Monday, December 31, 2018
“Hope Smiles from the threshold of the year to come, Whispering ‘it will be happier’…”
With the new year knocking on our door, it is time to leave behind the old and usher in the new with good spirit and good cheer. New Year’s Day, which according to the Gregorian calendar falls on January 1, is celebrated across the world with much fervour. People make new resolutions, greet their friends and family and welcome the coming year with good food and great thoughts.
Saturday, December 29, 2018
Study of Nature and origin of "squirting" in female sexuality.
ABSTRACT
INTRODUCTION:
During sexual stimulation, some women report the discharge of a noticeable amount of fluid from the urethra, a phenomenon also called "squirting." To date, both the nature and the origin of squirting remain controversial. In this investigation, we not only analyzed the biochemical nature of the emitted fluid, but also explored the presence of any pelvic liquid collection that could result from sexual arousal and explain a massive fluid emission.
Natural selection increases female fitness by reversing the exaggeration of a male sexually selected trait
METHODS:
Seven women, without gynecologic abnormalities and who reported recurrent and massive fluid emission during sexual stimulation, underwent provoked sexual arousal. Pelvic ultrasound scans were performed after voluntary urination (US1), and during sexual stimulation just before (US2) and after (US3) squirting. Urea, creatinine, uric acid, and prostatic-specific antigen (PSA) concentrations were assessed in urinary samples before sexual stimulation (BSU) and after squirting (ASU), and squirting sample itself (S).
RESULTS:
In all participants, US1 confirmed thorough bladder emptiness. After a variable time of sexual excitation, US2 (just before squirting) showed noticeable bladder filling, and US3 (just after squirting) demonstrated that the bladder had been emptied again. Biochemical analysis of BSU, S, and ASU showed comparable urea, creatinine, and uric acid concentrations in all participants. Yet, whereas PSA was not detected in BSU in six out of seven participants, this antigen was present in S and ASU in five out of seven participants.
CONCLUSIONS:
The present data based on ultrasonographic bladder monitoring and biochemical analyses indicate that squirting is essentially the involuntary emission of urine during sexual activity, although a marginal contribution of prostatic secretions to the emitted fluid often exists.
METHODS:
Seven women, without gynecologic abnormalities and who reported recurrent and massive fluid emission during sexual stimulation, underwent provoked sexual arousal. Pelvic ultrasound scans were performed after voluntary urination (US1), and during sexual stimulation just before (US2) and after (US3) squirting. Urea, creatinine, uric acid, and prostatic-specific antigen (PSA) concentrations were assessed in urinary samples before sexual stimulation (BSU) and after squirting (ASU), and squirting sample itself (S).
RESULTS:
In all participants, US1 confirmed thorough bladder emptiness. After a variable time of sexual excitation, US2 (just before squirting) showed noticeable bladder filling, and US3 (just after squirting) demonstrated that the bladder had been emptied again. Biochemical analysis of BSU, S, and ASU showed comparable urea, creatinine, and uric acid concentrations in all participants. Yet, whereas PSA was not detected in BSU in six out of seven participants, this antigen was present in S and ASU in five out of seven participants.
CONCLUSIONS:
The present data based on ultrasonographic bladder monitoring and biochemical analyses indicate that squirting is essentially the involuntary emission of urine during sexual activity, although a marginal contribution of prostatic secretions to the emitted fluid often exists.
Thursday, December 27, 2018
Ejaculatory physiology and pathophysiology: assessment and treatment in male infertility
Abstract
Azoospermia is a heterogeneous condition with multiple etiologies and a variety of treatments. In this chapter we present a summary of retrograde ejaculation and anejaculation, both of which are characterized by an absence of antegrade semen propulsion through the male reproductive tract. Each of these affects fertility, but is pathophysiologically distinct disorders with differing evaluation and treatment. Retrograde ejaculation has a myriad of well-characterized causes, from pharmacologic disruption to interference of neural mechanisms by surgical intervention for a variety of diseases. Medication is the mainstay of treatment, although only a minority responds and develops antegrade ejaculation. For the men who are not responders to medical therapy, but still have fertility goals, there are a variety of sperm retrieval techniques to assist their reproductive abilities. Failure of emission is characterized by an absence of the emission phase and no antegrade or retrograde expulsion of ejaculatory products. If fertility is desired, these men must rely on assisted ejaculatory procedures, and treatment choice is guided by etiology and response. Ultimately, retrograde ejaculation and failure of emission are in a spectrum of ejaculatory disorders which impair male fertility.
Keywords: Ejaculation, retrograde ejaculation, electroejaculation (EEJ), anejaculation, penile vibratory stimulation (PVS)
Introduction
Before the advent of intracytoplasmic sperm injection (ICSI) and the development of surgical sperm retrieval, ejaculation was an absolute essential step in human reproduction. With advances in technology and a focus on a gamete-centric reproductive approach, ejaculatory disorders their treatments continue to be understudied and undertreated in favor of more invasive technologies. In fact, over 200 years after John Hunter first described the anatomic organs that contributed to semen, we still know surprisingly little about ejaculatory physiology and pathophysiology .
Ejaculatory disorders are very common, but are also very commonly misdiagnosed or disregarded . Accurate diagnosis of ejaculatory disorders is essential in the evaluation of the infertile male to avoid unnecessary treatment and expense associated with surgical sperm retrieval. Retrograde ejaculation and failure of emission comprise a constellation of disorders with common consequences, but unique and varied pathophysiology and therapeutic strategies. In this review we cover normal ejaculatory physiology, pathophysiology, as well as medical and surgical treatments for these conditions.
