-ended and does not exclude additional, unlisted wholes or methods / process steps.

[0172] As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is broadly used to encompass any disorder, ailment, abnormality, pathology, condition, symptom, or syndrome in which physiological function is impaired, regardless of the nature of the cause (or whether an etiological basis for the disease has actually been established). Therefore, it covers conditions caused by infection, trauma, injury, surgery, radiation ablation, age, poisoning, or nutritional deficiencies.

[0173] As used herein, the term "treatment" (or "treating") (e.g., administering a drug to a subject) refers to an intervention that cures, improves, or alleviates the symptoms of a disease or removes (reduces the influence of its cause) its cause (e.g., reduces the accumulation of pathological levels of lysosomal enzymes). In this context, the term is used synonymously with the term "therapy."

[0174] Additionally, the term "treatment" (e.g., administering a drug to a subject) refers to an intervention that prevents or delays the onset or progression of a disease, or reduces (or eradicates) its incidence in the treated population. In this context, the term "treatment" is used synonymously with the term "prophylaxis."

[0175] As used herein, an effective or therapeutically effective dose of a drug is defined as an amount that can be administered to a subject without excessive toxicity, irritation, allergic reactions, or other problems or complications, a dose that is commensurate with a reasonable benefit / risk ratio but sufficient to provide the desired effect, such as treatment or prevention manifested as permanent or temporary improvement in the subject's condition. This dose will vary from subject to subject depending on individual age and general condition, administration pattern, and other factors. Therefore, while it is not possible to specify an exact effective dose, those skilled in the art will be able to determine an appropriate "effective" dose in any individual case using routine experimentation and background common sense. Treatment outcomes in this context include the eradication or reduction of symptoms, reduction of pain or discomfort, prolonged survival, improved mobility, and other markers of clinical improvement. Treatment outcomes are not necessarily a complete cure. Improvements may be observed in terms of biological / molecular markers, clinical, or observational improvements. In a preferred embodiment, the method of the present invention is applicable to humans, large racing animals (horses, camels, dogs), and domestic companion animals (cats and dogs).

[0176] In the context of the treatment and effective dosage defined above, the term "subject" (which, where the context permits, should be understood to include "individual," "animal," "patient," or "mammal") defines any subject to whom treatment is necessary, particularly a mammalian subject. Mammal subjects include, but are not limited to, humans, livestock, farm animals, zoo animals, sporting animals, pets such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, camels, bison, cattle, and dairy cows; primates such as apes, monkeys, orangutans, and chimpanzees; canines such as dogs and wolves; felines such as cats, lions, and tigers; equines such as horses, donkeys, and zebras; food animals such as cattle, 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 equine mammals, including horses, donkeys, Tibetan wild asses, and zebras.

[0177] The term "pelvic structure" is intended to include structures with muscular components within the pelvic cavity, including the pelvic floor, bladder, rectum and descending colon, cecum, 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 the pelvic organs.

[0178] "Pelvic disorders" refer to endocrine disorders and reproductive conditions associated with contractile changes in one or more pelvic structures. "Reproductive disorders" can be pathological or non-pathological reproductive conditions or events, including infertility, implantation failure (during natural or assisted reproduction), miscarriage, or premature birth. The methods and systems of this invention can be used or configured to treat or prevent infertility, and to prevent or reduce the risk of undesirable reproductive events, such as implantation failure, miscarriage, or premature birth in women.

[0179] "Endocrine disorders" or "endocrine ailments" refer to diseases related to the body's endocrine glands, which often lead to hormonal imbalances. Examples originating from glands in the pelvic cavity include endometriosis, adenomyosis, endometritis, chronic pelvic pain, benign prostatic hyperplasia, prostatitis, interstitial cystitis, inflammatory pelvic diseases, irritable bowel syndrome, inflammatory bowel disease, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent pelvic (ovarian, uterine, endometrial, prostate, testicular, bladder) cancer, polycystic ovary syndrome, follicular arrest, anovulation, dysmenorrhea, infertility, uterine leiomyomas, precocious puberty, endometritis, erectile dysfunction, incontinence (fecal incontinence, stress urinary incontinence, urge incontinence, and mixed urinary incontinence), pelvic floor muscle pain, pelvic floor dysfunction, dysuria (painful urination), dyspareunia (painful intercourse), dysdecoction (painful defecation), and orgasmic disorder (painful ejaculation).