Physiology of ejaculation
Ejaculation involves the forcible ejection of seminal fluid from the urethral meatus, which accompanies sexual climax and orgasm. Ejaculation, however, is not be confused with orgasm. Orgasm is a central nervous system phenomenon and is a distinct entity from ejaculation characterized by sensations experienced at the peak of sexual arousal. Orgasm is a purely cerebral and emotional cortical occurrence, though in normal male physiology, orgasm coincides with ejaculation. But nonetheless, even in the published literature and among experts, there seems to oftentimes be confusion between these two terms. In this review, we will discuss ejaculation, which is comprised of two separate phases: emission and expulsion.
Emission
Emission is a physiologic process involving the distal epididymis, the vas deferens, the seminal vesicles, the prostate gland, the prostatic urethra, and the bladder neck. The initial step in emission is closure of the bladder neck mediated by innervation from the sympathetic nervous system. This is followed by deposition and admixture of seminal vesicle, prostatic, vas deferens, and Cowper’s glands secretions into the prostatic urethra. The seminal vesicle secretions are basic and contain fructose, which provides energy for sperm motility. In addition, semenogelin is secreted by the seminal vesicles, which is responsible for coagulation of semen after ejaculation. The spermatozoa come from the vas deferens contribution to the ejaculate. The prostatic secretions are acidic and contain serine proteases (such as PSA) that help liquefy the coagulated semen in the female reproductive tract. In all, the seminal vesicles contribute 65-75% of the ejaculate volume, the prostate contributes roughly 25-30%, vasal fluid supplies 5-10%, and finally bulbourethral glands contribute less than 1% of the total ejaculate volume (Table 1).
The neural control of emission originates from the thoracolumbar spine at T10-L2, and coordinates the actions of emission. The sympathetic efferent fibers coalesce into the lumbar sympathetic trunk ganglia, and then proceed posterior to the vena cava into the interaortocaval space on the right and lateral to the aorta on the left. Continuing inferiorly, the sympathetic efferent fibers from the right and left merge to form the superior hypogastric plexus anterior to L5 and the sacrum. Postganglionic fibers travel to their target organs: bladder neck, prostate, seminal vesicles, and vas deferens to mediate sympathetic control of the emission phase of ejaculation, and thus far a specific role for the parasympathetic nervous system has not been elucidated .
Expulsion
Following emission, expulsion occurs and involves the coordinated rhythmic action of the bladder neck, external urethral sphincter, urethra, and bulbospongiosus and pelvic striated muscle to propel semen through the urethra and out the meatus. Expulsion is mediated by the somatic nervous system; the external urethral sphincter relaxes, followed by clonic contractions of the prostate, bulbocavernosus muscle, ischiocavernosus, levator ani, and transverse perineal muscles .
The neuroanatomic control of expulsion is dependent on a reflex arc in the spinal cord. These neural pathways are arranged in reflex circuits responsible for mediating expulsion by eliciting bulbospongiosus contraction, relaxation of the external sphincter, and coordinated contractions of the prostate and seminal vesicles . The sensory input involves the perineal branch of the pudendal nerve receiving signals from two diverging sets of nerve fibers (one along the dorsolateral aspect of the penis innervating the shaft and glans and the second from the ventrolateral portion of the penis innervating the urethra). The sensory axons of the afferent pernineal nerve then synapse on the pudendal motor neurons in the nucleus of Onuf as well as on to spinal interneurons that communicate with the thoracolumbar spinal cord (T10-L2) to trigger emission. The efferent portion of the circuit exits the spinal cord via the perineal nerve to terminate on muscle fibers of the bulbospongiosus muscle for somatic reflex control of these muscles leading to ejaculation.
Neurotransmitters
Although the exact mechanisms have yet to be elucidated, a brief review of the role that neurotransmitters play in ejaculatory physiology is worthwhile as psychotropic medications are commonly implicated in a variety of ejaculatory complaints.
Serotonin
Overall, it is thought that serotonin exerts an inhibitory effect on ejaculation in humans. In animal studies, serotonin seems to have inhibitory effects in the CNS, while excitatory effects predominate in the PNS . There are a variety of serotonin receptors divided into seven different classes, 5-HT1-7, located ubiquitously across the central and peripheral nervous systems. Of these, receptors 5-HT1A, 5-HT1B, and 5-HT2C are most strongly linked to ejaculatory function. Serotonin receptors have been identified in the expected locations such as the brain stem, hypothalamus, and spinal cord, as well as ejaculatory structures including the prostate, seminal vesicles, vas deferens, and urethra . Although first discovered as an incidental observation, serotonin reuptake inhibitors (SSRI) commonly used in the medical treatment of premature ejaculation, clinically demonstrate the inhibitory effect of serotonin .
Dopamine
Animal models have confirmed the excitatory role dopamine plays in sexual behavior and ejaculation, a phenomenon first observed in Parkinson’s patients treated with L-DOPA . Not only did Parkinson’s patients experience resolution of their motor symptoms, but also reported hypersexuality with more frequent masturbation, sexual hallucinations, and increased nocturnal erections . Specifically, a rat study demonstrated the D2 receptor mediates the excitatory effects of dopamine: in the presence of a D2 receptor antagonist, a known dopamine and serotonin receptor agonist lost its stimulatory effects on ejaculation . These biochemical findings further correlate with clinical findings of ejaculatory delay in patients treated with dopaminergic antagonists for schizophrenia or anxiety . Dopamine antagonists such as haloperidol, thioridazine, and sulpiride have been found to delay ejaculation .
Pathophysiology
Retrograde ejaculation and failure of emission are the two disorders of ejaculatory function which result in anejaculation and infertility. While all three have a common pathway of anejaculation, the disorders leading to these conditions comprise a heterogeneous group of conditions with differing etiologies and therapies. A full history and physical as well as necessary hormonal evaluation may lead to the correct diagnosis.
Evaluation
History is essential in the evaluation of disorders of ejaculation. A focused history about ability to achieve orgasm versus anejaculation will determine if it is caused by anorgasmia. Patients should be asked about situational factors, which may be affecting ejaculation. Also, nocturnal emissions should be questioned. A detailed pharmacologic, sexual, medical, and surgical history will all aid in the correct diagnosis. Sign and symptoms of hypogonadism (i.e., low energy, low libido), erectile dysfunction, diabetes (i.e., polyuria), psychiatric illness (i.e., depression), and neurological disease (i.e., sensory abnormalities, bowel or bladder dysfunction) may aid in the diagnosis of ejaculatory dysfunction.
A thorough history of a patient with an ejaculatory complaint, with special attention to chronicity, answers the question of congenital versus acquired ejaculatory dysfunction. Important considerations include the patient’s ability to achieve climactic satisfaction and the presence of any situational variability. These questions may establish a disorder of sexual desire or arousal, and steer away from a disorder driven by ejaculatory pathophysiology.
A complete physical exam with special attention to signs of hypogonadism (atrophic testes, undeveloped phallus), thyroid disorders, other endocrinopathies (gynecomastia), abnormal penile sensation (abnormalities in penile or scrotal development) and signs of diabetic neuropathy (impaired peripheral sensation, obesity) can provide important guidance towards the correct diagnosis. When appropriate, laboratory evaluations of FSH, testosterone, HbA1c, TSH and prolactin levels can further inform on the etiology of the patient’s condition. Post-orgasm urinalysis may also be useful in identifying whether retrograde ejaculation is present.
Retrograde ejaculation
Retrograde ejaculation is the flow of semen into the bladder due to an incompletely closed bladder neck. In two large series of azoospermic men, retrograde ejaculation was the observed cause in 18%, although as a source of infertility it was only implicated in 0.7% . Additionally, it has been noted the incidence is likely rising as a consequence increasing rates of diabetes, use of α-receptor antagonists, and bladder neck surgery for malignancies . This diagnosis is easily confirmed with identification of sperm in a post-masturbatory voided sample. A variety of mechanical, neurologic, and pharmacologic etiologies are responsible for retrograde ejaculation.
Etiology
Surgical injury
Instrumentation and surgery is the most common cause of an incompetent bladder neck, with a majority of men experiencing retrograde ejaculation after transurethral resection of the prostate . Lower rates of men experience this side effect when their prostate disease is treated with transurethral microwave therapy or transurethral incision of the prostate, which may argue for these options to be considered in younger men or those with good baseline sexual function . But no procedure on the prostate is without risk of retrograde ejaculation and men considering surgery who still desire children should be adequately counseled regarding the side-effects of these procedures.
Surgical injury to the nerves influencing ejaculatory function also carry the risk of retrograde ejaculation with the most common being retroperitoneal surgeries, colorectal surgery, and spine surgery . Development of nerve-sparing retroperitoneal lymph node dissection (RPLND) techniques and templates have made this mainstay of testicular cancer therapy less damaging to patients’ ejaculatory function .
Diabetic complications
Retrograde ejaculation is both common and under-recognized in diabetic men, with one series reporting a prevalence of 32%. Chronic uncontrolled diabetes results in an autonomic neuropathy that disrupts the sympathetic output to the bladder neck, impairing its ability to close during ejaculation. Similar to erectile complaints, patient reported ejaculatory problems should heighten the clinician’s concern for additional vascular or neurologic pathology.
Pharmacologic disruptors
Pharmacologic treatment for a variety of conditions can induce retrograde ejaculation in men, with the most common offenders being alpha-receptor antagonists for lower urinary tract symptoms, other sympatholytics for hypertension, antidepressants, and antipsychotics. However, investigators have recently proposed that perhaps the ejaculatory disorder induced in men taking alpha antagonists may be due to a contractility of the seminal vesicles, not retrograde ejaculation caused by disrupted closure of the bladder neck. In the laboratory they demonstrated a high prevalence of alpha-1 receptor subtypes in the seminal vesicles, and correspondingly from the clinical side, showed healthy men taking tamsulosin had lower volume ejaculate than controls and no sperm was present in their post-ejaculate void . Fascinatingly, this may imply that alpha-blockers may have more reproductive effects than previously recognized and not simply affect the bladder neck, though more studies are needed to confirm this interesting finding.
Treatment
The goal for treatment of patients with RE is to restore antegrade ejaculation of semen for attempts at natural conception as well as collection of sperm for assisted reproductive techniques. When possible, the offending medication should be discontinued if the benefit of resolved retrograde ejaculation outweighs the benefit the medication provides. In cases of neuropathy-induced, iatrogenic, or idiopathic retrograde ejaculation, sympathomimetic drugs have had the most, albeit modest, success. The mechanism of sympathomimetic action is to improve bladder neck contraction during the expulsive phase of ejaculation. These include ephedrine sulfate, imipramine hydrochloride, midodrine hydrochloride, brompheniramine maleate, and pseudoephedrine hydrochloride Imipramine is the preferred agent with high success rates in patients who have undergone retroperitoneal sympathetic denervation . A recent review of the literature reports treatment with sympathomimetics resulted in restoration of antegrade ejaculation in only 28% of subjects.
Common pharmacologic treatments for retrograde ejaculation If the goal of treatment is to harvest sperm for use with assisted reproductive techniques, then sperm can be used either from the converted antegrade ejaculate or from harvesting of post-orgasm bladder samples. Generally, before harvest of bladder samples, sodium bicarbonate (50 mg) is given 12 and 2 hours prior to collection. This alkalinization of the urine minimizes the toxic effect of acidic urine on sperm quality. The patient is asked to void (or atraumatically catheterized if unable to void) just before orgasm to minimize urine volume. After orgasm, the voided (or catheterized) urine is collected and centrifuged to be used for assisted reproductive techniques. In a systematic review, Jefferys et al., examined fifteen studies using a variety of artificial insemination techniques with the obtained sperm [intrauterine insemination (IUI), IVF, and ICSI]. Overall, pregnancy rate per cycle was 15%, with a live birth rate of 14% .