[0180] When applied to the pelvic structure, "contraction parameters" are intended to refer to the activity, tension, occurrence, frequency, amplitude, intensity, direction, power, power density, pattern, duration, periodicity, dominant frequency, peak-to-peak value, or area of ​​the pelvic structure under a contraction curve. Preferably, the contraction parameters are selected from frequency, amplitude, and basal tension.

[0181] "Slow-wave contractions." In any respect, contraction parameters can be slow-wave contraction parameters, such as slow-wave contraction frequency. Slow-wave contractions are typically induced by the internal smooth muscle layer of a target organ, such as the SM layer of the endometrium in the uterus or the myogenic SM layer in the prostate. Slow-wave contractions of the uterus and cecum are typically measured in the range of 0.00–0.05 Hz.

[0182] When applied to subjects with pelvic disorders, "status" should be understood to mean a positive or negative diagnosis of the pelvic disorder, the risk of developing or occurring 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 the diagnosis of endometriosis, IBD, risk of miscarriage or infertility in women (typically non-pregnant women), and the diagnosis of prostate endocrine disorders (e.g., prostate cancer or BPH) in men.

[0183] A "sensing module" refers to a sensor capable of detecting contraction parameters of a target pelvic structure. Sensing modules are generally external sensors. They can take the form of a patch configured for skin attachment to a subject. They can be wearable. They can be configured for subcutaneous application. They can be electrical sensors configured to detect electrical activity in the pelvic region. They can be configured to wirelessly transmit sensing data, such as to a mobile device or computer. They may include one or more spaced-apart sensing electrodes. They can be placed on the subject's abdomen near the target structure. Suitable examples of electrical sensing modules include the Biosignalsplux Solo kit and the Biosignalspleux uterine electromyography (EGG) sensor, both manufactured by Wireless Signals, Inc.

[0184] "Multiple time points during the subject's hormone cycle" means at least two time points, and typically at least 5, 10, 15, 20, or 25 time points. Time points are generally spaced apart during the hormone cycle. Typically, at least one time point occurs in each phase of the hormone cycle, for example, at least 2, 3, 4, 5, or 6 time points in each phase of the hormone cycle. Measurements taken at multiple time points map to variables measured during the cycle. Variables can be contraction parameters (frequency or intensity) or non-contraction hormone cycle parameters (bleeding, pain, or fatigue). Data collected at each time point can be processed into a representative data summary. In extended recording periods, such as daily, time points can be equally spaced. After recording is complete, the signal throughout the hormone cycle can be represented by mapping the summary data generated (electrical input and user input) at each time point to create a data profile for the subject. In non-pregnant women, time points can be day 1, day 7, day 14, and day 21 of their menstrual cycle (±1 or 2 days). For women with irregular hormone cycles, measurements can be taken on days 13, 14, and 15, compared, and one of the measurements (e.g., the highest MaxPower measurement) can be used. Measurements of electrical activity (e.g., signals) are generally recorded for at least 10, 15, 20, or 25 minutes.

[0185] When applied to female subjects, the "subject's hormonal cycle" refers to the cyclical changes in a woman's body during her reproductive years caused by the complex interactions of the following hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the female sex hormones estrogen and progesterone. The phases of the female hormonal cycle are the follicular phase, ovulation phase, and luteal phase. In animals with estrous cycles, the preestrus phase corresponds to the follicular phase, the estrus phase to the ovulation phase, and the estrus phase to the luteal phase. When applied to male mammals, the term refers to the cyclical hormonal changes over a period of time (e.g., 24 hours), as well as the changes that occur with increasing male age (i.e., male menopause). In one embodiment, the invention includes stimulating a target pelvic structure during a specific phase of the subject's hormonal cycle to normalize pelvic structure contractions. In women of reproductive age with endocrine disorders (e.g., endometriosis), stimulation is typically performed during the follicular phase.