Failure of emission
Etiology
Failure of emission is when there is complete disruption of emission during sexual activity. Orgasm and the expulsive phase of ejaculation occur, but there is failure of deposition of the reproductive glands to deposit the necessary fluid into the prostatic urethra during stimulation. It is clinically characterized simply as anejaculation, but on investigation for retrograde ejaculation, there will be no evidence of retrograde ejaculation in post-orgasm urine. Failure of emission is defined as the lack of sperm on antegrade and retrograde semen analysis. This can be caused by peripheral neuropathy caused by diabetes as well as any spinal cord injury (SCI). Basically, we view failure of emission and retrograde ejaculation as a spectrum of ejaculatory dysfunction with failure of emission being the ultimate failure of the ejaculatory system.
Treatment
Assisted ejaculation procedures are used to harvest sperm for assisted reproduction in anorgasmic and anejaculatory men. While sperm can by surgically retrieved from any portion of the reproductive tract (testis, epididymis, vas, or seminal vesicles) and used for IVF-ICSI, in the patient with ejaculatory failure, treatment of the ejaculatory dysfunction results in much higher yields of sperm. The two most commonly used techniques are penile vibratory stimulation (PVS) and electroejaculation (EEJ). Overall, studies show that sperm can be retrieved by PVS or EEJ in 97% of SCI men .
Penile vibratory stimulation (PVS)
PVS refers to the use of a vibrator applied to the penis to induce ejaculation. The vibrator is generally applied to the frenular surface of the glans and the resulting ejaculated sperm can be used in assisted reproduction for those patients with psychogenic anejaculation as well as SCI above the T12 level. The success use of PVS in the SCI patient depends on an intact spinal cord ejaculatory reflex arc (sensory nerves, spinal cord S2-S4 arc, and efferent nerves) as well as lack of descending cortical inhibitory input . Any sperm harvested by PVS can be used in IUI, IVF, and IVF-ICSI . PVS is a cost effective treatment and easy procedure for patients that can be done at home with subsequent home vaginal insemination.
The ideal candidate for PVS has a high SCI, above T10, and highest PVS rates are seen in patients with C3-C7 injuries . Though even simple vibrators without adjustable frequency and amplitude may be effectively used, the optimal setting seems to be 1.0-2.5 mm amplitude and 100 Hz frequency . Even if initially unsuccessful, 20% may respond to addition of a second vibrator . Also, midodrine may be used as an adjunct for PVS in patients who have already failed a single round of PVS . Possible side effects of PVS include abrasions of the penile skin and autonomic dysreflexia in at-risk spinal cord injured men. Men at risk for autonomic dysreflexia should be treated with a prophylactic dose of nifedipine (10-20 mg) prior to the procedure. If there are signs of autonomic dysreflexia, the vibratory stimulation should be removed immediately.
Rectal probe electrostimulation
If efforts to restore antegrade flow or PVS fail, then rectal probe electrostimulation or EEJ can be used. It is a generally more invasive procedure in which a rectal probe electrode is used to deliver electrical current directly to the prostate and seminal vesicles, resulting in ejaculation (see Figure 1). Patients who have SCI who are insensate below the waste can undergo this in the office setting, but men who are sensate below the waist will require general anesthesia. Prior to the procedure, the urine should be alkalinized with sodium citrate, potassium citrate, or IV bicarbonate as urine’s acidity and osmolarity is toxic to sperm. The patient is generally catheterized first to empty the bladder and 20-30 cc of sperm transport media [we use human tubal fluid (HTF) buffered with HEPES and plasmanate, pH 7.4] are then instilled into the bladder. Care should be taken to avoid urethral trauma as contact with blood can impact sperm quality. Mineral oil is preferred over water-based lubricants for the catheterization due to toxic effects on sperm.
Schematic showing insertion of transrectal probe for electroejaculation (EEJ). The electrodes are oriented towards the prostate and seminal vesicles.
The patient is then repositioned in the lateral decubitus position and rectoscopy is performed to identify any mucosal ulceration, rectal mass, or full rectal vault that may preclude the EEJ procedure. The rectal probe is then inserted and the electrodes are oriented towards the prostate and seminal vesicles. Using a Seager Electoejaculator© a peaked sine wave pattern of electrical energy is applied to the prostate with increasing amplitude until either antegrade semen flow is seen, rectal temperature reaches 38 degrees Celsius, or the 30 volt maximum is reached. Also, with the lower end of the stimulation, we do not completely stop the current to avoid spasticity in the patient. We generally note the voltage and number of stimulations necessary to reach ejaculation in the medical record in case repeat EEJ is needed. As rectal mucosal injury is a potential complication, anoscopy is again performed. The patient is then placed supine and catheterized for the retrograde sample. The initial retrograde and antegrade sample is diluted in HTF buffered with HEPES and plasmanate, pH 7.4 and sent for immediate processing.
Autonomic dysreflexia is also a potential complication in men with spinal cord injuries above T6 undergoing EEJ. Precautions should be taken to monitor blood pressure in any procedure involving hollow visceral dilation or neurologic stimulation of the lower reproductive tract. Prophylactic nifedipine prior to electrical stimulation is also recommended in those with history of autonomic dysreflexia or at high risk for it. If it does occur, the stimulation should be immediately withdrawn.
Sperm quality
While PVS and EEJ are well defined in terms of their ability to obtain ejaculate, which form of assisted reproduction is necessary depends on a number of both male and female factors. Obviously, the quality and quantity of sperm collected determines whether it can be used for IUI or ICSI. Ohl et al. has shown an 8.7% per cycle fecundity over 653 cycles of EEJ with IUI with a median of 3 IUI cycles to reach pregnancy . Chung et al.reported a fertilization rate of 75% per injected oocyte and clinical pregnancy rate of 55% per fresh semen retrieval attempt when ICSI was coupled to EEJ .
A few points should be kept in mind when recommending assisted ejaculation procedures SCI patients. Although there are few differences in sperm quality between PVS and EEJ, both have higher DNA fragmentation rates than normal controls . Also, SCI patients have worse outcomes when compared to non-SCI patients with lower fertilization rates. However, sperm collected by PVS and EEJ in SCI men demonstrate similar pregnancy and live birth rates using IVF-ICSI . What causes this difference is still an area of active research, though recent work has indicated that the inflammatory factors may play a role in the decreased sperm quality seen in the ejaculate of SCI men .
Special considerations: anejaculation following PC-RPLND
Though much of this literature deals with SCI injury patients and patients with diabetic neuropathy, there is a subset of patients that merit special discussion. These are testis cancer patients that have undergone orchiectomy, chemotherapy, and RPLND, rendering them anejaculatory even with nerve sparing techniques. In this unique set of patients, there are disorders of ejaculation as well as threats to sperm production since they were given chemotherapy. Hsiao et al.performed a study where a structured clinical protocol was applied to 26 men seeking fertility who presented to a quaternary cancer referral center with anejaculation after post-chemotherapy RPLND. In this study, 50% of men with RE converted to antegrade ejaculation with medical therapy. No men with failure of emission had conversion to antegrade ejaculation with medication. In those with failure of emission, EEJ was successful in 91% of men, and sperm was found in 75% of these men. The rest underwent testicular sperm extraction. In conclusion, for men with anejaculation after post-chemotherapy RPLND, we recommend men with retrograde ejaculation undergo a trial of medication to convert retrograde to antegrade ejaculation. If medications fail we proceed to EEJ and if no sperm or poor quality is seen on EEJ, we go to testicular sperm extraction and assisted reproductive techniques. In those patients with failure of emission, we recommend proceed immediately to EEJ, and if inadequate or poor quality sperm is seen on EEJ, proceed directly with testicular sperm extraction in the same setting under general anesthesia.
Conclusions
Ejaculatory dysfunction resulting in azoospermia can be due to retrograde ejaculation or failure of emission. A careful and focused history, physical exam, and appropriate diagnostic tests will lead to the correct diagnosis. Treatment decisions are informed by etiology and patients’ goals of care, and for those men desiring fertility, there are a wide range of efficacious options to reach this objective.
Wednesday, December 26, 2018
Midlife Women Transitioning to Menopause Have a Higher Risk of Metabolic Syndrome, Which Predisposes to Heart Disease and Type 2 Diabetes
- DEC 2018
Multi-ethnic study shows midlife women with more physical activity or a lower calorie diet have less risk of developing the disease
Midlife women transitioning to menopause may be able to lower their risk of developing heart disease and type 2 diabetes, if they exercise more or eat a lower calorie diet, according to a new study published in The Journal of Clinical Endocrinology & Metabolism.
According to recent data, one in five Americans has metabolic syndrome. These patients are diagnosed when they have three or more of these risk factors: large amount of abdominal body fat, low (“good”) cholesterol, high levels of fat in the blood, high blood pressure, and high blood glucose.
“Previous studies have largely focused on cardiovascular disease and type 2 diabetes in postmenopausal women. This study is unique because it focuses on an earlier stage in women’s lives, the menopausal transition in midlife, to potentially prevent such diseases from occurring,” says lead study author Jennifer S. Lee, MD, PhD, associate professor of Medicine, Stanford Medical Center and the Veteran Affairs Palo Alto Health Care System in Stanford, Calif. “Discovering which modifiable factors like physical activity and a lower calorie diet are more common in midlife women who recover from metabolic syndrome, in this study, could better inform what preventive strategies to consider in women earlier in their lives.”
In the prospective, multi-ethnic cohort study, researchers studied 3,003 (1412 non-Hispanic White, 851 Black, 272 Japanese, 237 Hispanic, 231 Chinese) midlife women undergoing the transition to menopause. They identified patterns of cardiometabolic risk and found central obesity to be the most common factor for causing metabolic syndrome. They also found that lifestyle changes like more physical activity and a lower calorie diet could help patients recover from metabolic syndrome. Additionally, physically active women in the study were less likely to get incident metabolic syndrome than inactive women.
The study received support from the National Institutes on Aging, the National Institute of Nursing Research, and the Office of Research on Women’s Health.
Monday, December 24, 2018
Pump It Up: Diabetes Technologies Continue to Revolutionize Care
As devices become smarter and smarter and improve patient outcomes, they also pose challenges for patient and clinician education. While clinicians ensure all patients are up-to-speed on the new technology, a new threat looms: Keeping data safe.
In an early episode of the CBS crime drama Elementary, a man is found dead of an apparent heart attack. But Sherlock Holmes deduces that it is a case of murder — the victim’s pacemaker was hacked.
More than one Agatha Christie novel involves an unsuspecting victim succumbing to an insulin injection.
With diabetes patients now using continuous glucose monitors (CGMs) connected to insulin pumps via smart phones, could Dr. Evil combine these two plots and hack the pump’s insulin delivery to commit murder most foul?
That apocalyptic vision may already be possible, some experts say, but it contrasts with a very positive real-world example related by a diabetes specialist: A type 2 diabetes patient over 80 years old was at his vacation home in Arizona when he passed out during a hypoglycemic episode. His wife was out of the house and without her phone. But when his CGM detected his perilously low blood sugar level, it caused an alarm to sound on his daughter’s smart phone in Portland, Ore. She called the neighbors in Arizona, who found her father unresponsive and dialed 911. The first responders revived him.
Fast-Changing Technology
These wildly disparate scenarios illustrate the promise and the peril of new technologies that are rapidly improving the lives of many diabetes patients. CGMs and insulin pumps are becoming smaller, more accurate, and easier to use “off the shelf,” with less need for patient or clinician intervention. Some CGMs are so reliable that they don’t require calibration by the patient. One commercially available “hybrid closed-loop system” of a CGM interacting with a pump is nearing the goal of an artificial pancreas, while some tech savvy patients are already using do-it-yourself systems. Even insulin pens are becoming smart enough to communicate with phones to deliver the correct amount of insulin.