[0186] A “signal processing module” refers to a means configured to receive and process electrical activity signals from a sensing module. The signal can be processed to amplify and / or digitize it. Digitization of the signal can be performed by an analog-to-digital converter. The signal can be processed to extract signals representing target pelvic structures (e.g., electrocontraction parameters). In some embodiments, this is achieved by applying a digital filter corresponding to the dominant or characteristic frequency of the structure. Alternatively, the digitized signal can be transformed into the frequency domain, and the contractile structures can be separated from the global pelvic EMG signal (e.g., by dividing the spectrum into bands 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 frequencies 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 signal is processed to separate slow-wave electrocontraction characteristics of the target organs. In many target pelvic organs, slow-wave activity occurs at frequencies ranging from 0.00 to 0.05 Hz, typically 0.01 to 0.03 Hz or 0.01 to 0.02 Hz. Slow-wave signals characterize 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 separated signals to compensate for artifacts from body position and other parts of the body (heart, GI tract, respiration, skeletal muscle) and to further extract target parameters (e.g., frequency, basement tension, amplitude). These methods may include linear modeling, digital filtering, spectral analysis, and statistical analysis. Signal quality can be further improved by recording the signal over an extended period (e.g., 30 minutes) at each time point and averaging the signal to reduce the signal-to-noise ratio.

[0187] A "data profile" refers to multiple measurements of one or more contraction parameters mapped over a defined time period (e.g., the duration of a hormonal cycle, such as the menstrual cycle of a non-pregnant woman). A data profile may include one or more non-electrical hormonal cycle parameters mapped within the same time period; examples include hormonal cycle parameters such as bleeding, fatigue, pain intensity, and pain occurrence. Typically, in a data profile containing more than one variable, different variables will be mapped at the same time points. Examples of data profiles are provided in... Figure 9 and Figure 10 Typically, the data profile includes at least one contraction parameter (e.g., 1, 2, or 3) and optionally at least one non-electro-hormone cycle parameter (e.g., at least 1, 2, 3, 4, or 5). In one embodiment, the contraction parameter is converted from the time domain to the frequency domain.

[0188] A “reference data profile” refers to a data profile of a subject with a known pelvic disease condition. For example, when a system or method is used to detect endometriosis in a subject, the reference data profile can be a positive or negative data profile from the subject’s condition. Typically, the subject’s data profile is associated with the pelvic disease condition by employing a classification model generated using reference data profiles from a population of subjects with a known pelvic disease condition (e.g., positive disease, negative disease, risk of developing disease, and disease severity). Typically, when a subject’s data profile includes more than one variable mapped over time, the reference data profile compared to the subject’s data profile will all include the same variable mapped over time. Comparisons between the subject’s data profile and one or more reference data profiles typically employ a computational model, which can be a multilinear computational model. Various methods can be used to match a subject’s data profile with one of the reference data profiles, including mathematical modeling or pattern recognition. In one implementation, the comparison step can be performed using a subset of the chemical growth response through mathematical modeling using linear discriminant analysis and Euclidean nearest neighbor distance minimization. Other methods for matching or associating query data profiles with one or more reference data profiles involve simple Euclidean matching or hierarchical clustering analysis. In one implementation, the reference data profile is obtained from the same subject previously, such as before treatment. This allows the subject or physician to monitor pelvic symptoms over time to determine changes in the subject's pelvic symptoms (e.g., before or after treatment). In applications determining fertility and related to IVF, 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 a subject's pelvic symptoms relative to a population, such as a group defined by age, geography, habits (e.g., alcohol use, smoking), race, sex, number of pregnancies, or any combination thereof (e.g., women aged 20-30 years) or any other group.

[0189] "Non-electrical hormone cycle parameters" refer to non-electrical parameters related to the hormone cycle in subjects. Examples include pain intensity, location, type, bleeding, urination patterns, defecation patterns, mood, bloating, fatigue, weakness, or impact on daily life. Pain may include pelvic pain, back pain, upper abdominal pain, vaginal pain, labial pain, perineal pain, breast pain, pain during intercourse, pain after intercourse, pain during ejaculation, pain during urination or defecation, chills, fever, or weakness. Bleeding patterns include menstrual bleeding, spotting, blood in semen, or hematuria. Urination patterns include increased or decreased frequency or flow of urination or the feeling of needing to urinate. Bowel patterns include constipation, diarrhea, increased or decreased frequency. Impact on daily life includes days of absence from work, school, exercise, or household chores. Measurements of these parameters can be entered by the subject, for example, using a mobile phone or computer user interface.

[0190] "Non-electrical, non-hormonal cycle parameters": Data profiles may also include non-electrical, non-hormonal cycle parameters. These parameters are phenotypic parameters of the subject, such as age, sex, reproductive status, hormonal cycle status, previous diagnoses or conditions, family history, medical records, medical imaging, BMI, symptoms, and medications. Using one or more of these variables in the data profile can be used to understand a reference data profile used to determine the subject's pelvic condition status. For example, if the subject is female and 35 years old, a specific classification model can be used to determine and provide the output of the pelvic condition status.

[0191] A “pelvic structure stimulation module” is a device configured to stimulate a target pelvic structure to modulate at least one contraction parameter of the pelvic structure. In the embodiments described herein, an electrical stimulation device is employed. This device can be configured to emit electrical pulses of 0.1 to 20 mA. The device can be configured to emit electrical pulses with 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 30-60 minutes at a time. The device may include one or more electrodes or an electrode array. The module can be configured for skin application and to stimulate the pelvic structure from the surface of the subject's body. The stimulation module can be configured to wirelessly receive signals from a remote location, such as a mobile communication device or a computer. These signals may be instructions relating to the type and intensity of electrical stimulation and the timing of the electrical stimulation. Stimulation of the target pelvic structure can also 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 contraction of the pelvic structure (e.g., modulate the contraction parameters to resemble corresponding contraction parameters from disease-negative individuals). Typically, this involves stimuli configured to normalize or reduce the frequency, amplitude, intensity, or base tension of contractions.

[0192] "Monitoring the Hormonal Cycle of a Subject": In one embodiment, the system and method of the present invention relate to monitoring the hormonal cycle of a subject. This allows for treatment of the subject during one or more specific phases of the hormonal cycle. Monitoring includes measuring at least one contraction parameter, or another variable related to the hormonal cycle, such as temperature, date of last menstrual period, or cervical discharge status, during the hormonal cycle. The contraction parameter is sensed by a sensing module, while other variables may be input by a user, and a processor may be configured to monitor the progress of the hormonal cycle based on the received measurements and then actuate a simulation module at a specific phase during the hormonal cycle.

[0193] The "system" includes a sensing module, and optionally a signal processing module and a processor, for determining the state of a pelvic symptom. The system may also include software for a computing device, particularly downloadable software suitable for use with mobile communication devices (e.g., mobile phones). The sensing module or signal processing module can be configured to wirelessly transmit data to the computing device. The software can be configured to enable the communication device to receive data from the sensing module or signal processing module, optionally store the data, transmit the data to the processor (e.g., a processor at a remote location), and receive data related to the subject's pelvic symptom state from the processor, as well as display some or all of the data. The processor can be configured to transmit data related to the pelvic symptom state to another location, such as a computing device in a hospital or doctor's office.

[0194] The "system" also includes a pelvic structure stimulation module, such as an electrical stimulation device, for the treatment or prevention of pelvic disorders. The module can be configured to receive treatment instructions from a remote location (e.g., a mobile communication device). The processor can be configured to generate treatment instructions, including treatment parameters such as the duration, intensity, and phase of the hormone cycle at the time of treatment. The software can be configured to enable a mobile phone to receive the treatment parameters from the processor and transmit them to the stimulation module.

[0195] 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 as a patch that can be applied to a subject through the skin. The device typically 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 therapeutic electrodes. The device may include a power source (e.g., a battery) operatively connected to any module of the device. The device may include a controller (e.g., a microcontroller) operatively connected to the pelvic structure stimulation module and optionally connected to the power source.

[0196] example

[0197] The invention will now be described with reference to specific embodiments. These embodiments are merely exemplary and for illustrative purposes only; they are not intended to limit the scope of the claimed patent or the described invention in any way. These embodiments constitute the best mode currently contemplated for practicing the invention.