It used to be that a patient would visit an endocrinologist every three or four months so the physician could adjust the treatment. But the new technologies “put the patient in the driver’s seat and put decision-making tools in their hands to tweak their treatment,” says Dennis Harris, PhD, associate editor of content strategy and outcomes at the Endocrine Society — and an early adopter of technology as a type 1 diabetes patient himself.
“I see amazing successes, but the vast majority of those successes are people who are familiar with using technical tools,” Peters says. “I’ve had patients whom I have literally forbidden to wear sensors because they overreact so much to changes in their glucose.” – Anne Peters, MD, director, clinical diabetes program; professor, clinical medicine, Keck School of Medicine, University of Southern California, Los Angeles
But there are concerns that those who could benefit the most from the technology could be the last to get it. “I work in Beverly Hills, in a practice where people have health insurance and are really well educated, and they are incredibly avid adopters of technology,” says Anne Peters, MD, director of the clinical diabetes program and professor of clinical medicine at the Keck School of Medicine at the University of Southern California. “I also work in East Los Angeles where people are of lower socioeconomic status. Many have fifth grade reading levels and don’t speak English as a primary language. Their ability to adopt and use technology is much, much less. And, of course, it is much more needed because lower income patients have much poorer outcomes.”
Better teaching tools are needed to reach these patients, and groups like the American Association of Diabetes Educators are working on creating them, including multilingual instructions. Funded by a grant from the Helmsley Charitable Trust, Peters has created free online tools for less literate patients in English and Spanish (available at http://uscdiabetes.com/#pens).
Seniors are another subset particularly at risk because “they are more prone to hypoglycemia and more prone to the adverse outcomes from hypoglycemia, such as falls and fractures,” says Andrew Ahmann, MD, professor of medicine and director of the Harold Schnitzer Diabetes Health Center at Oregon Health and Science University in Portland.
Peters agrees: “Even seniors who are more educated are much less comfortable with technology, they are not people who wander around with smart phones.” Plus, issues of cognitive decline must be taken into account.
“If seniors are exposed to and carefully taught how to use technology, they get by their concerns,” Ahmann says. “But you have to approach them a little bit differently. You have to get them to persist in its use long enough that they can get by those initial anxieties and uncertainties. I think the manufacturers are doing a good job of making their products simpler and simpler.”
The Conundrum of Shared Data
Ahmann says that he has been “surprised at how many patients, when they have the opportunity to share their information, are choosing not to. Or don’t even want to put it on their phone and prefer to use a much simpler receiver.”
But Ahmann can attest to the benefits of sharing. One family insisted that their 80-something father share his information, and the move paid off when he passed out on his large rural property — and a family member used the iPhone finder app to locate his unconscious body and get medical help.
Sharing with Physicians
By using smart phones, patients can tie into databases and algorithms that can help with their insulin dosing and also share their data with their physicians. Peters’ patients’ data is uploaded automatically, with no need for action by the patient, to a platform called Tidepool — open source software for a variety of devices distributed by a nonprofit organization. Jessica Castle, MD, an associate professor of medicine at Oregon Health and Science University, accesses her patients’ data via several software systems, including Glooko (broadly compatible commercial software), Medtronic’s CareLink, and Dexcom’s Clarity. She says the Dexcom system is particularly handy because “once people accept the request to share data from a device with our clinic, I can access it without them doing anything further, which is really nice, because one of the barriers for being able to review data is for patients to have to download information from their devices.”
She finds these systems particularly helpful for doing a weekly review of CGM and pump data from pregnant women with type 1 diabetes.
Issues of Cybersecurity
Of course, the use of cell phones and cloud computing to receive and share data raises questions of hacking and cybersecurity, issues beyond the control of clinicians and patients and left in the hands of the manufacturers of the devices. To guide manufacturers in making safer devices, the Diabetes Technology Society has developed a pair of cybersecurity standards, according to David Klonoff, MD, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center in San Mateo, Calif., who chaired the standards development committee.
The first standard, called DTSec, is for information going to or from a connected diabetes device, such as a handheld, dedicated controller. The second standard, called DTMoSt, “is intended to help manufacturers understand what types of security features are needed when you have a mobile phone controlling a device — a situation so new that there is not even a product on the market yet that would need it,” Klonoff says.
“If you want to find out how to do anything, you go to YouTube. But the extension to medical applications must be done cautiously. We will have the challenges of separating out the ones that are done very professionally and scientifically from those done by self-appointed experts.” – Andrew Ahmann, MD, professor of medicine and director, Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland
“If you give enough people enough time and enough equipment they can hack into anything,” Klonoff says. “So the idea isn’t for a medical device to be absolutely unhackable, because that is impossible. But there are levels of difficulty for hacking in. We have set a fairly high level because it is related to a medical product.” For a device to be certified as meeting the standard, it is sent to a lab that does “penetration testing” to see how hard it is to hack. “One company has already had products verified as meeting DTsec,” Klonoff says.
“I think at some point, patients are going to start demanding that products meet DTsec or DTMoSt, but right now, most patients don’t know about it,” Klonoff says.
Can Coverage Keep Up?
These kinds of standards may make it easier to get new devices approved for coverage by payers.
But payers are not always keeping up with the technology. For example, it took several years and concerted efforts by groups like the Endocrine Society working with the manufacturers to get Medicare to provide coverage for glucose monitors like the Dexcom G5 and the Abbott FreeStyle Libre Flash Glucose Monitoring System. But it was many months later that Medicare agreed to extend coverage to the use of smart phones. And although the Food and Drug Administration has approved the next step in the Dexcom family — the G6, which provides an upgrade over the previous model because it does not require calibration — one might think that it would be an easy process to receive Medicare approval as well. But Medicare has yet to act.