[0198] Materials and Methods

[0199] animal models

[0200] Female Sprague-Dwley rats weighing 200–250 g were housed at 23°C under a 12-hour light / dark cycle with free access to food and water. They were randomly assigned to either an endometriosis group or a sham-operated group, with eight rats in each group. All procedures were approved by the Animal Care Research Ethics Committee (ACREC) of the National University of Ireland, Galway. Before starting the experiment, the animals were subjected to 7 days of treatment (5 minutes / day) to reduce procedural stress, and vaginal cytology smears were performed to verify reproductive cycles.

[0201] Induction of endometriosis

[0202] Following the method of Vernon and Wilson (1985), endometriosis was surgically induced under isoflurane anesthesia. A 2cm distal portion of the right uterine horn was removed and immersed in warm (37°C) sterile saline. The endometrium was exposed by longitudinally opening the uterine horn with sterile scissors. Four 5mm² uterine horns were excised using a biopsy puncturist. The implant was sutured to the serosal surface near the mesenteric vessels of the small intestine and to the endometrial surface exposed to the peritoneum. In the sham surgery group, the right uterine horn was removed, and four sutures were attached to the mesentery without the implant. Throughout the procedure, the peritoneal cavity was kept moist with copious amounts of saline to reduce adhesions. After induction, endometriosis was allowed to progress for 56 days before uterine electromyography (EHG) recording and electrical stimulation testing were performed.

[0203] Uterine electromyography (EHG) recording

[0204] The laparotomy was performed under isoflurane anesthesia. For direct measurements, bipolar needle electrodes (AD Instruments) were inserted into the myometrium (8 mm between the two electrodes). For non-invasive measurements, an abdominal skin incision was created, and a pair of bipolar disc electrodes (MDE GmbH Walldorf, Germany) were placed subcutaneously above the uterus (20 mm between the two electrodes). Basal contraction of the uterus was monitored for 60 minutes. Electrical signals were recorded and analyzed using an online computer and amplifier system (ADInstruments PowerLab and Quad BioAmplifier). All analog signals were converted to digital signals at a sampling rate of 1000 Hz.

[0205] During the recording period, the animals were kept under isoflurane anesthesia. After the experiment, the animals were euthanized according to instruction 2010 / 63 / EU.

[0206] A digital filter was applied to the recorded signal (low-pass 0.1 Hz). To compare EHG between the groups (endometriosis group and sham surgery group), exploratory statistical analysis was performed on the raw signals (see Table 1). The signals were further analyzed by Fast Fourier Transform (FFT), where the frequency of electrical activity was characterized in Hz and the amplitude of activity was described as power spectral density (see Table 1). Figures 1-4 ).

[0207] Electrical stimulation test

[0208] A second bipolar electrode, made of polytetrafluoroethylene-insulated multistranded stainless steel, is inserted into the myometrium, 10 mm from the sensing electrode. For non-invasive electrical stimulation, a pair of bipolar disc electrodes (MDE GmbH Walldorf, Germany) is placed subcutaneously above the uterus (20 mm between the two electrodes). Baseline EHG is recorded for 20 minutes (as described previously). The electrodes are connected to a pulse generator (multichannel system: Stimulation Generator 4002), pre-programmed with constant current square wave pulses of 1–2 mA, 2 ms / pulse, and 2–15 Hz. Electrical stimulation is applied for 20 minutes before disconnecting the electrodes from the pulse generator and recording the post-recovery EHG for an additional 20 minutes.

[0209] During the recording period, the animals were kept under isoflurane anesthesia. After the experiment, the animals were euthanized according to instruction 2010 / 63 / EU.

[0210] A digital filter was applied to the recorded signal (low-pass 0.1 Hz). The results were analyzed using Fast Fourier Transform (FFT), where the frequency of electrical activity was characterized in Hz and the amplitude of the activity was described as the power spectral density. Figure 5 ).exist Figures 6-7The original signals were compared to demonstrate the effects of electrical stimulation at different points in the hormone cycle.

[0211] result

[0212] Figure 1 This study demonstrates that uterine contraction parameters measured using electrical sensors at all stages of the hormonal cycle can be used to differentiate between rats with and without endometriosis. Uterine contractions are expressed as power spectral density at peak frequency.

[0213] Figure 2 and Figure 3 The study showed that the differences in uterine contractions between rats with and without endometriosis were particularly pronounced during the preestrus and estrus phases of the hormonal cycle.

[0214] Endometriosis and sham-operated animals can also be distinguished using other contractile parameters shown in Table 1 below:

[0215] Table 1

[0216]

[0217] Table 2 shows the subjects' data profiles, including electroconstriction parameters determined at four time points from T1 to T4 and non-electro-hormonal cycle parameters (pain location, pain intensity, pain type, and bleeding intensity) determined at the same time points.

[0218] Table 2

[0219]

[0220] Figures 5 to 7 Studies have shown that uterine contractions in mammals can be regulated by electrical stimulation, and the effect of electrical stimulation is determined by the animal's hormonal state. For example, in Figure 6 In a study, electrical stimulation of control rats (without endometriosis) during the preestrus period (corresponding to the follicular phase of the human hormonal cycle) increased contractile activity, while electrical stimulation of rats with endometriosis during the preestrus period reduced or normalized contractile activity. Figure 7 As shown in Table 3 below:

[0221] Table 3 Summary of the effects of SiSync electrical stimulation on the hormone cycle:

[0222] Human cycle follicles ovulation Lutein rat cycle Before estrus estrus Incest (including after estrus) Comparison ↑ ↑ ↓ Endometriosis ↓ ↓ ——

[0223] Clinical data

[0224] Data source

[0225] The following data were collected from volunteers who consented to the study:

[0226] 1. Uterine signal – This is an electromyography (EHG) signal of the uterus recorded via the “Biosignalplux Solo” device, which bears the CE mark and is used for research purposes. This is both digital and time-series data.

[0227] 2. Chief Complaints – This data was collected through daily questionnaires completed by each volunteer. These questions covered a variety of topics, such as pain, bleeding patterns, overall health, and medication. This data primarily consists of ordinal and categorical data.

[0228] 3. Other patient data – This data was collected through questionnaires during the pre-study period and includes information such as height, weight, age, and nationality. This primarily consists of numerical and categorical data.

[0229] Research Recruitment

[0230] In the initial study, data were collected from 39 volunteers. All volunteers were divided into four groups, as defined below. Each group was further subdivided based on whether the volunteers received hormone intervention.

[0231] 1. Health: Self-selected volunteers with normal menstrual cycles and no pain throughout the menstrual cycle.

[0232] 2. Endometriosis: Volunteers diagnosed with endometriosis through surgery and experiencing pain throughout their cycle.

[0233] 3. Other: Volunteers who have been medically diagnosed with endometriosis or who believe they have endometriosis and experience pain throughout their cycle.

[0234] 4. Hysterectomy: Volunteers without a uterus.

[0235] As detailed in Table 4, 13 women were healthy, while 22 had endometriosis. Three women were classified as "other" for various reasons listed in Table 5.

[0236] Table 4

[0237] No medication used Medication total healthy 11 2 13 Endometriosis 15 7 22 Hysterectomy 1 1 other 2 1 3 total 29 10 39

[0238] All groups and volunteers who received hormone intervention (n=39).

[0239] *Medications refer to hormonal interventions, including the Mirena IUD, progesterone pills, combined oral contraceptives, and GnRH agonists. Some people receive more than one hormonal intervention.

[0240] Table 5

[0241]

[0242] Volunteers categorized as "other" (n=3) and the reasons therefor.

[0243] Volunteers with endometriosis were recruited with the support of the Irish Endometriosis Society and EndoAware, and were therefore mostly Irish and British. Healthy volunteers came from different countries, reflecting the diversity of the research team, which asked family and friends to volunteer for the study. The groups were well-matched in age (29-33 years) and representative in weight distribution.

[0244] Table 6

[0245]

[0246]

[0247]

[0248] Basic information of healthy (n=13) and endometriosis (n=22) volunteers: (a) nationality (b) age (c) weight

[0249] In an extended study, five more volunteers diagnosed with endometriosis due to fertility problems (rather than chronic pelvic pain) were recruited, one of whom was undergoing ovarian stimulation for IVF treatment.