Education Everywhere
Education — for payers, patients, and physicians — is a key to effective adoption of the new technologies.
“I see amazing successes, but the vast majority of those successes are people who are familiar with using technical tools,” Peters says. “I’ve had patients whom I have literally forbidden to wear sensors because they overreact so much to changes in their glucose.”
The landscape is changing so fast that even clinicians have a hard time keeping up with it — and knowing how to teach their patients about it.
Ahmann says that professional societies are working on this problem, and the internet could be a key help: “YouTube is potentially going to be a significant player in patient education. If you want to find out how to do anything, you go to YouTube. But the extension to medical applications must be done cautiously. We will have the challenges of separating out the ones that are done very professionally and scientifically from those done by self-appointed experts.”
— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about Medicare approving some CGMs for coverage in the September issue.
Saturday, December 22, 2018
Patient-centered Care is the Focus and Priority of the 2019 Standards of Medical Care in Diabetes, Published Today by the American Diabetes Association®
With the evidence from the latest, high-quality diabetes research, the American Diabetes Association’s 2019 Standards of Medical Care in Diabetes (Standards of Care) include new and revised clinical practice recommendations that put the patient at the center of care. With more treatment algorithms that provide decision support for individualized care, the 2019 Standards of Care create a roadmap for therapeutic approaches and medication selection based on each patient’s overall health status. The Standards of Care’s cardiovascular recommendations, which have been endorsed for the first time by the American College of Cardiology, include updates that aim to reduce heart attacks, strokes, heart failure, and other manifestations of cardiovascular disease; cardiovascular disease is the leading cause of death and disability for people with diabetes. Diabetes technology is now more thoroughly discussed in its own section and includes new recommendations on insulin delivery, blood glucose meters, continuous glucose monitors, automated insulin delivery devices (such as the artificial pancreas) and insulin injectiontechnique.
The 2019 Standards of Care provide the latest in comprehensive, evidence-based recommendations for the diagnosis and treatment of children and adults with type 1, type 2, or gestational diabetes, strategies to prevent or delay type 2 diabetes, and therapeutic approaches that can reduce complications and improve health outcomes. The Standards of Care are available online today, December 17, at 2:00 p.m. ET in Diabetes Care, and will be published as a supplement to the January 2019 print issue of Diabetes Care. The online version of the Standards of Care, or the living Standards of Care, will continue to be updated in real-time throughout the year with necessary annotations if new evidence or regulatory changes merit immediate incorporation. This ensures that the Standards of Care provide all stakeholders (i.e. providers, patients, researchers, health plans, policymakers, etc.) with the most up-to-date components of diabetes care, general treatment goals and tools to evaluate the quality of care.
“The latest evidence-based research continues to provide critical information that can optimize treatment options and improve patient outcomes and quality of life. The new 2019 Standards of Care emphasize a patient-centered approach that considers the multiple health and life factors of each person living with diabetes,” said ADA’s Chief Scientific, Medical and Mission Officer William T. Cefalu, MD. “We are also pleased about our close collaboration with the American College of Cardiology, aligning the ADA’s CVD recommendations with the ACC for the first time ever, and also complements our new Know Diabetes by Heart initiative with the American Heart Association. These updated CVD guidelines can help to significantly reduce mortality from CVD, the leading cause of death for people living with diabetes. The 2019 Standards of Care affirm the ADA’s commitment to providing rapid release of evidence-based recommendations that can yield improved patient outcomes and reduce complications and health care costs, and we hope providers will continue to download and use the mobile App for easy access to the Standards of Care at the point of care.”
Important updates and changes to the 2019 Standards of Care include:
Personalizing diabetes care:
- A new Goals of Care graphic decision cycle details the need for ongoing assessment and shared decision-making to achieve care goals, help reduce therapeutic inertia and improve patient self-management. (Section 4, page S35, Figure 4.1)
- New text guides health care professionals’ use of language to communicate about diabetes with people with diabetes and professional audiences in an informative, empowering, and educational style. (Section 4, page S34, Recommendation 4.1)
- To address the unique nutritional and physical activity needs and considerations for older adults (>65 years) with diabetes, a new recommendation on lifestyle management is included. (Section 12, page S141, Recommendation 12.10)
- A new treatment algorithm provides a path for simplifying insulin treatment plans, as well as a new table to help guide providers considering medication simplification and deintensification in older adults (>65 years) with diabetes. (Section 12, pages S143 – S144, Figure 12.1, and Table 12.2, respectively)
- Treatment recommendations for children and adolescents with type 2 diabetes are significantly expanded to incorporate ADA guidance on youth published in 2018, and recommendations now include screening and diagnosis, lifestyle management, pharmacologic treatment, psychosocial factors for consideration, cardiac function and more. (Section 13, pages S148 – S164)
- A new graphic provides guidance on the management of new-onset diabetes in overweight youth. (Section 13, page S157, Figure 13.1)
Diabetes cost and advocacy
- The ADA statement on the rising cost of insulin, Insulin Access and Affordability Working Group: Conclusions and Recommendations, is referenced in the Standards of Care advocacy section to reinforce ADA’s focus on making sure cost is not a barrier to successful diabetes management. (Section 16, page S182)
- Additional information is also included in the Standards of Care focusing on the financial costs of diabetes to individuals and society. (Section 1, pages S7–S12)
Cardiovascular disease and diabetes
- For the first time, the cardiovascular disease management chapter of the Standards of Care is endorsed by the American College of Cardiology. (Section 10, pages S103 – S123)
- The section includes new language to acknowledge heart failure as a major cause of cardiovascular morbidity and mortality in people with diabetes and the need to consider heart failure when determining optimal diabetes care. (Section 10, pages S103–S123)
- Updated recommendations detail the use of sodium–glucose cotransporter 2 (SGLT-2) inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists, diabetes medications that have proven cardiovascular benefit for people with type 2 diabetes and diagnosed CVD, with and without heart failure. (Section 10, page S114, Recommendations 10.39 and 10.40).
- A new recommendation outlines the benefits of GLP-1 receptor agonists and SGLT-2 inhibitors for people with type 2 diabetes and chronic kidney disease. (Section 11, page S124, Recommendation 11.3)
- The ADA now endorses the use of ACC’s atherosclerotic cardiovascular disease (ASCVD) risk calculator, the ASCVD Risk Estimator Plus, for the routine assessment of 10-year ASCVD risk in people with diabetes. (Section 10, page S104)
“The American College of Cardiology and the American Diabetes Association share a goal to reduce the burden of cardiovascular disease that too often follows a diabetes diagnosis,” said American College of Cardiology Vice President Richard Kovacs, MD, FACC. “ACC is proud to stand behind this important document that will provide a roadmap for clinicians to effectively assess and manage cardiovascular disease in patients with diabetes and, in turn, save lives.”
Technology and diabetes
- A new section focused on diabetes technology includes new recommendations on insulin delivery (syringes, pens and insulin pumps), blood glucose meters, continuous glucose monitors (real-time and intermittently scanned), and automated insulin delivery devices (such as the artificial pancreas). (Section 7, pages S71 – S80)
- Telemedicine is becoming more widely available and has the potential to increase access to care for patients with diabetes. The Standards of Care addresses remote delivery of health-related services and clinical information via telemedicine. (Section 1, pages S8 – S9)
- To ensure that insulin is delivered into the proper tissue in the right way for optimal glucose management and safety, discussion on insulin injection technique is included. (Section 9, page S91)
Medical nutrition therapy (diet)
- Extending the patient-centered care focus, the Standards of Care acknowledge that there is no one-size-fits-all eating pattern, and that a variety of eating patterns can help manage diabetes. It is recommended for patients to be referred to and work with a registered dietitian to create a personalized nutrition plan. (Section 5, page S47-48)
- A recommendation is updated to emphasize the benefits of consuming more water and fewer beverages sweetened with either nutritive (caloric) or nonnutritive (noncaloric) sweeteners. (Section 5, page S49, Recommendation 5.23 in Table 5.1)
Pharmacologic approaches and glycemic targets
- The recommended pharmacologic treatment for type 2 diabetes is significantly updated to align with and reflect the new ADA-EASD Consensus Report, specifically consideration of important comorbidities, such as ASCVD, chronic kidney disease and heart failure and key patient factors, such as hypoglycemia risk, body weight, costs and patient preference. (Section 9, pages S95 – S96, Figures 9.1 and 9.2)
- The approach to injectable medication therapy is also revised: for patients who require the additional glucose-lowering efficacy of an injectable medication, a GLP-1 receptor agonist is now recommended as the first choice before insulin for most patients with type 2 diabetes. (Section 9, page S95, Figure 9.2)
- Gabapentin is included as a new medication to be considered for the treatment of neuropathic pain in people with diabetes based on the latest data that indicates strong efficacy and the potential for cost savings. (Section 11, S131, Recommendation 11.31)
- A new table aids in the assessment of hypoglycemia risk details factors that increase the risk of treatment-associated hypoglycemia. (Section 4, page S39, Table 4.3)
Updates to the Standards of Care are established and revised by the ADA’s Professional Practice Committee (PPC). The committee is a multidisciplinary team of 15 leading U.S. experts in the field of diabetes care and includes physicians, diabetes educators, registered dietitians and others whose experience includes adult and pediatric endocrinology, epidemiology, public health, lipidresearch, hypertension, preconception planning and pregnancy care. For the 2019 Standards of Care, two designated representatives from the American College of Cardiology (ACC) reviewed, provided feedback and endorsed the recommendations for cardiovascular disease and risk management on behalf of the ACC. The PPC performs an extensive, global clinical diabetes literature search each year for the annual Standards of Care update, supplemented with input from ADA leaders and staff and the medical community at-large. The online and mobile versions of the Standards of Care will include any research updates or policy changes that are approved throughout 2019; they are tagged and updated in overlays as the living Standards of Care. Members of the PPC must disclose potential conflicts of interest with industry and/or relevant organizations; these disclosures are available on page S184 of the 2019 Standards of Care. The complete 2019 Standards of Care and the 2019 Abridged Standards of Care, which focuses on the key recommendations for primary care physicians, are all available online at http://care.diabetesjournals.org/content/42/Supplement_1on December 17, 2018, at 2:00 p.m. ET.
About Diabetes Care®
Diabetes Care, a monthly journal of the American Diabetes Association (ADA), is the highest-ranked, peer-reviewed journal in the field of diabetes treatment and prevention. Dedicated to increasing knowledge, stimulating research and promoting better health care for people with diabetes, the journal publishes original articles on human studies in clinical care, education and nutrition; epidemiology, health services and psychosocial research; emerging treatments and technologies; and pathophysiology and complications. Diabetes Care also publishes the ADA’s recommendations and statements, clinically relevant review articles, editorials and commentaries. Topics covered are of interest to clinically oriented physicians, researchers, epidemiologists, psychologists, diabetes educators and other health care professionals.
About the American Diabetes Association
Approximately every 21 seconds, someone in the United States is diagnosed with diabetes. Nearly half of the American adult population has diabetes or prediabetes, and more than 30 million adults and children are living with the disease. The American Diabetes Association (ADA) is the nation’s leading voluntary health organization on a mission to prevent and cure diabetes, as well as improve the lives of all people affected by the disease. For nearly 80 years, the ADA has driven discovery by funding research to treat, manage and prevent all types of diabetes, while working relentlessly for a cure. Magnifying the urgency of this epidemic, the ADA works to safeguard policies and programs that protect people with the illness, those at risk of developing diabetes and the health care professionals who serve them by initiating programs, advocacy and education efforts that can lead to improved health outcomes and quality of life.
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