[0250] Data collection, preprocessing, and filtering

[0251] Data Collection: Uterine signals were collected using a portable “Biosignalplux Solo” device, CE marked for research purposes. Volunteers were instructed to record signals on four key days of their menstrual cycle: day 1, day 7, day 14, and day 21. Signal recording lasted 30 minutes. Volunteers were instructed to remain supine during recording sessions, and, if possible, to collect signals at the same time for each recording session each day. An example of four recorded signals for a given volunteer is provided below. Figure 22 As shown in the image.

[0252] Preprocessing: The signal undergoes several preprocessing steps before analysis. First, a transfer function is used to transform the signal, scaling it to a range suitable for ±0.25 mV. Then, the first second and the last 30 seconds of the signal are removed. Finally, the signal is truncated at the 20-minute mark. Signals shorter than 20 minutes are discarded.

[0253] Filtering: The Biosignalplux Solo device (and EMG sensor) collected signals between 0.01591 and 0.1591 Hz (~0.96 cpm–9.5 cpm; cpm = contractions per minute). In all analyses performed in this report, the raw signals were filtered using a Butterworth low-pass filter with a cutoff frequency of 0.03 Hz. The basic principle 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 our preclinical studies.

[0254] Data Tags: Key Days in the Menstrual Cycle. The first day of menstrual bleeding is considered Day 1 of the cycle—estrogen levels are low, and bleeding is usually heavier. By day 7, bleeding usually stops, estrogen levels rise, and a dominant follicle containing an egg is growing. Day 14 is the day the egg is released from the ovary, known as ovulation day. On day 21, the egg travels through the fallopian tube and meets a sperm, and after fertilization, the resulting embryo implants in the uterine wall. However, if you are not pregnant, estrogen levels drop again, and the uterine lining prepares to shed.

[0255] However, menstrual cycles are highly individualized and can be longer or shorter than the typical 28-day cycle. Therefore, ovulation may occur earlier or later than day 14 of the cycle. For this reason, women who reported irregular cycles were asked to record their signals on days 13, 14, and 15 of their cycles. These signals were compared, and the signal with the highest MaxPower was retained. An example of two recordings (days 14 and 15) from healthy volunteers is presented below. Figure 23 As shown in the image.

[0256] Signal Feature Analysis

[0257] The DWT mean—(the average of the discrete wavelet transform coefficients calculated using Haar wavelets)—showed a statistically significant difference between healthy volunteers and women with endometriosis on day 14.

[0258] Plotting the MaxPower averages at four time points for healthy and women with endometriosis revealed a pattern similar to uterine motility during the hormone / menstrual cycle. The signal was elevated around ovulation in women with endometriosis compared to healthy volunteers. Hormonal intervention reduced the signal in both healthy volunteers and women with endometriosis. This demonstrates the utility of this signal as a non-invasive numerical marker of uterine motility.

[0259] It is understood that many different filtering and mathematical techniques can be used to separate and identify one or more electroconstriction parameter measurements to generate a subject's data profile, which includes separated electroconstriction parameter measurements representing target pelvic structures. The system and method of this invention utilize the fact that electroconstriction parameters are signals composed of slow-wave contraction frequency electrical signal measurements derived from smooth muscle or organs characterized by low-frequency content. The low-frequency content of the uterus and cecum can be characterized in a frequency range of 0.00–0.05 Hz. The system separates and identifies these low-frequency signals to create a subject's profile, which can be compared with other profiles to provide a diagnosis of the health status of organs in the pelvic region. Furthermore, the generated profile can be used in a simple and non-invasive manner to assess the condition of subjects who have previously been asymptomatic. The system can be further configured to provide estimates or calculations of predictive values ​​regarding the likelihood of a health condition developing based on the generated data profile.

[0260] Uses in overweight individuals

[0261] One challenge in developing a non-invasive device placed on the abdomen is the ability to sense target signals in overweight individuals. For volunteers who reported weight and height (n=33), their BMI was calculated, as shown in Table 3. From a data analysis perspective, there was no correlation between the extracted features and BMI, confirming that it is possible to sense digital biomarkers in all individuals, even those who are overweight. This was established for both the average DWT and MaxPower.

[0262] equivalent

[0263] The foregoing description has detailed the presently preferred embodiments of the invention. Based on this description, those skilled in the art will anticipate numerous modifications and variations in their practice. These modifications and variations are intended to be included in the appended claims.

Claims

1. A system for determining the endometriosis status of a non-pregnant woman, the system comprising: A sensing module for measuring the electrical activity of the subject's uterus at multiple time points during the subject's menstrual cycle, wherein the sensing module is a wearable, non-invasive sensor. A signal processing module configured to receive electrical activity measurements from the sensing module and separate from each electrical activity measurement a signal representing the uterus containing a slow-wave contraction frequency in the range of 0.00 to 0.05 Hz; and; A processor module, operatively connected to the signal processing module, and configured to: It receives multiple signals representing the uterus, including slow-wave contraction frequencies, as input; Generate a data profile for the subject, the data profile containing multiple signals representing multiple time points during the subject's menstrual cycle; The data profile is compared with a database of reference data profiles, which contains data profiles of subjects with or without endometriosis. as well as The endometriosis status of the subject is output based on the comparison. Wherein, when the subject's data profile includes more than one variable that is mapped over time, the reference data profiles compared with the subject's data profile will all include the same variable that is mapped over time; The comparison of the subject's data profile with one or more reference data profiles is performed using a computational model, which is a multilinear computational model.

2. The system of claim 1, wherein the sensing module is configured to measure the electrical activity of the subject's uterus at least once at each stage of the subject's menstrual cycle, wherein the measurement of ovulation is performed on day 14±1.

3. The system according to claim 1 or 2, wherein, The signal processing module includes a filter configured to separate a signal representing the uterus containing a slow-wave contractile frequency, wherein the slow-wave contractile frequency is in the range of 0.00 to 0.05 Hz.

4. The system according to claim 3, wherein, The subjects' menstrual cycles were measured at multiple time points, including day 1, day 7, day 14, and day 21, with the measurement on day 14 being possible on day 14±1.

5. The system according to claim 1, wherein, The processor module is configured to receive multiple measurements of at least one non-electrical hormonal cycle parameter acquired at multiple time points during the subject's menstrual cycle as additional input, wherein the generated subject data profile includes measurements of electrical contraction parameters representing the uterus and the measurements of the non-electrical menstrual cycle parameter.

6. The system according to claim 5, wherein, The non-electric menstrual cycle parameters are selected from the location of pain, pain intensity, pain type, and bleeding incidence.

7. The system of claim 1, wherein the system includes downloadable software for a mobile communication device, the downloadable software being configured to cause the mobile communication device to: Receive the contraction parameter measurement value from the signal processing module; The measured value of the contraction parameter is transmitted to the processor module; The processor module receives the subject's endometriosis status. as well as Displays the received endometriosis status.

8. The system according to claim 7, wherein, The downloadable software is configured to allow the subject to input non-electric menstrual cycle parameter measurements and / or non-electric non-hormonal cycle parameter measurements using the user interface of the mobile communication device, and to transmit the input measurements to the processor module.

9. The system of claim 1, wherein the processor module is configured to output the subject's endometriosis status, the endometriosis status being selected from a positive endometriosis diagnosis, a negative endometriosis diagnosis, endometriosis development risk, and the subject's response to endometriosis treatment.

10. A system for treating or preventing endometriosis in a non-pregnant female subject, the system comprising: The system for determining the endometriosis status of a subject according to any one of claims 1 to 9; as well as A wearable, non-invasive uterine stimulation module, used to apply stimulation therapy to the uterus to normalize uterine contractions. The processor is configured as follows: The menstrual cycle of the subject is monitored using signals received from the signal processing module and / or additional subject data obtained at multiple time points during the subject's menstrual cycle; as well as The uterine stimulation module was momentarily actuated during the follicular phase of the subject's menstrual cycle to normalize uterine contractions.

11. The system of claim 10, wherein the system includes a wearable device, the wearable device including a sensing module, the wearable non-invasive uterine stimulation module, and optionally the signal processing module.

12. The system of claim 10, wherein the system includes downloadable software configured to enable the mobile communication device to: Receives actuation commands for the wearable non-invasive uterine stimulation module from the processor module; and The uterine stimulation module is activated according to the instructions.

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